Dementia

OXFORD TEXTBOOKS IN CLIN ICAL NEUROLOGY

Oxford Textbook of

Cognitive Neurology and Dementia

Oxford Textbooks in Clinical Neurology

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Oxford Textbook of

Cognitive Neurology and Dementia

Edited by

Masud Husain

Professor of Neurology & Cognitive Neuroscience, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, UK

Jonathan M. Schott

Reader in Clinical Neurology, Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, UK

Series Editor

Christopher Kennard

Great Clarendon Street, Oxford, OX2 6DP, United Kingdom

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Preface

Cognitive neurology, or behavioural neurology as it is known in the United States, has a reputation of being a complex sub- specialty. To the outsider it presents a formidable challenge, seemingly requiring knowledge of several di erent areas of expertise ranging from basic aspects of neuroscience—molecular, cognitive, and neuroimaging—through to neuropsychology, neuropsychiatry, and bedside neurological assessment. Even for experts, the dramatic growth of basic neuroscience research in these areas has meant that it can be extremely di cult to keep up with new developments or key conceptual advances. Perhaps more challenging still is to know how such advances can best be applied in practice when confronted with a patient with a cogni- tive complaint.

Our aim in producing this textbook is to bring some order to the apparent chaos for both the novice and those established in the eld. While there are several excellent texts that selectively cover either dementia or the neuroscience underlying cognitive disor- ders, we wanted to produce a modern, pragmatic resource that covers both these areas in an accessible manner for clinicians. Our second objective was to produce a textbook that spans diverse areas of expertise in an integrated fashion. Wherever possible, therefore,

we have tried to link information in chapters on basic sciences to those on clinical syndromes.

e text is rmly based on the clinical approach to the patient with cognitive impairment and dementia, but it also provides essential background knowledge that is fundamental to clinical practice. It is written for those who want to learn more about cog- nition and dementia, including neurologists, geriatricians, and psy- chiatrists who are involved in assessing and treating such patients, but also for others curious to nd out about cognitive disorders and their underlying neurobiology. We hope that, whatever your background, you will nd this the one essential textbook that you want to revisit.

Bringing together such a diverse range of information has been a challenge for us. We are extremely grateful to our contributors for being so considerate in taking up our suggestions for changes to their manuscripts and for their patience. Finally, we acknowl- edge with thanks the forbearance of our families who observed our involvement in this project with much more than tolerance and grace.

Masud Husain Jonathan M. Schott

Abbreviations ix Contributors xv

SECTION 1

SECTION 2

Cognitive dysfunction

10 Bedside assessment of cognition 105 Seyed Ahmad Sajjadi and Peter J. Nestor

11 Neuropsychological assessment 113 Diana Caine and Sebastian J. Crutch

12 Acquired disorders of language and speech 123 Dalia Abou Zeki and Argye E. Hillis

13 Memory disorders 135
Lara Harris, Kate Humphreys, Ellen M. Migo, and Michael D. Kopelman

14 Vision and visual processing de cits 147 Anna Katharina Schaadt and Georg Kerkho

15 Disorders of attentional processes 161 Paolo Bartolomeo and Ra aella Migliaccio

16 Apraxia 173 Georg Goldenberg

17 Acquired calculation disorders 183 Marinella Cappelletti

18 Disorders of reading and writing 189 Alexander P. Le

19 Neuropsychiatric aspects
of cognitive impairment 197 Dylan Wint and Je rey L. Cummings

Normal cognitive function

. 1 Historical aspects of neurology 3 Charles Gross

. 2 Functional specialization and network connectivity in brain function 17 Giovanna Zamboni

. 3 e frontal lobes 27
Teresa Torralva, Ezequiel Gleichgerrcht, Agustin Ibañez, and Facundo Manes

. 4 e temporal lobes 39
Morgan D. Barense, Jason D. Warren, Timothy J. Bussey, and Lisa M. Saksida

. 5 e parietal lobes 51 Masud Husain

. 6 e occipital lobes 59 Geraint Rees

. 7 e basal ganglia in cognitive disorders 69 James Rowe and Timothy Rittman

. 8 Principles of white matter organization 81 Marco Catani

. 9 Neurochemistry of cognition 91 Trevor W. Robbins

Contents

viii contents

SECTION 3

Cognitive impairment and dementia

. 20 Epidemiology of dementia 211 ais Minett and Carol Brayne

. 21 Assessment and investigation of
the cognitively impaired adult 221
Jonathan M. Schott, Nick C. Fox, and Martin N. Rossor

. 22 Delirium, drugs, toxins 231
Barbara C. van Munster, Sophia E. de Rooij, and Sharon K. Inouye

. 23 CNS infections 239
Sam Nightingale, Benedict Daniel Michael, and Tom Solomon

. 24 Metabolic dementia 253
Nicholas J.C. Smith and Timothy M. Cox

. 25 Vascular cognitive impairment 275 Geert Jan Biessels and Philip Scheltens

. 26 Cerebral amyloid angiopathy
and CNS vasculitis 285
Sergi Martinez-Ramirez, Steven M. Greenberg, and Anand Viswanathan

. 27 Cognition in multiple sclerosis 295 Maria A. Ron

. 28 Autoimmune encephalitis 299
Sarosh R. Irani, omas D. Miller, and Angela Vincent

. 29 Pathology of degenerative dementias 315 Tamas Revesz, Tammaryn Lashley, and Janice L. Holton

. 30 Genetics of degenerative dementias 329 Rita Guerreiro and Jose Bras

. 31 Other genetic causes of cognitive impairment 339
Davina J. Hensman Moss, Nicholas W. Wood, and Sarah J. Tabrizi

32 Changing concepts and new de nitions for Alzheimer’s disease 353
Bruno Dubois and Olga Uspenskaya-Cadoz

33 Presentation and management of Alzheimer’s disease 361
Susan Rountree and Rachelle S. Doody

34 Primary progressive aphasia 381 Jonathan D. Rohrer and Jason D. Warren

35 Frontotemporal dementia 391 Bruce Miller and Soo Jin Yoon

36 Dementia with Lewy bodies and Parkinson’s disease dementia 399
Haşmet A. Hanağası, Başar Bilgiç, and Murat Emre

37 Corticobasal degeneration, progressive supranuclear palsy, multiple system atrophy, argyrophilic grain disease,
and rarer neurodegenerative diseases 413 Elizabeth A. Coon and Keith A. Josephs

38 Prion diseases 425
Simon Mead, Peter Rudge, and John Collinge

39 Traumatic brain injury 435
David J. Sharp, Simon Fleminger, and Jane Powell

40 Neurosurgery for cognitive disorders 453 Tom Foltynie and Ludvic Zrinzo

41 Cognition in severe mental
illness: Schizophrenia, bipolar disorder, and depression 463
Philip D. Harvey and Christopher R. Bowie

Index 471

3C ree-City Study
5-CSRTT 5-choice serial reaction time task 5-HIAA 5-hydroxyindoleacetic acid
5-HT Serotonin
Aβ amyloid β
ABCA ATP-binding cassette
ACA Anterior cerebral artery
ACC Anterior cingulate circuit
ACE–R Addenbrooke’s Cognitive Examination

Revised
Ach Acetylcholine

AChE Acetylcholinesterase inhibitors AD Alzheimer’s disease
ADC Apparent di usion coe cient ADEAR Alzheimer’s Disease Education &

Referral Center
ADHD Attention de cit/hyperactivity disorder

ADL Activities of daily living AE Autoimmune encephalitis AEDs Antiepileptic drugs

. AF Arcuate fasciculus

. AG Argyrophilic grains

AGD Argyrophilic grain disease
AI Anterior insula
AIP Anterior intraparietal sulcus
ALS amyotrophic lateral sclerosis AMACR α-Methylacyl-CoA
aMCI amnesic mild cognitive impairment AMPA α-amino-3-hydroxy-5-methyl-4-

isoxazolepropionic acid AMTS Abbreviated Mental Test Score

Ang Angular gyrus
ANI Asymptomatic neurocognitive impairment AOS Apraxia of speech
APA American Psychiatric Association
APGBD Adult polyglucosan body disease

. APO Apolipoprotein

. APP Amyloid precursor protein

ARSACS Autosomal recessive spastic ataxia of

Charlevoix–Saguenay ART Antiretroviral therapy

ASYMAD Asymptomatic AD

ATP Adenosine 5′-triphosphate ATXN Ataxin
AWD Alcohol-withdrawal delirium BACE Beta secretase

BIBD Basophilic inclusion body disease
BIC Binding of item and context
BIN Bridging integrator
BIRT Brain Injury Rehabilitation Trust
BMIPB BIRT Memory and Information Processing

Battery
BOLD Blood oxygenation level dependent

BORB Birmingham Object Recognition Battery BPSD Behavioural and psychological symptoms

of dementia
BSE Bovine spongiform encephalopathy

bvFTD Behavioural variant frontotemporal dementia

CAA Cerebral amyloid angiopathy CAA-RI CAA-related in ammation CADASIL Cerebral autosomal dominant

arteriopathy with subcortical infarcts and

leukoencephalopathy
CAG Cytosine–adenine–guanine

CAM Confusion Assessment Method CAMCOG–R Cambridge Cognition–Revised CAMDEX Cambridge mental disorders of the older

population examination
CANTAB Cambridge Automatic Neuropsychological

Test Battery
CARASIL Cerebral autosomal recessive

arterioapthy with subcortical infarcts and

leukoencephalopathy
CASPR2 Contactin-associated protein 2

CASS Cas sca olding
CAT Computed axial tomography CBD Corticobasal degeneration cblC Cobalamin C disease

. CBS Corticobasal syndrome

. CBT Cognitive behaviour therapy

CC75C Cambridge City over-75s

Cohort Study
CCAS Cerebellar cognitive a ective syndrome

Abbreviations

abbreviations

CERAD Consortium to Establish a Registry of EF Alzheimer’s Disease EL

CFS–NMT Cramp-fasciculation ELSA syndrome–neuromyotonia EMEA

ChE-Is Cholinesterase inhibitors EMG CI Con dence interval EPESE CIS Clinically isolated syndrome
CJD Creutzfeld–Jakob disease EMP CLS Complementary learning system ESCRT CLU Clusterin

CMB Cerebral microbleed ETV CNS Central nervous system EWS CoA Coenzyme A FA CPAP Continuous positive airway pressure FAB CPE CNS penetration e ectiveness FAD CR Complement component receptor FBD CRAFT Convergence, Recollection, and FBDS

Familiarity eory FCSRT CRF Corticotrophic releasing factor FDA CRT Cognitive remediation therapy FDD CS Contention scheduler FDG

CS Contrast sensitivity FDOPA cSAH Subarachnoid blood in the convexity FEF CSHA Canadian Study of Health and Aging FEP
CSF Cerebrospinal uid FERM CT Computed tomography FFA CTE Chronic traumatic encephalopathy FFI CTSD Cathepsin D FIQ CVLT California verbal learning test FLAIR DA Dopamine fMRI DAI Di use axonal injury FMRIB DALY Disability-adjusted life years FRDA DAN Dorsal attentional network FSL DAT Dopamine transporter FTA-Abs DDA Direct detection assay FTD DHA Docosahexanoic acid FTLD DIAN Dominantly Inherited Alzheimer Network FTLD-t DIR Double inversion recovery FTLD-u DIs Dystrophic neurites FUS DLB Dementia with Lewy bodies GABA DL-PFC Dorsolateral prefrontal circuit GAD DM Decision making GBA DMN Default mode network GBD DMTs Disease modifying therapies GBE DMTS Delayed-matching-to-sample GCIs DPVS Dilated perivascular spaces GCL DRPLA Dentatorubral-pallidoluysian atrophy GCS DRS Dementia rating scale GDNF DSM Diagnostic and Statistic Manual GFAP DTI Di usion tensor imaging GHD DTX Dendrotoxin GLM DWI Di usion-weighted imaging Gpe

EC Entorhinal cortex Gpi
ECF Extracytoplasmic function GMS/AGECAT EClipSE Epidemiological Clinicopathological Studies

in Europe
ECT Electroconvulsive therapy GRE

EDS Excessive daytime sleepiness GSS EEG Electro-encephalography GWAS

Executive functions
Encephalitis lethargica
English Longitudinal Study of Ageing European Medicines Agency Electromyogram
Established Populations for Epidemiologic Studies of the Elderly
Epilepsy, progressive myoclonus Endosomal-sorting complex required
for transport
Endoscopic third ventriculostomy
Ewing’s sarcoma protein
Fractional anisotropy
Frontal assessment battery
Flavin adenine dinucleotide
Familial British dementia
Faciobrachial dystonic seizures
Free and Cued Selective Reminding Test Food and Drug Administration
Familial Danish dementia Fluorodeoxyglucose
18F- uorodopa
Frontal eye elds
First episode psychosis
Fermitin
Fusiform face area
Fatal familial insomnia
Full-scale IQ
Fluid-attenuated inversion recovery Functional magnetic resonance imaging Functional MRI of the Brain
Friedreich’s ataxia
FMRIB So ware Library
Fluorescent treponemal antibody-absorption Frontotemporal dementia
Frontotemporal lobar degeneration Frontotemporal degeneration-tau Frontotemporal degeneration-ubiquitin Fused-in-sarcoma
Gamma aminobutyric acid
Glutamic acid decarboxylase Glucoserebrosidase
Global Burden of Disease
Glycogen brancher enzyme
Glial cytoplasmic inclusions
Granule cell layer
Glasgow Coma Scale
Glial-derived neurotrophic factor
Glial brillary acidic protein
Growth hormone de ciency
General linear model
Global pallidus external
Globus pallidus internal
Geriatric Mental State Examination/ Automated Geriatric Examination Computer Assisted Taxonomy
Gradient-recalled echo Gerstmann–Sträussler syndrome Genome-wide association studies

1H-MRS Proton magnetic resonance spectroscopy HAD HIV-associated dementia
HADS Hospital Anxiety and Depression Scale HANDs HIV-associated neurocognitive disorders HCV Hepatitis C virus

HD Huntington’s disease
HDL Huntington’s disease-like syndrome
HIC High-income countries
HIV Human immunode ciency virus
HIVE HIV encephalopathy
HMG-CoA Hydroxy-3-methylglutaryl-coenzyme A
HR Hazard ration
HRT Hormone replacement therapy
HSV Herpes simplex virus
HTLV Human T-lymphotropic virus
IBMPFD Inclusion body myopathy with Paget disease

of the bone and frontotemporal dementia IBVM 123I-iodobenzovesamicol

ICA Independent component analysis
ICD International Classi cation of Diseases ICDs Impulse control disorders
ICH Intracerebral haemorrhages
iCJD Iatrogenic CJD
ICN Intrinsic connectivity networks
ICU Intensive care unit
IDED Intra- and extra-dimensional
IFOF Inferior fronto-occipital fasciculus IGF-II Insulin-like growth factor II
Ig Immunoglobulin
IGT Iowa Gambling Task
ILF Inferior longitudinal fasciculus
ILSA Italian Longitudinal Study of Ageing IPD Inherited prion disease
IPL Inferior parietal lobule
IPS Intraparietal sulcus
IRIS Immune reconstitution in ammatory

syndrome
IT Inferotemporal

IWG International Working Group
JC John Cunningham
LAMIC Low and medium-income countries LDX Lisdexanphetamine dimesylate

LE Limbic encephalopathy
LGI1 leucine-rich glioma inactivated 1
LOC Lateral occipital cortex
LP Lumbar puncture
LPA Logopenic progressive aphasia
LTD Long-term depression
LTM Long-term memory
LTOCs long-term observational controlled studies LTP Long-term potentiation
M4PA Methyl-4-piperidyl acetate
MAPT Microtubule-associated tau
MATRICS Measurement and Treatment Research for

Improving cognition in schizophrenia MB Microbleeds

MBD Marchiafava–Bignami disease
MCA Middle cerebral artery
MCCB MATRICS consensus cognitive battery

MCI MCS MD MEF MEG MELAS

MERRF MIBG MID
mIPS MMA MMSE MND
Mnd
MNI MoCA mOPJ
MoS
MP
MRC
MRC CFAS

MRI MRS MS MSA MSE MSUD MTG MTHFR MTL NAA/Cr NA NART NAWM NBIA

nbM NCIs NE nfvPPA

NGF NICE

NIFID

NIIs NINCDS–ADRDA

NINDS

NMDA NMDAR NMT NPI

Mild cognitive impairment
Minimially conscious state
Multiple demand
Myocyte enhancer factor Magnetoencephalography
Mitochondrial encephalopathy lactic acidosis and stroke-like episodes Myoclonic epilepsy with ragged red bres Metaiodobenzylguanidine

Multi-infarct dementia
Medial intraparietal sulcus Methylmalonic acid Mini-Mental State Examination Mild neurocognitive impairment Motor neurone disease

Montreal Neurological Institute Montreal Cognitive Assessment Medial occipitoparietal junction Morvan’s syndrome Methylphenidate

Medical Research Council
Medical Research Council’s cognitive function and ageing study
Magnetic resonance imaging
Magnetic resonance spectroscopy Multiple sclerosis
Multiple system atrophy
Mental state examination
Maple-syrup urine disease
Middle temporal gyrus Methylenetetrahydrofolate reductase Medial temporal lobes
N-acetyl aspartate/Creatinine Noradrenaline
National Adult Reading Test Normal-appearing white matter Neurodegeneration with brain iron accumulation
Nucleus basalis of Meynert
Neuronal cytoplasmic inclusions Norepinephrine
Non- uent variant primary progressive aphasia
Nerve growth factor
National Institute for Health and Care Excellence
Neuronal intermediate lament inclusion disease
Neuronal intranuclear inclusions National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association
National Institute of Neurologic Disease and Stroke
N-methyl-D-asparate
NMDA receptor
Neuromyotonia
Neuropsychiatric Inventory

abbreviations xi

xii

abbreviations

NPH Normal pressure hydrocephalus PVS NSAbs Neuronal surface-directed antibody PVS OFC Orbitofrontal circuit RA OMPFC Orbitomedial prefrontal cortex RAVLT OMS Opsoclonus-myoclonus syndrome RBD OPRI Octapeptide repeat insertion mutation rCBF OR Odds ration RCT OTC Ornithine transcarbamylase REM PACS Primary angiitis of the central RMT

nervous system ROI PANDA Parkinson neuropsychometric dementia ROS assessment RPD Paquid Personnes âgées QUID RPR

PAS Periodic acid–Schi RRMS PASAT Paced auditory serial addition test RSN PCA Posterior cerebral artery rtQUIC PCA Posterior cortical atrophy

PCA Principal component analysis SAG
PCR Polymerase chain reaction SAS PD-CRS PD Cognitive Rating Scale SCA
PDD Parkinson’s disease with dementia sCJD
PEF Parietal eye elds SCLC PERM Progressive encephalomyelitis with rigidity SCOPA-Cog

and myoclonus
PET Positron emission tomography SD

PFC Prefrontal cortex SDAT PFNA Progressive non uent aphasia SE PiB Pittsburgh Compound-B SEC PICALM Phosphatidylinositol binding clathrin SI

assembly protein SLC PiD Pick’s disease SLF

PIGD Postural-instability gait di culty SMA PIQ Performance IQ Smg PLEDS Periodic lateralizing epileptiform discharges SN PML Progressive multifocal leukoencephalopathy SNP PNFA Progressive non- uent aphasia SNpc PNS Peripheral nerve hyperexcitability SNpr PPA Parahippocampal place area SNr PPA Primary progressive aphasia SNRIs PPC Posterior parietal cortex

PPMS Primary progressive MS SO PPN Pedunculopontine nucleus SOL PPT-1 Palmitoyl-protein thioesterase 1 SORL PPVT Peabody picture vocabulary test SPECT PrP Prion protein

PSA Potential support ratio SPL PSEN Presenilin SPM PSIR Phase-sensitive inversion recovery SPMS PSP Progressive supranuclear palsy SPS PSP–CBS PSP–corticobasal syndrome SPSMQ PSP–CSTD PSP–corticospinal tract dysfunction Spt PSP–P PSP–parkinsonism SS PSP–PAGF PSP–pure akinaesia with gait freezing SSI PSP–PPAOS PSP–primary progressive apraxia of speech SSPE PSP–RS PSP–Richardson’s syndrome SSRI PSTI Pancreatic secretory trypsin inhibitor SSRT PTA Post-traumatic amnesia STG PTK Protein tyrosine kinase STM PTSD Post-traumatic stress disorder STN

Persistent vegetative state Prominent perivascular spaces Retrograde amnesia
Rey auditory verbal learning test REM sleep behaviour disorder Regional cerebral blood ow Randomized controlled trial Rapid eye movement Recognition memory test Regions of interest

Reactive oxygen species
Rapidly progressive dementia
Rapid plasma reagin
Relapsing and remitting MS
Resting state network
Real-time Quaking-Induced
Conversion Assay
Supervisory attentional gateway Supervisory attentional system Spinocerebellar ataxia
sporadic CJD
Small cell lung cancer
SCales for Outcomes of PArkinson’s disease-cognition
Semantic dementia
Senile dementia of Alzheimer type
status epilepticus
Structured event complex Stimulus-independent
Solute carrier
Superior longitudinal fasciculus Supplementary motor area
Supramarignal gyrus
Salience network
Single nucleotide polymorphism Substantia nigra pars compacta
Substantia nigra pars reticulata
Substantia nigra Serotonin-norepinephrine reuptake inhibitors
Stimulus-oriented
Space-occupying lesion
Sortilin-related receptor
Single photon emission computed tomography
Superior parietal lobule
Statistical parametric mapping
Secondary progressive MS
Sti -person syndrome
Short portable mental status questionnaire Sylvian parietotemporal
Super cial siderosis
Small subcortical infarct
Subacute sclerosing panencephalitis Selective serotonin reuptake inhibitors Stop-signal reaction time
Superior temporal gyrus
Short-term memory
Subthalmic nucleus

STRIVE STandards for ReportIng Vascular changes VaMCI on nEuroimaging VAN STS Superior temporal sulcus VBM SVD Small vessel disease VCD

svPPA Semantic variant primary progressive VCI aphasia vCJD

SWI Susceptibility-weighted images VDRL tACS Transcranial alternating current stimulation VENs TAF TATA-binding protein-associated factor VFD TCA Tricarboxylic acid VGKC TCMA Transcortical motor aphasia VIP tDCS Transcranial direct current stimulation vIPS TDP TAR DNA-binding protein VIQ TFND Transient focal neurological de cits VL TMS Transcranial magnetic stimulation VLSM ToM eory of Mind

TPHA treponema pallidum haemaglutination assay VOSP TPPA treponema pallidum particle agglutination VTA

. TPI treponema pallidum immobilization VVS

. TPJ Temporoparietal junction VWFA

TRD Treatement-resistant depression WAIS TREM Triggering receptor expressed on WCST

myeloid cells WHO
Uf Uncinate fasciculus WHOSIS

UHDRS Uni ed Huntington’s Disease Rating Scale WMH V1 Primary visual cortex WRAT VA Ventral anterior YLD VaD Vascular dementia YLL

MCI of vascular origin
Ventral attentional network Voxel-based morphometry
Vascular cognitive disorder
Vascular cognitive impairment variant CJD
Venereal disease research laboratory Von Economo neurons
Visual eld disorders
Voltage-gated potassium channel Vasoactive intestinal polypeptide Ventral intraparietal sulcus
Verbal IQ
Ventrolateral
Voxel-based lesion symptom mapping
Visual object and space perception Ventral tegmental area
Ventral visual stream
Visual word form area
Wechsler Adult Intelligence Scale Wisconsin Card Sorting Test
World Health Organization
WHO Statistical Information Systems White matter MRI hyperintensities Wide Range Achievement Test
Years lost due to disability
Years of healthy life lost

abbreviations xiii

Dalia Abou Zeki, Johns Hopkins University School of Medicine, Baltimore, USA

Morgan D. Barense, University of Toronto, Canada; Rotman Research Institute, Baycrest Hospital, Toronto, Canada

Paolo Bartolomeo, INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, and Université Pierre et Marie Curie-Paris 6, UMR S 1127, Institut du Cerveau et de la Moelle épinière (ICM), Pitié- Salpêtrière Hospital, Paris, France

Geert Jan Biessels, Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre, Utrecht, e Netherlands

Başar Bilgiç, Associate Professor of Neurology, Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul, Turkey

Christopher R. Bowie, Departments of Psychology and Psychiatry, Queens University Kingston, Ontario, Canada

Jose Bras, Department of Molecular Neuroscience, Institute of Neurology, University College London, UK

Carol Brayne, Department of Public Health & Primary Care, University of Cambridge, UK

Timothy J. Bussey, Department of Psychology, University of Cambridge, UK; MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, UK

Diana Caine, Department of Neuropsychology, National Hospital for Neurology and Neurosurgery, London, UK

Marinella Cappelletti, Department of Psychology, Goldsmiths College, University of London, UK; UCL Institute of Cognitive Neuroscience, UK

Marco Catani, NatBrainLab, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, UK

John Collinge, MRC Prion Unit, Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology and NHS National Prion Clinic, National Hospital for

Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, UK

Elizabeth A. Coon, Assistant Professor and Consultant of Neurology, Division of Autonomic Neurology, Mayo Clinic, Rochester, USA

Timothy M. Cox, Department of Medicine, University of Cambridge, UK

Sebastian J. Crutch, Dementia Research Centre, UCL Institute of Neurology, UK

Je rey L. Cummings, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, USA

Rachelle S. Doody, Professor, Baylor College of Medicine, Department of Neurology, Houston, USA

Bruno Dubois, Dementia Research Center (IM2A) and Behavioral Unit, Salpêtrière University Hospital, Université Pierre et Marie Curie, Paris, France

Murat Emre, Professor of Neurology, Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul, Turkey

Simon Fleminger, Department of Neuropsychiatry, Institute of Psychiatry, King’s College London, UK

Tom Foltynie, Senior Lecturer & Honorary Consultant Neurologist, Sobell Department of Motor Neuroscience, UCL Institute of Neurology, UK

Nick C. Fox, Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, UK

Ezequiel Gleichgerrcht, Department of Neurology and Neurosurgery, Medical University of South Carolina, USA

Georg Goldenberg, Department of Neurology, Technical University Munich, Germany

Steven M. Greenberg, Hemorrhagic Stroke Research Program, Massachusetts General Hospital, USA

Contributors

xvi

contributors

Charles Gross, Department of Psychology and Princeton Neuroscience Institute, Princeton University, USA

Rita Guerreiro, Department of Molecular Neuroscience, Institute of Neurology, University College London, UK

Haşmet A. Hanağası, Professor of Neurology, Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul, Turkey

Lara Harris, King’s College London, Institute of Psychiatry, Psychology and Neuroscience, UK

Philip D. Harvey, Leonard M. Miller Professor of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, USA

Davina J. Hensman Moss, Clinical Fellow, Department of Neurodegenerative Disease, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, UK

Argye E. Hillis, Professor of Neurology, Executive Vice Chair, Dept. of Neurology, Director, Cerebrovascular Division, Johns Hopkins University School of Medicine, Baltimore, USA

Janice L. Holton, Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, UK

Kate Humphreys, South London and Maudsley NHS Foundation Trust, UK

Masud Husain, Professor of Neurology & Cognitive Neuroscience, Nu eld Department of Clinical Neurosciences, University of Oxford, John Radcli e Hospital, UK

Agustin Ibañez, Institute of Translational and Cognitive Neuroscience (ITCN), Ineco Foundation, Favaloro University, Buenos Aires, Argentina; University Adolfo ibañez, Chile; Centre of Excellence in Cognition and its Disorders, Australian Research Council (ACR), Sydney, Australia

Sharon K. Inouye, Aging Brain Center, Institute for Aging Research, Hebrew SeniorLife, Boston, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA

Sarosh R. Irani, Honorary Consultant Neurologist and Senior Clinical Fellow, Nu eld Department of Clinical Neurosciences, University of Oxford, UK

Keith A. Josephs, Professor and Consultant of Neurology, Divisions of Behavioural Neurology & Movement Disorders, Mayo Clinic, Rochester, USA

Georg Kerkho , Saarland University Department of Psychology, Clinical Neuropsychology Unit and Neuropsychological Outpatient Service, Campus Saarbrücken, Germany

Michael D. Kopelman, King’s College London, Institute of Psychiatry, Psychology and Neuroscience, UK

Tammaryn Lashley, Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, UK

Alexander P. Le , Reader in Cognitive Neurology and Honorary Consultant Neurologist, Institute of Neurology & National Hospital for Neurology and Neurosurgery, University College London, UK

Facundo Manes, Institute of Translational and Cognitive Neuroscience (ITCN), Ineco Foundation, Favaloro University, Buenos Aires, Argentina; UDP-INECO Foundation Core on Neuroscience (UIFCoN), Diego Portales University, Santiago, Chile; Australian Research Council (ACR) Centre of Excellence in Cognition and its Disorders, Sydney, Australia, National Scienti c and Technical Research Council (CONICET), Buenos Aires, Argentina

Sergi Martinez-Ramirez, Hemorrhagic Stroke Research Program, Massachusetts General Hospital, USA

Simon Mead, MRC Prion Unit, Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology and NHS National Prion Clinic, National Hospital For Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, UK

Benedict Daniel Michael, Post-Doctoral Research Fellow, Massachusetts General Hospital, Harvard Medical School; Institute of Infection and Global Health, University of Liverpool, UK; Walton Centre for Neurology and Neurosurgery, Liverpool, UK

Ra aella Migliaccio, INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, and Université Pierre et Marie Curie-Paris 6, UMR S 1127, Institut du Cerveau et de la Moelle épinière (ICM), and Department of Neurology, Institute of memory and Alzheimer’s disease, Pitié-Salpêtrière Hospital, Paris, France

Ellen M. Migo, King’s College London, Institute of Psychiatry, Psychology and Neuroscience, UK

Bruce Miller, Department of Neurology, UCSF School of Medicine, San Francisco, USA

omas D. Miller, Patrick Berthoud/Encephalitis Society Clinical Research Fellow, Nu eld Department of Clinical Neurosciences, University of Oxford, UK; Specialist Registrar in Neurology, National Hospital For Neurology and Neurosurgery, University College London, London, UK

ais Minett, Specialty Registrar in Radiology, Academic Clinical Fellow, Department of Radiology, University of Cambridge, UK

Barbara C. van Munster, Department of Internal Medicine, Academic Medical Centre, Amsterdam, The Netherlands; Department of Geriatrics, Gelre Hospitals, Apeldoorn, e Netherlands

Peter J. Nestor, German Centre for Neurodegenerative Diseases (DZNE), Magdeburg, Germany

Sam Nightingale, Institute of Infection and Global Health, University of Liverpool, UK

Jane Powell, Goldsmiths, University of London, UK Geraint Rees, UCL Institute of Cognitive Neuroscience, UK

Tamas Revesz, Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, UK

Timothy Rittman, Clinical Research Fellow, University of Cambridge, UK

Trevor W. Robbins, Professor of Cognitive Neuroscience and Experimental Psychology Director, Behavioural and Clinical Neuroscience Institute Head of Dept. Psychology, University of Cambridge, UK

Jonathan D. Rohrer, Dementia Research Centre, UCL Institute of Neurology, UK

Maria A. Ron, Emeritus Professor of Neuropsychiatry, UCL Institute of Neurology, UK

Sophia E. de Rooij, Department of Internal Medicine, Academic Medical Centre, Amsterdam, e Netherlands; Department of Internal Medicine, University Medical Centre Groningen, e Netherlands

Martin N. Rossor, Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, UK

Susan Rountree, Associate Professor, Baylor College of Medicine, Department of Neurology, Houston, USA

James Rowe, Professor of Cognitive Neurology, University of Cambridge, UK

Peter Rudge, MRC Prion Unit, Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology and NHS National Prion Clinic, National Hospital For Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, UK

Lisa M. Saksida, Department of Psychology, University of Cambridge, UK; MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, UK

Seyed Ahmad Sajjadi, Neurology Department, Addenbrooke’s Hospital, Cambridge, UK

Anna Katharina Schaadt, Saarland University Department of Psychology, Clinical Neuropsychology Unit and Neuropsychological Outpatient Service, Campus Saarbrücken, Germany

Philip Scheltens, Alzheimer Centre and Department of Neurology, VU University Medical Centre, Neuroscience Campus Amsterdam, the Netherlands

Jonathan M. Schott, Reader in Clinical Neurology, Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, UK

David J. Sharp, National Institute of Health (NIHR) Professor and Consultant Neurologist, e Computational, Cognitive and Clinical Neuroimaging Laboratory, Division of Brain Sciences, Imperial College London, UK

Tom Solomon, Institute of Infection and Global Health, University of Liverpool, UK; Walton Centre for Neurology and Neurosurgery, Liverpool, UK

Nicholas J.C. Smith, Department of Neurology, Women’s and Children’s Health Network and Discipline of Paediatrics, School of Medicine, University of Adelaide, Australia

Sarah J. Tabrizi, Professor of Clinical Neurology, Honorary Consultant Neurologist, Department of Neurodegenerative Disease, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, UK

Teresa Torralva, Institute of Translational and Cognitive Neuroscience (ITCN), Ineco Foundation, Favaloro University, Buenos Aires, Argentina; UDP-INECO Foundation Core on Neuroscience (UIFCoN), Diego Portales University, Santiago, Chile; Australian Research Council (ACR) Centre of Excellence in Cognition and its Disorders, Sydney, Australia

Olga Uspenskaya-Cadoz, Quintiles; CNS Medical Strategy and Science; Levallois-Perret, France

Angela Vincent, Professor of Neuroimmunology and Honorary Clinical Immunologist, Nuffield Department of Clinical Neurosciences, University of Oxford, UK

Anand Viswanathan, Hemorrhagic Stroke Research Program, Massachusetts General Hospital, USA

Jason D. Warren, Dementia Research Centre, UCL Institute of Neurology, UK

Dylan Wint, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, USA

Nicholas W. Wood, Galton Chair of Genetics, Vice Dean Research Faculty of Brain Sciences, NIHR UCLH BRC Neuroscience Programme Director, UCL Institute of Neurology, UK

Soo Jin Yoon, Associate Professor, Department of Neurology, Eulji University Hospital, Eulji University School of Medicine, Daejeon, Korea

Giovanna Zamboni, Nu eld Department of Clinical Neurosciences (NDCN), University of Oxford, UK

Ludvic Zrinzo, Senior Lecturer & Consultant in Neurosurgery, Sobell Department of Motor Neuroscience, UCL Institute of Neurology, UK

contributors xvii

SECTION 1

Normal cognitive function

Before science

consequently they are incapable of action if the brain is disturbed or shi s its position, for this stops up the passages through which senses act. is power of the brain to synthesize sensations makes it also the seat of thought: the storing up of perceptions gives memory and belief, and when these are stabilized you get knowledge.12

Alcmaeon is reported to have been the rst to use dissection as a tool for intellectual inquiry. He dissected the eye and described the optic nerves and chiasm and suggested they brought light to the brain.7–12

e Hippocratic school

e other centre of Greek medicine was the island of Cos in the Aegean Sea and its most famous inhabitant Hippocrates (~425 BCE). e Hippocratic corpus of writing is the rst large body of Western scienti c writings that has survived. It consists of over 60 treatises of unknown authorship and date, perhaps a remnant of the library which once existed on Cos.8

e Hippocratic treatise of greatest relevance to neurology is the famed essay ‘On the Sacred Disease’ (i.e. epilepsy). e author of this treatise has no doubt that the brain is the seat of epilepsy; on the general functions of the brain he is equally clear:

It ought to be generally known that the source of our pleasure, merri- ment, laughter and amusement, as of our grief, pain, anxiety and tears is none other than the brain. It is specially the organ which enables us to think, see, and hear and to distinguish the ugly and the beautiful, the bad and the good, pleasant and unpleasant . . . it is the brain too which is the seat of madness and delirium.13

Neurological and other disorders were explained and treated in terms of the theory of the four humours: phlegm (from the brain), blood (from the heart), yellow bile (from the liver), and black bile (from the spleen). ese ideas, as elaborated later by Galen (129– 210), pervaded medicine and were central to medical education well into the nineteenth century.7–10,13,14

Curiously, Aristotle (384–322 BCE) argued against the brain and in favour of the heart as the dominant organ for sensation, cogni- tion, and movement. He systematically attacked the encephalocen- tric views of Alcmaeon and the Hippocratic doctors on a number of anatomical and embryological grounds, but the critical evidence available at this time was from the clinic, the study of brain-injured humans, and clinical medicine held no interest for Aristotle.15

Galen

Galen of Pergamon (129–213) was by far the most important physician, anatomist, and physiologist in classical antiquity.14 Furthermore, he was the rst to carry out systematic experiments on the nervous system, thereby initiating experimental neurol- ogy.16 Galen’s descriptions of the gross anatomy of the brain were

CHAPTER 1

Historical aspects of neurology

Charles Gross

e oldest known neurological procedure is trepanning or trephin- ing, the removal of a piece of bone from the skull. It was practised from the late Palaeolithic period onwards and throughout the world. e motivation for trephining in non-literate cultures is obscure but may have been related to the treatment of epilepsy or headaches caused by skull injury, or relief of symptoms thought to have been caused by demonic forces. From classical Greece to the Renaissance, trephining was used to treat such maladies as head injury, epilepsy, and mental disease.1,2

e rst written reference to the brain is in the Edwin Smith Surgical Papyrus written in about 1700 BCE but a copy of an older treatise dated to about 3000 BCE. It appears to be a handbook for a battle eld surgeon and consists of a coolly empirical description of 48 cases from the head down to the shoulders, when the text breaks o . For each case the author describes the examination, diagnosis, and feasibility of treatment.3,4 e Smith papyrus stands out as a rock of empiricism in the ocean of magic and superstition in which Egyptian medical writings swim for about the next twenty-four centuries. It re ects cra and some empirical knowledge but it is not what we today call medical science.

Classical neuroscience
e Presocratics and the beginning of science

What we mean by ‘science’ today is the contribution of the Presocratic philosophers. ey were responsible for the idea that the physical and biological universe is governed by consistent and universal laws that are amenable to understanding by human rea- son. is was a revolutionary change from the previous prevailing view of the universe as a plaything of gods and ghosts who acted in an arbitrary and capricious fashion. e Presocratics lived from the sixth to the fourth centuries BCE in various Greek city-states. ey conceived their inquiries on the universe as demanding rational criticism and public debate and involving observation and meas- urement. (Systematic experimentation, especially in biology, was almost unknown for several centuries).5–11

Among the major Presocratics were ales, Anaximander, Anaximenes, Heraclitus, Pythagoras, Empedocles, Zeno, and Democritus. Many of them were interested in sensory processes as sources of knowledge and several were physicians. One such physi- cian was Alcmaeon (~570–500 BCE), head of a medical school in southern Italy. He was the rst writer to advocate the brain as the site of sensation and cognition. He is said to have written:

e seat of sensations is in the brain. is contains the governing faculty. All the senses are connected in some way with the brain;

4 SECTION 1 normal cognitive function

Fig. 1.1 Title page of Galen’s Omnia Opera published in 1541 in Venice by Junta. e eight scenes, clockwise from the top, are: Galen bowing to a wealthy patient; Galen predicting the crisis in a patient’s sickness; Galen diagnosing lovesickness; Galen bleeding a patient; Galen demonstrating the e ect of cutting the recurrent laryngeal nerve in a pig; Galen palpating the liver; Galen and his teachers; Aesculpaius in a dream urging Galen’s father to send him to medical school.
Reproduced from Gross CG, Brain, Vision, Memory: Tales in the History of Neuroscience, Copyright (1999), with permission from MIT Press.

very accurate, particularly with respect to the ventricles and cer- ebral circulation, both important in his physiological system. He usually presented his dissections as if they were of the human, but in fact, because of the taboo on dissecting the human body, they were invariably of animals, usually the ox in the case of brain anatomy.17

Galen’s truly revolutionary work was to carry out the rst system- atic experiments on the functions of the nervous system. He used piglets in his experiments on brain lesions. He found that anterior brain damage had less deleterious e ects than posterior. He viewed sensation as a central process since he knew from his clinical obser- vations and animal experiments that sensation could be impaired

by brain injury even when the sense organs were intact. Since ani- mals could survive lesions that penetrated to the ventricles, Galen thought the soul was not located there but rather in the cerebral sub- stance. He taught that all mental diseases were brain diseases.16,18,19

Galen’s most famous experiment was the public demonstration of the e ects of cutting the recurrent laryngeal nerve on squealing in a pig. Although the encephalocentric view that the brain con- trolled sensation, movement, and cognition remained strong in the Greco–Roman medical community, the opposing cardiocen- tric view, that the heart was the centre of sensation and cognition, was also active in Rome at this time, being advocated by the Stoic school and its leader Chrysippus (280–207 BCE). In order to refute the Stoics’ view that the heart and not the brain controlled cogni- tion, Galen arranged this public demonstration.16,19

He showed that cutting the recurrent laryngeal nerve would eliminate vocalization. Since vocalization was seen as re ecting the cognitive activity language, Galen’s demonstration that cutting a nerve originating in the brain would eliminate squealing in a pig was the rst, and most famous, demonstration that the brain con- trols cognition. e Renaissance edition of Galen’s works included an engraving of him carrying out the experiment on a huge pig in front of a very distinguished audience (Fig. 1.1).

Medieval and Renaissance neuroscience e medieval doctrine of brain function

At about the time of Galen’s death, classical science and medicine seem to disappear. People prefer to believe rather than to discuss, critical faculty gives way to dogma, interest in this world declines in favour of the world to come, and worldly remedies are replaced by prayer and exorcism. e world view of medieval Christendom found Galen’s teleology congenial to its own and by a smothering of critical facility froze Galen’s research and all biology into a sterile system for over 1500 years. Galen was not to blame. Rather than develop his discoveries and methods, the European medieval world chose to accept his views as xed and unchangeable facts in every branch of medicine.

e central feature of the medieval view of brain function was the localization of the mental faculties in the ventricles (Fig. 1.2). e faculties of the mind (derived from Aristotle) were distributed among the spaces within the brain (derived from the ventricles described by Galen). e anterior ventricle received input from the sense organs and was the site of the common sense, which integrated across modalities. e sensations yielded images and thus fantasy and imagination were also located in the anterior ventricle. e middle ventricle was the site of cognition: reasoning, judgement, and thought. e posterior ventricle was the site of memory. ese speci c localizations seem to have come from the fourth-century Byzantine physician Poseidon on the basis of his observations of human brain injury.20,21

e Islamic transmission

Greek medical learning was largely preserved in Islamic centres in the early Middle Ages. Hippocratic, Galenic, and other medical writings were largely lost to Europe both because of lack of familiar- ity with Greek and loss of the manuscripts themselves. is began to change in the tenth and eleventh centuries when translations from the Greek medical works into Syriac, Arabic, and Hebrew, and then into Latin nally reached Europe.21 With the birth of universities, rst in Bologna, anatomical dissections began, initially for forensic

Fig. 1.2 Ventricular doctrine. Messages from the nose, tongue, eye, and ear go to the rst ventricle in which common sense, fantasy, and imagination are found. e second ventricle contains thought and judgment; memory is in the third ventricle. Reproduced from Reish G, Margarita Philosophica (Pearls of Philosophy), Copyright (1503), Johannes Schott.

purposes and following translations of Galen. However, it was not until Vesalius (1514–1564) that anatomy became largely free from the dominance of Galen. His On the Fabric of the Human Body (Fig. 1.3) along with Copernicus’s (1473–1543) On the Revolutions of the Celestial Spheres mark the beginning of the scienti c revolution, the revival in Europe of science.

omas Willis and ‘neurology’

omas Willis (1621–74) wrote the rst comprehensive text on the brain, Cerebri Anatomie, which dealt not only with brain anatomy but also with neurophysiology, neurochemistry, and clinical neu- rology, and introduced, in its English translation, the term ‘neu- rology’.22 Cerebri Anatomie actually involved the collaboration of a group of savants known as the Virtuosi, such as Robert Boyle and Christopher Wren, who later became founding members of the new Royal Society (see Fig. 1.4).

Willis rejected the still pervasive belief in the ventricles as the seats of higher psychological functions and instead implicated ‘the critical and grey part of the cerebrum’ in memory and will. Sensory signals came along sensory pathways into the corpus striatum where common sense was located. ey were then elaborated into percep- tion and imagination in the overlying white matter (then called the corpus callosum), and nally passed onto the cortex where they were stored as memories. Willis ascribed voluntary movements to the cortex but involuntary ones to the cerebellum. His ideas on brain function came from his own experiments on brain lesions in animals, from the correlation of the e ects of human brain dam- age with post-mortem pathology, and from the comparison of the brains of various animals with those of humans.22–24

Although Willis was a major gure in his time, his ideas on the cerebral cortex soon fell out of favour and theories of the cortex

CHAPTER 1 historical aspects of neurology 5

6 SECTION 1 normal cognitive function

Fig. 1.3 Title page of Andreas Vesalius’s De Humani Corpori Fabrica (On the Structure of the Human Body), 2nd edn.1543 Basel: Oporinus. It shows a public dissection by Vesalius (centre). His assistant is relegated to sharpening knives (front). e bodies were from executions and usually males, unlike here. e dissection is being held outdoors with a wooden structure for spectators. For further details of the symbols and details in this famous woodcut from Titian’s workshop, see CG Gross, Brain, Vision, Memory: Tales in the History of Neuroscience 1998. Cambridge, MA: MIT Press.

Reproduced from Gross CG, Brain, Vision, Memory: Tales in the History of Neuroscience, Copyright (1999), with permission from MIT Press.

as glandular or vascular became dominant. Marcello Malpighi (1628–94), the discoverer of capillaries, was the rst to examine the cortex under the microscope.24–25 He saw it as made up of little glands or ‘globules’, and Antoni van Leewenhoek (1632–1723) and others followed suit. is was a common view in the seventeenth

and eighteenth centuries, perhaps because it t with the much earlier view of Aristotle that the brain was a cooling organ and the Hippocratic theory that it was the source of phlegm.5,15 e other common view was that the cortex was largely made up of blood vessels; as Frederik Rusch (1628–1731) put it: ‘[t]he cortical

Fig. 1.4 Ventral view of the brain.
Reproduced from Willis T, Cerebri Anatomie, Copyright (1664), Martyn and Allestry, drawn by Christopher Wren.

substance of the cerebrum is not glandular, as many anatomists have described it … but highly vascular’.26 Albrecht von Haller (1708–77), who dominated physiology in the eighteenth century, also held a vascular view of the cortex. He found mechanical and chemical stimulation to be without e ect throughout the cortex and declared it completely insensitive.27

e beginning of modern neuroscience

Gall and phrenology: Localization of function

in the cortex

e revolutionary idea that di erent regions of the cerebral cortex have di erent function began with Franz Joseph Gall (1748–1828) and his collaborator, JC Spurzheim (1776–1832) and their system of phrenology.28–30

e central aim of phrenology was to correlate brain structure and function. Phrenology had ve basic assumptions:

1. e brain is an elaborately wired machine for producing behav- iour, thought, and emotions

2. e cerebral cortex is a set of organs each corresponding to an a ective or intellectual function

3. Di erences in traits among people and within individuals depend on di erential development of di erent cortical areas

4. Development of a cortical area is re ected in its size

5. Size of a cortical area is correlated with the overlying skull (‘bumps’)

ese otherwise reasonable hypotheses had one fatal aw: the nature of the evidence. Gall and Spurzheim relied almost entirely on obtaining supportive or con rmatory evidence. ey collected large numbers of skulls of people whose traits and abilities were known, examined the heads of distinguished savants and inhabit- ants of mental hospitals and prisons, and studied portraits of the high and low born on various intellectual and a ective dimensions (Fig. 1.5). roughout, they were seeking con rmation of their ini- tial hypothesis usually deriving from a few cases. For example, the idea for a language organ in the frontal lobes comes from Gall’s experience of a classmate who had a prodigious verbal memory and protruding eyes (being pushed out by a well-developed frontal lobe, Gall thought). e idea for an organ of destructiveness came from the skulls of a parricide and of a murderer, from noticing its prominence in a fellow student ‘who was so fond of torturing ani- mals that he became a surgeon’, and from examining the head of a meat-loving dog he owned.28

ey sought con rmations; contradictions were dismissed. Gall and Spurzheim’s cortical localizations were of ‘higher’ intellectual and personality traits. ey accepted the prevailing view that the highest sensory functions were in the thalamus and the highest motor functions in the corpus striatum.29,30

Phrenology met with considerable opposition from political and religious authorities, particularly on the Continent, largely because it was viewed as implying materialism and determinism and denied the unity of the mind (and soul) and the existence of free will. On the other hand, phrenology spread widely particularly in the United States and Great Britain both as a medical doctrine and as a form of

CHAPTER 1 historical aspects of neurology 7

8 SECTION 1 normal cognitive function

Fig. 1.5 e phrenological organs.
Reproduced from Human Nature Library, New York, Copyright (1887).

‘pop’ psychology. It generated widespread interest both among the general populace and among such writers and savants as Honore de Balzac, Charles Baudelaire, George Eliot, August Comte, Horace Mann, Alfred Russell Wallace, and George Henry Lewis. It rapidly became a fad and drawing-room amusement, particularly in Great Britain and the US. Phrenological societies and journals continued to ourish in both countries well into the twentieth century.31

Gall’s mistaken assumption of a correlation between the skull and brain morphology was soon recognized, at least in the scien- ti c community. In spite of its absurdities and excesses, phrenology became a major spur for the development of modern neurosci- ence in a variety of ways. It generated an interest in the brain and behaviour. It directed attention to the cerebral cortex. It stimulated study of both human brain damage and of experimental lesions in animals. It inspired tracing pathways from sense organs and to the muscles in order to identify ‘organs’ of the cerebral cortex. It spurred the anatomical subdivision of the cerebral cortex (cyto- architectonics, myeloarchitectonics) to nd organs of the brain.29,30

e cytoarchitectonic, positron emission tomography (PET), func- tional magnetic resonance imaging (fMRI), and other maps of the cerebral cortex that are now ubiquitous in neuroanatomy, neurophysi- ology, and neuropsychology textbooks bear more than a coincidental resemblance to phrenological charts. ey are the direct descend- ants of the iconoclastic, ambitious, and heavily awed programme of phrenology seeking to relate brain structure and behaviour.

Language and the brain

In the middle of the nineteenth century, Gall’s theory of punc- tate localization of function in the cerebral cortex continued to be debated. Reports of correlations between the site of brain injury

and speci c psychological de cits in patients as well as experimen- tal animals were published and actively discussed in both phreno- logical and mainstream medical publications.

e debate about localization reached a climax at a series of meet- ings of the Paris Societé d’Anthropologie in 1861. At the April meet- ing, Paul Broca (1824–80), professor at the Sorbonne and founder of the society, announced that he had a critical case on this issue. A patient with long-standing language di culties—nicknamed ‘Tam’, because that was all he could say—had just died. e next day, Broca displayed Tam’s brain at the meeting and it had widespread damage in the le frontal lobe. Over the next few months Broca presented several similar cases of di culty in speaking, all with le frontal lesions. is discovery was the rst clear evidence for a spe- ci c psychological defect a er a speci c brain lesion. Not only did these cases nally establish the principle of discrete localization of function in the cortex, but in addition, the discovery was hailed as a vindication of Gall: both of his idea of punctate localization and his localization of language in the frontal lobes.29,30,32

By 1865, Broca had accumulated enough cases to notice that all his brains from aphasic patients had their frontal damage on the le side and he described the le hemisphere as dominant for lan- guage.32,34 (An obscure country doctor, Max Dax, apparently made the same observations in 1836, and his son Gustave Dax fought Broca over the priority for this claim.)33

In 1874, Carl Wernicke reported another type of language dis- turbance a er le hemisphere lesions in which speech is uent but nonsensical, o en known as sensory or Wernicke’s aphasia, as opposed to motor or Broca’s aphasia. Whereas Broca’s aphasia usu- ally followed lesions of the third frontal convolution or Broca’s area, Wernicke’s aphasia usually followed damage to the posterior temporal

lobe. Today a variety of aphasias have been described with more sophisticated descriptive analysis than ‘motor’ versus ‘sensory’.34

It was generally assumed that language localization in le -handed individuals was the opposite of that in right-handers; that is, that language was in the right hemisphere in le -handed individuals. However, as pointed out by Alexander Luria on the basis of his large sample of head injuries in the Second World War, language is pri- marily in the right hemisphere in roughly half of all le -handers. is was con rmed by the Wada test (unilateral hemispheric anaes- thesia), and fMRI and PET brain imaging. Today we know that lan- guage localization in le -handers is some kind of complex function of genetics and prenatal trauma, and that bilateral representation of language is much more common in le -handers (and females). Furthermore, even in right-handers, a variety of language functions exist in the right hemisphere. Finally, le hemisphere damage before puberty can be compensated by right hemisphere function.35–37

e discovery of motor cortex

Modern neurophysiology began with Gustav Fritsch (1838–1927) and Edmund Hitzig’s (1838–1907) discovery in 1870 that stimu- lation of the motor cortex produces movement. eir discovery was the rst experimental evidence that the cortex was involved in movement, the rst demonstration that the cortex was electri- cally excitable, the rst strong experimental evidence for functional localization in the cortex, and the rst experimental evidence for somatotopic representation in the brain.

In their now classic experiment, Fritsch and Hitzig strapped their dogs down on Frau Hitzig’s dressing table. ey stimulated the cortex with ‘galvanic stimulation’: brief pulses of monophasic dir- ect current from a battery. e usual response to this stimulation was a muscle twitch or spasm. eir central ndings were that: a) the stimulation evoked contralateral movements, b) only stimu- lation of the anterior cortex elicited movements, c) stimulation of speci c parts of the cortex consistently produced the activation of speci c muscles, and d) the excitable sites formed a repeatable, if rather sparse, map of movements of the body laid out on the cortical surface (Fig. 1.6). ey went on to show that lesion of a particular site impaired the movements produced by stimulation of that site. e loss of function was not complete, suggesting to them that there were other motor centres that had not been impaired by the lesion.39

Fritsch and Hitzig had no hesitation in announcing the general signi cance of their discovery:

By the results of our own investigations, the premises for many con- clusions about the basic properties of the brain are changed not a little . . . some psychological functions, and perhaps all of them . . . need circumscribed centers of the cerebral cortex.39

Soon a er their paper appeared, the young Scottish physician David Ferrier set out to follow up their work.40 Ferrier had been heavily in uenced by John Hughlings Jackson, and he realized that Fritsch and Hitzig had con rmed Jackson’s ideas. In a variety of species, including macaques, Ferrier replicated their basic ndings that stimulation of the cortex can produce speci c movements and that there is a topographic ‘motor map’ in the cerebral cortex.41–44

Both Fritsch and Hitzig’s and Ferrier’s papers on the motor cortex were initially greeted with considerable and equal scepticism. eir results went against the generally accepted views that the striatum was the highest motor centre and that the cortex was inexcitable. e critics usually interpreted the results of Fritsch and Hitzig and of Ferrier as artefactual due to ‘spread of current’ to the striatum, then considered the highest motor centre. To overcome these criticisms,

Fig. 1.6 Movements produced by electrical stimulation of the cerebral cortex of the dog.
Notes: Δ, twitching of neck muscles; +, abduction of foreleg; †, exion of foreleg; #, movement of foreleg; □, facial twitching.

Reproduced from Fritsch GT, and Hitzig E, On the electrical excitability of the cerebrum [1870]. In: von Bonin G, trans., Some Papers on the Cerebral Cortex, Copyright (1960), with permission from Charles C omas.

Victor Horsley, Charles S Sherrington, and others began meticu- lous ‘punctate’ mapping of the cortex using the minimum current to elicit the smallest discernable movement.e.g. 45–47 Sherrington’s map of the motor cortex in the chimpanzee, followed by Wilbur Pen eld’s human motor homunculus and Clinton Woolsey’s maps of monkeys and other animals, became the standard picture of the motor cortex.48–50 Ferrier’s maps of the motor cortex in the macaque were applied surprisingly quickly to human brain sur- gery. Starting in 1876, the Scottish surgeon William McEwen and the London surgeon RJ Godlee used Ferrier’s maps to successfully locate and remove tumours.51

Recently, Michael Graziano has revisited Ferrier’s idea that the motor cortex may control complex, highly integrated behaviour.52

e neuron doctrine

e neuron doctrine—the idea that the nervous system is made up of discrete nerve cells that are the anatomical, physiological, genetic, and metabolic bases of its functions—may be viewed as the single-most important development in the entire history of neuro- science. e work of two men was crucial to the nal acceptance of the doctrine: Camillo Golgi (1843–1926) and Santiago Ramón y Cajal (1852–1934).53

Although eodor Schwann suggested, in 1838, that all animal tissues are made up of cells, the nervous system resisted interpret- ation in terms of cell theory for about another 50 years. is was because with the stains and microscopes available, the nervous sys- tem o en looked like an anastomosing network or ‘reticulum’. e resolution of this enigma came, eventually, from the discovery by

CHAPTER 1 historical aspects of neurology 9

10 SECTION 1 normal cognitive function

Fig. 1.7 Golgi’s drawing of the reticulum formed by axon collaterals in the dentate gyrus of the hippocampus.
Reproduced from Golgi C, e neuron doctrine–theory and facts. Nobel Lecture, 11 December 1906. In: Nobel Lectures Physiology or Medicine 1901–1921. Copyright (1999), with permission from the Nobel Foundation.

Golgi in 1873 of a new silver stain that stained only a small propor- tion of cells but did so in their entirety.53

Using this stain, Golgi a) con rmed Otto Deiters’s earlier obser- vation of a single axon (‘axis cylinder’) coming from each nerve cell, b) found that dendrites (‘protoplasmic prolongations’) ended freely, c) discovered axon collaterals and thought they merged with the axon collaterals of other nerve cells to form a di use reticu- lum, and d) classi ed nerve cells by their processes. Golgi believed that the function of dendrites was nutritive and not the conducting of messages. He had a holistic view of brain function and thought that the reticulum, made up of anastomosing axon collaterals, was the basic mechanism of brain function (Fig. 1.7). is, he thought, accounted for such phenomena as recovery from brain damage. His holism led him to disbelieve the localization results of Fritsch and Hitzig and of Ferrier.53

Fourteen years later, Ramón y Cajal came across the Golgi sil- ver stain and immediately began making the o en-capricious Golgi method more reliable, particularly by working with younger ani- mals who have less myelin, since myelin is resistant to silver stain- ing. Unlike Golgi, Cajal concluded that axon collaterals did not anastomose but ended freely: neurons were separate independent units. Although microscopes were not able to visualize the gap between neurons, Cajal inferred (intuited might be a better term) its existence on several grounds. One was by using immature or even foetal animals where he observed axons growing out of cell bodies before approaching other neurons or muscles. Another was that when cutting a nerve bre it would degenerate, but only up to the border with the next cell.53 (See Fig. 1.8).

Beyond con rming the idea of the neuron as an independent unit, Cajal developed the ‘Law of Dynamic Polarization’, the idea

that information transmission was from the dendrites to the cell body and out along the axon. He then used this ‘law’ to work out several neural circuits that began with sensory receptors in the ret- ina or in the olfactory bulb.53

In 1906, Golgi and Cajal shared the Nobel Prize. Golgi’s Nobel address was a vigorous defense of the reticular theory with the claim that the neuron theory ‘is generally recognized as going out of favor’.53,54 Over 100 years later, the neuron doctrine still stands as the bedrock of neuroscience. Its fundamental tenet of the dis- continuity between neurons was nally con rmed by the electron microscope in the 1950s only to be soon modulated by the discov- ery of a very small number of gap junctions in which the cell mem- branes of adjacent neurons are immediately opposed and synaptic transmission is electrical.55,56 e Law of Dynamic Polarization is still considered to be a fundamental property of neural circuits, although the existence of axon-less neurons, dendro-dendritic and axon–axonal synapses has complicated the picture.53

Twentieth-century neuroscience Prefrontal cortex

e association of the prefrontal cortex with the higher intellec- tual faculties has a long history. Classical busts of gods, heroes, and famous writers and artists usually show a high forehead in contrast to both lower-class individuals and women, both of whom were usually depicted to have retreating foreheads.57 e eighteenth-century Swedish theoretical neuroscientist and philosopher, Emanuel Swedenborg, attributed imagination, memory, thought, and will to the anterior regions of the brain.58 Gall and Spurzheim placed the ‘intellectual’ faculties in the most anterior brain regions. When the

Fig. 1.8 Cajal’s drawing of the sensory-motor connections of the spinal cord according to his neuron theory (right) and to Golgi’s reticular theory (left). A: anterior roots; B; posterior roots. According to Golgi, collaterals of the motor axon (a) anastomose forming part of a di use interstitial network (c). According to Cajal, the axon collaterals (f) do not.
Reproduced from Cajal S Ramon y. Recollections of My Life, Trans. EH Craigie, Copyright (1937), American Philosophical Society.

systematic study of human brain injury and of experimental lesions in monkeys began in the nineteenth century, intellectual function was usually located in the prefrontal cortex. For example, from their observations of frontal lobe damage, the frontal lobes were thought by Hitzig to contain the highest intellectual centre, by Ferrier to be the centre of attention and therefore of ideation and perception, by Paul Flechsig to be the area for volition and the higher levels of personality, by Giovanni Bianchi to be the centre of centres, and by Wilhelm Wundt to be an ‘apperception’ centre.59

In 1848, one of the most notable cases of prefrontal injury occurred in a man working with explosives on the railroad, whose skull was accidentally pierced by an iron bar pierce. Remarkably, Phineas Gage survived the accident but his personality and behav- iour changed irrevocably. From being a considerate, responsible foreman, he became ‘ tful, indulging at times in the grossest pro- fanities … manifesting but little deference for his fellows, impatient of restraint or advice when it con icts with his desires, at times per- tinaciously obstinate, yet capricious and vacillating, devising many plans of future operation, which are no sooner arranged that they are abandoned’.60 Gage’s case was not widely reported and its true importance was not fully appreciated until much later, but it stands as a landmark case in the history of observations of human prefron- tal function.61

In the rst objective tests of prefrontal function in animals, a er prefrontal lesions, monkeys and chimpanzees were found to be severely and permanently impaired on performance of the ‘delayed response test’ in which the animal is required to remember, a er a brief delay, at which of two sites a bait is hidden.62 is was con- sidered to be a test of ‘recent memory’62 and later one of ‘working memory’.63 e dorsolateral prefrontal cortex was subsequently shown to be crucial for performance of this task.59,64

An incidental observation on a single chimpanzee’s behaviour- during this task led directly to the widespread clinical use of fron- tal lobe surgery to treat a variety of psychiatric disorders. Prior to lesion of its frontal lobe, this animal would have temper-tantrums whenever she made an error on the delayed response test. She no longer did so following the operation.62 When the Portuguese neu- rologist Egas Moniz heard of this observation at the International Congress of Neurology in London in 1935, he was inspired to initiate a series of frontal ‘leucotomies’ (cutting the white matter under the frontal cortex) to treat mental illness, and versions of the procedure technique were rapidly adopted elsewhere. In 1949, Moniz received the Nobel Prize for the introduction of frontal leu- cotomy. is and other psychosurgical procedures on the frontal lobe were carried out on an estimated 60 000 people in the US alone (Fig. 1.9). e practice radically declined in the 1980s largely

CHAPTER 1 historical aspects of neurology 11

12 SECTION 1 normal cognitive function

Fig. 1.9 W. Transorbital lobotomy used extensively by Walter Freeman: ‘A transorbital leucotome is inserted through the orbital roof into the brain and the handle is swung medially and laterally to sever bers at the base of the frontal lobe.’
Reproduced from Proc. R. Soc. Med. (Suppl.). 42, Freeman W, Transorbital leucotomy: the deep frontal cut. pp. 8–12, Copyright (1949), with permission from SAGE Publications.

because of the introduction of chlorpromazine and other psycho- active drugs.65–67

Assessment of the e ects of frontal lobotomies is di cult because very few patients were studied objectively before and a er surgery by independent investigators. Elliot Valenstein, who investigated the e cacy of the older lobotomies, summarized the situation as follows:

In general, there seems to be strong suggestive evidence (if not abso- lutely convincing) that some patients may have been signi cantly helped by psychosurgery. ere is certainly no grounds for either the position that all psychosurgery necessarily reduces people to a ‘veg- etable status’ or that is has a high probability of producing marvelous cures … ere is little doubt, however, that many abuses existed. Quite apart from the e ectiveness of the surgery there were always some risks. Patients did occasionally die from the operation, epilepsy was not an uncommon a ermath and various symptoms from infections and neurological damage could be attributed directly to the surgery.68

A small number of limited psychosurgical procedures are still car- ried out on the frontal lobe but they appear to be much more e ca- cious than the older procedures.65

Today, the prefrontal cortex is o en divided into several systems with di erent functions and damage to each system tending to pro- duce a di erent set of symptoms. To summarize (and simplify) one parcellation, damage to the dorsolateral system produces execu- tive dysfunction, to the orbitofrontal system, disinhibition, and to the medial frontal system, apathetic motivation.66 Another, more integrative theory has been o ered by Earl Miller and Jonathan Cohen69 (see also chapter 3).

Visual cortex

Bartolemo Panizza (1785–1867) was the rst individual to produce detailed experimental and clinicopathological evidence for a visual

area in posterior cerebral cortex. He carried out anatomical and lesion experiments on a variety of species as well as observations on brain-injured humans. His work was largely ignored, perhaps because it was published in Italian in a local journal, and because, following both Gall and Pierre Flourons, visual functions were con- sidered subcortical, the cortex being reserved for ‘higher psychic’ functions.70

Soon a er Fritsch and Hitzig’s publication on the motor cortex, David Ferrier con rmed their results (see section on discovery of motor cortex above). Ferrier then applied their electrical stimula- tion methods to search for sensory cortices in monkeys. He found that stimulation of the angular gyrus produced eye movements and inferred that this area was the seat of visual perception. He sup- ported this by showing that bilateral lesions of this area produced blindness (for the few post-operative days that the infected ani- mals lived). Apparently con rming this view, he found that large occipital lesions had no visual e ects unless they encroached on the angular gyrus.71

By contrast, soon a er, Hermann Munk found that large occipi- tal lesions produced blindness in both dogs and monkeys. Sanger Brown and Edward Schafer then con rmed Munk’s report of total blindness a er total occipital lesions in monkeys.72 (We now know that Ferrier’s failure to produce blindness a er occipital lesions was because his lesions spared the representation of the fovea, whereas those of Munk and Brown and Schae er did not.)

By the turn of the century, anatomical, clinico-pathological, and experimental data were converging on the identity of a visual area in the posterior cerebral cortex corresponding to the region of the stripe of Gennari, described by Francisco Gennari in 1782 and named by G Elliot Smith as area striata.72

In 1941, SA Talbot and Wade Marshall, using visually evoked responses, mapped the visual topography of striate cortex in

cats and monkeys (i.e. the projection or ‘map’ of the retina onto cortex). David Hubel and Torsten Wiesel, recording from sin- gle neurons, subsequently con rmed this retinotopic organiza- tion. rough the brilliant use of single neuron physiology, they revealed the functional architecture of striate cortex. ey showed that single striate cells integrated binocular input and were sen- sitive to oriented lines and edges. eir research promised the possibility of understanding perception in terms of neurons and became the model for subsequent explorations of the visual cor- tex and for all of contemporary neurophysiology. ey shared the Nobel Prize with Roger Sperry in 1961. Hubel and Wiesel then showed a second and third retinotopic area (V2 and V3) adjacent to striate cortex (V1) in the regions previously called para- and prestriate cortex.73

A new phase of cortical visual physiology began in the 1970s when John Allman and Jon Kass described a multiplicity of extra-striate visual areas in the squirrel monkey.74 Even more visual areas were subsequently discovered in the macaque and human by Semir Zeki, Van Essen, and Charles Gross and their colleagues, a total of over 30 having been found to date.75 Leslie Ungerleider and Mortimer Mishkin showed that these areas were organized into two main processing streams: a dorsal stream extended into posterior parietal cortex and was specialized for the analysis of space and movement, and a ventral stream extended into the temporal lobe and was specialized for pattern recognition, that is, for form and colour.76 Proceeding down each stream, the successive visual areas tend to have larger receptive elds, less topographic organization, and neurons with more spe- cialized properties.77–79

e inferior temporal cortex lies at the terminus of the ventral stream. Its neurons are no longer retinotopically organized and they respond selectively to complex shapes. In both monkeys and humans, the inferior temporal cortex contains several areas that selectively respond to images of faces.76,77 ere are also areas that specialize in representing locations and body parts. In both macaques and humans, these specialized areas were delineated with imaging methods.78 e later stages in both the dorsal and ventral hierarchy of visual areas send projections to the hippocam- pus by way of perirhinal and parahippocampal cortex.77,79

Brain laterality

Broca and Wernicke’s discoveries that le -hemisphere damage, at least in right-handers, resulted in de cits in producing and under- standing language respectively, led to the idea that the le hemi- sphere was the dominant hemisphere and the right hemisphere was the non-dominant or minor hemisphere. At rst, the dominant hemisphere was thought to be the most important hemisphere not only for language but also for other cognitive functions. For exam- ple, Hugo Liepmann (1863–1925) attributed ‘purposeful’ move- ments to the dominant hemisphere,57 and his classi cation of limb apraxia remains highly in uential to this day.

As early as 1865, John Hughlings Jackson, the ‘father’ of English neurology suggested that the so-called minor hemisphere might be more important than the major hemisphere for perceptual func- tions. However, it was not until the 1930s that evidence from the study of human patients showed that a variety of disorders in non-language functions were more common or more severe a er right- than a er le -hemisphere damage.79,80 ese sequleae of

right-hemisphere lesions included perceptual de cits (such as in object and face recognition and in visuo-constructive tasks), atten- tional de cits, and emotional disorders. us it became clear that the le hemisphere was the major one for language and related functions, whereas the right hemisphere was dominant for a var- iety of perpetual, attentional, and emotional functions. is lateral- ization of cognitive functions could also be shown in intact subjects by the unilateral anaesthetization of one hemisphere, a procedure know as the ‘Wada’ test, developed by the neurologist JA Wada in 1949.80

A new and powerful method of comparing the functions of the two hemispheres was developed by Roger Sperry and his colleagues in the 1950s. e clinical literature on patients with damage or agenesis of the corpus callosum had been contradictory, with many studies reporting no e ect of a damaged or absent callosum. For example, Andrew Akelatis had sectioned the corpus callosum for treatment of epilepsy in a number of patients and reported a total absence of any cognitive e ects of this surgery.57

By contrast, Sperry and his students showed, rst in cats and monkeys and then in human patients, that section of the corpus cal- losum resulted in each hemisphere having ‘its own mental sphere— that is, its own independent perceptual, learning, memory and other mental processes’.81 Suddenly, it became possible to compare the functions of the two hemispheres directly. e key to Sperry’s discovery was, in subjects with the corpus callosum sectioned, to direct sensory input into each hemisphere independently. For example, in the visual modality, he sectioned the optic chiasm sagitally so that information from the le eye went only to the le hemisphere and information from the right eye only to the right hemisphere. In humans, he achieved the same result by having the subject with sectioned corpus callosum xate so that information presented to each visual half- eld went to the contralateral hemi- sphere.82 Sperry received the Nobel Prize in Medicine/Physiology for this work in 1981.

It should be mentioned that this important work became rather distorted in the popular literature by its neglecting the fact that although the hemispheres have specialized functions, in fact they work together in the intact individual.

Functions of the hippocampus in memory

A major advance in the neurology of memory came from the study of Patient HM who received bilateral lesions of the hip- pocampus and adjacent tissues to alleviate epileptic seizures in frankly experimental surgery by William Scoville in 1953. A er the surgery, as studied primarily by Brenda Milner and later her student Suzanne Corkin, HM had very severe anterograde amne- sia: he appeared to be unable to store any new information for more than a few minutes, and his short-term memory never became long term.83

Subsequent research indicated that only his ‘declarative’ mem- ory (memory for facts and events) was impaired, whereas his ‘procedural’ memory (such as memory for motor and perceptual skills, and classical conditioning) was intact.84,85 Similar dissocia- tions between the two types of memory have been found in other patients a er hippocampal damage (but see also chapter 13). e hippocampus is necessary for the formation of long-term declara- tive memories, which appear to be stored in portions of the cerebral cortex.85

CHAPTER 1 historical aspects of neurology 13

14 SECTION 1 normal cognitive function Imaging

e most important advance in neurology in the last half-century has been the development of brain imaging, both structural (ana- tomical) and functional.

Structural imaging

CAT scanning (computed axial tomography), introduced in 1971, involves rst X-raying the brain (or other body part) at di erent angles from which is produced a three-dimensional image recon- structed by computer. is was a remarkable advance in neurology replacing inferior techniques for estimating brain lesions or tumours such as pneumoencephalography, cerebral angiography, and clinical examination. MRI (magnetic resonance imaging) of the brain was developed at about the same time as CAT scanning but has much higher resolution. It derives from a technique developed in chemis- try in the 1970s, ‘nuclear magnentic resonance’, involving the prop- erties of hydrogen atoms in a magnetic eld. MR techniques also permit visualization of white-matter connections in the brain using di usion-weighted imaging and tractography (see chapter 8).

Functional imaging

Functional imaging of the brain measures changes in local activity in di erent brain structures as functions of cognitive activity. e rst to do this was Angelo Mosso in 1881. He observed brain pul- sations through skull openings in human patients, noted that they increase locally during cognitive tasks, and inferred increased blood ow with increased brain function.86 A few years later, Charles C Roy and Sherrington, from their animal experiments, suggested ‘automatic mechanisms’ that regulated blood ow depending on variations in neural activity. In the 1920s, John Fulton studied a relationship of increased blood ow with the act of reading in a human patient.86

A er the Second World War, several techniques were developed that enabled blood ow to be locally measured as a function of

fMRI is also a method of measuring local blood ow in the brain. It is based on the same technique as MRI except that the imaging is focused on measuring the ratio of oxygenated to deoxygenated haemoglobin known as the ‘blood oxygenation level dependent’ or BOLD e ect. e BOLD response is a slightly delayed index of local brain activity. fMRI is today largely replacing PET for studies of brain activation because it is has much better spatial and temporal resolution, individuals can be safely studied repeatedly, activity on single trials can be measured, and it does not require a large medi- cal centre for its use.87

fMRI studies have provided numerous new insights into cogni- tive neuroscience and promise many more in the future.

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79. Kravitz DJ, Saleem KS, Baker CI, et al. e ventral visual pathway: an expanded neural framework for the processing of object quality. Trends Cogn Sci. 2013;17:26–49.

80. Hecaen H and Albert ML. Human Neuropsychology. New York, NY: Wiley, 1978.

81. Sperry RW. Cerebral organization and behavior. Science. 1961;133: 1749–57.

82. Sperry RW. Hemisphere deconnection and unity in conscious aware- ness. Am Psychol. 1968;23:723–33.

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83. Corkin S. Permanent Present Tense: e Unforgettable Life of the Amnesic Patient, H.M. New York, NY: Basic Books, 2013.

84. Corkin S. What’s new with the amnesic patient H.M.? Nat Rev Neurosci. 2002;3:153–60.

85. Squire LR. Memory and the hippocampus: a synthesis from ndings with rats, monkeys, and humans. Psychol Rev. 1992;99:195–231.

86. Posner MI and Raichle ME. Images of Mind. New York, NY: Scienti c American Library, 1994.

87. Raichle ME. e Origins of Functional Brain Imaging in Humans. In: S Finger, F Boller, and KL Tyler (eds). History of Neurology. New York, NY: Elsevier, 2010, pp. 257–70.

CHAPTER 2

Functional specialization and network connectivity in brain function
Giovanna Zamboni

Do mental processes depend from ‘localized’ brain regions or are they ‘global’ resulting from the integrated functioning of the brain as a whole? Brain lesion studies and neuroimaging methods have given evidence of both interpretations, allowing contempo- rary neuroscience to reach the conclusion that localized regions of the brain do carry out speci c cognitive functions but they do so through multiple and complex interactions with many other brain regions forming large-scale networks.

Focal nature of cognitive functions

Evidence for functional specialization

from lesion cases

Historically, the notion that di erent cognitive abilities are related to the function of speci c brain regions took a relatively long time to become widely accepted by the scienti c community (see chapter 1). Such a concept was long resisted by ‘holistic’ perspec- tives of the brain which viewed each part as contributing to all functions. It was only with the anatomo-clinical works of Broca and Wernicke on language disorders in the 1860s and 1870s that that the concept of functional specialization was put on a sure footing.1 Prior to this, the rst intuition that mental functions were based in the brain had been advanced by Franz Joseph Gall in his controver- sial doctrine of phrenology.2

In 1861, Broca described a patient who lost the ability to speak following a stroke. Although able to understand language and repeat single words, and free of signi cant limb weakness, this individual could not articulate sentences or express himself in writ- ing. Post-mortem examination revealed a lesion in the le posterior lateral region of the frontal lobe, subsequently termed Broca’s area.3 Broca described other similar cases, and by inferring the correla- tion between post-mortem anatomical lesions and language dis- orders (anatomo-clinical correlation method), he concluded that language is localized in the le hemisphere.

About a decade later, Carl Wernicke described another case of language disturbances following a stroke. is patient could speak uently but in a meaningless way and could not understand spoken or written language. A er his death, the damaged area was found to be in the posterior le temporal lobe at the junction with the parietal lobe, subsequently termed Wernicke’s area. On the basis of his and Broca’s ndings, Wernicke proposed a model of language as a multi-component process, in which each component would have

a speci c, distinct anatomical localization.4 He distinguished a cen- tre for motor–verbal functions, localized in the le frontal regions, responsible for language articulation and production, from a centre for auditory–verbal functions, localized in the le temporal region, responsible for language perception. Lesions to the former would cause a non- uent aphasia with intact comprehension (Broca’s aphasia), while lesions to the latter would cause a uent aphasia with impaired comprehension (Wernicke’s aphasia).

In the same decades, studies by Fritsch and Hitzig in dogs further reinforced the notion that di erent functions are localized in di er- ent cortical regions by demonstrating that the stimulation of anterior regions of the cerebral cortex causes contralateral movements, and that their disruption causes contralateral paralysis.5 Functional specializa- tion was further supported by animal studies identifying oculor-motor centres in the frontal lobes,6 auditory centres in the temporal lobes,7 and visual centres in the occipital lobes (see also chapter 1).8

Many other cognitive functions were localized by investigat- ing patients who had su ered from focal brain lesions. One of the most famous cases was reported by Harlow in 1848 who described Phineas Gage who, a er having sustained a frontal lobe injury, presented profoundly altered social and interpersonal skills, to the point that people who knew him beforehand described him as ‘no longer being Gage’. is rst suggested that frontal brain regions are involved in social behaviour.9

Another landmark case was described by Scoville and Milner in 1957. Following bilateral temporal lobe resection in the attempt to treat his epilepsy, a patient named Henry Molaison (famously known as HM) became severely amnesic. He had permanently lost the ability to acquire new information (anterograde amnesia) and recall memories of the years immediately prior to surgery (retro- grade amnesia), despite having normal reasoning skills, language, and short-term/working memory.10 HM provided the rst evi- dence that the hippocampus and surrounding medial temporal structures are essential for the consolidation of information in long-term memory.11

Following these single case studies, the study of lesions in humans evolved and expanded. Large groups of patients were assessed to establish correspondences between the brain and symptoms in a more quantitative, robust way, permitting statistical inference at the level of population.12,13 Standardized scales to measure cogni- tive abilities were developed and used to compare patients’ perfor- mance to healthy controls.14

18 SECTION 1 normal cognitive function

e lesion method is based on the assumption that if a certain brain region is necessary for a certain function, then a lesion to that area should lead to a de cit in that function, whereas this should not occur when the brain region is undamaged (simple dissociation). Further expansion of the lesion method came with the concept of double dissociation, considered to be the strongest evidence for functional specialization and segregation. It requires the comparison between two patients (or groups of patients) dif- ferent in terms of lesion localization: if one patient is signi cantly more impaired in function A, while the other is signi cantly more impaired in function B, then it is concluded that the two functions are independently associated with the two damaged areas.

Using the double dissociation technique, several investigators including Ennio De Renzi in stroke-lesioned patients,14,15 Freda Newcombe in soldiers who had sustained focal and stable brain wounds during the Second World War,16 Brenda Milner in surgi- cal patients who had had lobectomies,17 Gazzaniga in patients who had undergone callosotomy,18 all demonstrated di erential de – cits following le and right hemisphere lesions and specialization of the right hemisphere for visual–perceptual and spatial tasks and le hemisphere for speech and skilled movements. Newcombe, for example, provided the rst evidence of dissociated visual–perceptual and spatial de cits following, respectively, temporal-posterior lesions and dorsal-parietal lesions of the right hemisphere,19 sup- porting the concept of a dorsal and ventral visual stream.

rough the study of lesion cases, the concept of functional speciali- zation became a dominant theme in neuroscience. It is mainly thanks to this approach that today we are able to localize de cits such as apha- sia, unilateral neglect, and impaired executive function at the bedside.

Evidence for functional specialization

from structural imaging

e need to study large groups of patients together with the advent of computer tomography (CT) and magnetic resonance imaging (MRI) encouraged development of methods that allow compari- son of lesions across di erent patients,20 including transposition of brains into common, stereotactic spaces.21 One common method consisted of identifying regions of lesion overlap. e extent and location of damage in a group of patients could be visualized in a colour-coded ‘lesion density map’, in which the region damaged in the highest number of patients would be surrounded by regions damaged by a progressively decreasing numbers of patients.22,23

Two approaches have been used to relate symptoms to lesions. One groups patients by location of their brain lesions and then examines di erences in symptoms. For example, a study by Grafman and colleagues on veterans who su ered penetrating head injuries in Vietnam showed that soldiers with lesions in the ventro- medial regions of the frontal lobes were more aggressive and violent than those with lesions in other brain areas.24 e second approach groups patients by symptoms and then examines lesion location. For example, Damasio and colleagues classi ed patients with focal brain lesions according to whether they had selective de cits in naming famous persons, animals, or tools. By using lesion density maps, they showed that each of these category-speci c de cits was associated with overlapping of lesions in di erent temporal lobe regions, arguing for a role of higher-order association areas outside of classic language areas in word retrieval.25

MRI o ers a higher spatial resolution than CT and allows for more comprehensive characterization of lesions by ‘dividing’ the

brain into three-dimensional units of volume (voxels). In one of the rst studies that used a voxel-based approach, Adolphs and colleagues demonstrated involvement of somatosensory cortices as well as the amygdala in emotion recognition, by comparing the voxel-based lesion density map of patients with impaired emotion recognition with that of unimpaired cases. e resulting di erence map revealed that voxels within the somatosensory cortex were sig- ni cantly associated with impairment.26

Building on statistical approaches used in functional imaging (see next section), recently developed techniques such as voxel-based lesion symptom mapping (VLSM)27,28 allow for improved symp- tom mapping by computing statistical tests iteratively for each and every voxel. e technique relies on comparison of continuous or discrete behavioural variables on patients grouped according to whether they have damage in that given voxel and then correcting for multiple comparisons. is is an example of a ‘mass-univariate’ approach because each voxel is assumed to be independent of another. Importantly, VLSM does not require patients to be grouped a priori according to lesion location or performance cut-o s, but produces statistical values for each given voxel indicating whether damage to that voxel has a signi cant e ect on the cognitive variable of interest.29–33

Although fundamental to study symptom–lesion associations, voxel-based symptoms mapping methods are limited by their assump- tion that each voxel can be damaged independently of other voxels. It has been recently argued that this assumption is not biologically valid, as lesions in the human brain tend to follow patterns depending, for example, on vascular supply in the case of stroke. It is possible that ‘collaterally damaged’ voxels may be always associated with voxels that are instead critical for a certain de cit and therefore may systemati- cally confound lesion–symptom associations, suggesting that multi- variate rather than mass-univariate approaches may be better suited to identify true anatomical correlates of de cits/symptoms.34

Structural MRI data can also be analysed with procedures that provide subject-speci c estimated maps of grey matter volume or thickness,35–38 which are more suitable for studying subtle struc- tural changes and, di erently from VLMS, do not rely on ‘radio- logically visible’ and discrete lesions. Among them, voxel-based morphometry (VBM) involves segmentation of the grey matter, spatial transposition of all the subjects’ images to the same stereo- tactic space, and ‘modulation’ to obtain voxel-speci c values of grey matter density (or volume). ese values can then be used in regression analyses to compare groups of individuals or perform correlations with continuous variables of behavioural/cognitive performance. is is achieved with voxel-based statistical analysis aimed at identifying, for example, distribution of voxels of signi – cant volumetric di erences between two groups, or voxels whose grey matter density signi cantly correlates with performance.

VBM has been particularly useful in identifying brain–symptom associations in neurodegenerative diseases, in which pathologi- cal processes causing grey matter loss or atrophy are widespread and involve di erent brain regions to a variable degree. ey are therefore are better represented by continuous variables rather than binary measurements, which are more suited to de ne dis- crete lesions. In patients with dementia or other neurodegenera- tive diseases, VBM has been reliably used to identify patterns of grey matter atrophy. For example, several VBM studies39–41 have found that patients with Alzheimer’s disease (AD) have focal atro- phy in the medial temporal lobes, posterior cingulate/precuneus,

and other association areas in a pattern that mirrors the spread of neuro brillary tangles,42 while the behavioural variant of fronto- temporal dementia (FTD) is associated with atrophy in the fron- tal lobes.43,44 Semantic dementia is associated with asymmetrical anterior temporal lobe atrophy. By contrast, progressive non uent aphasia is associated with le perisylvian atrophy.45 In addition, VBM has also been extensively used to make inferences on the association of focal atrophy with speci c cognitive de cits.46–49 As an example, a VBM correlational analysis in patients with frontotemporal dementia reported that severity of apathy cor- related with atrophy in the right dorsolateral prefrontal cortex, whereas severity of disinhibition correlated with atrophy in mes- olimbic structures.50

Several other MRI-based tools have been used to study volumes of a priori de ned regions of interest (ROIs) or rates of atrophy over time in neurodegenerative diseases. In AD, ROI-based measures of hippocampal volumes are signi cantly reduced compared to age-matched controls,51–54 and the rate of change measured from serial MRIs obtained six months or one year apart signi cantly increased.55–58

By the use of correlational analyses, VBM and ROI-based meth- ods allow for indirect inferences about the localization of speci c symptoms in patients with dementia. However, di erently from lesion–symptom mapping techniques, they do not prove the neces- sity of a brain region for a speci c cognitive function.

Evidence for functional specialization from functional

imaging in healthy subjects

Functional imaging has revolutionized the eld of brain function mapping over the last 20 years. Activation-based positron emis- sion tomography (PET) and task-based functional MRI (task fMRI) detect changes in metabolism or blood ow while subjects are engaged in sensorimotor or cognitive tasks and can be used to produce activation maps revealing which parts of the brain are engaged. ese functional techniques have allowed extension of the concept of functional localization from the study of brain-injured patients to the study of healthy people.

PET activation studies measure focal variations in cerebral blood ow. A radiotracer is injected in the bloodstream while the subject is engaged in di erent tasks (usually an experimen- tal condition and a control condition), with the assumption that blood ow will increase in brain regions where there is increased neural activity.59 Task-based fMRI relies on the Blood Oxygen Level Dependent (BOLD) contrast, which is dependent on local changes in cerebral blood ow, cerebral blood volume, deoxyhae- moglobin concentration, local haematocrit, and changes in oxy- gen consumption. When a brain area is more active, it consumes more oxygen, causing an increase of blood ow and a change in the BOLD signal.60,61 PET activation studies and task-based fMRI do not directly measure neural activity, but instead measure changes in parameters (metabolism and BOLD) correlated with neural activity that occur with a delay, limiting the temporal reso- lution of these techniques.

PET activation studies and task-based fMRI studies do not provide absolute measurements of physiological parameters but measure changes that occur in response to a task relative to another task, used as a control condition. By subtracting signal changes occurring during the control task from those occurring during the experimental task, it is possible to identify areas of

increased activation associated with the task of interest, assum- ing that areas active in both control and experimental conditions have been cancelled out. To establish localization and strength of the association between the experimental condition and the meas- ured brain changes, the functional images that have been acquired over time during di erent conditions and across di erent subjects need to be realigned and mapped into standard stereotactic, voxel- based spaces. en, methods allowing statistical inference need to be used.

e most commonly used method to identify functionally spe- cialized brain responses is statistical parametric mapping (SPM), which allows use of standard statistical tests on each voxel and assembles the resulting statistical parameters into images.62 ese are then used to compare di erent conditions and to identify regionally speci c changes of signal attributable to the experi- mental task (Fig. 2.1).63 Importantly, if a signi cant associations is found, this does not mean that the identi ed area is necessary for the speci c function or cognitive process, nor that it is speci c for it, because it may also be involved in other functions or tasks.

Since the advent of functional imaging techniques in the late 1980s and early 1990s, a huge number of studies have reported focal activations in response to speci c tasks across a range of cog- nitive domains,64 providing striking evidence for the concept of functional specialization. A review of these studies is outside the focus of the present chapter but a few early studies are worth con- sidering as examples.

In a PET activation experiment, Zeki and colleagues showed that occipital area V4 is speci c for colour vision, by comparing activations obtained during presentation of multicolour abstract images with those obtained during presentation of the same images in black and white, and that V5 or area MT is speci c for motion perception, by comparing activations obtained during presentation of moving relative to stationary black and white patterns (see also chapter 6 for further examples).65

One important limitation of the subtraction method used in the early functional activation studies is that it depends on the assumption of ‘pure insertion’, that is, that a component process can be added into a task without a ecting other processes. To modu- late possible interactions between di erent cognitive components in neuroimaging experiments and disentangle the e ect that one component has on the other, more sophisticated experimental techniques such as factorial design were implemented.66 For lan- guage, a factorial design was used, as an example, to compare object naming with colour naming. It allowed identi cation of modality- independent naming areas in prefrontal and posterior temporal regions, and areas involved in object recognition in bilateral ante- rior temporal regions.67

e results of several functional imaging studies have chal- lenged the traditional view of a one-to-one correspondence between brain regions and cognitive processes. On the one hand, single cognitive processes frequently elicit activation of several brain regions or distributed patterns of activations.64,68 On the other hand, activations of single brain regions are frequently elic- ited by a wide range of cognitive tasks, even when these have been carefully modulated with factorial experimental designs.68,69 us, although extensively supported by lesion cases and func- tional imaging studies, the concept of functional specialization alone may not be su cient to explain brain functioning and organization in human.

CHAPTER 2 functional specialization, network connectivity 19

20 SECTION 1

normal cognitive function

FMRI data Time

Motion correction High-pass filtering Spatial smoothing

Preprocessed data

Voxel-wise single-subject analysis Design matrix

Effect size statistics

resholding

Time

Contrast

Voxel time-series data

Statistic image

GLM

Significant voxels/clusters

Single-subject effect size statistics

Stimulus/task timings

Fig. 2.1 Schematic representation of single-session analysis of fMRI data. fMRI data are acquired while stimuli are presented to the subject, who performs a task in the scanner. Data are then pre-processed (including motion correction, temporal ltering, and spatial smoothing) and entered into a regression model (general linear model, GLM) that expresses the observed BOLD response in terms of a linear combination of explanatory variables (in the design matrix) derived from stimulus/task timings and the haemodynamic response function (HRF), together with an error term. Voxel-speci c e ect-size statistics describe how well the modelled responses to the stimulus/task (explanatory variables) explain the continuous data. resholding is performed in a way that accounts for multiple comparison correction.

Courtesy of the Analysis Group of the Centre for Functional MRI of the Brain (FMRIB) from the FSL (FMRIB Software Library) course.

Network organization of cognitive

functions

Towards the concept of distributed

functional networks

Wernicke had rst suggested that complex cognitive functions such as language result from distributed systems of linked focal brain regions. He proposed a model of language as a multi-component process, in which each component has a speci c anatomical locali- zation but is connected to the other components, reconciling evi- dence for functional specialization that he and others had provided with the notion that cognitive functions depend on integrated functioning across brain regions.4 He even hypothesized the exist- ence of a conduction aphasia that would be associated with a lesion of the pathways connecting the le hemisphere frontal and tempo- ral lobe centres, characterized by preserved uency and compre- hension but impaired repetition and paraphasic speech (the use of incorrect words or phonemes while speaking).

In addition to conduction aphasia, other ‘disconnection syn- dromes’ resulting from damage of white matter tracts between cor- tical areas were described. As an example, alexia without agraphia, in which patients are able to write and speak but cannot read, was rst described by Dejerine 1891 and associated with lesions to the white matter in proximity of the angular gyrus that interrupt the

connections between the visual cortex and language areas. In 1965, the anatomical bases of disconnection syndromes were reviewed by Geschwind70,71 who provided a theoretical framework that paved the road for modern concepts of distributed brain networks.72 Around the same time, Alexander Luria, one of the founders of neuropsychology, proposed a model of human mental processes based on complex functional systems or ‘functional units’ that involved groups of brain areas working in a coordinated, hierarchi- cal, and organized way.73

Related to this ideas is the notion that a lesion can cause func- tional damage ‘remote’ from the anatomical site of the lesion. is concept was extensively studied by Monakow who coined the term diaschisis—loss of function due to transient, indirect damage to remote parts of the brain not anatomically close to the site of the primary injury but functionally connected to it.74 His work fostered the view of the brain as a complex, dynamic system in which func- tion could be lost transiently. Evidence for diaschisis comes from functional imaging studies that show hypometabolism in regions remote from the cortical lesion,75 demonstrating directly the exist- ence of remote functional e ects.76

ese ideas led to the refutation of functional localization as the sole and su cient explanation of brain function. Brain–symptom correlations started to be searched not only in speci c, single brain regions but also in larger-scale networks connecting di erent

regions across the brain. With the additional bene t of knowledge about anatomical structural connections from tracing methods in the autopsied brain, Mesulam proposed a model of brain func- tion based on distinct, multifocal large-scale functional systems.77 In his scheme, there is a spatial attention network anchored in the posterior parietal and dorsolateral frontal regions, a language net- work involving Wernicke’s and Broca’s areas, a memory network linking the hippocampus and inferior parietal cortex, a face/object recognition network anchored in temporal cortices, and a working- memory/executive-function network connecting prefrontal and inferior parietal cortices.78

Subsequently, McIntosh demonstrated the existence of net- works by measuring the covariance of activity between regions in PET activation studies, thus identifying patterns of co-variation or functional connectivity.79 For example, he studied people who had learned that an auditory stimulus signalled a visual event and found activation in le occipital visual areas when auditory stimuli were presented alone. He then showed that this occipital activation cor- related with activation in the prefrontal cortex and that it accounted for most of the change in occipital activity.80

It is now widely accepted that the brain functions through large-

scale networks including multiple specialized cortical areas recip-

rocally connected with parallel, bidirectional, and multisynaptic

pathways. us de cits can be caused either by damage to special-

ized cortical areas, by damage to their connecting pathways, or both.72,81,82

Neuroimaging methods to study brain connectivity

Several methodological advances have allowed study of brain con- nectivity and large-scale brain networks from di erent perspec- tives. Functional connectivity refers to the functional relationship between brain regions inferred by searching for correlations in the fMRI signal between two or more brain regions (functional covariance). e structural bases of this relationship are ultimately assumed to exist through mono- or multisynaptic pathways.83,84

Correlations in the fMRI signal (BOLD signal) can be studied among regional changes occurring in response to cognitive tasks but also among regional changes that occur in the absence of tasks,

while participants are simply at rest (resting fMRI). In fact, it has been shown that the BOLD signal not only changes as a conse- quence of cognitive or ‘task-related’ demand, but also shows low frequency spontaneous uctuations (0.01–0.1 Hz) that are tempo- rally correlated and organized within speci c spatial patterns in the brain.85,86 e networks of brain regions whose spontaneous activity rises and falls coherently have been termed resting state networks.

To study functional correlation, a ‘seed’ voxel or anatomical ROI is ‘seeded’ to generate a correlation map showing all other regions in which signal changes signi cantly correlate with those within the seed region (seed-based correlation analysis). is approach is hypothesis-driven and requires a priori selection of the ROI or ‘seed’. Alternatively, a more exploratory, data-driven approach can be used to create a matrix of correlations across each voxel/region with all other voxels/regions in the brain. Correlation matrices can be decomposed into spatial modes using, for instance, principal component analysis (PCA) or independent component analysis (ICA) to identify large-scale networks or maps of spatially inde- pendent and temporally correlated functional signals.87–89

Among the several resting state networks identi ed with ICA- based approaches, the default mode network (DMN, Fig. 2.2A)— which includes posterior cingulate cortex and precuneus, the medial prefrontal cortex, and lateral parietal regions—is considered to be speci cally engaged during task-independent introspection or self-referential thought. e DMN was st identi ed in task- related fMRI by studying task-induced deactivations (i.e. decreases in BOLD signal during experimental conditions compared to base- line or resting conditions).90 It can also be identi ed with ‘seed- based’ methods examining correlations from regions such as the posterior cingulate.91,92

In addition to the DMN, other commonly identi ed networks are the ‘executive control’ networks linking dorsofrontal and pari- etal regions, the ‘salience’ network linking anterior cingulate to insular and limbic regions, and networks related to primary visual, auditory, and sensorimotor regions (Fig. 2.2).86,88,89,93,94 Resting state networks (RSN) have been shown to be consistent across subjects95 and to match activations found in task-based fMRI

CHAPTER 2 functional specialization, network connectivity 21

ABCDEFG

x = 2

y = 58

z = 26

x = –10

y = –80

z = –6

x = –10

y = –72

z = 16

x = 50

y = –32

z = 14

x = –6

y = 26

z = –14

x = –48

y = 10

z = 28

x = 44

y = 8

z = 34

Fig. 2.2 Resting state networks (RSNs). Spatial maps of resting state networks (RSNs) obtained using independent component analysis (ICA). e three most informative orthogonal slices for each RSN are shown. A) DMN; B) ventromedial visual RSN; C) dorsolateral visual RSN; D) auditory RSN; E) orbitofrontal RSN; F) left frontoparietal RSN; G) right frontoparietal RSN. Coordinates are in MNI.
Reproduced from Biological Psychiatry, 74(5), Zamboni G, Wilcock GK, Douaud G, et al. Resting functional connectivity reveals residual functional activity in Alzheimer’s disease, pp. 375–83, Copyright (2013), with permission from Elsevier.

22 SECTION 1 normal cognitive function

studies, suggesting that they re ect functionally signi cant brain networks.96–98

E ective connectivity represents another way to study functional correlations and network function. Di erent from functional con- nectivity, this method incorporates additional information such as anatomical constraints and considers interactions of several brain regions simultaneously. It is aimed at explicitly quantifying the in uence that one region has on another and establish whether their connections are causal and have a speci c directionality (from region A to area B rather than B to A).100 E ective connectivity approaches include dynamic causal modelling (DCM) that allows testing of speci c models of how di erent parts of a functional net- work are dynamically linked and coupled. DCM is less ‘model-free’ and more hypothesis-driven (and more computationally sophisti- cated) than functional connectivity. It tests dynamic interactions and is therefore task-dependent and condition-speci c, and has been mainly applied to task-based fMRI studies, although it has been recently extended to modelling of resting-state data and com- paring multiple di erent models.101,102

e principles used to investigate functional and e ective con- nectivity from fMRI data can also be applied to data obtained with neurophysiological techniques such as electro-encephalography (EEG) and magnetoencephalography (MEG), allowing mapping of networks at high temporal resolution as well as studying frequency band-speci c interactions.103,104

Structural connectivity refers to the white matter connections between brain regions. ese can be visualized with tracing meth- ods in animals or ex vivo methods in autopsied human brains, or inferred in vivo with structural imaging techniques such as di u- sion tensor imaging (DTI). DTI can be used to estimate the struc- tural integrity of brain connections (i.e. axons and bre tracts) by measuring di usion of water molecules through tissues.105 It pro- vides measures of fractional anisotropy (FA), a particularly sensi- tive index of microstructural integrity of cerebral white matter, and of radial and axial di usivity, which give indications of axonal dam- age and demyelination, respectively. Common methods to assess structural disruption are voxel-wise106 or di usion tensor imaging tractography (see chapter 8).107 Structural connectivity can also be estimated by studying the correlation among regional structural measures such as local cortical thickness and volume across sub- jects (anatomical covariance), in a way similar to functional con- nectivity.108,109 Structural covariance does not demand existence of a direct anatomical connection between the regions whose struc- tural measures are correlated. As with functional covariance, the identi ed connections might not re ect axonal pathways and cau- tion is required in interpreting the results. Nevertheless, networks identi ed using this approach have been found to re ect genetic in uences as well as experience-related plasticity reliably.110

Brain networks derived from all the methods described above can be examined using graph theory in which connectivity ele- ments (single brain regions or maps of resting state networks) are de ned as network nodes and their mutual relationships as network edges. In this way, brain networks can be mathematically described as graphs which, in their simplest form, correspond to correla- tions matrices representing the strength of edges between pairs of nodes. At the highest level of abstraction, even the whole brain can be de ned as a network and its properties described in terms of number of edges per node, resistance to damage, e ciency, hierar- chy, and sub-networks, among other graph theory measures.111,112

Although graph-theoretical approaches have several limitations, including the high dependence on how nodes are initially de ned (with structural atlas-based or functional parcellations) and their high degree of abstraction, they have the potential of becoming more meaningful and interpretable in the near future.113

Large-networks abnormalities

in neurodegenerative diseases

Connectivity methods have now been applied to neurological diseases. is has been particularly promising in the context of neurodegenerative diseases, which are associated with gradual and speci c patterns of progression of pathology across the brain. Indeed, it has been increasingly suggested that di erent pathologies target speci c large-scale networks.114,115

Since its identi cation, the DMN has been shown to be particu- larly relevant for AD, since it includes regions know to be vulner- able to atrophy, amyloid deposition, and reduced metabolism in patients with AD.116 DMN functional connectivity is reduced in patients with AD compared to healthy controls.117 Similarly, ROI- based studies using the hippocampus or the posterior cingulate as ‘seeds’ show decreased functional connectivity with regions of the DMN such as the medial prefrontal cortex, but increased func- tional connectivity with frontal and frontoparietal regions.118–121

More recent studies that used ICA-based methods con rm that patients with AD have signi cant decreased functional integrity and connectivity in regions of the DMN.122–125 Among them, the few studies that also explored other resting state networks99 found that that functional connectivity within frontal and frontoparietal networks is increased in patients with AD relative to controls, thus having the opposite connectivity e ect than the DMN.99,123,124,126 Importantly, these most recent studies examined changes in func- tional connectivity occurring over and above the structural changes that occur in neurodegenerative diseases by including VBM meas- ures of atrophy as a covariate of no interest.

A number of resting-state fMRI studies have explored functional connectivity in other neurodegenerative diseases. For example, in patients with behavioural variant of frontotemporal dementia, functional connectivity was decreased in the salience network and increased in the DMN, a pattern opposite to the one found in patients with AD.127 In patients with Parkinson’s disease, functional connectivity is reduced in a network involving basal ganglia, and normalizes upon administration of dopaminergic medication.128

Do resting state networks identi ed with resting fMRI relate to actual brain functioning in response to cognitive demand? In healthy people, it has been increasingly shown that functional net- works at rest re ect those utilized ‘actively’ during execution of tasks.96–98 A recent study which combined resting and task-based fMRI also showed that this is true in patients, suggesting changes in functional connectivity secondary to neurodegenerative disease might directly re ect residual cognitive functioning in patients.99 E ective connectivity has also been used in neurodegenerative diseases.129

In a seminal study combining anatomical covariance and func- tional connectivity,130 Seeley and colleagues investigated pat- terns of atrophy of ve di erent neurodegenerative syndromes (Alzheimer’s disease, corticobasal degeneration, and the three variants of frontotemporal dementia) shown in blue in Figure 2.3). Using the identi ed regions of greater atrophy in each disease as a ‘seed’, they then showed that in healthy people, seed-based

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Syndrome-specific regional atrophy patterns: patients vs. controls

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(c)

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CHAPTER 2 functional specialization, network connectivity 23

+14

+10

Intrinsic functional connectivity networks: healthy controls

Structural covariance networks: healthy controls

3.6

4.6

Fig. 2.3 Results of the study from Seeley, et al.130 Syndrome-speci c atrophy patterns (in blue), whose cortical maxima (circled) provided seed ROIs for functional
(in yellow) and structural (in green) covariance analyses in a group of healthy controls.
Reproduced from Neuron, 62(1), Seeley WW, Crawford RK, Zhou J, Miller BL, Greicius MD, Neurodegenerative diseases target large-scale human brain networks, pp. 42–52, Copyright (2009), with permission from Elsevier.

covariance patterns of structural (Fig. 2.3, green) and functional (Fig. 2.3, yellow) measures mirrored syndrome-speci c patterns of atrophy. is suggested that networks of functional and structural connectivity in the healthy brain are di erentially vulnerable to speci c neurodegenerative disease. More precisely, AD a ects the DMN, the behavioural variant of frontotemporal dementia a ects the salience network, semantic dementia targets the le temporal polar network, progressive non- uent aphasia the le frontopa- rietal network, and corticobasal degeneration the sensory-motor network.

In a subsequent study, the same authors further explored network properties of each region found to be atrophic in the ve neuro- degenerative diseases to identify regions whose normal functional connectivity pro le best overlapped with disease-speci c patterns of atrophy (which they termed ‘epicentres’). ey then used graph- theoretical methods to explore possible models of disease spread and reported evidence for a model of trans-neuronal spread from highly vulnerable disease epicentres that, in healthy people, repre- sent highly connected nodes or network hubs.131

Graph theory principles have also been applied to measures of cortical thickness covariance to explore network properties in patients with AD. Patients with AD have increased local connectiv- ity of nodes (increased clustering) but decreased global e ciency (increased edges length between connected nodes), suggesting that AD is characterized by a de cit in long-range connectivity and associated with a reversion to less optimal connectivity and more localized connections.132 AD patients also showed changes in the e ciency of speci c nodes, with signi cant decreased e ciency in heteromodal temporal and parietal regions, and increased e – ciency in frontal and occipital regions, in line with ndings from functional connectivity.

One recent study speci cally tested if network hubs, identi ed using DTI, in the normal brain are indeed vulnerable to speci c brain disorders.133 Analysis of data from published MRI studies

suggests these hubs are atrophic across twenty-six di erent neu- rological and psychiatric conditions. More precisely, nine diseases including AD and schizophrenia have atrophy located in speci c highly connected regions; that is, temporal lobe hubs were spe- ci cally associated with AD, whereas frontal and temporal corti- cal hubs were associated with schizophrenia. Similar results were obtained when highly connected hubs were derived from func- tional connectivity calculated from a meta-analysis of task-related functional imaging studies, rather than from DTI. e authors concluded that highly connected regions within networks identi- ed with di erent connectivity modalities are more likely to be ana- tomically a ected by brain disorders.

Future directions

e contraposition between the concepts of functional speciali- zation and connectivity has been a major theme in the history of neuroscience. While evidence discussed in the rst part of this chapter demonstrates the existence of functionally special- ized areas, a growing body of knowledge discussed in the second part shows the importance of connections for brain function- ing. Network approaches account for connectivity and nodal or regional specialization, o ering the promise to reconcile these seemingly opposing perspectives.134 Several worldwide initiatives have been recently set up with the aim of describing comprehen- sively all macroscopic functional and structural connections of the healthy brain, by mapping what has been termed ‘human con- nectomes’135 (for a complete list of current research projects into macroscale connectomics, see reference 136). Some argue that this will help to attain a fundamental understanding of brain architec- ture and its relation with cognition and behaviour. Ultimately, it is hoped that it will be clinically useful to obtain individual-relevant reliable indices that can be used for identi cation of people at risk of speci c diseases, prognostication, and measurement of treat- ment response.

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CHAPTER 3

e frontal lobes

Teresa Torralva, Ezequiel Gleichgerrcht, Agustin Ibañez, and Facundo Manes

e frontal lobes are pivotal in the management of higher-level behavioural functions, such as the planning and execution of inten- tional motor behaviour including but not limited to limb and eye movements and speech articulation. ey are also responsible for major information-processing operations, such as mnemonic func- tions. Among these are the short term, on-line maintenance and manipulation of information in working memory, which allows for an idea to be weighed up against alternatives,1 the organization of information for encoding and retrieval within long-term memory,2 and the establishment of abstract relationships and mental exibil- ity.3 Furthermore, the frontal lobes have a role in various compo- nents of attention,4 the processing of emotions,5 social cognition,6 and future-oriented thought.7

In light of the plethora of important functions mediated by the frontal lobes, impairment of frontal functions can be found, although in varying degrees, in many neurological and psychiat- ric disorders, predominantly in traumatic brain injury,8 fronto- temporal dementia,9,10 bipolar disorder,11,12 schizophrenia,13 and depression.14

An exceptionally large area of the brain, the frontal lobes account for approximately one-third of the human cerebral cortex. While it has been classically accepted that this area is larger in humans than in non-human primates, more recent studies suggest the frontal lobes are of comparable size throughout the primate line- age.15 Instead, it is proposed that the human neural architecture is more sophisticated or perhaps organized di erently than among non-human primates, thus allowing for a similarly sized cerebral cortex to accommodate the more advanced cognitive processes that characterize human but not other primates.16 In particular, Semendeferi and colleagues supported this assumption by sug- gesting higher-level cognition in humans may be attributed to dif- ferences in individual cortical areas and a richer interconnectivity rather than a greater overall size (Fig. 3.1a and b).17

Besides sharing cerebral cortices that may be proportionally simi- lar in size, humans and monkeys have distinct architectonic regions within their prefrontal cortex. Experimental and anatomical stud- ies in monkeys have identi ed that each region is distinct in its con- nections with cortical and subcortical structures.18 Connections are classi ed as either a erent or e erent and are mediated via speci c bre pathways. Critical information about perceptual and mne- monic processes occurring in posterior association cortical areas and subcortical structures is passed to particular prefrontal regions by means of a erent connections. E erent connections deliver information from the prefrontal cortical areas to post-Rolandic

cortical association areas and subcortical structures, thus enabling selective information processing.19

Each frontal lobe takes the form of a pyramid, with the frontal pole, central sulcus, and lateral, medial, and orbital walls contribut- ing to its shape. All functional types of cortex are represented within the frontal lobes. e limbic cortex is represented in the form of an inconspicuous sliver of pyriform cortex at the most caudal end of the orbital surface, primary motor and motor association areas are located on the lateral and dorsomedial surfaces, the heteromodal cortex covers most of the lateral surfaces, and the paralimbic cortex is located on the caudal regions of the medial and orbital surfaces. e paralimbic component of the frontal lobe is continuous with the cingulate gyrus on the medial surface and with the insula and temporal pole on the orbital surface.20

e prefrontal cortex (PFC) occupying the rostral pole of the brain was once described as the area responsible for intelligence; however, damage to this part of the cortex does not result in intel- lectual de cits but, rather, PFC lesions have detrimental e ects on executive and social functioning. e prefrontal cortex has been identi ed as an action-orientated region which plays an important role in the decision to carry out an action, the type of action to be carried out, and appropriate timing for such action.21

Frontal lobe functions can be grouped into five cortical- subcortical circuits, based on their function and anatomical makeup (Fig. 3.2). Each circuit is made up of equal component structures, including the cerebral cortex, a portion of the striatum, a station in the globus pallidum or substantia nigra, and, nally, the thala- mus. ese circuits project from and to the frontal lobes.22 Each circuit contains a direct and indirect pathway that includes the sub- thalamic nucleus. is chapter will focus on three of these circuits, those principally related to non-motor cognition and behaviour.

e dorsolateral prefrontal circuit (DL-PFC)

is circuit originates in Brodmann’s areas 9 and 46 on the dor- solateral surface of the anterior frontal lobe. e mid-dorsolateral prefrontal region is considered to be critical for the monitoring of information in working memory, which is necessary for high level planning and manipulation of information. is function may be exercised via the dorsal limbic pathways that link this region to the PFC with the hippocampal system via the posterior cingulate ros- trosplenial region. e posterior dorsolateral frontal cortex appears to underlie what are sometimes referred to as attentional processes. ese areas receive input from medial and lateral parieto-occipital

28 SECTION 1 normal cognitive function

(a)

Human

Macaque

globus palllidus externa (GPe) and the ventromedial subthalmic nucleus (STN) preserves some anatomical segregation from the motor and limbic circuits. e mediodorsal thalamus closes this loop by connecting back to areas 9 and 46 of the dorsolateral frontal lobe. Projections from the ventralis anterior nucleus also terminate in the inferotemporal cortex.25

e dorsolateral circuit is principally considered to subserve executive functions (EF), which include the mental capacities nec- essary for goal formulation, as well as the planning and achievement of these goals.26 is circuit also plays a part in guiding behaviour, set-shi ing, motor planning, strategy generation, and activation of remote memories.27

Lesions to the aforementioned frontal lobe circuit o en result in a recognizable and distinct frontal lobe syndrome: the dor- solateral frontal syndrome (executive dysfunction syndrome). is syndrome speci cally results in the impairment of execu- tive functions with patients presenting with poor organizational strategies (e.g. Tower tests), reduced inhibition (e.g. Hayling test), lack of planning and motor programming de cits (e.g. frontal assessment battery or INECO frontal screening). Furthermore, damage to this area can result in di culties generating hypoth- eses and impaired exibly for maintaining or shi ing sets, among others.28

e orbitofrontal circuit (OFC)

Originating in Brodmann’s areas 10 and 11, the orbitofrontal circuit consists of medial and lateral sub-circuits. e medial orbitofron- tal circuit sends bres to the ventral striatum and to the dorsal part of the nucleus accumbens.29 e lateral orbitofrontal circuit sends projections to the ventromedial caudate. ese sub-circuits con- tinue to the most medial portion of the caudomedial GPi and to the rostromedial SNr. Axons are sent from the GPi/SNr to the medial area of the magnocellular parts of the ventralis anterior thalamic nucleus. e circuit closes with projections back to the medial or lateral orbitofrontal cortex.30 e orbitofrontal cortex has extensive connections with other cortical areas, especially in the inferior tem- poral and insular cortices, with the amygdala and hippocampus. It also receives auditory information from the secondary and tertiary auditory areas, somatosensory information from the secondary somatosensory and parietal cortex, and heteromodal inputs from the superior temporal cortex.31

(b) 450,000 400,000 350,000 300,000 250,000 200,000 150,000 100,000 50,000

Fig. 3.1 (a) Relative size of the prefrontal cortex in di erent primates. (b) Volume of the frontal lobe across species. Values include both hemispheres.
(a) Adapted from Journal of Human Evolution, 32(4), Semendeferi K, Damasio H, Frank R,
and Van Hoesen GW, e evolution of the frontal lobes: a volumetric analysis based on three-dimensional reconstructions of magnetic resonance scans of human and ape brains,

pp. 375–88, Copyright (1997), with permission from Elsevier. (b) Adapted from Nat Neurosci, 5(3), Semendeferi K, Lu A, Schenker N, and Damasio H, Humans and great apes share a large frontal cortex, pp. 272– 6, Copyright (2002), with permission from Nature Publishing Group.

cortical regions, as well as from the adjacent caudal superior tem- poral gyrus via the superior longitudinal, the occipito-frontal. and the arcuate fasciculi.23

Sequential connections are to the striosomes of the dorsolateral head of the caudate nucleus,24 lateral aspect of the dorsomedial glo- bus pallidus interna (Gpi), and rostrolateral sustancia nigra (SNr) via the direct pathway. e indirect pathway through the dorsal

Chimpanzee

Gibbon

Gorilla Orangutan

40 35 30 25 20 15 10 5

Cortex

Striatum

Pallidum S. Nigra

alamus

MOTOR OCULOMOTOR

DORSOLATERAL LATERAL PREFRONTAL ORBITOFRONTAL

ANTERIOR CONGULATE

ACA HC EC STC ITG

rl-Gpi, VP rd-SNr

pm-MD

SMA

PUT

vi-Gpi cl-SNr

vlo vlm

APA MC SC

FEF DLC PPC CAUD

(b)

Cdm-Gpi vl-SNr

I-VAmc MDpI

DLC

dl-CAUD (h)

idm-Gpi rl-SNr

VApc MDpc

PPC APA

LOF STG ITG ACA vm-CAUD

(h)

mdm-Gpi rm-SNr

m-VAmc MDmc

Fig. 3.2 Cortical-subcortical circuits of the frontal lobes.

Human Chimpanzee Gorilla

Orangutan Gibbon Macaque

Frontal lobe volume (mm3)

Volume in percent of hemisphere

Lesions to this circuit o en result in the typically called orbito- frontal syndrome which is linked to personality changes, includ- ing emotional lability, irritability, outspokenness, reduced concerns or worries, and, at times, presenting with imitation and utilization behaviours (the act of grasping objects that are within reach or in the eld of vision in a context that is inappropriate),32 Eslinger and Damasio5 used the term ‘acquired sociopathy’ when describing patients with previously normal personalities who, following dam- age to the ventromedial frontal cortex, developed decision-making and planning di culties, which presented in the form of challeng- ing, inappropriate, or maladaptive social behaviours. is was also observed in the famous case of the young man called Phineas Gage (Fig. 3.3).

Lesions to this circuit o en result in a syndrome, the anterior cin- gulate syndrome, characterized by reduced spontaneous activity, evident in disorders such as akinetic mutism and transient abulic hypokinesia or abulia.37 A typical presentation of this syndrome is that of an apathetic individual with reduced emotional responses. e patient may require prompting to initiate verbal communication and, when verbal responses are elicited, they are likely to be monosyl- labic in form. Assistance with feeding is o en required due to lack of spontaneous movement, which may also lead to incontinence and other problems typically caused by lesions to areas outside the PFC.

Neurotransmitter circuits

Neurotransmitters modulate the signaling in neural networks and a ects cognition and behaviour (see also chapter 9). Di erent neu- rotransmitter circuits are involved in the frontal lobes, given their dense interconnectivity with the rest of the brain. In particular, the PFC projections to subcortical arousal systems modulate monoam- ine and cholinergic inputs to other regions as well as onto itself.38 Glutamatergic excitatory circuits project from frontal cortex to speci c regions of the striatum. GABAergic inhibitory bres pro- ject to the globus pallidus/substantia nigra, then to thalamus, and nally from the thalamus back to the prefrontal cortex. As such, the fast-acting transmitters of the frontal-subcortical circuits, namely GABA and glutamate, a ects frontostriatal connections.

In addition to these projections, executive functions are a ected by major ascending monoamines (dopamine, norepinephrine, ser- otonin, histamine, orexin, as well as acetylcholine), spread out to several forebrain regions (hippocampus, striatum, amygdala, and thalamus), as well as to the neocortex.39 For instance, it comes as no surprise that several neuropsychiatric conditions associated with abnormal catecholaminergic (dopamine, serotonin, and noradren- alin) and cholinergic modulation40 present with widespread frontal de cits. Monoamine modulators have strong in uences on prefron- tal cognitive functioning (Fig. 3.4). Several of these in uences seem to a ect cognitive functioning and self-control in healthy normal individuals, and more evidently so in neuropsychiatric conditions.

Asymmetries of the frontal lobes

In this section, we will brie y revise the few ndings that have been reported in the literature about structural and functional

CHAPTER 3 the frontal lobes 29

is is one of the most famous cases in behavioural neurology, neuropsychiatry, and neuropsychology. It was pivotal in iden- tifying a link between brain damage and behavioural de cits. Gage sustained a frontal lobe injury in a railroad construction accident while he was using explosives to excavate rocks. A er an unplanned explosion, a large tamping iron used to pack sand over the explosive charge entered through the le side of his skull. is injury surprisingly did not cause immediate death and Gage survived, but sustained profound behavioural changes: a man previously described as proper, well organized, responsible, and serious now exhibited poor judgment, di culties with decision- making, planning, and organizational skills, inappropriate emo- tional outbursts, and lack of inhibitory control.

Fig. 3.3 Passage of the bar through the skull of Phineas Gage, as reconstructed by Harlow in 1868.
Reproduced from Publication of the Massachusetts Medical Society, 2, Harlow JM, Recovery after severe injury to the head, pp. 327–46, Copyright (1868), Massachusetts Medical Society.

e anterior cingulate circuit (ACC)

Neurons in the anterior cingulate cortex (Brodmann’s area 24) serve as the origin of the anterior cingulate-subcortical circuit. E erent projections include those to the ventral striatum, involving the ven- tromedial caudate, ventral putamen, nucleus accumbens, and olfac- tory tubercle, usually named limbic striatum. Fibres from the ventral striatum project to the rostromedial GPi, rostrodorsal SNr, and ven- tral pallidus inferior to the anterior commisure. e GPe connects to the medial STN, which returns to the ventral pallidum, which connects to the magnocellular mediodorsal thalamus. e circuit closes with projections to the anterior cingulate. is circuit is con- sidered to mediate motivated behaviour, reversal learning,34 reward processes and evaluation,35 and it also functions, in part, to signal the occurrence of con icts in information processing, thereby trig- gering compensatory adjustments in cognitive control.36

Parietal

Temporal

Prefrontal

Spatial working memory

Attentional set-shifting

SSRT

Ventral tegmental area (dopamine)

Locus coeruleus (norepinephrine)

Dorsal raphé (serotonin)

Occipital

Reversal

learning/ extinction

Fig. 3.4 Schematic summary of the di erential impact of ascending monoamine systems on di erent tasks mediated by di erent sectors of the PFC. SSRT: stop- signal reaction time task.
Source data from Annu Rev Neurosci., 32, Robbins TW, Arnsten AF, e neuropsychopharmacology of fronto-executive function: monoaminergic modulation,

pp. 267–87, Copyright (2009), Annual Reviews.

30 SECTION 1 normal cognitive function

asymmetries of the frontal lobes. It is o en assumed that anatomi- cal asymmetries invariably re ect functional asymmetries, but this may not always the case. Language functions have been the most widely studied asymmetries of the frontal lobes, with a le – hemisphere superiority and pro ciency for the majority of vocal, motor, and language production functions.41 Nevertheless, some language capacities exist in most right hemispheres42 such as pros- ody, as well as the expression of the emotional content of language. In patients with brain injury, le frontal lobe damage also typically leads to more profound verbal uency and working memory de – cits than right-sided damage whereas right frontal damage causes de cits primarily in the use and representation of visuospatial data in a variety of tasks.

It has been also reported that the right prefrontal cortex has a predominant role in attentional mechanisms,43 with studies show- ing a striking increase in blood ow and metabolic activity in the right prefrontal cortex including Brodman areas 8, 9, 44, and 46 during selective attention tasks in di erent sensory modalities (e.g. see reference 44). In relation to memory, Tulving and his colleagues proposed that the le and right frontal lobes may play di erent roles in memory processing: encoding information into memory seems to be ‘the’ role of the le prefrontal cortex whereas retrieval is related to the right prefrontal cortex.45 One of the most remark- able asymmetries in the anterior cingulate is at the morphological level: there are two cerebral sulci in the le hemisphere and some- times only one in the right hemisphere. is has been related to cer- tain aspects of e ortful versus automatic vocalization.46 In spite of the large numbers of frontal functions that appear to be lateralized, the only functional asymmetry related strongly to an anatomical asymmetry is that of language and Broca’s area in particular.

Frontal lobe functions

Executive functions (EF)

EF refers to a complex set of processes consisting of various higher- level cognitive functions. ere is a general consensus regarding the type of functions that are grouped under this term. Welsh and Pennington47 de ne EF as ‘the ability to maintain an appropriate problem solving set for attainment of a future goal’, comprising the capacity to inhibit a response, to plan future actions strategically, and to maintain a mental representation of the desired goal stated and the information presented. Furthermore, the EF has also been implicated in emotional and behavioural processes.48 Zelazo, Qu, and Muller49 have conceptualized the involvement of the EF in either ‘cool’, purely cognitive executive processes, or ‘hot’ executive processes, which involve a ect and motivation. Mitchell and Phillips50 suggest that not only does the PFC have a role in cognition and emotion, but that it is also responsible for coordinating the two processes. Laboratory- based executive functions tests have been criticized as lacking in eco- logical validity since the coordination between the two processes is poorly measured in any currently available test.

Executive dysfunction or impaired EF may involve cognitive def- icits such as an inability to focus or maintain attention, impulsiv- ity, disinhibition, reduced working memory, di culties regulating performance, di culties with advanced planning, poor reasoning ability, di culties generating or implementing strategies, perse- verative behaviour, in exibility, and failure to learn from mistakes. Furthermore, in regards to behaviour, maladaptive a ect, poor decision-making, and social behavioural problems have also been identi ed.51

Working memory

is process is essential for e ective executive functioning and engagement in everyday activity.52 Within Baddeley’s model of working memory, working memory is de ned as a limited capac- ity system that allows the temporary storage and manipulation of information necessary for such complex tasks as comprehension, learning, and reasoning. An integrated neural network consisting of the dorsolateral prefrontal cortex, anterior cingulate, parietal and temporal cortices, hippocampus, and basal ganglia all have a role in working memory.53 Patients with working memory de cits can have di culties in remembering information presented only a few minutes earlier and tend to lose track of what they are doing. ey can miss important information during a conversation and can feel overwhelmed and frustrated. e most widely used tests to evaluate this function are the reverse digits span test and the ‘let- ters and numbers’ subtest of the Wechsler Adult Intelligence Scale (WAIS),54 among others (for more information, see chapter 11).

Selective and sustained attention

Selective attention is the ability to attend solely to one type of stimuli while ignoring competing, non-essential stimuli. Sustained attention or vigilance refers to the ability to maintain concentra- tion on a task. e frontal lobes in collaboration with the posterior parietal system and the anterior cingulate gyrus play a role in both types of attention.55 Many researchers use simple tests that measure performance over time to detect sustained attention de cits.

Inhibitory control

is term refers to the ability to suppress or interrupt a previously activated response and resist distraction from external stimuli,56 therefore patients with poor inhibitory control can be impulsive, careless, and intrusive. A network, which includes the lateral PFC, anterior cingulate, and basal ganglia, are responsible for this func- tion.57 Go–no go tests and the Hayling test58 are the most widely used measures for detecting de cits in the inhibitory control domain. e Stroop test59 is also used for measuring this capacity.

Mental exibility

is refers to the ability to respond to di erential environmental demands and to implement di erent problem-solving strategies by switching between thoughts and actions.60 e lateral PFC, the orbitofrontal and parietal cortices, basal ganglia, and cerebellum

Planning is the ability to set future goals, to plan, problem solve, and organize time and resources in order to achieve a task.60 e dorsolateral PFC, anterior cingulate, and caudate nucleus all have a role in planning.63 Frontal lobe lesions can result in planning de cits, di culties initiating activity, and di culty coping with complex situations. e most frequently used tests for detecting planning abilities are the tower tests64 and more ecological valid tests such as the hotel task.65

Multitasking

e term ‘multitasking’ refers to an individual’s ability to simulta- neously perform tasks in order to achieve goals and sub goals. e

are areas associated with this function.
in this domain may appear in exible and rigid, with di culties changing between activities and adapting to new situations. e well-known WCST (Wisconsin Card Sorting Test)62 is the test for measuring mental exibility.

Planning abilities

Patients with problems

anterior PFC, speci cally Brodmann’s area 10, is associated with the abilities necessary for a ective multitasking. Damage to the fron- topolar cortex has been linked to severe disruption of multitask- ing ability and this disruption is exacerbated by a greater degree of damage.66 Several studies have also demonstrated the presence of anterior frontal activity during multitasking67,68 and when switch- ing between di erent cognitive contexts.69 A recent study supports the idea of the potential pivotal role of BA10 in higher order cogni- tive functions.68

Metacognition

is is another important frontal lobe function and refers to the ability to think about one’s own mental processes and state of knowledge. Patients with frontal lobe lesions can demonstrate metacognitive de cits, such as overestimating their performance and capacity to learn.70

Memory systems

Memory refers to the acquisition, storage, retention, and retrieval of information. Within memory, there are three major pro- cesses: encoding, storage, and retrieval. Memory is fundamental for learning as it allows an individual to retain knowledge in order to form associations between behaviour and outcome. Although it has generally been associated with the temporal lobes and speci cally the hippocampus, later research studies focused on the involve- ment of the PFC in memory. Wheeler and colleagues71 performed a meta-analysis of existing memory studies concerned with recall, cued recall, and recognition. is research indicated that frontal lobe damage disrupted performance in all three areas of memory, with the greatest impairment found in free recall, followed by cued recall and then recognition. Furthermore, investigators found that frontal lobe patients have di culties encoding semantic informa- tion,72 determining the temporal order of remembered events,73 and identifying the source of the encoded information.74

It is generally agreed that the frontal lobes do not play a sub- stantial role in the consolidation, storage, and retention of new information,75,76 however they are considered important in the organizational and strategic aspects of episodic memory, essen- tial in encoding, retrieval, and veri cation of memory output.76 Typically, frontal lobe patients have trouble utilizing encoding strategies, which results in a weaker memory trace and subsequent retrieval de cits.

Time travel or chronestaesia

e ability to link the past and the future is known as time travel,77 or chronestaesia.78 It is an important frontal lobe function, essen- tial for autobiographical and prospective memory, and planning. Autobiographical memory is an awareness of the self, held as con- tinuous over time, with an awareness of the past and future. It is mediated by a neural system that includes the anteromedial PFC, which integrates sensory and speci c information.79 Prospective memory is the recall of the intention to act at a certain time or in a certain situation. Planning requires a consideration of present and future actions in order to achieve a goal. Planning activates PFC areas 9, 46, and 10.80 From visual perception to social cognition, the frontal regions of the brain make predictions about incoming actions based on contextual information available and on previ- ous experiences.81,82 Frontal regions provide early feed forward- feedback integration with temporal and visual areas.83 us, the frontal lobes integrate experiences and memory stored in temporal

regions in order to make predictions. For instance, the frontal prediction of actions and thoughts can become memories for the future.84

Language

In 1861, Paul Broca performed a post-mortem examination on a patient who had su ered severe speech/language problems for many years, with speech output limited to the word ‘tan’. At post- mortem, a lesion centred in the le posterior-inferior frontal cortex was detected.85 is case led to an acceptance of the correlation between inferior lateral frontal lobe damage and language disor- der. Certain connections are considered to play a speci c role in language, particularly Brodmann areas 6 and 4 are responsible for motor output and areas 44, 46, and 6, and their subcortical con- nections integrate motor output. It has been proposed that the dorsal lateral frontal and sensory association interconnections are involved in controlling cognition, and the prefrontal and medial frontal connections to the limbic system are involved in response to internal drives.86

Alexander87 suggested that di erent types of language disorders could emerge from frontal lobe lesions:

1. With medial frontal lobe lesions but predominantly to the le lobe, reduction in speech activation or reduced overall ability to utilize speech can be observed. e severity can range from mut- ism, or delayed verbal initiations, to brief, unsustain responses.

2. Following le frontal injury speci cally in the dorsolateral area, disorders such as transcortical motor aphasia (TCMA) can result. is type of lesion leads to imprecise, unconstrained lan- guage with limited, repetitive word use.

3. Lesions to the anterior le frontal lobes can result in more sim- plistic verbal abilities.

4. Finally, with right lateral and anterior frontal lesions, de cits can include poor organization of language, with socially inappropri- ate confabulations.

Although abnormal verbal output can result from lesions in either the right or le frontal lobes, the type of de cits reported di er widely. Damage to the right hemisphere does not cause aphasia, word nding, or grammatical de cits. Lexical, syntactic compre- hension, and articulation are intact. Impairment, instead, is related to prosody, such as in the intonations used when asking a question, or making a statement.88

In addition to the role in cognitive processes, the frontal lobes play a critical role in mediating social behaviour. Some of the fol- lowing abilities are central to developing and maintaining interper- sonal relationships and have been strongly associated with the PFC.

Decision-making (DM)

DM involves weighing up possible positive and negative outcomes associated with a speci c choice of action. A speci c option can then be selected dependent on what the individual considers most bene cial. e Iowa Gambling Task (IGT) was developed to assess how individuals make decisions when faced with real-life situa- tions89 and to detect orbitofrontal cortex dysfunction. However, recent research90,91,92 has further associated performance of this task with other regions, including the dorsolateral prefrontal cor- tex, the amygdala, the basal ganglia, and the anterior cingulate cor- tex, among others. Classical frontal lobe patients favour decisions related to high immediate rewards with longer-term punishments.89

CHAPTER 3 the frontal lobes 31

32 SECTION 1 normal cognitive function

e performance of frontal lobe patients on this assessment has been linked to an impairment of somatic markers, which results in an ‘insensitivity to future rewards’ and therefore instant grati ca- tion is preferred even when paired with longer-term negative con- sequences.93 Torralva and colleagues94 demonstrated that a group of early behavioural-variant frontotemporal dementia patients pre- sented with abnormal decision-making as measured speci cally by the IGT, despite a normal performance on standard cognitive tasks. Consistently, patients with behavioural variant FTD (bvFTD) as well as other diseases including Alzheimer’s, primary progressive aphasia, Parkinson’s, and Huntington’s disease patients can exhibit disadvantageous DM due to involvement of di erent portions of the complex circuitry feeding DM.95–97

eory of mind (ToM)

eory of mind refers to the ability to account for the thoughts, beliefs, intentions, and desires of others while understanding that they may di er from our own. is information is used to form judgments about the likely behaviour and response of another per- son.98 It has been suggested, although not without controversy,99 that ToM is a cognitive module in its own, with an innate neural basis,100 which may in fact be dissociated from other higher func- tions of the PFC such as decision-making.10,94 Studies indicate that patients with orbitofrontal lesions perform worse than those with dorsolateral prefrontal lesions when attempting to identify decep- tion, cheating, faux pas, and empathy.101–103

Moral behaviour

is refers to the ideals of human behaviour based on shared soci- etal values, incorporating concepts of deed and duty, fairness, and self-control.104 Previous studies105 have suggested that the orbital and medial regions of the PFC are responsible for moral judg- ment. Furthermore, a ‘morality network’ consisting of the right ventromedial PFC, orbitofrontal cortex, and amygdala has been suggested (for a review see reference 106). e right ventromedial PFC was included in this morality network for its role in linking external stimuli with socio-emotional value, which in turn could a ect moral judgment. e orbitofrontal cortex appears to inhibit immediate/automatic responses and enables consideration of social prompts, and the amygdala is involved in moral learning and threat response (for review see reference 106). Moll, de Oliveira- Souza, and Eslinger107 expanded on these structures and proposed a brain–behaviour relationships model focused on the interac- tions between emotional, behavioural, and cognitive components. Accordingly, the authors suggested, amongst other structures, the importance of the anterior cingulate cortex, the superior tempo- ral sulcus, the insula, the precuneus, the thalamus, and the basal forebrain. Consistently, studies both in neurodegenerative (e.g. reference 95) and neuropsychiatric populations (e.g. reference 97) a ecting OFC functions, namely empathy/ToM, show patterns of moral judgment that deviate from the norm.

Empathy

Empathy is a means of demonstrating appropriate social behav- iours and responses in complex or di cult situations. ere are dozens of de nitions of empathy. Baron-Cohen108 de ned empathy as ‘our ability to identify what someone else is thinking or feeling, and to respond to their thoughts and feelings with an appropriate behaviour’. is de nition suggests two stages in the empathy pro- cess: recognition phase and the response action. Empathy therefore

requires not only identifying another person’s feeling or thoughts (which overlaps for many authors with the concept of ToM), but providing an emotional response to it. One of the most important regions involved in the empathy circuit is the medial prefrontal cor- tex, which appears to play an important role for social information processing and for comparing our own perspective to that of oth- ers. Damage to this area, as well as other regions involved in this circuit, such as the inferior frontal gyrus, the frontal operculum, the anterior cingulated, the anterior insula, and the temporo-parietal junction, amongst others, can cause a lower degree of empathy.108

Personality changes

Changes in personality and psychosocial function following pre- frontal lesions have been reported from Gage (see Fig. 3.3) to the present. Damage to the orbital and medial PFC leads to emotional lability as well as to de cits in social and emotional functioning.109

eories of frontal lobe function

Many theories about the functioning of the frontal lobes have been developed with the intention of gaining a better understanding of this complex region. ere is no consensus on which of these theo- ries best captures frontal function. Indeed, many of them are not mutually incompatible. Some of the main PFC models are brie y addressed in this chapter in an attempt to introduce some of the most prominent contemporary models and frameworks to under- stand frontal lobe functions.

Multiple demand system and adaptative coding model

Based on functional neuroimaging (fMRI) and lesion studies that have shown that large parts of the frontal lobe are involved in very diverse cognitive task, some authors have proposed the existence of a multiple-demand (MD) system,110 which comprises circum- scribed regions of lateral and dorsomedial frontal cortex, anterior insula, and the intraparietal sulcus. Following results from single- cell electrophysiology studies in the behaving monkey, this model proposes that neurons of the MD system have the ability to adapt to the current task in order to code the speci c information required for that task.111 Also, recent evidence coming from human neu- roimaging studies have supported this view, demonstrating an adaptive change in the patterns of activation coding task-relevant stimulus distinctions in the frontoparietal. ese and other results have led some authors to suggest that the main function of the MD system is to construct the mental control programmes of organized behaviour.110

Attentional control model

is model112 proposes the existence of two major mechanisms involved in behavioural regulation: the contention scheduler (CS) and the supervisory attentional system (SAS). e CS is concerned with automatic or well-learnt/well-established responses. is pro- cess schedules action while also inhibiting con icting schemata, which structure and organize routine tasks. However, with novel or complex tasks, schemata are unlikely to have developed and, therefore, additional attentional control is required, hence initiat- ing the SAS. e SAS sets priority for actions and brings conscious awareness and re ection to the forefront, rather than solely relying on simple automatic responses originated in the CS. In a three-step process, a strategy is generated: rst, it incorporates a temporary schema for this complex or novel task; second, the schema is imple- mented and monitored; and nally, the schema is either rejected or

modi ed. e SAS is proposed to be located in the PFC and the CS has been linked to the basal ganglia.

Somatic marker hypothesis

Although not without controversy, this model speci cally focuses on the role of emotion in decision-making.113 It proposes that when a di cult situation is encountered, in order to make a choice or decision, somatic markers stored as memories of past speci c behavioural experiences and outcomes are activated. is system can be in e ect even without the conscious awareness of the past event. Somatic markers are proposed to be stored in the ventro- medial PFC and the model surmises that damage to this area can result in an inability to access somatic markers, which thus results in decision-making skill de cits.114

Temporal organization model

is model proposes that the PFC temporally organizes behaviour with that process constrained by short-term memory, motor atten- tion, and the inhibition control of interference.115 e framework describes mechanisms for monitoring and memory and atten- tional selection that prioritize goals and ensure that behavioural sequences are performed in the correct order. Temporal integration is mediated by the activity of PFC neurons and also by interactions between the PFC and posterior cortex—the speci c posterior corti- cal areas that are involved in these interactions are determined by the modalities of the sensory and motor information. is model emphasizes processes of attention, short-term memory, and inhibi- tory control, however, the author also describes PFC function in terms of ‘motor memory’ (schemata), with a hierarchy of motor representations within the PFC. Attention and working memory are properties of the representations (neural networks), rather than explicit ‘processes’ in terms of computational procedures. Fuster’s model is a hybrid of the representational and processing approaches and is consistent with the evolution and neurophysiol- ogy of the PFC. Motor memories that are stored in the PFC become more complex or abstract in anterior frontal regions. Fuster pro- poses that the functions of the ventromedial PFC parallel those of the dorsolateral PFC, but with the addition of emotional informa- tion, given the connectivity between ventromedial PFC and limbic regions (such as the amygdala). He supports the idea that automatic actions are stored in the basal ganglia and the premotor cortex, with PFC representation reserved for actions or behaviours that are not habitual or well learned. Consistent with this viewpoint, the premotor cortex and basal ganglia are known to be important in movement preparation; however, the PFC has been implicated in both novel and well-learned tasks.

Anterior attentional functions

Stuss4 further developed Fuster’s115 model regarding the associa- tion between the frontal lobe and basic schemas, by incorporating a theory of the executive system. According to Stuss, a schema is a network of multiple, connected neurons that can be activated by sensory input, by other schemata, or by the executive control system (Fig. 3.5). Also, it has been suggested that schemata pro- vide feedback to the executive system and compete to control of thought and behaviour. is process is governed by the conten- tion scheduling process described in Norman and Shallice’s atten- tional control model. Once activated, schemas can remain active for varying periods of time depending on the goal and whether further input is received from the executive control system. is

Fig. 3.5 Supervisory systems in human attention.
Adapted from Annals of the New York Academy of Science, 769, Stuss DT, Shallice T, Alexander M, and Picton T, A multidisciplinary approach to anterior attentional functions, pp. 191–211, Copyright (1995), with permission from John Wiley and Sons.

might be seconds sometimes or for longer periods, and activation has to be maintained by repeated input from the executive control system. Attention is the main focus in Stuss’s theory. is theory proposed seven types of attentional functions, each of which has its neural correlates: sustaining (right frontal), concentrating (cingu- late), sharing (cingulate plus orbitofrontal), suppressing (DL-PFC), switching (DL-PFC plus medial frontal), preparing (DL-PFC), and setting (le DL-PFC).

Working memory model

When an individual engages in complex cognitive tasks such as lan- guage comprehension, learning, and reasoning, the information is simultaneously and temporarily stored and manipulated within the brain in a system that has been termed working memory. Originally, according to the model advanced by Baddeley and Hitch,116 there were three components to working memory, the most important of which was the central executive, accompanied by the visuos- patial sketchpad and the phonological loop as ‘slave’ subsystems. Recently, in response to criticisms of the model, a fourth system named the episodic bu er was incorporated.52 e central execu- tive is capable of controlling the attention a orded to two or more activities occurring simultaneously, whilst also controlling the access to information in long-term memory store. e visuospatial sketchpad holds visual images whilst the phonological loop con- tains information about speech-based information (Fig. 3.6).

CHAPTER 3 the frontal lobes 33

Supervisory System

Perceptual Information

Schemata

Effector System

Central executive

Visuospatial sketchpad

Episodic buffer

Phonological loop

Visual Episodic semantics LTM

Language

Fluid systems

Crystallized systems

Fig. 3.6 Working memory model.
Reproduced from Trends Cogn Sci., 4(11), Baddeley A, e episodic bu er: a new component of working memory? pp. 417–23, Copyright (2000), with permission from Elsevier.

34 SECTION 1 normal cognitive function

Structured event complex (SEC) framework

a ‘gateway’ between the internal mental life that occurs independ- ently of environmental stimuli and the mental life that is associated with interaction with the external world.

Conclusions

Given the complexity of the human frontal lobes and their intri- cate, expansive neural connections, a complete appreciation of the wide range of functions associated with these areas is fundamental in order to understand human cognition fully in both health and disease conditions.

New approaches have been developed from disciplines such as social cognition and studies of decision-making, theory of mind, empathy and moral behaviour providing a broader and ecologically valid approach to the understanding of the frontal lobe functions.

Our identity as autonomous human beings, our drives, ambitions, and essence are greatly dependent on our frontal lobes and further research is required to deepen our understanding of such complex cerebral region. With this in mind, the near future is likely to be an exciting time for the eld of cognitive and social neurosciences, as our knowledge continues to develop in regards to perhaps the most uniquely human of all brain structures, our frontal lobes.

Acknowledgements

We appreciate the assistance of Clara Pinasco in formatting and ref- erencing the manuscript.

is research was partially supported by grants CONICYT/ FONDECYT Regular (1130920 and 1140114), Foncyt-PICT 2012-0412, Foncyt-PICT 2012-1309, CONICET, and INECO Foundation.

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121. Burgess PW, Dumontheil I, and Gilbert SJ. e gateway hypothesis of rostral prefrontal cortex (area 10) function. Trends Cogn Sci. 2007 Jul;11(7):290–8.

CHAPTER 3 the frontal lobes 37

CHAPTER 4

e temporal lobes

Morgan D. Barense, Jason D. Warren, Timothy J. Bussey, and Lisa M. Saksida

Introduction to the temporal lobes

e temporal lobes are essential for our memory and understand- ing of the world, including our knowledge about our very selves, and our ability to communicate e ectively with other human beings. As a result, the consequences of damage to the temporal lobes—as can occur following insults including surgery, stroke, viral infection, or Alzheimer’s disease—can be devastating (see Boxes 4.1 and 4.2 for some key historical examples). As we will see, however, the temporal lobe is not a unitary structure with a single function. How therefore can we understand how these dif- ferent functions are organized within the temporal lobes? We start by considering the anatomy.

Temporal lobe circuitry

e temporal lobe is the region of cerebral cortex that lies inferior to the Sylvian (lateral) ssure (Fig. 4.2a). Posteriorly, the temporal lobe is bounded by the ventral edge of the parietal lobe and the anterior edge of the occipital lobe. e temporal lobes comprise approximately 20 per cent5,6 of total cerebral cortex volume in humans. Regions on the lateral surface can be divided into those that represent auditory information (Brodmann areas 41, 42, 22) and those that represent visual information (Brodmann areas 20, 21, 37, 38) (Fig. 4.2b and c).

e rst sulcus inferior to the Sylvian ssure is the superior temporal sulcus (STS), which contains multimodal cortex receiv- ing inputs from visual, auditory, and somatic regions in addition

Box 4.1 Case study 1: Dense global amnesia

In 1953, a 27-year-old man, known to researchers by the initials HM, underwent experimental brain surgery—bilateral removal of his medial temporal lobes (MTL) (Fig. 4.1)—to treat his severe epilepsy. HM emerged from the surgery profoundly, and irrevocably, amne- sic. Until his death in 2008, each new experience he had and each new person he met was destined to be forgotten, leaving his existence in an eternal present. In the words of HM himself, ‘Every day is alone in itself, whatever enjoyment I’ve had and whatever sorrow I’ve had.’1

During neuropsychological examination he would look up between tests and anxiously say, ‘Right now, I’m wondering. Have I done or said anything amiss? You see, at this moment everything looks clear to me, but what happened just before? at’s what worries me. It’s like waking from a dream; I just don’t remember.’2

HM did not know that decades had elapsed since his surgery, he did not know his age, or whether he had grey hair.3 He knew about the Second World War and the crash of the stock market in 1929, but he could not remember the scientists that worked with him continu- ously until his death. Mercifully, his personality and intellect were unchanged, and he was a gracious and patient man who generously devoted himself to a life as an object of intensive scienti c study, making him likely the most important single case study in the history of brain science.

(a)

(b)

Fig. 4.1 HM’s medial temporal lobe lesion. (a) Coronal image depicting the temporal lobe of HM (shown on left) and an age-matched control (shown on right).
A = amygdala; H = hippocampus; cs = collateral sulcus; PR = perirhinal cortex; EC = entorhinal cortex. (b) Sagital section from the left side of HM’s brain. e asterisk depicts the resected portion of the anterior temporal lobes. e arrow depicts the remaining intraventricular portion of the hippocampus.
Reproduced from J Neurosci, 17(10), Corkin S, Amaral DG, Gonzalez RG, et al. HM’s Medial Temporal Lobe Lesion: Findings from Magnetic Resonance Imaging, pp. 3964–979, Copyright (1997), with permission from the Society for Neuroscience.

40 SECTION 1

normal cognitive function

Box 4.2 Case study 2: Wernicke’s aphasia

In 1874, a young psychiatrist, Carl Wernicke, working in Breslau, recorded the clinical details of his patient, SA, a 59-year-old woman who had suddenly lost all ability to understand speech.4 She gave ‘completely absurd’ answers to questions, and her con- versation (though grammatical) was frequently garbled and marred by neologisms. She had di culty naming familiar items, even though she remained able to use them competently.

A er a more detailed assessment, Wernicke found that she had no other evidence of ‘profound mental deterioration’: he concluded instead that she had a selective impairment in com- prehending speech signals, a ‘sensory aphasia’. SA’s language dis- turbance resolved steadily over the next few months, but her case prompted Wernicke to review the clinical records of his previous patients. ese included one patient with a similar language syn- drome who had come to post-mortem showing focal infarction of the rst and second temporal convolutions within the le cer- ebral hemisphere.

Wernicke proposed that the culprit lesion in such cases, involving temporal lobe areas in proximity to auditory cortex, produces a fundamental defect of the ‘sound images’ for words. is insight led him to develop the rst coherent model of a dis- tributed, dominant hemisphere language circuit, linking speech perception ultimately with speech output. Wernicke’s model pro- vided a framework for understanding various selective disorders of language due to acute brain lesions or focal cerebral degen- erations. ough rst clearly described over a century ago, these disorders continue to inspire debate today.

to polymodal input from frontal and parietal regions. e middle and inferior temporal gyri (corresponding to Brodmann areas 20 and 21; also called area TE) comprise inferotemporal (IT) cortex, a region critical for visual object recognition. e medial temporal lobes (MTL) are a collection of heavily interconnected structures, which include allocortical structures such as the hippocampus and adjacent entorhinal, perirhinal, and parahippocampal cortex (Fig. 4.2d), and are traditionally believed to form a system devoted to long-term memory. At the tip of the temporal lobe is the temporal pole, a region critical for conceptual knowledge and social concep- tual information processing.

However, brain regions do not operate in isolation but are inter- connected in functional circuits comprising a number of cortical and allocortical regions. Of course, the connectivity between brain regions is rich and complex, and the temporal lobes are no excep- tion in this regard. Nevertheless, when considering function it is useful to think in terms of three major pathways associated with this region (Fig. 4.3).

1. Cortical modality-speci c sensory streams (devoted to only one sensory modality). Although the temporal lobes receive inputs from all modalities, for the present purposes we will focus on the visual and auditory pathways (Fig. 4.3a).

2. e continuation of these streams into cortical regions of the superior temporal sulcus (STS) and middle temporal gyrus (MTG) (Fig. 4.3b).

3. e continuation of these streams into the structures within the medial portion of the temporal lobes (MTL) (Fig. 4.3c).

Functions of the temporal lobes

Circuit 1. Cortical modality-speci c sensory streams for vision and audition

e ventral visual stream (VVS)

As visual information leaves the striate cortex in the occipital lobes, it is organized into two functionally specialized hierarchical pro- cessing pathways. e ‘dorsal stream’ courses dorsally towards parietal regions and is crucial for processing the spatial locations of objects, as well for visually guiding actions towards objects in space.7 e ‘ventral visual stream’ (VVS) extends ventrally through IT cortex towards anterior temporal regions and is crucial for the visual identi cation of objects (8) (Fig. 4.4a). ese pathways have been dubbed the ‘where/how’ (dorsal) and ‘what’ (ventral) path- ways. is section will focus on the ventral stream, the dorsal stream is discussed further in chapter 5.

e organization of the ventral stream is hierarchical, such that low-level inputs are transformed into more complex representations through successive stages of processing. As information progresses through the stream, receptive eld size and neuronal response laten- cies increase, and the neurons increase the complexity of their tun- ing, with neurons in posterior regions of the stream ring in response to relatively simple stimuli and anterior regions of the stream ring to more complex and speci c stimuli. For example, whereas neurons in V1 and V2 re in response to simpler stimulus properties such as colour, orientation, and spatial frequency (Fig. 4.4b), cells in IT cor- tex respond to much more complex stimuli.9 Indeed, cells in IT cor- tex are usually selective for a very speci c stimulus, such as a hand (Fig. 4.4c).10,11 Moreover, this selectivity is usually invariant over changes in stimulus size, orientation, contrast, and colour, that is, neural responses are not altered by changes in these parameters. Not surprisingly, lesions to this area of the brain lead to severe de cits in identifying and naming di erent categories of objects, a condition known as visual agnosia.

Evidence from neuroimaging indicates that distinct areas within the ventral temporal cortex may be specialized for spe- ci c categories of stimuli. e fusiform face area (FFA) responds more strongly to faces than to other non-face objects,12 whereas the parahippocampal place area (PPA) responds more to images of buildings and scenes than to faces and other objects.13 Other category-speci c regions have been identi ed for inanimate objects, body parts, and letter strings,14–16 ere is currently a debate regarding whether these regions should be treated as mod- ules for the representation of speci c categories17 or whether they should be considered as parts of a more general object-recognition system critical for recognizing ne-grained distinctions among well-known objects.18,19

In the context of memory systems, the structures of the VVS have been considered to comprise a ‘perceptual representation system’ which mediates perceptual priming, discrimination, and categori- zation of stimuli.20 is so-called non-declarative memory system is contrasted with a declarative memory system for facts and events, thought to reside in the temporal lobe proper. ese putative mem- ory systems will be discussed in more detail below.

e cortical auditory stream

e organization of the human cortical auditory system is less well understood than the cortical visual system and much information has been obtained from animal models, in particular the macaque

(a)
Frontal lobe

Parietal lobe

CHAPTER 4 the temporal lobes 41

(b)

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Sylvian (lateral) fissure

Superior temporal sulcus

41
42 22
38 21 37

–27

Occipital lobe

(d)

–31

–21

–9

38
20

–4 10 17 25

Hippocampus Perirhinal cortex

Entorhinal cortex Parahippocampal cortex

Amygdala
Fusiform cortex
Inferior temporal cortex

Middle temporal cortex Superior temporal cortex Temporal polar cortex

Fig. 4.2 Temporal lobe anatomy. (a) Lateral view of the left hemisphere depicting the four lobes of the cerebral cortex and major gyri and sulci. (b) Lateral view of the left hemisphere showing Brodmann’s areas in the temporal lobes. (c) Medial view of the right hemisphere showing Brodmann’s areas in the temporal lobes. (d) Coronal sections depicting di erent temporal lobe regions, superimposed on a Montreal Neurological Institute average brain template.
(a) Reproduced from Gazzaniga, Ivry, Mangun Eds, Cognitive Neuroscience: e biology of the mind, 3rd edition, Copyright (2008), with permission from W. W. Norton & Company.

(b&c) Reproduced from Catani, Marco, iebaut de Schotten, Michel, Atlas of Human Brain Connections: Sectional Neuroanatomy, Copyright (2015), with permission from Oxford University Press. (d) Reproduced from Journal of Neuroscience, 26(19), Lee AC, Buckley MJ, Ga an D, et al. Di erentiating the Roles of the Hippocampus and Perirhinal Cortex in Processes beyond Long-Term Declarative Memory: A Double Dissociation in Dementia, pp. 5198–203, Copyright (2006), with permission from the Society for Neuroscience.

monkey.21 However, certain basic principles of auditory cortical ana- tomical and functional organization have been identi ed. As is the case for visual information, cortical analysis of auditory information is distributed among multiple cortical areas, hierarchically organ- ized into overlapping but separable processing streams (Fig. 4.5).

Primary auditory cortex is located in the medial portion of each Heschl’s gyrus and can be identi ed from histoanatomical features and to some extent by functional properties such as tonotopic cod- ing of pitch information. Higher-order areas relatively specialized for auditory processing are located in the surrounding superior

Superior temporal gyrus Middle temporal gyrus

Inferior temporal gyrus

normal cognitive function

(b)

(c)

Fig. 4.3 Major functional circuits in the temporal lobes of the rhesus monkey.
(a) Modality-speci c streams devoted to either audition or vision progress
from primary sensory regions towards the temporal pole. (b) Modality-speci c auditory, visual, and somatic information inputs to multimodal regions of the superior temporal sulcus. (c) Auditory and visual information inputs to the medial temporal lobe.

Reproduced from Kolb B and Whishaw IQ, Fundamentals of Human Neuropsychology, 7th edn, Copyright (2015), with permission from Macmillan Higher Education.

temporal gyrus (STG), extending anteriorly to the temporal pole and posteriorly into planum temporale, posterior STG, and the temporoparietal junction (TPJ). Candidate homologues of these areas in the macaque and other species can be di erentiated on anatomical and electrophysiological grounds; however, informa- tion about human auditory cortical subregions remains limited.

Analogous with the ‘what/where’ cortical processing streams in the visual system, auditory cortical organization appears to be broadly dichotomous, comprising a ventral stream directed along anterior STG, and a dorsal stream directed into the TPJ and pro- jecting to parietal and frontal cortical areas. e ventral stream is concerned chie y with representing information about auditory object identity whereas the dorsal stream is concerned with repre- senting sound location and movement.21,22

Successive stages within these processing hierarchies are associ- ated with increasing integration and abstraction of auditory infor- mation and the streams communicate widely with higher-order multimodal cortical areas in STS, MTG, and parietal lobe. Again analogous with the visual cortical system, fundamental tasks of cortical auditory processing include the representation of invari- ant object features and the association of these representations with meaning based on prior experience of the sensory world.

In the case of the most widely studied auditory signal, speech, it has been shown that acoustic properties of speech sounds as dis- crete auditory objects are encoded in more posterior areas in pos- terior and mid STG, whereas speech intelligibility—the meaning associated with the sounds—is extracted in more anterior areas in STG in the dominant cerebral hemisphere,21 ultimately link- ing spoken language with other modalities of semantic knowledge. Similar organizational principles are likely to govern the processing of non-verbal environmental sounds.

In contrast, preparation to produce speech and other vocal sounds via the dorsal auditory pathway is initiated by mechanisms in the vicin- ity of planum temporale and posterior STG: a putative ‘sensori-motor

42 SECTION 1 (a)

interface’ that lies within the compass of ‘Wernicke’s area’ in classical aphasiology.21,22 Speci c agnosias for pre- or non-linguistic auditory phenomena are uncommon but well-documented: examples include so-called pure word deafness and agnosias for di erent aspects of music. Speci c syndromes of this kind suggest underlying neural mechanisms that are functionally dissociable.23

Analogies between the visual and auditory cortical systems should not be overemphasized. e visual and auditory modali- ties present the brain with speci c computational problems (in the auditory modality, for example, the problem of resolving multiple ‘transparent’ sound sources overlaid in the auditory environment and the requirement to integrate information dynamically over time); these problems are likely to be solved by modality-speci c neural mechanisms. e peripheral visual and auditory processing pathways are organized along di erent lines: processing of infor- mation over subcortical relays is more extensive for auditory than for visual stimuli, and in addition, whereas visual information is relayed to the contralateral cerebral hemisphere, auditory informa- tion is distributed to both hemispheres.

e status of auditory spatial processing in the dorsal processing stream is less straightforward than the status of visuospatial process- ing in the dorsal visual stream:21,22 there is extensive interaction between the dorsal and ventral auditory streams when processing sound identity and location, and it has been suggested that the dor- sal auditory stream is not primarily a ‘where’ pathway but, rather, a ‘how’ pathway (processing dynamic changes in the auditory envi- ronment) or a ‘do’ pathway (programming motor responses based on relevant sound information).

Furthermore, the human cortical auditory system shows a unique specialization in the processing of speech sounds, and this may be partly based on distinctive neural mechanisms that are di erentiated between the cerebral hemispheres. In particular, it has been suggested that the le hemisphere may preferentially process auditory signals that (like speech) contain frequent, rapid spectro-temporal transitions whereas the right hemisphere may preferentially process slower spectro-temporal variations or infor- mation unfolding over longer timescales (e.g. in musical melodies). However, any such dichotomy is likely to be an oversimpli cation.24

Circuit 2. Superior temporal sulcus, middle temporal

gyrus, and a erent connections

A key principle of temporal lobe function is the integration of infor- mation from di erent sensory modalities and across processing stages to create uni ed representations of the world. Cortical areas in STS and MTG have extensive reciprocal anatomical communica- tions with modality-speci c (e.g. purely visual or purely auditory) superior, inferior, and posterior temporal cortices. Functionally, these regions have been implicated in the processing of visual, auditory, and somatic information and in the cross-modal integra- tion of sensory information when resolving inter-modal incon- gruities or building coherent multimodal perceptual and semantic representations.25–27

Cognitive processing stages such as ‘perceptual’ and ‘semantic’ have been distinguished neuroanatomically as well as neuropsy- chologically.27 However, the anatomical organization of temporal lobe circuitry suggests that modality-speci c and multimodal cor- tical areas cooperate with mutual information exchange during the perceptual and semantic analysis of sensory objects. e existence of such cooperation has been supported by functional imaging

Auditory Visual

as ce ip
ts

CHAPTER 4 the temporal lobes 43

(a)

p
ai

PRh

TEO
oi

orm

la HIPPO

V4
V3 V2

V1 ec

(b)

Stimulus

(c)

1.0 0 0 0.01

0.01 0.49 0.22 0.15

0 0.05 1.36 0.82

301/s 2s

Fig. 4.4 e ventral visual stream. (a) e ventral visual stream is a processing pathway critical for the perceptual analysis of objects. It originates in primary visual cortex (V1) and progresses along the ventral surface of the temporal lobe towards anterior temporal regions. Information processing in this stream is organized hierarchically, such that early regions process version simple information and more anterior regions process more complex information. (b) For example, here we illustrate a V1 neuron that is tuned to a bar of light oriented in a particular direction and res maximally (vertical lines correspond to action potentials) when a bar of light in its preferred orientation hits the cell’s receptive eld but not at all when the bar is dissimilar to its preferred orientation. (c) By contrast, anterior VVS regions are tuned to more complex features. Here we demonstrated a TE neuron that res maximally ( ring rates illustrated on the bar graph) to the shape circled in red. e preferences of these cells are remarkably selective and show weaker response rates as the image deviates from the preferred shape. Cells in TE are thought to respond to ‘moderately complex’ features.

(a) Adapted from Philos Trans R Soc Lond B Biol Sci., 298(1089), Mishkin M, A Memory System in the Monkey, pp. 83–95, Copyright (1982), with permission from e Royal Society, Figure courtesy of Mort Mishkin. (b) Reproduced from Dowling, John E, Neurons and Networks. An Introduction to Neuroscience, Copyright (1992), with permission from Harvard University Press. (c) Reproduced from Annu Rev Neurosci., 19, Tanaka K., Inferotemporal Cortex and Object Vision, pp. 109–39, Copyright (1996), with permission from Annual Reviews.

evidence in both healthy subjects and in de ned clinical popula- tions such as patients with semantic dementia.28,29

Indeed, one view is that the temporal poles—structures heavily damaged in semantic dementia—comprise an amodal semantic ‘hub’ that mediates communication across various sensory, motor, linguistic, and a ective domains.30 Damage to this temporal pole hub results in a dissolution of semantic knowledge across all conceptual domains and all modalities of testing.31 is hub is thought to become especially critical when the semantic system must extract conceptual similarity structure that is not directly re ected in any single modality (e.g. sensory, motor, linguistic, a ective).

For example, items that are very similar in kind may vary enor- mously in terms of their surface details: a penguin and a hum- mingbird are very di erent in terms of how they look and how they move, but they are classed as similar kinds of things.32 In contrast,

light bulbs and pears share many surface similarities but are classed as very di erent kinds of objects. us, critical to any semantic sys- tem is the capacity to represent conceptual similarity structure that is not re ected in any single surface modality (e.g. shape or move- ment), and this cross-modal associative conceptual knowledge may be subserved by the temporal pole.

ere are many instances where integration of cross-modal information is required to make sense of the environment. One key example is the representation of attributes of particular people, which generally entails conjoint processing of face and voice iden- tity.33 Functional imaging studies have shown that such process- ing engages multimodal cortical areas in STS and MTG as well as modality-speci c visual and auditory areas. In addition to involve- ment of higher-order multimodal areas, there are likely to be direct connections between modality-speci c auditory and visual areas,34 underlining the potential for cross-modal interactions at multiple

tmp

tma

44 SECTION 1

normal cognitive function

object representation

semantic processing

Posterior

Fig. 4.5 Cortical auditory stream. A simpli ed schematic showing key processing stages in the putative ventral cortical stream for auditory object processing in the human brain. e auditory scene is initially parsed into constituent sound sources by non-primary cortex in the planum temporale and posterior superior temporal lobe, and adjacent cortical areas in and surrounding the superior temporal sulcus analyse the features of these sources and build auditory object representations. ese auditory object representations become associated with meaning as a result of higher order semantic processing in the anterior temporal lobe and beyond.

levels of the processing hierarchy. Such interactions might be par- ticularly relevant for resolving identity under ambiguous listening or viewing conditions. Analogous cross-modal interactions are likely to facilitate speech recognition from observation of lip move- ments and other non-auditory cues.35

Circuit 3. e medial temporal lobe and

its a erent connections

Case study 1 (Box 4.1) introduces the famous patient, HM, who su ered profound amnesia following damage to the temporal lobes. One of the most remarkable features of HM’s disorder (and that of other cases like him) was its seeming selectivity to the learning of new facts and events.36 Patients with MTL resections showed severe anterograde amnesia, together with some retrograde amne- sia for at least the immediate pre-operative period, but they mani- fested no other obvious changes in perceptual abilities, intellect, or personality.

Furthermore, all patients were able to remember relatively small amounts of information perfectly for seconds or minutes, so long as they were not interrupted. e instant their attention was diverted to a new topic, however, the material was lost. For example, one report37 describes an occasion on which HM was asked to remem- ber the number ‘584’ and was then allowed to sit quietly with no interruption for several minutes. At the end of this interval he was able to recall the number correctly without any hesitation, stat- ing, ‘It’s easy. You just remember 8. You see, 5, 8, 4, add to 17. You remember 8; subtract it from 17 and it leaves 9. Divide 9 in half and you get 5 and 4, and there you are: 584. Easy.’

Despite this elaborate mnemonic device, as soon as HM’s atten- tion was diverted to another topic, he was unable to remember, approximately one minute later, either the number ‘584’ or the fact that he had been given a number to remember in the rst place. is suggested that the structures in the MTL were critical to con- solidate new long-term memories, but were not important for the rehearsal and maintenance of information over short time periods (a cognitive ability termed working memory).

Working memory was not the only form of memory that appeared to be spared in amnesic subjects. Numerous studies dem- onstrated that amnesia spared knowledge that was based on rules or procedures, but dramatically a ected declarative memory— knowledge that was available as conscious recollections about facts (semantic memory) and events (episodic memory) (see, for example, references 3 and 38). For example, MTL amnesics could acquire selected motor skills (e.g. mirror drawing) over a period of days, despite having no recollection of having carried out the task. Subsequent studies expanded the collection of preserved abilities in amnesia to include memory for skills and habits, simple forms of conditioning, which eventually fell under the umbrella term of non-declarative memory and refer to a collection of abilities that are unconscious and expressed through performance rather than conscious recollection.

ese ndings led to the idea of an MTL declarative memory system containing several anatomically distinct structures, namely those damaged in HM: the hippocampus, together with the adja- cent, anatomically related entorhinal, perirhinal, and parahip- pocampal cortices (see references 36 and 39). According to this

parsing of auditory scene

feature analysis

Human brain

CHAPTER 4 the temporal lobes 45

Temporal lobe

Visual cortex

Declarative memory Conscious

Long-Term Memory

Non-declarative memory not conscious

Episodic Memory personal events

Semantic Memory facts knowledge

Perceptual Representation System priming

Procedural Memory motor skills conditioning

Fig. 4.6 Traditional taxonomy of memory systems. Declarative (implicit) memory refers to conscious memory for facts (semantic memory) and events (episodic memory), whereas non-declarative (implicit) memory refers to a collection of abilities that operate outside of conscious awareness.39 e prevailing view in cognitive neuroscience is that the brain can be best understood as consisting of modules specialized for distinct cognitive functions. In this example, two di erent expression
of long-term memory—conscious declarative memory and unconscious non-declarative memory—are presumed to have di erent neuroanatomical loci. Declarative memory is traditionally believed to be dependent on the medial temporal lobes, whereas priming (a form of non-declarative memory) is thought to be dependent on a perceptual representation system in more posterior neocortex.

view, the regions in the MTL work in concert, as a highly integrated system, to bind together the distributed elements of memory that are processed and represented by distinct cortical sites. is sys- tem is proposed to work in the service of declarative memory only, with no role in other cognitive functions, such as perception or working memory (Fig. 4.6). According to this account, injury to any component of the MTL memory system will result in a de cit on any type of declarative memory, and only declarative memory. According to this view, the process of consolidating the distributed elements of memory into a coherent and stable ensemble can take years, but eventually, memories are thought to become independ- ent of the MTL memory system (reference 40, although see too reference 41).

us with respect to the pathway currently under discussion— the MTL and its a erents—the view had emerged of a discontinu- ous pathway containing two qualitatively di erent ‘modules’: the declarative memory system in the MTL, and the perceptual rep- resentation system in the VVS, which mediates the putatively non-declarative functions of visual priming, categorization, and perceptual discrimination. is modular view has recently come into question, as will be discussed below.

More recent ideas regarding the functional organization of the VVS–MTL stream

Despite the popularity of the putative MTL memory system, there were several ndings that contradicted this view. ese ndings support two di erent but related ideas:

1. e heterogeneity of function within the putative MTL system, and

2. e VVS–MTL pathway as a continuous, rather than discontinu- ous, system.

Functional heterogeneity within the MTL

Beginning in the 1960s, researchers sought to understand the func- tions of the separate structures within the MTL. Many of these

studies focused on recognition memory, indicated by the ability to judge whether an item has been seen previously. Despite the fact that recognition memory is considered a canonical example of declarative memory, damage to the hippocampus appears to be neither necessary nor su cient to produce recognition mem- ory de cits.42–44 However, lesions that damaged one MTL cortical structure, the perirhinal cortex, consistently impaired recognition memory.45–49 In addition, with the advent of more detailed ana- tomical techniques, investigations into the mnemonic contribu- tion of the hippocampus alone—unconfounded by concomitant perirhinal damage—became possible. Using a precise excitotoxic lesion technique, it was shown that lesions to the hippocampus (without damage to underlying cortical regions) produced no rec- ognition memory impairment.50

A subsequent meta-analysis of three studies in monkeys with hippocampal lesions demonstrated that whereas greater rhinal cortex damage was associated with worse performance on a recog- nition memory task, greater hippocampal damage was associated with better performance on the same task.51 Further work indicated that the hippocampus and perirhinal cortex could be doubly dis- sociated.52 ese di erent structures, therefore, must contribute to memory in very di erent ways. Some of the most prominent ideas regarding division of labour between the hippocampus and other MTL structures are discussed below.

In a seminal review, Aggleton and Brown53 addressed the neu- ral substrates of two distinct memory processes, recollection (the ‘remembering’ of an event, associated with the retrieval of contex- tual details) and familiarity (the feeling of ‘knowing’ that an item has been experienced, in the absence of other associated details).54,55 ey proposed that the hippocampus, together with the fornix, mamillary bodies, and anterior thalamic nuclei, form a system that supports recollection, whereas familiarity re ects an independent process that depends on a distinct system involving the perirhinal cortex and the medial dorsal nucleus of the thalamus.

46 SECTION 1 normal cognitive function

A closely related model, the Convergence, Recollection, and Familiarity eory (CRAFT),56 also contrasts hippocampal and cortical function. Under this view, recollection is thought to be sup- ported by the hippocampus through pattern separation, a mecha- nism by which similar memories are di erentiated into distinct, non-overlapping representations,57 is computation is considered to be qualitatively di erent from the object/item familiarity and contextual familiarity computations supported by cortical MTL structures such as the perirhinal and parahippocampal cortices.

In a similar vein, the complementary learning system (CLS) is a network model that also makes important distinctions between hip- pocampal and MTL cortical contributions to memory.58 Under this framework, the MTL neocortex has a slow learning rate and uses overlapping distributed representations to extract the shared struc- ture of events (e.g. generalities based on accumulated experience, such as the best strategy for parking a car). us, because it does not su ciently di erentiate the representations of di erent information, this cortex is unable to support recall of information that has only been encountered on one or two occasions. In contrast, the hip- pocampus learns rapidly, using pattern separated representations to encode the details of speci c events while minimising interference (e.g. the memory for where the car is parked today is kept separate from the representation of where the car was parked yesterday).

Other prominent views of MTL function argue that the engage- ment of di erent MTL structures is best characterized by the type of information being processed (e.g. items, contexts, or the associa- tions between items and their contexts), rather than the processes themselves. One theory posits that the hippocampus has a criti- cal role in binding together arbitrarily-related associations (termed relational memory), whereas MTL cortical structures maintain rep- resentations for individual items.59,60

is theory has subsequently been developed into a three- component model, termed the ‘binding of item and context’ (BIC) model.61,62 Rather than proposing a simple mapping between dif- ferent MTL structures and familiarity and recollection, this view posits that MTL subregions di er in terms of the information they process and represent. More speci cally, the perirhinal cortex is thought to represent information about speci c items (e.g. who and what), the parahippocampal cortex is thought to represent infor- mation about the context of these items (e.g. where and when), and the hippocampus represents the associations between these items and contexts. us, each region has a functionally distinct role, but collectively, MTL regions support memory by binding item and context information.

In summary, the wealth of recent evidence suggests that, in con- trast to the idea of a unitary memory system, di erent MTL struc- tures make functionally dissociable contributions to memory and as such, di ering patterns of MTL damage will lead to distinct pro- les of memory impairment.

e VVS–MTL pathway as a continuous, rather than discontinuous, system

A second assumption of the historical view of the VVS–MTL pathway has also recently been questioned, namely the assump- tion that this system is best thought of as discontinuous, con- taining two qualitatively di erent modules, the MTL memory system and the VVS perceptual representation system. However, beginning in the mid-1990s, experimental data began to suggest

that structures within the MTL contribute not just to declara- tive memory but are also important for perceptual and other functions such as perceptual discrimination (e.g. being able to identify whether there are di erences between visually similar objects).48,63

To account for these data, it was proposed that structures within the MTL such as perirhinal cortex may be best understood as an extension of the representational hierarchy within the VVS (Fig. 4.7).64,65 In other words, rather than characterizing the func- tion of MTL structures in terms of psychological labels like ‘mem- ory’ and ‘perception’, it may be better to consider them in terms of the representations that they contain and the computations that they perform.66 Under this view, MTL structures are thought to contain the rich neural representations of objects and scenes that are neces- sary for both memory and perception. us, damage to these repre- sentations causes de cits on both mnemonic and perceptual tasks.

is notion was encapsulated in a computational/theoretical framework64,67 referred to as the ‘representational-hierarchical’ view.68 In accord with the prevailing view in the VVS literature,9,69 posterior regions in the VVS are assumed to represent simple fea- tures, whereas more anterior regions in the VVS and MTL are

Fig. 4.7 e representational-hierarchical view. e representational- hierarchical view suggests that a given brain region could be useful for multiple cognitive functions, rather than being specialized exclusively for functions such as memory or perception.64,65,84 Representations of visual stimulus features are organized hierarchically throughout the ventral visual stream, such that simple features are represented in more posterior regions and conjunctions of these features are represented in more anterior regions.9,69 e representational- hierarchical view proposes that highly complex conjunctions of these features— at approximately the level of an everyday object—are represented in the perirhinal cortex. ese object-level representations are important for both memory and perception, and thus, damage to the perirhinal cortex will impair both these cognitive functions.
Adapted from Neuron, 75(1), Barense MD, Groen II, Lee AC, Yeung LK, Brady SM, Gregori M,
et al. Intact memory for irrelevant information impairs perception in amnesia, pp. 157–67, Copyright (2012), with permission from Elsevier, reproduced under the Creative Commons CC BY 3.0 License; Trends in Cognitive Sciences, 3(4), Murray EA and Bussey TJ, Perceptual-mnemonic functions of the perirhinal cortex, pp. 142–51, Copyright (1999), with permission from Elsevier.

Feature

Features

conjunctions Objects

CD ABCD

AB
D

B C

Simple feature conjunctions (AB, CD)

Feature (A,B,C,D)

Objects (ABCD)

anterior posterior

assumed to represent more complex conjunctions of these features. According to the representational-hierarchical view (Fig. 4.7), because damage to the perirhinal cortex destroys or compromises highly complex visual representations, one must rely on the repre- sentations of simple features housed in more posterior regions of VVS to solve cognitive tasks. us, impairments in perception (as well as memory) are caused by perirhinal cortex damage because such damage leads to impoverished representations of complex stimuli, and the remaining representations of simple features are inadequate for making certain types of discrimination between visual objects.

To test the model, a ‘lesion’ was made by removing the layer of the computational network corresponding to perirhinal cor- tex, and the effects of this lesion were compared with previously reported effects of lesions in perirhinal cortex in monkeys.64 The model was able to simulate the effects of lesions of per- irhinal cortex on visual discrimination behaviour in a range of different experimental contexts (see, for example, references 70 and 71). Central to the model is the notion of ‘feature ambigu- ity’. An ambiguous feature—for example, one that is rewarded as part of one stimulus but not as part of another stimulus—will not contribute towards the solution of a task such as a visual discrimination. In order to solve a problem that contains ambig- uous features, more complex conjunctions of features (such as those represented in perirhinal cortex), which are much less likely to be ambiguous, are required.

Subsequent work therefore manipulated feature ambiguity explicitly to test this prediction of the model. A number of stud- ies provided support for the prediction that perirhinal cortex is required for any visual discrimination task that necessitates reso- lution of feature ambiguity at the object level in monkeys63,70–72 and humans,73–78 although there have been some con icting reports.79–82 More recently, this work has been extended to show that impoverished visual representations following MTL damage cause de cits not only in complex discrimination tasks.

What all these tasks had in common was the requirement to form a representation of the relationships between complex stimuli— either in terms of comparisons across complex objects,93,94 or in terms of the relationships of the objects that comprise a scene.75,76 ese ndings challenge the longstanding assumption that the hippocampus is uniquely involved in long-term memory, and suggest instead that this structure—along with the rest of the MTL—should best be understood in terms of the information it represents, rather than in terms of cognitive modules or circum- scribed processes.

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CHAPTER 4 the temporal lobes 49

Gross anatomy

CHAPTER 5

e parietal lobes

Masud Husain

On its medial surface (Fig. 5.2) the parietal lobe consists of a large cortical area, the precuneus,7 which lies adjacent to the poste- rior cingulate cortex8 and retrosplenial cortex.9 In recent years, these medial regions have become the focus of much interest in Alzheimer’s disease. Indeed, several investigators have reported that atrophy and hypometabolism in these areas is closely associated with mild cognitive impairment and early Alzheimer’s disease.10–13

Functional network connectivity

Although we have known about the connections of parietal cor- tex at a gross anatomical level for over a century, our understand- ing of its detailed connectivity has, until relatively recently, been based largely on studies in non-human primates.14 However, there is considerable debate about whether the parietal lobes in human and monkey are homologous structures.15,16 e IPL in humans is proportionately much larger, and it has been argued that it may have both a di erent structure and function to the IPL in monkey. Conversely, there is much evidence to suggest that there might be some homologous sub-regions across the two species (see refer- ences 5 and 16 for discussion).

IPS SPL

Fig. 5.1 Lateral view of parietal cortex of human and macaque monkey. e human parietal cortex consists of an anterior portion (uncoloured) situated in front of the postcentral sulcus, and a posterior portion behind this. e posterior parietal cortex is divided by the intraparietal sulcus (IPS) into two parts: the superior parietal lobule (SPL) and the inferior parietal lobule (IPL). e IPL consists of the angular gyrus (Ang) and supramarignal gyrus (Smg), and borders the superior temporal gyrus (purple) at a region that is often referred to as the temporo-parietal junction (TPJ). In macaque monkeys, the posterior parietal cortex consists of an SPL (Brodmann’s area 5) and an IPL (Brodmann’s areas 7a and 7b) but, according to Brodmann, the homologues of these macaque regions are all con ned to the human SPL (shaded in yellow), so he considered that the IPL in humans consists of novel cortical areas. Subsequent anatomists disagreed with this scheme, considering the IPL to be similar across both species. It remains to be established whether there are new functional sub-regions within the human IPL.

Adapted from Trends Cogn Sci. 11(1), Husain M and Nachev P. Space and the parietal cortex, pp. 30–6, Copyright (2007), with permission from Elsevier, reproduced under the Creative Commons CC BY License.

On its lateral surface, the human parietal lobe consists of an ante- rior and a posterior portion. e anterior part, bounded by the cen- tral sulcus in front and postcentral sulcus behind, has largely been implicated in basic sensorimotor functions. e posterior parietal lobe, which lies between the postcentral sulcus and the occipital and temporal lobes, has a far greater role in cognitive function. It is divided by the intraparietal sulcus (IPS) into the superior parietal lobule (SPL) and the inferior parietal lobule (IPL) (Fig. 5.1).

e IPL consists of the angular and supramarginal gyrus (Brodmann’s areas 39 and 40 respectively). e nearby border zone between the temporal and parietal lobes is referred to as the tem- poroparietal junction (TPJ). In humans, parts of the IPL and TPJ appear to have distinctly di erent functions in the le and right hemisphere, with limb apraxia, language, and number process- ing disorders more o en associated with le -sided lesions and visuospatial, attentional, and social (e.g., theory of mind) de cits associated with right-sided ones.1–6 e portion of the lateral pari- etal cortex that lies deep to the temporal lobe within the insula is referred to as the parietal operculum and posterior insula.

IPS
5

7a 7b

Ang
TPJ

Smg IPL

52 SECTION 1 normal cognitive function

Recent human neuroimaging studies which have examined structural and functional connectivity suggest that both these views might be correct: there appear to be novel regions within the human IPL as well as conserved ones that are homologous to those in the rhesus monkey.17,18 In addition, as noted previously, there is abundant evidence to suggest that the IPL in humans is strongly lateralized between the hemispheres, while the case for such hemi- spheric specialization in monkeys is weak.

e main projections to parietal cortex in non-human primates come from areas involved in sensory processing (e.g. visual, soma- tosensory, and vestibular), while the major outputs are to premotor regions (frontal eye elds and superior colliculus, which control saccadic eye movements, and premotor cortex, which controls reaching and grasping). In turn, these premotor areas project back to parietal cortex, which also sends projections back to brain regions involved in sensory processing. us, the parietal cortex is an important location for the convergence of information from di erent sensory modalities, as well as for the association of sen- sory and motor signals.19 ese ndings also appear to hold for human parietal regions.20,21 e parietal cortex appears to be a major hub in cortical organization, operating on ‘bottom-up’ inputs from sensory regions as well as ‘top-down’ control signals from the frontal lobe.

In the monkey, the anterior parietal lobe is the site of pri- mary somatosensory processing. This region projects heavily to the SPL, whereas visual signals project from occipital cortex predominantly to the IPL. The occipital visual projection to the IPL in the monkey is considered to be part of a ‘dorsal visual stream’ of pathways involved in spatial perception, or visual control of eye and limb movement,22–24 The IPS appears to be an extremely important site for the convergence of information from the SPL and IPL, as well as from premotor centres. Regions

within the IPS encode sensory, motor, attention and short-term memory information in both monkeys and humans.20,21 The medial parietal cortex appears to receive both visual and soma- tosensory inputs and also has reciprocal connections to premo- tor cortex.

In humans, the dorsal visual stream emanating from occipi- tal regions appears to project more heavily to the SPL, IPS, and precuneus rather than to the IPL.5,25,26. Parts of the more ventral parietal regions in humans—the IPL and TPJ—may instead have evolved to subserve higher cognitive functions, including language, number processing, and praxis in the left hemisphere, and spatial, attentional, and ‘social’ cognitive func- tions in the right hemisphere.1–6 Human neuroimaging studies that have assessed resting state function connectivity and func- tional activation now implicate both IPL/TPJ and medial pari- etal regions as key network hubs—cortical areas where there is massive convergence of information from many different brain regions.12,27,28

Medial parietal areas and more posterior parts of the IPL have been implicated as part of the so-called default mode network. is set of brain regions is strongly deactivated during goal- directed tasks, but is active when an individual is at wakeful rest, thinking but not focusing on a problem in the outside world.13 In contrast, more anterior parts of the IPL and adjacent TPJ in the right hemisphere have been identi ed as part of a ventral attention network4,29 which is active during attentive states, while in the le hemisphere, homologues of these regions appear to form part of a language network (Fig. 5.3).29 Both IPL and TPJ have high degrees of functional and structural connectivity with ventrolateral frontal regions, including Broca’s area in the le hemisphere and its homologue in the right hemisphere (see also chapter 8).29,30

31 23

Brodmann 1909

31 23

Fig. 5.2 Medial view of the parietal cortex of human. e human medial parietal cortex includes the precuneus, the posterior cingulate cortex (Brodmann’s area 23), the retrosplenial cortex embedded in the posterior callosal sulcus (Brodmann’s areas 29 and 30), and the transitional zone (area 31) which separates precuneus from cingulate cortex. e precuneus is located between the marginal ramus of the cingulate sulcus anteriorly and the parieto-occipital ssure posteriorly. e two insets on the right show two di erent parcellations of these regions according to Brodmann and von Economo subsequently.

Adapted from Proc Natl Acad Sci USA. 106(47), Margulies DS, Vincent JL, Kelly C, Lohmann G, Uddin LQ, Biswal BB, et al. Precuneus shares intrinsic functional architecture in humans and monkeys, pp. 20069–74, Copyright (2009), with permission from Proc Natl Acad Sci USA.

31 23

PEm
PEp

LC2 LC1 PEγ

Economo 1925

u e

c c

g a

l c

ost

parieto-occipital fissure

cuneus

c
d

IPS

spatial locations.19,20,33,34,35–38 Some of the most prominent disor- ders that follow damage to the posterior parietal lobe are charac- terized by a spatial component,39 although non-spatial functions also contribute.40 At one end of the spectrum are sensory defects; for example, in the visual domain, inferior quadrantanopias which arise because of damage to part of the optic radiations as they pass through the parietal white matter from the lateral geniculate nucleus to the calcarine sulcus. At the other end of the spectrum are complex disorders of attention that can have devastating con- sequences for a patient, presenting an enormous challenge for rehabilitation.

It is important to appreciate that many perceptual disorders that follow parietal damage are di cult to explain simply in terms of de cits in sensory processes alone. us, for example, visual diso- rientation, mislocalization, and constructional apraxia (discussed below) have all been attributed to de cits of ‘spatial remapping’.41,42 is may be due to di culties in updating representations that combine visual information and motor commands sent to the eye muscles to produce a dynamic, spatial ‘map’ of the body and the external world.19,43 Not knowing which way the eyes were pointing in the orbit when the retinal ‘snapshot’ was taken can lead to poor integration of the relative locations of items around us, a factor that probably contributes to several parietal disorders of perception and attention.

It is also the case that many perceptual de cits (e.g. unilateral neglect syndrome) are not con ned to one sensory modality but are multimodal, involving vision, audition, and touch. Indeed, some have considered the parietal lobe to be essential in forming a mul- timodal representation of the body schema,44,45 consistent with the known convergence of di erent types of sensory input to parietal regions. Many of the studies that have been performed in patients, however, have focused on disturbances of vision and touch because these are o en the most clinically conspicuous ndings.

Visual disorientation and mislocalization

Holmes rst described in detail a syndrome of ‘visual disorienta- tion’ in cases of bilateral posterior parietal damage following gun-

46,47
shot wounds. Typically, when asked to touch an object in front

of him, a patient would reach in the wrong direction and grope hopelessly until his hand came into contact with it, almost as if he was searching for a small object in the dark, and experience great di culty in walking through a room without bumping into objects. Less dramatic impairments have been demonstrated in unilateral lesions. Patients with parietal lesions misreach when pointing to visual targets presented on a perimeter.48 However, a potential confound is that parietal damage may lead to a disorder of visu- ally guided reaching (see optic ataxia below) in addition to visual mislocalization.

To circumvent this issue, Warrington developed a perceptual test, rst brie y presenting a dot and then a card on which appeared numbers at di erent locations. She asked patients to report the number which best approximated the dot’s location.49 Visual mis- localization on such tasks is more prominent following posterior lesions of the right hemisphere.49,50 A version of this dot locali- zation test, without brief visual presentation, continues to be used in neuropsychological batteries today (e.g. visual object and space perception or VOSP battery). Depth perception and judgment of line orientation may also be impaired a er unilateral (right?) pari- etal lesions.39

CHAPTER 5 the parietal lobes 53

SPL

Ang
IPL

TPJ

Smg

FEF VFC

Fig. 5.3 Dorsal and ventral attention networks. e ventral frontoparietal attention network extends from the IPL (inferior parietal lobule) and TPJ (temporoparietal junction) to the VFC (ventral frontal cortex) and is considered to be lateralized to the right hemisphere. Homologous regions in the left hemisphere are considered to form part of a language network. e dorsal attention network, by contrast, is considered to be bilateral. It extends from the SPL (superior parietal lobe) and IPS (intraparietal sulcus) to the FEF (frontal eye elds).

By contrast, the SPL and IPS appear to be heavily connected to dorsolateral frontal regions. ese parietal and frontal areas are considered to be part of a dorsal attention network which, unlike the ventral attention network, appears to be symmetric across both hemispheres (Fig. 5.3).4 e dorsal frontoparietal attention net- work (not to be confused with the ‘dorsal visual stream’ which con- nects occipital regions to dorsal parietal areas—see chapter 6) may play a role in directing attention to locations or objects of interest in the environment.

e IPL and medial parietal regions, particularly posterior cin- gulate and retrosplenial cortex, also have strong connections to the medial temporal lobe (MTL),24,25,31 accessing the hippocampus via the parahippocampal region.32 e functional role of parieto- hippocampal interactions is yet to be established but these may play an important role in episodic memory. Intriguingly, atrophy and hypometabolism in medial parietal regions that connect to the MTL and are part of the default mode network is closely associated with mild cognitive impairment and early Alzheimer’s disease.10–13 Some have argued that it is the strong network connectivity of these parietal regions to MTL areas a ected in Alzheimer’s pathol- ogy that makes them particularly vulnerable relatively early in the course of the illness.12

Next, the functional anatomy of the parietal cortex in the context of disorders of perception, action, language, and number process- ing that follow damage to the human parietal lobe is considered. Where possible, the anatomy of lesion localization is related to the de cits observed.

Perception and attention

Parietal regions play a crucial role in perception, integrating infor- mation from di erent sensory modalities and directing atten- tion, particularly for localizing or attending to objects at di erent

54 SECTION 1 normal cognitive function Disorders of touch and proprioception

Classically, parietal lesions lead to ‘discriminative’ sensory loss.44 Two-point discrimination, position sense, texture discrimin- ation, stereognosis (ability to identify by touch objects placed in the hand), and graphesthaesia (recognition of numbers scratched on the hand) may all be impaired. Usually, this ‘cortical sensory loss’ is limited to one or two body parts, is more prominent in the arm than the leg, and follows damage to the contralateral anterior parietal lobe or its connections. However, there are also reports of astereognosis following damage to the SPL or IPL. One patient with a large SPL cyst complained that she kept ‘losing’ her arm if she did not look at it: she could not maintain a representation of the limb in the absence of vision.51 In contrast to astereognosis, tactile agno- sia refers to selective impairment of tactile object recognition in the absence of a clinically demonstrable basic sensory impairment. With their eyes closed, patients with tactile agnosia are unable to recognize familiar objects placed in the hand contralateral to the lesion which o en involves the IPL and or posterior insula.52

Constructional apraxia

A common way to demonstrate visuospatial impairments following parietal damage is to ask patients to copy a drawing (e.g. a complex gure such as the Rey–Ostrrieth gure, or equivalent) or a three- dimensional block design. Typically, they encounter di culty in understanding the spatial relationships of the drawing or block design and produce poor reproductions. Such an inability to use visual information to guide acts which require an understanding of the spatial relationship of objects is referred to as constructional apraxia, a syndrome most o en associated with right IPL dam- age.53,54 Paterson and Zangwill gave a particularly clear account of a young man with a focal lesion of the right IPL.55 ey observed that the patient drew complex objects or scenes detail by detail, and appeared to lack any real grasp of the object as a whole. ey char- acterized this problem as a ‘piecemeal approach’—a fragmentation of the visual contents with de cient synthesis.55 It is as if snapshots of the visual scene fail to be integrated correctly, so the relative loca- tions of di erent parts of the scene or an object are not correctly perceived.

Disorders of attention

Parietal regions appear to play a crucial role in deploying select- ive attention to spatial locations or objects as well as sustaining attention over time.5,33,34,38 For example, neurons that are select- ive for a region of space increase their ring when monkeys attend more closely to that location.33,38 ree disorders of attention follow damage to the posterior parietal lobes: extinction, neglect, and simultagnosia. e rst two o en occur a er unilateral dam- age, whereas the last is less common and is observed in its full- blown form a er bilateral parietal lesions or atrophy o en as part of Bálint’s syndrome.56 None of them can be adequately explained as simple sensory impairments.

Extinction is the failure to report a contralesional stimulus (one presented to the side opposite the brain lesion) in the presence of a competing ipsilesional stimulus (on the same side of space as the brain lesion). It can occur in visual, tactile, or auditory domains. For example, patients acknowledge the presence of a single visual stimulus (e.g. the examiner’s nger) when it is presented brie y in either le or right visual hemi elds. However, when both stimuli

are simultaneously presented transiently, one in each hemi eld, they report seeing only the ipsilesional one. Extinction can occur with either le or right parietal lesions, and has been associated with damage to the IPS or TPJ,21 but might also occur with lesions to other brain regions.

Neglect (also referred to as unilateral neglect or hemispatial neglect) is a failure to acknowledge a contralesional stimulus— regardless of the presence or absence of a competing stimulus in ipsilesional space—which cannot be explained simply by sensory loss or motor de cit,4,57 It is o en multimodal, involving visual, tactile, and auditory domains. If neglect is very dense it can be di cult to distinguish from sensory de cits, and some patients with large lesions su er from both (e.g. a visual eld de cit and neglect). However, the clinician is o en alerted to the presence of neglect by the patient’s persistent turning of eyes and head towards the ipsilesional side (without an associated gaze palsy), by nd- ing that unawareness of contralesional stimuli can vary and is not absolute, by observing in the visual domain that the apparent eld loss does not obey the vertical meridian (unlike homonym- ous hemianopia), and by the patient’s failure to orient fully into contralesional space on simple pen-and-paper tasks such as line bisection and cancellation. Some patients also fail to draw the contralesional side of objects. A patient with hemianopia (without neglect) may be slow in performing these tasks but will usually explore contralesional space.

Finally, an important clinical clue comes from the patient’s his- tory. Most patients with neglect are not aware they have a prob- lem (see anosognosia below), whereas those with a hemianopia (without neglect) complain bitterly that they have di culty seeing on one side of space. Neglect is most severe and most long-lasting following right parietal/TPJ lesions, particularly stroke, although it can also occur a er right inferior frontal, basal ganglia, and tha- lamic damage.

Simultagnosia (or simultanagnosia) refers to a disorder of vision in which individuals have di culty apprehending the entire scene, in visualizing its separate elements simultaneously. Although they may describe some of the details meticulously, individuals with simultagnosia may still not appreciate what is happening overall in a picture (e.g. the Boston cookie the scene). eir perception appears piecemeal, as if they have snapshots of di erent items in a scene but cannot integrate these into a coherent whole.58 Simultagnosia is one component of Bálint’s syndrome.56 Previously, simultagnosia was most commonly associated with massive bilat- eral lesions of temporoparieto-occipital cortex (e.g. from watershed infarctions). Nowadays, it is most commonly observed as a feature of posterior cortical atrophy59 (see chapter 15) which is usually a posterior variant of Alzheimer’s disease.

Anosognosia

Unawareness of illness is referred to as anosognosia. Patients may steadfastly deny they have su ered a stroke or hemiparesis, even if the examiner demonstrates that one limb is weak. e condition is o en, but not invariably, associated with unilateral neglect, with many such patients denying they have a visual disorder. Anosognosia appears most commonly a er right-hemisphere lesions. Although it is traditionally associated with right IPL damage,60 recent studies of anosognosia for hemiparesis suggest involvement of right poste- rior insula or premotor frontal regions.61,62

Visuomotor and motor control

Neurons in the parietal cortex integrate sensory information (e.g. location of a visual object) with motor commands (e.g. to the eyes or limbs) and, together with premotor regions in frontal cortex, appear to play a crucial role in directing gaze and the hand to objects—including tools—around us.20,63,64 Imaging studies have identi ed several regions within dorsal and dorsomedial parietal cortex involved in directing the eyes and the hands to reach, as well as action observation (e.g. when people view others using tools) (Fig. 5.4). Some of the disorders that follow parietal damage re ect such functions.16,65

Optic ataxia

Bálint rst used the term ‘optic ataxia’ to refer to an impairment of visually guided reaching that he observed following bilateral posterior cortical damage. Since then, many reports have followed of patients with unilateral or bilateral parietal lesions. e term Bálint’s syndrome is used to refer to a combination of optic ataxia, simultagnosia, and ocular apraxia,56 most commonly observed nowadays in cases of posterior cortical atrophy.59 However, many patients have been reported with optic ataxia alone. e most com- monly described defect appears to be a ‘ eld e ect’: inaccurate reaching with either hand to visual targets located in the visual hemi eld contralateral to the lesion. However, an ‘arm e ect’ has also been reported: misreaching with the contralesional arm to tar- gets in either visual eld. is may also occur in combination with a ‘ eld e ect’.66

At the bedside, the disorder is best demonstrated by asking the patient to xate centrally (e.g. on the examiner’s nose) and point to a target presented peripherally (e.g. the examiner’s nger). If the patient is allowed to move his eyes and look at the target, the

disorder may not be evident. As well as misdirecting their reaches, optic ataxic patients may also encounter di culty in planning the appropriate grasp required to pick up an object.66 Lesions in either hemisphere appear to cause the syndrome, with the critical lesion site being the SPL and adjacent IPS, consistent with functional imaging studies in healthy people which demonstrate these regions play a crucial role in reaching and grasping (Fig. 5.4).20,64

Impairments of gaze control or ocular apraxia

In addition to simultagnosia and optic ataxia, patient’s with Bálint’s syndrome experience di culty in shi ing gaze to objects in periph- eral vision.56 ey seem to lock their gaze on the item they are xat- ing and have di culty initiating saccades to other objects—ocular apraxia. Holmes described a similar problem in his cases with vis- ual disorientation, but in addition reported other disorders of ocu- lomotor control.46,47 Typically, when one of his patients was asked to look at something or was spoken to, he would stare in the wrong direction and then move his eyes awkwardly until he found, o en as if by chance, the object he was looking for. Some of Holmes’ cases also failed to accommodate and converge their eyes correctly, and smooth pursuit could also be impaired. Holmes considered these problems to be secondary to visual perceptual de cits. However, these disorders may be accounted for by loss of neurons associated with maintaining xation, directing saccades, or pursuit eye move- ments, all of which have been demonstrated in monkey posterior parietal cortical neurons.19 Functional imaging studies in humans suggest that there are several parietal eye elds located within the dorsal IPS (Fig. 5.4).35,67

Limb apraxia

Limb apraxia refers to an impairment in the ability to perform skilled movements which cannot be attributed to weakness,

(a)

Human

aIPS vIPS mIPS PEF

mOPJ

IOPJ

IPTO

(b)

Tool execution

Tool planning

(c)

Action observation

Central Postcentral Intraparietal

Transverse occipital Parieto-occipital

Fig. 5.4 Parietal regions activate in imaging studies of action control. (a) Schematic of parietal regions implicated in functional imaging studies of directing saccades, pointing or grasping. e parietal eye elds (PEF) are now known to consist of several di erent regions that are activated by eye movements. Area AIP (anterior intraparietal sulcus) has been considered to play a role in grasping while areas mIPS (medial intraparietal sulcus) and mOPJ (medial occipitoparietal junction) have been implicated in reaching. Area vIPS (ventral intraparietal sulcus) responds to multimodal moving stimuli. (b) Lateral inferior parietal regions in the left hemisphere active during tool use or thinking about tool use. (c) Left parietal regions active during action observation.

Adapted from Curr Opin Neurobiol. 16(2), Culham JC and Valyear KF. Human parietal cortex in action, pp. 205–12, Copyright (2006), with permission from Elsevier.

CHAPTER 5 the parietal lobes 55

56 SECTION 1 normal cognitive function

sensory disturbance, or involuntary movements such as tremor,1 It may occur in up to 50 per cent of unselected patients with le – hemisphere damage, but frequently goes unrecognized either because patients may not be aware of a problem in daily life, or because praxis is commonly not tested, or because many le – hemisphere patients are dysphasic.

Liepmann, at the turn of the last century (see reference 68), originally proposed that there are three types of apraxia: ideational, ideomotor, and limb-kinetic (or melokinetic). He considered that inadequate formulation of a motor programme would result in ide- ational apraxia. Traditionally, this is considered to be best observed when a patient is asked to produce a sequence of gestures on com- mand, rather than when the examiner performs a gesture for him to imitate. By contrast, in ideomotor apraxia, a patient may know what to do but cannot produce the correct actions either on verbal request or when asked to imitate gestures. He is aware of his poor performance and may try to correct it, so the problem is one of defective execution rather than ideation. is is the most common type of limb apraxia for which clinicians usually test. Finally, limb- kinetic apraxia consists of loss of control of ne nger movements and o en follows damage to the corticospinal pathways, and will not be considered further in this discussion.

In ideomotor apraxia, the representation of the gesture to be performed is considered to be intact but its execution is defective. Traditionally, an important piece of evidence in favour of this dis- tinction is the failure of patients to produce correct gestures even when asked to imitate the examiner’s movements. us, these patients perform poorly regardless of whether they have to pro- duce a gesture on verbal command (by recalling a movement rep- resentation) or imitate it. Typically, however, their performance is better when imitating movements or using objects than when they are asked to pantomime transitive acts (i.e. mime the use of a tool or instrument). Intransitive movements (communicative gestures such as waving goodbye) may be relatively well preserved. us, ideomotor apraxia appears to spare movements that are automatic or habitual such as waving, or repetitive as in nger-tapping.

Some patients with ideomotor apraxia may use a body part as a tool, such as using their ngers to act like scissor blades, when asked to pantomime using scissors. is type of error may have been overemphasized, since even neurologically normal individu- als will sometimes do this. Other patients produce inappropriate movements about multiple joints. For example, when asked to pan- tomime the use of a screwdriver, they may rotate their arm at the shoulder rather than at the elbow.

e localization of apraxia appears in many ways to be the mirror image of the neglect syndrome, involving inferior parietal and fron- tal regions in the le hemisphere.69 Liepmann considered ideomo- tor apraxia to be a disconnection syndrome, in which sensory visual and audioverbal representations (in the posterior le hemisphere) were disconnected from kinesthetic-motor ‘engrams’ (around the central sulcus). e critical anatomical site of the disconnection, he suggested, was the white matter underlying the le IPL. Liepmann was quite clear that his model did not envisage a centre for ‘gesture control’ within the IPL, but subsequent investigators have chal- lenged this scheme, arguing that movement representations encod- ing the spatial and temporal patterns of skilled movements, are stored within the le IPL (see reference 68 and Fig. 5.4).

e use of the term ideational apraxia has been extremely con- fusing. It is o en used to refer to an impairment in the ability to

perform a series of motor acts. For example, when asked to make a cup of tea, a patient may perform each element of the sequence but in an incorrect order. However, De Renzi has argued that ideational apraxia refers to an inability to recall previously well- established actions, for example, object use, an ‘amnesia of usage’.70 ere are certainly examples of patients who have di culty using a single object without having to perform a sequence of acts using multiple objects. For example, Pick originally reported a case who used a razor as a comb! Some favour a di erent term—conceptual apraxia—to specify a defect in the knowledge required to select and use tools and objects.71 is appears most frequently to follow lesions of the le posterior parietal lobe. Functional imaging stud- ies in healthy people have delineated le parietal regions involved in tool use and observing the actions of others.64

Language and number processing

In functional imaging studies, part of the le IPL (angular gyrus) is activated by tasks that require semantic processing including comprehension during reading,72 while a region around the le TPJ (known as area Spt: Sylvian parietotemporal, within the pla- num temporale) has been implicated in auditory sensorimotor processing and phonological short-term or working memory.73 By contrast, neuroimaging has implicated the le IPS in number processing.74

Conduction aphasia

Lesions of the le parietal lobe have been associated with the syndrome of conduction aphasia which is characterized by uent speech but with phonemic errors, intact comprehension but poor repetition. Classically this has been considered to be a ‘disconnec- tion syndrome’ in which the arcuate fasciculus is a ected, thereby disconnecting superior temporal lobe language zones from Broca’s area. More recent lesion analysis suggests that damage to cortical area Spt might be su cient without having to invoke white matter disconnection,73 although this is contested.

Dyscalculia and Gerstmann’s syndrome

ere is now considerable evidence that lesions of the le parietal lobe can lead to de cits in number processing and dyscalculia (see chapter 17). e existence of Gerstmann’s syndrome (dyscalculia, dysgraphia, nger agnosia, or the inability to distinguish between ngers and le -right disorientation) —has, however, been disputed. When reported, it has been associated with le parietal lesions near the TPJ.

Memory

It is generally agreed that the parietal lobes play a role in short- term or working memory. Imaging studies have repeatedly demon- strated this with verbal material more likely to activate le parietal regions more than right, and vice versa for spatial material. Most o en the IPS has been implicated.75 Lesion studies too have impli- cated posterior parietal areas in the le hemisphere in phonological working memory and right hemisphere regions in spatial working memory.76,77 Some recent studies suggest that parietal areas, which project heavily to the medial temporal lobe, might also play a role in aspects of episodic memory largely on the basis of imaging data,78 but this proposal remains controversial.

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52. Caselli RJ. Ventrolateral and dorsomedial somatosensory association cortex damage produces distinct somesthetic syndromes in humans. Neurology. 1993 Apr;43(4):762–71.

53. Hier DB, Mondlock J, and Caplan LR. Behavioral abnormalities a er right hemisphere stroke. Neurology. 1983 Apr;33(3):337–44.

CHAPTER 5 the parietal lobes 57

58 SECTION 1 normal cognitive function

54. Ruessmann K, Sondag HD, and Beneicke U. On the cer-
ebral localization of constructional apraxia. Int J Neurosci. 1988 Sep;42(1–2):59–62.

55. Patterson A and Zangwill OL. Disorders of visual space percep- tion associated with lesions of the right cerebral hemisphere. Brain. 1944;67:331–58.

56. Rizzo M and Vecera SP. Psychoanatomical substrates of Bálint’s syn- drome. J Neurol Neurosur Ps. 2002 Feb;72(2):162–78.

57. Parton A, Malhotra P, and Husain M. Hemispatial neglect. J Neurol Neurosur Ps. 2004 Jan;75(1):13–21.

58. Dalrymple KA, Barton JJS, and Kingstone A. A world unglued: simul- tanagnosia as a spatial restriction of attention. Front Hum Neurosci. 2013;7:145.

59. Crutch SJ, Lehmann M, Schott JM, et al. Posterior cortical atrophy. Lancet Neurol. 2012 Feb;11(2):170–8.

60. Vossel S, Weiss PH, Eschenbeck P, et al. e neural basis of ano- sognosia for spatial neglect a er stroke. Stroke J Cereb Circ. 2012 Jul;43(7):1954–6.

61. Karnath H-O, Baier B, and Nägele T. Awareness of the functioning of one’s own limbs mediated by the insular cortex? J Neurosci. 2005 Aug 3;25(31):7134–8.

62. Berti A, Bottini G, Gandola M, et al. Shared cortical anatomy for motor awareness and motor control. Science. 2005 Jul 15;309(5733):488–91.

63. Andersen RA and Cui H. Intention, action planning, and decision making in parietal-frontal circuits. Neuron. 2009 Sep 10;63(5):568–83.

64. Vingerhoets G. Contribution of the posterior parietal cortex in reaching, grasping, and using objects and tools. Front Psychol. 2014;5:151.

65. Andersen RA, Andersen KN, Hwang EJ, et al. Optic ataxia: from Balint’s syndrome to the parietal reach region. Neuron. 2014 Mar 5;81(5):967–83.

66. Perenin M-T and Vighetto A. Optic ataxia: a speci c disruption in visuomotor mechanisms. I. Di erent aspects of the de cit in reaching for objects. Brain. 1988;111:643–74.

67. Konen CS and Kastner S. Representation of eye movements and stimulus motion in topographically organized areas of human posterior parietal cortex. J Neurosci. 2008 Aug 13;28(33):8361–75.

68. Goldenberg G. Apraxia: e Cognitive Side of Motor Control. Oxford: Oxford University Press, 2013.

69. Haaland KY, Harrington DL, and Knight RT. Neural representations of skilled movement. Brain. 2000 Nov;123 (Pt 11):2306–13.

70. De Renzi E and Lucchelli F. Ideational apraxia. Brain. 1988 Oct;111 (Pt 5):1173–85.

71. Heilman KM, Maher LM, Greenwald ML, et al. Conceptual apraxia from lateralized lesions. Neurology. 1997 Aug;49(2):457–64.

72. Binder JR, Desai RH, Graves WW, et al. Where is the semantic system? A critical review and meta-analysis of 120 functional neuroimaging studies. Cereb Cortex. 1991. 2009 Dec;19(12):2767–96.

73. Hickok G and Poeppel D. e cortical organization of speech process- ing. Nat Rev Neurosci. 2007 May;8(5):393–402.

74. Nieder A and Dehaene S. Representation of number in the brain. Annu Rev Neurosci. 2009;32:185–208.

75. Baddeley A. Working memory: looking back and looking forward. Nat Rev Neurosci. 2003 Oct;4(10):829–39.

76. Shallice T and Warrington EK. Independent functioning of verbal memory stores: a neuropsychological study. Q J Exp Psychol. 1970 May;22(2):261–73.

77. Hanley JR, Young AW, and Pearson NA. Impairment of the visuo- spatial sketch pad. Q J Exp Psychol A. 1991 Feb;43(1):101–25.

78. Cabeza R, Ciaramelli E, Olson IR, et al. e parietal cortex and episodic memory: an attentional account. Nat Rev Neurosci. 2008 Aug;9(8):613–25.

CHAPTER 6

e occipital lobes

Geraint Rees

In the human brain, the occipital lobe is a pyramidal shaped struc- ture located at the most posterior point of each cerebral hemisphere. Traditionally it is de ned as extending from the occipital pole to the parieto-occipital ssure, and in primate brains it is a structure involved in processing visual information. e discovery and func- tional characterization of di erent visual areas of the occipital lobe is one of the major achievements of twentieth-century neurology and visual neuroscience and has helped clarify and understand the clinical presentation of many sensory disorders caused by occipital lobe damage or dysfunction.

At the end of the nineteenth century, it was noted that unilat- eral lesions of the striate cortex of the occipital lobe in monkeys lead to hemianopia.1 is identi cation of the occipital lobe with visual function was extended to humans in clinical observations2 that suggested that the calcarine sulcus, which extends anteriorly from the occipital pole on the medial aspect of the occipital lobe, was the crucial location which when damaged produced contralat- eral hemianopia. ese clinical observations established that the occipital lobe received input from the contralateral hemiretina, but the precise correspondence between how the visual eld was rep- resented on the retina and how it was represented in the calcarine sulcus remained obscure because of the relatively large size of the lesions in the patients who were studied, which limited the ability to localize function.

e invention and subsequent utilization of the high-velocity ri e in the armed con icts that swept the world at the beginning of the twentieth century produced new opportunities to discover the functional anatomy of visual cortex. In soldiers with head inju- ries that were associated with visual eld defects, it proved possible to determine the intracerebral trajectory of the bullet that caused such a defect because its velocity meant that it took a straight course between entry and exit wounds. Inouye3 studied such brain- injured patients from the Russo–Japanese war, and deduced that the visual elds were represented in striate cortex in the form of a map. Speci cally, he proposed that the central visual eld was represented more posteriorly in the contralateral occipital lobe. Moreover, he suggested from careful consideration of the di erent patients that the cortical maps were distorted, with the central vis- ual eld occupying a larger area of occipital cortex than the periph- eral visual elds.

e British neurologist Gordon Holmes subsequently studied over 2000 brain-injured British soldiers in the First World War,4 con rming and extending these observations to propose an antero- posterior organization with central vision located more posteri- orly and peripheral vision more anteriorly in the calcarine sulcus.

Holmes also concluded that cortical lesions resulted in homony- mous (congruous) defects and produced a more detailed descrip- tion of the representation in the visual cortex of the horizontal and vertical axes of the retina.

ese clinical observations thus rmly established the corre- spondence between the gross anatomy of the human occipital lobe and the de cits in vision that resulted from brain injury. In particular, they proposed a retinotopic organization of the visual cortex whereby there is a topographic correspondence between locations in the retina and corresponding locations in the early visual cortex that represent a particular part of the visual eld. Speci cally, nearby regions on the retina project to nearby cor- tical regions and in the cortex, neighbouring positions in the visual eld are represented by groups of neurons that are adja- cent in the grey matter. is primary visual cortex (subsequently known as V1) was located in the calcarine sulcus in the posterior occipital lobe.

Using non-invasive brain imaging

to measure retinotopic maps

In the 1980s and early 1990s, investigators realized that the top- ographic organization of visual areas in humans that had been revealed almost a century earlier could now be studied using non- invasive methods. e use of positron emission tomography (PET) and then the advent of functional magnetic resonance imaging (MRI) allowed signals to be recorded from healthy volunteers that re ected local neuronal activity in the human brain. Some of the rst studies to demonstrate this new technique employed activa- tion of the occipital lobe in response to visual eld stimulation with a ashing checkerboard.5 By asking participants to xate and pre- senting visual stimuli at particular locations rather than through- out the visual eld, investigators devised e cient approaches that could map topographic cortical representations of the visual eld in the occipital lobe.6–8 is technique became known as retinotopic mapping and is now a standard procedure (Fig. 6.1).

ese early studies showed, as suspected from earlier clinico- pathological investigation, that the mapping from the retina to the visual cortex was not only topographic but could be best described by a log-polar transformation. Such a transformation results in the standard x/y (Cartesian) axes in the retina being modi ed into a polar coordinate system in the cortex, where position on the retina (corresponding to position in the visual eld) is represented on the cortical surface in terms of eccentricity (the di erence from the centre of vision) and polar angle (relative to a horizontal or verti- cal axis). e logarithmic nature of the transformation is such that

Introduction

60 SECTION 1 normal cognitive function

Fig. 6.1 Retinotopic maps in the early visual cortex. Two di erent stimuli used to delineate retinotopic maps in the human occipital lobe are expanding rings (left) and rotating wedges (right). Each stimulus traverses the visual eld repeatedly while brain activity is measured using fMRI. Analysis allows each point on the cortical surface that responds to the visual stimuli to be labelled according to the location in the visual eld that when stimulated produces the maximal activation. When the colour labels correspond to visual eld eccentricity (left panels) or phase/angle (right panels), two di erent types of macroscopic organization are visible. On the left, regions responding to more central portions of the visual eld are located more posteriorly; while on the right, a pattern of stripes orthogonal to the organization shown in the right panels illustrates a series of visual eld representations that when analysed more closely correspond to the organization shown in Fig. 6.2.

Reproduced from J Vis. 3(10), Dougherty RF et al. Visual eld representations and locations of visual areas V1/2/3 in human visual cortex, pp. 586–98, Copyright (2003), with permission from the Association for Research in Vision and Ophthalmology.

representations of the central retina (visual eld) are expanded rel- ative to those of the more peripheral retina (visual eld).

e elegance of this log-polar transformation in accounting for the topographic cortical representations in human visual cor- tex is evident when inspecting such retinotopic maps (Fig. 6.1). A variety of visualization methods have been developed in the last 25 years that computationally separate the grey and white matter, and o en make responses from sulcal regions visible by compu- tationally ‘in ating’ or ‘ attening’ representations of the cortical surface (see Fig. 6.4). By examining the activations produced by retinotopic mapping using functional MRI on such surface rep- resentations, the topographic relationship between visual eld stimulation and the locations that respond on the cortical surface becomes apparent. In particular, examining the angle (phase) com- ponent of retinotopic maps reveals a stripey pattern on the med- ial occipital cortex whereby representations of the horizontal and vertical meridians are arranged in parallel stripes on the cortical surface (Fig. 6.1 right-hand panel). ese alternating bands corres- pond to the borders between what are now known to be multiple retinotopic maps whose representations lie alongside each other in the occipital lobe.

A complementary organizational principle is revealed when examining the eccentricity map, where stripes at right angles to the angle (phase) map show that there is a gradient of representations of eccentricity (Fig. 6.1 le -hand panel), with more central regions of the visual eld being represented more posteriorly in the retino- topic map and more peripheral regions anteriorly.

Organization of retinotopic maps

in human early visual cortex

is organization of the early visual cortex has now been repeat- edly con rmed and is summarized in Fig. 6.2 (also see Fig. 6.6). A complete representation of the visual eld is contained within the primary visual cortex or V1, which is consistently located in the depths of the calcarine sulcus extending superiorly and anteriorly onto the medial surface of the occipital lobe, and posteriorly to the occipital pole. Its boundaries superiorly and inferiorly are repre- sentations of the vertical meridian; the lower vertical meridian lies superiorly and represents the boundary between V1 and dorsal V2. Inferiorly the upper vertical meridian lies between V1 and ventral V2. V2 therefore contains a complete representation of the contra- lateral visual eld, but split between an anatomically dorsal portion (representing the contralateral lower visual quadrant) and a ven- tral portion (representing the contralateral upper visual quadrant). Similarly V3 is also split into dorsal and ventral portions, so V1–V3 form a concentric arrangement in occipital cortex.

is organization elegantly complements and accounts for previ- ous clinical observations and deductions of cortical anatomy from those observations. For example, the split representation of V2 and V3 can account for the clinical observation that homonymous quadrantic eld defects arising from cortical lesions can have sharp horizontal edges. Although it was thought initially that such eld defects might arise from lesions to primary visual cortex in the cal- carine sulcus, this appeared inconsistent with the o en irregular

Fig. 6.2 Topography of human primary visual cortex and surrounding areas. e functional anatomy of early visual areas is overlaid on an anatomical MRI image from a single participant for right and left hemispheres respectively. Panels (a) and (b) show occipital cortex from right and left hemispheres; panels (c) and (d) present the same data in a cortically ‘in ated’ view and from a posterior vantage point. Human brain areas revealed by retinotopic mapping are displayed in false (blue/yellow) colour and labelled. A concentric arrangement of V1, V2, and V3 is apparent.

Reproduced from Proc Natl Acad Sci USA. 95(3), Tootell RBH, Hadjikhani NK, Vandu ell W, et al. Functional analysis of primary visual cortex (V1) in humans, pp. 811–17, Copyright (1998), with permission from PNAS.

borders of cortical lesions because the representation of the hori- zontal meridian runs along the depths of the calcarine sulcus, and in order to produce a sharp edge to the eld defect the lesion would need to run exactly along such a boundary. But the split representa- tion of V2/V3 provides an elegant answer to this conundrum, as proposed by Horton and Hoyt.9 Speci cally, even if a lesion has irregular boundaries, if it is located in V2/3 and crosses the bound- ary of the horizontal meridian between V3 and V2 or V2 and V1, then it will produce a quadrantic eld defect because of the split representation of the upper and lower visual elds in V2 and V3. us the retinotopic organization of early human visual cortices has localizing power for clinical practice.

Damage to the early visual cortex generally results in a visual eld defect. Profound bilateral cortical damage such as that caused by bilateral cerebral infarction in the territory of the posterior cerebral arteries can also cause Anton’s syndrome, albeit rarely.10 Patients with Anton’s syndrome have no functional vision and sometimes cannot even distinguish light and dark; they have normal pupil- lary responses to light. However, despite being profoundly corti- cally blind, strikingly they deny having any visual di culty. Anton’s syndrome is therefore an anosognosia. A variety of explanations have been advanced but without a clear consensus on the underly- ing mechanisms.11 Typically the cortical damage associated with Anton’s syndrome involves early (retinotopic) visual cortices bilat- erally. However, the syndrome has also been described following bilateral optic nerve damage and frontal contusions,12 so can also be caused by peripheral lesions to the early visual system.

Retinotopic mapping has further revealed a multiplicity of visual maps in humans, extending throughout occipital cortex. In con- trast to the V1—V3 retinotopic maps, the precise number, extent, and organization of such maps remains a topic of debate (see ref- erence13 for a review). ese may include areas known as hV4, VO-1, and VO-2 on the ventral occipital surface next to the ven- tral portion of V3; maps that have been labelled LO-1, LO-2, TO-1, and TO-2 on the lateral occipital surface that are coextensive with object-selective cortices discussed below; and V3A/V3B on the dorsal surface plus further maps running into parietal cortex (see reference 14 for a review).

Technically these maps are o en much smaller and their responses harder to measure, so their precise functional properties and exact characterization remain o en controversial. Nevertheless, the sheer multiplicity of maps in the human occipital lobe suggests that they must be important for visual processing, but a demonstration that such a topographic organization is critical for normal visual func- tion remains elusive. Clinically, neurodevelopmental disorders that massively disrupt topographic visual eld maps such as albinism15 or failure of development of the optic chasm (see e.g. reference 16) have relatively little e ect on spatial vision. Finally, position in the visual eld is not the only feature that is mapped on the cortical surface. Consistent with observations in monkeys, it appears that ocular dominance and orientation17 can be mapped on the occipi- tal cortical surface though the spatial scale of such mapping is suf- ciently ne that measurement with contemporary neuroimaging remains challenging.

CHAPTER 6 the occipital lobes 61

(a) (b)

62 SECTION 1 normal cognitive function

Functional segregation in the human

occipital lobe

Alongside the use of non-invasive brain imaging to delineate spatial maps in the occipital lobe has come parallel investigation of whether di erent areas of the occipital lobe respond di er- entially to the many features that make up a visual scene. Early clinical investigators such as Holmes’ suggested that selective disturbances of motion perception could not be distinguished from more general disorders of the perception of objects and that purely cortical lesions did not cause loss of colour vision.18 Subsequent clinical observations showed that selective distur- bances of colour19 and motion20 could result from focal damage to the occipital lobe.

In humans, these observations following brain damage were complemented by pioneering work using positron emission tomog- raphy to visualize changes in blood ow associated with neural activity during perception of di erent visual features (Fig. 6.3). is demonstrated an area of extrastriate cortex on the lateral surface of the occipital lobe close to the boundary with the temporal lobe that responded more strongly to moving than stationary stimuli.21 is area is now known as V5/MT, re ecting its apparent homol- ogy with similar motion-responsive regions in monkey. A second region on the ventral surface of the occipital lobe responded more to coloured patterns than to matched grayscale patterns, consid- ered to be consistent with a colour-responsive region in monkey cortex known as area V4.22

ese early observations demonstrated the principle of func- tional specialization in the extrastriate visual cortex; di erent cortical regions process di erent aspects of the visual scene. Such functionally specialized areas, when damaged, give rise to corre- sponding clinical de cits in, for example, colour or motion per- ception. Further investigation has revealed that some of these functionally specialized regions also contain spatial maps. For example, the colour-responsive region in the ventral visual cortex has retinotopic organization23 although the precise nature of that organization has remained a topic of vigorous debate. Similarly the

motion-responsive region V5/MT, although smaller, also appears to contain visual eld maps (e.g. see reference 24).

Functional specialization is not restricted to simple features of visual scenes such as colour and motion, and subsequent investiga- tion has revealed specialization for the categories of visual objects (see reference 25 for a review and Fig. 6.4 for a summary). Anterior and lateral to early retinotopic cortices lie areas that respond more strongly when healthy humans view pictures of objects compared to scrambled objects or textures.26 Such object-selective areas are particularly centred in lateral occipital cortex (LOC) where a large area demonstrates relatively non-speci c responses to all types of objects. Damage focused on this region, such as that seen in patient DF,27 can be associated with visual agnosia. Also, close to area V5/ MT is a cortical region whose responses show selectivity for visu- ally presented body parts.28 is ‘extrastriate body area’ appears to play a causal role in perceiving people in real-world scenes, as transient inactivation of the area with transcranial magnetic stim- ulation causes impairments in tasks that require identi cation of people (compared to cars) in visually presented scenes.29

In contrast, more ventrally in occipital (and occipito-temporal) cortex lie regions that appear to be selective for particularly types of object such as faces30 or houses and scenes of particular places. Similarly, damage to this region is associated with di culties in discriminating the spatial con guration of di erent elements of a face,32 as well as the association of prosopagnosia with more medial temporo-occipital lesions close to regions also showing face-selective responses. ere are also more dorsal object-selective regions along the transverse occipital sulcus thought to be involved in the context of grasping and object manipulation whose func- tional role is less well understood (e.g. see reference 33). Selectivity of this kind for visual responses appears to be remarkably robust. Even following bilateral destruction of primary visual cortices (and accompanying cortical blindness), some measure of selec- tive responses to faces and body parts remains in di erent cortical regions.34 is indicates that the inputs from which such selectivity derive come not just from early retinotopic visual cortices but also from subcortical pathways.

(a)

(b)

Sagittal

Transverse

Sagittal Coronal

vs.

Fig. 6.3 Functional specialization. Responses to moving and coloured stimuli, relative to control stimuli that lack motion or colour, produce distinct spatial patterns of activation in occipital cortex. (a) Activity in the brain measured using PET when participants view a coloured Mondrian (inset) compared to a grey Mondrian is seen on the left ventral occipital surface. Activated regions are projected onto a ‘glass brain’ in sagittal, coronal, and tranverse sections. (b) Similar plotting conventions are used to display regions in lateral occipital cortex that respond more strongly when participants view moving random dots compared to static dots. Note that earlier visual cortical areas (see Fig. 6.2) are not activated in these comparisons because they respond roughly equally to both moving and static dots, thus indicating the selectivity of visual areas later in the anatomical hierarchy.

Adapted from J Neurosci. 11(3), Zeki S, Watson JD, Lueck CJ, et al. A direct demonstration of functional specialization in human visual cortex, pp. 641–9, Copyright (1991), with permission from the Society for Neuroscience.

Coronal

vs.

Transverse

ventral

Fig. 6.4 Object-selective areas in the human occipital lobe. is gure summarizes a number of di erent studies that have used functional MRI to describe di erent areas in human occipital cortex and adjoining areas that respond selectively to di erent types of objects. e colour code indicates the type of object that an area responds to and the colours are overlaid on either computationally ‘in ated’ lateral or ventral views of the left hemisphere, or a left hemisphere that has been computationally ‘cut’ and ‘ attened’. e early visual areas V1–V3 (see Fig. 6.2 and text) are not selective for particular objects or object classes, but the lateral occipital (LO) area is selective for objects, the fusiform face area (FFA) for faces, and the parahippocampal place area (PPA) for places. Reproduced from Annu Rev Neurosci. 27, Grill-Spector K and Malach R, e human visual cortex, pp. 649–77, Copyright (2004), with permission from Annual Reviews.

Organizational principles of occipital cortex

We have already seen that there are two dominant features of the functional organization of the occipital cortex in humans that correspond to clinical observations following occipital damage. e rst is functional specialization; di erent areas process di er- ent aspects of the visual scene, and so focal cortical damage can produce remarkably speci c de cits in visual perception as well as more general disorders of object vision such as agnosia. e sec- ond is that most occipital regions contain a multiplicity of topo- graphic maps of the visual eld, and even functionally specialized regions are o en also topographically mapped. us focal damage, particular to early cortical regions V1–V3, produces visual de cits that are mapped to the corresponding region of the visual eld, but are there any more general organizing principles that govern the relationship between all these visual eld maps and functionally specialized areas?

e patterns of anatomical connectivity between di erent regions have been proposed as one way to uncover organizational principles, in particular distinguishing between feed-forward and feed-back connections established through anatomical bre trac- ing in monkeys. is suggested a hierarchical organization of visual cortex based on anatomy (see reference 35; Fig. 6.5). One

lateral

in uential framework proposes that visual cortical areas within this anatomical hierarchy are segregated into dorsal and ventral process- ing streams.36

Ungerleider and Mishkin observed that lesions to inferotempo- ral cortex in monkey led to de cits in their ability to distinguish between di erent visual objects on the basis of their appearance, but did not a ect their performance on a task that required knowl- edge only of the spatial locations of di erent objects. Conversely, posterior parietal cortex lesions produced de cits in tasks requir- ing knowledge of spatial relations but not on visual discrimination tasks. ey thus proposed that the anatomical distinction between dorsal and ventral streams is mirrored in a simple distinction between spatial and object vision—‘where’ and ‘what’ respectively (Fig. 6.6).

e simple distinction that Ungerleider and Mishkin made between ‘what’ and ‘where’ has become progressively more com- plicated as clinical syndromes have been more fully considered. For example, damage to the human parietal cortex can lead to optic ataxia where patients have di culty reaching and grasping objects placed in the contralateral visual eld. However, such patients also have di culties with aspects of vision less obviously spatial, such as the size and shape of objects they are able to grasp correctly.37 is, and other observations, has led to proposals38 that the functional distinction between dorsal and ventral streams may re ect a sub- tler distinction between a system that uses visual information for skilled action (‘vision for action’—the dorsal stream) and ‘vision- for-perception’ (ventral stream). More broadly, it is recognized that even with such functional distinctions, coordinated and goal- directed action requires the integrated operation of both streams.

Such schemes have proven very useful heuristically in terms of understanding and integrating a large amount of neuroscien- ti c data on the occipital lobe, but in isolation they cannot always tell the whole story. For example, while an anatomical hierarchy is apparent,35 it is equally clear that signals from the retina reach di erent points in the anatomical hierarchy and at di erent times, which do not always correspond.39 us some areas ‘higher’ in the proposed anatomical hierarchy might receive signals earlier than other areas apparently ‘lower’ in the hierarchy. In the context of a highly dynamic system where signals associated with visual per- ception pass backwards and forwards,40 the idea of a simple linear progression of stages of the analysis of a visual scene is likely to be an oversimpli cation.

Comparisons between humans

and other species

e existence of visually responsive areas in the occipital lobe of non-human primates has been known for over a century,1 and pio- neering work using single unit electrophysiology (see e.g. reference 41) delineated many of the principles of functional specialization at the level of single neurons that have subsequently been elaborated and elucidated using functional imaging techniques in humans. Combining electrophysiology with other tools including cytoarchi- tectural and anatomical connectivity analyses has led to the parcel- lation of extra striate cortex in non-human primate into a number of di erent visual areas. More recently it has been possible to use functional MRI (fMRI) methods in both humans and non-human primates to compare the organization of visual maps (see e.g. ref- erence 42) and functionally specialized regions (e.g. reference 43).

CHAPTER 6 the occipital lobes 63

Objects, place, & faces Faces & objects Places & objects Objects Faces Places

64 SECTION 1

normal cognitive function

7b VIP

FEF

STPa STPp

FST

AITd CITd PITd

AITv CITv PITv

LIP DP

MSTd

MSTI

HC ER

36 46 TF TH

MDP MIP PO MT V4t V4

PIP

V3A

VP M V2 P-B P-I

M V1 P-B P-I
M P LGN

RGC

Fig. 6.5 Possible organizational principles. is proposed ‘circuit diagram’ from Felleman and Van Essen illustrates how 32 di erent cortical areas responding to visual stimulation in the macaque are connected anatomically, and sets out a proposed hierarchy of areas.
Reproduced from Cereb Cortex. 1(1), Felleman DJ and Van Essen DC, Distributed hierarchical processing in the primate cerebral cortex, pp. 1–47, Copyright (1991), with permission from Oxford University Press.

While there are strong similarities across species, it has also become increasingly apparent that there are important di erences. For example, topographic maps in humans are substantially larger than in macaque; and homology of areas beyond V1–V3 and V5/MT is signi cantly more di cult to establish with clarity.

Cytoarchitecture of human occipital cortex

is chapter has focused on relatively macroscopic measurements of occipital lobe structure and function, and how they correspond to clinicopathological syndromes following brain damage. However, it has also been known for over a century that the detailed histo- logical structure—the cytoarchitecture and myeloarchitecture—of the human brain di ers across the cortical surface. is led to the publication of classic cytoarchitectonic maps of the human cerebral cortex (e.g. reference 44), and in particular the distinction between striate and extra striate cortex touched upon above. More recently there has been substantial progress in the computerized image

analysis of histological specimens and the introduction of markers that re ect di erent architectonic aspects of cortical organization (such as receptor autoradiography). Together with developments in image analysis techniques that allow for inter-subject variabil- ity in macroscopic anatomy, this has enabled new insights into the detailed structure of human visual cortex.45 For example, probabil- istic cytoarchitectonic maps are now available of occipital cortex.46 Signals obtained from structural MRI sequences, including high- resolution MRI, re ect the myeloarchitecture and cytoarchitecture found in histological sections (e.g. reference 47) which has led to renewed interest in using structural MRI to identify speci c regions of human visual cortex such as V5/MT (e.g. reference 48).

Individual variability in human occipital

cortex anatomy

Most investigations of the occipital lobe focus on the common- alities in structure and function across individuals and how these

VOT

(a)

CHAPTER 6 the occipital lobes 65

Posterior Parietal Cortex

Pulv

Retina

Primary Visual Cortex

LGNd

Fig. 6.6 Schematic illustration of how visual signals from the retina reach dorsal and ventral processing streams. e dorsal and ventral pathways are schematically illustrated on an outline of a macaque monkey brain, but the organizational principles are broadly consistent in humans. e broad functional distinction between dorsal and ventral streams may re ect the use of visual information for action (dorsal stream) or perception (ventral stream) but goal-directed action usually requires the coordinated action of both streams.

Reproduced from Goodale M and Milner D, e Visual Brain in Action, Copyright (1995), with permission from Oxford University Press.

di er following brain damage, but it has long been noted informally that the precise sulcal and gyral anatomy can vary somewhat across individuals [e.g. Fig. 6.7]. For example, while there are regularities, such as the position of the calcarine sulcus running anteriorly from the occipital pole, the precise direction and shape of the sulcus var- ies across individuals (e.g. reference 49). Similarly, at a histologi- cal level, the architectonic features that delineate striate (primary) visual cortex extend for a variable distance above and below the calcarine sulcus, presumably accounting for the variability that can be observed macroscopically in non-invasive estimates of the spa- tial extent of primary visual cortex [Fig. 6.7].

Indeed, in normal human subjects the range of interindividual variation in V1 area is approximately threefold.50 Importantly, this variability in V1 area in humans is correlated with the cross- sectional area of the optic tract and the volumes of the magno- cellular and parvoceullar layers of the lateral geniculate nucleus (reference 51; Fig. 6.7). is coordinated variation indicates that development of the di erent parts of the human visual system are interdependent. Notably, the range of variability in the size of these visual system components is substantially greater than the variabil- ity of the overall size of the human brain, which is about 30 per cent.52 It has been suggested that such coordinated variation in size might be associated with di erences in visual ability across indi- viduals, and this has recently become the focus of renewed investi- gation (see reference 53 for a review).

One recent investigation studied how variability in cortical mag- ni cation and overall size of V1 was related to ne visual acuity. Individuals with a larger overall cortical area in V1 had lower over- all Vernier acuity thresholds; they were able to make ner percep- tual judgements.54 is relationship between objective measures of visual perception and individual di erences in visual cortex size extends also to the subjective qualities of visual perception. Although it is di cult to compare the subjective visual experi- ences of di erent people directly, inter-individual di erences in the perceived strength of a perceptual illusion—whereby physically

160 150

140 130

120 110 100

(b) RFD

S P

2000
2500

AAB

11 10

9 8

7 6

Infero- temporal Cortex

3000

Fig. 6.7 Individual variability. (a) Each point represents data from a single post- mortem human. ere is correlated variability in the surface area of the primary visual cortex (V1), the volume of the lateral geniculate nucleus and the surface area of the optic tract. Note the variation of almost twofold in the surface area of primary visual cortex across individuals. (b) ree example right hemispheres in which the central 2–12 degrees of the visual eld representation in V1–V3 have been mapped. While in each individual the macroscopic concentric organization of V1–V3 demonstrated in Fig. 6.2 is apparent, there is also substantial individual variability in the surface area of V1 (magenta), V2 (cyan), and V3 (red).

(a) Reproduced from J Neurosci. 17(8), Andrews TJ et al. Correlated size variations in human visual cortex, lateral geniculate nucleus, and optic tract, pp. 2859–68, Copyright (1997), with permission from the Society for Neuroscience. (b) Reproduced from J Vision. 3(10), Dougherty et al. Visual eld representations and locations of visual areas V1/2/3 in human visual cortex, pp. 586–98, Copyright (2003), with permission from the Association for Research in Vision and Ophthalmology.

identical stimuli produce perceptually different appearances depending on their local context—can be quantitatively compared. In a study that compared individuals’ susceptibility to geometri- cal visual illusions (the Ponzo and Ebbinghaus illusions), just such variability in illusion strength was found.55 Moreover, the strength of the illusion correlated negatively with the size of early retinotopic visual area V1, but not visual area V2 and visual area V3.

Summary

e fundamental organization and the macroscopic anatomy that gives rise to clinicopathological correlations between brain damage and visual behaviour have been known in outline for over a cen- tury. However, recent advances in brain imaging technology and the ability to integrate information from many di erent sources has led to dramatic advances in our understanding of the relationship

3500

ARW

1cm

Dorsal Stream

LGN volume (mm3)

Ventral Stream

Optic Tract (mm2)

VI area (mm2)

66 SECTION 1 normal cognitive function

between structure and function in the human visual system. is in turn clari es the anatomical basis for many clinical syndromes but also lays the foundation for a mechanistic understanding of the relationship between structure, function, and the e ects of damage to the human visual system.

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2. Henschen S. Klinische und Anatomische Beiträge zur Pathologie des Gehirns (Pt 1). Almquist & Wiksell, Upsala, 1890.

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9. Horton JC and Hoyt WF. Quadrantic visual eld defects. A hallmark of lesions in extrastriate (V2/V3) cortex. Brain. 1991;114 (Pt 4):1703–18.

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19. Meadows JC. Disturbed perception of colours associated with localised cerebral lesions. Brain. 1974;97:615–32.

20. Zihl J, von Cramon D, and Mai N. Selective disturbance of movement vision a er bilateral brain damage. Brain. 1983;106:313–40.

21. Lueck CJ, Zeki S, Friston KJ, et al. e colour centre in the cerebral cortex of man. Nature. 1989;340(6232):386:3863.

22. Zeki SM, Watson JD, Lueck CJ, et al. A direct demonstration of functional specialization in human visual cortex. J Neurosci. 1991;11(3):641–9.

23. McKeefry DJ and Zeki S. e position and topography of the human colour centre as revealed by functional magnetic resonance imaging. Brain. 1997;120(12): 2229–42.

24. Amano K, Wandell BA, and Dumoulin SO. Visual eld maps, popula- tion receptive eld sizes, and visual eld coverage in the human MT+ complex. J Neurophysiol. 2009;102(5):2704–18.

25. Grill-Spector K and Malach R. e human visual cortex. Annu Rev Neurosci. 2004;27:649–77.

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area: A module in human extrastriate cortex specialized for face percep- tion. J Neurosci. 1997 Jun 1;17(11):4302–11.

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36. Ungerleider LG and Mishkin M. Two Cortical Visual Systems. In: MA Goodale and AD Milner (eds). e Analysis of Visual Behavior. Cambridge: Cambridge University Pess, 1982, pp. 549–86.

37. Perenin M -T and Vighetto A. Optic ataxia: A speci c disruption in visuomotor mechanisms. 1. Di erent aspects of the de cit in reaching for objects. Brain. 1988;111:643–74.

38. Goodale MA and Milner AD. Separate visual pathways for perception and action. Trends Neurosci. 1992;15(1):20–5.

39. Schmolesky MT, Wang Y, Hanes DP, et al. Signal timing Across the Macaque Visual System. J Neurophysiol. 1988;79:3272–8.

40. Lamme VAF and Roelfsema PR. e distinct modes of vision o ered by feed-forward and recurrent progressing. Trends Neurosci. 2000;23(11):571–9.

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CHAPTER 6 the occipital lobes 67

CHAPTER 7

e basal ganglia
in cognitive disorders James Rowe and Timothy Rittman

Introduction

e basal ganglia are a vital set of forebrain nuclei, richly connected with the cortex, thalamus, and brainstem. As one of the oldest parts of the brain in evolutionary terms, it is not surprising that neuro- logical disease a ecting the basal ganglia has severe consequences for behaviour and cognition. In this chapter, we review the princi- ples underlying the anatomy and connectivity of the basal ganglia because they illuminate the myriad clinical features of basal ganglia dysfunction across a broad range of disorders.

omas Willis is credited with the rst description of the ‘cor- pora striata’ in 1664, correctly identifying their role in movement but also suggesting they receive sensory information. A century ago, Kinnier Wilson suggested that the basal ganglia were mainly concerned with inhibiting signals from the motor cortex.1 Further work suggested the basal ganglia act as a ‘funnel’ for messages from motor association cortex, integrating information for delivery via the ventrolateral thalamus to motor cortex.2 e idea that the basal ganglia were primarily concerned with motor function remained largely unchallenged until the 1980s. is motor chauvinism was reinforced by the false impression that signi cant cognitive impair- ment was uncommon in Parkinson’s disease, whereas it is now rec- ognized as a common and early feature of the disease.3

e basal ganglia are central to the understanding and treat- ment of many cognitive disorders, some of which are associated with movement disorders (e.g. akinetic rigidity, tremor, dystonia, and chorea). e separation of cognitive and movement disorders is arti cial but still common in didactic teaching of neurology and neuroscience, contrary to the clinical evidence and functional anatomy of the basal ganglia. For example, dementias such as frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB) are o en associated with extrapyramidal motor dysfunc- tion, and many diseases cause a syndrome in which cognitive and motor de cits have similar weighting, such as Huntington’s disease (HD), progressive supranuclear palsy (PSP), corticobasal degen- eration (CBD), neurodegeneration with brain iron accumulation, paediatric autoimmune neurological disorders associated with streptococci and encephalitis lethargica. Psychiatric disorders of addiction, obsessive–compulsive disorders and impulsivity are also associated with basal ganglia dysfunction and cognitive abnormali- ties, but lie outside the scope of this chapter.

e diversity of clinical disorders and cognitive functions associ- ated with the basal ganglia re ects their unique functional anatomy and neurochemistry. We will rst review the normal gross anatomy

of the basal ganglia, and examine how this supports both integra- tion and segregation of cognitive processes. We then consider the neurochemical organization and connectivity of the basal ganglia. Finally, we show how the basal ganglia contribute to cognitive dis- orders, revealed by neuropsychology, and structural and functional brain imaging.

Macroscopic anatomy

e macroscopic organization of the basal ganglia is intimately con- nected with that of the cortex and thalamus. e principal input nucleus is the striatum, comprising the caudate and putamen (see Fig. 7.1), but the subthalamic nucleus also receives direct cortical inputs. e striatum projects to the globus palludus (also called the pallidum) which has two parts: internal and external. e substan- tia nigra and the subthalamic nuclei are smaller but critical nuclei in the basal ganglia complex. e inputs, connections, and outputs of these basal ganglia nuclei are arranged in a series of cortico- striato-thalamo-cortical loops, with gross structural homologies (Fig. 7.2). Studies injecting tracers, for example in premotor regions, rst suggested a cognitive role for the basal ganglia by revealing connections from the pallidum via the thalamus to premotor cor- tex.4,5 ese connections were reciprocal, in a closed-loop system that could facilitate feedback from the basal ganglia to association cortex.6 Further closed-loop systems were identi ed, suggestive of distinct motor, oculomotor, cognitive, and limbic functions.

At rst glance, these loops suggest separate parallel processing of information by subdomains of the basal ganglia (Fig. 7.2). For example, the ventral striatum receives input from the orbital and medial prefrontal cortex and anterior cingulate. is loop is closely associated with reward, motivation, and reinforcement in a lim- bic system, with the clinical counterparts of apathy, learning de – cits, addiction, and cognitive in exibility. In contrast, the central regions of the striatum receive their main input from dorsolateral prefrontal cortex, forming a loop that has been linked to associative and executive functions underlying adaptive behaviours (e.g. plan- ning, set-shi ing, and working memory). Topographical mapping in the caudate preserves the di erences between projections from, for example, dorsolateral cortical prefrontal areas 9, 46, and sup- plementary eye elds. e dorsal components form a further loop with inputs from premotor and motor cortex, and are most closely associated with motor control and action selection. e early dys- executive syndrome in Parkinson’s disease3,7 is likely to re ect dys- function of this associative (cognitive) loop.

70 SECTION 1 normal cognitive function

Fig. 7.1 e top left panel illustrates the relative size and position of the principal basal ganglia in the rat, connecting cortex via the striatum to the globus pallidus (with external part, Gpe, and internal part, GPi), subthalamic nucleus (STN), and substantia nigra pars reticulata (SNpr) and thalamus (T). Dopaminergic innervation of the striatum is from the ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc). e other three panels illustrate the equivalent structures in an adult human brain on a structural magnetic resonance image in axial, saggital, and coronal sections and distinguishing the caudate (C) and putamen (P) that make up the striatum.

Human structural and functional neuroimaging con rms this functional anatomy. For example, di usion-weighted magnetic resonance imaging (MRI) with tractography identi es the major corticostriatal pathways,8 with limbic, associative, and motor pathways between cortex, striatum, and substantia nigra (and the adjacent ventral tegmental area of dopaminergic neurons). In addi- tion, meta-analysis of PET imaging identi es analogous functional loops.9 More recently, detailed analysis for the functional connec- tivity patterns of individual basal ganglia structures has been pos- sible using seed-based connectivity in functional MRI scans.10

Despite the apparent parallel organization of these loops, they are not wholly segregated. Indeed, it is a priori necessary for limbic, associative, and motor systems to interact to enable goal-directed behaviours that develop or adapt appropriate responses, essential for tasks such as rule learning.

A revised model of basal ganglia function has been developed that proposes multiple mechanisms of interaction (Fig. 7.3). First, the axonal projections from cortex to the striatum can cross between limbic and associative areas, or between associative and motor areas, facilitating cross-talk between systems. us, the general topogra- phy outlined above has so boundaries. In addition, adjacent corti- cal areas project on to smaller and partially overlapping basal ganglia regions so that there is approximately a ten-to-one reduction in the

number of neurons receiving input in the basal ganglia. e onward projections back to the cortex terminate in wide terminal elds sug- gesting important processing and integration of information as it ows through the basal ganglia. Finally, the reciprocal connections between basal ganglia structures are not symmetric.11 is asymme- try promotes a directional ow from limbic to associative to motor regions. Together, these mechanisms enable both segregation and integration of cognitive, motor, sensory, and a ective information as it passes through the basal ganglia.

Connectivity within the basal

ganglia: Direct and indirect pathways

Medium spiny neurons predominate in the striatum, making up 95 per cent of rat striatal neurons.12 ey receive the bulk of gluta- matergic cortical inputs, and are the main striatal output cell, with GABAergic projections. Medium spiny neurons are densely den- dritic, synapsing with other medium spiny neurons and interneu- rons within the striatum to create a complex internal structure. ere is considerable plasticity within this densely connected network, arising from spike-timing-dependent processes that are dependent on glutamatergic NMDA receptors and the presence of dopamine receptor activation.13

Generic pattern

Cortex

Striatum

Pallidum/ nigra

alamic nuclei

Motor

SMA

Putamen

Vl-Gpi cl-SNr

VLo VLm

Oculomotor

FEF

Caudate

cdm-Gpi vl-SNr

L-VA MD

Cognitive (associative)

DLPFC

Dorsal Caudate

Idm-Gpi rlSNr

VA MD

Limbic (o)

OFC

Ventromedial Caudate

mdm-Gpi rm-SNr

VAmc MDmc

Limbic (a)

ACC

Ventral Striatum

rl-Gpi rd-SNr

pmMD

CHAPTER 7 the basal ganglia in cognitive disorders 71

Fig. 7.2 e cortico-striato-thalamo-cortical loops follow a generic pattern (left), which is mirrored in parallel motor, oculomotor, cognitive, and limbic circuits.4 Functional di erences are related to the speci c subregions of cortex, striatum, pallidum, nigra, and thalamus. Note that this model of basal ganglia connectivity emphasizes segregated information processing within each of the parallel loops. SMA, supplementary motor area; FEF, frontal eye elds; DLPFC, dorsolateral prefrontal cortex; OFC, orbitofrontal cortex; ACC, anterior cingulate cortex; Gpi, globus pallidus internal; SNr, substantia nigra pars reticulata; and thalamic nuclei including ventrolateral, VL, ventral anterior, VA, mediodorsal, MD.

Reproduced from Prog Brain Res., 85, Alexander GE, Crutcher MD, DeLong MR, Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, ‘prefrontal’ and ‘limbic’ functions, pp. 119–46, Copyright (1991), with permission from Elsevier.

e striatum is the main receiving centre of the basal ganglia, but it has complex projections to other parts of the basal ganglia, and on to thalamus and cortex. e ‘dual circuit’ model (also called the ‘rate’ model, or ‘Albin DeLong’ model: see Fig. 7.4) has been highly in uential in clinical and pre-clinical analyses of basal ganglia function since the early 1990s. In this model, GABAergic outputs from the striatum form two main pathways which are associated with two types of dopaminergic neurones.

e direct pathway contains medium spiny neurons with pre- dominant dopamine D1 receptors, which in response to gluta- matergic cortical inputs and dopaminergic inputs from substantia nigra pars compacta (or ventral tegmental area, VTA) send inhibi- tory GABAergic projections directly to the globus pallidus interna and substantia nigra pars reticulata, which in turn send inhibitory connections to the thalamus.

e indirect pathway’s medium spiny neurons have dopamine D2 receptors and send inhibitory projections to the globus pallidum externa, with onward inhibitory projections to the subthalamic nucleus. e subthalamic nucleus’ projections to the globus palli- dus interna and substantia nigra are excitatory. e result is antago- nism between the direct and indirect pathways. In the motor loop, the direct pathway promotes movement and the indirect pathway inhibits movement, with analogous regulation of cognitive tasks in the cognitive (associative) loop and reward or punishment tasks in the limbic (a ective) loop.

is dual-circuit model explains many experimental ndings and clinical phenomena. For example, stimulation of D2 receptors preferentially expressed in the indirect pathway enhances activ- ity in the external segment of the globus pallidus, inducing a net decrease in basal ganglia output. Conversely, loss of dopamine increases inhibitory output of the basal ganglia, and inhibition of thalamocortical activity. However, new anatomical, transgenic,

and optogenetic investigations suggest a much more complex set of interactions within and even between the direct and indirect pathways (Fig. 7.4). It becomes once again much more di cult to predict the input–output function of the system. Moreover, recent evidence suggests coordination through transient co-activation of the direct and indirect pathways, rather than simple antagonism,14 with heteromeric D1–D2 receptors and at best partial separation of D1 and D2 striatal projections to internal and external segments of the globus pallidus.15 Nonetheless, the dual-circuit model remains a useful starting point for understanding the functional anatomy of the basal ganglia and the cognitive consequences of basal ganglia disorders.

Dopaminergic neurons of the substantia nigra and VTA project to the striatum and pallidum. e ring rate of these dopaminergic cells is not uniform: their background ‘tonic’ ring rate is supple- mented by brief ‘phasic’ bursts of ring. e phasic dopaminergic signal is critical for cognitive function as it signals a prediction error in the brain. For example, animal studies show that an unex- pected reward leads to phasic activity in dopaminergic projections to the striatum which gradually diminishes if the animal can learn to predict the reward.16 Phasic reductions of ring can also occur if, for example, an expected reward is omitted or delayed. is dopa- minergic signal is fundamental to learning, memory, the control of attention, and switching between behavioural strategies in response to environmental or internal feedback. Tonic ring rates a ect the signal-to-noise for phasic ring: pharmacological enhancement of tonic dopaminergic ring might therefore paradoxically attenuate the behavioural bene ts of dopamine dependent phasic rewards (reduced signal-to-noise) or phasic punishments.17

An interesting corollary of phasic dopaminergic responses is that they may contribute to the sense of agency (the sense that we control our own actions) which is a ected by many neurological diseases.18

72 SECTION 1 normal cognitive function

Fig. 7.3 Cortico-striatal and striato-nigral projections are not entirely parallel or fully segregated, but instead introduce cross-talk between a ective, cognitive, and motor pathways. Striato-nigral projections illustrated here broadly follow a rostrocaudal gradient according to function (red = limbic, green = associative, blue = motor). As part of an a ective loop, the accumbens shell (S) receives input from the amygdala, hippocampus, and orbitofrontal cortex; the accumbens core receives input from orbitomedial prefrontal cortex (OMPFC); as part of the cognitive loop, the dorsolateral prefrontal cortex (DLPFC) projects to the central striatum while as part of the motor loop premotor and motor cortex project to the dorsolateral striatum. Midbrain projections from the shell target both the ventral tegmental area (VTA) and ventromedial SNc (inset, red arrows). Midbrain projections from the VTA to the shell form a ‘closed’, loop (red arrow). Projections from the medial substantia nigra project to the core to form the rst part of a spiral (orange arrow). e spiral of connectivity continues through the adjacent loops, illustrated by the yellow, green,

and blue arrows. e magni ed inset oval region shows the synaptic interactions in reciprocal loops: the reciprocal component terminates directly on a dopamine cell, resulting in inhibition, while the feedforward component terminates indirectly on a dopamine cell via a GABAergic interneuron (brown). is leads to disinhibition and facilitation of dopaminergic cell burst ring. IC, internal capsule; SNc, substantia nigra, pars compacta; SNr, substantia nigra, pars reticulata.
Reproduced from J Neurosci., 20(6), Haber SN, Fudge JL, McFarland NR, Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum, pp. 2369–82, Copyright (2000), with permission from the Society for Neuroscience.

Whether a sensory event is perceived as being casued by one’s own action as the ‘agent’ or perceived as externally caused depends on the harmony or discrepancy between sensory information and the sensory predictions made from precise internal models of the consequences of one’s own actions.19,20 Dopaminergic drugs and basal ganglia disorders such as Parkinson’s disease and corticobasal degeneration a ect the sense of agency, for example with alien limb phenomena.21,22 Before reviewing the e ects of such neurodegen- erative disorders in detail, we turn next to the neuropsychological consequences of focal lesions to the basal ganglia.

Lesions of the basal ganglia

Ischaemic strokes, haemorrhage, tumours, and focal necrotic, met- abolic, or immunological responses can lead to selective damage of basal ganglia nuclei, unilaterally or bilaterally. Motor syndromes

have been widely described, such as hemiballismus a er subtha- lamic nucleus stroke, and hemidystonia or hemi-parkinsonism a er striatal lesions. However, cognitive syndromes and personal- ity change are under-recognized in clinical practice. Many patients with basal ganglia lesions have signi cant and long-lasting cogni- tive change.23

e cognitive and behavioural e ects of basal ganglia lesions should not be seen as mere disconnection of the cortical regions from which they receive a erents. Although there are o en marked similarities between the e ect of a cortical lesion and lesion of the part of the basal ganglia to which it projects, the basal ganglia are not passive conduits: the integration and compression of informa- tion through cortico-striato-thalamo-cortical loops, and the dis- tinct pharmacology of the basal ganglia mean that basal ganglia lesions o en have very widespread e ects. Given the close proxim- ity of functionally distinct circuits, and the heterogeneity of lesions,

Cortex

Striatum
D1 D2

GPe STN

GPi SNr

SNc VTA Inhibitory (GABA)

CHAPTER 7 the basal ganglia in cognitive disorders 73 Cortex

alamus

Striatum

alamus

Excitatory

Fig. 7.4 e left panel illustrates the in uential ‘dual circuit model’, in which the output of the basal ganglia is determined by the balance between the direct pathway, with striatonigral inhibitory connections that promote behaviour, and the indirect pathway, via the external globus pallidus (GPe) and subthalamic nucleus (STN), that suppress behaviour. e balance between these two pathways is modulated by dopaminergic inputs from the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA), which act on D1 and D2 dopamine receptors that are di erentially expressed in the direct and indirect pathways. e right-hand panel brings together the evidence for a more complex connectivity, including dopaminergic modulation at multiple sites, and reciprocal connections among the globus pallidus pars externa, subthalamic nucleus, and globus pallidus pars interna (Gpi). SNr, substantia nigra pars reticulata.

Modi ed from Nat Rev Neurosci. 11(11), Redgrave P, Rodriguez M, Smith Y, Rodriguez-Oroz MC, Lehericy S, Bergman H, et al. Goal-directed and habitual control in the basal ganglia: implications for Parkinson’s disease, pp. 760–72, Copyright (2010), with permission from Nature Publishing Group.

the neuropsychological approach to basal ganglia function has arguably not been as informative for functional mapping as it has been for cortical functions.

Bellebaum and colleagues studied the ability to learn new rules in ten patients with unilateral lesions, using probabilistic stimu- lus association task with di erential rewards. Patients were able to learn the associations, but were impaired at learning the reversal of associations, especially with dorsal lesions, a de cit also observed in Parkinson’s disease. Carry-over e ects impaired learning of sec- ondary tasks. Intriguingly, a patient with bilateral lesions showed superior performance compared to controls, due to an e ective compensatory declarative memory strategy.24

e complex cognitive consequences of basal ganglia lesions are demonstrated in Benke and colleagues’ description of two cases with haematomas a ecting distinct regions of the le striatum and pallidum. Despite only having unilateral lesions, both patients were acutely abulic, with minimal spontaneous activity of speech, long response latencies, motivational de cits, and relative indi erence to their illness.25 A disabling lack of concern, motivation, and ini- tiative persisted long term, without depression. On untimed tests, both patients had preserved arithmetic, reading, writing, naming, and comprehension but both manifested a dynamic aphasia with sparse delayed and reduced verbal output and reduced uency. Cognitive exibility, set-shi ing, design uency, and attention were severely a ected, with di culty initiating responses and respond- ing to error feedback. ese features overlap with the dysexecutive syndrome of frontal cortical lesions, as well as Huntington’s and Parkinson’s disease.

e syndrome manifested by these two patients did not, however, correspond to the separate predictions of a ective, associative and motor functions in segregated parallel loops via ventral and dorsal striatum. is may be because the lesions were larger than were

seen by non-invasive brain imaging: more extensive overlapping changes in white matter connections might have been revealed by techniques such as di usion-weighted imaging. However, there was a surprising similarity between the two patients’ neuropsychologi- cal de cits, despite their lesions being in quite di erent places. is suggests extensive cross-talk between the basal ganglia circuits for a ective, associative, and motor functions, con rming the extent to which the basal ganglia create an integrated system for complex goal-directed behaviours.26

Lesions to the ventral striatum and caudate nucleus may also a ect social and emotional cognition,27,28 while pallidal lesions may also lead to profound apathy.29 is re ects the rich intercon- nections of this basal ganglia region with the orbitofrontal cortex and ventromedial prefrontal cortex, which are associated with social and emotional cognition in health,30 and social cognitive impairments in degenerative neurological disease.31 For example, Kemp and colleagues reported the e ects of a haemorrhagic arte- riovenous malformation in the le caudate nucleus of a 44-year-old man.32 He gradually lost empathy and changed character, becom- ing ‘mean’, ‘sel sh’, and paranoid. His abstract reasoning remained excellent, together with language, memory, visual attention, and most executive functions (except for some slowing). He could rec- ognize basic emotions (e.g. anger, sadness) and accurately answer questions about scenarios pertaining to other people’s knowledge or beliefs. However, he was greatly impaired in recognizing other people’s complex mental states (e.g. desire) and could not under- stand the occurrence of social faux pas.33 Although the only lesion was in the caudate nucleus, brain perfusion imaging suggested hypometabolism in the upstream and downstream connections of the caudate, speci cally in the le thalamus, prefrontal and orbito- frontal cortex, highlighting the need to recognize cortico-striato- thalamo-cortical loops as a coherent system.

GPi

GPe STN

SNr

SNc Dopaminergic

VTA

Direct

Indirect

74 SECTION 1 normal cognitive function

Some authors present Parkinson’s disease as a model of basal gan- glia dysfunction but this approach can be misleading. Parkinson’s disease is associated with widespread pathology, in basal ganglia, brainstem nuclei, and cortex, and a ects multiple neurotransmitter systems. Few studies have directly compared Parkinson’s disease with focal basal ganglia lesions.34 Both impair rule-based categorization tasks, but focal lesions selectively impair the learning of a complex discrimination task based on a conjunction of stimuli, not a simple categorization task. In contrast, Parkinson’s disease a ects the sus- tained performance of a simple one-dimensional task as well as caus- ing suboptimal strategies on the more complex conjunction task.

In summary, even unilateral lesions of the basal ganglia can cause long-lasting and severe cognitive de cits, a ecting executive functions, learning, and social cognition. However, human lesion data currently lack the anatomical speci city for precise functional mapping of the basal ganglia.

Neurodegenerative disorders

of the basal ganglia

Much of the information available about the role of basal ganglia in cognition has come from the study of neurodegenerative disorders, especially Parkinson’s disease and Huntington’s disease, but also progressive supranuclear palsy and frontotemporal dementia. One must bear in mind that these disorders are not neuropathologically restricted to the basal ganglia, or to a single neurotransmitter such as dopamine. For example, serotonergic,35 noradrenergic,36 and extras- triatal dopamine37 systems all contribute to cognitive de cits in Parkinson’s disease. Nonetheless, striatal dysfunction is a major con- tributor the neuropsychological pro le of these neurodegenerative disorders (see Fig. 7.5). Whilst the cognitive manifestations of these disorders are discussed in more detail in Section 3, a brief overview of each with particular focus on the basal ganglia, is provided below.

Parkinson’s disease

Half of all people with Parkinson’s disease have mild cognitive impairment soon a er diagnosis,3 and cognitive de cits may be present before diagnosis or the onset of motor symptoms. However, the cognitive impact of Parkinson’s disease is multifaceted. e dual syndrome hypothesis38,39 sets out the distinction between common early frontostriatal de cits and a later dementia. Early frontostriatal de cits are associated with loss of striatal dopamine (and loss of ser- otonin and noradrenaline) and are seen in about a third of patients at presentation, doubling a er four years.7,40 ey are characterized by impairments in executive functions: cognitive exibility includ- ing reversal learning, response inhibition, planning, attentional set- shi ing, action selection, and decision-making according to risk or reward. Indeed, the impact of early Parkinson’s disease on learning and memory is in part due to these executive function de cits.41

e dementia associated with Parkinson’s disease is not merely a wors- ening of these frontostriatal de cits but rather a set of temporoparietal cortical de cits, most associated with cholinergic loss. ese encompass poor episodic memory, visuospatial de cits, poor uency, and risk of hallucination. Approximately one in ten people with Parkinson’s disease develops dementia by three years and half by ten years.97

e ability to adapt behaviour to a novel or changing environ- ment is central to the concept of executive functions. is has been widely studied in the context of visual discrimination learning, from the Wisconsin Card Sort Test and Montreal Card Sort Test through to translational models such as the Cambridge Automatic Neuropsychological Test Battery’s (CANTAB) intra- and extra- dimensional shi task (IDED). During the IDED task, partici- pants learn a series of visual discriminations based on compound stimuli. When a given discrimination is learned to criterion, the rules change and, in response to feedback, subjects must change their cognitive strategy and learn a new discrimination. Mild to

Fig. 7.5 In contrast to healthy adults (top left, HC), a carrier of CAG expansions in the Huntingtin gene (top middle, HD) shows marked atrophy of the caudate nucleus (yellow arrows) while still asymptomatic several years before Huntington’s disease onset. Below, a voxel-based morphometry (VBM) analysis of 21 presymptomatic carriers con rms the signi cant degree of caudate atrophy (yellow cluster) in the absence of signi cant cortical atrophy. In contrast, the caudate is grossly preserved in early Parkinson’s disease but dopamine transporter (DAT) imaging shows signi cant dopaminergic denervation of the striatum, especially the putamen (DAT-PD, red arrows), in contrast to a healthy adult (DAT-HC).

Courtesy of Prof. Roger Barker.

moderate Parkinson’s disease does not a ect the acquisition of simple discrimination, but it severely impairs the ability to make an attentional shi between two alternate perceptual dimensions in the stimuli, such as ‘colour’ and ‘shape’ (the ‘extra-dimensional shi ’).42–44

is de cit in Parkinson’s disease is ambiguous: it could be due to perseveration (the inability to disengage attention from a previ- ously relevant dimension) or to learned irrelevance (the inability to attend and learn about information which has previously been shown to be irrelevant). People with Parkinson’s disease are espe- cially impaired when an extra-dimensional shi is accompanied by learned irrelevance.45 However, the de cit in Parkinson’s dis- ease does not in itself indicate that it is due to striatal dopamin- ergic abnormalities. Indeed, dopaminergic medication makes little di erence to extra-dimensional shi impairments.46 In addition, severe dopamine depletion from the caudate in marmosets does not impair discrimination learning or extradimensional shi s. However, caudate dopamine depletion does impair shi ing back to a previously reinforced dimension, suggesting that it is learned irrelevance which is a ected by striatal dopamine depletion in Parkinson’s disease.47,48

Parkinson’s disease impairs reversal learning, in which reward contingencies are reversed across a set of stimuli. e striatum is implicated in reversal learning, from animal models and human neuroimaging.49 People with Parkinson’s disease are impaired on reversal learning, but dopaminergic medication may actually worsen this impairment. is paradoxical e ect may result from the precision of normal dopaminergic ring, with phasic bursts against background tonic activity, such that dopaminergic medica- tion reduces signal-to-noise of the ventral striatal phasic dopamine release that signals reversal.17 Interestingly, the adverse e ect of dopamine treatment is restricted to conditions in which the rever- sal is signalled by unexpected punishment, not reward.50 e pres- ence of cognitive impairment, including reversal learning de cits, depends on the stage of disease and the type of stimulus used, with a di erence in the importance of cortex versus striatum according the use of abstract versus concrete rules.50,51 e shi and reversal tasks described above relied on trial and error learning, accord- ing to feedback. However, Parkinson’s disease also impairs cogni- tive exibility when the required task shi is explicitly cued52 or implied by a sequence of stimuli.53,54

To optimize behaviour, it is o en necessary to weight di erent cognitive strategies according to recent experience and anticipated events, rather than make ‘black and white switches’ between cogni- tive strategies as in the IDED task and reversal paradigms. Rowe and colleagues studied such weighting between cognitive strate- gies, using a continuous performance task with two concurrent stimulus dimensions and a partial reward schedule.55 People with Parkinson’s disease were able to modulate the balance between alternate cognitive sets, according to the reward relevance of antici- pated stimuli. However, the associated activations of the caudate nucleus and the ventrolateral prefrontal cortex were dependent on the severity of disease and dopaminergic treatment: there was a non-linear (inverted U-shaped) relationship between the activa- tion and the disease severity. e deviation from normality of this inverted U-shape curve increased progressively across the cortex (from motor to premotor to dorsal then ventral prefrontal cortex) and striatum (from caudal putamen to ventral striatum). A simi- lar U-shape function in caudate and ventral prefrontal cortical

activations in Parkinson’s disease was observed for cognitive deci- sions regarding alternate manual responses,56 and represents a gen- eralized non-linear function of dopamine in human cognition.55

e non-linear U-shaped relationship between performance (or activation) and disease severity, or between performance (or activation) and dopaminergic drug dose, has major implications for treating cognitive function in Parkinson’s disease. First, clin- ical decisions for dose escalation are typically made according to motor features (e.g. tremor, rigidity) and the levodopa dose is rarely chosen so as to optimize cognitive function even though cognitive impairments are a major determinant of patient and carer quality of life. Second, it may not be possible to optimize both cognitive and motor functions with a given dose using systemic medication. Instead, a combined approach with local basal ganglia therapies (such as deep brain stimulation or gene therapy) and systemic drugs may be required to approximate optimal treatment in di er- ent basal ganglia circuits for a ective, cognitive, and motor func- tions. ird, since dopaminergic dysfunction in early Parkinson’s disease mainly a ects the dorsal striatum disease,57 dopaminergic medication may e ectively ‘overdose’ the ventral striatum and pre- frontal cortex. Indeed, compensatory changes in the substantia nigra and VTA may lead to mild hyperdopaminergic states in the ventral striatum and mesocortex in early Parkinson’s58 in addition to pharmacotherapeutic overdose of the ventral striatum.

A striking consequence of ventral striatal dopamine ‘overdose’ is the induction of impulse control disorders (ICDs) in about one in seven patients on dopamine agonists. ese include hypersexual- ity, paraphilias, pathological gambling, binge eating, and impulsive shopping which can be devastating in their long-term conse- quences even a er medication is reduced and the behaviour abated. As explained above, dopaminergic neurons projecting from the ventral tegmental area signal unexpected rewards, or cues that have been associated with reward.59 is dopamine reward signal in the striatum is exaggerated in relatively impulsive normal adults60 and appears to be magni ed in Parkinson’s disease. For example, positron emission tomography (PET) studies reveal abnormally enhanced dopamine release in the ventral striatum of patients with pathological gambling.61 However, extrastriatal dopamine may also contribute to the pathogenesis of ICDs in Parkinson’s disease62 including the cingulate and medial prefrontal cortical mecha- nisms by which actions are associated with reward. Functional MRI (fMRI) studies suggest that Parkinson’s disease (even without ICDs) reduces the cingulate cortical response to reward anticipa- tion, but increases the regional response to actual reward.54

is devaluation of anticipated future rewards in Parkinson’s dis- ease contributes to the preference for smaller immediate rewards over larger delayed rewards,63 especially in those patients with ICDs and those taking dopamine agonists. For reversal learning, there is again a di erential e ect of Parkinson’s disease on posi- tive (rewarding) versus negative (punishment) feedback: patients at risk of ICDs become less responsive to negative feedback,64 as well as more responsive to rewards. is distortion of the evaluation of outcomes, worsened by dopamine agonists, increases risk taking despite lower ventral striatal, orbitofrontal, and anterior cingulate activity.65,66

Huntington’s disease

Huntington’s disease (HD) is a complex, multifocal neurologi- cal disorder, caused by an inherited expansion of a trinucleatide

CHAPTER 7 the basal ganglia in cognitive disorders 75

76 SECTION 1 normal cognitive function

cytosine–adenine–guanine (CAG) repeat in the Huntingtin gene. e disease causes progressive motor dysfunction, cognitive decline, and psychiatric disturbances starting usually between 30 and 50 years old. Cognitive symptoms or signs o en develop prior to motor signs. Although the normal functions of this gene are not fully elucidated, striatal involvement is characteristic,67 with severe loss of the caudate nuclei as one of the hallmarks of the disease (Fig. 7.5).

Huntington’s disease impairs executive functions, emotion and social cognition, and memory. e autosomal dominant genetic aetiology of Huntington’s disease allows one to study presymp- tomatic stages of disease, in the absence of medication or gross performance de cits. In addition, there are correlations between caudate volume and cognitive function and functional brain imag- ing by fMRI, pointing to the relevance of the striatum to cognitive function and cognitive decline in Huntington’s disease.68–70

Caudate loss is evident in presymptomatic carriers (Fig. 7.5),71,72 which progresses in severity and spatial extent during the symp- tomatic phase from the dorsal head of caudate to ventral striatum and putamen.72–75 In contrast, cortical atrophy is more commonly associated with later stages of disease.74 Within the body and head of the caudate, medium spiny neurons of the indirect pathway are especially a ected. In keeping with the dual pathway model, this leads to disinhibition of the external globus pallidus, and down- stream disinhibition of the thalamus. e direct pathway becomes overactive, exaggerating the thalamic disinhibition.

e imbalance between direct and indirect pathways can a ect associative, a ective, and motor loops through the basal ganglia. However, because of the topographical organization of neuropath- ology, there are trends towards di erential times of onset of cog- nitive and behavioural impairments according to the functional anatomy of the cortico-striato-thalamo-cortical loops. For example, Holl and colleagues reported de cits in verbal uency and Stroop interference,76 but in contrast to Parkinson’s disease, patients with Huntington’s disease were unimpaired on a gambling task that required risk decision-making. e dissociation is likely because of the di erential distribution of pathology across the ventromedial versus dorsolateral caudate nucleus and the respective connections of these regions. However, these clinicopathological correlations are only partial. Among patients ten or more years before estimated disease onset, there is evidence of caudate volume reduction in the absence of cognitive decline.77–79 is suggests early compensation for the striatal changes, either within the striatum or the regions with which it is interconnected.

Cognitive changes in such presymptomatic cases or early stage disease are likely to be due to striatal involvement, and Huntington’s disease has o en been used as a model to study the role of the stria- tum in cognition, especially when supported by speci c structure– function correlations. For example, early ‘striatal’-stage disease impairs rule based language learning, in contrast to later cortical stages which a ect other forms of learning.80 Importantly, learning capacity correlates with the severity of caudate atrophy. Other early de cits include executive functions such as uency, interference control, and Trail Making Test B,78,81,82 emotion recognition,83,84 and visuomotor integration.85

In symptomatic disease, the severity and range of cognitive de – cits broadens, due to emerging cortical as well as extended striatal involvement. Planning, attention, and rule learning, psychomo- tor speed, episodic memory, and emotional or social cognition

progressively decline. However, some major cognitive domains remain relatively una ected until late stages of disease, including semantic memory, language (not including uency), visuospatial functions, and orientation.82

Further evidence for the striatal contribution to cognitive change comes from functional brain imaging with fMRI. For example, ven- tral striatal activity related to anticipated reward is blunted in gene carriers approaching disease onset.86 However, changes in activa- tion are not necessarily localized to the striatum, even in early dis- ease. For example, the executive function of set-shi ing activates extensive prefrontal, parietal and cingulate cortex, and basal gan- glia in healthy adults. e putamenal and pallidal activations were increased in patients even in premanifest cases, but there were also extensive increases in cortical activations.87

Similarly, during working memory performance the activa- tion di erences observed in manifest and presymptomatic carri- ers include, but are not con ned to, the caudate and putamen.88 is should not be surprising, in view of the connectivity through cortico-striato-thalamo-cortical loops, as the e ects of a lesion or perturbation in one node of the circuit are propagated throughout the circuit, including recurrent connections to the cortical regions that project to the striatum. e importance of this circuit-based understanding of cognitive dysfunction is underscored by the cor- relations between cognitive decline and (i) atrophy of cortex;89 (ii) atrophy of caudate;90 (iii) changes in the white matter structural connections between frontal cortex and the striatum;91,92 and (iv) changes in frontostriatal functional connectivity.70,86

Progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is sometimes still described as a ‘Parkinson’s plus’ syndrome and movement disorder. However, this overlooks the marked clinical and pathological distinctions from Parkinson’s disease,93 and the extensive cognitive problems which are a major determinant of patient and carer quality of life.94 ‘Mental features’ were noted in the original description 50 years ago,95 and cognitive change remains part of the supportive diag- nostic criteria. Indeed, one in ten patients present with cognitive symptoms,96 and two-thirds will develop a dementia.97,98

PSP is caused by hyperphosphorylation and aggregation of the microtubule-associated protein tau, leading to cell dysfunction and death. It a ects many parts of the basal ganglia, including the striatum, pallidum, substantia nigra, subthalamic nucleus (other a ected regions include the red nucleus, pontine tegmentum, ocu- lomotor nuclei, medulla, dentate nucleus and cortex99). Atrophy of the dorsal midbrain is severe with marked reductions in dopa- minergic innervation of striatum and cortex. Caudate atrophy is evident on MRI,100 together with severe striatal hypometabolism from FDG-PET101 and abnormal striato-frontal connections.102,103

e cognitive e ects of PSP include behavioural change (apathy, irritability, childishness, impulsivity), executive dysfunction, mem- ory, visuospatial, language and social cognitive de cits. Cognitive slowing typically develops early in the disease. Executive de cits occur in about three quarters of patients. For example, Robbins and colleagues105 identi ed de cits in short-term memory and spatial working memory with poor memory strategies, but also poor plan- ning on the Tower of London task, and severe de cits in attentional set-shi ing. However, simple rule acquisition remains relatively intact.104,105 Others have reported de cits in tests of frontal lobe function such as the Trail Making B task106 and a range of executive

and non-verbal reasoning tasks.98,107,108 Even verbal uency, which requires executive as well as lexical functions, is profoundly impaired in PSP.97 Recent work has also shown that emotional and social cognitive systems are abnormal in PSP.31,109 Both emotion recognition and higher-order social inferences (known as eory of Mind) are a ected across visual and auditory domains. One-third of patients manifest poor episodic memory and poor visuospatial functions.110–112 However, such de cits may be in part related to executive impairments, a ecting retrieval or task strategies.

Despite the wide-ranging cognitive de cits in PSP and the sever- ity of pathology in the basal ganglia, it is less clear to what extent the basal ganglia changes are the cause of the cognitive decline. Albert and colleagues used PSP to illustrate the concept of ‘subcortical dementia’, attributing the majority of cognitive change to subcor- tical pathology. is was distinguished from ‘cortical dementias’ such as Alzheimer’s disease with amnesia, aphasia, apraxia, and agnosia. However, the extent of cortical pathology and of cortical neurotransmitter loss has become more widely recognized, and functional cognitive impairments shown to correlate with corti- cal atrophy100,113 or cortical hypopmetabolism,114 including global cognitive function and social cognitive de cits.31 Nonetheless, dor- sal striatal atrophy occurs in PSP,113,115 and caudate atrophy can be severe, correlating with global cognitive decline in PSP,104 hypome- tabolism,101 and the presence of neuropathology in the majority of cases.116 Further, albeit indirect, evidence comes from the observa- tion that greater pathology in the caudate and substantia nigra is associated with a classical phenotype (also called PSP–Richardson’s syndrome) with prominent cognitive and behavioural changes, as opposed to a syndrome more closely resembling Parkinson’s disease.117

Frontotemporal dementia

Frontotemporal dementia (FTD) has long been associated with severe atrophy of the frontal, temporal, and insula cortex. However, the basal ganglia are also a ected, especially in the behavioural var- iant of frontotemporal dementia, with hypometabolism and atro- phy.118,119 e non- uent variant of primary progressive aphasia (progressive non- uent aphasia) is also associated with atrophy in caudate, nucleus accumbens, and, to a lesser extent, the putamen. In the semantic variance of primary progressive aphasia (semantic dementia) the caudate is grossly preserved. In addition to atrophy, functional connectivity of the striatum is abnormal in FTD.120 It has been suggested that cognitive de cits related to striatal dys- function in FTD are lateralized, with right-sided changes associ- ated with behavioural change, apathy, empathy, and stereotypies, whereas le -sided changes are associated with executive, language, and psychomotor features.121

However, the contribution of the striatal atrophy to cognitive impairment in FTD is not fully characterized. It may be that some of the observations re ect changes that are secondary to atrophy of the cortical areas with which striatal regions interconnect. It is necessary to try to uncouple the cortical from striatal contributions to cognitive impairment, for example by closer analysis of individ- ual di erences or longitudinal designs. For example, Dalton and colleagues used voxel-based morphometry to study the anatom- ical basis of the impairment of probabilities-associative learning in FTD. Performance variability within the patient group correlated with grey matter volume in the striatum, including ventral stri- atum, head of caudate, and rostral putamen.122

CHAPTER 7 the basal ganglia in cognitive disorders 77 Conclusion

e basal ganglia are a ected by diverse neurological disorders, with common cognitive and behavioural consequences includ- ing the impairment of executive functions (e.g. attentional shi s, reversal), apathy and impulse control disorders, disrupted learning, social and emotional cognition. e cognitive de cits are similar to the e ects of lesions of the frontal cortical regions with which the striatum is densely connected. A set of ‘frontostriatal’ circuits has been proposed, in which the functional consequences of dis- ease re ect the anatomy, pharmacology, and connectivity of the normal basal ganglia. ese circuits are organized by two broad principles that facilitate integration and segregation of informa- tion processing: rst, that there is homology between cortico- striato-thalamo-cortical loops for motor, cognitive, and limbic functions; second, that there is an anatomical and pharmacologi- cal distinction between direct and indirect pathways connecting the striatum, pallidum, subthalamic nucleus, and substantia nigra. Neurodegenerative disorders show partial selectivity within these networks, by region and by pharmacologically de ned neuronal subtypes, leading to characteristic neuropsychological pro les in premanifest, early, and late stages of disease.

Acknowledgements

James Rowe is supported by the Wellcome Trust (103838) and Timothy Rittman is supported by the Medical Research Council.

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84. Henley S, Novak M, Frost C, King J, Tabrizi S, and Warren J. Emotion recognition in Huntington’s diease: A systematic review. Neurosci Biobehav R. 2012; 36:237–53.

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CHAPTER 8

Principles of white matter organization Marco Catani

Introduction

Connectional neuroanatomy delineates the origin, course, and ter- mination of white matter pathways in the central nervous system. In clinical practice, understanding white matter anatomy can help to improve early diagnosis, optimize treatment strategies, and predict outcomes. In this chapter, the reader will be introduced to meth- ods for studying white matter anatomy, a modern classi cation of the major brain pathways underlying cognition and behaviour, and principles of white matter organization and function. A particu- lar emphasis is given to more recent tractography approaches and their application to the in vivo study of white matter anatomy in the healthy and pathological brain.

e study of white matter anatomy

e term white matter applies to the substance of the brain that contains axonal bres connecting neurons located in the grey mat- ter. In fresh tissue, white and grey matter appear di erent in colour due to the presence of a whitish myelin sheath around the axonal bres. Myelinated axons tend to group together into small bundles and several bundles gather into larger tracts called fasciculi.

Several methods have been applied to the study of white mat- ter connections in the animal and human brain (Table 8.1).1–4 e techniques developed by early neuroanatomists for gross blunt dis- sections of white matter tracts led to important anatomical insights, including the identi cation of most of the white matter tracts con- tributing to higher cognitive functions.5–7 Blunt dissections are performed on postmortem brains using specimens preserved in alcohol5,6 or frozen for several days.8,9 ese procedures harden the white matter and permit manual separation of di erent tracts with the blunt back of a knife or a spatula. One of the limitations of these methods is the proneness to artefacts (i.e. o en separation does not occur along natural cleavages) and the di culty to obtain quantita- tive measurements. Also, blunt dissections require neuroanatomi- cal knowledge, experience, and patience to achieve reliable results.

e study of white matter made a signi cant leap forward with the introduction of myelin staining methods for degenerating bres (e.g. Weigert–Pal or Marchi staining).10 e observation of serial sections of stained specimens permitted visualization of tracts in the brains of patients with cortico-subcortical lesions (mainly vas- cular) or in experimentally lesioned animal brains. Compared to blunt dissections, the histological methods are able to show the anatomy of bres and their terminations in more detail. However,

most of these methods have the same limitations as blunt dissec- tions and the reconstruction of speci c tracts in the human brain is highly dependent on the availability of pathological specimens with precisely localized lesions.

In the 1960s, a signi cant increase in knowledge about connec- tivity arose from the use of cellular transport mechanisms to detect connections between nerve cells.11 Once injected, the tracers enter the neuron and are transported from the body of the neuron to its terminations (i.e. anterograde direction), or in the opposite direc- tion (i.e. retrograde direction).3 ese methods show the anatomy of connections at the level of the single axons and remain the gold standard to understand connectivity of the animal brain. e pos- sibility of combining multiple tracers o ers also a unique advantage for depicting multiple pathways at the same time (e.g. feed-forward and feedback connections from and to a speci c area).

In the 1990s, viruses were adopted as transneuronal tracers12 with the possibility of visualizing di erent axonal pathways com- posing an entire functional system (e.g. rst, second, and third order neurons). Unfortunately, these methods are invasive and cannot be applied to the human brain. Also, correlative analysis between anatomical features of individual connections and behav- ioural performances are di cult to perform.

In the last 15 years tractography based on di usion magnetic res- onance imaging has been developed for the in vivo quanti cation of certain microstructural characteristics of a tissue13 and the vir- tual reconstruction of white matter trajectories.14–17 Tractography studies are based on the measurement of water di usion, typically within a cubic voxel in which the microstructural organization of the cerebral tissue hinders the free movement of water. In voxel- containing parallel axons, water di usion is higher in the direction parallel to the bres and restricted in the perpendicular direction. The diffusion tensor is a useful way to describe the three- dimensional displacement of water molecules and obtain an estimate of the microstructural organization of the bres.18

Tractography is based on algorithms that link together the prin- cipal tensor orientation of adjacent voxels in a continuous trajec- tory. One advantage of this method is the possibility of quantifying di usion properties of white matter in the living human brain that relate to underlying biological features (e.g. tract volume, myelina- tion. etc.)13 and correlate them with behavioural performances.19–22 Like other methods, tractography su ers some limitations, includ- ing artefactual reconstructions and the di culty of interpreting cur- rent di usivity indices in relation to pathological changes.4

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82 SECTION 1 normal cognitive function Table 8.1 Methods for studying brain connections

Method

Advantages

Limitations

Blunt dissections

◆ Applicable also to human brains

◆ Direct anatomical method

◆ Identify large tracts

◆ Only for postmortem tissue

◆ Operator-dependent

◆ Variable quality of the prepared sample

◆ Destructive

◆ Qualitative analysis only

◆ Limited ability to visualize crossing bundles and cortical projections (false negatives)

◆ Produce artefactual trajectories (false positives)

◆ Time consuming

Staining degenerating myelin (e.g. Marchi’s method)

◆ Direct anatomical method

◆ Identify large and small tracts ◆ Operator-independent

◆ Only for postmortem tissue

◆ Fibre delineation limited to the lesion site and extension

◆ Variable quality of the prepared sample

◆ Destructive

◆ Qualitative analysis only

◆ Time consuming

◆ 3D reconstruction limited

Neurohistology

◆ Direct anatomical method

◆ Used to identify details of local networks

◆ Allows to distinguish the bres’ neurochemical properties (e.g. cholinergic vs dopaminergic)

◆ Only for postmortem tissue

◆ Small eld of view

◆ 3D reconstruction limited

◆ Time consuming

◆ Destructive

Axonal tracing

◆ Direct anatomical method

◆ Identify large and small tracts

◆ Allow direct testing of speci c hypotheses (e.g. connectivity of individual cortical regions)

◆ Can reveal bre directionality

◆ Possibility to combine multiple tracers

◆ Not suitable for humans

◆ Fibre delineation depends on the injection site

◆ Variable quality of results depending on the tracer used

◆ Qualitative analysis is di cult

◆ Limited number of tracts per sample

◆ Destructive

◆ Time consuming

◆ 3D reconstruction limited

Viral tracers

◆ Visualization of multisynaptic pathways

◆ Can reveal bre directionality

◆ Spurious labelling of neurons due to cell lysis (false positives)

◆ Weak labelling due to low viral concentration (false negatives)

◆ Tropism of viruses varies according to animal species

◆ Quantitative analysis is di cult

Tractography

◆ In vivo

◆ Applicable to human and animal brains

◆ Noninvasive

◆ Timee cient

◆ Allows the study of large populations

◆ Correlationwithbehaviouralandotherfunctionalmeasures

◆ Quantitative

◆ Multiple hypothesis testing

◆ Notdestructive

◆ Indirect anatomical method

◆ Low spatial resolution

◆ Presenceofartefacts

◆ Operator-dependent

◆ Limited visualization of bending, merging, and crossing bres

◆ Indirect quantitative indices of bre volume and integrity

Classi cation of white matter pathways

White matter connections can be classi ed into three major groups: association, commissural, and projection pathways.23 ese three groups are composed of long-range connections medi- ating connectivity between distant regions. A fourth group of

connections, the U-shaped bres, is responsible for the local con- nectivity between neighbouring gyri, usually within the same lobe (intralobar) or between lobes (interlobar).24 Additional tracts that do not t into the classical nomenclature have been described.24–27 ese tracts are intermediate between long association pathways and short U-shaped bres as they connect distant regions but

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within the same lobe (i.e. the vertical occipital tract of Wernicke or the frontal aslant tract in the frontal lobe).24,25,28–30

Association pathways

Association pathways connect cortical regions within the same hemisphere and their bres have either a posterior–anterior or an anterior–posterior direction.17 e terminology used to indicate the association tracts o en refers to their shape (e.g. the uncinate from the Latin uncinatus meaning ‘hook-like’), their origin and termina- tion (e.g. inferior fronto-occipital fasciculus), or their course and location (e.g. inferior longitudinal fasciculus). Most of the long asso- ciation tracts are composed of short and long bres. e short bres run more super cially, closer to the cortex, and connect neighbour- ing regions. ese short bres can also be classi ed separately as individual U-shaped tracts.24,27 e long bres run just underneath the U-shaped bres and the depth of their course varies according to the distance they travel (the deepest bres travel furthest distance).

e association tracts are involved in higher cognitive functions, such as language, praxis, visuospatial processing, memory, and emotion.31 e major association tracts of the human brain are the arcuate fasciculus, the superior longitudinal fasciculus, the cingu- lum, the uncinate fasciculus, the inferior longitudinal fasciculus, and the inferior fronto-occipital fasciculus (Fig. 8.1).

e arcuate fasciculus (AF) is a dorsal association tract connect- ing perisylvian regions of the frontal, parietal, and temporal lobe. In humans two parallel pathways have been distinguished within the arcu- ate fasciculus. e medial direct pathway (i.e. the arcuate fasciculus sensu strictu or direct long segment) connects Wernicke’s region in the

(a)

Group1 strong lateralization (60%)

CHAPTER 8 principles of white matter organization 83 ASSOCIATION

(b) 18

10
40%

6 2

85%

60 50

Arcuate

Superior longitudinal

Cingulum

Inferior longitudinal

Uncinate

Inferior fronto-occipital

Fig. 8.1 Tractography reconstruction of the major association pathways of the human brain.
Adapted from Catani, Marco, iebaut de Schotten, Michel, Atlas of Human Brain Connections, Copyright (2012), with permission from Oxford University Press..

temporal lobe (BA 41, 42, 22, 37) with Broca’s region in the frontal lobe (BA 6, 44, 45). e indirect pathway consists of an anterior segment linking Broca’s to Geschwind’s region in the inferior parietal lobule (BA 39, 40) and a posterior segment linking Geschwind’s to Wernicke’s region.32 e direct long segment of the arcuate fasciculus is larger on the le hemisphere compared to the right in about 80 per cent of the population. e remaining 20 per cent shows a bilateral distribution.19

Among the le lateralized people the degree of asymmetry is quite heterogeneous with 60 per cent of them showing an extreme degree of le lateralization and the remaining 20 per cent a moderate le asymmetry (Fig. 8.2). In general, those who have a more bilateral

Group2 bilateral, left lateralization (20%)

Group3 bilateral, symmetrical (20%)

∗

females males

30%

10%
5%

0123 0 Groups

123 Groups

Fig. 8.2 Lateralization of long segment of the arcuate fasciculus and behavioral correlates. (a) Distribution of the lateralization pattern of the direct long segment (red). (b) Distribution of the lateralization groups between genders. (c) Performances in the CVLT according to the three lateralization groups (*, P = 0.01 versus Group 1;
†, P = 0.001 versus Group 1).
Adapted from Proc Natl Acad Sci USA. 104(43), Catani M, Allin MP, et al. Symmetries in human brain language pathways correlate with verbal recall, pp. 17163–8, Copyright (2007), with permission from PNAS.

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No. of subjects

CVLT (tot score)

84 SECTION 1 normal cognitive function

distribution of the long segment connections perform better on a verbal memory task that relies on semantic clustering for retrieval (i.e. California verbal learning test, CVLT).19 Furthermore, the direct long segment in the le hemisphere mediates auditory-motor integration, which is crucial during early stages of language acqui- sition and word learning.22 e role of the indirect pathway could be more complex and related to linking semantics and phonology,33 processing syntactically complex sentences,34,35 and various aspects of verbal working memory.36 e role of the direct and indirect pathways in word repetition remains to be clari ed.37,38

e superior longitudinal fasciculus (SLF) has three distinct branches as originally described in the monkey brain using axonal tracing methods.39 In humans, the rst branch of the superior lon- gitudinal fasciculus (SLF I) connects the superior parietal lobule and precuneus (BA 5 and 7) to the superior frontal (BA 8, 9, 32) and perhaps to some anterior cingulate areas (BA 24). e SLF I processes the spatial coordinates of trunk and inferior limbs and contributes to the preparatory stages of movement planning (e.g. anticipation),40 oculomotor coordination,41 visual reaching,42 and voluntary orientation of attention.43

e second branch (SLF II) originates in the anterior intrapa- rietal sulcus and the angular gyrus (BA 39) and terminates in the posterior regions of the superior and middle frontal gyrus (BA 6, 8, 9). In the le hemisphere, the SLF II is involved in processing the spatial coordinates of the upper limbs, and in other functions similar to the SLF I.40,44 In the right hemisphere the SLF II partici- pates in attention,45,46 visuospatial processing,47 and spatial work- ing memory.48

e third branch (SLF III) connects the intraparietal sulcus and inferior parietal lobule to the inferior frontal gyrus (BA 44, 45, 47). e SLF III corresponds to the anterior segment of the arcuate fas- ciculus and the two terms are currently used interchangeably.24 Future studies will be necessary to establish whether, according to its functional role, the SLF III/anterior segment should be consid- ered as part of the sensory-motor SLF system or the arcuate lan- guage network.

In the human brain the three branches have a di erent pattern of lateralization (Fig. 8.3).21 In right-handed subjects the SLF I is symmetrically distributed between le and right hemispheres; the SLF II shows a trend of right lateralization and the SLF III is sig- ni cantly right lateralized. Most importantly, the lateralization of the SLF II correlates with asymmetry in behavioural performances for visuospatial tasks (Figs 8.3c and d). In particular, the majority of the people have a larger SLF II volumes on the right hemisphere and show a greater deviation to the le (i.e. pseudo-neglect e ect) in the line bisection, whereas those subjects deviating to the right show an opposite pattern of lateralization (i.e. larger volume of the le SLF II). Moreover, the same the correlation was found between the lateralization of SLF II volumes and the performances on a modi ed Posner paradigm, a task that measures spatial orienting of attention. Again, larger SLF II volumes in the right hemisphere corresponded to faster detection times of stimuli ashed in the le hemi eld.

It is unknown how di erences between the two hemispheres in SLF II volume can lead to asymmetrical processing of visual scenes. A larger tract in the right hemisphere could depend on several

(a)

(c)

7 5 4 2 0

–2 –4

–5 –7

–0.4

0.07 0.04 0 –0.04 –0.07

–0.4 –0.2
SLF II lateralization index

(b)

(d)

r = –0.734***

–0.2 0 0.2 0.4 SLF II lateralization index

r = –0.471*

SLF I
SLF II

SLF III

***

–0.3 –0.2 –0.1 0 0.1 0.2 0.3

Left lateralized Right lateralized Lateralization index (volume)

0 0.2 0.4

SLF I SLF II SLF III

Fig. 8.3 Asymmetry of the superior longitudinal fasciculus (SLF) and correlations with behavioral lateralizations. (a–b) In the human brain the three SLF branches show varying degrees of asymmetry (95% con dence intervals). (c–d) e asymmetry of the SLF II correlates with the deviation on the line bisection task (c), and the lateralization of the detection time (d). *P < 0.05 and ***P < 0.001.
Adapted from Nat Neurosci. 14(10), iebaut de Schotten M, Dell’Acqua F, et al. A lateralized brain network for visuospatial attention, pp. 1245–6, Copyright (2011), with permission from Nature Publishing Group.

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Lateralization index of detection time

Line bisection (mm)

factors, including greater bre myelination, more axons, and larger axonal diameter which are correlated with conduction speed or greater recruitment of cortical areas.49,50 Similar results have been found with other visuospatial attentional tests.104 Overall these ndings suggest that right hemispheric specialization for spatial attention might, in part, be explained by an unbalanced speed of visuospatial processing along the SLF II.

e cingulum is a sickle-shaped tract composed of bres of di er- ent length. e longest bres run from the amygdala, uncus (BA35), and parahippocampal gyrus (BA36 and 30) to subgenual areas of the orbitofrontal lobe (BA 25 and 11).51–53 Shorter bres, that join and leave the cingulum along its length, connect to adjacent areas of the cingulate cortex (BA 23 and 24), superior medial frontal gyrus (BA 32, 6, 8, and 9), paracentral lobule (BA4), precuneus (BA 7), cuneus (BA 19), lingual (BA 18 and 19), and fusiform gyri (BA 19 and 37).

e cingulum can be divided into a dorsal and a ventral com- ponent.54,55 e dorsal component connects areas of the dorsome- dial default-mode network.56,57 is consists of a group of medial regions whose activity decreases in the transition between a ‘rest- ing state’ and the execution of goal directed tasks, irrespective of the nature of the task. e default-mode network has been linked to a number of functions including working memory, focusing attention to sensory-driven activities, understanding other people’s intention (mentalising or theory of mind), prospective thinking (envisioning the future), and memory for personal events (autobio- graphic memory).57–59 e ventral cingulum connects amygdala and parahippocampal cortex to retrosplenial regions and forms a network dedicated to spatial orientation.60,61

e uncinate fasciculus (UF) is a hook-shaped tract that connects the anterior part of the temporal lobe (BA 38) with the orbital (BA 11 and 47) and polar (BA 10) frontal cortex.17 e bres of the unci- nate originate from the temporal pole (BA 38), uncus (BA 35), para- hippocampal gyrus (BA 36 and 30), and amygdala. A er a U-turn, the bres of the uncinate enter the anterior oor of the external/ extreme capsule between the insula and the putamen. Here, the uncinate runs inferiorly to the fronto-occipital fasciculus before entering the orbital region of the frontal lobe, where it splits into a ventro-lateral branch, which terminates in the lateral orbitofrontal cortex (BA 11 and 47), and an antero-medial branch that continues towards the cingulate gyrus (BA 32) and the frontal pole (BA 10).51

Whether the uncinate fasciculus is a lateralized bundle is still debated. An asymmetry of the volume and density of bres of this fasciculus has been reported in a human postmortem neurohis- tological study in which the uncinate fasciculus was found to be asymmetric in 80 per cent of subjects, containing on average 30 per cent more bres in the right hemisphere compared to the le .62 However, di usion measurements have shown higher fractional anisotropy in the le uncinate compared to the right in children and adolescents,63 but not in adults.21 e uncinate fasciculus connects the anterior temporal lobe to the orbitofrontal region and part of the inferior frontal gyrus and may play an important role in lexical retrieval, semantic association, naming, and social cognition.35,65–67

e inferior longitudinal fasciculus (ILF) does not constitute a single pathway, but contains bres of di erent length. e occipi- tal branches of the inferior longitudinal fasciculus connect with a number of regions dedicated to vision, including the extrastriate areas on the dorso-lateral occipital cortex (e.g. descending occipi- tal gyrus), the ventral surface of the posterior lingual and fusiform gyri, and the medial regions of the cuneus.64 ese branches run

anteriorly parallel and lateral to the bres of the splenium and optic radiation and, at the level of the posterior horn of the lateral ven- tricle, gather into a single bundle. In the temporal lobe, the infe- rior longitudinal fasciculus continues anteriorly and projects to the middle and inferior temporal gyri, temporal pole, parahippocam- pal gyrus, hippocampus, and amygdala.

An observation originally emphasized by Campbell,68 and con- sistent with axonal tracing2 and tractography ndings, is that long associative bres, such as those of the inferior longitudinal fascicu- lus, arise from the extrastriate cortex but not the calcarine striate cortex. e inferior longitudinal fasciculus carries visual informa- tion from occipital areas to the temporal lobe and plays an impor- tant role in visual object and face recognition, reading, and in linking object representations to their lexical labels.69–71

In humans, the inferior fronto-occipital fasciculus (IFOF) is a long-ranged bow-tie-shaped tract that originates from the infe- rior and medial surface of the occipital lobe (BA 19 and 18), with a minor contribution probably from the medial parietal lobe.9,17,74 As it leaves the occipital lobe and enters the temporal stem, the inferior fronto-occipital fasciculus narrows in section and its bres gather at the level of the external/extreme capsule just above the uncinate fasciculus. As it enters the frontal lobe, its bres spread to form a thin sheet, curving dorsolaterally, that terminates mainly in the ventrolateral frontal cortex (BA 11) and frontal pole (BA 10).17 Smaller bundles terminate in the rostral portion of the superior frontal gyrus (rostral portion of BA 9).2,39

ere are signi cant simian–human di erences in the anatomy of the inferior fronto-occipital fasciculus.75,76 Axonal tracing stud- ies in monkey suggest that frontal bres running through the extreme capsule do not reach the occipital lobe. For this reason, the term extreme capsule tract is a preferred name for the mon- key brain.2 e inferior fronto-occipital fasciculus may have a role in reading, writing, and other semantic and syntactic aspects of language.28,72–74

Commissural Pathways

Commissural pathways are composed of bres connecting the two halves of the brain. e major telencephalic commissures of the human brain include the corpus callosum, the anterior com- missure, and the hippocampal commissure (Fig. 8.4). A general assumption underlying the concept of commissural connections is that the information is transferred between homologous corti- cal or subcortical regions. ere are, however, a signi cant num- ber of heterotopic commissural bres connecting non-homologous regions, at least in the corpus callosum.77

e corpus callosum is the largest commissural tract in the human brain, consisting of 200–300 million axons of varying size and degrees of myelination.78,79 e corpus callosum forms the roof of the lateral ventricles and its bres are conventionally divided into an anterior forceps (or forceps minor) in the frontal lobe, a middle portion (body) in the frontoparietal region, and a posterior forceps (or forceps major) in the occipital lobe; on either side of the brain the tapetum stretches out into the temporal lobes. Other criteria have been adopted to subdivide the corpus callosum.

e most common methods segment the corpus callosum as seen in mid-sagittal section. Classical anatomical subdivisions of the corpus callosum include (from anterior to posterior) the ros- trum (orbitofrontal cortex), genu (prefrontal cortex), body (motor and premotor cortex), isthmus (temporal cortex), and splenium

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CHAPTER 8 principles of white matter organization 85

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Corpus callosum

Anterior commissure

radiate anteriorly to the frontal cortex (anterior thalamic peduncle), superiorly to the precentral frontal regions and parietal cortex (superior thalamic peduncle), posteriorly to the occipito-temporal cortex (posterior thalamic peduncle), and infero-anteriorly to the temporal cortex and amygdala (inferior thalamic peduncle).

e three major descending cortico-subcortical projection sys- tems of the corona radiata are the corticospinal and corticobulbar tracts, the cortical e erents to the basal ganglia and the cortical e er- ents, via the pons, to the cerebellum.90,91 e projections to the basal ganglia and cerebellum are indirectly reciprocal, so that the cortex also receives projections from these centres via the thalamus, to cre- ate complex cortico-basal ganglion and cortico-cerebellar circuits. ese projection systems are only partially segregated anatomically as they share several subcortical relay stations (e.g. the thalamus).92

e fornix is also considered as a projection tract for its projec- tions to the hippocampus, mammillary bodies, and hypothalamic nuclei. e fornix is part of the limbic system dedicated to memory and its bres connect the hippocampus with the mammillary body, the anterior thalamic nuclei, and the hypothalamus; it also has a small commissural component known as the hippocampal com- missure.17,51,60 Fibres arise from the hippocampus (subiculum and entorhinal cortex) of each side, run through the mbria, and join beneath the splenium of the corpus callosum to form the body of the fornix. Other mbrial bres continue medially, cross the mid- line, and project to the contralateral hippocampus (hippocampal commissure). Most of the bres within the body of the fornix run anteriorly beneath the body of the corpus callosum towards the anterior commissure.

Above the interventricular foramen, the anterior body of the for- nix divides into right and le columns. As each column approaches the anterior commissure it diverges again into two components. One of these, the posterior columns of the fornix, curves ventrally in front of the interventricular foramen of Monroe and posterior to the anterior commissure to enter the mammillary body (post- commissural fornix), adjacent areas of the hypothalamus, and anterior thalamic nucleus. e second component, the anterior columns of the fornix, enters the hypothalamus and projects to the septal region and nucleus accumbens.60 e fornix also contains some a erent bres to the hippocampus from septal and hypotha- lamic nuclei.52

Short association pathways

A number of short U-shaped bres and intralobar assocation tracts have been described in the human brain using postmortem dissec- tions and, more recently, tractography.107 e role of these tracts is largely unknown. Among the short intralobar association tracts connections, the frontal aslant tract, the frontal orbito-polar tract, and the vertical occipital bundle of Wernicke have been well char- acterized using tractography (Fig. 8.6).

e frontal aslant tract connects the most posterior part of Broca’s territory (i.e. precentral cortex, BA 6, pars opercularis, BA 44) in the inferior frontal gyrus with the pre-supplementary motor area (SMA) in the superior frontal gyrus (BA 8 and 6), the medial prefrontal cor- tex, and the anterior cingulate cortex.26,29,30 is tract is le later- alized in most right-handed subjects, suggesting a role in language. Medial regions of the frontal lobe facilitate speech initiation through direct connections to the pars opercularis and triangularis of the infe- rior frontal gyrus. Patients with lesions to these areas present with various degrees of speech impairment from a total inability to initiate

Fig. 8.4 Tractography reconstruction of the major commissural pathways of the human brain.
Adapted from Catani, Marco, iebaut de Schotten, Michel, Atlas of Human Brain Connections, Copyright (2012), with permission from Oxford University Press.

(occipital and temporal cortex). More recently, di usion tensor imaging has been used to divide the corpus callosum into di erent subregions according to the pattern of its cortical projections.80–84

e anterior commissure is a small bundle of bres shaped like the handlebars of an old bicycle straddling the midline. It is a famil- iar landmark in neuroradiology (e.g. distances in Talairach coor-

e commissural pathways allow the transfer of inputs between the two halves of the brain and play a signi cant role in the func- tional integration of motor, perceptual, and cognitive functions between the two hemispheres.88,89 Several callosal disconnection syndromes have been described in neurology, from anarchic hand syndrome to alien hand syndrome.54

Projection pathways

Projection pathways connect the cortex to subcortical neurons and are usually divided into ascending and descending bres (Fig. 8.5). e largest projection tracts of the cerebral hemispheres are the corona radiata and the fornix.

Within the hemispheres sensory information travels through a complex system of ascending thalamic projections. A er a short course within the internal capsule, the thalamic radiations enter the corona radiata and terminate in the cortex of the ipsilateral hemi- sphere. e e erent thalamic projections to the cerebral cortex

dinates are measured from the anterior commissure as origin). It crosses the midline as a compact cylindrical bundle between anterior and posterior columns of the fornix and runs laterally, at rst through the anterior perforated substance, and then between the globus pallidus and putamen before dividing into an anterior and posterior branch. e more anterior bres connect the amyg- dalae,86 hippocampal gyri, and temporal poles,87 while more poste- rior bres connect the ventral temporal and occipital regions.

Corona radiata

Fornix

Fig. 8.5 Tractography reconstruction of the major projection pathways of the human brain.
Adapted from Catani, Marco, iebaut de Schotten, Michel, Atlas of Human Brain Connections, Copyright (2012), with permission from Oxford University Press.

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Frontal aslant tract Fronto-orbitopolar tract Vertical occipital tract

Fig. 8.6 Tractography reconstruction of three short intralobar bres of the frontal and occipital lobe.

speech (i.e. mutism) to mild altered uency.93,94 e frontal aslant tract is damaged in patients with a non- uent/agrammatic variant of primary progressive aphasia, PNFA,67 and in traumatic brain injury patients with di culties in response inhibition control.105

e frontal orbito-polar bundle is a ventral tract connecting posterior (BA 25 and 11) and anterior orbitofrontal gyri (BA 11) and the frontal pole (BA 10). e posterior orbital gyrus receives inputs from the limbic regions (i.e. amygdala, hippocampus, nucleus basalis of Meynert, olfactory cortex, and insula) and plays an important role in processing olfactory and gustatory inputs and integration of emotions and memories associated with sensory experiences.95

e anterior orbitofrontal cortex receives direct auditory and vis- ual inputs from posterior occipital and temporal cortex through the inferior fronto-occipital and uncinate fasciculus.74,96 e frontal orbito-polar tract represents a transmodal network for binding memories and emotions with olfactory, taste, visual, and auditory inputs. is multisensory association and limbic integration could guide more complex cognitive and behavioural functions, such as reward behaviour associated with sensory and abstract reinforcers (e.g. monetary gain and loss)97 or response inhibition (e.g. go/no-go tasks).98

The vertical occipital bundle of Wernicke was originally described by Sachs in 1892 as an intralobar group of bres con- necting the inferior occipital gyrus (BA 19, 37) with dorsolateral occipital cortex (BA 19) and perhaps posterior parietal cortex (BA 39).25 is tract links dorsal and ventral visual streams and is likely to be involved in reading.27,28

Contribution of white matter to cognition

and behaviour

Optimal cognitive processes rely on an e cient propagation of the action potential along the axons.99 Higher speed of conduction is important, for example, to guarantee a quick response to exter- nal stimuli or to propagate signal to distant regions without delay. e function of white matter tracts is not limited to information transmission but also includes aspects that impact on information processing. Collateral axons, for example, branch o the main axon and generally feed back onto their own neuronal bodies or cortical inhibitory neurons. rough these collateral axons, neu- rons mediate self-modulation of their own ring. Collateral axons and branching are also important to lter, amplify, and distribute signal to multiple cortical and subcortical targets.100 Hence, in a modern view of white matter networks, axonal bres constitute not only conducting devices but also nexuses of convergence and divergence, feedback loops, feed-forward connections, and tran- sition points from serial to parallel processing.101

Historically, the study of white matter function has been hin- dered by the lack of methods for in vivo quantitative measurements of bre anatomy in the central nervous system. Most of the proper- ties of bres have been derived from studies of peripheral nerves, but this may not apply directly to bres of the central nervous sys- tem.50 Tractography can indirectly measure properties of white matter bundles that in uence the speed of signal propagation. Indeed, preliminary evidence of a direct correlation between dif- fusion-derived anatomical features of individual tracts and behav- ioural performances are forthcoming. e two most important biological axonal features a ecting the speed of conduction of the nervous signal are the axonal diameter and its myelination. In gen- eral, axons with larger diameter o er a weaker resistance along the longitudinal axis and therefore facilitate faster conduction along a direction longitudinal to the main axis. Similarly, heavily myelin- ated axons increase the resistance across the membrane and exped- ite faster longitudinal conduction.49,50

While the axonal diameter of bres is generally determined by maturational processes that occur during early brain development and plateau in adolescence, the degree of myelin produced by oli- godendrocytes changes quite rapidly in relation, for example, to the frequency of ring of speci c groups of bres engaged in certain cognitive processes. is explains, for example, why changes in myelin can occur a er intense training.102

Tractography can help advancing our understanding of cogni- tive disorders. In older age, white matter changes occur in relation to reduced number of myelinated bres, gliosis, and ischaemic damage. Depending on the location, white matter changes have a signi cant impact on cognition.103 e study of white matter connections with tractography is becoming an important tool for quantifying tissue damage, perhaps in regions where white mat- ter changes are not visibile on conventional MRI. Furthermore, the use of tractography or tractography-derived atlases could improve localization of white matter damage along critical path- ways. Finally, individual di erences in tract anatomy (e.g. lateral- ization) could have important implications for understanding variability in cognitive and behavioural performances. It may also help to identify patterns of vulnerability and resilience to brain disorders.106

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CHAPTER 8 principles of white matter organization 89

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Introduction

function. ey may alternatively change voltages in ion channels so as to alter the excitability of the cell. Additionally, the concentra- tion of neurotransmitter in the synaptic cle is regulated not only by catabolic enzymes, for example, monoamine oxidases in the case of the monoamines and acetylcholine esterase in the case of acetylcho- line, but also pre-synaptic transporters that enable reuptake of the released neurotransmitter back into the pre-synaptic cell.

Many factors contribute to the ‘ delity’ of the signalling imping- ing on the post-synaptic cells and involve, for example, neuro- modulatory neurotransmitters that act conditionally on the cell, depending on its current state (see reference 3). ese neuromodu- lators, which include the classical monoamines dopamine (DA), noradrenaline (NA), and serotonin (or 5-hydroxytryptamine, 5-HT), usually tend to have a spatially and temporally less precise mode of action than the amino acid ‘fast signalling neurotransmit- ters’, and may operate over a longer timescale than glutamate or GABA. ey too may work via several receptors, there being over 15 serotonin receptors, for example.2

It is also now clear that more than one neurotransmitter may be released from a single neuron, in contradistinction to Henry Dale’s original principle. is principle of co-transmission, which gener- ally involves a neuropeptide as the co-transmitter, has been shown to hold, for example, for dopamine cells (where the neuropeptide is cholescystokinin), noradrenaline (neuropeptide Y), and acetylcho- line (Ach), vasoactive intestinal polypeptide (VIP). As these neuro- peptides may also play some role in the peripheral nervous system, this exempli es the principle of central and peripheral signalling by the same molecule acting as a hormone as well as a neurotransmit- ter. For more detail on basic neurochemistry and neuropharmacol- ogy the reader is urged to consult Cooper, Bloom, and Roth.2 e main neurotransmitters mentioned above are listed in Table 9.1.

Functions of neurotransmitter systems

and pathways

Although neurotransmitters may participate in a range of func- tions, their distribution nevertheless is not all random in the brain and their anatomical pathways may be quite speci c, o en for evo- lutionary reasons that are not entirely clear (Fig. 9.1). For example, there are two distinct ascending noradrenergic pathways, only one of which richly innervates the neocortex and forebrain. However, there is very sparse innervation of the basal ganglia by noradrena- line, which by contrast receive rich dopaminergic and serotonin- ergic inputs. Indeed, the discoveries concerning innervation of the caudate-putamen by the dopaminergic pathways of the substantia nigra and the production of Parkinson’s disease by degeneration of

CHAPTER 9

Neurochemistry of cognition

Trevor W. Robbins

Cognition and behaviour are among the more obvious outputs of brain functioning and are inextricably linked, not only to themselves, but to neuronal networks that depend ultimately on chemical neurotransmission.1 In fact, less than 70 years ago it was considered controversial to believe that the brain used chemical neurotransmitters at all. It was shortly agreed that only two such substances existed (with excitatory and inhibitory functions), and we have now come to realize that the brain employs probably over 50 such molecules, sometimes in the same neurons.2 e 1960s saw enthusiasm for the ‘chemical coding’ of behaviour, doubtless stimulated by the discovery of the triplet genetic code. However, this is now considered to be a rather naïve viewpoint, given that neurotransmitters can be dispersed in many di erent neuroana- tomical locations in distinct neuronal circuitries with obviously di erent functions, including, for example, the peripheral nervous system, and the now common observation that the same molecule can function as a blood-borne hormone as well as a speci c neuro- transmitter. Incidentally, this does of course imply that a drug spe- ci cally a ecting a single neurotransmitter is bound to a ect more than one function, producing obvious side-e ects of medications.

ere are now agreed criteria for classifying chemical neuro- transmitters, depending on considerations such as whether they are synthesized in neurons, released following action potentials into the synapse, where they may bind to receptor proteins and are eventually metabolized or recycled for example by so-called reup- take systems utilizing transporter molecules.2

Today, most classi cations of neurotransmitters agree that there are ‘fast signalling’ molecules, generally working directly on ion channel (‘ionotropic’) membrane receptors and responsible for the functioning of large-scale neural networks such as those in the cer- ebral cortex, hippocampus, striatum, and cerebellum.2,3 Glutamate is the most prevalent excitatory amino acid neurotransmitter and gamma aminobutyric acid (GABA) the major inhibitory amino acid transmitter employed in such networks. ey have major functions in the control of cortical neuronal activity, including oscillations at various frequencies, and are implicated in such diverse functions as learning and memory and speech on the one hand, and the control of epileptiform activity on the other.

Although it is quite common for computational modelling of neu- ral networks to operate on the assumption that nodes of connec- tions may be switched on or o , corresponding to the likely modes of action of glutamate and GABA respectively, it is evident that these and other neurotransmitter systems function in a far more sophis- ticated way, o en at multiple receptors, both pre- and postsynap- tic and involving biochemical e ects on G-proteins essential to cell

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92 SECTION 1 normal cognitive function Table 9.1 Major chemical neurotransmitters

potentiation (LTP), the incremental response shown by neurons consequent upon prior experience of high-frequency, tetanizing stimulation.6 (A decremental response is termed complementarily, long-term depression (LTD).)

ese phenomena were originally found in hippocampal cir- cuitry (dentate gyrus and CA1-3) but have now been characterized in many regions, including the neocortex (including both visual cortex and prefrontal cortex), the amygdala, parts of the striatum, and cerebellum. ese brain regions are of course implicated in diverse aspects of perception and memory as well as other com- ponents of cognition. However, the question is to what extent LTP/ LTD processes actually re ect behavioural learning?

is question was addressed in an important study in which it was shown that D-2-amino-5-phosphonopentanoic acid (AP-5), a competitive antagonist at the glutamate N-methyl-D-asparate (NMDA) receptor subtype, signi cantly impaired learning in a spatial navigation escape task sensitive to hippocampal damage in the rat when infused into the ventricle at doses also blocking LTP measured in vitro in tissue slices.7 Pre-trained, established per- formance was una ected, indicating that the e ects could not be attributed to ancillary processes such as motivation, perception, or motor function. us it was concluded that the NMDA receptor, probably acting as a ‘coincidence detector,’ mediated plasticity or associative learning mechanisms.

ese results have now been con rmed for a number of other learning paradigms, from aversive contextual Pavlovian condition- ing,8 fear-potentiated startle,9 discriminated approach behaviour10 including ‘autoshaping’,11 and experience shaping the development of the visual cortex12 to conditioned taste aversion, and the chick imprinting response.13 ese observations are all consistent with a role for glutamate receptors in many forms of learning and mem- ory, dependent on several distinct brain regions.14

e relative contributions of LTP and LTD to learning in di er- ent systems remains an interesting question. On the one hand, it appears that quite common molecular mechanisms may be impli- cated in super cially di erent forms of learning and memory. One intriguing possible exception may be stimulus-response habit learn- ing, which is generally associated with circuits including the dorsal striatum (speci cally, the putamen). Lovinger15 has described pos- sibly distinct forms of LTP/LTD implicated in striatal mechanisms of goal-directed, as compared to stimulus-response habit, learning.

e ‘post-trial’ paradigm, where drugs are administered to dis- turb the consolidation of memory at some time following training or experience, can be used to dissect the components of underlying memory processes.16 e e ect of such drugs on memory can be measured in a subsequent retention or retrieval test performed some time a er (usually one to three days) initial training (see Fig. 9.2a). If a drug produces de cits—or improvements—in later retention when administered soon a er training but not at a later time-point, including at the time of retention testing itself, this is good evidence for a speci c e ect on memory consolidation. However, if a drug only a ects retention, then it is likely that it is producing general performance e ects, although possibly on memory retrieval pro- cesses. A great deal of evidence indicates that NMDA receptors are implicated in the initial encoding and consolidation of the memory trace, but not in its subsequent retrieval.14

NMDA receptors are implicated in consolidation and also in a related, hypothetical process of ‘reconsolidation’ (Fig. 9.2b), redis- covered through work in experimental animals that may have

Classical neurotransmitters

‘Fast signalling’

Receptors

Glutamate (excitatory) (GLU)

NMDA, AMPA, Kainate

Gamma-aminobutyric acid (inhibitory) (GABA)

GABA-a, GABA-b

‘Slow modulatory’

Acetylcholine (Ach)

Nicotinic, muscarinic

Dopamine (DA)

D1–D5

Noradrenaline (NA) (norepinephrine)

alpha1,2; beta 1,2

Serotonin (5-hydroxytryptamine, 5-HT)

At least 15, including 5-HT1a, 5-HT1b, 5HT2a, 5-HT2c, 5-HT3, 5-HT6 etc.

Neuropeptides

Very slow modulators/co-transmitters

Cholecystokinin (CCK)—co-transmitter for DA

CCK-A, CCK-B

Neuropeptide Y—co-transmitter for NA

NPY1R, NPY2R

Vasoactive intestinal polypeptide (VIP)—co-transmitter for Ach

VPAC1, VPAC2

Oxytocin, Vasopressin, etc

OXTR, V1–V3

Reproduced from Robbins TW, Cognitive psychopharmacology. In: K Ochsner and
S Kosslyn (eds). Handbook of Cognitive Neuroscience, Copyright (2014), with permission from Oxford University Press.

that pathway have led to a considerable research focus on the role of dopamine in motor control.

In experimental terms, the functions of these systems can be stud- ied by the use of speci c ligands, receptor agonists, and antagonists, and by the use of selective neurotoxins such as 6-hydroxydopamine (for DA- and NA-containing cells), 5,7 dihydroxytryptamine, (5-HT cells), and 192-IgG-saporin, the immunotoxin (Ach cells). Additionally, neurotransmitter systems can be studied in combi- nation with other techniques to achieve correlative analyses with behaviour, including positron emission tomography, electrophysi- ology, microiontophoresis, in vivo microdialysis, in vivo voltamme- try, optogenetics, and transgenic mice with knock-out or knock-in of speci c receptor proteins.1,4

Glutamate systems: e neurochemistry of cognition and learning

5
Hebb was among the rst to consider the network properties of

the brain and how neuronal circuits might participate in percep- tion and learning. A major insight concerned the possible plastic- ity inherent in such networks and its contribution to learning and memory. In particular, he predicted that the coordinated ring of two or more neurons might result in the storage of a memory trace via transient, reverberating neuronal activity that somehow was converted to a longer-term structural change in the nerve cells, biasing them to re in future to similar inputs. Indirect evidence for this type of change was later provided by the discovery of long-term

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(a)

Ascending Arousal Systems: Neuromodulatory transmitters in the rat brain

Dopamine

Serotonin-(5-HT)

(b)
NC

PFC

Cingulum

Noradrenaline

Acetylcholine

Monoaminergic and cholinergic systems in the brain

NC
TH THNC

PFC

HT
HT NC OB CER

HC LC

CER AMY
HC ENTHC COR

VS
AMY OLF+ CER

LAT TEG CER COR

PFC S TH DB NBM

OB AMY

Noradrenaline SC

NC
NC

Serotonin

PFC

DS
OB

VS AMY

CER

VTA SN
SC

Dopamine

CER COR

Midbrain dorsal tegmental system

CER COR

Fig. 9.1 Ascending monoaminergic and cholinergic arousal systems in the (a) rat and (b) human brain (sagittal section), based on histochemical and immunocytochemical analysis.91,92 Similar systems are conserved in the primate, including human brain. Abbreviations: (a) PFC, prefrontal cortex; MFB, medial forebrain bundle; CTT, central tegmental tract; DNAB, dorsal noradrenergic ascending bundle; VNAB, ventral noradrenergic bundle. A1–A10, catecholamine cell groups. Cx, cortex. Ms, medial septum. VDAB, vertical limb of the diagonal band of Broca; HDAB, horizontal limb of the diagonal band of Broca. NBM, nucleus basalis magnocellularis (cell group Ch4); tpp, pedunculopontine tegmental nucleus (cell group Ch5); dltn, laterodorsal tegmental nucleus (cell group Ch6); ICj, islands of Calleja; SN, substantia nigra; IP, interpeduncular nucleus; DR, dorsal raphé nucleus. DS, dorsal striatum, VS, ventral striatum. B1–B9, indoleamine cell groups. (b) Monoaminergic and cholinergic systems in the human brain. Abbreviations: PFC, prefrontal cortex; NC, neocortex; OB, olfactory bulb; TH, thalamus; DS, dorsal striatum (caudate-putamen); VS, ventral striatum (nucleus accumbens); S, septum; DB, diagonal band of Broca; NBM, nucleus basalis of Meynert; AMY, amygdala; HC, hippocampus; HT, hypothalamus; SN, substantia nigra; VTA, ventral tegmental area; CER cerebellum (nuclei); CER COR, cerebellar cortex. OLF +ENT, olfactory and entorhinal cortex; LAT TEG, lateral tegmental nuclei; origin of the ventral noradrenergic bundle; LC, locus coeruleus; RN, raphé nuclei; SC, spinal cord.
(a) Reproduced from Robbins TW and Everitt BJ. Arousal systems and attention. In: M Gazzaniga (ed.). e Cognitive Neurosciences. pp. 703–20. Copyright (1995), with permission from MIT Press. (b) Reproduced from Heimer L. e Human Brain and Spinal Cord: Functional Neuroanatomy and Dissection Guide. pp. 232–4. Copyright (1983), with permission from Springer.

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SC Acetylcholine

94 SECTION 1 (a)

normal cognitive function

Attention, encoding (working memory)

Learning

Consolidation Memory

Post-trial treatments

Retrieval
(working memory)

(b) Retention test, (5 minutes)

Pre-trial treatment

Recent evidence suggests that both destabilization and restabi- lization implicate the NMDA receptor, but intriguingly these two processes can be dissociated pharmacologically by GluN2B and GluN2A receptor antagonists, respectively. us the former pro- tects consolidated CS-fear memories from the e ects of amnesic agents,19,20 whereas it is the GluN2A receptor that is necessary for reconsolidation itself.20

Another important question is the role of other glutamate recep- tor subtypes. For example, the changes in neuronal plasticity e ected by NMDA receptors are ultimately mediated by the fast depolarization of post-synaptic cells via the AMPA receptor sub- type.21 However, AMPA receptor antagonists generally cause more general impairments. us, for example, NMDA-receptor blockade within the hippocampus impaired encoding, but not retrieval of avour-place associative learning in rats. Whereas AMPA receptor blockade using CNQX (6-cyano-7-nitroquinoline-2,3-dione) dis- rupted both encoding and retrieval.22

ese di erential e ects of manipulating the NMDA and AMPA receptor have also been shown for potentially ‘declarative’ forms of memory such as recognition. Winters and Bussey23 infused selective NMDA and AMPA receptor antagonists into the perirhinal cortex of rats at various stages of training and performance of an object rec- ognition task. ey found that the NMDA receptor antagonist did not impair initial encoding of the object but did impact on its con- solidation into long-term memory. However, the same treatment had no e ect when made just prior to the retention test, whereas the AMPA receptor antagonist (CNQX) disrupted retrieval, similar to the e ects of these agents on associative memory in the hippocam- pus. Intriguingly, in the amygdala, AMPA receptor antagonism has been shown to have relatively little e ect on memory destabilization or restabilization, despite also impairing retrieval of a CS-fear asso- ciation.20 us, the glutamate receptor subtypes have remarkably speci c e ects on di erent components of memory processes.

Studies with mice that lack the AMPA receptor subunit A have also been shown to have signi cant e ects on spatial working memory tasks (though not in long-term spatial memory), add- ing to previous evidence of NMDA receptors in working memory functions.24 is is of particular interest given that drugs such as the NMDA non-competitive antagonist (and dissociative anaes- thetic) ketamine causes working memory de cits in humans.24

Roles in processes such as working memory for glutamate recep- tors raise the interesting issue of whether other cognitive functions, including so-called executive functions, are mediated by gluta- mate receptors. us, evidence in rats of apparent impairments in attentional set-shi ing following acute or chronic treatment with NMDA receptor antagonists26 may be related to similar di cul- ties with the Wisconsin Card Sorting test exhibited by patients with schizophrenia. It appears likely that most neocortical functions involving processing and plasticity are in uenced by glutamatergic mechanisms; it is a challenging question whether this conclusion could lead to clinical application.

Potential cognitive enhancing e ects of glutamate

receptor agonists

Many important clinical disorders from epilepsy to schizophrenia and Alzheimer’s disease involve disruptions of glutamatergic sig- nalling and so it is logical to ask whether they could be remedied by drugs with appropriate glutamatergic mechanisms. Obvious and

Home cage context (e.g. 1–7 days)

Acquisition trial, 5 minutes

(b)

Memory consolidation/reconsolidation processes

Working memory

Consolidation

Long term memory

Pre-trial treatment

Active State (labile) Reconsolidation Inactive State (Stable)

Reactivation

Retrieval/destabilization

Fig. 9.2 (a) e one- trial learning, post-trial treatment memory design, in which manipulations are made post-trial to de ne time-limited memory consolidation processes, as measured during the memory retention test (see e.g. reference 16). (b) Symmetrical processes of memory consolidation and reconsolidation. Reactivating former consolidated memory traces (e.g. by reminder stimuli) can render their retrieval vulnerable to disruption, e.g. by NMDA receptor antagonists or protein synthesis inhibition, thus ‘erasing’ the memory trace (see also reference 17).

clinical implications in the treatment of neuropsychiatric disor- ders such as post-traumatic stress disorder and drug addiction. Reconsolidation is said to occur when a previously consolidated memory trace becomes ‘active’ upon a reminder cue. It is the pro- cess by which previously consolidated memories become stabi- lized at retrieval and then require ‘restabilization’ to persist in the brain.17

In the destabilized state the memory trace is ‘labile’ and can be disrupted by treatment with protein synthesis inhibitors and other amnesic agents including NMDA receptor antagonists (infused into the amygdala), with the result that memory reten- tion is impaired when tested a few days later. e implication is that when a memory trace becomes active, it undergoes updat- ing and ‘reconsolidation’ or restabilization as an essentially new memory trace.

e reminder cue is necessarily presented in the absence of the event it signals, and so this is akin to one-trial ‘extinction’, an active process by which an association is suppressed (o en resulting in a reduction of behavioural output). Intriguingly, extinction is also NMDA-receptor-dependent. us NMDA antagonists are known to block the extinction of learned fear, again when infused into the amygdala.18 In a complementary fashion, extinction is accelerated by a glutamate receptor agonist, D-cycloserine, a nding that has been used to enhance e ects of behavioural therapy of patients with anxiety disorders.

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possibly insurmountable problems include the action of such drugs to produce epileptic seizures and neurodegeneration; however, there are some indications that such ‘cognitive enhancing’ e ects might be feasible. us D-cycloserine, which acts at the strychnine- insensitive glycine recognition site of the NMDA receptor complex to boost NMDA signally, has been shown to improve learning and memory in several situations in rodents and primates. Small bene – cial e ects have also been reported in clinical studies of Alzheimer’s disease and schizophrenia (see reference 14 for a review).

e discovery of another class of glutamate receptors, the metabotropic receptors, also o ers some grounds for optimism in modulation of glutamate-mediated neurotransmission. For exam- ple, animal models of schizophrenia27 and Rett’s syndrome28 have shown bene cial e ects of both mGluR5 receptor potentiators (positive allosteric modulators) and mGluR receptor antagonists. An alternative approach depends on drugs causing positive allos- teric modulations of the AMPA receptor, called ‘AMPA-kines’. ese agents have been tested in both human memory (verbal list learning), where a signi cant improvement was observed in elderly individuals with relatively low baseline levels of performance,29 and also in studies of visual recognition memory in non-human pri- mates. In the latter study, Porrino and colleagues30 demonstrated impressive, dose- and delay-dependent improvements in recogni- tion memory in rhesus monkeys (Fig. 9.3) that were accompanied by changes in cerebral blood ow in the temporal lobe and dorso- lateral prefrontal cortex. However, to date, the use of AMPA-kines as cognitive enhancers has not been validated in a clinical trial.

GABA: Inhibitory neurotransmission

and cognition

GABA is the key inhibitory neurotransmitter in the brain synthe- sised from glutamate by the enzyme glutamic acid decarboxylase (GAD). It is responsible for the e cient functioning of several types of inhibitory interneuron which prevent overactivity in many neural circuits, especially in the cerebral cortex, hippocampus, and striatum (for which GABA-containing medium spiny cells are the major outputs) (see reference 2). Although it is not logically nec- essary for neuronal inhibition to translate into behavioural inhi- bition, it is the case that drugs simulating e ects of GABA-ergic agonists o en have behavioural disinhibitory actions.

Benzodiazepine drugs such as chlordiazepoxide (Librium) and diazepam (Valium) are the best known anxiolytic agents, which also have sedative, amnesic, and anticonvulsant actions. ese drugs act at those GABAA receptors with a particular constella- tion of GABA receptor subunits. us, they act as positive allos- teric modulators and enhance phasic inhibition by improving the e cacy of GABA itself in opening inhibitory chloride channels. e sedative, anticonvulsant, anxiolytic, and amnesic e ects of benzodiazepines appear to depend on di erent con gurations of subunits at the benzodiazepine receptor which are prevalent in dif- ferent brain regions.31 For example, it is thought that the anxiolytic actions depend to a large extent on GABA receptors in the amyg- dala, which is classically associated with fear and anxiety.

By contrast, the amnesic actions appear to be linked to an alpha- 5 subunit in GABA receptor subtypes mainly in the hippocampus. A drug acting speci cally as an inverse agonist at this GABA recep- tor subtype has been shown to antagonize the amnesic e ects of alcohol which partly depend on the activation of GABA receptors.32

CHAPTER 9 neurochemistry of cognition 95 Normal Vehicle

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1–5 6–10

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Dose-dependent improvements in recognition memory in rhesus monkeys following treatment with an AMPA-kine (CX-717). Recognition memory was measured in a delayed non-matching to sample test that also varies memory load (the length of the list of visual objects that has to be remembered before retention testing). Monkeys were required to remember which of two visual discriminanda is more novel and choose it in a 2-choice test over a previously presented, and hence ‘familiar’ stimulus after various delays between presentation of the sample and the choice test.
Reproduced from PLoS Biology. 3(9), Porrino LJ, Daunais JB, Rogers GA, et al. Facilitation of
task performance and removal of the e ects of sleep deprivation by an ampakine (CX717)
in nonhuman primates. pp. e299, Copyright (2005), with permission from PLOS, reproduced under the Creative Commons CC BY License.

Intriguingly, the amnesic e ects of benzodiazepines do not appear to be secondary to the drugs’ sedative actions as the sleep-inducing or hypnotic actions of certain benzodiazepines (such as triazolam or Halcion) are dependent on an independent GABA receptor subunit population in hind-brain sites distinct from the hippocampus.31

GABA in inhibitory neurons plays an important role in the gen- eration of so-called gamma oscillations in the gamma rhythm com- ponents of the electro-encephalograph (EEG).33 Gamma rhythms are observed in many brain regions during states of wakefulness and sleeping, yet their precise functions and mechanisms are still unknown. Gamma-band rhythms are produced by neuronal inhibi- tion. Gamma oscillations are usually transient and are the product of a coordinated interaction of neuronal excitation and inhibition, detected as local eld potentials. Gamma rhythm is generally cor- related with the irregular ring of single neurons, and the network frequency of gamma oscillations varies extensively.

Gamma oscillations per se have to be distinguished from mere increases of gamma-band power and spiking activity, and their magnitude is modulated by slower rhythms which may serve to

Fig. 9.3

p<0.001 vs 2 Image 21–25 26–30

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*p<0.01, **p<0.001 vs Normal Vehicle

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96 SECTION 1 normal cognitive function

‘couple’ activity in di erent cortical circuits. Gamma oscillations are thus thought to be important mechanisms for coordinating activity across widespread neural networks such as the hippocam- pus and prefrontal cortex in such behavioural processes as working memory.34 us, cognitive de cits in disorders such as schizophre- nia probably result from the disruption of neuronal population dynamics as a consequence of cortical pathology, including the loss of parvalbumin containing GABA-ergic cortical interneurons.35

Monoamines: Serotonin

(5-hydroxytryptamine, 5-HT)

Serotonin is a ubiquitous and ancient neurotransmitter (even being present in invertebrates such as Aplysia) with over 15 distinct recep- tors. It rami es extensively from cell bodies in the mid-brain dorsal and raphé nuclei to virtually all regions of the mammalian brain (see Fig. 9.1). It has been implicated as a neuromodulator in virtu- ally all behavioural processes from sensory input to motor output, including motivation and cognition.2

Serotonin also plays a central role in mood and emotion, but it is part of major paradox in being sometimes associated with anx- iety when up-regulated and depression when down-regulated, even though these two states overlap considerably.36 Depression—and many anxiety disorders including panic—is o en treated with selective serotonin reuptake inhibitors (such as uoxetine or Prozac), their chronic e ects being associated with up-regulation of serotoninergic function. By contrast, anxiety is sometimes treated with drugs that reduce serotonin release; for example, by acting as agonists at 5-HT autoreceptors (buspirone).

Classically, in animal studies serotonin has also been associated with enhancing the activity of a punishment system, as opposed to a hypothetical (dopamine-modulated) reward system, which medi- ates behavioural suppression or inhibition. is is also consistent with evidence that depletion of serotonin is also linked to behav- ioural disinhibition, in the form of both impulsive behaviour (i.e. premature or risky behaviour), and compulsive behaviour (in the form e.g. of obsessive–compulsive disorder (OCD); OCD is o en treated with high doses of selective serotonin reuptake inhibitors (SSRIs)).37

ese diverse e ects of serotonin are generally considered to be explained by its modulation of distinct systems, perhaps via dif- ferent receptors, but the evidence for this hypothesis is still quite fragmentary. e issue is complicated by the fact that serotonin is implicated in processes as diverse as sensory processing (modu- lated by 5-HT2A receptors, and sometimes hallucinogenic e ects, via 5HT2A agonist drugs such as psilocybin and LSD),38 and eating behaviour, probably mediated via 5-HT2C receptors in the hypo- thalamus.39 ese diverse and apparently non-speci c e ects may nevertheless result from rather speci c modulatory roles of sero- tonin. For example, in explaining the sensory e ects of serotonin modulation it is signi cant that the serotoninergic innervation of the neocortex is heavily biased towards layer 4, that is, the thalamic sensory input (contrasting, e.g. with that of noradrenaline which is mainly biased towards the deeper layers).40

Moreover, serotonin is especially implicated in functions of the ventral prefrontal cortex with its rich serotoninergic innerva- tions. is perhaps explains the special role of serotonin in rever- sal learning which is especially linked to the orbitofrontal cortex (OFC) functioning. us, local depletion of serotonin in the OFC

led to signi cant de cits in reversal learning in marmoset mon- keys which had to learn to shi responding from one visual object to another (previously unrewarded) in order to gain reinforce- ment. is was accompanied by apparent perseverative behaviour and by a tendency to be biased in responding to particular cues.41 Intriguingly, this ‘stickiness’ in behaviour did not extend to shi ing attention between di erent visuoperceptual dimensions present in both stimuli.42 It is possible that these de cits simulate some of the problems exhibited by patients with OCD.

Monoamines: Dopamine: Cognition

and activation

Dopamine (DA) has striking links to behaviour, psychopathology, and neurological disease. e seminal mapping of the mesen- cephalic DA pathways into ramifying mesostriatal, mesolimbic, and mesocortical projections (see Fig. 9.1), as well as the identi – cation of several DA receptors and their signalling pathways have raised important questions about the functions of this important neuromodulatory neurotransmitter.43 e possibly misleading tri- adic division of these projections has suggested discrete and even parallel functions in movement (e.g. Parkinson’s disease, dorsal striatum), reward (e.g. drugs of abuse, nucleus accumbens), and cognition (e.g. schizophrenia and attention de cit/hyperactiv- ity disorder (ADHD), prefrontal cortex). However, although this tripartite parcellation is attractively parsimonious, there is con- siderable evidence for overlapping functions (e.g. of cognition in the caudate-putamen and reinforcement in OFC). Similarly, the mediation of reward by DA-dependent functions of the nucleus accumbens also entails an implication in learning and cognitive decision-making processes.

A key issue is under what states or conditions the central DA systems become active and how this activity a ects cognition, behaviour, and movement. ere are considerable neurochemical data indicating that central DA is a ected by such factors as stress and arousal. A particularly useful principle, applied especially to the understanding of the relationship between DA activity and behavioural or cognitive output is the Yerkes–Dodson Law,44 which generally takes the form of an inverted U-shaped function linking level of arousal (or ‘stress’) with behavioural performance (Fig. 9.4). us, whereas performance at low or high values of arousal is rela- tively poor, it is optimal at intermediate values.

When discussing the functions of the dopamine system, we have employed the term ‘activation’ to describe a similar ‘energetic’ con- struct to that of arousal, which is however meant to capture how dopamine a ects the rate and vigour of behavioural (and cognitive, e.g. thinking) output. Unlike ‘arousal’, activation does not connote a simple wakefulness construct associated with neocortical changes, for example in EEG (cf reference 45). As posited in Robbins and Everitt’s review45 of the considerable empirical data already then available, activation is induced by many related states or stimuli, including food deprivation, ‘stress’, psychomotor stimulant drugs, aversive stimuli such as tail-pinch and foot-shock, novelty and conditioned stimuli, including predictors of appetitive events such as food and also aversive events. e function of ‘activation’ is to enhance behaviour in preparation for the presentation of a goal or reinforcer (whether appetitive or aversive).

Activation a ects processing in target structures innervated by the mesolimbic, mesocortical, and mesostriatal pathways,

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‘Difficult task’

Optimal performance

that easy tasks were optimally performed at higher levels of arousal than di cult tasks, suggests it might not be. Recent evidence from Parkinson’s disease has shown that therapeutic doses of L-Dopa can improve some aspects of cognition, while impairing others, even in the same patient.54

(ii) Are there inverted-U shaped functions for the sub-cortical DA systems, as well as for prefrontal DA D1 receptors? Some recent evidence55 suggests that this is the case.

(iii) And, relevant to other neuromodulators such as noradren- aline and acetylcholine to be reviewed below, are their actions on behaviour and cognition also to be described in terms of inverted-U-shaped functions, possibly in other brain regions than the prefrontal cortex or striatum?

Monoamines: Noradrenaline

(NA): Cognition and arousal

e central noradrenergic (NA) systems arise from two major systems in the brain-stem, the dorsal and ventral noradrenergic ascending bundles (Fig. 9.1). e former, arising in the locus coer- uleus, is more likely to be implicated in cognitive function, inner- vating as it does, among other structures, the cerebral cortex and hippocampus. is is of considerable clinical interest, given the implication of NA pathology in such varied disorders as Parkinson’s and Alzheimer’s diseases, Korsako ’s syndrome, post-traumatic stress disorder (PTSD), and attention de cit hyperactivity disorder (ADHD). e ventral noradrenergic bundle, by contrast, inner- vates the hypothalamus and portions of the limbic system and is implicated in vegetative functions. ese systems, as for the other monoamines, are implicated in response to stress and arousal. e locus coeruleus itself plays an important role in sleep–waking and in the production of the EEG and the P300 cortical potential (see reference 56 for a recent review).

Electrophysiological investigations have shown that the locus coeruleus responds mainly to salient stimuli, regardless of their precise temporospatial characteristics. is salience is provided especially by the novelty, as well as the intensity, of stimuli from all of the sensory modalities, and also by conditioning. us, familiar stimuli, which lose salience by habituation, do not activate locus coeruleus NA cells. Overall, the coeruleo-cortical NA projections behave like a classical arousal system, being most active in waking, and least active during REM sleep.57

In view of its extensive forebrain projections, NA, like 5-HT, has been implicated in a variety of functions including arousal, stress responses, anxiety, executive control, and memory consolidation. An early theoretical proposal was that the the locus coeruleus functioned akin to the ‘cognitive arm’ of a central sympathetic gan- glion.58 e relationship between arousal (or the noradrenaline sta- tus) and cognition may also operate according to the inverted-U Yerkes–Dodson principle described above, as shown by Arnsten59 in her studies of e ects of adrenoceptor agents on working memory.

However, a notable hypothesis has been that the coeruleo- cortical NA system enhances selective attention by enhancing ‘signal-to-noise’ processing. Precisely how this is done is not abso- lutely clear, although many studies point to the general reduction in neuronal ring produced by microiontophoresis of NA onto cor- tical cells, which may have the e ect of reducing ‘noise’. Segal and Bloom60 have shown that locus coeruleus stimulation can increase

Arousal, Activation, Stress

Fig. 9.4 e Yerkes–Dodson (1908) inverted U-shaped relationship between levels of arousal (or activation, or stress) and levels of performance on a variety of di erent tasks. Note that optimal performance is obtained at intermediate doses of the drug, Note also that optimal levels of arousal are higher for ‘easy’ than for ‘more di cult’ tasks.
Reproduced from Robbins TW, Cognitive psychopharmacology. In: K Ochsner and S Kosslyn (eds). Handbook of Cognitive Neuroscience. Copyright (2014), with permission from Oxford University Press.

essentially in ‘gain-ampli catory’ mode. In the mesolimbic projec- tions, for example to the ventral striatum, including the nucleus accumbens, the role of enhanced DA activity is to increase respon- siveness to cues paired with reinforcement and thus also to enhance appetitive approach to the goal. is is very similar to Berridge’s concept of ‘incentive salience’46 and is related to other earlier writ- ings on the role of DA in motivation.47

Another major empirical advance has been that the fast phasic ring of cells in the ventral tegmental area and substantia nigra appears to encode an error prediction signal.48 Such a neural signal is highly relevant to some models (Pavlovian or temporal di er- ence) about how we learn new information. us, with training, the phasic DA cell ring occurs in response to conditioned stimuli (e.g. visual ash) that are predictive of reward rather than to the reward itself (e.g. food). However, if the reward is omitted, there is a ‘dip’ in ring, as if the signal encodes an error in the prediction. is pattern of activity conforms to the changes in associative learning described by the Rescorla–Wagner rule.48

ere is an evident need to understand the relative functional contribution of such phasic responses—implicated in plasticity and new, mainly appetitive learning of Pavlovian associations— with the tonic mode of action of the same DA systems assumed to underlie the activational (e.g. motivational) e ects of DA.49,50 It is also unclear at present precisely how DA contributes to aversive learning.

e Yerkes–Dodson principle has been o en criticized in experi- mental psychology for its apparent capacity to account for diverse datasets rather too readily. However, it does conform to many dose- response relationships found for drug e ects on behaviour, which o en have characteristic inverted-U shape functions. e principle was applied initially to important data suggesting that the level of DA D1 receptor activity produced Yerkes–Dodson-like e ects on working memory in both rats and monkeys.51 A more recent manifestation of the principle was shown in work on the catechol- O-methyl transferase polymorphism which hypothetically modu- lates prefrontal DA function and produces a predictable pattern of e ects on working memory performance.52,53

However, these data raise several important issues:

(i) Is the function relating DA to performance the same for all forms of behaviour? e nding of Yerkes and Dodson (1908)

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98 SECTION 1 normal cognitive function

or decrease evoked cell ring within terminal regions of the den- tate gyrus of the hippocampus, depending on the salience of the stimulus.

e evidence linking NA to attentional functions, including vigi- lance, has come from two main sources:

. (i) E ects on attentional performance in a rodent test of sustained attention, the 5-choice serial reaction time task (5-CSRTT). Speci cally, rats with profound forebrain NA deletion were impaired at detecting visual targets when these were tempor- ally unpredictable or in the presence of distracting noise.61

. (ii) Electrophysiological recording from locus coeruleus NA cells in monkeys during attentional performance. Here the nding was that optimal attentional performance occurred during tonic ring phases, whereas performance was suboptimal dur- ing heightened tonic ring.62

ese e ects on attention may underlie many of the other actions of central NA on functions such as learning, memory, and cognition. For example, considerable evidence links aversive memory consoli- dation to noradrenergic modulation of the amygdala;16 moreover, memory reconsolidation in rats63 and humans64,65 is blocked by the beta adrenoceptor blocker propanolol.

Central NA also contributes importantly to performance by rats on an attentional set-shi ing task where subjects are required to shi their attention from one aspect or dimension (such as its shape or colour) of a complex stimulus to another (a model of the human Wisconsin Card Sort Test of cognitive exibility and pre- frontal cortical functioning mentioned above).66 Whether similar e ects can be shown in humans will depend on whether drugs that selectively activate noradrenergic receptors can be employed. It is of interest that the psychomotor stimulant drug methylphenidate, used (as Ritalin) in the treatment of ADHD, acts not only to block the actions of the dopamine transporter but also the noradrena- line transporter, and so it is possible that both actions contribute to the e ects of methylphenidate to improve attention and working memory, and also to enhance cognitive control or executive func- tion (see review in reference 67).

Atomoxetine is a drug also used in the treatment of ADHD which has more selective actions in acting mainly to block the noradrenaline transporter, thus avoiding the up-regulation of stri- atal DA that potentially contributes to drug abuse following medi- cation by methylphenidate. Atomoxetine has been shown to have notable actions in reducing impulsive behaviour, and thus enhanc- ing cognitive control, in both rodents and humans.68,69 us, even in healthy volunteers, atomoxetine speeded the stop-reaction time, a measure of the ability to cancel an already-initiated motor response. A similar action has been shown in ADHD.70 Moreover, this apparent improvement in inhibitory control appears to depend on activation of the right inferior frontal gyrus, a cortical region previously implicated in cognitive control.71 It is currently a matter of considerable research interest whether common e ects on atten- tion contribute to these e ects on cognitive control, or whether both functions are independently modulated by central NA.

Acetylcholine (Ach): Roles in attention

and cognition

Acetylcholine (Ach) has been considered as a neurotransmitter for almost a century. Subsequent research in both basic and human

neuroscience has strongly implicated Ach in processes of atten- tion and arousal, parallel to analogous roles for the catecholamines (dopamine and noradrenaline). ere are three major cholinergic tracts, including the midbrain dorsal tegmental system with func- tions in the sleep–waking cycle, the basal forebrain (nucleus basa- lis) system, and the adjacent medial septo-hippocampal projections (Fig. 9.1). However, Ach also functions as a neurotransmitter in interneurons, for example, in the striatum.2

Early work showed bene cial e ects of the anticholinesterase physostigmine on attention in rats as measured in a visual tar- get detection procedure, whereas the antimuscarinic cholinergic receptor antagonist, scopolamine impaired it.72,73 Nicotine was later shown to enhance performance in a sustained attention task in non-smoking humans that required detection of rapidly pre- sented (100/min), speci ed sequences of digits at a single loca- tion.74 Converging evidence in humans from studies of the e ects of scopolamine on cognition also implicated possible e ects of the drug on cholinergically mediated attentional processes.75,76 Soon a er these early behavioural demonstrations of Ach involvement in attention, electrophysiological studies of the V1 area of cat showed apparent e ects of Ach to enhance signal processing in recep- tive elds of visual cortical neurons,77 although some subsequent work78 has failed to con rm this.

Damage to the nucleus basalis in rats using either excitotoxic or immunotoxic lesioning procedures, that typically produced sub- stantial loss of cholinergic terminals in the frontal cortex, sub- stantially disrupted 5-CSRTT performance by rats in terms of impaired detection of brief visual events presented randomly at one of ve locations, de cits later shown to be especially evident at longer test sessions. Such impaired discrimination performance could be remedied by systemic administration of optimal doses of physostigmine or nicotine, as well as by cholinergically enriched neural transplants into the rodent cortex (see review by Everitt and Robbins, reference 79).

Further experiments using intracerebral monitoring of Ach with in vivo microdialysis showed the neurotransmitter to be released in the prefrontal cortex when attentional demands were increased.80 Other experiments using di erent measures of attention in rats and mice have generally con rmed the importance of acetylcholine for attentional function. Sophisticated neurochemical studies involv- ing the monitoring via in vivo voltammetry of choline release as a surrogate index of acetylcholine81 have also been linked to target detection, and its improvement by alpha-4, beta-2 nicotinic ago- nists.82 Indeed, the evidence implicating selective e ects of Ach in attentional performance in rodents is perhaps more convincing than for any of the other major neurotransmitters.

Parallel evidence of cholinergic involvement in attention can be found from investigations of rhesus monkeys with lesions of the nucleus basalis that exhibit speci c de cits in Posner’s test of cov- ert attentional orienting. is nding is consistent with evidence that nicotine enhances attentional orienting in both monkeys and humans, as well as from evidence of augmentation of responses of primary visual cortex neurons in their receptive elds to attended stimuli by iontophoretically applied Ach.83

e demonstration that the intellectual status of patients with Alzheimer’s disease is related to cortical cholinergic loss.84 has highlighted a possible role for cholinergic agents in its remediation. e possible relevance of the basic neuroscience ndings on ace- tylcholine reviewed above was demonstrated by the improvements

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produced by the anticholinesterase drug tacrine on performance of patients with probable Alzheimer’s disease on the same ve- choice serial reaction time task as used in rodents, with concomi- tant improvements in clinical rating scales of attention ‘alerting’.85 Subsequent clinical experience has shown that such medications (e.g. rivastigmine) are also e ective in the treatment of the uctu- ating attentional capacities of patients with Lewy body dementia, who tend to have even more profound reductions of cholinergic function than do patients with Alzheimer’s disease.86

Ach is also implicated in memory functions, including work- ing memory, recognition memory, and semantic retrieval, but it remains to be resolved whether its e ects on attention contrib- ute to these actions, as seems plausible, for example, for memory encoding or resisting interference in working memory. ere may be speci c e ects on memory-related processes, perhaps medi- ated by similar neuronal mechanisms to those of attention, but in brain regions more specialized for memory processing, such as the hippocampus.87

New vistas on novel

neurotransmitters: Neuropeptides

is brief review has considered functions in cognition of the main ‘fast signalling’ (i.e. glutamate and GABA) and ‘neuromodula- tory’ (i.e. the monoamines and acetylcholine) neurotransmitters. As mentioned in the introduction to this chapter, there are at least 50 substances that have neurotransmitter properties and more are being discovered by the year. e largest category that we have not considered in any detail are the neuropeptides, whose actions are generally slow but o en speci c and hormone-like.2 Examples include the gut hormones cholescystokinin and vasoactive intesti- nal polypeptide, adrenaline, corticotrophic releasing factor (CRF), vasopressin, and the opioid peptides such as enkephalin and beta endorphin. Many of these substances have functions in aspects of memory, in conjunction, for example with NMDA receptors and central adrenoceptors. However, there is no very great evidence of major roles in cognitive functions per se, although possible roles, for example in stress, will have indirect actions on such cognitive functions as working memory via the Yerkes–Dodson like in u- ence. Analogously, the discovery of orexin, a hypothalamic neu- ropeptide, has been shown to have functions in motivation and arousal that may similarly impinge indirectly on cognition.

Perhaps one of the most intriguing discoveries has been the pos-

sible role of oxytocin in social cognition. is peptide has been

shown to improve social recognition memory not only in ani-

88
mals, but also in human subjects, where there is evidence of selec-

tive improvement of memory for faces but not non-facial stimuli.89 A classic study indicated that oxytocin administered to humans actually enhanced ‘trust’ in an economic game designed to meas- ure this.90 Such discoveries, with implications for the treatment of disorders such as autism and possibly even of some neurodegen- erative conditions, indicate rich promise for the future study of the psychopharmacology of cognition, and its therapeutic application.

Further reading

Robbins TW. Cognitive psychopharmacology. In: K Ochsner and S Kosslyn (eds). Handbook of Cognitive Neuroscience. Oxford: Oxford University Press, 2013, pp 401–18.

Robbins TW. e neuropsychopharmacology of attention. In: K Nobre and S Kastner (eds). Handbook of Attention. Oxford: Oxford University Press, 2013, pp. 509–40.

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CHAPTER 9 neurochemistry of cognition 101

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SECTION 2

Cognitive dysfunction

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CHAPTER 10

Bedside assessment of cognition

Seyed Ahmad Sajjadi and Peter J. Nestor

Introduction

As with any clinical problem, the history usually provides the most valuable information for assessing suspected cognitive disorders. e key di erence with a history in suspected dementia, compared to other medical consultations, is that cognitive impairment can mean that history from the patient is incomplete or unreliable. For this reason, collateral history from an informant such as a spouse or other individual with close contact to the patient is essential. is is equally true for patients that fall into the ‘worried well’ category who, although cognitively intact and therefore able to tell their own story, may provide a distorted view of the severity of their symptoms. In such instances, an informant can help by providing independent observation of the patient’s ability to manage in everyday life.

A bedside cognitive assessment complements the history and is used to test hypotheses emerging from the patient/informant inter- view regarding the suspected clinical syndrome. Bedside cognitive testing can be impossible to interpret if one does not have a clear understanding of how cognitive abilities in one domain can have knock-on e ects to other domains. For instance, a test purporting to examine executive function may be impossible for an aphasic patient if the test depends on comprehension of instructions or detailed verbal responses. One must be aware, therefore, that a ‘cognitive hierarchy’ exists. In other words, relatively preserved function in particular cognitive domains can be a prerequisite for satisfactory performance of others.

e most striking example of this hierarchy is the necessity of adequate attention for the reliable assessment of all other cognitive domains. In the outpatient setting, it is seldom relevant to examine attention formally in order to decide if further testing can proceed because it is usually obvious from talking to the patient that a pro- found attention de cit is not present. It is also unlikely that, in the outpatient environment, a patient will attend who is su ering from a major delirium. Inpatient referrals for cognitive assessment, how- ever, frequently have reduced arousal and attention de cits in the context of an acute confusional state (delirium) making further in- depth assessments futile. Severe aphasia should also be viewed as an exclusion to further testing in other domains that are language- dependent. Obviously, it is prudent to ensure satisfactory state of basic visual and auditory abilities prior to embarking upon assess- ments of those aspects of cognitive function that are reliant upon these sensory modalities.

Instruments for global assessment

of cognition

Several cognitive assessment tools are available that provide a global score for cognition. Although more expansive batteries will

provide more information, there will be a time penalty; the choice of which battery to use, therefore, mostly depends on local logistical factors—in other words how much time is available to administer a battery. Table 10.1 provides a summary of the briefer assessment tools that are possible to integrate into a standard consultation, and their main pros and cons.

Importantly, a bedside battery can provide invaluable informa- tion about the stage of illness. To this end, incorporating a global battery is particularly useful as it provides a numerical score that can be used to track change over time and provides a straight- forward way of communicating severity to colleagues. e utility of these points cannot be overemphasized. Compiling a medical report in which cognitive assessment is communicated solely on the basis of what the patient could or could not do over a range of ad hoc bedside cognitive assessments can make it impossible for a third party to judge the severity of the impairment. It is impor- tant to stress, however, that the numerical summary scores derived from these batteries are not directly comparable across di erent dementia syndromes. For instance, a score of 25/30 on the Mini- Mental State Examination (MMSE)1 in a typical presentation of Alzheimer’s disease does not necessarily indicate the same level of impairment in everyday life as it would in a behavioural presen- tation of frontotemporal dementia. Using this example, a patient with Alzheimer’s disease and an MMSE of 25/30 will typically have memory impairment but nonetheless, remains fairly independent, whereas a patient with behavioural variant frontotemporal demen- tia with this score, may require high levels of assistance. Within diagnostic categories, however, these scores can be very useful in forming a mental picture of where a patient stands in the course of the illness and, most helpfully, they can be repeated in individual patients to track change over time.

In many instances, a careful history and a global measure are all one needs to make a reasonably con dent diagnosis. Moreover, in situations where the global measure is not adequate to reach a diag- nosis, the pattern of the patient’s performance provides a starting point to tailor cognitive tests of interest for the individual.

Problem oriented cognitive assessment Attention and orientation

Preserved attention and orientation are prerequisites for normal cognitive function and impaired orientation is one of the hallmarks of delirium. Orientation is typically assessed by testing awareness of time and place (and person). Time orientation is speci cally assessed by asking the date, time of day, day of the week, month, season, and year. Place orientation includes items such as town, state/county, name of the hospital, oor, ward, etc. Most of these questions are well covered by the global assessment instruments

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106 SECTION 2 cognitive dysfunction
Table 10.1 Popular global bedside cognitive assessment tools

Test

Description (cut-o point for dementia)

Advantage

Disadvantage

AMTS1

Brief 10-item assessment tool (6–8/10)

Short screening tool for identi cation of cognitive problems; easy to use on general medical wards and in primary care setting

Brevity means it can only be used for very crude staging

MMSE2

Scored out of 30, e most widely used cognitive assessment tool (24/30)

Widely recognized test; objective scoring criteria; very useful staging procedure; brief

Heavily biased to verbal domain; not suitable for di erential diagnosis; not sensitive to very mild impairments

MoCA3

Scored out of 30, aimed at detection of early dementia (26/30)

Relatively comprehensive albeit brief assessment tool; not biased towards particular cognitive domain

Not suitable for patients at the more advanced stages of dementia

ACE4

Scored out of 100, ACE-III is the most recent version of the test (82–88/100)

Robust validation in various neurodegenerative conditions; appropriate for tracking change; sensitive to subtle cognitive impairment and di erential diagnosis

Too long for some clinical environments

Source data from AMTS: Abbreviated Mental Test Score; MMSE: Mini-Mental State Examination; MoCA: the Montreal Cognitive Assessment; ACE-R: Addenbrooke’s Cognitive Examination-revised.

discussed above. Typically, patients with early degenerative diseases are more impaired in time orientation than place, though the latter is also frequently impaired in more advanced stages especially if the assessment is being carried out far from their home (in which case, patients may o en confuse the home town and local hospital with their present location).

One exception is the syndrome of semantic dementia in which one can occasionally encounter patients who are fully oriented in time, but, owing to the semantic de cit, cannot name town, state/ county, name of hospital, etc. Person orientation (i.e. name) is sel- dom informative in the outpatient setting. When an individual can- not produce their own name in the context of an organic disorder, it typically indicates that they are so demented or delirious as to be unable to respond to any verbal instruction. Apparent ignorance of one’s own name in someone who is otherwise capable of communi- cating typically indicates a psychogenic state.

Common bedside tests of attention include spelling a ve-letter word, such as ‘world’, backwards (included in the MMSE), and serial 7s (‘take 7 from 100 and keep going down by 7’, included in both MMSE and MoCA). Forward and backward digit span and recitation of the months of the year or the days of the week in reverse order are further examples. e choice of the appropri- ate test is partly dictated by the presumed cognitive syndrome. For instance, in suspected dominant (le ) hemisphere syndromes such as various types of aphasia one should opt for less language taxing tests such as digit span. Vigilance is another way of assessing atten- tion and concentration. For instance, the examiner asks the patient to listen for a particular letter of the alphabet whilst they read out a list of random letters with the target letter appearing frequently but unpredictably in the list (included in the MoCA). e patient indicates the occurrence of the target letter by tapping each time the letter is read.

Attention testing is clinically useful to monitor change in patients with delirium, such as metabolic encephalopathies. For this pur- pose, digit span—which measures attention and working memory capacity—can be particularly helpful because it provides a quan- ti able score. In testing digit span, individual numbers should be uttered separately in a monotonous way at a rate of one digit/ second (in contrast to grouping numbers in clusters as one would in giving a telephone number). Normal digit span is at least six

forwards, with backward digit span being one or two digits less than the forward span.

Declarative memory

Episodic memory

Episodic memory refers to memory for speci c events from one’s past—such as what one did this morning, on one’s last holiday, one’s wedding day, and so on. Episodic memory impairment is a de n- ing feature of early-stage typical Alzheimer’s disease and is also frequently observed in non-Alzheimer dementias. It is the most common reported problem in a cognitive disorders clinic. It is, therefore, important to have a plan for how it should be examined.

Episodic memory can, in turn, be divided to retrograde, re ect- ing one’s ability to remember events from before the onset of the memory-impairing disease, and anterograde meaning the ability to acquire new memories a er disease onset. Except for rare exam- ples of highly restricted mesial temporal lobe lesions causing rela- tively pure anterograde de cits, both anterograde and retrograde memory are a ected simultaneously in most amnestic syndromes including Alzheimer’s disease. is is an important and clinically useful point for assessing memory at the bedside. In clinic, one o en hears statements from informants of the type ‘it’s his short- term memory, the long-term memory is perfect’. e rst point to note is that this lay distinction between ‘short-term’ and ‘long-term’ is only a distinction between recent (e.g. recalling events from this morning) and remote (e.g. recalling events from school days) epi- sodic memory. Furthermore, the lay usage should not be confused with the neuropsychological term ‘short-term memory’ which is o en used as a synonym for working memory—the ability not only to hold information in mind but also to manipulate it. e key relevance of highlighting this point is that this frequently reported observation from informants is very o en untrue—understanding the falsehood is particularly useful in bedside memory examina- tion and, in turn, reaching an accurate diagnosis.

e reason that informants report a problem restricted to ‘short- term memory’ presumably relates to a couple of factors. First is that they were eye-witnesses to the events constituting the apparent ‘short-term memory’ de cit, so they have their own recollection to act as a control to the patient’s forgetting. Second is that it is very easy to fool oneself and believe that remote episodic memory is

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intact based on the patient producing some generic or over-learned details. For example, a patient with a signi cant remote memory de cit, may have some frequently retold anecdotes from their past life that give the illusion of a good remote memory. Generic memo- ries can also give this illusion; for instance, asking a patient what they did last Christmas can prompt responses about eating too much, seeing family, etc. In this example, the patient is not nec- essarily providing speci c information about what they remember of the event; the information is generic as it could describe many Christmas days.

e relevance of this to episodic memory testing is that asking the patient for details of their past life can be very informative in detecting a de cit. e key is that the examiner sets the agenda rather than letting the patient discuss what they wish to recount. One should ask the patient for speci c details from their past life such as name of their school, rst and subsequent employment positions, where they were married, places they have lived, and so on. Although such examples are not true episodic memories (rather, they are personal semantic details), these simple questions will frequently expose memory gaps in even very early Alzheimer’s disease and will o en provoke a ‘head-turning sign’; the patient turning repeatedly to their spouse hoping for assistance.

True episodic memories can be probed in a similar manner by asking for speci c details of the events of their last holiday, last Christmas, last birthday, wedding day, birth of a child, etc. It takes little practice as an examiner to separate the generic information of a patient attempting to camou age their de cit from true episodic memory impairment. For instance, using the last holiday exam- ple, imagine a patient who always spends their summer holiday at the same seaside resort. In this scenario, responding with generic information such as they went to the beach or ate at restaurants does not indicate true recollection. In contrast, true episodic recall involves recounting details speci c to that trip, for example, ‘one day it rained so we visited the art gallery, there was a photography exhibition’, ‘we took a boat trip to view a seal colony, the sea was rough and our friend became ill’, etc. It is precisely this ne-grained, true episodic memory that people with early Alzheimer’s disease struggle with, and, as such, the utility of including such questions in the examination routine cannot be overemphasized.

e other method of testing memory at the bedside is by giving the patient something to learn and then asking them to recall the information a er a distraction period. Typical examples are word lists or a name/address, and examples exist as subtests in all of the bedside global assessment tools. ere are a few points worth high- lighting with this form of testing. First, the degree of di culty in such tests is in uenced by the amount one has to remember as well as the length of the distraction period. To this end, the memory component of the MMSE—three-word recall a er a distraction period of only a few seconds (while one spells ‘WORLD’ backwards or does serial 7s)—is very easy for intelligent, mildly impaired patients. As such, a perfect score on this measure should not be interpreted as meaning there is no memory impairment.

Second, some of these tests include multiple encoding trials (i.e. repeat the information more than once to enhance learning) and recognition (i.e. a er asking the patient to recall the informa- tion without cue—‘free recall’—asking them to identify previously learned information that was not freely recalled, intermixed with foils that they did not learn earlier). e pro le of de cits across these di erent components is sometimes helpful for di eren- tial diagnosis. For instance, in very mild Alzheimer’s disease, the encoding trials can show no abnormality whereas delayed recall is typically very impaired. In contrast, in dementia with Lewy bod- ies, encoding is o en impaired with patients unable to reach ceiling performance even a er a third trial, yet they o en show little, or no, decline from the third encoding trial to delayed recall (Fig. 10.1).

In general, bedside tests of learning and recall are quite sensi- tive surrogate markers for an episodic memory de cit, and this is even true for the three-word recall in the MMSE. Speci city, how- ever, can be a problem as patients with non-degenerative causes of memory complaints, such as psychiatric disorders, also can score poorly on such measures. is is important because separating degenerative from non-degenerative causes is the commonest clini- cal problem encountered in a memory clinic. It is also one of the most di cult problems, particularly as a diagnosis of depression does not necessarily imply that depression is the primary cause of the symptoms; it is also a common co-morbidity in early demen- tia. It is important to stress that there is no foolproof examination technique to sort out this problem, and sometimes it is only with

Normal

Very early AD

Mild DLB

Joseph Barnes
19 Woodland Close Browndale Yorkshire

Trial 1

Trial 2

Trial 3

Delayed Recall

CHAPTER 10 bedside assessment of cognition 107

Fig. 10.1 Examples of performance seen in learning and recall of a name and address in very mild Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). http://internalmedicinebook.com/

108 SECTION 2 cognitive dysfunction

follow-up that the diagnosis emerges. at said, the formal exami- nation of personal milestones and episodes, as already described, can be particularly useful because patients su ering depression or anxiety are o en better on these ecological measures.

ese measures can also be very helpful where there is a suspi- cion that a patient’s apparent poor performance on tests of learning and recall is an elaboration (due to a lack of e ort). Such patients may return catastrophic performance when knowing their mem- ory is being formally examined, but demonstrate good memory for real-life past events when questions are presented in what appears to be a general conversation. Another clue to look out for in such situations, is where the patient can go into incredibly ne-grained detail when recounting the circumstances (i.e. minute details of the events leading up to, and following on from, memory lapses), thereby demonstrating good episodic memory.

Semantic memory

Semantic memory refers to knowledge of facts, concepts, and objects. For instance, that Paris is the capital city of France, that an elephant is a large mammal with a trunk, that a ‘hobby’ is a pastime one indulges in for recreation, and so on. ese examples demon- strate the distinction from episodic memory in that such examples are not recollected from a particular time and place. In other words, knowing that Paris is the capital of France is a fact that one encoun- ters in various contexts; recalling the events of a speci c trip that one made to Paris are episodic memories.

Semantic memory can be tested in many ways. Simply naming pictures or objects in the o ce is useful, but it is important to stress that while a semantic de cit will cause naming di culty, a naming problem does not necessarily imply a semantic de cit. e latter can also result from a word-retrieval de cit. e examination can get at this by asking the patient questions about objects they cannot name. For instance, a patient with a word-retrieval de cit may not be able to name a ‘stethoscope’ yet can provide description: ‘the thing the doctor uses to listen to your chest’. Patients with semantic de cit, as seen in the syndrome of semantic dementia (also known as semantic variant primary progressive aphasia), in contrast, will o en respond that they have no idea when asked for a description. Another way to distinguish a semantic de cit from a word-retrieval problem is cue- ing. Performance of a patient with anomia due to a retrieval de cit will bene t from cueing (‘it is a steth …’?) whereas cueing typically is of less help to a patient with a semantic de cit.

Understanding how semantic knowledge deteriorates in neu- rodegenerative disease is crucial to understanding how to test it. Two, somewhat interrelated factors, namely, age of acquisition and word frequency, are important determinants of this process. e semantic material that is most robust is that acquired very early in life and that which occurs at the highest frequency in everyday life. Asking a patient to identify high-frequency items such as a pen or a dog can be done successfully in spite of a signi cant seman- tic decline. One must choose harder items, therefore, to expose the de cit. Even with no special equipment in a medical consultation, this can be achieved with objects such as the stethoscope, a stapler, a paperclip, etc.

Other examples of bedside semantic tests include naming to description (e.g. ‘what do you call the Australian animal that hops and has a pouch?’). To take naming out of the equation, one can give semantically complex commands such as, ‘point to an elec- tronic communication device’. Note that traditional three-stage commands (e.g. ‘take the paper in your le hand, fold it in half, and

lay it on the table’) are not good tests of semantic comprehension as they lack semantic complexity; these are typically taxing work- ing memory by stringing together a sequence of commands but the semantic content (‘paper’, ‘hand’, ‘table’) is very simple.

Language

Naming and semantic knowledge are major components of lan- guage and were covered in the previous section. Other aspects that are useful to assess in reaching a clinical diagnosis include uency and grammatical ability, repetition, and reading.

Speech uency and grammar

Non- uent aphasia is best identi ed by listening to the patient con- verse rather than by doing tests. When severe, the problem is obvi- ous with severely laboured, slow speech. In the very earliest stages of a non- uent aphasia, however, it can be di cult to pick up or can appear as though the patient is su ering from slight anxiety. In such circumstances, it is o en the patient’s own history—and not the informant’s observations—that gives the clue in that they may complain of trouble forming sentences or mispronouncing words. Such complaints should be taken seriously even if they seem to be so subtle as to not be evident in the course of conversation; they are o en the harbinger of a progressive non- uent aphasia.

When non- uent aphasia is evident, it manifests as slow, laboured utterances with reduced sentence length. Phonological and phonetic errors may be evident: the former being incorrect placement of real phonemes (caterpillar → capperpillar), the latter being sounds not corresponding to any normally articulated pho- nemes. e latter is a feature of so-called apraxia of speech.

Non- uent aphasia in degenerative disease typically, does not give rise to the agrammatic ‘telegraphic’ speech described in stroke aphasia. Although grammar is impaired on formal tests, the mani- festation in speech is typically to produce correct but very simpli- ed grammar. e speech of Alzheimer-related progressive aphasia (logopenic aphasia) is usually uent in grammatical terms but halt- ing due to frequent word- nding pauses. In semantic dementia, speech is uent and can sound remarkably normal. ese patients o en do not have word- nding di culties apparent in conversa- tion, presumably because word- nding di culty implies that the individual knows the concept for which they are trying to retrieve the word; if the concept is lost, one does not search for it.

Bedside testing of grammar involves asking the patient gram- matically complex, but semantically simple, questions such as reversible passive and centre-embedded sentences. Examples of the former include ‘Jack was sacked by Jill; who was the boss?’, ‘John was hit by Sam; who got hurt?’, and so on. Note here that the revers- ibility refers to the fact that the subject and object of the sentence give no clue as to the correct response, in contrast to a sentence such as ‘the sheep was eaten by the wolf; who survived?’ where, although passive, one could answer correctly simply by knowing that a sheep cannot eat a wolf. Also, note here that if one uses this testing approach, chance performance is 50 per cent, so one needs to present several examples to be sure of a problem. One could also look for a discrepancy between performance on passive construc- tions and easier active constructions (‘Jill sacked Jack; who was the boss?’). Centre-embedded sentences mean embedding a clause between subject and simple predicate, for example ‘the bowl the sh is in is red; what is red?’. e idea here is that the patient strug- gling with grammar might incorrectly answer ‘the sh’ because it occurs close to ‘red’ in the sentence.

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Repetition

Impaired repetition can be either at the single-word level or a prob- lem with sentence repetition. Impairment at the single-word level implies impairment also with sentences. Isolated sentence repeti- tion can occur and implies problems with auditory–verbal work- ing memory. is is thought to be the basis of sentence repetition de cits seen in association with Alzheimer pathology.

e repetition equivalent to testing semantics with lower- frequency items is to ask the patient to repeat long words—little can go wrong in repeating ‘cat’! To create graded di culty one can start with two syllable words ‘gallop’ and ‘rapid’ and proceed to complex multi-syllabic words such as ‘perspiration’ and ‘literary’. Also, by combining repetition with de nition, one has a quick screening test for both articulation and semantics; for example, ask the patient to repeat ‘caterpillar’ then ask for a de nition of a caterpillar; other examples include ‘rhinoceros’, ‘catastrophe’, etc. Asking the patient to repeat one of the complex multisyllabic words such as ‘catastro- phe’ a number of times over and looking speci cally for inconsist- ent repetition mistakes from one trial to the next is considered a sign of apraxia of speech.

Reading

Reading orthographically regular and irregular words can also be very helpful and represents a simple bedside test to administer to expose semantic de cits through the phenomenon of ‘surface dys- lexia’. It is particularly useful in the English language, less so in lan- guages with more transparent orthography to pronunciation rules. Irregular words refer to words that are not pronounced as they are

(i) (ii)

written and in order to pronounce them correctly, one requires semantic knowledge. For instance, if knowledge of the word ‘pint’ is lost, it will be pronounced as it is written (to rhyme with ‘hint’). In other words, it is read according to its ‘surface structure’ rather than its deeper meaning, hence, ‘surface dyslexia’. Note that the rule about semantic dementia and high-frequency words applies here as well. One does not observe surface errors to ultra-high-frequency words such as ‘was’ even if it is not pronounced as written. One needs to test by having the patient read lower-frequency words of which, in English, at least, there are many: ‘yacht’, ‘sew’, etc.

Visual perception

Hemianopia and visual neglect are tested as part of the standard neurological examination. De cits in higher-order visual process- ing, particularly spatial processing, are important to test for at the bedside in suspected posterior cortical atrophy. In fact, visuoper- ceptual testing in individuals suspected of having this syndrome is particularly useful because o en patients and informants strug- gle to articulate the nature of the problem clearly. In contrast, the de cit can be quickly exposed with simple bedside tests. Visuo- constructive ability is a useful screening test (i.e. clock, wire-cube drawing, etc.). De cits on such tasks are o en referred to as con- structional apraxia. Drawing such items also has a motor and planning component, so impairment does not necessarily imply a perceptual problem. e hallmark of posterior cortical atrophy is simultanagnosia and this is fairly easily demonstrated with simple bedside tests (Fig. 10.2).

(iii)

CHAPTER 10 bedside assessment of cognition 109

B BAA

BA B

S O M E T H I N G

something

(iv)

Fig. 10.2 Tests of simultanagnosia. Panels each represent an A4 sheet. (i) e patient is asked to point to the ‘As’ (then later ‘Bs’). Typically they nd the small letters, but miss the large ones. In (ii) the patient is asked to read the word. ey typically struggle, having to read letter by letter down the page, or cannot manage it at all, whereas when the word is written normally (iii) it can be read. Note in both examples that the impairment cannot be attributed to a visual acuity problem as the patient fails to identify the larger items. (iv) simultanagnosia can mean that patients only pick details out of pictures when naming. In the example shown, a simultanagnosic patient (posterior cortical atrophy) named this item as ‘chopsticks’. When asked to explain, it became evident that they were only noticing the rotor-blades of the helicopter. is is important to be aware of as apparently bizarre answers can lead to the incorrect belief that the patient is simulating their de cits.

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Fig. 10.3 Examples of meaningless gestures to test apraxia. Note that ‘meaningless’ is culture-speci c, and items should be chosen to avoid o ensive gestures in the target population!

Dressing apraxia is another useful bedside test that accompanies de cits in perception. It is easily assessed by asking the patient to put on a sweater or jacket that has had one of its sleeves turned inside out.

Limb apraxia

Limb apraxia is the inability to execute motor responses despite intact basic motor functions (see also chapter 6). It is therefore important to have rst con rmed that basic motor (and sensory) functions are intact from the general neurological examination. Limb apraxia is a prominent feature of the corticobasal syndrome and can be examined by having the patient copy meaningless hand gestures (Fig. 10.3). Having the patient imitate meaningful actions (pretending to stir a cup of co ee or comb one’s hair, etc.) can also be tested. is form of apraxia has a semantic and a motor com- ponent and, in the authors’ experience, such testing does not add meaningfully to the assessment of apraxia.

Executive function and ‘frontal’ behaviour

Executive function covers problem solving, abstraction, multitask- ing, and so on. Impairments are o en thought of as synonymous with frontal lobe dysfunction. While it is true that the frontal lobes are critical for these functions, these kinds of complex tasks really require the whole cognitive brain; they are the strongest example of needing all cognitive faculties working and this is seldom the case in degenerative disease.

ere are a multitude of bedside tests purporting to test executive function. Popular examples include:

◆ Go–no go: ‘When I tap the table once, you tap the table once; if I tap the twice, you do not tap’, the idea being that the stimulus- bound patient cannot suppress the impulse to tap twice in the latter condition

◆ Proverb interpretation: the patient cannot abstract the proverbial message and provides a literal interpretation

◆ Cognitive estimates: asking questions in which one would not normally know the answer but could make a reasonable guess, e.g. ‘How fast can a racehorse gallop?’ or ‘How far is London from Paris?’, etc.

◆ Di erences and similarities: ‘In what way are a sculpture and a piece of music similar?’ or ‘What is the di erence between a dwarf and a child’?
ere are problems with all of these tests when used to aid diag- nosis. Ideally, for example, they should be sensitive and speci c to the behavioural form of frontotemporal dementia but they typically fail on both counts. One of the problems is the fact that tests such as proverbs, cognitive estimates, and di erences/similarities tend to be in uenced by premorbid intelligence. To this end, it is not uncommon to nd members of the normal population who will explain the meaning of proverbs in a concrete manner or who may make grossly inaccurate cognitive estimates. ere is also the con- sequential problem of deciding how gurative a response should be for it to be deemed non-literal. Perhaps the main problem is

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20 15 10

the same for a semantic category. For instance, words beginning with the letter ‘P’ and animals beginning with any letter. ere is some variability in the number that healthy people can produce, but the pattern of the two tasks rather than the absolute score is o en informative. Healthy people typically can produce at least 15 P-words and do slightly better than their letter uency score in the animal uency condition. In early Alzheimer’s disease, one o en sees a reversal of this pattern even if the absolute scores are not particularly low, perseverations are also common; in semantic dementia there is typically a profound reduction in animal word uency; in behavioural variant frontotemporal dementia there is o en a disproportionate reduction in letter uency; in progressive supranuclear palsy this is usually extreme, o en as few as only one P-word in one minute (Fig. 10.4).

Conclusion

In summary, much valuable diagnostic information can be gleaned from a thoughtful cognitive examination. If more detailed, quan- titative information is needed across the cognitive domains, a formal neuropsychological evaluation is an appropriate next step. is is particularly true in clinically ambiguous situations, such as where de cits are so subtle as to be of uncertain signi cance. Neuropsychological scores in such instances can act as an invalu- able baseline that can be repeated at a future time-point to assess change. Referral for neuropsychological assessment should not be used, however, as a substitute to a careful assessment. e best chance of making an accurate diagnosis lies in a careful history, and cognitive examination and this should be viewed as the foundation to inform interpretation for ancillary tests including neuropsychol- ogy, imaging, and laboratory investigations.

Further reading

Larner AJ (ed.). Cognitive Screening Instruments: A Practical Approach. London: Springer-Verlag, 2013.

Hodges JR. Cognitive Assessment for Clinicians, 2nd edn. Oxford: Oxford University Press, 2007.

References

1. Qureshi K and Hodkinson M. Evaluation of a 10 question mental test of the institutionalized elderly. Age Ageing. 1974;3:152–7.

2. Folstein M, Folstein S, and McHugh P. ‘Mini-Mental State’: A practi- cal method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–98.

3. Nasreddine Z, Phillips N, Bédirian V, et al. e Montreal Cognitive Assessment (MoCA): A brief screening tool for mild cognitive impair- ment. J Am Geriatr Soc. 2005;53:695–9.

4. Mioshi E, Dawson K, Mitchell J, et al. e Addenbrooke’s Cognitive Examination Revised (ACE-R): A brief cognitive test battery for dementia screening. Int J Geriatr Psychiatry. 2006;21:1078–85.

CHAPTER 10 bedside assessment of cognition 111

Normal

AD SD

bvFTD PSP

Fig. 10.4 Patterns of performance on letter uency versus animal uency (y-axis indicates words produces in one minute) in the early stages of the respective disorders: AD, Alzheimer’s disease; SD, semantic dementia; bvFTD, behavioural variant frontotemporal dementia; PSP, progressive supranuclear palsy.

that the behavioural changes, associated most typically with frontal lobe degeneration, are extremely complex, and so, try as these tests might, they are just too simpli ed to capture this complexity.

A far more robust approach to identifying behavioural variant frontotemporal dementia and other frontal lobe conditions is to take note of the patient’s actual behavior in the social setting of the consultation. Careful observation and recording of how the patient appears, interacts, and the content of their conversation are essen- tial to reach an accurate diagnosis. In this regard, the examina- tion is highly similar to the mental state examination (MSE) that forms a routine part of a psychiatric assessment. e reason this is important is because although the details of personality change will come from an informant—hence the informant’s account is essential to identifying the characteristic changes of frontotemporal dementia—if one relies solely on the informant’s account, there is a risk of making a false-positive diagnosis.

is risk is minimized by corroborating the informant’s history with careful observation of the patient. e changes one might observe include restlessness, such as being unable to remain seated and preferring to get up and wander; impulsively wanting to ter- minate the consultation; not respecting personal space; being dis- tracted by environmental stimuli such as going to the window to look at tra c or wanting to see what is on a computer monitor. At it most severe, utilization behaviour may be observed in which the patient will start using anything handed to them; giggling fatu- ously; repetitive use of a catchphrase or cliché in conversation; making disinhibited remarks about people in the clinic, and so on.

One nal bedside test that has some utility in frontotemporal dementia and also for a range of other conditions is verbal u- ency: asking the patient to produce as many di erent words as they can think of in one minute that begin with a certain letter and then

Animal Letter

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CHAPTER 11

Neuropsychological assessment

Diana Caine and Sebastian J. Crutch

Introduction

Neuropsychological assessment of patients presenting with cogni- tive disorders provides crucial information on which to base diag- nosis as well as evaluate whether there have been changes in an individual’s condition. For example, while ‘dementia’ is de ned as a cognitive syndrome a ecting memory, thinking, behaviour, and the ability to perform everyday activities, intensive neuropsycho- logical research has resulted in the identi cation of di erential and pathognomonic patterns of cognitive decline in di erent condi- tions.1,2 Particularly in the early stages of disease, dementia syn- dromes with di erent underlying aetiologies o en selectively a ect speci c functional systems, consistent with the characteristic sites and distribution patterns of the relevant pathology.3 A number of dementia syndromes therefore have what might be regarded as a characteristic cognitive signature.

Neuropsychological assessment, especially in the earliest disease stages of disease, when a patient is rst being investigated for cogni- tive failure in daily life, is directed towards (i) establishing whether or not the patient’s complaints are more likely to be neurogenic than psychogenic; and (ii) characterizing a patient’s cognitive status with a view to determining whether the cognitive pro le is consist- ent with one or another of these cognitive signatures. is chapter will address how this assessment is done and will include some case studies. It also seeks to expand the ‘psychological’ in ‘neuropsy- chological’ to address, albeit brie y, the impact of those cognitive changes on the patients’ sense of themselves and on their relations with others.

e aim of neuropsychological assessment is to demonstrate the presence or absence of cognitive decline on objective measures of cognitive function. In the context of dementia, notwithstanding advances in neuroimaging, the documentation of cognitive change on neuropsychological assessment not infrequently precedes posi- tive ndings on other investigative measures. e usefulness of neuropsychological testing for diagnosis rests on interpretation of the pattern of performance across tests of the di erent cognitive domains, rather than on the result of any particular test or any par- ticular cognitive domain on its own. For that reason, neuropsycho- logical assessment typically includes a range of measures including current general intellectual function as well as tests of performance in the major cognitive domains: memory, language comprehension and production, executive function, visuoperceptual and visuospa- tial function, attention, and processing speed. At the same time, while an assessment needs to be comprehensive it also needs to be e cient, in the interest of the patient’s well-being and cooperation on the one hand, and practicality on the other.

Test selection, structure, and properties

e selection of neuropsychological tests for an assessment will depend on a variety of factors including the nature of the referral (e.g. evaluation for evidence of cognitive impairment, monitoring of disease progression), the patient’s clinical status (e.g. under inves- tigation, diagnosed, dementia type/syndrome, disease severity), the availability of information about their cognitive status (e.g. bedside cognitive screening, previous neuropsychological assessment), and the overall context of the assessment (e.g. clinical, research, clinical trial, medico-legal). Appropriate test selection is important in all contexts.

Within the standard clinical setting, there is freedom to choose tests but also pressure for the psychologist to work reactively, adapt- ing the roster of assessments according to the patient’s presentation and emerging cognitive pattern. Such responsive practice is essen- tial to identify and verify apparent de cits and build up a meaning- ful pro le of the individual within the time and other constraints of a given service. By contrast, group research studies and clinical trials usually involve the administration of a predetermined battery of tests. In this context, careful selection to ensure appropriateness of the tasks for the target population and the frequency they are administered is critical to ensure that patients are not repeatedly confronted with tasks which are too di cult and may cause frus- tration and distress, and to avoid practice e ects (see section on practice e ects).

Whilst test selection is o en dictated by mundane factors such as test availability or local service traditions, familiarity with the structure and psychometric properties of di erent neuropsycho- logical measures is critical in maximizing the validity and e ective- ness of the assessment.

Task di culty, and ceiling and oor e ects

e di culty of a particular task can determine its suitability for use in particular situations. For example, demanding uncued and cued recall tests of episodic memory may be required to discrimi- nate between healthy individuals and those with pre-symptomatic Alzheimer’s disease (AD) (e.g. free and cued selective remind- ing test (FCSRT)4–5 (see also chapter 32). By contrast, evaluation or monitoring of memory impairment in mild to moderate AD patients may be more appropriately assessed using forced choice recognition procedures (e.g. recognition memory test).6 Dedicated tools for the assessment of those with more severe cognitive impairment are also available (e.g. Severe Impairment Battery).7 Some tasks o er alternate forms with di erent degrees of di culty (e.g. long, short, and easy forms of the recognition memory test).

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cognitive dysfunction

20 19 18 17 16 15 14 13 12 11 10

9 8 7 6 5 4 3 2 1 0

Time 1

Time 2

Fig. 11.1 Illustration of ceiling and oor e ects and their impact on the interpretation of longitudinal assessment data. e gure describes the cases of three putative patients all administered an imagined test at two time-points. Patient 1 exhibits ceiling e ects at both time 1 and time 2, making it impossible to assess from this data alone whether (a) there is any impairment in this function, (b) performance is worsening over time, or (c) the task is simply too easy to detect (a) and/or (b). Likewise, Patient 3’s score at or near oor at both time-points, indicating a de cit but preventing any meaningful evaluation of further decline over time. Only the performance of Patient 2 is adequately captured within the di culty level/dynamic range of this task.

Appropriate task di culty (or use of tasks with a wide dynamic range or which are graded in di culty; see section on dynamic range and graded di culty test structure) limits the occurrence of ceiling e ects (where maximal scores mask subtle de cits) and oor e ects (where minimal scores mask residual abilities; see Fig. 11.1).

Dynamic range and graded di culty test structure

Tasks with a wide dynamic range permit the evaluation of multi- ple levels of cognitive de cit through the use of continuous meas- ures (e.g. response time) or through variability in the di culty of discrete test items (see Fig. 11.2). As the term suggests, graded di culty tasks order discrete items from easy to hard, so that dis- continuation rules can be employed to prevent unnecessary admin- istration of overly di cult items. Consequently, such tasks protect against ceiling and oor e ects and are ideally suited to cognitive domains in which there is considerable inter-individual variability in the healthy population (e.g. vocabulary size, calculation skills), and where longitudinal evaluation of cognitive change over multi- ple time-points is required.

Confounding and collateral de cits

Composite scores

Some neuropsychological assessment goals or research questions may be addressed best using composite scores rather than indi- vidual tests or between-test pro les. For example, the designers of outcome measures for some early-stage and preventative AD trials advocate use of composite measures (which may include a com- bination of tests such as the ADAS delayed word list recall,8 logi- cal memory delayed paragraph recall,9 Wechsler Adult Intelligence Scale—Revised (WAIS–R) digit symbol substitution,10 and mini- mental state examination11). Such composites require validation for use in phase 3 trials, but composites have a long pedigree in clinical neuropsychology (e.g. WAIS IQ scales are a composite of multiple subtests; see Fig. 11.2).

Practice e ects

Many neuropsychological tasks are subject to practice e ects when administered on more than one occasion. Whilst the magnitude of the e ects has been evaluated for some tasks,12 other tasks attempt to minimize practice e ects by using parallel stimulus sets (e.g. Graded Di culty Spelling Test).13 In many longitudinal studies, disease e ects are determined from the absence of practice e ects rather than reductions in absolute tests scores (i.e. a divergence over time between patient and control groups). However, the inter- pretation of changes between initial and follow-up assessment per- formance in individual clinical patients (relative to a single set of cross-sectional normative data) is more problematic.

e strategy of neuropsychological

assessment

Neuropsychological investigation begins with an evaluation of the patient’s estimated optimal level of function prior to any recent

Few neuropsychological tests tap a single type of cognitive process; many tasks possess inherent sensory, linguistic, and attentional- executive demands such that poor performance may occur for a number of di erent reasons. Picture-naming tests are a simple example; nominally a measure of word-retrieval skills, the task also requires visuoperceptual, semantic, executive control, and articu- latory skills. e impact of collateral cognitive de cits not only necessitates the interpretation of the target test in the context of the broader cognitive pro le, but also motivates the test selection (e.g. evaluating word retrieval in posterior cortical atrophy by naming to verbal description rather than naming to visual confrontation).

Patient 1 Patient 2 Patient 3

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Standard deviations

Percentile ranks

T scores Standard scores

(SD = 15) Scale scores

(SD = 3)

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34.13%
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+2σ

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Average 34.13%

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CHAPTER 11 neuropsychological assessment 115

Test score

1 5102030507080909599

10 20 30 40 50 60 70 80 90

55 70 85 100 115 130 145

1 4 7 10 13 16 19

Fig. 11.2 Comparison of standardized scores [standard deviations (z scores), percentile ranks, T scores, standard scores (commonly termed ‘IQ scores’) and scale scores] across the normal distribution. Standardized scores provide a means for e cient comparison of performance levels across di erent tasks and domains. Note: not all neuropsychological tests yield normally distributed scores in healthy populations; the relative value or meaningfulness of standardized scores is reduced in tasks where the normative data are positively or negatively skewed.

change or decline. In addition to information elicited about the patient’s education and employment history, which is very o en a useful guide in this regard, an estimation of pre-morbid IQ is also based on performance on a reading test known to be highly cor- related with IQ. e National Adult Reading Test (NART)14 is such an instrument, comprising 50 words all of which have low sound– spelling correspondence. Performance on this test, in native English speakers—and in many, but not all, neurological conditions—is thought to be relatively robust to brain damage. e exception is any condition in which reading may itself be a prominent symptom; for instance, semantic dementia. e interpretation of test results depends crucially upon establishing whether the patient’s perfor- mance is at variance with the level of performance expected based on this estimation of optimal functional level. Failure to do this risks underestimating decline in patients of better than average intellect or, conversely, overestimating deterioration in patients whose gen- eral intellectual function has always been lower than average.

Identi cation of cognitive de cits is accomplished in the rst instance by comparing a patient’s scores with those of age—and sometimes also education-matched—normative scores, taking into account the patient’s premorbid IQ. In addition to the scores them- selves, the qualitative features of a patient’s performance and the nature of the errors can also be illuminating as to the nature of the de cit. us, for instance, errors on a test of object naming may arise from visuoperceptual problems (e.g. seeing a pair of handcu s as ‘spectacles’ or ‘a bicycle’) or from semantic loss (e.g. calling a pic- ture of an anteater ‘a dog’).

In describing our approach to neuropsychological assessment below mention is made of tests which represent just a small sample of the many tests currently available (for reference to speci c tests see reference 15). A comprehensive neuropsychological assessment should include evaluation of the following:

General intellectual function

e neuropsychological assessment should evaluate the extent to which there may be a discrepancy between a patient’s current level

of intellectual of function and the optimal pre-morbid level that has been estimated. e Wechsler Adult Intelligence Scale,16 now in its fourth incarnation, has for decades been regarded as the gold standard for testing general intellectual function. e full battery of tests is very long but robust estimates of current IQ can be obtained from shortened versions, as recognized by the test-makers them- selves in the form of the Wechsler Abbreviated Scale of Intelligence (WASI)17 which comprises four subtests from which verbal, per- formance, and full-scale IQ (VIQ, PIQ, and FIQ) scores can all be generated. In addition to providing estimates of current global intel- lectual function, much useful information can be gathered from a patient’s performance on individual subtests and/or discrepancies between scales or subtests. For example, individuals with semantic dementia typically exhibit signi cantly lower VIQ than PIQ (with especially weak performance on vocabulary and similarities; see case study 2 this chapter), whilst conversely individuals with poste- rior cortical atrophy typically struggle with the visual demands of many performance subtests (e.g. matrix reasoning, see case study 1 this chapter).

Memory

From a theoretical point of view, memory is a complex cognitive domain comprising a number of components including registra- tion, encoding, retention, and retrieval. Memory complaints are by far the commonest reason for referral for neuropsychological assessment, although in the layperson’s vocabulary ‘memory’ func- tions as a catch-all for almost any self-reported cognitive change. From the perspective of assessment, two aspects of memory are of particular importance: episodic memory, the encoding and recall of new information; and semantic memory, the knowledge of concepts, facts, and meanings, which is usually considered in the context of language rather than memory as such (see section on language). Episodic memory is typically assessed with tests of rec- ognition (e.g. recognition memory test (RMT)6 tests for words and faces, and recall of both verbal and visual information (e.g. BIRT Memory and Information Processing Battery BMIPB;18 Doors and

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116 SECTION 2 cognitive dysfunction

People Test).19 Impairment on tests of delayed recall is a particu- larly sensitive measure of memory decline and by far the most com- mon presenting feature in typical AD.20 Working memory can also be tested in both verbal and visuospatial domains using digit span or its analogue, spatial span (Wechsler Memory Scale–III).21

Language

In the context of dementia, language complaints are less common than concerns about memory but, as is very well documented, can be the symptom that heralds primary progressive aphasia.22 Apart from attention to the patient’s spontaneous speech for evidence of word- nding di culty, paraphasic errors, or problems with articu- lation or speech production, screening for language de cits in the context of neuropsychological assessment of dementia usually relies on tests of naming and uency in addition to verbal compre- hension tasks within the general intellectual assessment (e.g. the vocabulary or similarities subtests of the WAIS).

e naming of line drawings of objects and animals (e.g. Graded Naming Test)23 is a sensitive test of semantic knowledge24 as well as being a test of lexical access.25 Category uency (commonly, the number of animal names a patient is able to produce in 60 seconds) is another easily administered task that has also been shown to be a robust measure of semantic memory.26 Although not designed to do so, both are also liable to elicit phonological di culties or problems with articulation or apraxia of speech, where they are present. Where de cits on these tests, in the context of relative preservation of per- formance on other tasks, suggest that language is a prominent early symptom of decline, other language tasks including tests of repeti- tion, reading, spelling, and sentence comprehension are also admin- istered. In the primary progressive aphasias a disturbance of one or another aspect of language is the most prominent feature early in the course of the disease, with the particular pattern of the disturbance indicating which progressive aphasic disorder is in question.

Visuospatial function

De cits in visual processing can also sometimes be amongst the earliest presenting signs in a dementing process.27–28 Elementary visuospatial function can be assessed using the ‘visuospatial’ com- ponents of the visual object and space perception (VOSP) battery:29 position discrimination, dot counting, number location, or cube analysis. In addition, the copy condition of the BMIPB complex gure-recall task (or similar) also acts as a test of visuoconstructive task which might be a more sensitive measure of early visuospatial decline in some patients.

Visuoperceptual function

this function. Visual processing problems are characteristically the earliest signs of disease in posterior cortical atrophy, irrespective of the underlying pathogenesis.

Praxis

Apraxia refers to a loss of the ability to execute or carry out pur- poseful movements, whether meaningful or not, despite intact motor and sensory capacity. Although not usually part of routine neuropsychological assessment, it can constitute a signi cant com- ponent of a dementing syndrome (e.g. corticobasal degeneration, Creutzfeldt–Jakob disease), and where there are symptomatic com- plaints which suggest it may be present, it should be systematically evaluated (see, for example, reference 30 and chapter 16 for further details).

Frontal and executive function

e frontal lobes can be thought of as mediating two di erent aspects of behaviour: (i) the rst is executive function, the ability to plan, organize, monitor, and voluntarily alter responses, in addition to abstract thinking, reasoning, and problem-solving; and (ii) social behaviour, the ability successfully to interact with others through empathy, understanding what others have in mind, conversational turn-taking, and so on. e rst of these is assessed using tests which require cognitive exibility (for example, Trail Making Test),31 strategy formation (letter uency); abstract concept formation (for example, modi ed card sorting test),32 and the inhibition of pre- potent responses in favour of alternative competing responses (for example, Stroop test,33 Hayling sentence completion34). e latter is not so easily tested in a standard neuropsychological assessment but these are features that are readily elicited from the history or, indeed, from the patient’s behaviour during testing. Tests of social cognition or theory of mind (e.g. e Awareness of Social Inference Test;35 Reading the Mind in the Eyes36) can be useful where this is the most prominent feature of a presentation.

Information-processing speed

A reduction in the rate at which cognitive or psychomotor tasks are performed is a common feature of any kind of brain impair- ment, while psychomotor retardation is also a known feature of depression. Reduced information-processing speed may also be particularly prominent in individuals with pronounced subcortical damage (e.g. some forms of vascular dementia). While measures of speed are therefore not always helpful in di erential diagnosis, they do help in understanding a patient’s competencies and di culties in daily life. ere are numerous measures amongst the most com- mon of which are timed-number or letter-cancellation tasks.

Mood

Mood, which can independently have an impact on the e cacy of cognition, can consequently also be a signi cant factor in the diag- nostic process. In the rst instance, di erentiation of the impact of mood from possible organic causes of cognitive decline is frequently a crucial question in the early diagnostic work-up for dementia. Second, both anxiety in response to cognitive failure and depres- sion in response to awareness of cognitive decline and its implica- tions can exacerbate impaired performance. us, in addition to formal measures of cognition, the neuropsychological assessment should include evaluation, by both interview and questionnaire,

Inability correctly to name line drawings might arise from semantic memory loss—loss of knowledge of what a thing is—or from a fail- ure of visual perception, sometimes a di cult distinction to make. A failure to perceive an object accurately may re ect loss of stored object-speci c structural representations (e.g. inability to perceive common objects from unfamiliar angles) or because of more basic impairments of edge, form, and colour processing which deprive intact structural representations of the necessary input. e VOSP also comprises tests of visuoperceptual function (object decision, incomplete letters, silhouette naming) and of more basic visual processing (shape detection) which evaluate this domain. As sug- gested earlier, the nature of errors on other tasks with a perceptual component, such as object naming, represent further assessment of

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of the patient’s mood. Commonly used instruments include the Beck Depression Inventory,37 Geriatric Depression Scale,38 and the Cornell Scale for Depression in Dementia.39 Here, the history of the symptomatology can be key in determining whether a mood disorder is the primary diagnosis or whether disturbed mood is a response to cognitive decline.

Interpretation of test results

In interpreting test results, both quantitative and qualitative features need to be considered. From the quantitative point of view, the pat- tern of results—the pattern of intact and impaired scores—across the whole range of tests administered is considered in addressing the question of whether the pattern obtained ts with one of the known dementia syndromes. Qualitatively, the patient’s behaviour during testing (e.g. signs of impulsivity, restlessness, and agitation, level of insight and awareness, bewilderment, comprehension or recall of task instructions) as well as the nature of the errors made (e.g. evidence of semantic rather than visual errors on naming; phonological or semantic paraphasias; confabulation on memory tests) may contribute signi cantly to interpretation of test results.

A patient who presents with memory or other cognitive com- plaints of insidious onset o en also presents with low mood. Here, again, the pattern of performance—for example, reduced scores on tests of attention, poor immediate recall without further loss over time—as well as the patient’s behaviour during testing can both be helpful in discriminating between neurogenic and psychogenic dis- orders. Of course, these may not be mutually exclusive; frequently mood is low precisely because the person is aware that their cogni- tion is failing.

Case studies
1. CaseMC:Posteriorcorticalatrophy

MC was a 53-year-old, right-handed senior civil servant who pre- sented with concerns about memory. She had a bachelor’s degree in the humanities and the postgraduate certi cate in education teach- ing quali cation. She was able to give a clear and coherent account of her di culties. ere was no relevant past medical history and took no medication. About ve years prior to presentation, she had gone through a very stressful period involving antisocial behav- iour directed towards her home and family. She developed panic attacks and recalled an occasion when she was in a supermarket, feeling overwhelmed, nauseated, and disorganized. ese symp- toms recurred and progressed to the extent that over the six months prior to the initial neurology consultation she began to feel that she was not coping at work: she found her job—which she had been doing competently and comfortably to that point—stressful. She did not always get the gist of meetings. She had started trying to write things down but nonetheless felt she was always covering up for herself. She became concerned about her ability to multitask, or to understand e-mails. She missed a couple of appointments and was more reliant on her diary.

She was managing the housework without di culties but reported that forgetfulness and losing things were an issue. Most notably, she found she became rather panicky whilst trying to fol- low routes, instructions, and maps. As well as di culties with maps she had bumped the car on a few occasions and lost con dence somewhat whilst driving. She felt that her ability to do mental

arithmetic had perhaps declined. She reported no problems with speech, her sleep was normal, and she had no hallucinations. She did not smoke and drank alcohol occasionally. ere was no family history of cognitive impairment. She described being stressed and feeling depressed particularly over the previous six months.

Her scores on neuropsychological assessment can be seen in Table 11.1 (see also Fig. 11.3). Estimated optimal level of premor- bid function, based on education, employment history, and from her performance on the NART reading test was thought to be in the high-average range. From the scores in Table 11.1 it is clear that nei- ther verbal (average) nor performance (impaired) IQ scores are at premorbid levels, but that the decrement is much more striking in the non-verbal domain, with scores poorer than expected on all three non-verbal tests administered. She scored in the impaired range on both recognition memory tests, con rming her subjective account of forgetfulness in daily life. Object naming, category uency, and visuoperceptual function were all intact while visuospatial function

Table 11.1 Neuropsychology scores for patient MC

CHAPTER 11 neuropsychological assessment 117

Test

Result

Estimated Premorbid Functioning

NART FSIQ

115

Current Intellectual Functioning

WAIS–III

Verbal IQ

Vocabulary Similarities Arithmetic Digit Span

103
Average High-average Average Average

Performance IQ

Picture completion Block design
Picture arrangement

67 Borderline Impaired Impaired

Memory

WRMT—words WRMT—faces

<5th %ile <5th %ile

Language

Graded naming test Semantic uency (‘animals’)

50th %ile 25–50th %ile

Visuoperceptual Skills

VOSP inc. letters

>5th %ile cut-o

Visuospatial Skills

VOSP position discrimin. AMIPB gure copy

<5% cut o <10th %ile

Executive Function

Fluency—‘S’ Stroop test

90th %ile 72nd %ile

Processing Speed

Counting backwards

NAD

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118 SECTION 2 cognitive dysfunction Posterior cortical atrophy (Patient MC)

Semantic dementia (Patient NA)

≥50th %ile 25–50th %ile

5–25th %ile <5th %ile

Visuospatial processing

Functional cognitive symptoms (Case ID)

Executive function

Processing speed

≥50th %ile 25–50th %ile

5–25th %ile <5th %ile

Visuospatial processing

Memory

Language

Executive function

Processing speed

Memory

Language

Executive function

Processing speed

≥50th %ile 25–50th %ile

5–25th %ile <5th %ile

Visuospatial processing

Memory

Language

Fig. 11.3 Target diagrams summarizing the contrasting cognitive pro les of MC, NA, and ID across several cognitive domains. Cognitive impairment (estimated from percentile scores) is represented by the retreat of colour in each segment into the centre of the circle.

was very poor on both the VOSP test of spatial perception and the visuoconstructional task of gure copying. She was unable to place the numbers or hands correctly on a clock face and could not copy interlocking pentagons. In contrast, executive function was strikingly robust. Processing speed on a test that was not reliant on visual pro- cessing was normal. She scored in the mild range for both depression and anxiety on the Hospital Anxiety and Depression Scale (HADS), most likely underestimating somewhat low mood.

Interpretation

Although possibly exacerbated by mood, the pro le is clearly organic. is was evident because of the relative speci city of her de cits; the nature of the di culties she had with visual tasks which would not be seen in a functional disorder; and in her good scores on e ortful verbal tests which indicated that level of e ort was not at issue. Here, the pro le was quite focal. Poor visuospatial function was the principal feature, with other aspects of cognition relatively intact apart from memory, which is usually but not always relatively spared in posterior cortical atrophy. is pro le was con rmed on magnetic resonance imaging (MRI) which showed focal symmetri- cal volume loss in the parietal region bilaterally, in addition to some hippocampal atrophy which was also symmetrical.

2. Case NA: Semantic dementia

NA was a 71-year-old, right-handed professional woman who pre- sented with a three- to four-year history of progressive di culty thinking of words, especially nouns. She reported di culty reading or following what she was watching on television. She had forgot- ten how to cook. Spontaneous speech was marked by word- nding di culty and insertion of general substitutions (e.g. ‘thingy’) and semantic paraphasias (e.g. ‘knife’ for ‘scissors’). Articulation and prosody were both preserved.

On formal examination, her score on the NART reading test sug- gested an estimated optimal premorbid IQ in the low-average range, clearly an underestimate given her education and employment his- tory (see Table 11.2 and Fig. 11.3). e nature of her errors—trying to read the words by their spelling producing what are called ‘regu- larization’ errors—is a classic sign of semantic dementia.

In striking contrast to the previous patient, NA showed exactly the reverse nding on the verbal and performance IQs of the WAIS–III: here, the patient scored in the impaired range on the

verbal scale and in the high-average range on the non-verbal scale of the battery. e discrepancy points to very speci c verbal de cits particular in relation to the vocabulary (production of de nitions to words) and similarities (generation of abstract concepts which link two words) subtests. By the same token, recognition mem- ory for words was impaired while recognition memory for faces remained intact. Unsurprisingly, object naming was profoundly impaired. Given the very prominent language impairment, addi- tional language testing showed that single word comprehension was impaired (British Picture Vocabulary Test 22/32 correct) while repetition of both words and sentences was intact. Both visuoper- ceptual and visuospatial processing remained intact while execu- tive function and processing speed were both reduced.

Interpretation

e pro le was consistent with a diagnosis of semantic dementia, with the MRI showing selective, severe atrophy of the cortex and white matter of the anterior, medial, and inferior aspects of the le temporal lobe against a background of generalized atrophy.

3. Case ID: Functional cognitive symptoms

is 44-year-old man presented with complaints of forgetfulness in daily life dating back over the previous three to four years, possibly more noticeable in the months preceding the assessment. He had no other cognitive complaints although he did report a single con- versational lapse while drinking with friends. Estimated optimal level of function based on NART and on his education and employ- ment history was thought to be in the average range (see Table 11.3 and Fig. 11.3). Both verbal and performance IQ were in this range, indicating robust general intellectual function.

Recognition memory for words was quite robust (75–90th per- centile) while recognition memory for faces was a little weaker, although still within normal limits (10–25th percentile). Both immediate and delayed recall of a short story were rather more impoverished than expected (both 10–25th percentile), with reten- tion also a little weak (10–25th percentile). In contrast, both imme- diate and delayed recall of a complex gure were quite adequate (both 25–50th percentile) and here, retention a er a delay was actually better than immediate recall (retention > 75th percentile)! Inconsistencies amongst memory tests pointed to attentional uc- tuations and lapses that were most marked in response to complex

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Table 11.2 Neuropsychology scores for patient NA

CHAPTER 11 neuropsychological assessment 119 Table 11.3 Neuropsychology scores for patient ID

Test

Result

Estimated Premorbid Functioning

NART FSIQ

85*

Current Intellectual Functioning

WAIS–III

Verbal IQ

Vocabulary Similarities Arithmetic Digit Span

69 Borderline Impaired Low-average Low-average

Performance IQ

Picture completion Block design
Picture arrangement

111 High-average High-average Average

Memory

WRMT—words WRMT—faces

<5th %ile

50th %ile

D&P verbal recall Immediate Delayed

<10th %ile 10th %ile

D&P visual recall Immediate Delayed

10–25th %ile 25th %ile

Language

Graded naming test Semantic uency (‘animals’)

<1st %ile <10th %ile

Visuoperceptual Skills

VOSP inc. letters

>5th %ile cut-o

Visuospatial Skills

Doors and people copy

No errors

Executive Function

Fluency—‘S’ Weigl sorting

<1st %ile
1⁄2 categories

Processing Speed

Letter cancellation

4th %ile

Test

Result

Estimated Premorbid Functioning

NART FSIQ

108

Current Intellectual Functioning

WAIS–III

Verbal IQ

Vocabulary Similarities Arithmetic Digit span

108 High-average High-average Average Average

Performance IQ

Picture completion Block design
Picture arrangement

95 Average Average Average

Memory

WRMT—words WRMT—faces

75–90th %ile 10–25th %ile

AMIPB story recall Immediate Delayed

10–25th %ile 10–25th %ile

AMIPB gure recall Immediate Delayed

25–50th %ile 25–50th %ile

Language

Graded naming test Semantic uency (‘animals’)

25–50th %ile 25–50th %ile

Visuoperceptual Skills

VOSP object decision

>5th %ile cut-o

Visuospatial Skills

AMIPB gure copy

No errors

Executive Function

Fluency—‘S’ Stroop test

11th %ile

2–4th %ile

Processing Speed

SDMT

47th %ile

auditory verbal material. However, conversational speech was u- ent with no lapses and no word- nding di culties.

Object naming was intact. ere was no evidence of visuoper- ceptual or visuospatial impairment. Performance on executive tasks was a little poorer than expected. He was slow to complete the incongruent condition of the Stroop colour–word test, although he made only one error (2nd–4th percentile). Letter uency was reduced (S: 11th percentile) in comparison with relatively intact category uency (animals: 25–50th percentile). He scored in the moderate average range on the Hayling sentence completion task. Processing speed was normal.

ID expressed considerable anxiety about what he perceived to be the changes in his memory. Although the problems occurred more prominently at work, he reported that his mood was inclined to be low when he was away from the workplace. On a formal mood inventory he scored in the normal range for both anxiety and depression. Although there were no overt features of low mood and although he was generally cooperative and responsive on test- ing, there were several occasions in the course of the assessment when he seemed to give up in the face of an attention-demanding task. e MRI scan of the brain was normal with no evidence for atrophy.

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120 SECTION 2 cognitive dysfunction

Interpretation

e neuropsychological pro le is therefore one of erratic scores on memory tests together with some executive ine ciency in the con- text of otherwise normal cognition. e overall impression, from the inconsistencies amongst the test scores and from his behav- iour on testing, was that these lower than expected scores are most unlikely to be neurogenic in origin.

Psychological impact

Cognitive de cits can have a profound impact on the psycho- logical dynamics of a couple and a family, particularly in the con- text of dementia as the patient’s cognitive, a ective, and mnestic processes disintegrate. Speci c cognitive problems impact on a person’s ability to function in particular ways: poor day-to-day memory makes it di cult to plan, organize, or anticipate what is going to happen, or to participate in the give-and-take of very much day-to-day conversation; visuospatial de cits may make it di cult to navigate familiar environments, even at home, or to function e ectively in terms of knowing where to nd things; apraxia may make it di cult to dress or to use everyday equip- ment (pens, cutlery) or appliances (remote control devices, microwave).

Di culty with such everyday activities—with concomitant reli- ance and dependence on others to negotiate even simple aspects of daily life—dramatically a ects a person’s sense of themselves in the world and in their relations with others. Such changes can be profoundly distressing as well as anxiety-provoking to the patient. On the other hand, in some cases—most notably behav- ioural variant frontotemporal dementia (bvFTD)—the patient’s unawareness of de cit is itself pathognomic of the disease, pos- ing the problem of dramatic changes for the carer and family but to which the patient appears indiferent. e neuropsychological assessment can therefore also be helpful in guiding the patient’s and/or the patient’s family’s understanding of the de cits, the development of strategies to assist in management of de – cits where possible, and the basis of supportive psychotherapy towards adaptation and adjustment to very changed relationship dynamics.

References

1. Hodges JR, Patterson K, Oxbury S, et al. Semantic dementia. Progressive uent aphasia with temporal lobe atrophy. Brain. 1992;115:1783–806.

2. Neary D, Snowden JS, Northen B, et al. Dementia of frontal lobe type. J Neurol Neurosur Ps. 1988;51:353–61.

3. Snowden JS, ompson JC, Stopford CL, et al. e clinical diagnosis of early-onset dementias: diagnostic accuracy and clinicopathological relationships. Brain. 2011;134:2478–92.

4. Buschke H. Cued recall in Amnesia. J Clin Exp Neuropsyc. 1984;6(4):433–40.

5. Grober E and Buschke H. Genuine memory de cits in dementia. Dev Neuropsychol. 1987;3:13–36.

6. Warrington EK. Recognition Memory Test. Windsor: NFER-Nelson Publishing Co Ltd, 1984.

7. Saxton J, McGonigle KL, Swihart AA, et al. e Severe Impairment Battery. Su olk: ames Valley Test Company, 1993.

8. Rosen WG, Mohs RC, and Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry. 1984 Nov;141(11):1356–64.

9. Wechsler D. Wechsler Memory Scale—Revised. New York, NY: Harcourt Brace Jovanovich, 1987.

10. Wechsler D. e Wechsler Adult Intelligence Scale—Revised. New York, NY: Harcourt Brace Jovanovich, 1981.

11. Folstein MF, Folstein SE, and McHugh PR. Mini-mental state. A practi- cal method for grading the cognitive state of patients for the clinician.
J Psychiat Res. 1975;12(3):189–98.

12. Bird CM, Papadopoulou K, Ricciardelli P, et al. Test-retest reliability, practice e ects and reliable change indices for the recognition memory test. Br J Clin Psychol. 2003 Nov;42(Pt 4):407–25.

13. Baxter DM and Warrington EK. Measuring dysgraphia: A graded- di culty spelling test. Behav Neurol. 1994;7(3–4):107–16.

14. Nelson HE. e National Adult Reading Test. Windsor: NFER-Nelson Publishing Co. 1991.

15. Lezak MD, Howieson DB, and Loring DW. Neuropsychological Assessment, 4th edn. New York, NY: Oxford University Press, 2004.

16. Wechsler D. Wechsler Adult Intelligence Scale, 4th edn. San Antonio, TX: Pearson, 2008.

17. Wechsler D. Wechsler Abbreviated Scale of Intelligence, 2nd edn (WASI- II). San Antonio, TX: NCS Pearson, 2011.

18. Coughlan AK, Oddy M, and Crawford JR. e BIRT Memory and Information Processing Battery (BMIPB). West Sussex: BIRT, 2009.

19. Baddeley A, Emslie H, and Nimmo-Smith I. Doors and People Test: A test of visual and verbal recall and recognition. Bury St Edmunds: ames Valley Test Company, 1994.

20. Welsh KA, Butters N, Hughes JP, et al. Detection and Staging of Dementia in Alzheimer’s Disease: Use of the Neuropsychological Measures Developed for the Consortium to Establish a Registry for Alzheimer’s Disease. Arch Neurol. 1992;49(5):448–52.

21. Wechsler, D. Wechsler Memory Scale, 3rd edn. San Antonio, TX: e Psychological Corporation, 1997.

22. Rohrer JD, Knight WD, Warren JE, et al. Word- nding di – culty: a clinical analysis of the progressive aphasias. Brain. 2008 Jan;131(Pt 1):8–38.

23. McKenna P and Warrington EK. Graded Naming Test. Windsor: NFER- Nelson Publishing Co. 1983.

24. Lambon Ralph MA, Patterson K, and Hodges JR. e relationship between naming and semantic knowkedge for di erent categories in dementia of Alzheimer’s type. Neuropsychologia. 1997;35(9):1251–60.

25. Dell GS, Schwartz, MF, Martin, N, et al. Lexical access in aphasic and nonaphasic speakers. Psychol Rev. 1997;104(4):801–38.

26. Baldo JV, Schwartz S, Wilkins D, et al. Role of frontal versus temporal cortex in verbal uency as revealed by voxel-based lesion symptom mapping. J Int Neuropsych Soc. 2006;12: 896–900.

27. Benson DF, Davis RJ, and Snyder BD. Posterior Cortical Atrophy. Arch Neurol. 1988;45(7):789–93.

28. Crutch SJ. Seeing why they cannot see: Understanding the syn- drome and causes of posterior cortical atrophy. J Neuropsychol. 2013. doi:10.1111/jnp.12011.

29. Warrington EK and James M. Visual Object and Space Perception Battery. Bury St Edmunds: ames Valley Test Company, 1991.

30. Goldenberg G. Imitating gestures and manipulating a mannikin— e representation of the human body in ideomotor apraxia. Neuropsychologia. 1995;33(1):63–72.

31. Reitan RM. Validity of the Trail Making test as an indicator of organic brain damage. Percept. Mot Skills. 1958;8:271–76.

32. Nelson H. A modi ed card sorting test sensitive to frontal lobe defects. Cortex. 1976;12:313–24.

33. DelisDC,KaplanE,andKramerJH.Delis–KaplanExecutiveFunction System (D–KEFS). San Antonio, TX: e Psychological Corporation, 2001.

34. Burgess P and Shallice T. e Hayling and Brixton Tests. Test manual. Bury St Edmunds, UK: ames Valley Test Company, 1997.

35. McDonald S, Flanagan S, Rollins J, et al. TASIT: A New Clinical Tool for Assessing Social Perception a er traumatic brain injury Journal of Head Trauma Rehabilitation. 2003;18:219–38.

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36. Baron-Cohen S, Wheelwright S, Hill J, et al. e ‘Reading the Mind in the Eyes’ Test revised version: a study with normal adults, and adults with Asperger syndrome or high-functioning autism. J Child Psychol Psychiatry. 2001 Feb;42(2):241–51.

37. Beck AT, Steer RA, and Brown GK. Manual for the Beck Depression Inventory–II. San Antonio, TX: Psychological Corporation, 1996.

38. Sheikh JI and Yesavage JA. Geriatric Depression Scale (GDS): Recent Evidence and Development of a Shorter Version. Clinical Gerontology: A Guide to Assessment and Intervention. New York, NY: e Haworth Press, 1986.

39. Alexopolous GS, Abrams RC, Young RC, et al. Cornell Scale for Depression in Dementia. Biological Psychiatry. 1998;23:271–84.

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CHAPTER 11 neuropsychological assessment 121

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CHAPTER 12

Acquired disorders
of language and speech Dalia Abou Zeki and Argye E. Hillis

Introduction

Although the words ‘speech’ and ‘language’ are o en used inter- changeably, each of these systems has a distinct function, relies on a distinct set of representations and processes, and engages a distinct neural network.

Language is a non-instinctive, culturally driven system of volun- tarily produced symbols, comprising receptive and expressive abili- ties allowing comprehension and communication of information respectively. Understanding and processing sound, word, phrase, sentence, and conversation involves retrieving vocabulary, con- cepts, grammar, and, on a higher scale, processing abstract infer- ences, idioms, or verbal problem-solving. ere are ve linguistic domains that comprise language (see Box 12.1).

Speech consists of the highly coordinated rapid motor func- tion responsible for the actual act of vocal expression of language. Regulation of speech occurs via basal ganglia, cerebellum, and cortical systems, with the corticobulbar tracts via the nuclei of the vagal, hypoglossal, facial and phrenic nerves maintaining con- trol and coordination of the muscles involved in speaking. ose include laryngeal, pharyngeal, palatal, lingual, oral, and respiratory muscles. Typically, the utterance of 2 words per second by a nor- mal speaker is equivalent to 14 linguistically distinct sounds (pho- nemes), each one requiring the contraction or relaxation of 100 muscles.1 Speech entails the combination of phonation (voicing), resonance (nasality), and articulation. It is also o en characterized by uency and prosody (Box 12.2).

Box 12.1 Linguists refer to ve domains that comprise the language system

1. Phonology: the sound system and linguistic rules of sound combinations, pronunciation, and perception.

2. Morphology: the linguistic rules of word structure and construction.

3. Semantics: the systematic meaning of words re ecting con- tent and utterance intent.

4. Syntax: the linguistic rules of sentence-element relationship or grammar.

5. Pragmatics: the rules for maintaining a conversation in terms of responsiveness, relevance, and so on.

Language localization

e outward production of language is a re ection of neural acti- vation in vast network of brain structures and regions in the cor- tex, basal ganglia, cerebellum, and brainstem. ere is clinical and imaging evidence of overlap in that network or with other networks of specialization that is responsible for the wide symptom spectrum following an acquired lesion. One lesion in an area can result in multiple de cits; lesions from multiple di erent sites can produce similar de cits; and multiple lesions4in elements of the same net- work can severely impact function. One of the most surprising ndings from functional neuroimaging studies is that the ‘language network’ is remarkably similar across language tasks and across individuals (Fig. 12.1).

Box 12.2 Speech consists of the following overlaid functions

1. Phonation: production of vocal sounds in relation to the length and mass of the membranous parts of the vocal cords. e duration of opening or closing of the vocal folds to pro- duce a voiced versus voiceless consonant is o en briefer than 20 msec.2 Intratracheal pressure must be held long enough so that the ‘ballistic opening gesture’ produces the desired consonant.3

2. Articulation: interruption of vocal sounds by pharyngeal, palatal, lingual, and oral muscle contractions. Phonemes, or speech sounds, like [m], [b], and [p] are labial; [l] and [t] are lingual. While consonants are produced by this mechanism, vowels are solely laryngeal in origin.

3. Fluency: speech uency (unlike language uency) o en refers to the ability to speak e ortlessly, and smoothly, without forward ow interruption. In some cases it refers to rate of speech. On average, a normal speaker utters 120 words per minute during a conversation; that is, 2 words per second.

4. Variations in pitch, loudness, and duration of syllables in speech: these can be used to convey meaning (e.g. sarcasm versus factual content), a ect (angry versus happy feeling), or even whether an utterance is a statement or a question (e.g. you are coming?).

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cognitive dysfunction

(b)

(c)

Fig. 12.1 e ‘language network’—areas that are activated across a variety of language tasks across most healthy individuals. ese areas include posterior inferior frontal cortex (Brodmann’s area (BA) 44 and 45), a more dorsal posterior frontal area in BA 6, posterior middle/superior temporal cortex (in BA 22 and often BA 20/21), angular gyrus (BA 39), and posterior inferior temporal cortex (in BA 37). Panel (a) Areas activated during word generation.131 Panel (b) Areas of activation throughout picture naming.132 Panel (c) Areas of activation during passive watching and listening to video with language.

Yet, lesions to di erent nodes in the language tasks produce very di erent language impairments that are fairly predictable immedi- ately a er the lesion. However, the degree to which language will recover a year or more later is not predictable. Despite huge lesions that cover all of the ‘language network’, some individuals are able to recover language a year or so a er stroke. ese results allow two conclusions: (1) many areas that are recruited across all language tasks are not equally necessary for those tasks, and (2) it seems likely that there are no areas of the brain that are truly necessary for recovery of language at one year.

Certain manipulations in task paradigms allow functional mag- netic resonance imaging (fMRI) or positron emission tomography (PET) to reveal areas more important for some language tasks than others. Lesion studies allow one to test what areas are normally ‘necessary’ for a task; that is, one assumes that when function on a task is impaired only when a particular area is damaged, that area is necessary for the task. However, lesion studies depend on identify- ing a su cient number of people with lesions in all of the possible locations to test the hypotheses (or creating temporary lesions with transcranial magnetic stimulation, for example). Using a combina- tion of these methods, some organization of the language network has been revealed. For example, ventral and dorsal language path- ways have been proposed by some authors.5,6 It has been suggested that the ventral temporal pathway might be critical for mapping sound to lexical representations and meanings of words, while the dorsal frontoparietal pathway has been proposed to be critical for syntactic and articulatory processes.

Using a variety of techniques, it has been established that core language functions are le -lateralized in the majority of both right- and le -handers (95 per cent and 75 per cent, respectively).7 Only humans have this hemispheric specialization, most likely because of our reliance on language. While nearly all animal species com- municate in some form, language is what sets us apart as a species. However, some aspects of language, such as conceptual semantics, may be broadly and even bilaterally distributed.

124 SECTION 2 (a)

Disorders of language

Aphasia (in Greek ἀφασία, i.e. speechlessness) encompasses difficulty producing and/or understanding spoken language. Impairments in reading (alexia) and writing (agraphia) are o en associated with aphasia. Much of our understanding of aphasia has come from the study of vascular cases, although the principles arising from such cases have o en pro tably been applied to other causes, including neurodegenerative disorders which are dealt with in detail elsewhere (see chapter 34).

Vascular aphasia syndromes have not typically corresponded to linguistic domains because lesions typically involve vascular ter- ritories, rather than being restricted to the ‘dorsal frontoparietal language network’ or the ‘ventral temporal’ language network, for example. e vascular syndromes refer to a collection of frequently co-occurring symptoms that are observed together because they represent functions that depend on tissue supplied by the same cer- ebral vessel (which can be occluded and cause a stroke), therefore each vascular aphasia syndrome is also associated with other neu- rological de cits (e.g. Broca’s aphasia with right arm spastic mono- plegia or right spastic hemiplegia).

Terminology for the vascular syndromes may vary. Broca’s apha- sia, for example, is also referred to as ‘anterior’, ‘motor’, or ‘non- uent’ aphasia. Wernicke’s aphasia, on the other hand, is sometimes termed, ‘posterior’, ‘sensory’, or ‘ uent’ aphasia. e classic Broca– Wernicke–Lichtheim–Geschwind model was the result of the e orts of Broca, Wernicke, and Lichtheim in the nineteenth cen- tury, with later modi cation by Geschwind in 1967. Broca pro- posed that part of the second or third convolutions of the le inferior frontal gyrus has a role in speech production, or what he, and Bouillaud before him, called the faculty of spoken language.8,9 Wernicke observed that lesions in the posterior aspect of the supe- rior temporal gyrus resulted in impaired comprehension and uent but gibberish speech. He suggested this posterior superior tempo- ral gyrus has a role in speech perception through its connections with other language areas.10 Lichtheim synthesized the previous claims, adding an interfacing conceptual area.11 Comprehension, language uency (based on grammaticality, e ortful articulation, prosody, and melody), repetition, naming, reading, and writing are the language domains that characterize the vascular aphasia syn- dromes described in the next section.

Vascular aphasia syndromes Broca’s aphasia

Broca’s aphasia occurs a er a lesion or dysfunction in the poste- rior inferior frontal cortex, the distribution of the superior divi- sion of the le middle cerebral artery, now known as Broca’s area (see below). It is de ned as arduous, non- uent, telegraphic speech output, interrupted by word- nding pauses. Both speech and writing are characterized by agrammatic sentences, revealed by substitution and omission of function words (e.g. the, an) such as prepositions, in exions, and auxiliary verbs. ree character- istics constitute the hallmark of this syndrome: (1) agrammatism, (2) verbal apraxia, and (3) preserved comprehension. Apraxia of speech is a disturbance in motor programming of speech articula- tion. Patients are aware of their problem and struggle to try and correct their misarticulation by trial-and-error, repetitively yet

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uneventfully. Groping articulatory movements are o en produced instead.

It has long been recognized that infarction solely a ecting Broca’s area causes a brief de cit in motor speech (‘apraxia of speech’) that recovers very quickly.12 Even lesions involving Broca’s area and its immediate surrounding areas deep into the brain, cause mutism that is replaced by a rapidly improving dyspraxic and e ortful artic- ulation, but no signi cant disturbance in language function per- sists.13 Lesions in this area typically cause de cits in action naming that are more severe than de cits in object naming. Infarctions that involve other structures beyond Broca’s area in this vascular terri- tory can cause the full-blown clinical syndrome of Broca’s aphasia. e structures most commonly associated with this presentation are the rolandic operculum, capsulostriatal and periventricular areas. When the entire territory is involved there may be a persis- tence of some symptoms.

Transcortical motor aphasia

Transcortical motor aphasia, also known as adynamic or extrasyl- vian motor aphasia, occurs following an injury to a ‘watershed area’ between the le middle cerebral artery (MCA) and the le anterior cerebral artery (ACA), in the mesial frontal lobe, also referred to as the supplementary motor area (SMA),14–16 is syndrome is char- acterized by poor spontaneous speech, with relatively good repeti- tion and comprehension.

Wernicke’s aphasia

Ten years a er Paul Broca’s description of the e ect of motor area lesion on the proper speech output, Karl Wernicke proposed that the le superior posterior temporal lobe is an area critical for lan- guage comprehension and processing. More recently, it has been recognized that other areas are critical for language comprehen- sion as well. Nevertheless, lesions in the inferior division of the le MCA, which supplies the posterior part of the temporal lobe and inferior parietal lobule, cause impairments in word meaning with- out disrupting uency of speech articulation, resulting in mean- ingless jargon in both spontaneous speech and repetition, now termed Wernicke’s aphasia. is syndrome consists of comprehen- sion and repetition impairments, anomia, semantic paraphasias (semantically related word substitutions) and phonemic parapha- sias (phonologically related word or nonword substitutions), and neologisms (jargon words). Alexia and agraphia are noted. ese individuals, in contrast to those with Broca’s aphasia, have poor insight regarding their de cits and seem unconcerned. Box 12.3 provides a case example of an individual with Wernicke’s aphasia at onset of stroke.

Lastly and interestingly, cases of crossed Wernicke’s aphasia in right-handed patients following lesions in the homologous area in the right hemisphere are reported.17

Transcortical sensory aphasia

is aphasia type is characterized by uent, circumlocutory speech with semantic jargon and poor comprehension. e key feature that distinguishes it from Wernicke’s aphasia is preserved repetition. It has been proposed that relatively spared repetition is due to pre- served integrity of arcuate fasciculus,16 but there is little direct evi- dence for this proposal. Others have proposed a right hemisphere contribution in language repetition given that transcortical sensory aphasia can occur post massive infarction involving the perisylvian

18,19

Transcortical mixed aphasia

Also known as isolation aphasia (or ‘isolation of the speech area’), it combines features of both transcortical sensory and motor aphasia. Repetition is preserved but there is reduced spontaneous speech, echolalia, and palilalia, or even mutism, along with impaired com- prehension, reading, and writing.21–24

Transcortical mixed aphasia, the term rst coined by Goldstein,14 follows lesions isolating the perisylvian language areas, thus the name ‘syndrome of isolation of the speech area’.25 Infarctions typi- cally include the watershed territory between the le ACA and MCA in addition to the watershed territory between the le MCA and PCA. Lesions in the le thalamus, putamen, and periventricu- lar white matter, and thalamo-mesancephalic infarcts have also been described.24,26

Prognosis is generally poor with persisting non- uency and unrecovered comprehension.

Conduction aphasia

ree major characteristics comprise the vascular syndrome of conduction aphasia: a relatively uent, though phonologically para- phasic speech; poor repetition, rst described by Lichtheim;11 and relatively spared comprehension.14,27–32 Repetitive self-corrections, word- nding di culties, and paraphrasing are attempts to approx- imate target phonemes, termed ‘conduit d’approche’.

In 1874, Wernicke indicated that the symptoms in one of his patients might possibly be due to the disconnection between the superior temporal and the inferior frontal gyri.10 is theory was later elaborated by Geschwind in 1968, giving rise to what is called the Wernicke–Geschwind model of aphasia.25 He considered that

CHAPTER 12 acquired disorders of language and speech 125

Box 12.3 A case of Wernicke’s aphasia

Mr T awoke from cardiac surgery and seemed ‘confused’. He was unable to follow even simple directions. His speech was uent and well-articulated, but consisted only of jargon. When asked to state the month, he said, ‘I haven’t seen her (frip) (freep) around here, I know that.’ He was not able to name any objects orally or in writing correctly although he gestured correctly their use. He called many of them ‘another ap thing or something’. He was guessing on both spoken and written word/picture-matching tasks. His repetition was similar to his spontaneous speech: u- ent, well-articulated English jargon, with occasional neologisms. MRI of the brain showed severe hypoperfusion of the le tem- poral cortex, including Wernicke’s area. He was not a candidate for thrombolytics due to his recent surgery but underwent inves- tigational therapy to increase perfusion. Repeat MRI on day 3 showed that he had a reperfused le temporal cortex (either a result of the intervention or due to spontaneous recanalization; Fig. 12.2). Repeat language testing on day 3 showed resolution of his language impairment, with good comprehension, repetition, naming, and spontaneous speech.

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Transcortical sensory aphasia is typically caused by poste- rior lesions involving the anterolateral thalamus, temporoparieto- occipital junction (watershed territory between the MCA and the posterior cerebral artery (PCA) territories), or second and third temporal gyri.20 Semantic variant PPA, Alzheimer’s disease, and Creutzfeldt–Jakob disease can cause a similar syndrome.

area.

126 SECTION 2 cognitive dysfunction

Fig. 12.2 Scans of individual with Wernicke’s aphasia at day 1, which resolved by day 3. Top panel: Di usion-weighted image (left) showing small acute infarct in left insula and perfusion-weighted image (right) at day 1, showing hypoperfusion of left temporal cortex, including Wernicke’s area. Lower panel: Di usion-weighted image (left) and perfusion-weighted image (right) at day 3, showing reperfusion of left temporal cortex.

lesions to the arcuate fasciculus, a large bundle of bres connect- ing the frontal and posterior temporal cortex (and angular gyrus), caused the repetition impairments in this so-called disconnection syndrome.33–35 However, most recent aphasiologists have ascribed the repetition impairment to limited working memory, and have found the associated lesions to be in areas critical for working memory: inferior parietal lobule (supramarginal and angular gyri), inferior frontal cortex, posterior temporal lobe, and/or their white matter connections. Box 12.4 describes a case of an individual with conduction aphasia.

On language testing, Mrs M’s speech was well-articulated but she made some phonological errors that were self-corrected, and she had hesitations. Sentences were short and had simple syntax. She was accurate in following simple commands, but made errors on three-step commands. She understood simple, active sentences, but guessed at comprehension of passive sentences. Repetition of monosyllabic and bisyllabic words was accurate, but repetition of polysyllabic words and of sentences was completely incorrect. She o en paraphrased the sentence rather than repeating it. (e.g. ‘It’s a sunny day in Baltimore’ was repeated as ‘it’s nice out’.). Her forward digit span was three; her backward digit span was two. Her naming

was mildly impaired. She had di culty spelling and reading unfa- miliar words (pseudowords) but correctly read and spelled words. She had language therapy ve days per week for three weeks, and her language de cits resolved.

Box 12.4 Case study of conduction aphasia

Mrs M is a 72-year-old woman who noted sudden di culty in conversing on the telephone. Her friend mentioned the title of book they were going to read for book club, and she was una- ble to repeat it correctly or write down the name of the book. She reports that she was ‘stuttering’ and having trouble nding words. She looked up the phone number of her physician and could read it, but was not able to retain it long enough to cor- rectly dial the number. She decided to wait until her husband got home from work. When he arrived four hours later her speech was unchanged so he called an ambulance. On arrival to the hos- pital, she was found to be in atrial brillation. An MRI showed an acute infarct (and comparable perfusion defect) in the le parietal cortex, including supramarginal gyrus, thought to be embolic (Fig. 12.3).

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Global aphasia

Destruction of anterior and posterior language areas causes reduc- tion of all faculties of language, including comprehension and speech output.27 Even though the most common cause behind this debilitating language disorder is a large le hemisphere ischae- mic stroke due to carotid artery or middle cerebral artery steno- sis or occlusion, cases following smaller haemorrhagic strokes are reported.36 Global aphasia can be the initial presentation in a patient who later recovers into Broca’s aphasia or transcortical motor aphasia. In this case, there is generally evidence of spared Wernicke’s area.37 Early comprehension recovery may result from reperfusion of Wernicke’s area,38 while later recovery of compre- hension may result from reorganization of the language network such that another area of the brain assumes of the function of the damaged area.39 Broca’s and Wernicke’s area may thus be hypoper- fused in the acute period, such that the area is dysfunctional, caus- ing global aphasia. When the area becomes reperfused through development of collateral blood ow or through treatment, the individual may show the vascular syndrome corresponding to the infarct rather than the initial vascular syndrome corresponding to the hypoperfused tissue (see Fig. 12.4).

Subcortical aphasia

Subcortical lesions have been reported to cause language de cits, ranging from anomia to global aphasia.40–46 Fluctuating jargon aphasia with impaired uency is o en observed in patients with thalamic lesions.47

Two distinct mechanisms can account for subcortical aphasia. One is that plaques in the middle cerebral artery cut o blood sup- ply to the lenticulostriate arteries, causing infarcts in the basal gan- glia and subcortical white matter, but also cause hypoperfusion of the cortex, causing a variety of aphasia syndromes.48 Aphasia due to cortical hypoperfusion has been demonstrated with single pho- ton emission computed tomography (SPECT),49 positron emission tomography (PET),45,50,51 and perfusion-weighted imaging.48,52 Improvement in cortical perfusion and metabolism corresponds to recovery of aphasia.48,52–57 It has been also shown that recanaliza- tion of an occluded M1 branch of MCA in subjects with aphasia and a striatocapsular infarct can reverse the aphasic syndrome.45

Diaschisis, distant cortical hypometabolism caused by reduced input from the infarcted area, can account for aphasia due to tha- lamic lesions54,58 and perhaps aphasia due to other subcortical lesions.59–61

CHAPTER 12 acquired disorders of language and speech 127

Fig. 12.3 Di usion-weighted image (left) and perfusion-weighted image (right) at day 1 of individual with acute conduction aphasia.

Fig. 12.4 Di usion-weighted image (left) showing infarct in superior division MCA territory that included Broca’s area, and perfusion-weighted image (right) showing larger area of hypoperfusion that included Wernicke’s area in a patient who had global aphasia acutely. When he showed reperfusion of Wernicke’s area, his comprehension improved, thus he had a Broca’s aphasia.

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128 SECTION 2 cognitive dysfunction Alexia and agraphia

Alexia is de ned as the loss of reading ability following a brain insult while agraphia is impairment in writing ability following brain damage. Both these syndromes are discussed in more detail in the chapter concerning alexia and agraphia but are brie y con- sidered here for sake of completeness within the framework of lan- guage disorders (chapter 18).

Pure alexia is at times referred to as visual alexia or word blind- ness, given that reading activates the le lateral occipitotemporal sulcus, mainly the so-called visual word form area (VWFA) area.62 is area is reliably activated in reading tasks, but is also activated in spelling and other lexical tasks (see reference 63 for review of this controversial issue). Spelling dyslexia or surface dyslexia refers to a patient who tries to spell or sound each word and guess its meaning from the way it sounds. is presentation follows occipitotemporal damage.64

A neural model for reading and writing was first suggested by Dejerine in 189265 and supported in 1965 by Geschwind.66 This model distinguishes between alexia without agraphia fol- lowing occipital lobe lesions involving the splenium and its radiations, and alexia with the agraphia following a lesion to the angular gyrus. In the latter, other parietal signs are com- mon on presentation (e.g. apraxia, anomia, and Gertsmann syndrome). Although Geschwind hypothesized that the angular gyrus is crucial for differentiating letters, Japanese researchers have argued that the neural circuit for this faculty is far more complicated. Ideographic (Kanji) and syllabic (Kana) reading and writing can be affected by various lesion areas, offering an additional emphasis on this extensive processing neuronal net- work. The latter was then specified as dual process, considering the angular gyrus as a the node for letter phonological process- ing and the posterior inferior temporal area as a node for letter semantic processing.67

Although ischaemia in the territory of the posterior cerebral artery is the most reported aetiology behind this reading impair- ment, compression to this artery by tentorial herniation or tumours is also reported.68,69 Transitory alexia without agraphia was reported in an HIV-positive patient with toxoplasma encephalitis and another with neurocycticercosis.70,71

In agraphia, spelling can normally be accomplished via a direct lexical method of recalling a word’s spelling or via a sublexical pho- nological method of sounding out its phonemes (speech sounds) and transforming them to graphemes (abstract letter identities). Retrieval of the learned spelling is likely to be important for the spelling of most familiar words and is critical for spelling irregular familiar words; while the computing plausible spellings of unfamil- iar words (like proper names) and spelling of regular words may depend almost entirely on the sublexical phonological method of spelling. Either of these spelling mechanisms can be disrupted independently, indicating that the neural networks that support these cognitive processes are distinct.72

A common spelling impairment a er stroke is a de cit in hold- ing the string of graphemes in working memory (‘the graphemic bu er’) while the word is spelled. is spelling impairment equally a ects regular and irregular words, and familiar and unfamiliar words, but a ects longer words more than short words. It results in deletions, insertions, transpositions, and substitutions of graph- emes.73 Agraphia can be part of an aphasia syndrome, thus termed

aphasic ‘agraphia’ where spelling and grammatical errors are de n- ing features. Pure agraphia has also been reported.63

‘Constructional agraphia’ has been described, with disturbances in the perception of spatial relations resulting in wrongly arranged words or letters, either haphazardly, or diagonally, or superim- posed. A right-to-le arrangement is also noted where only the right side of the page is used. In this case, researchers relate the writing disorder to le hemispatial neglect, a ecting responsive- ness to stimuli and space on the le side of the viewer. Right hemis- patial neglect can also occur but tends to a ect the right sides ( nal letters) of individual words, irrespective of the location with respect to the viewer. ‘Apraxic agraphia’ is reported a er frontal and pari- etal lesions, due to impaired motor planning required to form the proper shapes of letters and words.

Pure word deafness

Pure word deafness refers to an inability to recognize spoken words in the absence of a peripheral de cit in auditory acuity or more general auditory discrimination impairment. In his 1884 memoir, Lichtheim mentioned the patient who produced no paraphasias or paragraphias and had no dyslexia, but had a repetition impairment and di culty communicating using any means other than writing. When asked to write to dictation, though, the patient complained of an inability to hear. Pure word deafness, also known as ‘auditory verbal agnosia’, can occur a er lesions in the le superior tempo- ral gyrus and the superior temporal sulcus, both anterior. Bilateral temporal lesions can cause pure word deafness or a more general auditory discrimination de cit referred to as cortical deafness.74

Causes of aphasia

Any acute or transient insult or progressive pathologic process that a ects the language network can cause aphasia. e most common lesion is ischaemic stroke,75 and only ischaemic stroke typically causes the vascular syndromes described above. Haemorrhagic stroke, central nervous system infections,76,77 tumours, and trau- matic brain injury78 are known aetiologies. Neurodegenerative diseases79 and demyelinating diseases are reported also.80,81 Transient ischaemic attacks, complicated migraines, and seizures cause transient aphasia. Primary progressive aphasia refers to three syndromes: the non- uent, agrammatic variant is most commonly caused by a tauopathy such as frontotemporal degeneration-tau (FTLD-t), progressive supranuclear palsy, or corticobasal degen- eration; the semantic variant is usually caused by frontotemporal degeneration-ubiquitin (FTLD-u); the logopenic variant is most commonly caused by Alzheimer’s disease pathology.82 Primary progressive aphasia is considered in detail in chapter 34.

Disorders of speech

Speech output is a highly organized task that requires coordination of respiratory musculature, larynx, pharynx, palate, tongue, and lips, via control by extrapyramidal structures, cerebellum, basal ganglia, and the corticobulbar tracts. Motor speech disorders are the result of an insult at any level of this system or multiple levels. Muscle weakness, paralysis, spasticity, and poor coordination are all reported ndings.83 A way to categorize this type of movement disorder is into the phenotypical presentation, as various dysar- thrias or apraxia of speech.

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e dysarthrias

Darley and colleagues classi ed the dysarthrias based on their e ects on rate, range, tone, and timing of movement into the fol- lowing categories: accid, spastic, mixed spastic and accid, ataxic, hypokinetic, hyperkinetic, and unilateral upper motor neuron dysarthrias.83,84

It was reported by the European Brain Council that about 20– 30 per cent of people who have a stroke experience muscular dis- turbances impairing speech output.85 More than 100 muscles are responsible for a proper articulation and phonation, important for the strength, speed, range, accuracy, steadiness, and tone of the speech.86 In clinical practice, assessment of speech should be based on objective criteria about auditory–perceptual character- istics, repetition rate, oral mechanisms, and intelligibility testing. e last can be examined using the Assessment of Intelligibility in Dysarthric Speakers, for example.87

Flaccid dysarthria

Any impairment at the level of the cranial or spinal nerves innervat- ing any of the muscles assisting speech output results in weakness of the corresponding muscles a ecting several aspects of speech.84 Lesions involving the motor nuclei in the medulla and lower pons can cause this disorder. Disorders of the neuromuscular junction can also cause accid dysarthria.

Because the insult involves a nal common pathway, sole a ected muscles can be observed. Although the presentation depends on the nerves a ected, common features may be observed like hyper- nasality due to reduced velar movement and subsequent nasal emission.86 Audible inspiration and hypophonia due to paralysis of unilateral or bilateral vocal folds in abducted position follows involvement of the vagal nerve. Pronunciation of lingual sounds becomes di cult following insults to the hypoglossal nerve.

Wallenberg’s lateral medullary syndrome is the most common aetiology and occurs with a constellation of neurological symp- toms (dizziness, nystagmus, crossed sensory loss, etc.), in addition to accid dysarthria.

Besides vascular causes, dysarthria has been described in mus- cular disorders, such as adult-onset myotonic dystrophy. Slowing down of relaxation of the muscles of the facial, jaw, and neck mus- culature a er rest or activity are responsible for the dysarthria that is characterized by monotony, hypernasality, hoarseness, shorter stretches of speech, slow speech rate, and reduced intelligibility.88 Warming-up phenomenon can be used for improving speech out- put.89 Myasthenia gravis is the most common cause of accid dysar- thria at the level of the neuromuscular junction. A bilateral insult to the vagal nerve, usually infectious in origin, can cause a nasal speech due to bilateral palatal paralysis. Bilateral insults to cranial nerve VII as seen in Guillain–Barre syndrome, Lyme disease, or sarcoidosis cause problems with consonant output, such as ‘p’ and ‘b’.

Ataxic dysarthria

Ataxic dysarthria follows an insult to cerebellar structures, mainly the superior cerebellar peduncle or brachium conjunctivum.90 Loss of motor organization and coordination of speech-responsible mus- cles is the key feature. e classic presentation is a ‘drunken quality’ of speech. e characteristic scanning speech is slurred, monoto- nous, with poor pitch control, and with unnatural separation of

the syllables of words. Tremor of the laryngeal and respiratory muscles is common.91 Breath may seem not enough for complet- ing the utterance; a pause followed by explosive output is common. Intermittent hypo- and hypernasality is observed, suggesting an improper timing of the velar and articulatory gestures for conso- nants.92 However, there is also abnormal variability in duration and intensity of vowel prolongation.

Common aetiologies of ataxic dysarthria include multiple scle- rosis, spinocerebellar ataxia syndromes, paraneoplastic cerebellar degeneration, as well as stroke or tumour in the cerebellum.

Unilateral upper motor neuron dysarthria

ere are several neurological disorders of speech that are due, in part, to unilateral damage to the pyramidal tracts.93–95 Speech is mildly imprecise; phonation is harsh and low-pitched. is speech disturbance follows an insult to the upper motor neuron(s) that transmits the signal via cranial or spinal nerves to the articulation muscles.

Darley86 and Melo96 described this entity as impairment in artic- ulation precision with ‘incomplete pronunciation’. Added to this, Ropper97 reported slowed speaking rates and monotonous voice as common features.

Pure dysarthria is generally observed with face and tongue weak- ness and is the result of 1 per cent of lacunar strokes involving the corona radiate or the internal capsule.98,99 Genu of the internal capsule or hemispheric strokes that include the mouth area of the motor strip in the precentral gyrus are the most common lesion sites causing this type of dysarthria.

Spastic dysarthria

Damage to bilateral corticobulbar tracts by vascular, demyelinat- ing, or motor neuron disease result in pseudobulbar palsy, the symptoms of which include ‘spastic’ dysarthria and pseudobulbar lability (laughter and crying).84 De ning features are imprecision, monotony, hypernasality, ‘strangled’ breathy voice, pitch breaks, excess stress, and slow rate.83

Aetiologies include bilateral strokes, midbrain or upper pon- tine strokes, central pontine myelinolysis, bilateral in ammatory or infectious encephalitis, and progressive supranuclear palsy. Amyotrophic lateral sclerosis causes a mixed upper and lower motor neuron dysarthria, but the spastic component is o en prominent.

Apraxia of speech

Apraxia of speech (AOS) is a motor speech disorder that can occur in the absence of aphasia or dysarthria. is disorder of speech has been the subject of continuous debate regarding its characteris- tics, corresponding anatomical lesions, and mechanism of de cits. It o en occurs in the context of Broca’s aphasia84 but can occur in isolation.100,101 While aphasic patients have a problem selecting the proper phonemes, apraxic individuals have a di culty in the motor execution of this same phoneme.102 ey tend to have characteristi- cally abnormal prosody103 but are aware of their de cits, in contrast to the patients with conduction aphasia.101 In contrast to dysarthria, which results in consistent and predictable errors, apraxia of speech results in inconsistent and non-predictable utterances.84,86,88

Brie y, though no single symptom has been solely attributed to AOS, Wertz103 described ve features of the disorder: (1) e ortful

CHAPTER 12 acquired disorders of language and speech 129

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130 SECTION 2 cognitive dysfunction

trial and error with groping, (2) self correction of errors, (3) abnor- mal rhythm, stress, and intonation, (4) inconsistent articulation errors on repeated speech productions of the same utterance, and (5) di culty initiating utterances.

De ning AOS in terms of anatomical lesions has been controver- sial. Broca’s area has been found to be associated with AOS in acute and chronic stroke,20,104 although other chronic lesion studies have found that failure to recover from AOS is associated with lesions in le temporoparital cortex,101 the anterior superior insula,105 and the basal ganglia.84,106,106

AOS is usually caused by stroke, due to a clot in the superior division of the le middle cerebral artery. However, any lesion that a ects the le inferior frontal cortex, such as tumour, abscess, or focal atrophy can cause AOS. AOS is one of the two possible key features (along with agrammatic speech) of non- uent agrammatic variant of primary progressive aphasia.82

Treatment of aphasia

Recovery of language function following vascular impairments has been the subject of extensive controversy. Knowing that this recovery still occurs with the persistence of the lesion,108 the various factors predicting outcome remain controversial. ough transformation in aphasia types in the acute phase, mainly from non- uent to uent, not the opposite, and from severe to a milder form, is noted in 30–60per cent of aphasics,109 the severity of the

110,111

training appliance to compensate for hypernasality,132 and environ- mental listener training are used modalities. Computerized so – ware to increase single function ability has also been implemented.

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initial presentation predicts the nal outcome.
spontaneous recovery in the rst few months has been related to the lesion size and location,112 age, and premorbid intelligence.113 Moreover, systems or multivariate databases of combined clinical and functional imaging data have been introduced to provide indi- vidual outcome prediction post vascular aphasia.114,115 It has been reported that all but severely aphasic patients improve by 70 per cent of their maximum potential by 90 days, as long as those who are aphasic receive at least some speech and language therapy.116 However, controversy still exists concerning the e cacy of speci c treatment modalities and the correlation between the intensity of the treatment and outcome.117

Nevertheless, there is strong evidence that recovery takes place by a number of di erent mechanisms, and can be augmented by speech and language therapy, as well as non-invasive brain stimula- tion techniques, such as transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS).118–125

Pharmacotherapy with stimulants,126 cholinesterase inhibitors, and dopamine agonists127 has also been suggested for therapy augmentation. More clinical trials are needed for further proof of e cacy.

Treatment of dysarthria

Management strategies for patients with acquired dysarthria vary

according to the severity and type of dysarthria. However, the over-

all cornerstone of therapy is enhancing orofacial muscle strength

and mobility. Intelligibilty improvement with these techniques has

been reported in single case or small group studies.128,129 Post-

stroke dysarthria is best managed by targeting respiratory, phona-

tory, articulatory, and resonatory systems for a more intelligible

130
utterance,131 Behavioural compensation through reduction of rate

of speech, provision of prosthetic devices, example palatal li , or

e extent of

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79. Rohrer J, Rossor M, and Warren J. Alzheimer’s pathology in primary progressive aphasia. Neurobiol Aging. 2012 Apr;33(4):744–52.

80. Larner AJ and Lecky BR. Acute aphasia in MS revisited. Int MS J. 2007 Sep;14(3):76–7.

81. Sta N, Lucchinetti C, and Keegan B. Multiple sclerosis with predominant, severe cognitive impairment. Arch Neurol. 2009 Sep;66(9):1139–43.

82. Gorno-Tempini ML, Hillis AE, et al. Classi cation of primary progres- sive aphasia and its variants. Neurology. 2011 Mar 15;76(11):1006–14.

83. Darley F, Aronson A, and Brown J. Di erential Diagnostic Patterns of
Dysarthria. J Speech Hear Res. 1969;12(2):246–69 and 462–96.

84. Du y J. Motor Speech Disorders. St. Louis, MO: Mosby, 1995.

85. Warlow C, Dennis M, and van Gijn J. Stroke: A Practical Guide to
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86. Darley F, Aronson A, and Brown J. Motor Speech Disorders.
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87. Yorkston K, Beukelman D, and Bell K. Clinical Management of
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88. de Swart BJ, van Engelen BG, van de Kerkhof JP, et al Myotonia and
accid dysarthria in patients with adult onset myotonic dystrophy.
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89. de Swart B, van Engelen B, and Maassen B. Warming up improves
speech production in patients with adult onset myotonic dystrophy.
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90. Lechtenberg R and Gilman S. Speech disorders in cerebellar disease.
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91. Ackermann H and Ziegler W. Articulatory de cits in Parkinsonian
dysarthria: An acoustic analysis. J Neurol Neurosur Ps. 1991
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92. Auzou P, Ozsancak C, Jan M, et al. Evaluation of motor speech func-
tion in the diagnosis of various forms of dysarthria. Rev Neurol (Paris).
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93. Darley F, Brown J, and Goldstein N. Dysarthria in multiple sclerosis.
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94. Fisher M. Lacunar strokes and infarcts: A review. Neurology.
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95. Hartman DE and Abbs JH. Dysarthrias of movement disorders. Adv
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96. Melo T, Bocousslavsky J, Melle G, et al. Pure motor stroke: A reap-
praisal. Neurology. 1992 Apr;42(4) 789–95.

97. Ropper A. Severe dysarthria with right hemisphere stroke. Neurology.
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98. Ozaki I, Baba M, Narita S, et al. Pure dysarthria due to anterior
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99. Urban P, Wicht S, Hopf H, et al Isolated dysarthria due to extracer-
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100. Square-Storer P, Roy E, and Hogg S. e dissociation of aphasia from
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101. Square P, Roy A, and Martin R. Apraxia of speech: Another form of praxis disruption. In: LJG Rothi and KM Heilman (eds). Apraxia: e Neuropsychology of Action. East Sussex: Psychology Press, 1997,
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102. McNeil M, Pratt S, and Fossett T. e di erential diagnosis of apraxia of speech. In: B Maassen. Speech Motor Control in Normal and Disordered Speech. New York, NY: Oxford University Press, 2004.

103. Wertz R, LaPointe L, and Rosenbek J. Apraxia of Speech: e Disorder and its Management. New York, NY: Grune & Stratton, 1984.

104. Hillis A, Work M, Barker P, et al. Re-examining the brain regions crucial for orchestrating speech articulation. Brain. 2004 Jul;127(Pt 7):1479–87.

105. Dronkers N. A new brain region for coordinating speech articulation. Nature. 1996 Nov 14;384(6605):159–61.

106. Square P, Martin R, Bose A. Nature and treatment of neuromotor speech disorders in aphasia. In: R Chapey. Language Intervention Strategies in Aphasia and Related Neurogenic Communication Disorders, 4th edn. Philadelphia, PA: Lippincott, Williams & Wilkins, 2001.

107. Peach R and Tonkovich J. Phonemic characteristics of apraxia of speech resulting from subcortical hemorrhage. J Commun Disord. 2004 Jan-Feb;37(1) 77–90.

108. Holland AL, Fromm DS, DeRuyter F, et al. Treatment e cacy: aphasia. J Speech Hear Res. 1996;Oct;39(5):S27–36.

109. Pashek GV and Holland AL. Evolution of aphasia in the rst year post- onset. Cortex. 1988;Sep;24(3):411–23.

110. Kertesz A and McCabe P. Recovery patterns and prognosis in aphasia. Brain. 1977 Mar;100(1):1–18.

111. Pedersen PM, Vinter K, and Olsen TS. Aphasia a er stroke: type, severity and prognosis. e Copenhagen aphasia study. Cerebrovasc Dis. 2004;17(1):35–43.

112. Plowman E, Hentz B, and Ellis C. Post-stroke aphasia prognosis: a review of patient-related and stroke-related factors. J Eval Clin Pract. 2012;Jun 18(3):689–94.

113. Lazar RM and Antoniello D. Variability in recovery from aphasia. Curr Neurol Neurosci Rep. 2008 Nov;8(6):497–502.

114. Price CJ, Seghier ML, and Le AP. Predicting language outcome and recovery a er stroke: the PLORAS system. Nat Rev Neurol. 2010 Apr;6(4):202–10.

115. Saur D, Ronneberger O, Kümmerer D, et al. Early functional magnetic resonance imaging activations predict language outcome a er stroke. Brain. 2010 Apr;133(Pt 4):1252–64.

116. Lazar RM, Minzer B, Antoniello D, et al. Improvement in aphasia scores a er stroke is well predicted by initial severity. Stroke. 2010 Jul;41(7):1485–8.

117. Bhogal SK, Teasell R, and Speechley M. Intensity of aphasia therapy, impact on recovery. Stroke. 2003 Apr;34(4):987–93.

118. Marsh EB and Hillis AE. Recovery from aphasia following brain injury: the role of reorganization. Prog Brain Res. 2006;157:143–56.

119. Sarasso S, Santhanam P, Määtta S, et al. Non- uent aphasia and neural reorganization a er speech therapy: insights from human sleep elec- trophysiology and functional magnetic resonance imaging. Arch Ital Biol. 2010 Sep;148(3):271–78.

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122. Kang EK, Kim YK, Sohn HM, et al. Improved picture naming in aphasia patients treated with cathodal tDCS to inhibit the right Broca’s homologue area. Restorative Neurol Neurosci. 2011;29 (3):141–52.

123. Fridriksson J, Richardson JD, Baker JM, et al. Transcranial direct current stimulation improves naming reaction time in uent aphasia: A double-blind, sham-controlled study. Stroke. 2011 Mar;42:819–21.

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128. Robertson S. e e cacy of oro-facial and articulation exercises in dysarthria following stroke. Int J Lang Commun Disord. 2001;36 Suppl:292–7.

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CHAPTER 13

Memory disorders

Lara Harris, Kate Humphreys,
Ellen M. Migo, and Michael D. Kopelman

eories of memory

Shortly a er learning, we are temporarily able to access informa- tion over a period of seconds. A er this, we can either recall this information in order to complete a task (short-term memory, STM), or the information may become consolidated into a longer- lasting memory (long-term memory, LTM). Memory takes vari- ous forms which can be de ned separately, and di erent forms of memory are associated with di erent patterns of brain damage. Distinguishing types of memory is therefore important to develop theories of memory and also to understand the kinds of problems that di erent patients are likely to have.

LTM may be divided (Fig. 13.1) into explicit, declarative mem- ory, which involves conscious recollection of facts and events, and implicit, non-declarative memory, where information is encoded without conscious memory of the learning event. Within explicit memory, there are episodic and semantic memory components. Episodic memory refers to memory for autobiographical events, o en associated with contextual information (e.g. time and place), whereas semantic memory is de ned as memory for factual infor- mation (e.g. meanings of words), which can be recalled without contextual information.

Episodic memories can be assessed through tests of recall and recognition. A recall memory test requires recollection of a target item or items perceived earlier. A recognition memory test involves identi cation of whether or not a given stimulus (or item) has been perceived before, either in a Yes/No format (‘Yes–No recognition’) or by selecting the item from one or more alternatives (‘forced- choice recognition’). Both episodic and semantic memory have retrograde (memory for past events) and anterograde (memory for new events) components.

In contrast to explicit memory, implicit memory is where prior events support performance without conscious awareness of learn- ing. Examples include priming, where subconscious awareness of previous information a ects performance on future trials, and pro- cedural memory, which supports acquisition of skills.

Traditionally, the role of the hippocampus was thought to be con- ned to LTM processes, grounded by early reports of dissociations between preserved STM and chronically impaired LTM in patients with hippocampal damage (e.g. patient HM).9 However, more recent ndings suggest the hippocampi are also involved in STM processes). In this section, we outline the main ndings from neu- ropsychology, cognitive psychology, and neuroscience in the study of di erent types of memory, with particular reference to the role of the hippocampus.

Short-term and working memory

Within cognitive neuropsychology, STM is de ned as the tempo- rary storage of information over a period of around 20–30 seconds. e term ‘working memory’ refers to the storage and manipula- tion of information in order to complete a complex task.10 e con- cept of working memory assumes that a limited capacity system temporarily maintains and stores information, and provides an interface between perception, LTM and action. Models of short- term memory can be divided into multi-store and unitary theories. Multi-component theories view STM and LTM as separate systems with distinct representations, whereas unitary models suggest that both STM and LTM use the same representations, di ering only in terms of the level of activation of these representations and some of the processes that act upon them.10

e Baddeley and Hitch8 model (Fig. 13.2), which has been the most highly in uential account of working memory, comprises three functionally independent bu ers: the phonological loop (responsible for information that can be rehearsed verbally), a visuospatial sketchpad (to maintain visual information), and an episodic bu er (for binding information from the other systems). Within this model, auditory information enters the phonological store directly and is then transferred to an output bu er, where the information may be either recalled or recycled through rehearsal. Remembering a list of words is easier when they form a meaningful sentence (e.g. ‘chunking’).15 Within the Baddeley and Hitch model, this is because information from LTM supports the integration of words into sentences through the episodic bu er. According to their model, a supervisory system (or central executive) controls, coordinates, and regulates these systems, and is responsible for task shi ing, retrieval strategies, selective attention, and inhibition.

ere is support for neurologically and functionally distinct pro- cesses in STM and LTM. Patients with medial temporal lobe (MTL) damage present with preserved STM but impaired LTM,12–16 while some patients, for example with parietal damage, show a pro le of preserved STM despite disorders in LTM (e.g. patient KF).15

Support for the Baddeley and Hitch model8 comes from neuropsy- chological double-dissociations in memory-impaired patients who show that visual and verbal STM can be independently impaired, following right and le hemisphere damage respectively.16 Further support has come from dual-task experiments with healthy par- ticipants, where concurrent verbal tasks interfere with verbal STM and visual tasks with visual STM17 (see section on classi cation of disorders of memory, this chapter, for a discussion of patients showing damage to component subsystems in STM). Evidence

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136 SECTION 2

cognitive dysfunction

Explicit/Declarative memory

Implicit/Non-declarative memory

Procedural
memory Priming

Long Term Memory

Semantic memory

Anterograde Retrograde

Distinction between recall and recognition

Episodic memory

from neuroimaging strongly suggests that verbal and visual STM processes may be neurologically distinct. Verbal STM is thought to be subserved by the le inferior frontal and parietal cortex, whereas spatial STM is made possible by the right posterior dor- sal frontal and right parietal cortices and object/visual STM by the le inferior frontal and le parietal/le inferior temporal cortices.18–22

Perhaps the most in uential unitary model of STM was described by Atkinson and Shi rin.21 Essentially, they proposed that STM consists of activated long-term representations, an idea that has been recently further developed.22–27 Within their model, informa- tion is rst submitted to sensory memory and is then transferred to a short-term store where information is fed into and out of long- term memory. Given this, STM consists of temporary activations of representations that may be associated with long-term memories, or information that was recently perceived. Crucially, representa- tions that are more strongly activated (modulated by recency and frequency of occurrence) are more accessible. Oberauer26 has sug- gested that four pieces (chunks) of information are available for access, but only one chunk of information can be the focus of atten- tion at any one time.

Although the neural substrates of STM and LTM were tradi- tionally assumed to be separate, there is some evidence that STM and LTM may share some neural processes. Patients with damage

to the MTL frequently perform well on standard STM tasks, but some amnesic patients have also shown impairment where STM tasks require the representation of novel materials,28–32 and novel associations among stimuli, and between stimuli and context.31,32 is nding has received strong support from neuroimaging.33,34 e data suggest that MTL, and the hippocampus in particular, are employed in the encoding and retrieval of associative information during STM as well as in LTM. ese ndings challenge the simple STM/LTM dissociation that has been reported in classical lesion studies.

Long-term memory

Explicit/declarative memory

Explicit memory can be subdivided into episodic memory, de ned as memory for a person’s life events, and semantic memory, the memory for facts, concepts, and word meaning.35 Crucially, epi- sodic memory is described as relational, involving the representa- tion of various associations between time, space, and the self, which is consistent with ndings of hippocampal involvement in the short term, during associative memory tasks. Broadly, declarative mem- ory is subserved by MTL structures: the hippocampal region (the dentate gyrus, the subicular complex, and the hippocampus itself; see chapter 4), midline diencephalic structures,36 entorhinal cor- tex, perirhinal cortex, and parahippocampal cortex,37–41 and the thalami, mammillary bodies, the mammillo-thalamic tract, retros- plenium, and the fornix. ere may also be dorsolateral prefrontal cortex involvement.42

e hippocampus appears to have a speci c role in the binding of information in memory. In a detailed case study of a patient with selective damage to the hippocampus (YR), Mayes and colleagues reported that associative memory for items of the same type (e.g. words) were preserved, while associative memory for di erent types of information (i.e. pictures and professions, faces and voices) was clearly impaired.43 e authors suggest that di erent types of information processed in the neocortical regions is committed to the hippocampus for binding.44,45 Further evidence supporting a specialized role of the hippocampus in associative memory has been found elsewhere (e.g. references 46, 47, see 48 for a review). It should be noted, though, that specialization of the hippocampus for relational memory has not always been found.49–51

Anterograde Retrograde

Fig. 13.1 An overview of long term memory (LTM).
Adapted from Neurobiology of Learning and Memory. 82(3), Squire LR, Memory systems of the brain: A brief history and current perspective, pp. 171–7, Copyright (2004), with permission from Elsevier.

Visuospatial Sketchpad

Visual Semantics

Central Executive

Episodic Buffer

Episodic Long Term Memory

Phonological Loop

Language

Fig. 13.2 e revised model of working memory, incorporating links with long- term memory (LTM) by way of both the subsystems and the episodic bu er. Adapted from Trends in Cognitive Sciences. 4(11), Baddeley A, e episodic bu er: a new component of working memory? pp. 417–23, Copyright (2000), with permission from Elsevier.

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Retrograde amnesia

Traditionally, it has been believed that in retrograde amnesia (RA), there is relative sparing of early memories, as is postulated by Ribot.52 e two leading theories of remote declarative memory are consolidation theories53–55 and multiple trace theory (MTT).56–58 Consolidation theory suggests that encoded experiences are ini- tially stored in the hippocampus and cortical regions (perirhinal cortex, parahippocampal cortex), and with repeated learning, this information is transferred to the neocortex for permanent storage (consolidated). MTT suggests instead that experiences form mem- ory traces and older memories are associated with a greater number of memory traces acquired over time.

e perspectives di er in terms of the neural mechanisms assumed to subserve semantic memory and episodic memory; in particular, the e ects of hippocampal or MTL damage on remote memory (retrograde amnesia). Consolidation theories state that hippocampal or MTL damage leads to an impairment in retrieval of remote episodic (event-based) and remote semantic (knowledge or fact-based) information, both with a temporal gradient (i.e. relative sparing of early memories compared to more recent ones). MTT, on the other hand, states that hippocampal or MTL damage leads to an extensive loss of remote episodic memories across all time periods, while remote semantic memories are spared.

Both theories agree that damage extending beyond the MTLs will a ect remote episodic and semantic memories, but the MTT states that damage to the MTLs is su cient to cause an extensive remote episodic memory loss (examples of cases showing disorders in LTM are described in section on classi cation of disorders of memory, this chapter). However, there is still considerable contro- versy over these issues.59,04

Topographical memory

Topographical memory involves relating information about land- marks and space from semantic and episodic memory for the purposes of navigation. In topographical amnesia, buildings and landmarks can frequently be recognized and recalled, but the mem- ory for associations between them and how they relate to space is defective.61–64

Neuroimaging and neuropsychological evidence suggests that while the parahippocampus is implicated in relating visual and spatial information into a topographical representation, the hip- pocampus is involved in their consolidation. In an important study, Maguire and colleagues65 took structural magnetic reso- nance imaging (MRI) scans of the brains of professional London taxi drivers, who undertake two to three years of training to learn the various spatial relations between destinations in the city. e authors reported that the taxi drivers had signi cantly larger pos- terior hippocampi, relative to a control group, concluding that the posterior hippocampus stores a map of spatial representations to enable navigation.

Topographical memory appears to be underpinned by a network including the medial parietal lobe, the posterior cingulate gyrus, occipitotemporal areas, the parahippocampal gyrus, and the right hippocampus.65 is is consistent with neuropsychological reports of hippocampal patients who show impaired topographical memory in the context of better preserved memory for visual information.66 On functional imaging, there is hippocampal activation during studies of navigation in virtual environments in PET64,65 and activa- tion of the right hippocampus during route- nding on fMRI.67,68

ere is some suggestion that the role of the hippocampus in relating spatial representations may not be con ned to LTM pro- cesses, as hippocampal damage impedes the memory for topo- graphical information even over short delays.69

Implicit/non-declarative memory

While explicit memory processes are mediated by the MTL and diencephalic regions, the implicit (non-declarative) memory sys- tem is traditionally understood to be independent of the MTL, though the neural regions implicated in tests of implicit mem- ory vary widely with the type of stimuli presented. Dissociations between implicit and explicit memory performance in amnesic patients6 are consistent with theories positing separate neural sys- tems for explicit and implicit memory.

More recent work has suggested that there may be some overlap between the neural mechanisms involved in implicit and explicit memory, which may indicate a unitary system. In particular, there is some evidence that MTL may be implicated in implicit memory where retrieval is of relational information rather than individual items. ere is accumulating evidence from neuroim- aging studies showing MTL activation during associative memory tasks (for reviews, see references 70, 71). Hippocampal activity during implicit relational memory encoding has been demon- strated in healthy participants,47 and implicit relational memory e ects were absent in hippocampal patients tested under the same conditions.46

Procedural memory

Procedural memory refers to the acquisition and retention of perceptuomotor skills. ese memories are accessed and applied without the need for recalling information relating to the event where the skill was acquired. Procedural memory is less well understood than explicit memory, but it is likely to involve a net- work comprising frontal, basal ganglia, parietal, and cerebellar regions.36,70,73 Unlike explicit memory, learning in the procedural memory system is gradual, and the automaticity with which pro- cedural memory is applied is only achieved a er repeated expo- sure and practice.

Skill acquisition has been tested experimentally using mirror- reading and pursuit rotor tasks. Mirror-reading tasks involve read- ing mirror-transformed words, and pursuit rotor tasks involve following a moving dot around a circle with a wand. Performance on these tasks should improve with practice. One study74 com- pared the performance of patients with Huntington’s disease with Korsoko ’s syndrome patients and controls on mirror-reading and pursuit rotor tasks. Both Korsako ’s and control participants showed the expected pattern (increased speed of mirror-reversed words with increased exposure), whereas the performance of the Huntington’s group was stable over incremental trials. Such lack of improvement with practice would be compatible with a special role of brain regions particularly a ected in Huntington’s in implicit memory (e.g. the basal ganglia).

Classi cation of disorders of memory

ere are various types of memory disorders, each associated with di erent clinical characteristics and neuropsychological dissocia- tions. In this section, we describe the most common memory disor- ders using vignettes of important neuropsychology cases from the literature.

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CHAPTER 13 memory disorders 137

138 SECTION 2 cognitive dysfunction Short-term memory

Much of the data on STM comes from memory span tasks, where lists of words, pictures, or numbers are presented and the partici- pant is required to recall them in the order they were presented. Memory span is determined by the longest list of items reliably recalled in the correct order and is considerably reduced in patients with short-term memory disorders, relative to control norms.

Several STM-impaired patients have been described. Patients with phonological STM de cits are characterized by a marked impairment for verbally presented STM despite preserved visual STM. ese patients are una ected by phonological similarity or word length of the to-be-recalled items—e ects commonly observed under STM conditions.20,75–77 e rst phonological STM patient to be described was patient KF15,77 who, despite hav- ing a normal ability to articulate words and comprehend language, could recall sequences of only two auditorily presented items.15,77 Strikingly though, KF performed within the normal range under conditions of visual presentation.

e authors attributed these results to avoidance of employing a defective phonological loop during STM tasks.4,78 A similar patient (see Box 13.1) with a pure de cit for phonological information showed the same pattern of impaired auditory span, but with nor- mal language comprehension with sentences comprised of simple structures (patient PV).4 ese dissociations strongly suggested selective impairment of an auditory short-term system, putatively localized in the le parietal or superior temporal regions15,79 in a model with functionally separate short-term stores. Some other studies have also reported de cits of spatial span following lesions of the right parietal region.80,81

As will be discussed below, MTL patients with impaired long-

2,14

Anterograde amnesia is characterized by the failure to create new memories or acquire new information following the onset of a dis- ease or brain injury. In contrast, retrograde amnesia refers to the loss of memories which occurred before the onset of a disease or head trauma. A highly in uential case of anterograde amnesia fol- lowing bilateral MTL lesions is patient H.M. (Box 13.2).

e association between anterograde amnesia and the MTL described in these original observations was subsequently repli- cated in several studies of amnesic patients with MTL damage (e.g. patient SS82 and patient RB83; see also Box 13.3), and in experimen- tal animals with tailored lesions to the MTL.84 is work has sought to investigate the speci c structures within the MTL involved in anterograde and retrograde amnesia.

Anterograde amnesia has been associated with bilateral loss of the pyramidal cells in the CA1 hippocampal area,83 and damage to the anterior thalamus.85–88 In herpes simplex encephalitis, the severity of anterograde amnesia is strongly modulated by the extent of pathology in the medial limbic regions, with bilateral damage typically predictive of very severe amnesia.89–91

In contrast, some studies have found that retrograde amne- sia is associated with damage to the right temporal and frontal areas.41,92–94 In a detailed case study, Levine and colleagues attrib- uted retrograde amnesia in a traumatic brain injury patient to a focal right frontal lesion, and right frontotemporal disconnection.95 ough some authors have described cases of disproportionate, ‘isolated’, or ‘focal’ retrograde amnesia,87,96,97 many of these cases have in fact shown evidence of coexisting impairments in antero- grade memory98–102 (see reference 101 for a review).

Box 13.2 Vignette: Patient HM

Patient HM1,2 underwent a bilateral medial temporal lobe resec- tion in 1953 at the age of 27, which included the hippocampus and most of the amygdaloid complex and entorhinal cortex, in order to control frequent and debilitating epileptic seizures. Surgery was partially successful in modifying his epilepsy but resulted in severe anterograde amnesia.

He failed to acquire new event-related, autobiographical memories (i.e. episodic memory, e.g. appointments, people he had just met) and memories for facts (i.e. semantic memory). HM famously reported that ‘every day is alone in itself’.1 In contrast, wider cognition, including perceptual abilities, short- term memory, procedural memory, and language skills were well-preserved.

e case of HM strongly in uenced memory research, empha- sizing the role of the medial temporal lobe structures in explicit, declarative memory, and demonstrating that the neural mecha- nisms responsible for memory can be dissociated from struc- tures involved in other aspects of cognition.

term memory and preserved STM have also been described. ese ndings indicate that STM processes are broadly independ- ent of MTL structures. Moreover, there is some evidence that while phonological (verbal) STM stores might be localized to posterior le hemisphere regions, visusospatial STM stores are in posterior right hemisphere areas.

Anterograde and retrograde amnesia

Box 13.1 Vignette: Patient PV

Patient PV7 was a right-handed woman with 11 years of edu- cation, who su ered a large, le hemisphere CVA at the age of 23. Acutely, she had a right hemiparesis which cleared within a month, and some signs of aphasia, including phonemic parapha- sias and word- nding di culties, and sentence repetition was particularly impaired, though wider cognition was preserved.

Two years a er her stroke, most of her language problems had resolved, though striking de cits in sentence repetition (for sentences containing more than eight syllables) and in compre- hending complex language (e.g. using the Token test and Raven’s progressive matrices) persisted. ese di culties were observed in the context of good repetition and comprehension of single words and short sentences suggesting that PV’s problems were mnemonic in nature.

Her auditory span was severely restricted (to lists of two or three items) but she performed within the normal range with visual presentation. Her sentence repetition impairment was restricted to sentences of two to three words. Sentence com- prehension was better and she experienced problems only with long, complex sentences. e absence of detrimental e ects of phonological similarity and increased word length indicates sub- components in STM, and suggests that a defective phonological loop11 is the locus of PV’s impairments in span, sentence repeti- tion, and comprehension.

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e partial dissociation of anterograde and retrograde amne- sia has received support from studies of Korsoko ’s syndrome patients, where the extent of retrograde amnesia is not well cor- related with the severity of anterograde amnesia.102–105

Selective de cits in episodic memory?

Patients with impaired episodic memory show particular di cul- ties in remembering events with a speci c spatial or temporal con- text in both anterograde and autobiographical memory. ere are reports of patients who show dissociations between episodic and semantic memory (Box 13.4).

In a study of retrograde amnesia, Bright and colleagues106 com- pared episodic and semantic memory performance in medial tem- poral, medial plus lateral temporal, and frontal lesion patients. MTL lesions were associated with impaired retrieval of recent epi- sodic memories whereas patients with medial plus lateral temporal damage showed impaired recall of both recent and remote episodic memories (i.e. a at temporal gradient).

Episodic memory disorder occurs in herpes simplex (HSV) encephalitis107 and a similar pattern—though o en to a lesser

extent—has been reported in limbic encephalitis.108 In terms of neuroimaging ndings, HSV encephalitis causes hyper-intense signal alteration on T2-weighted MRI scans and loss of volume in the MTL which is consistent with an association between episodic memory and the MTL.89,109,110

Selective de cits in semantic memory?

In the early stages, semantic dementia (SD) patients show frequent word- nding di culties, and may demonstrate impaired reading of low-frequency, irregularly spelled words (surface dyslexia). In the later stages of the disease, speech becomes increasingly empty of meaning, though it remains uent and grammatically sound (Box 13.5). Many semantic dementia patients have atrophy of the temporal pole, with relative preservation of MTL structures (see reference 111 for a review).

Under neuropsychological examination, these patients show impairments on tests of semantic knowledge (e.g. pyramids and palm trees).112 Crucially, and as is consistent with preserved MTL regions on imaging, episodic memory in these patients is o en rela- tively spared,113–115 In a study comparing the memory performance of an MTL amnesic patient with a patient with semantic demen- tia, Westmacott and colleagues116 showed that, unlike the amnesic patient, the semantic dementia patient EL had preserved episodic memory, at least on cueing, and a similar nding was made in patient IH (Box 13.5) by Moss and colleagues.3 Further, EL’s memory for semantic facts was signi cantly modulated by autobiographical sig- ni cance, whereas this was not true of the amnesic patient KC, indi- cating that episodic memory may contribute to semantic memory in cases of SD. ere is also evidence from a longitudinal study sug- gesting intact autobiographical memory in semantic dementia until the very late stages of the illness (patient AM).117

Semantic memory is also commonly a ected in both Alzheimer’s disease118 and HSV encephalitis,7,119 manifesting in surface dys- lexia and di culties on wider lexical semantic memory tasks. is impairment has been attributed to le inferolateral temporal lobe or temporal pole damage.120

CHAPTER 13 memory disorders 139

Box 13.3 Vignette: Patient DJ

Patient DJ10 su ered unilateral le temporal lobe damage due to herpes encephalitis in 1990, when he was aged 36. Initially, DJ was unable to remember events and could not read, speak, or comprehend spoken language. Recall of earlier memories was better preserved.

One year post-onset, his language abilities improved (though surface dyslexia persisted). Strikingly, he was still very unable to acquire new memories, though memory for remote news and autobiographical events was only moderately impaired. He made frequent confabulation errors when required to recall auditorily presented stories, both in immediate and delayed (20–30 min- utes) recall conditions (logical memory, WMS–R).

Consistent with his le temporal lobe pathology, DJ’s recogni- tion memory was poor, though his memory for faces was bet- ter preserved than for words (using the Recognition Memory Test). Seven years post-onset, DJ was still severely amnesic and anomic, and showed on testing a pattern of poor verbal memory and preserved visual memory (WMS–R), though memory for recent episodic and semantic memory was much improved and he was able to name highly familiar items.

Box 13.5 Vignette: Patient IH

Patient IH6 was diagnosed with semantic dementia aged 62. An MRI scan revealed marked atrophy of the le temporal lobe but crucially with better preservation of the le hippocampus and MTL, and minor atrophy in the right temporal lobe and neocortex.

He showed di culties in word- nding, reading, naming, and language comprehension, despite good non-verbal reasoning, visual spatial processing, and day-to-day memory and orienta- tion. is pattern of neuropsychological performance is charac- teristic of semantic dementia, though he was sometimes able to spontaneously recall events from his late teens.

IH showed a reversed temporal gradient (relative preserva- tion of recent memories) in autobiographical memory using the Autobiographical Memory Interview, but not when recall- ing news events (semantic memory). However, IH’s memory for early, remote events could be signi cantly improved with detailed cueing. e neuropsychological pro le of IH suggests that lexical–semantic disturbances were the basis of his impaired retrieval from autobiographical memory, rather than de ciencies in autobiographical memory storage.

Box 13.4 Vignette—Patient KC

Patient KC3–5 is an amnesic patient with complete destruction of the le hippocampus, parahippocampal gyrus, entorhinal and perirhinal cortex following a road tra c accident.

He subsequently developed anterograde amnesia and a tem- porally graded retrograde amnesia for episodic information: he could not acquire new semantic or autobiographical memories, and could only reliably recall old semantic (fact-based) memo- ries from his life prior to the accident. Notably, he could remem- ber detailed factual information from his education but could not recall emotional details, such as those relating to his brother’s death. KC was also unable to imagine himself in the future (auto- noetic consciousness).

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140 SECTION 2

cognitive dysfunction

Box 13.6 Vignette: Patient Jon

Jon8 is a developmental case of early onset amnesia. He was delivered prematurely and su ered two long-lasting convulsions at the age of four. Jon began to show evidence of memory prob- lems a year-and-a-half later.

At the age of 19, Jon was assessed by Vargha-Khadem and col- leagues.8 On imaging, Jon showed abnormally small hippocampi bilaterally. Impressively, at this time he had an IQ of 120, could read successfully, and showed relatively preserved memory for factual information (semantic memory), even for information learned a er his hippocampal damage. However, Jon was unable to nd his way around familiar routes, was not well oriented in time, and could not acquire information about daily events (epi- sodic memories).

Consistently, during assessment, he showed a striking impair- ment on the Rivermead Behavioural Memory Test, which includes tasks such as remembering a route, an appointment, and a message to be relayed. Despite his preserved ability to perceive and recognize objects, Jon’s topographical memory was mark- edly impaired, as was his context-dependent episodic memory.

Box 13.7 Vignette: Patient LH

Patient LH9 was aged 18 when he was involved in a road tra c accident. He su ered a traumatic brain injury and underwent an extensive right temporal lobectomy and insertion of a shunt for hydrocephalus. MRI and SPECT conducted when he was aged 41 revealed damage to the right parietal and occipital lobes and a le hemisphere white matter lesion (extending from the inferior temporal gyrus to just below the occipital horn), but the dience- phalic regions medial temporal lobe structures were spared.

LH’s main complaint was an inability to recognize faces. He also showed other impairments in visuoperceptual skills. He showed an absent priming e ect in perceptual identi cation of words and pseudowords and absent word completion priming in the context of normal (explicit) recognition memory.

Topographical memory

Turriziani and colleagues66 reported a patient with signi cant bilat- eral hippocampal atrophy and moderate cortical atrophy follow- ing cerebral hypoxia. Crucially, there was a chronic impairment in memory for spatial information that was signi cantly improved with visual cues, but a relatively well-preserved ability to learn ver- bal and visual information (including topographical information), which was only mildly impaired. e authors concluded that there was a (largely) preserved ability to form topographical represen- tations (modulated by the preserved parahippocampus), but an impaired ability to consolidate them into LTM (owing to bilateral hippocampal damage). A developmental syndrome has also been described (Box 13.6).

e association between hippocampal damage and topographi- cal memory has been observed even at very short delays. In a neu- ropsychological study of four focal hippocampal patients, Hartley and colleagues69 found that two patients were impaired in both topographical perception and memory, but that two showed a selective impairment for topographical memory (i.e. despite pre- served ability to perceive and process topographical representa- tions), even at very brief (two-second) delays. is nding suggests the speci c role of the hippocampus in topographical memory con- solidation, and during specialized STM tasks tapping visualspatial information.

Implicit memory

A double dissociation between explicit and implicit memory in two neuropsychological cases, LH and HM, has been reported.6 While HM was profoundly amnesic with severely impaired explicit mem- ory and preserved performance on implicit memory tasks (percep- tual identi cation, word completion, priming), LH demonstrated the reverse dissociation (Box 13.7).

Keane and colleagues6 explained the di erence in these patients’ implicit memory performance in terms of occipital circuits that were intact in HM and damaged in LH. Ostergaard has contested the idea that there is complete preservation of implicit memory

in medial temporal amnesics, suggesting that implicit memory is o en not preserved when studies are properly controlled with respect to baseline.121

Procedural memory is usually preserved in amnesia,82,121–124 but can be impaired in Parkinson’s and Huntington’s disease.74,125

Recall and recognition memory

In both episodic and semantic memory, there are distinctions between recall and recognition tests. ese tests ask participants to remember studied items in di erent ways. Recall tests are con- sidered to be more di cult than recognition tests, requiring more e ort, and patients o en perform rather worse on them than in recognition tests. Performance on recall and recognition tests is usually interpreted in terms of the contributions of recollection and familiarity.126,127 Recollection is where participants retrieve information beyond the represented stimulus, such as the context in which it was presented. Familiarity is simply the feeling that a stimulus has been encountered before.

Patients with apparently similar lesions of the hippocampi can show very di erent memory performance patterns.128 A meta- analysis by Aggleton and Shaw129 looked for associations between recognition performance and pathology in amnesic patients. ey found that patients with more focal brain damage, particularly to the hippocampus, mamilliary bodies, and fornix, were more likely to show preserved recognition, despite profound impairments on recall tests. However, their meta-analysis was confounded by oor e ects in some of their patients, and not all studies show dispropor- tionate impairment on recall memory in hippocampal patients.49 e reasons behind this inconsistency are not yet resolved.

Disproportionate recall over recognition de cits have also been reported in ageing130 and a number of disorders, such as schizo- phrenia131 and autism.132 Damage to frontal brain regions has been shown to impair free recall performance more than cued recall, which in turn is more impaired than recognition, though recogni- tion is commonly also a ected in these patients.133

Testing memory

A wealth of standardized neuropsychological assessments of mem- ory is available to the clinician to assist diagnosis. Some of the most well-known include the Wechsler Memory Scale,134 the California Verbal Learning Test II,135 and the Rey Complex Figure.136 Most of these concentrate on episodic memory. However, specialist

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tests also exist for autobiographical memory (e.g. autobiographi- cal memory interview),137 prospective memory (e.g. Cambridge Prospective Memory Test),138 and semantic memory (e.g. pyramids and palm trees).112 Comprehensive critical reviews can be found in standard texts.139,140 e reader is also referred to chapter 11. In this section, we outline practical considerations when testing for di erent types of memory disorder.

Diagnostic assessments

It is important to rst establish the clinical history from both the patient and an informant relating to a memory complaint such as the time and nature of its onset and other related disease or psychiatric complaint, and then to assess whether there is objective evidence of a memory disorder on formal testing; that is, whether performance falls by at least 1.5 to 2 standard deviations based on estimated pre- morbid IQ (see chapter 11). Standardized tests of memory that give scores that can be compared directly against optimal IQ (i.e. that give age-scaled standardized scores) should be employed. Memory for both visual and verbal material should be tested as these can be impaired relatively independently,141 and it is necessary to test free recall, ideally a er a delay as well as immediately.

Recognition memory or cued recall should be assessed if perfor- mance on free recall is poor, as it may be that the information is being encoded but cannot be retrieved without a cue. Suitable test batter- ies for evaluating episodic memory include the Wechsler Memory Scale,134 the doors and people test,140 and the BIRT (Brain Injury Rehabilitation Trust) Memory and Information Processing Battery (BMIPB),143 and the Recognition Memory Test 2007.144 Performance on the Wechsler Adult Intelligence Scale145 digit span subtest can be used as a measure of phonological STM and working memory either alone, or in combination with the arithmetic subtest with which it comprises the Wechsler Working Memory Index. Visuospatial STM and working memory can be evaluated using the symbol span subtest from the WMS–IV or the Corsi Block Tapping Test.146

If objective evidence of memory impairment is found, a second question is whether the pattern of impairment is more consistent with neurological or psychogenic causes (e.g. depression). In gen- eral, patients who are simply depressed will tend to make a large number of ‘don’t know’ responses, to be reluctant to guess, and to show a pattern of generally poor performance. For these reasons, it is sometimes helpful to administer symptom validity tests such as the test of memory malingering,147 the word memory test,148 and the Camden Pictorial Memory Test.149 Poor or below-chance per- formance on these tasks is strongly indicative of motivational fac- tors rather than neurological disorder.

If the ndings are more indicative of a neurological complaint, the question is whether the pattern of memory test scores has any lateralizing or localizing value or is consistent with a particular di erential diagnosis. In general, di culties remembering verbal material are associated with le hemisphere pathology while there is a less strong association between visual memory di culties and pathology in the right hemisphere.150

Another important consideration in a diagnostic assessment is whether the memory di culties are progressive or static in nature. is is particularly important in distinguishing between a cogni- tive impairment a er a stable lesion and a dementia. Obviously this point can only be addressed by serial assessments. Memory batter- ies with parallel forms that increase slightly in di culty, to counter- act practice e ects, are available (e.g. the BMIPB).143

CHAPTER 13 memory disorders 141 Planning and monitoring rehabilitation

Results from memory assessments can inform memory rehabilita- tion programmes, which can be tailored to maximize the use of the individual’s strengths and compensate for their areas of weakness. Findings from traditional standardized memory tests can be useful; for example, knowing that an individual scores at the 75th percen- tile on tests of verbal memory and only at the 5th percentile on tests of visual memory means that teaching verbal encoding strategies for visual material is likely to be of bene t. Furthermore, many cli- nicians nd it more helpful to use so-called ecologically valid tests of memory to inform rehabilitation. ese tests are designed to map on to real-life abilities in a much more direct way and aim to provide a measure of disability rather than impairment. Commonly used ecologically valid memory tests include the Rivermead Behavioural Memory Test151 and the Cambridge Prospective Memory Test.138

Interpreting memory test scores in context

It is usually relatively meaningless to obtain memory test scores in isolation. First, poor performance on memory tests may be sec- ondary to di culties with other cognitive and perceptual domains such as processing speed, executive functions, language or visual cognition152 rather than due to a primary ‘memory de cit’. us, we would recommend at least screening these areas if di culties are found on memory tests. Another reason to test more widely than just memory is that patients o en report ‘memory problems’ when they mean that they experience word- nding di culties or other cognitive problems.139 ird, performance on memory tests must be considered relative to the individual’s likely optimum level of functioning (see chapter 11); performance in the average range may constitute a strength for someone with an intellectual disabil- ity but a relative weakness for someone previously likely to have functioned in the superior range.

As well as the quantitative scores provided by memory tests, it is necessary to gather qualitative information regarding how the individual approached the task and the types of errors they made in order to aid interpretation of the results. For example, confabula- tion, intrusions, or perseverative responses, or an inability to initi- ate responses without frequent prompting and encouragement, can indicate fronto-executive dysfunction.

In addition to cognitive tests, it is desirable to administer a mood screen such as the Hospital Anxiety and Depression Scale153 or the Beck Depression Inventory II154 since depression and anxiety can a ect performance on memory tests.155 It is also good prac- tice to administer a questionnaire asking about subjective memory di culties, such as the Prospective and Retrospective Memory Questionnaire.156

Conclusion

Memory can be divided into various subtypes, and, while there are well-established ndings (e.g. MTL involvement in episodic mem- ory), there is still considerable controversy in some areas of the literature regarding the functional description and neural organi- zation of memory processes. ere is accumulating evidence attest- ing to the importance of hippocampi in representing novel items and associations both in the long- and (to some extent) the short- term, and in memory consolidation. Detailed neuropsychological case descriptions have contributed signi cantly to the evolution of

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142 SECTION 2 cognitive dysfunction

memory theories. Standardized neuropsychological assessments are available that allow targeted evaluation of di erent types of memory (e.g. episodic and semantic), memory for di erent modal- ities of information (e.g. verbal and visual), and the underlying neurobiological process (e.g. static or progressive). However, when assessing memory-impaired patients, it is important to interpret evidence in the context of premorbid IQ and any wider cognitive or psychological disorders that may be causing impaired perfor- mance. Understanding memory disorders is of crucial importance for the clinician for making diagnoses and for planning rehabili- tation. Moreover, neuropsychological descriptions of memory- impaired patients remain critically important for informing and evaluating memory theory.

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CHAPTER 13 memory disorders 145

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Introduction

CHAPTER 14

Vision and visual processing de cits
Anna Katharina Schaadt and Georg Kerkho

Treatment

e following short recommendations may be helpful, primarily for patients with non-progressive disorders (cf reference 2):

Bilateral postchiasmatic lesion: Use magni cation so ware (for PCs) or screen-reading machines for permanent enlargement of printed text, pictures, and letters.

Visual exploration de cit: Improve visual search by providing the patient with a systematic (horizontally or vertically) saccadic search strategy. Acuity will improve when visual search is more systematic, quicker, and when omissions are reduced.

Nystagmus: Reduce nystagmus with orthoptic (prisms) or pharma- cological means.12

Spasmodic xation (Bálint–Holmes syndrome): Test acuity with sin- gle letter charts, as acuity for single letters should be normal as long as the patient can xate the single target. Furthermore, improving simultaneous perception by repetitive treatment enlarges the use- ful eld of view13 and improves visual activities of daily living.

Dynamic visual acuity: Treat smooth pursuit eye movements in the horizontal domain (le , right) for di erent velocities. e rec- ognition of moving objects is important for vocational tasks14 and mobility in the environment. It improves in parallel with the increase of the smooth pursuit gain (relation of target velocity to eye–movement velocity).

Spatial contrast sensitivity (CS)

impairments

Spatial CS denotes the ability to discriminate between striped pat- terns (gratings) of di ering luminance (contrast) and stripe width (spatial frequency). It is o en impaired in acute vascular posterior brain lesions (80 per cent).15 In the majority of patients, recovery is rapid, although permanent de cits persist in about 20 per cent. An example for the assessment of CS is illustrated in Fig. 14.1b. CS also diminishes in AD.16,17

Treatment

CS can be trained e ectively in normal subjects but this has rarely been tried in brain-damaged patients. In those 20 per cent with permanent de cits, the use of additional, indirect lighting is help- ful because it improves contrast. Light- ltering lenses may increase contrast sensitivity.18

Visual disorders are frequent function losses a er brain damage and occur in about 20–50 per cent of the patients with cerebrovascular disorders1 and some 50 per cent of patients with traumatic brain injury (TBI).2 In stroke patients > 65 years the incidence rises to 40– 60 per cent.3 In Alzheimer’s disease (AD), visual impairments (low- level and high-level) occur in some 40 per cent of patients.4 ey are core features of posterior cortical atrophy (PCA). Consequently, routine screening of the various types of visual de cits is necessary both for diagnosis and rehabilitation planning. Patients with intact awareness can easily be questioned with a simple questionnaire (see Table 14.1), responses to which prove clinically useful in 95 per cent of cases.5,6

Visual acuity impairments

Visual acuity refers to the spatial resolution of the visual process- ing system7 and is usually tested using high-contrast acuity plates (Fig. 14.1a). It is important to appreciate that impairments of visual acuity and spatial contrast sensitivity (see below) will o en lead to di culties for patients in performing higher-level neuropsycho- logical tests, thus it is essential to test basic visual function before interpreting de cits on cognitive visual tests.8

Concerning de cits of visual acuity, primary and secondary causes have to be distinguished in patients with brain damage before initiating treatment.

Primary causes

Bilateral postchiasmatic lesions9 which may cause partial up to total loss of visual acuity in both eyes which cannot be corrected by lenses. is is o en associated with bilateral homonymous visual eld defects.10

Secondary causes

Disturbed visual exploration, xation di culties due to Bálint– Holmes syndrome, impaired contrast sensitivity, eccentric xation due to cerebral hypoxia, or nystagmus. Impairments in acuity for moving targets (dynamic acuity) are caused by de cient smooth pursuit eye movements,11 due to cerebellar or parietal lesions.

Recovery is frequent in patients with secondary, but rare in those with primary causes of disturbed visual acuity. As impaired acu- ity a ects all subsequent visual activities as well as neuropsycho- logical testing, treatment of the secondary causes should be started immediately.

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148 SECTION 2 cognitive dysfunction
Table 14.1 Schema for the anamnesis of visual disorders after acquired brain lesions. Indent the questions in the table into the following

phrase: ‘Did you experience … since your brain lesion?’

Question

Purpose of Question, Underlying Disorder

1. any changes in vision?

◆ Awareness of de cits? Information about case history

2. diplopia?transiently/permanently?

◆ Type of gaze palsy? If transient: fusional disorder?

3. reading problems? syllables/words missing, change of line, reduced reading span?

◆ Hemianopic alexia? Di erential diagnosis of neglect dyslexia, aphasic alexia, or pure alexia

4. problems in estimating depth on a staircase? reaching with your unimpaired hand for a cup, hand, door handle?

◆ Depth perception? Optic ataxia?

5. bumping into obstacles? failure to notice persons? at which side?

◆ Visual exploration de cits in homonymous visual eld disorders?

6. blinding after exposure to bright light?

◆ Foveal photopic adaptation?

7. dark vision? that you need more light for reading?

◆ Foveal scotopic adaptation?

8. blurredvision?transiently/permanently?

◆ Contrast sensitivity? Acuity? Fusion?

9. that colours look darker, paler, less saturated?

◆ Colour hue discrimination? Impaired contrast sensitivity?

10. that faces look darker, paler, unfamiliar?

◆ Face discrimination/recognition disorders?

11. problems in recognizing objects?

◆ Object discrimination/recognition disorders?

12. problems in nding your way in familiar/unfamiliar environments?

◆ Topographic orientation de cits?

13. visual hallucinations (stars, dots, lines, fog, faces, objects) or illusions (distorted objects, faces)?

◆ Simple or complex visual hallucinations, illusions? Awareness about illusory character?

Adapted from Neurorehabilitation & Neural Repair. Neumann G, Schaadt A-K, Reinhart S, and Kerkho G, Clinical and psychometric evaluations of the Cerebral Vision Screening Questionnaire in 461 non-aphasic individuals post-stroke, Copyright (2016), with permission from SAGE Publications.

Disorders of foveal photopic or scotopic

adaptation

Foveal photopic adaptation means the continuous adapting to a brighter illumination than the current one, scotopic adaptation the adaptation to a darker illumination than the present one. Both pro- cesses are dissociable and impaired in some 20 per cent of patients with posterior cerebral artery infarctions or cerebral hypoxia.19 A question- naire for the assessment of the most frequent subjective complaints

(a)

in these patients can be found at: http://tinyurl.com/SADQ-Kerkho . e case report in Box 14.1 illustrates the subjective visual impairments associated with a foveal photopic adaptation de cit. Concerning recov- ery, there is no evidence (even a er years) that such de cits recover.19

Treatment

Photopic adapation

Avoid direct lighting, use a dimmer to adjust light individually; avoid ickering neon lights; use sunglasses outside buildings; avoid

(b)

Fig. 14.1 Examples for assessing visual acuity (a) and spatial contrast sensitivity (b). For assessing visual acuity, size but not spatial contrast of the symbols diminishes; for assessing spatial contrast, sensitivity size of the characters is constant whereas spatial contrast diminishes.

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Box 14.1 Foveal photopic adaptation

Case study

Since his stroke (right posterior cerebral artery infarction with associated le homonymous hemianopia), this patient has been unable to stay longer than 10 minutes in bright environments without feeling highly uncomfortable and getting severe head- ache. e adaptation de cit is subjectively more disturbing to him than the visual eld loss. At work, for example, he would always darken the room he is sitting in. When colleagues come to his o ce, they would always complain about the darkness and turn on the lights. In the examiner’s o ce, the patient considered the luminance as comfortable when the room was nearly fully darkened (50 lux).

continuously adapting sunglasses (Varilux) because they are too slow in readapting inside a building. Driving at night (‘blinding’) is not advisable. If there is photophobia, light- ltering lenses can also reduce this sensation.18

Scotopic adaptation

Increase indirect lighting by additional light bulbs; use also port- able dimmer to adjust lighting individually.

Disorders of convergent fusion

and stereopsis

CHAPTER 14 vision and visual processing deficits 149 1 minute

5 minutes

10 minutes

Fig. 14.2 Schematic illustration of the development of diplopic images in patients with fusion disorders as a function of time. Black and gray traces refer to the optic image of the left/right eye. Note blurring and nally diplopia after sustained binocular vision.

Visual discomfort

Looking at homogeneous, regular patterns like lines, written text, agstones, or stripes of a certain spatial frequency (three to four cycles per degree visual angle)27 may elicit unpleasant sensations (termed ‘visual discomfort’; see Fig. 14.3a, b), blurred vision, and headaches in some healthy people, but much more so in patients with cerebral visual disorders. Visual discomfort in brain-lesioned patients may reduce sustained visual activities considerably and lead to asthenopic symptoms. ere is no evidence so far that such symptoms recover naturally.

Treatment

In reading, visual discomfort can be eliminated by using a simple mask that covers all lines except the one that is currently read (see Fig. 14.3c).

Homonymous visual eld disorders

Visual eld disorders (VFDs) are present in 20–50 per cent of all neurological patients with stroke1 and may also be present in patients with PCA. Visual eld sparing is < 5° for the a ected vis- ual hemi eld in 70 per cent of stroke cases with VFDs who receive speci c neurovisual treatment in neurorehabilitation centres.7,10 In acute neurology settings, visual eld sparing on the blind side may be more variable. Fig. 14.4 demonstrates the most frequent types of VFD, although in patients with PCA such classical patterns are not usually present, or may vary, sometimes leading to the errone- ous conclusion that the patient is psychogenic. Patients may present three types of associated de cits: visual exploration de cits, reading disorders, and visuospatial de cits.

Visual exploration de cit

Time-consuming, ine cient visual search due to loss of overview and unsystematic search strategies; numerous, small-amplitude staircase-saccades in the blind hemi eld; omissions of targets in the blind eld.28–31

Stereopsis refers to the perception of spatial depth based on binocu- lar integration. Convergent fusion is a prerequisite of stereopsis and means the fusion of the le and right eye’s image into one combined (fused) picture of the world.20 Fusion and stereopsis (local, global) are reduced in patients with vascular occipital, parietal, or temporal brain lesions,21 and impair manual activities in near space (reach- ing and grasping, technical work, depth perception), which is also relevant for vocational rehabilitation. Astereopsis is also caused by TBI.22 Fusion is impaired in some 20 per cent of patients with pos- terior vascular lesions and about one-third of TBI patients.2 ose patients have severe reading problems a er some 10 minutes (see Fig. 14.2). ey rapidly develop diplopia and are impaired in all near-work activities.

e percentage of patients showing recovery is unknown in aste- reopsis. In TBI patients with fusional disorders, three-quarters have persistent impairments for years a er their injury.23

Treatment

Fusion and stereopsis can be trained together using simple orth- optic or binocular devices.24–26 First, determine from the history whether there are asthenopic symptoms (sensation of eye pres- sure, fatigue in reading or with PC work), blurred vision, problems in near-work activities, and how long the patient can read before blurred vision or diplopia emerges. Improvement of fusion and stereopsis can occur with repetitive display of dichoptic images with increasing disparity angle; 8–20 sessions advisable.24–26 e out- come is favourable in 80 per cent of patients, with improvements in reading duration, stereopsis, and fusional range; relief from asthe- nopia; and better function in vocational life. However, this therapy is contra-indicated in patients with premorbid de cits in binocular integration or those with permanent diplopia of exophoria > 15°.

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150 SECTION 2

cognitive dysfunction

Fig. 14.3 Illustration of the visual discomfort phenomenon with stripes (a), text (b), as well as its removal with a cover template (c).
Reproduced from Habermann C and Kolster F, Ergotherapie im Arbeitsfeld Neurologie, Copyright (2008), with permission from ieme Medical Publishers.

Hemianopic reading disorder

For reading, the central visual eld (+/–5° around the fovea) is crucial because only here visual acuity and form recognition are su cient for letter recognition (‘perceptual reading window’). Slow reading with errors is evident in patients with eld sparing < 5°, as well as those with paracentral scotomas and quadrantanopia; however, reading of short, single words is normal (no aphasia or alexia).32–34 Fig. 14.5 illustrates the impairment in reading depend- ing on the type of VFD (see also chapter 18).

Visuospatial de cits

e patient’s feeling of the subjective visual straight ahead in space or his subjective midline in bisecting horizontal lines and objects is shi ed towards the blind eld (horizontally in le /right VFDs, vertically in altitudinal VFDs, oblique in quadrantic VFDs) in 90 per cent of the patients.35–38 is spatial shi is also evident in pointing29 and in daily life (walking through doorways, sitting in front of a table). Line bisection can be used for the di erential diag- nosis of hemianopia versus visual neglect (see chapter 15). While the subjective midline in homonymous hemianopia is shi ed towards the blind eld (contralesional), it is ipsilesionally displaced away from the neglected side, in patients with visual neglect (see Fig. 14.6).36,40,41 e line bisection error is not due to eccentric xa- tion42 and attentional cueing does not change it.43 A recent study identi ed lesions in Brodmann area 18 (lingual gyrus) as crucial.44 Patients with homonymous quadrantanopia show a related, oblique shi of their subjective visual straight ahead towards the scotoma (see Fig. 14.6b).37

Field recovery is present in the rst two to three months post- lesion in up to 40 per cent of the patients with a stable aetiology such as stroke.45 A er six months post-lesion, spontaneous recov- ery is extremely unlikely.45,46

Treatment

Field recovery is very limited, and therefore restorative eld train- ing is appropriate only in a very small group of patients, detailed below. For the majority of VFD patients (95 per cent) compensa- tory visual eld treatment of the associated disorders in reading and visual scanning is advocated as the standard treatment for patients with VFDs (see Table 14.2). While restorative visual eld training induces only very small or no visual eld increases (~1°) and improves visual search or reading only minimally,47 hemian- opic reading training and visual exploration training induce sig- ni cant, lasting, and functionally relevant improvements in these treated domains. us, these treatments improve ‘visual’ activi- ties of daily living and increase functional independence of the patient.2,7,10,34,48 Cross-modal (visual-auditory) training has also

(c)

(f)

(a)

(d)

(b)

(e)

Fig. 14.4 Most frequent types of homonymous visual eld defects: (a) left hemianopia, (b) left superior quadrantanopia, (c) left inferior quadrantanopia, (d) left paracentral scotoma, (e) tunnel vision, (f) left hemiamblyopia (loss of colour and form vision along with relatively intact light perception).
Reproduced from Habermann C and Kolster F, Ergotherapie im Arbeitsfeld Neurologie, Copyright (2008), with permission from ieme Medical Publishers.

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(a)

(b) Table 14.2 Summary of restorative (visual eld training) and compensatory approaches (hemianopic reading and visual exploration

training) in patients with postchiasmatic scotomata

0° 15°

CHAPTER 14 vision and visual processing deficits 151

grandchildren

Restorative visual eld training:

. (1) Anamnesis: visual perimetry, tachistoscopic tests: identi cation of amblyopic transition zones which are most likely candidates for eld recovery

. (2) Type of treatment: improvement of saccadic localization at eld border or in amblyopic transition zone; discourage head movements to target; recognition of colour, form, orientation, or luminance of the target; amount of treatment: 30–500 sessions (hours)

. (3) Transfer: very small improvements in reading and subjective awareness of visual problems; minimal improvement in visual search

. (4) Outcome and follow-up: small or no visual eld increase; partial eld recovery in exceptional patients with incomplete lesions

Hemianopic reading training:

(1) Anamnesis: problems with change of line, types of errors (omissions, substitutions, problems with long words or numbers), maximum reading duration, asthenopic disorders (eye strain)

(2) Typeoftreatment:improvementofoculomotorreadingstrategies(i.e. optokinetic reading therapy) substituting the lost parafoveal visual eld; tachistoscopic reading of single words, moving window technique, oating words, search for words in a text, scanning reading technique, reading

of numbers with embedded zeros: variation of physical and linguistic parameters: word length and frequency, position on screen (left, centre, right), number of words, presentation time, complexity of text, variation of instruction (read versus scan text), verbal working memory training

. (3) Transfer: reading of newspaper, book, own manuscripts; text editing on a PC, increase of maximal reading duration

. (4) Outcome and follow-up: increase in reading speed; reduction in reading errors; small eld recovery in one-third of patients; improvements in reading eye movements

Visual exploration training:

(1) Anamnesis: limited overview, bumping into persons and obstacles, defective orientation in visual space, i.e. crowded situations, tra c

(2) Typeoftreatment:increasingamplitudeofsaccadiceyemovements towards scotoma: variation of size, increase of velocity of saccade, reduction of saccadic reaction time, reduction of head movements; systematic, spatially organized visual search on wide- eld displays: organized search strategy (horizontal or vertical); start search in blind eld; visual displays requiring serial and parallel search

(3) Transfer:orientationinclinic,ownurbandistrict,newenvironments, management of visual activities of daily living: nd objects on table or in room, nd therapist ́s room, nd objects in supermarket, cross street, use public tra c, nd way home

(4) Outcome and follow-up: reduction of omissions and search time; improved eye- movements; signi cant improvements in functional visual tasks (e.g. nd objects on table); subjective improvements in patient’s functional independence in daily life

grandchildren

Fig. 14.5 Importance of the central visual eld for reading (‘perceptual reading window’). In healthy people with Western reading habits, the reading window is larger in the right paramacular hemi eld so that right hemianopia (b) or a right paracentral scotoma (d) a ect a bigger part of the reading window. In contrast, left hemianopia only a ects a smaller part of the reading window (c), resulting in less marked reading impairment.

Reproduced from Habermann C and Kolster F, Ergotherapie im Arbeitsfeld Neurologie, Copyright (2008), with permission from ieme Medical Publishers.

been used for improvement of reading and scanning in hemiano- pia.49,50 Visual and auditory targets are presented time-locked in locations of the visual eld, and the patient has to saccade to them. is training induces similar improvements as conventional visual scanning training but requires additional technical facilities.

(a)
Left hemianopia

Left hemi-neglect (b)

Objective midline

0° 5°

5° 1

Left0°Right

Left upper quadrantanopia Left lower quadrantanopia Right upper quadrantanopia Right lower quadrantanopia Control subjects

Down

Fig. 14.6 Illustration of the horizontal line bisection error: (a) In left hemianopia, the subjective midpoint is shifted towards the blind hemi eld, in left hemi- neglect it is biased towards the ipsilesional hemi eld. (b) Oblique shifts of the subjective visual straight ahead direction towards the scotoma in di erent types of homonymous quarantanopia, without visual neglect.

Compensatory versus restorative visual eld training

In recent years, restorative visual eld training has been revived a er publication of advantageous results following new training proce- dures.51 However, numerous replication studies have failed to nd sig- ni cant visual eld enlargements30,52–54 or found only minimal visual eld increases as described above. In our view, restorative eld training is only promising when lesions are incomplete and a high degree of

0°

15° 2

Adapted from Neuropsychologia. 48(11), Kuhn C, Heywood C, Kerkho G. Oblique spatial
shifts of subjective visual straight ahead orientation in quadrantic visual eld defects,
pp. 3205–10, Copyright (2010), with permission from Elsevier. residual visual capacities (light, motion, form, or colour perception) is

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152 SECTION 2 cognitive dysfunction

preserved in speci c regions of the scotoma.2,48 Moreover, compensa- tory eld training leads to a much quicker reduction of visual impair- ments and needs fewer treatment sessions. Recently, home-based treatments of visual search and reading have been successfully tested in VFDs.30,55,56 ese approaches are cost-e ective, but require regular advice by the therapist (i.e. by telephone or visit).

Ine ective or disadvantageous therapies

Most hemianopic patients get confused when using prisms to sub- stitute the visual eld loss. However, small prisms tted to a spec- tacle can be useful in some cases.57 Compensatory head shi s towards the scotoma (either spontaneously adopted by the patient or to instruction) are of no use in the rehabilitation of VFDs because they lead to visual exploration de cits in the ipsilesional visual eld, strain of the neck muscles, and delay treatment progress in visual scanning training.58 Training of ‘blindsight’ (the ability of rare cases of cortical blindness which respond to stimuli in their visual eld, e.g. by pointing to them, even if they are not able to consciously per- ceive them) is probably not useful for the majority of the patients59 because it does not lead to improved functioning in daily life.

Anton’s syndrome

Unawareness of visual eld defects is not an unfrequent phenom- enon, with up to one-third of the patients showing a denial of their impairment (Anton’s syndrome).7,60,61 One the other hand, there has been the reverse condition reported in which patients with spared vision a er visual eld loss deny any visual sensation in the intact parts of their visual eld.62 Insu cient awareness is negatively associated with development and use of compensatory strategies and rehabilitation outcome.63 Consequently, detailed assessment and education of the patient are inevitable to assure compliance and the conditions for a good outcome.

Positive visual phenomena (visual

hallucinations)

Whereas the previously described disorders refer to function losses (i.e. negative visual phenomena), visual hallucinations are positive

(a) (b)

(d) (e)

symptoms in the absence of an external stimulus.64 Simple formed visual hallucinations (light dots, bars, lines, stars, fog, coloured sensations, etc.)65 are frequently reported by patients—although only when questioned systematically—with posterior, vascular lesions, most o en a er occipital lesions. More complex visual hallucinations and illusions are rare in structural lesions and most o en associated with temporal lobe lesions; see Fig. 14.7).66,67,68 Recovery is rapid and complete in 95 per cent of the patients with stroke aetiology, so that at six weeks post-lesion the occurrence is quite rare.66,67 Positive visual phenomena have also been described in AD,69 and well-formed visual hallucinations, typically non- threatening and of silent animals or people, are core diagnostic fea- tures of dementia with Lewy bodies (DLB),128 and very common in Parkinson’s disease with dementia. Visual hallucinations are not uncommon in prion diseases, and in particular those patients presenting with visual impairment—the so-called Heidenhain variant.70

Treatment

As hallucinations and illusions are irritating but—in the case of structural lesions—mostly transient phenomena, informing and reassuring the patient is important.

Complex visual scenes have a higher reality character than sim- ple hallucinations and are therefore more frightening to the patient. ese patients may be reluctant to talk about their experience for fear of being misdiagnosed as a psychogenic. Note that psychiatric patients much more o en have auditory than visual hallucinations, while the opposite holds true for patients with organic visual hal- lucinations a er posterior brain lesions. Further, brain-damaged patients very rarely report ‘hearing voices’. e complex well formed halluciantions of DLB and Parkinson’s disease with dementia may respond very well to treatment with cholinesterase inhibitors.

Persistent visual hallucinations

Check if there is an epileptic focus (EEG), the possibility of a new infarction developing, or a psychiatric disease. Lasting visual hallu- cinations that interfere with visual recognition have been reported in Parkinson’s disease.71,72

(c)

(f)

Fig. 14.7 Examples for positive visual phenomena (visual hallucinations); (a) and (b): simple visual hallucinations, (c): coloured visual hallucinations, (d), (e), (f) complex visual hallucinations.
Reproduced from Habermann C and Kolster F, Ergotherapie im Arbeitsfeld Neurologie, Copyright (2008), with permission from ieme Medical Publishers.

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Colour perception de cits

Colour perception can be impaired within a scotoma a er a postchi- asmatic VFD or within central vision caused by bilateral postchias- matic lesions of various aetiologies.73–75 e de cit is most apparent in central vision and may manifest as a subtle impairment in hue dis- crimination. Such disorders are o en found a er unilateral occipi- totemporal lesions of vascular origin as well as a er mild cerebral hypoxia or in Alzheimer’s disease.76,77 Total achromatopsia is much more rarely found, usually associated with bilateral occipitotemporal or di use lesions (see case study in Box 14.2).78 Recovery of colour and form vision within a scotoma is o en observed in patients with partial visual eld recovery.79 As a rule, the progression of visual recovery (if there is one) in VFDs is as follows: light detection → light localization → brightness discrimination → form discrimination → colour perception. In those patients with colour vision de cits in cen- tral vision no recovery has been reported over six years in one study.80

Treatment

Defective colour vision in visual eld regions

In patients with residual colour perception in a scotoma and incom- plete lesions, there is some evidence that improvement of colour discrimination can be trained by displaying coloured targets at the eld border and having the patient saccade to them and discrimi- nate the colour.

Defective colour perception in central vision

Forced discrimination of di erently coloured forms is partially e ective in cerebral anoxia, however with limited transfer to

non-trained colours.80 O en, patients can learn to base their col- our judgments on other cues such as the brightness or saturation despite permanently impaired hue discrimination.

Visual form, object, and face perception

de cits (visual agnosias)

e inability to recognize visual stimuli despite su ciently intact elementary visual functions (e.g. visual acuity, spatial contrast sen- sitivity) as well as una ected language processing and intact recog- nition in other modalities is de ned as visual agnosia.7 Depending on the severity and speci ty of the visual recognition de cit, several types of agnosia can be distinguished.

Visual object agnosia refers to impairments in recognizing com- plex objects or pictures. Traditionally, a distinction has been made between apperceptive agnosia and associative agnosia. e former indicates a de cit in perception which leads to impaired object discrimination; the latter implies loss of semantic knowledge or understanding what the object is, despite patients seemingly having intact perceptual abilities. us while apperceptive agnosic patients have di culty in copying objects or matching objects from di erent views (see Fig. 14.8a), patients with pure associative agnosia may copy and perform perceptual match tasks well but still not be able to say what an object is for—sometimes referred to as ‘perception stripped of meaning’,81,82 a core feature of the semantic dementia subtype of frontotemporal dementia. Such behaviour needs to be distinguished from anomia where patients may not be able to name an object but nevertheless can describe what it is or how it might be used. Hence, patients with associative agnosia cannot even match objects by semantic properties as illustrated in Fig. 14.8c. Visual form agnosia refers to a severe type of apperceptive visual object agnosia, characterized by an inability to discriminate even simple forms like rectangles or squares (see Fig. 14.8b). Prosopagnosia corresponds to a selective de cit in recognizing faces.7

Visual agnosias are commonly described as rare conditions (less than 3 per cent of all neurological patients),7,59,83 previously con- sidered to occur most frequently a er bilateral occipitotemporal lesions of vascular, traumatic, or anoxic origin.81 However, recent evidence indicates that visual agnostic de cits might be more frequent than previously assumed when every patient with pos- terior brain lesions is quantitatively tested (e.g. Martinaud and col- leagues84 reporting a frequency of 65 per cent following posterior cerebral artery infarction). Moreover, with greater recognition of neurodegenerative conditions it is becoming evident that these too may lead to visual agnosia. Impairments in object processing have also been reported for neurodegenerative diseases like AD asso- ciated with or without PCA,85–88 DLB,85 corticobasal syndrome (CBS),89 or Huntington’s disease (HD) (e.g. recognition of overlap- ping gures).90

Standardized diagnostic is available with the Birmingham Object Recognition Battery (BORB),91 or the Visual Object and Space Perception Battery (VOSP).92

Detailed case reports about recovery are rare. Partial recovery concerning object or face recognition of real-life objects has been occasionally noted, while recognition of photographs of objects or faces rarely improves. Recovery is particularly unlikely in anoxic brain damage, probably due to the widespread di use lesions and the additional cognitive impairment impeding the acquisition of compensatory strategies.93 Partial recovery is more likely in

CHAPTER 14 vision and visual processing deficits 153

Box 14.2 Cerebral achromatopsia

Case study

A 66-year-old man was washing his red car in a green meadow. Suddenly, he began to feel sick and noticed that his just-cleaned car appeared dirty, rusty brown, while the surrounding meadow looked more grey than green. e patient later reported that it seemed to him as if someone had switched o the colour TV into black-and-white mode. Furthermore, he described that although he had initially been able to recognize his car and house; later on he was not able anymore to see things in his upper eld of vision. As illustrated below, the patient showed severe impairments in a colour-matching task. In contrast, discrimination of grey shades (not shown) as well as colour imagery were unimpaired. His symp- toms were due to bilateral basal, temporo-occipital infarctions, associated with bilateral damage of lingual and fusiform gyri.

Examiner’s arrangement of colours Patient’s attempt to match colours

Original Patient’s copy

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154 SECTION 2 cognitive dysfunction (a) Sample

(b) Sample

(c)

Fig. 14.8 Illustration of matching tasks in which agnostic patients depending on type of agnosia typically show de cits. (a) View-matching task: e patient has to match the sample to the target picture that is presented in a di erent view. Patients with apperceptive agnosia fail in such tasks as they are not able to form
a coherent visual perception of an object. (b) Form-matching task (Efron shapes). Form agnostic patients typically have de cits in comparing and matching simple forms. (c) Function-match task: e subject has to match those two pictures that share a common function. De cits in this task are characteristic for associative agnostic patients.

traumatic or vascular lesions and in those few cases with unilat- eral right sided lesions showing face agnosia.81 A case of transient postoperative prosopagnosia that spontaneously recovered a er six to seven days has been described,94 demonstrating that recovery is in principle possible, but this may depend on lesion size.

Treatment

Visual form recognition can be improved in some cases by repeti- tive discrimination training for simple geometric forms equated for total luminance. Verbal or computerized feedback is essential with progressive increase in the similarity of the stimuli to be discrimi- nated. Treatment can be accomplished either with self-constructed paper-made stimuli, or using computerized devices (e.g. Efron shapes) which give detailed quantitative feedback and allow vari- ations of colours, sizes, and forms (cf. Kerkho & Marquardt).95 Controlled treatment studies are rare for complex object- and face-recognition de cits. Improvements have been reported using errorless-learning paradigms focusing on speci c search for key features of objects or faces.7,59 In general, the use of context infor- mation (knowledge about objects and faces and the relevant social situation) and non-visual cues is advisable and may be helpful for some patients.7

Visuospatial disorders

Visuospatial disorders are frequent impairments following stroke a ecting extrastriate cortical and subcortical brain areas (30–50 per cent a er le , 50–70 per cent a er right hemisphere stroke).96 Moreover, poor visuospatial skills are o en observed in conditions such as AD, PCA, DLB, and CBS.85,97,98 Since intact visuospatial abilities are relevant for many activities of daily living (e.g. dress- ing, transfers, reading the clock), they are important predictors for rehabilitation outcome, particularly a er right-hemisphere brain

damage.99 Four categories of visuospatial disorders have been pro- posed that are compatible with the neuroanatomical conception of a dorsal and ventral visual pathway proposed by Ungerleider and Mishkin (see also individual chapters 3, 4, and 5).100

Perceptive visuospatial disorders

is group of impairments occurs a er distinct lesions of (especially right-sided) parieto-occipital brain areas. More posterior lesions of these brain regions lead to de cits in estimation or discrimination of length, distance, or form. In contrast, more anterior (parieto- temporal) lesions are related to di culties in estimating position or orientation as well as perceiving the subjective visual vertical/ horizontal in the frontal and saggital plane; see Fig. 14.9a).101,102

Transformational visuospatial disorders

Some visuospatial tasks require spatial operations (rotation, mir- roring, scale transformation). De cits in perspective change or mental rotation tasks are related to parietal and parietooccipital lesions of both hemispheres; see Fig. 14.9b).102

Constructive visuospatial disorders

ese de cits refer to a heterogenous group of functional de cits, manifest as impairments in the ability of patients to manually con- struct or copy a gure comprising simpler elements (e.g. draw- ing or copying a geometric gure in two or three dimensions, see Fig. 14.10a & b). ‘Constructional apraxia’ is the term o en given to these de cits (not to be confused with limb apraxia). Despite their clinical and daily relevance as well as frequent co-occurrence with perceptive visuospatial, dysexecutive, and working memory de cits as well as neglect,103 the core mechanisms of constructive visuospatial symptoms are still unknown.102 Some authors have provided evidence for defective spatial remapping of locations across eye movements when information in retinal coordinates has to be transformed to locations in the external world.104

Topographic visuospatial disorders

Topographic visuospatial disorders refer to orientation de cits in the real as well as imagined three-dimensional space and are related

(a)

(b)

Subjective horizontal

Subjective vertical

Estimation of distance

Axis mirroring

Estimation of orientation

Estimation of form

Position mirroring

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Fig. 14.9 (a) Examples for perceptual visuospatial tasks: subjective visual horizontal/vertical, estimation of orientation/distance/form. (b) Examples for cognitive visuospatial tasks: axis/position mirroring.

(a) Face

Flower

CHAPTER 14 vision and visual processing deficits 155 135° 45°

(c)

(b) Rey-Osterriethcomplexfigure

Original copy

Fig. 14.10 (a) Performance of two patients with a constructive visuospatial disorder when requested to draw a ower respectively a face from memory. (b) Copying performance of a patient with constructive visuospatial disorder in the Rey–Osterrieth complex gure test. Note also neglect of left-sided elements. (c) Illustration of visual line-orientation-estimation performance before (above) and after systematic training for two oblique orientations (45° and 135°; following).

to parahippocampal lesions or can occur as secondary de cits in neglect or Bálint–Holmes syndrome.102,105

Treatment

Successful therapeutic approaches are feedback-based training of perceptual visuospatial abilities, visual background movement, constructive visuospatial training, reaction-chaining methods for topographic visuospatial disorders as well as ADL (activities of daily living) therapy.106 ese approaches including their therapeu- tic principles are summarized in Table 14.3. Concerning feedback- based training of visuospatial abilities, Funk and colleagues107 have reported rapid and long-lasting improvements in visual line-orien- tation discrimination a er systematic training along with transfer to other spatial domains such as visuoconstructive performance, clock reading, and horizontal writing (see Fig. 14.10c). In addi- tion, non-invasive galvanic vestibular stimulation has been shown to improve subjective visual vertical judgements in patients su er- ing from right-sided stroke.108 Treatments are, however, unlikely to help patients with progressive neurodegenerative disorders.

Visual motion perception de cits

with AD, and particularly the PCA variant. While processing of lin- ear moving patterns seems to be preserved, perception of optic ow is impaired in more than one-third of AD patients.112,113

Little is known about recovery. In those rare patients with bilat- eral lesions, no recovery has been reported,114 while those with uni- lateral lesions may show recovery. Even the motion-blind patient reported by Zihl and colleagues re-adapted to moving stimuli in daily life by certain compensatory techniques, despite her perma- nent motion de cit under laboratory conditions.114 Again, there are no realistic prospects for recovery in neurodegenerative cases.

Treatment

Due to the rarity of severe impairments in visual motion process- ing and probably the multiplicity of cortical and subcortical areas involved in motion perception, treatment approaches have not been developed. However, the treatment of an associated ability (i.e. smooth pursuit eye movements when tracking a moving tar- get) is useful to improve visual scanning on computer screens and visual orientation in daily life.14 is can be accomplished by use of a large PC screen, where the patient follows a moving target in di erent directions with a stabilized head. In addition, training for situations in daily life where motion is important (crossing a street, using an escalator) may improve orientation and reduce the likeli- hood of accidents due to reduced motion perception.

Optic ataxia

Optic ataxia refers to a visuomotor disorder characterized by an impairment in visually guided reaching that is not attributable to other primary motor or visual disorders.115 At the bedside, this is assessed by asking the patient to xate on the examiner’s nose while the examiner’s nger is presented as a target for a reach in either the le or right visual hemi eld. Typically, healthy individuals can reach accurately even to a peripheral target while maintaining cen- tral xation, but patients with optic ataxia misreach under such conditions.

Complete loss of movement perception (akinetopsia)109 due to bilateral cerebral lesions is rather an unusual phenomenon.78 More incomplete impairments of visual motion perception may occur with a frequency of 13 per cent a er focal lesions of motion- sensitive regions, including area V5/MT in the occipito-parieto- temporal cortex, but permanent de cits are probably rare.110 However, many brain-damaged patients report subjectively prob- lems in estimating the velocity and position changes of moving vehicles in tra c situations as a pedestrian or when driving in a car. is may result either from impaired motion perception, possibly of impaired optic ow detection (radial patterns emerging when a subject moves),111 disturbed visuospatial perception, smooth pur- suit eye movements, or a combination of these factors. Moreover, de cits in motion perception have also been reported for patients

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156 SECTION 2 cognitive dysfunction
Table 14.3 erapeutic approaches for visuospatial disorders

2. Optic ataxia: see earlier in the chapter
3. Visual neglect and visuospatial disorders such as impaired reten-

tion of distance, orientation, and position122

4. Oculomotor disorders: severe and impaired xation of gaze (sticky xation) as well as problems in generating saccades vol- untarily or on demand (oculomotor apraxia)7,123

Furthermore, patients show severe reading problems, while read- ing of short real words (four to six letters) is better than reading of non-words.124

Due to the bilateral or di use disseminated occipitoparietal lesions, recovery is limited in these severely and chronically disa- bled patients. It is estimated that some 30 per cent of patients with degenerative dementias might show aspects of Bálint–Holmes syn- drome,125,126 although rarely the complete syndrome, and this is much more common in PCA; the incidence in non-dementing, neurological disease is probably <0.5 per cent (Kerkho , unpub- lished results).

Treatment

Research on e ective rehabilitation techniques is sparse (for review see references 13 and 127). It is likely that the disorder is o en over- looked or misdiagnosed. Eye blinking may eliminate confusing visual images or the patient’s subjective feeling of seeing the same object at multiple locations in space.2,7 Zihl59 noted some recovery of visual exploration and xation a er systematic training in three patients with Bálint–Holmes syndrome, but no recovery of the spa- tial disorder. Despite these occasional experiences e ective treat- ment strategies are poorly developed and evaluated.

References

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erapeutic approach

erapeutic principle

Feedback-based training of perceptual visuospatial abilities

Improvement of spatial perception by graded training with verbal or visual feedback; basic concept: recalibration of spatial perception

Visual background movement to improve perceptual visuospatial de cits

Improvement of attention for spatial expansion and orientation (subjective visual vertical/ horizontal) through repetitive stimulation; use of the attention-improving e ect of optokinetic stimulation

Constructive visuospatial training

Improvement of perceptual, cognitive, and constructive visuospatial abilities as well as planning performance by graded practice with constructive material (e.g. Tangram, block design training)

ADL therapy

Direct practice of problematic ‘spatial’ daily procedures (e.g. wheelchair navigation, getting dressed)

Reaction-chaining and memory strategies for learning routes in the environment

Parsing longer routes into shorter distances, practicing them by conditioning and later ‘chaining’ or linking them together; eventually additional use of mnestic strategies

Adapted from Der Nervenarzt. 78(4), Kerkho G, Oppenländer K, Finke K, et al.
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Beside the severe impairment in reaching, many patients also demonstrate a problem in grasping peripherally presented visual objects. By contrast, reaching to the patient’s own body parts seems to be largely preserved,116 although reaching to auditory targets is also impaired.117 Furthermore, the accuracy of reaching can be improved by delaying the patient ́s movement initiation a er stimulus presentation.118,119 Optic ataxia is associated with lesions in the parieto-occipital junction and the superior parietal lobule120 and can occur both a er unilateral or bilateral brain damage and as a result of neurodegenerative diseases including AD. Due to the neuroanatomical overlap, optic ataxia can co-occur with neglect a er right parietal lesions (see chapter 5). For di erential diagno- sis, it is therefore important to note that neglect patients usually can reach and grasp accurately to visually presented objects in the neglected hemi eld if they notice them.116

Treatment

Controlled treatment studies are rare. Since optic ataxia is less severe in the foveal than the a ected peripheral visual hemi eld,120 prior xation of the target before reaching or grasping usually improves reaching accuracy.

Bálint–Holmes syndrome, ocular motor apraxia

Bálint–Holmes syndrome designates a cluster of symptoms121 including:

1. Simultanagnosia: Impaired simultaneous perception of more than one object123

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CHAPTER 15

Disorders of attentional processes
Paolo Bartolomeo and Ra aella Migliaccio

Introduction

e term ‘attention’ refers to a heterogeneous set of cognitive pro- cesses which allow an organism to successfully cope with a con- tinuously changing external and internal environment, while maintaining its goals.1 is exibility calls for mechanisms that (a) allow for the processing of novel, unexpected events, that could be either advantageous or dangerous, in order to respond appropri- ately with either approaching or avoidance behaviour; (b) allow for the maintenance of nalized behaviour despite distracting events.2 To behave in a coherent and goal-driven way, we need to select stimuli appropriate to our goals while ignoring other less important objects. us, in a sense, objects in the world compete for recruiting our attention in order to be the focus of our subsequent behaviour, because of the obvious capacity limitations in our ability of deal- ing with multiple objects. Neural mechanisms of attention resolve this competition by taking into account both the agent’s goals and the salience of the sensorial stimuli.3 Neurological damage may impair these mechanisms and produce various sorts of attention disorders.4

e present chapter will focus on some of these disorders, such as the inability to process several visual objects at a time (simultagno- sia), the unawareness of an object when presented in competition to another one (extinction), or when occurring on one side of space (visual neglect). Other disorders may a ect the general ability to respond to external stimuli and to sustain attention over time,5 or to plan and coordinate di erent activities and inhibit inappropriate responses (monitoring/executive control).6,7

With ageing, people o en report a growing number of cogni- tive di culties. In some cases, elderly persons complain of ‘loss of e ciency’, for example, forgetting where objects are placed, having the impression of being unsafe when driving, experiencing trouble when in new places or navigating new routes. Neurological condi- tions, on the other hand, can lead to severe impairments in dif- ferent types of attention. ese problems o en occur in patients with acute vascular strokes (ischaemic or haemorrhagic), but they can also be observed in other neurological conditions, such as head trauma, brain tumours, or neurodegeneration. In several neurodegenerative conditions (e.g. corticobasal syndrome, CBS; Alzheimer’s disease, AD; parkinsonian syndromes such as demen- tia with Lewy bodies, DLB), attention de cits can appear as part of more complex cognitive impairment pro le. In others, such as in posterior cortical atrophy (PCA), they may constitute the cen- tral core of the syndrome.8 Because we know far more about visual

attention than any other sensory modality, in this chapter we focus on examples of visual inattention, although many of the conditions we discuss can also extend to other modalities.

Cortical networks for visuospatial attention

and visual recognition

ere is now considerable information on the functional anatomy, dynamics and pathological dysfunction of brain networks that sub- serve the spatial orienting of gaze and attention in the human brain. Important components of these networks include the dorsolateral prefrontal cortex (PFC) and the posterior parietal cortex (PPC). Physiological studies indicate that these two structures show inter- dependence of neural activity. In the rhesus monkey, analogous PPC and PFC areas show coordinated activity when the animal selects a visual stimulus as the goal of attention by, for example, moving their gaze to it.9

Functional MRI (fMRI) studies in healthy human participants (reviewed in reference 2 at p.1167) indicate the existence of fron- toparietal networks for spatial attention (Fig. 15.1, right panel). A dorsal attentional network (DAN), composed of the intrapari- etal sulcus/superior parietal lobule and the frontal eye eld/dor- solateral PFC, shows increased blood oxygenation level-dependent (BOLD) responses during the spatial orienting period. A more ven- tral attentional network (VAN), which includes the inferior pari- etal lobule (IPL) and the ventral PFC (inferior and middle frontal gyri) demonstrates increased BOLD responses when participants have to respond to targets presented at unexpected locations. us, the VAN is considered important for detecting salient, unexpected but behaviourally relevant events. Others have also argued for a role of the VAN in vigilance or sustaining attention over time.11 Importantly, the VAN is considered to be strongly lateralized to the right hemisphere,10 whereas the DAN appears to be more bilateral and symmetric (but see references 12 and 13 for possible asym- metries favouring the DAN in the right hemisphere).

Not surprisingly, PFC and PPC are directly and extensively inter- connected. In particular, studies in the monkey brain have identi- ed three distinct frontoparietal long-range pathways(see Fig 15.1, le panel).14,15 Recent evidence from advanced in vivo tractogra- phy techniques and postmortem dissections suggests that a similar architecture exists in the human brain (Fig. 15.1, middle panel).16 In humans, the most dorsal branch (SLF I) originates from BA (Brodmann’s area) 5 and 7 and projects to BA 8, 9, and 32. e mid- dle pathway (SLF II) originates in BA 39 and 40 within the IPL and

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162 SECTION 2 cognitive dysfunction

Fig. 15.1 Fronto-parietal networks in the monkey (left, from reference 15) and in the human right hemisphere (middle, from reference 16). Right: attentional networks in the right hemisphere according to Corbetta and Shulman.104
Reproduced from Front Hum Neurosci. 6(110), Bartolomeo P, iebaut de Schotten M, and Chica AB, Brain networks of visuospatial attention and their disruption in visual neglect, Copyright (2012), with permission from Frontiers Media S.A, reproduced under the Creative Commons CC BY-NC 3.0 License.

reaches prefrontal BA 8 and 9. e most ventral pathway (SLF III) originates in BA 40 and terminates in BA 44, 45, and 47.

ese results are consistent with the fMRI evidence on atten- tional networks reviewed above. In particular, the SLF III connects the cortical nodes of the VAN, whereas the DAN is connected by the human homologue of SLF I. e SLF II connects the parietal component of the VAN to the prefrontal component of the DAN, thus allowing direct communication between ventral and dor- sal attentional networks. Importantly, in good agreement with asymmetries of BOLD response during fMRI—with larger right- hemisphere response for the VAN and more symmetrical activity for the DAN10—the SLF III (connecting the VAN) is anatomic- ally larger in the right hemisphere than in the le hemisphere, whereas the SLF I (connecting the DAN) is more symmetrically organized.16 e lateralization of the SLF II is instead strongly correlated to behavioural signs of right-hemisphere specializa- tion for visuospatial attention such as pseudo-neglect in line bisection (i.e. small le wards deviations of the subjective mid- line observed in healthy individuals),17–19 and asymmetries in the speed of detection of events presented in the right or in the le hemi eld.16

ese frontoparietal attentional systems are o en considered important for spatially-based visual abilities (but see reference 20 for nonspatial functions of the IPL). ey are to be distinguished from the dorsal and ventral visual streams which originate from the occipital cortex.21,22

De cits of high-level visual abilities

e occipitoparietal cortical visual stream—or ‘dorsal visual stream’—processes information about objects and their locations in a moment-to-moment manner, and mediates the visual con- trol of skilled actions. More ventral, occipitotemporal networks are instead critical for other visual abilities, such as visual recogni- tion21,22 (see chapter 14). ey appear to carry information about perceptual features, allowing the building of long-term representa- tions necessary to identify and recognize objects.

Damage to the occipitotemporal cortical visual stream impairs the perceptual recognition of visual items such as objects, faces, colours, and written words, whereas more dorsal, occipitopari- etal de cits concern the processing of spatial location (spatial

awareness and reaching movements) (see Box 15.1, cases 1 and 2). Anatomically, the ventral stream is composed of the occipitotem- poral cortices and the white matter bundles running between these regions, which include the inferior longitudinal fasciculus and por- tions of the inferior fronto-occipital fasciculus.23,24

Visuospatial de cits in neurodegenerative conditions o en develop and progress along these two main cortico-cortical axes. In particular, the distribution of neuropathology in neurodegen- eration seems to follow speci c trajectories for each syndrome, targeting speci c cerebral networks.25 For example, the pattern of network change in PCA is di erent to that in CBS, both of which can present with attention de cits, together with other features that might help distinguish between them. Within this framework, the anatomical de nition of ventral and dorsal variants can assist cli- nicians in localization, and allow them to de ne the distribution of pathology by bedside testing.26 Given these correspondences between disease, anatomically damaged patterns, and related cog- nitive impairment, the interpretation of neuropsychological tests of visuospatial cognition has important implications both for di er- ential diagnosis and to monitor disease progression (see Box 15.1 and Fig. 15.3).

Visual neglect

Vascular, traumatic, neoplastic, or degenerative damage to fron- toparietal networks in the right hemisphere is frequently associated with a disabling condition known as visual neglect.27–29 About half of the patients with a lesion in the right hemisphere su er from neglect for the contralesional, le side of space.30 ey are unaware of items to their le . Neglect patients may not eat from the le part of their dish, they o en bump their wheelchair into obstacles situ- ated on their le , and have a tendency to look to right-sided details in a visual scene, as if their attention were ‘magnetically’ attracted by these details.31 Many of them are also inattentive to auditory or somatosensory stimuli to the le . Neglect patients are usually unaware of their de cits (anosognosia), and o en obstinately deny being hemiplegic. Individuals with le brain damage may also show signs of contralesional, right-sided neglect, albeit more rarely and usually in a less severe form.32,33

Neglect is a substantial source of handicap and disability for patients, and entails a poor functional outcome. Diagnosis is important, because e ective rehabilitation strategies are becoming

SLF I SLF II SLF III DAN VAN

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available,34 and there are promising possibilities for pharmaco- logical treatments.35 Furthermore, in many cases the nature of neg- lect de cits (impaired active exploration of a part of space) renders the diagnosis di cult or impossible if signs of neglect are not sought.

Neglect is especially frequent a er focal vascular lesions of the right hemisphere, but signs of neglect have been described in AD.36–39 More recently, signs of visual neglect have also been described in PCA. Out of 24 PCA patients, signs of neglect on at least one paper-and-pencil test were present in 16 patients, and

14 also had visual extinction or hemianopia.40 In one patient with PCA and le -sided neglect as a presenting sign, MRI-based DTI tractography demonstrated damage to frontoparietal white matter bundles relatively selective to right-hemisphere pathways (refer- ence 41 p. 4752) (see patient 3, Box 15.2).

Diagnostic tests

Patients’ performance on paper-and-pencil tasks can easily dem- onstrate the presence and the extent of visual neglect. Here we

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CHAPTER 15 disorders of attentional processes 163

Box 15.1 Ventral/dorsal PCA (posterior cortical atrophy) variants

On the basis of the schematic dichotomy between dorsal (occipito-parieto-frontal) and ventral (occipito-temporal and occipito-frontal) cortical visual networks, here we present three patients a ected by PCA, but showing a di erent pattern of white matter damage along these two main axes.26

Patient 1 was a 62-year-old woman who had been experiencing isolated di culties in reading and writing for about seven years. At the time of the study, she complained of episodes of topographical disorientation, and her neuropsychological pro le was dominated by a severe visual impairment. She was unable to copy the Rey complex gure. She was impaired in object and space perception and in face recognition tests. She performed poorly on reading words and pseudo-words. Despite her marked visual and gnosic di culties, she had excellent episodic memory for recent events, and no di culty in remembering appointments. She had a normal verbal working memory as measured by backwards digit span. Her speech was uent and syntactically well formed. She performed normally on tests of word uency tasks, as well as on tests of comprehension. Insight was preserved. e tractography study of this patient demonstrated white matter damage along all the components of the ventral cortical visual stream (namely, the inferior longitudinal and the fronto-occipital fasciculi) (Fig. 15.2a).

Patient 2 (Fig. 15.2b) was a 62-year-old lady. She had been experiencing episodes of misplacing of objects for the past two-and-a-half years, along with reading problems, prosopagnosia, le -right disorientation, and anomia. She was poorly oriented at the time of testing, with a severe visual agnosia. She also experienced de cits in working memory, visuospatial and verbal episodic memory. At the time of MRI, she had a severe optic ataxia, mild visuospatial neglect, and exhibited irritability and loss of interests. She had both dorsal and ventral dysfunction.26 In contrast, another PCA patient, with selectively impaired ‘ventral’ abilities (object recognition de cits, reading di culties, and impaired face recognition) had spared SLF (Fig. 15.2c).

(a) R

(b)

IFOF

ILF SLF

(c)

0.35

fractional anisotropy

0.45

Fig. 15.2 An illustrative reconstruction of the ventral (inferior longitudinal fasciculus, ILF and the inferior fronto-occipital fasciculus, IFOF) and dorsal (fronto-parietal superior longitudinal fasciculus, SLF, branches II and III) stream pathways. Long-range white matter tracts of patients are rendered as maps of fractional anisotropy (FA, index of microstructural white matter integrity) and displayed on the native T1-weighted MRI. FA values range from 0.40 (yellow) to 0.50 (dark red). e lower the value, the greater the damage. (a) PCA patient 1 had a long clinical history of isolated de cits in reading and writing, followed by an impairment in object and space perception and face recognition, and showed a bilateral ventral white matter damage. (b) PCA patient 2, with optic ataxia and signs of mild left neglect two-and-a-half years after disease onset, had a di usely damaged frontoparietal SLF (mean FA = 0.39). (c) Another PCA patient with preserved SLF (mean FA = 0.44).

See Box 15.1 for more clinical details.
Reproduced from Neurobiology of Aging. 33(11), Migliaccio R, Agosta F, Scola E, et al. Ventral and dorsal visual streams in posterior cortical atrophy: A DT MRI study, pp. 2572–84, Copyright (2012), with permission from Elsevier.

164 SECTION 2 cognitive dysfunction Pt #3

Pt. #4

Fig. 15.3 Performance on paper-and-pencil tests of PCA-AD patient 3 (see Box 15.2) and PCA-CBS patient 4. From left to right: clock-drawing test, copy of a drawing, line bisection. Note that patient 3, when copying the landscape, omitted the whole left part of the scene (scene-based pattern). Patient 4, on the other hand, tended to omit the left part of each element of the scene (object-based pattern); she also showed some spatial disorganization in placing the numbers during the clock drawing test.

Reproduced from Cortex. 48(10), Migliaccio R, Agosta F, Toba MN, et al. Brain networks in posterior cortical atrophy: a single case tractography study and literature review, pp. 1298–309, Copyright (2012), with permission from Elsevier.

brie y describe three visuomotor procedures simple enough as to be administered at the bedside (for other tests, see reference 4, p. 5198; reference 30, p. 1425; reference 42; reference 43, p. 4380). Care should be taken in the proper positioning of the test sheet; in the usual clinical conditions, the midline of the sheet should cor- respond to the trunk midline of the patient. Performance on these tasks is described by taking into account neglect for the le side of space, which is more common, severe, and durable than right- sided neglect in vascular patients.32 e relative frequency of le and right neglect in neurodegenerative conditions is currently unknown. In some studies right-sided neglect was observed with an unexpected, relatively high frequency in neurodegenerative dis- eases as compared to vascular patients (reference 40, p. 4310; see also reference 37, p. 515 for discussion of possible mechanisms), whereas other studies found the usual predominance of le -sided neglect to be present also in degenerative patients.44

Importantly, patients who perform normally on these paper-and- pencil tests may nevertheless show spatial or nonspatial de cits on more demanding tests of visuospatial attention, such as speeded response time tests. It is important to be aware of the possibility of these seemingly ‘subclinical’ de cits, which might well have clin- ical implications, for example in taking decisions about the patient’s ability to drive. In neurodegenerative conditions, such de cits of spatial attention have been described in patients with Alzheimer’s disease.45–47 Parkinson’s disease,48,49 Huntington’s disease,50,51 and progressive supranuclear palsy.52

Drawing tasks

When drawing gures, whether from memory or by copying them, neglect patients omit or distort the details on the le side (Fig. 15.3).52 When copying patterns composed of several elements

aligned horizontally, some patients neglect the whole le part of the model, while others copy all the items but leave un nished the le part of each (Fig. 15.3 and 15.4).53,54

ese distinct patterns of performance have been referred to, respectively, as scene- (or viewer-) based neglect and object-based neglect.55

Cancellation tasks

In cancellation tasks, patients are requested to search for and cross out items scattered on a paper sheet, such as lines,56 letters,57 or shapes.58,59 Patients with right hemisphere damage typically begin to scan the sheet from the right side, unlike normal participants or patients with le brain damage, who start from the le side.60 Patients with le neglect may omit a variable number of le -sided targets; some patients may continue to cancel the same right-sided items over and over again. Fig. 15.5 shows the performance on a shape cancellation test of a patient with PCA and mild signs of le neglect.

Line bisection

In line bisection tasks, patients have to mark the midpoint of a hori- zontal line; neglect patients deviate the subjective midpoint to the right of the true centre of the line (see Fig. 15.3).61 e amount of deviation depends on several factors. e longer the line, the more rightward the bisection point; for the shortest lines there may be a paradoxical le ward deviation (the ‘crossover e ect’).62 e loca- tion in space of the line with respect to the patient’s trunk midline also in uences performance; rightward deviation increases when lines are located in the le hemispace and decreases when they are in the right hemispace.61,63 Although patients’ performance on line bisection may dissociate from their performance on other tasks, such as cancellation tests,64 it remains a very useful test

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particularly in situations, such as PCA, where simultagnosia may sometimes render di cult or impossible the completion of cancel- lation tests.65

Extinction

Sensory extinction refers to the failure of brain-damaged patients to report the stimulus contralateral to their lesion when stimulated on both sides, despite being able to report a single stimulus pre- sented on either side. Extinction can occur in di erent sensory modalities: visual,66 somatosensory,67 acoustic,68 olfactory,69 and even cross-modally.70 Accounts of extinction typically emphasize either a sensory problem not severe enough to impair perception of single stimuli,71 or an attentional disorder favouring ipsilateral over contralateral stimuli,72 or both.73 Although visual extinction usu- ally occurs a er vascular strokes in the territory of medial cerebral artery, it has also been observed in neurodegenerative conditions such as PCA.40

Diagnostic tests

In clinical practice, the presence of extinction is traditionally inves- tigated using various sorts of double simultaneous stimulation. e confrontation method is a common test of visual extinction. e examiner asks the patient to xate the examiner’s nose and then brie y moves his/her ngers either in one hemi eld or in both hemi elds simultaneously. For example, six single unilateral stim- uli and six double simultaneous stimuli can be presented in pseu- dorandom order.40 In practice, patients can be considered to show visual extinction when they fail at least twice to report a contralat- eral stimulus during bilateral simultaneous presentation, while accurately detecting all unilateral stimuli.31 When the patient fails to report all stimuli on one side (whether single or double), homon- ymous hemianopia is a likely diagnosis which, however, requires con rmation with more detailed testing of the visual eld in each eye at the bedside or with formal visual perimetry. ree patients out of the 24 PCA patients examined by Andrade and colleagues40

CHAPTER 15 disorders of attentional processes 165

Fig. 15.4 Performance of a patient with probable AD on the copy of a landscape. Note the signs of left object-based neglect, similar to Patient 4 in Fig. 15.3.

Fig. 15.5 Performance of a PCA patient on the Bells test.58 e patient omitted three targets on the left side and one on the right side (red arrows). Note the false recognition on the left (green arrow) and the misreachings (blue arrows), perhaps depending on optic ataxia.

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166 SECTION 2 cognitive dysfunction

missed all the le -sided stimuli, thus suggesting the presence of le homonymous hemianopia, which is a rare occurrence in neuro- degenerative diseases.74 Of the remaining patients, eight had le extinction and three showed mild right extinction.

Somatosensory extinction can be tested by asking the patient to close the eyes and report light touches given by the examiner on the patient’s limbs or face. To examine acoustic extinction, the exam- iner may lightly snap his/her ngers making a clicking sound near the patient’s ears.

In typical amnesic Alzheimer’s disease, general attentional de – cits can occur early along with memory de cits. Later in the course of the disease, neglect signs may appear.37,39 In some cases atten- tional de cits can precede the typical amnesic syndrome,75 espe- cially in the early-onset variant occurring before the age of 65.76 More speci cally, visuospatial attention de cits can have a central role in the impairment of higher-level cognitive processes concern- ing visual and spatial memory. As already mentioned, visuospa- tial neglect can represent the core symptom of clinical pro le of patients a ected by PCA (see Box 15.2, case 3). Even if less fre- quently, patients with CBS can also show signs of visuospatial neglect (see Box 15.3, case 4).44

Among the variety of tests used in clinical practice, line bisection might be more apt than target cancellation to demonstrate neg- lect in patients with neurodegenerative dementia, such as PCA,40 because performance on isolated horizontal lines is less prone to be in uenced by other concomitant de cits such as simultagnosia. In comparison with controls, PCA patients with signs of le -sided and right-sided neglect presented prominent hypoperfusion in right and le frontoparietal cortical networks, respectively.77 In another recent study, rightward bias (sign of le -sided neglect) in line bisec- tion test was strongly correlated with atrophy and hypoperfusion in a large-scale frontoparietal network in the right hemisphere, involving the parietotemporal cortex, the middle frontal gyrus, and in the postcentral region (Fig. 15.8).65

us, in these studies signs of neglect seemed to correlate with dysfunction in large-scale frontoparietal networks, beyond the sites

of parietal atrophy ((see reference 41, p. 4755 and p. 4752), consist- ent with evidence from patients with vascular lesions.28,78

Similar results on the task of line bisection were reported also in patients with classic AD.38 Obviously, in neurodegenerative patients, other aspects of the disease, such as simultagnosia and object recognition de cits, can interfere with patients’ performance on visual search tasks, such as target cancellation.

Simultagnosia

Simultagnosia is a rare neuropsychological condition character- ized by impaired spatial awareness of more than one object at time79 which can occur in patients with posterior brain damage of vascular or degenerative origin. Wolpert80 described simultagno- sia as an inability to interpret a complex visual scene (processing multiple items and the relations between them), despite preserva- tion of the ability to apprehend individual items. Simultagnosia can occur in isolation, or in association with other elements of Bálint’s syndrome (see below), that is, oculomotor apraxia and optic ataxia. Simultagnosia has been reported in patients with bilateral parietal and occipital damage.79 ere have also been some documented cases following either le or right unilateral parietal brain damage, but at least in some of these unilateral cases81,82 the lesions included damage to the corpus callosum. White matter tractography studies revealed associations with bilateral damage to major pathways within the visuospatial atten- tion network, including the superior longitudinal fasciculus, the inferior fronto-occipital fasciculus, and the inferior longitudinal fasciculus.83 us, simultagnosia typically occurs a er bilateral damage to parieto-occipital regions, o en associated with bilat- eral white matter disconnections.

Diagnostic tests

In clinical practice, simultanagnosia is assessed by the descrip- tion of complex visual scenes, such as the cookie the test.84 e tests consists of a complex image displaying a mother cleaning

Box 15.2 Patient 3: Unilateral spatial neglect and PCA-early onset AD variant (PCA-AD)

Patient 3 is a 58-year-old, right-handed medical doctor, who came to our observation a er about a year-and-a-half from disease onset, characterized by multiple minor car accidents against le -sided obstacles.

Clinical and neuropsychological examination revealed signs of severe le visual neglect (see Fig. 15.3), along with optic ataxia and ocular apraxia, as well as le ideomotor apraxia. ere was a moderate rightward deviation (19 per cent) on line bisection; her perfor- mance was pathological on the landscape drawing copy and on the clock-drawing test. She showed no auditory extinction, although she had some di culty to identify auditory stimuli presented on the le side. ere were rare le tactile extinctions on double stimulation. Mild memory impairment, especially with visuospatial material, and a very mild simultanagnosia were also present. Executive functions and calculation were relatively spared. Rare di culties in word nding and occasional phonologic paraphasias occurred.

Cerebrospinal uid analysis revealed positive AD biomarkers (raised tau and phosphorylated tau proteins, and reduced amyloid β peptide). High-resolution MRI demonstrated bilateral cortical atrophy mainly located in the parietal lobes, con rmed by a detailed analysis performed by using voxel-based morphometry (VBM) (Fig. 15.6a). In agreement with current clinical criteria (see reference 103) a diagnosis of PCA was made.

During a two-year follow-up, the neuropsychological pro le remained highly asymmetric with language and verbal memory largely preserved, while le visual neglect continued to represent the most severe symptom, and remained a substantial source of handicap in her everyday life.

A detailed anatomical study was conducted in order to study the grey and white matter status. VBM con rmed the bilateral posterior grey matter atrophy, including occipitotemporal and parietal cortices (Fig. 15.6a). Importantly, the tractography study of long-range white matter bres demonstrated white matter damage largely restricted to the right hemisphere, including the superior and inferior

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multiple drawn objects are shown superimposed on each other. Patients are asked to name or indicate in a multiple-choice display all the objects seen, but may

In the overlapping gures test,
fail to identify most of them in case of simultagnosia.

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CHAPTER 15 disorders of attentional processes 167

longitudinal fasciculi and the inferior fronto-occipital fasciculus, while the homologous le -hemisphere tracts were spared (Fig. 15.6b). ese data suggest that visuospatial de cits typical of PCA (such as neglect) may not result from cortical damage alone, but by a net- work-level dysfunction including white matter damage along the major large-scale pathways. e sparing of all the explored fasciculi in the le hemisphere, despite the cortical involvement of the occipital and parietal lobes, is consistent with the patient’s cognitive pro le, characterized by relatively intact language and calculation abilities.41

(a)

(b)
Inferior fronto-occipital fasciculus

Inferior longitudinal fasciculus

Superior longitudinal fasciculus

Corpus callosum

0.50

0.40

Fig. 15.6 PCA-AD patient 3. (a) Voxel-based morphometry as compared with a group of healthy controls. Regions of grey matter atrophy are shown in a colour code indicating the degree of atrophy, ranging from red (lower) to yellow (greater). Atrophy is displayed on the three-dimensional rendering of the Montreal Neurological Institute standard brain. (b) Long-range white matter tracts in the same patient, rendered as maps of fractional anisotropy (FA, an index of microstructural white matter integrity) displayed on the native T1-weighted MRI for both hemispheres. FA values range from 0.40 (yellow, greater damage) to 0.50 (red, lesser damage). In comparison to a group of healthy controls, maximum damage was found in the right frontoparietal superior longitudinal fasciculus. Inferior longitudinal fasciculus and inferior fronto-occipital fasciculus were also a ected in the right hemisphere. ere was also bres loss in the posterior part of corpus callosum. Left hemisphere tracts did not di er from controls. See Box 15.2 for more clinical details.

Reproduced from Cortex, 48(10), Migliaccio R, Agosta F, Toba MN, et al., Brain networks in posterior cortical atrophy: a single case tractography study and literature review, pp. 1298–309, Copyright (2012), with permission from Elsevier.

dishes in a kitchen, and not noticing that the sink is over owing and that a boy is about to fall while attempting to steal cookies behind her back. Patients with simultagnosia typically focus on one or two details of the scene, without being able to describe the others. 31,85

Bálint syndrome

Bálint syndrome is a rare neurovisual disorder characterized by three elements: optic ataxia, oculomotor apraxia, and simultag- nosia.79 In 1909, Rezső Bálint described with the name of ‘psy- chic paralysis of gaze’ the case of a patient who had lost the ability to voluntarily move his gaze from one point to xation to a new stimulus presented in the visual periphery.86 is disorder is also known under the name of oculomotor apraxia. Patients cannot take

FA values

168 SECTION 2 cognitive dysfunction

Box 15.3 Patient 4: Unilateral spatial neglect in PCA-CBD

Patient 4 is a 55-year-old woman, right-handed, was evaluated at about three years from clinical onset. She had a similar clinical history to patient 3; however, she deteriorated very rapidly in the visuospatial domain, while retaining almost normal performance in other cognitive domains. She mainly complained of visual de cit; her caregiver reported de cits occurring in everyday life and clearly result- ing from visuospatial neglect.

Clinical and cognitive evaluation demonstrated signs of le visual neglect (see Fig. 15.3, lower panel, and Fig. 15.5), consisting in a moderate (17 per cent) rightward deviation on visual line bisection, and pathological scores on landscape drawing copy and clock drawing test, with an object-based pattern of omissions. Optic ataxia, visual and auditory le extinctions, along with alexia, and ele- ments of Gerstmann syndrome (dysgraphia, nger agnosia, acalculia) were also present. She presented also constructional, ideomotor, and mielokinetic apraxia, with greater impairment for the execution of bimanual tasks and for the accurate movements and con gura- tions involving the ngers. Memory and language were relatively preserved. Executive functions were slightly impaired. At neurologi- cal examination she was hypomimic and with a mild right-lateralized rigidity. CSF analysis was negative for AD biomarkers (tau and phosphorylated tau proteins, and amyloid β peptide levels were within normal range). MRI showed greater brain atrophy located in the posterior regions bilaterally, and in the frontal areas (with right predominance) (Fig. 15.7). Based on clinical features, such as hypomimia and rigidity, as well as the presence of limb apraxia, a clinical diagnosis of corticobasal syndrome was proposed. A presynaptic dopamine transporter (DAT)-scan study demonstrated an asymmetric decrease of the uptake, with right side predominance, corresponding to the rigidity. is nding con rmed the in vivo diagnosis of corticobasal syndrome.

Fig. 15.7 Native high-resolution structural MRI of PCA-CBS patient 4. Note the bilateral posterior brain atrophy. ere was also mild right frontal atrophy (data not shown). See Box 15.3 for more clinical details.

their eyes o xed object (Holmes87 called this disorder ‘spasm of xation’), in order to produce saccades towards other objects. Slow tracking movements may instead be preserved. e other two ele- ments of Bálint syndrome are simultanagnosia (described in the previous paragraph) and optic ataxia—the inability to produce a correct movement of the hand to reach an object, typically presented in the periphery of visual eld, under visual guidance. Similar to simultanagnosia, the typical lesion locations in Bálint syndrome are parietal or parieto-occipital bilateral. e most common cause is vascular (watershed strokes between middle and posterior cerebral arteries territories), tumour metastasis, or neurodegeneration (e.g. PCA, CBD; see also Boxes 15.2 and 15.3). Regarding optic ataxia, lesions of the superior parietal lobule and to its connections with frontal areas (supplementary motor area and frontal eye elds) appear to play a key role.88

Diagnostic tests

Clinically, oculomotor apraxia can be assessed asking the patient, who is seated in front of the examiner, to move the eyes towards

Cerebral blood flow Grey matter density

–6 t scores 0

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Fig. 15.8 Statistical parametric mapping results obtained in a sample of
15 patients with PCA, who underwent structural MRI and single photon emission computed tomography. e gure represents the regions of
signi cant correlation between grey matter atrophy (red), regional brain hypoperfusion (green) and rightwards deviations on the bisection of 20-cm long horizontal lines.

Reproduced from J Neurol Neurosur Ps. 83(9), Andrade K, Kas A, Valabrègue R, et al., Visuospatial de cits in posterior cortical atrophy: structural and functional correlates, pp. 860–3, Copyright (2012), with permission from BMJ Publishing Group Ltd.

a moving target a er having xated the examiner’s nose. e four visual quadrants are evaluated.89

To assess optic ataxia, the examiner asks the patient to xate his or her nose, then to use a designated hand (le or right) to reach a moving target (e.g. a pen) without losing xation. e examiner moves the target across the four visual quadrants.89

Attention and monitoring de cits

in vascular stroke and neurodegeneration

selective, sustained, and divided attention more severe than those found in AD patients. As a consequence, DLB patients typically perform better than AD patients on tests of verbal memory but worse on visuospatial performance tasks. Fluctuations in cognitive function—which may vary over minutes, hours, or days—occur in 50–75 per cent of patients and are associated with shi ing degrees of attention and alertness.102

Conclusion

Disorders of attention are common in neurodegenerative condi- tions. ese disorders o en go undetected by the clinician, but can have a severe impact on patients’ well-being and autonomy. ese patients who are not able to explore their visual environment thor- oughly can be far more handicapped in their daily life than patients with sensory de cits a ecting perception directly, but leaving atten- tion unimpaired, such as impaired visual acuity or homonymous hemianopia. us, the clinician should be aware of the variety of attention disorders which can occur in di erent neurodegenerative conditions, and of the (o en very easy) diagnostic tests that can be used to detect them.

Acknowledgements

The authors received funding from the Fondation ‘France Alzheimer’, Fondation ‘Philippe Chatrier’ and from the programme ‘Investissements d’Avenir’ ANR-10-IAIHU-06.

References

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Focusing attention in space and sustaining it in time, as well as monitoring behaviour, are o en considered to be mediated by cortical and subcortical frontal structures90–92 and by their con- nections with parietotemporal regions.4,11,16 Two principal neu- rodegenerative diseases can show de cits in these cognitive domains: AD and frontotemporal dementia (FTD, particularly behavioural-variant FTD).

Many clinical and cognitive studies have compared attention and monitoring in AD and FTD. Based on di erent patterns of neuro- degeneration, peculiar general clinical and cognitive pro les have been described. Early memory impairment and following language, praxis, and visuospatial de cits are typically described in AD. In AD, the trajectory of the damage includes the hippocampal and perihip- pocampal regions, where the neurodegeneration originates causing memory failure, to the more posterior associative temporoparietal areas. Conversely, early changes in social conduct, insight, a ect- ive behaviour, along with impaired initiative, verbal uency, atten- tion, planning, set-shi ing, problem-solving, and working memory depend on pathological changes in the orbitofrontal and dorsolateral prefrontal cortex, characteristically a ected in patients with FTD.93

Notwithstanding their profound biological, anatomical, and cognitive di erences, AD and FTD can have similar consequences in executive function. Executive de cits re ect an impaired inte- gration of the frontal lobes with di erent brain areas, and in par- ticular with more posterior brain regions. ese functional and anatomical connections are damaged in both AD and FTD, thus perhaps accounting for their similarity in this speci c domain. For this reason, it might prove di cult to di erentiate, on the basis of these functions, patients with FTD and AD, particularly when AD patients are younger and atypical.

From the functional point of view, several large-scale brain net- works, described as being dysfunctional in AD and FTD, are impli- cated in attention and monitoring behaviour, such as networks implicated in salience processing,94 executive processes,95 attention/

96
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work.97 ese functional networks are mainly impaired in FTD98 and may represent a pathophysiological signature of this disease.

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100

Patients with DLB can show much more substantial de cits of attention. ey can demonstrate a combination of severe atten- tional de cits and visuospatial dysfunction that can help to di er- entiate DLB from AD. DLB patients usually su er from de cits in

lateral frontal damage,
tional networks see Fig. 15.1), whereas in the behavioural variant of FTD, the atrophy a ects rst and foremost the frontomedian brain regions, the anterior insula, and the thalamus.101

(i.e. in the prefrontal nodes of the atten-

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CHAPTER 16

Apraxia

Georg Goldenberg

Concepts and classi cation of apraxia De nition of apraxia

e term apraxia refers to ‘higher-level’ disorders of motor con- trol. ere is, however, no general agreement as to what counts as a high or a low level of motor control. Most agree though that apraxia should not be used to describe di culties that might be attributed entirely to weakness, or loss of sensation, rigidity, tremor, or dysto- nia. However, this would be a diagnosis of exclusion. Moreover, in many neurological conditions apraxia can occur in the context of one or more of these de cits. Consequently, the history of apraxia has brought forward a wide variety of diverging de nitions and classi cations (Box 16.1).

e most in uential of them was proposed some hundred years ago by the German psychiatrist Hugo Liepmann.1,2 He distin- guished two consecutive phases of voluntary motor action. e rst is the creation of mental images of the intended actions, and the second their transduction into appropriate motor commands. Liepmann named disturbances of the rst phase ‘ideational’ and that of the second phase ‘ideo-kinetic’ apraxia, which later authors re-baptized as ideomotor apraxia,2,3 a distinction that still remains

in widespread use (but see Box 16.1 for discussion of the utility of this distinction).

Although ‘apraxia’ has been applied to disturbances of widely dif- ferent actions (e.g. lid closure, gait, gestures, or even spatial con- structions), there is a core of clinical manifestations a ecting limb function which have been the focus of the concept. ey include:

◆ imitation of gestures
◆ communicative gestures on command and pantomime of tool use ◆ use of tools and objects

De cits in all of these occur predominantly a er le brain lesions and are frequently, though not invariably, associated with aphasia. In contrast to ‘low-level’ motor symptoms associated with unilat- eral hemispheric damage, they a ect not only the contralesional limb (on the side of the body opposite to the cerebral lesion) but also the ipsilesional limb. In sections below, we examine each of these domains and how to examine for de cits in patients. In addi- tion, we consider a particular aspect of tool and object use that involves:

◆ Multi-step actions involving several tools and objects

Box 16.1 Development of concepts of apraxia

Based on the associationist model of brain function prevalent at that time, Liepmann assumed that mental images emerge from revival of memory traces of previous sensations. He speculated that their translation into motor commands was accomplished by bres that connect posterior sensory brain regions to the motor cortex in the anterior part of the brain. ese bres pass below the parietal cortex. Parietal lesions interrupt them and to cause ‘ideo-kinetic’ (now known as ideo-motor) apraxia.4,5

In the middle of the twentiethth century, when the localizing approach to mental function gave way to more functional and holistic theories, Liepmann’s anatomical distinction between ideational and ideomotor apraxia fell into disfavour and was replaced by other sys- tems of classi cation. Noteworthy, all of them retained some kind of dichotomy between high and low levels of motor controls. us, for example, they considered as opposites: autonomous action versus. environmental dependency; coping with novelty versus routine action, and abstract symbolic gestures versus material interactions with concrete objects (see references 6, 7, 8, and reference 9 for extensive historical review).

In the last third of the twentieth century, the renaissance of cerebral localization of mental function revamped Liepmann’s ideas, which have strongly in uenced modern accounts of apraxia and its cerebral localization.10–14

Ideomotor and ideational apraxia

Liepmann reasoned that in actual tool use, the interaction between the moving hand and external objects can compensate for an inability to direct movements that might arise because of a failure to transduce mental images into appropriate motor commands. In such cases, the de cit should be conspicuously apparent when actions have to be made without external counterpart. According to this reasoning ideomo- tor apraxia should a ect imitation and the demonstration of communicative gestures but spare actual use of tools and objects.1 Most modern authors who respect the traditional classi cation of apraxia adhere to this suggestion and apply the label ‘ideomotor’ to defective imita- tion as well as defective demonstration of communicative gestures, or compute compound scores from both for a diagnosis of ideomotor apraxia.15–22

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174 SECTION 2 cognitive dysfunction

However, the unity of imitation and demonstration of communicative gestures has been challenged by double dissociations between them. ere are patients who are unable to correctly demonstrate communicative gestures but imitate awlessly.23 and others who have no problems with the demonstration of communicative gestures but commit many errors on imitation.24–27 eir common classi cation as ‘ideomotor’ apraxia is misleading because it veils fundamental di erences.

Most authors agree to apply the term ‘ideational apraxia’ for faulty use of tools and objects but there is disagreement about the scope and nature of these errors. Liepmann had adopted the description of this variant of apraxia from the Prague psychiatrist, Arnold Pick.28 who had reported gross errors in everyday multi-step actions like dressing or preparing a pipe by patients with dementia. Pick argued that most errors could be referred to perseveration and to neglect of the overarching goal of the multi-step sequence, rather than betray- ing problems that are speci c for tool use. Liepmann agreed that ideational apraxia is the expression of a ‘mental insu ciency which manifests itself in the domain of action but has its roots in de cits which are not speci c for action’.29

By contrast, an alternative tradition originating with a seminal thesis of the French neurologist, Joseph Morlaas,30 postulates that idea- tional apraxia can occur in patients without dementia and that it a ects also the isolated use of single tools. Morlaas suggested the term ‘agnosia of utilization’ to characterize the selective inability to recognize the way an object has to be used.30,31

In sum, the distinction between ‘ideational’ and ‘ideomotor’ does not correspond well with the clinical boundaries between dif- ferent manifestations of apraxia and is confusing. It seems more productive to abandon it and to divide apraxia according to the a ected domain of action. ere are four of them: imitation of gestures, production of communicative gestures, use of single tools, and multi-step actions involving several tools and objects. eir autonomy is underlined by di erences between the localizations of lesions interfering with each of them (Fig. 16.1).

Pantomime of tool use

Imitation of meaningless gestures

Use of single familiar tools

Hand postures Finger postures

Mechanical Problem Solving

Functional Knowledge

Fig. 16.1 Putative intra-hemispheric localization of left-sided lesions causing di erent manifestations of apraxia. Imitation of meaningless hand postures and mechanical problem solving depend on integrity of parietal region. By contrast, pantomime of tool use and retrieval of functional knowledge are vulnerable to temporal lesions. Imitation of nger con guration as well as performance of multi-step actions with multiple tools and objects are less strictly localized and can be impaired also by right hemisphere lesions.

Adapted from Goldenberg G. Neuropsychologie—Grundlagen, Klinik, Rehabilitation, Copyright (2007), with permission from Elsevier GmbH, Urban & Fischer, Munich.

Imitation of gestures

Success or failure of imitation of gestures may depend on the kind of gestures that are examined. A major distinction is that between meaningless and meaningful gestures (the meaning of meaningful gestures can be understood by other persons, thus they are, by def- inition, communicative, and I use the terms ‘communicative’ and ‘meaningful’ interchangeably).23,32–34 is distinction derives from the fact that meaningful gestures have representations in semantic memory that associate their shapes with de ned meanings. eir imitation may be accomplished by recognition of that meaning and reproduction of the corresponding shape. By contrast, the imita- tion of meaningless gestures requires reproduction of the shape of the gesture without support from semantic memory. Another factor

in uencing the success of imitation is whether single static postures or movement sequences are examined. Generally, sequences are more sensitive to brain damage but also less speci c for its localiza- tion.35–37 Here, we concentrate on the imitation of static meaning- less gestures (Fig. 16.2).

Clinical diagnosis

Defective imitation will rarely be conspicuous in spontaneous behaviour but can easily be demonstrated on clinical examination. Even patients with severe aphasia mostly understand the instruc- tion to imitate the examiner’s actions. As with all manifestations of apraxia, the limb ipsilateral to the lesion should be tested to exclude contamination of results by the e ects of hemiparesis. Many

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clinicians ask patients to start their imitation only immediately a er they have demonstrated the gesture. is brief delay introduces a working memory load that probably contributes to uncover- ing mild impairments. But patients with severe apraxia will show de cits even if the examiner’s posture is still visible to them. e most reliable sign for the diagnosis of apraxia are spatially wrong nal positions. Frequently, the movement path leading to the nal position is hesitating with searching and self-correction, but there are apraxic patients who reach wrong nal postures with swi and secure movements.38

Localization of lesions

It has been suggested that creation of this abstract representa- tion relies on ‘body-part coding’ that enables reduction of gestures to simple spatial relationships between a limited number of de ned body parts.40,48,49 e body-part speci city of the neural substrates of defective imitation can be accounted for by the assumption that body-part coding is bound to integrity of le parietal regions, but that frontal, subcortical, and right hemisphere regions are required when gestures pose high demands on the distribution of spatial attention or on selection between perceptually highly confusable items. Di erential demands of hand, nger, and footpostures on body-part coding, attention, and selection might explain why di erent regions are cru- cial for their successful imitation.39,44,50,51 e discrepancy between the associations of responsible brain lesions with body parts and the somatotopic organization of motor cortex further underlines the inde- pendence of apraxia from the anatomy of ‘low-level’ motor control.

Communicative gestures and pantomime

of tool use

e clinical examination of communicative gestures probes ges- tures that have a habitual shape and meaning, allowing unam- biguous assessment of their correctness. Gestures that ful l this condition are either ‘emblems’ that have a conventional meaning like thumb up for ‘OK’, or pantomimes of tool use that indicate objects by miming their use. Usually, diagnosis and research on apraxia concentrates on pantomime of tool use. A practical reason for this preference is that aphasic patients may not understand the verbal label of emblems, whereas comprehension of the name of a tool whose use they should demonstrate can be facilitated by show- ing the tool or a picture of it.

Clinical diagnosis

In clinical practice, a patient is asked by the examiner to demon- strate how he would make a common gesture (‘emblem’) or use a common tool. Comprehension of the instruction may pose prob- lems when examining patients with severe aphasia, even if the tool whose use should be pantomimed is pointed to or shown on a photo. Failure of comprehension is rather obvious when patients grasp for the demonstrated object, try to name or describe it,52 or outline with the nger a more or less recognizable shape on the table.

e typical locations of lesions causing defective imitation depend on the body part performing it. Fig. 16.2 displays static postures of the nger, the hand, and the foot that have been used for assess- ing this body-part speci city.39–41 Whereas defective imitation of hand postures is nearly exclusively bound to le hemisphere lesions, imitation of nger and foot postures is also susceptible to right hemisphere lesions.39,42–44 Within the le hemisphere, defect- ive imitation of hand postures is strongly linked to parietal lobe damage whereas defective imitation of nger postures can also be caused by frontal and subcortical lesions.40,41,45–47

eoretical implications

e route from perception to imitation of meaningless gestures is direct in that it bypasses reference to semantic memory storage of conventional shapes of familiar gestures.14 However, there are rea- sons to doubt that it is direct also in that it connects perception and execution of gestures without any interpolated cognitive process- ing. us patients who show apraxia for imitation of meaningless hand postures are also impaired when asked to replicate hand pos- tures on a manikin48 or to match pictures of meaningless gestures demonstrated by di erent persons under di erent angles of view,49 although the motor actions of manipulating a manikin of pointing to pictures are very di erent from those of imitating the target pos- ture on the own body. Findings such as these suggest that there is an intermediate stage—between perception and action—where a more abstract representation of the gesture is created that can serve not only for motor replication of the gesture but also for matching gestures or for their replication on a manikin.

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CHAPTER 16 apraxia 175

Fig. 16.2 Examples of hand, nger, and foot postures that show di erent sensitivity to left and right brain damage and within the left hemisphere to parietal and inferior frontal lesions. Scoring sheets for 10 hand and 10 nger postures with normative data are published as supplementary material to reference 53 and can also be obtained from the author.
Adapted from Neurology. 59(6), Goldenberg G and Strauss E, Hemisphere asymmetries for imitation of novel gestures, pp. 893–97, Copyright (2002), with permission from Wolters Kluwer

176 SECTION 2 cognitive dysfunction

Fig. 16.3 Pantomimes of tool use made by patients with left brain damage and aphasia. Top row: Brushing teeth. S. L. makes a correct pantomime: e hand is formed to a precision grip, the distance between the hand and the mound corresponds to the approximate length of a toothbrush, and the hand is moved parallel to the mouth. E. M. only points to the mouth. K. E. moves the hand parallel to the mouth but neither the shape of the hand nor its distance to the mouth consider the imaginary toothbrush. W. K. shows ‘body part as object’ and moves the index as if it were the toothbrush. Bottom row: Ironing. Again, S. L. shows a correct pantomime. e hand
is shaped as if it would rest on the handle of the at iron, the distance to the table corresponds to the height of the iron, and it is moved in parallel to the table. V. A. demonstrates the approximate shape of the at iron rather than pantomiming its use. A. S. slides the hand across the table as if it were the at iron. W. K. shows the correct grip and the correct movement but disregards the distance between the hand and the table.
Adapted from Goldenberg G. Neuropsychologie—Grundlagen, Klinik, Rehabilitation, Copyright (2007), with permission from Elsevier GmbH, Urban & Fischer, Munich.

Exclusion of insu cient comprehension is more di cult, how- ever, when patients outline the shape where the object would be used (e.g. a pipe in front of the mouth), or when they use the hand for symbolizing the object (using a body part as object, e.g. open- ing and closing index and middle nger for scissors). Even healthy people use such strategies and frequently prefer them to pure pantomime when communicating their needs to someone whose language they do not speak. ey can switch to pure pantomime when explicitly asked to do so, but when patients with aphasia per- sist, it remains arguable whether they understood the request to switch to the less e cient strategy.

Independence of apraxic errors from language comprehension becomes obvious when patients make searching movements for the correct grip or movement or when their pantomime displays some but not all distinctive features of the intended pantomime (e.g. pantomiming drinking from a glass with a narrow grip not accommodated to the width of the pretended glass). Fig. 16.3 shows examples of apraxic errors for pantomimes of tooth- brushing and ironing.

Qualitative assessment of a small number of pantomimes usu- ally su ces for a clinical diagnosis of apraxia. Quanti cation of its severity requires standardized instruments. Reliable quanti cation can be accomplished by crediting points for the presence of prede- ned features for each pantomime. Table 16.1 shows such features for the pantomimes displayed in Fig. 16.3.53

Localization of lesions

In right-handers with typical laterality of cerebral functions, dis- turbance of pantomime is bound to le hemisphere lesions and virtually always associated with aphasia.23,33,41,54–56 ere are,

however, single case reports of le -handed patients with right-

sided lesions who had apraxia for communicative gestures but no

aphasia.57–60 Contrary to widespread belief, there is no tight link

between disturbed pantomime and parietal lesions. Independence

of pantomime from integrity of the parietal lobe is demonstrated

by single case reports of patients with parietal lesions who can-

not imitate meaningless gestures but can produce pantomimes

awlessly,24,27 and has been con rmed by group studies analysing

lesions of patients with defective pantomime.45,53,61,62 A growing

number of systematic lesion symptom mapping studies indicate

indicate inferior frontal and temporal regions as crucial for panto-

mime. If there is extension into parietal regions at all it is con ned

to the parietotemporal junction in the angular and supramarginal gyrus.33,41,53,63,64

Table 16.1 Examples from scoring sheet for pantomime of tool use. One point is credited for each of the features listed in the middle and right column

Command: Show me how you would

Grip

Movement and/or Position

brush teeth with a toothbrush

lateral or narrow cylindrical

repetitive small amplitude movements in frontal plane

close to mouth but touching neither mouth nor face

iron with a at iron

narrow cylindrical with axis of grip parallel to table

movement in horizontal plane

distance to table appropriate for iron

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eoretical implications

A popular account of defective pantomime of tool use holds that patients have lost stored motor programmes required to direct the manual action of tool use,10,65,66 but there are several arguments why this view might be too simplistic and does not cover all possible sources of error. Patients who fail pantomiming the use of tools have not neces- sarily lost the motor programmes of real use; indeed, a majority of them can use the same tools correctly.67,68 Conversely, normal subjects can pantomime the use of objects which they are unable to manipulate in reality. For example, most persons can pantomime playing the vio- lin or a trumpet but only a minority master the motor programmes for their actual use. Nor does normal pantomime faithfully replicate the motor acts of actual use. For example, when pantomiming taking up a glass for drinking, most people open their hand to the approximate width of the glass, transport the hand to its mimed location, stop there and move the hand to mouth without changing grip aperture. By con- trast, for real grasping, the hand is initially opened wider than the glass and scaling is achieved by closing it around the glass in ight.

Such dissociations between pantomime and real use support the alternative suggestion that the manual action of pantomime is primarily intended to communicate the nature of the tool and its use.53,56,69 Details of the manual actions that are not necessary for comprehension may not be expressed, whereas details that illus- trate distinctive features of the object or its use may be exagger- ated. us, for the pantomime of grasping a glass, the width of the hand aperture demonstrates the width of the glass, and stop- ping the transport of the hand su ces for indicating the grasp. According to this view, the problems of apraxic patient concern retrieval, selection, and demonstration of distinctive features of objects and their use, rather than replication of motor pro- grammes for real use. Semantic knowledge about the tool and its use are necessary prerequisites for the selection of distinctive fea- tures whereas motor experience with actual use is not mandatory, as exempli ed by the possibility of pantomiming actions for which one has no motor competence.

e idea that failure in pantomime is mainly due to insu cient retrieval and demonstration of semantic knowledge ts well with the predominant location of responsible lesions in le inferior frontal and temporal lobes as these regions do have a central role for semantic memory also beyond tool use.70–72

Use of single tools

Misuse of everyday tools and objects was the subject of the rst printed use of the term ‘apraxia’.73 It remains an impressive symp- tom that may evoke a suspicion of general dementia. Patients may try to cut paper with closed scissors, eat soup with a fork, press the knife into the loaf without moving it to and fro, press the hammer upon the nail without hitting, and close the paper punch on top of the sheet without inserting the sheet.51,50,74–76 Apparently, they have lost their knowledge of how to use these highly familiar tools.

Clinical diagnosis

use (e.g. the sheet of paper kept in place by the examiner or the screw already partly placed into an unmovable support). Patients with right hemiparesis must perform with their non-dominant le hand, but their deviations from normal use surpass unmistakably the ineptness of a healthy person’s le hand.

Localization of lesions

In patients with unilateral brain damage, defective use of single familiar tools and objects is bound to le hemisphere damage and associated with aphasia.77,78 A group study of lesion symptom map- ping pointed to a crucial role for le parietal lesions, but clinical experience suggests that at least for lasting impairment of single tool use the lesions must be quite extensive and frequently encroach also on temporal and frontal regions.79

e association with le brain damage applies also to de cits on tests that assess the putative components of knowledge about how to use single tools (see below) but indicate that they depend on di erent regions within the le hemisphere. Whereas retrieval of functional knowledge depends on integrity of the temporal lobes, mechanical problem-solving is disturbed mainly by parietal lesions.79–81

eoretical implications

e gross misuse of familiar tools and objects evokes the impres- sion that patients have lost their knowledge about how to use them. ere are two possible sources of such knowledge. One of them is functional knowledge stored in semantic memory. It asso- ciates types of tools with their purpose, their ‘recipient’, and the action of their use. For example, a screwdriver serves for connect- ing or disconnecting parts, the recipient of its action is a screw, and the action is rotation. Retrieval of such functional knowledge can be probed without requiring the actual use of tools by asking sub- jects to match pictures of tools with pictures of other tools serving the same purpose or with pictures of the typical recipient of their action.81–84

An alternative source of knowledge about tool use is provided by mechanical problem-solving based on the direct inference of pos- sible functions from structure.78,81,84–87 e elements of mechan- ical problem-solving are not the prototypical functions of entire

88
tools but the functional compatibilities of their parts. Tools and

objects are segmented into functionally signi cant parts and prop-

erties, and combinations of these parts and properties with parts

and properties of other tools and objects are used for construction

of mechanical chains. Mechanical problem-solving has been probed

by confronting patients with novel tools and asking them to nd

out how to manipulate them or by presenting objects together with

an array of tools but without the tool usually employed, and asking

them to complete the task by using the tools in non-prototypical ways.78,79,81,84,87,89

ere is controversy as to which of these two sources is more important for supporting correct tool use.90,91 Probably both of them must be occluded to cause lasting de cits of single tool use in patients with patients with unilateral le -sided lesions.78

Multi-step actions involving several tools

and objects

In daily living, one rarely encounters a situation as in testing for use of single tools where one is handed a tool and asked to perform the

For clinical diagnosis one presents to the patient a familiar tool and, if the tool is not used upon their own body (e.g. a comb), also the object—or ‘recipient’—on which the tool acts (e.g. scissors and a sheet of paper, screwdriver and screw). Since many a icted patients are hemiplegic, tool and object must be prepared for one-handed

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CHAPTER 16 apraxia 177

178 SECTION 2 cognitive dysfunction

associated action on an adequately prepared ‘recipient’ of tool use. Typically, the use of single tools is embedded in a chain of actions involving several tools and objects and aiming at a superordinate goal. e need to keep track of completed and outstanding steps of actions, to avoid possible interferences between sequential action steps, and to maintain the superordinate goal against digressions create more opportunities for error than the isolated use of single tools. Whereas single tool use by healthy persons is virtually error- less, slips of actions in multi-step tasks are a common experience of everyday life, but they rarely attain the severity of errors that are committed by some patients with brain damage.

Clinical diagnosis

Assessment of multi-step actions with multiple objects trans- gresses the possibilities of routine clinical examination. In rehabilitation settings it is usually made by occupational thera- pists and concentrates on tasks that are important for everyday life like dressing or the preparation of meals and beverages.75,92–98 Error rates increase when patients are required to coordinate two tasks; for example, when preparing two courses of a meal in par- allel,99 or when they are confronted with unfamiliar and technical equipment.96 Rating of success is quite straightforward when the number of completed steps of actions is evaluated but becomes intricate and less reliable when qualitative classi cations of error types are attempted.95,100

Localization of lesions

In contrast to the tight link between le hemisphere damage and misuse of single tools, performance of multi-step actions with several tools and objects is about equally defective in patients with le -sided, right-sided, or di use brain damage.96,99,100 Comparison between studies testing patients with frontal and with posterior lesions does not con rm the intuitive expectation that problems should be par- ticularly severe in patients with frontal lobe damage.100,101

eoretical implications

e observation that execution of multi-step actions with sev- eral objects is vulnerable to brain damage in both hemispheres does not necessarily imply that the causes of failure are the same. Attempts to distinguish the types of errors committed by le and right brain-damaged patients did not yield convincing di er- ences,99,100 but analysis of correlations with other symptoms of unilateral brain damage support the existence of di erent causal mechanisms.

In patients with le brain damage, the severity of di culties on multi-step actions correlates with the errors on single tool use, with impairment of functional knowledge, and with severity of aphasia.31,96 Since patients with right brain damage do not have these additional symptoms, the correlations cannot apply to their errors on multi-step actions. In patients with right brain dam- age, success on multi-step actions is correlated with the severity of hemi-neglect although errors are not necessarily con ned to the le side of the working area.96,99 Since neglect is generally absent or mild in patients with le brain damage, it cannot— conversely—be a prominent cause for their di culties with multi- step actions.

A possible interpretation of these di erential correlations could be that problems of patients with le brain damage concern retrieval of ‘scripts’ specifying the sequence and nature of action

steps, whereas those of patients with right brain damage stem from insu cient maintenance of attention across the sequence of mul- tiple action steps and across the multiplicity of tools and objects involved in that sequence. is interpretation does not, however, exclude an additional contribution of less clearly lateralized apti- tudes like memory or problem-solving that are a ected by lesions on either side of the brain.

e heterogeneity of apraxia makes a complete examination of all possible manifestations a cumbersome endeavour that can hardly be ful lled within a routine neurological check-up. However, with some knowledge about the typical localization and clinical constellations underlying di erent manifestations it is possible to obtain relevant information within acceptable time limits and without a need for expensive technical equipment (see Box 16.2).

Apraxia in degenerative dementias

e overwhelming majority of studies on apraxia and hence of the evidence discussed in this chapter derive from patients with circum- scribed, mostly vascular, brain lesions. However, the decompos- ition of di erent components of apraxia allows speculations about their vulnerability to di erent variants of degenerative dementias, and the available empirical evidence allows some estimate of their plausibility.

Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by widespread expan- sion of neuronal degeneration resulting in a combination of

Box 16.2 Bedside diagnosis of apraxia

Apraxia is not a unitary disorder. Failure on one test of apraxia does not necessarily predict similar impairment on another. For example, pantomime of tool use may be de cient but imitation preserved or vice versa. Separate assessment of all possible vari- ants of apraxia certainly exceeds the temporal limits of bedside testing. One possible reaction to this restriction is the assess- ment of sum scores. For example, communicative gestures may be probed both on verbal command and on imitation,16,132,133 or imitation may be probed both for meaningful and meaning- less gestures,18 and their results are added up. Such sum scores permit a reliable decision whether the general level of a patient’s performance is within the range of healthy people, but they do not help to disentangle individual patterns of de ciencies and resources. Arguably, however, these individual di erences are important not only for the theory of apraxia but also for clinical decisions concerning possible therapies of apraxia.

A practical solution to these di culties is separate evaluation of a few clinically relevant domains of actions. I recommend testing imitation of meaningless static hand and nger postures, of pantomime of tool use and of use of single familiar tools. Observations of multi-step actions with multiple objects are usually beyond the limits of a clinical bedside examination, but can be made by prolonged assessment in daily life, and is o en noted by nurses, occupational therapists, or the family. Hence, it is important to question carers and healthcare sta about their observations of patients’ actions.

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impairments of multiple cognitive functions, consequently one References

would expect that the neural substrates underlying all aspects of apraxia can be a ected. Empirical studies have indeed revealed disturbances of imitation,102–108 communicative gestures,102,104– 106,109–112 use of single tools,102,113 and multi-step actions.97,114 e disturbance of single tool use is likely to a ect retrieval of func- tional knowledge as well as mechanical problem-solving.113,115 Nonetheless, it has repeatedly been found to be less severe than that of pantomiming tool use.109,110 In contrast to this relative preservation of single tool use, slips of actions and errors in daily life multi-step actions with multiple tools and objects are fre- quently among the earliest symptoms of AD reported by patients and their relatives.

Semantic dementia

Semantic dementia is a variant of frontotemporal dementia that

a ects le – more than right-sided inferior and anterior temporal

regions but spares parietal cortex.116 Comparison of this predi-

lection with the lesions sites causing di erent manifestations of

apraxia in patients with circumscribed brain damage (Fig. 16.1)

leads to the expectation that retrieval of functional knowledge

should be more severely a ected than mechanical problem solving

and imitation of meaningless gestures. Indeed, it has been convin-

cingly demonstrated that imitation of meaningless hand postures

can be intact, with preserved mechanical problem-solving but

defective functional knowledge.117,118 Preservation of mechanical

problem-solving possibly explains why real object use can be pre-

served in spite of loss of any semantic knowledge about the used

91,119–121 objects.

Corticobasal degeneration

Apraxia in corticobasal degeneration has been held to be the oppos- ite of apraxia in semantic dementia by sparing temporal but a ect- ing parietal components.118 However, the clinical picture is more intricate. Its analysis is complicated by the additional occurrence of prominent disturbances of motor control that have been labelled ‘limb kinetic apraxia’122 but do not ful l the criteria for ‘high-level’ apraxia. ey do not a ect both sides of the body equally and they interfere with any motor actions of the a icted limb regard- less of their cognitive demands.123–125 e belief that corticobasal degeneration selectively a ects parietal regions is also weakened by its overlap with progressive supranuclear palsy, frontotemporal dementia, and AD.116,126,127 ere is nonetheless good evidence for particularly severe impairments of mechanical problem-solving and imitation, but the sparing of other components of apraxia is much less regular.85,128

Posterior cortical atrophy

Posterior cortical atrophy is o en found on pathological diagno- sis to be a variant of AD. It begins with selective degeneration of parieto-occipital cortex and may present with very severe de cits of visual and spatial perception.129,130 Evaluation of apraxia is com- plicated by the deleterious in uence of visuoperceptual problems on tool use and imitation, but the few studies that looked for it have reported normal performance of communicative gestures includ- ing pantomime on command.129–131 In view of the severe damage to all established functions of the parietal cortex, this sparing is a strong argument against a crucial role of parietal regions for panto- mime of tool use.

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Psychiat. 2011;82:389–92. http://internalmedicinebook.com/

CHAPTER 16 apraxia 181

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CHAPTER 17

Acquired calculation disorders

Marinella Cappelletti

e basic components of number

and calculation processing

Number comprehension and production

Number comprehension is the ability to generate a semantic repre- sentation of numbers. e most common of such representations refers to the quantity associated with numbers, for instance ‘21’ indicates the numerosity of 21, that is, that there are 21 items. e quantity expressed by numbers is o en processed when compar- ing numbers, for instance when deciding which of two products is the most expensive. In doing so, we are usually faster and more accurate the more further apart two numbers are from each other; for example, £1.20 and £2.55, relative to £1.20 and £1.15. is phe- nomenon is referred to as ‘distance e ect’.1 Besides quantities, num- ber comprehension may, of course, also concern numbers used as verbal labels, for instance ‘21’ could refer to a bus number or the age of consent.2,3

Number production is the process of converting numerals’ seman- tic representation—for example, the numerosity of 21 items—onto an output format, most commonly the Arabic format, for exam- ple, the two-digit number ‘21’ and the verbal format, for example, ‘twenty-one’. e transformation of numbers from one format to another is also referred to as ‘transcoding’.4–6

Calculation

Oral and written arithmetical operations require a set of speci c and independent processes to be performed. ese include:

. (i) Processing of arithmetical symbols, i.e. +, ×, –, ÷

. (ii) Retrieval of arithmetical facts, such as ‘3 + 3 = 6’ or ‘3 × 3 = 9’.

. (iii) Execution of calculation procedures, which consist of the spe- ci c algorithms required to solve multi-digit calculation; for example, in written multi-digit multiplications the rightmost digit of the lower number is multiplied by the upper number starting from the rightmost digit;7–9 other rules can be carry- ing (e.g. in ‘23 + 19’) and borrowing (e.g. in ‘23 – 19’).

. (iv) Arithmetical conceptual knowledge, namely the understand- ing of the principles underlying arithmetical facts and proce- dures, like the principle of commutativity (e.g. ‘a + b’ = ‘b + a’).

Localization of brain lesions in number

and calculation disorders

An overview of both group studies and single-case studies has suggested that the majority of patients with number production

and/or number comprehension impairments had le posterior lesions almost always involving the parietal lobe.10,11 Likewise, most patients with arithmetical fact retrieval impairments had lesions mainly implicating the le parietal lobe.

e neuropsychological evidence suggesting the involvement of the parietal lobe in numerical processing has been corrobo- rated by neuroimaging studies showing that these brain regions are the most strongly activated in tasks requiring number pro- cessing.12–15 However, it is important to observe that not all pari- etal lesions result in numerical impairments.10,16 For instance, only about 20 per cent of patients with le parietal lesions show numerical de cits,17 possibly because other brain regions are able to compensate when the parietal lobes or other number areas are damaged.18

Number impairments can also occur following lesions to brain areas di erent from parietal. For example, damage to the frontal lobes o en leads to impaired calculation skills,7,19,20–23 as well as disorders in quantity processing.24–26 Similarly, damage to sub- cortical areas, especially the basal ganglia, can lead to impairment in quantity processing, arithmetical fact retrieval, and conceptual knowledge.27–30,32,33

Selective impairment of number processing

and calculation

Patients may present with speci c impairment in either the pro- cessing of numbers, or in calculation, or both. Table 17.1 provides an overview of the whole range of potential de cits that can be observed in acalculic patients.

Here the most commonly occurring number impairments are brie y described, speci cally a ecting: (1) number transcoding; (2) quantity processing; (3) calculation, which in turn may concern the processing of arithmetical signs, simple facts, procedures, or arithmetical conceptual knowledge.

Impairments of number transcoding

Several studies have reported patients with disorders in reading and writing numbers.5,6,34,35 e analysis of the errors made by patients when reading or writing numbers has allowed the identi cation of two major cognitive processes within number transcoding. One of these—syntactic—involves the speci cation of the relationship among the elements of a number or number class; for instance, to read number ‘600’, the correct number class (hundred) needs to be retrieved. Syntactic errors consist of selecting the wrong number class; for example, number ‘600’ read as ‘sixty’ (see reference 33 for a clear description of patient SF making syntactic errors).

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184 SECTION 2 cognitive dysfunction
Table 17.1 Overview of the potential disorders of (A) number

processing and (B) calculation

the integrity of the mental number line is with a bisection task, which consists of orally presenting two numbers (e.g. ‘1’ and ‘5’) and asking which number falls in the middle. Le -sided neglect patients with right hemisphere lesions typically select a number which is shi ed towards the right relative to the correct middle one; for instance, they state that ‘4’—and not ‘3’—is mid-way between ‘1’ and ‘5’.48–51 is performance mirrors the classical bias that neglect patients show when bisecting physical lines, although their performance in number bisection also depends on working mem- ory resources49 and on the orientation of the physical and number lines.48

Impairments of calculation

Each of the di erent cognitive processes involved in calculation (arithmetic symbols, facts, procedures, and conceptual knowledge) is functionally independent and di erentially susceptible to brain damage. Examples of selective impairments in these components of calculation are discussed below.

Disorders of arithmetical symbol processing

Very few cases with a selective impairment in processing arithmet- ical symbols have been reported.53,54 For example, Laiacona and Lunghi54 investigated a patient who misnamed and misidenti ed the arithmetical signs and performed written arithmetical opera- tions according to their misidenti cation; for example, the patient systematically added the times (see Fig. 17.1a).

Disorders of arithmetical fact retrieval

Several patients have been documented with a selective impair- ment of arithmetic fact retrieval. Typically, these patients have severe di culties in performing very simple single-digit addition, subtraction, multiplication, or division problems. ey may pro- duce errors such as ‘5 + 7’ = ‘13 roughly’, and their response times tend to be abnormally slow (e.g. >2 seconds).8,28,55,56 eir errors can be classi ed as: operand, if the incorrect answer is correct for a problem that shares one of the operands (e.g. 6 × 5 = 25); opera- tion, if the incorrect answer is correct for a problem involving the same operands but a di erent operation (e.g. 3 + 4 = 12); table, if the incorrect answer is the product of two other single digit numbers (e.g. 4 × 4 = 25); and non-table, if the incorrect answer is not an operand, table, or operation error (e.g. 9 × 8 = 52).57,58 Patients who make these errors o en show intact knowledge of arithmetical principles and procedures; they are usually able to retrieve and apply the appropriate arithmetical steps to solve complex arithmetical problems and they can de ne arithmetical operations adequately.8,28,56 For these patients, everyday activi- ties such as checking their change or bank statement pose great di culties.

Disorders of calculation procedures

A few cases of selective impairments of calculation procedures show that patients may for example use un exible procedures when solving problems. For instance, patient MT with a le frontopa- rietal lesion due to a stroke systematically subtracted the smaller number from the larger one, irrespective of whether the larger digit was at the top or on the bottom line (see Fig. 17.1b).21

Other impairments in the use of calculation procedures may consist of misaligning the digit in multi-digit operations, of errors using carrying procedures in addition problems, or of not applying problem-speci c steps in the correct order.

A. Disorders of number processing

Disorders of number production

Disorders of lexical processing

Disorders of syntactical processing

Disorders of number comprehension

Disorders of cardinal number meaning

Disorders of sequence number meaning

B. Disorders of calculation

Disorders of arithmetical symbol processing

Disorders of arithmetical fact retrieval

Disorders of calculation procedures

Disorders of conceptual knowledge

e other type of process—lexical—involves manipulation of individual elements in the number; for example, to read num- ber ‘600’, the correct class (hundred) and the unit (6) have to be retrieved. Lexical errors consist of the incorrect production of one or more of the individual elements in a number, such as number ‘600’ read as ‘seven hundred’ (see reference 8 for a clear description of patient HY making lexical errors).

Another frequent type of error in writing numbers to dictation or from a written input has been referred to as ‘intrusion errors’ and observed both in patients with dementia of Alzheimer type as well as with focal brain lesions.35,36 ese errors con- sist of reproducing part of the input code into the output one; for instance, the Arabic number ‘75’ written as ‘SEVENTY5’ or ‘seventy’ as ‘7ty’. Some authors explained these errors in terms of the combination of an impaired transcoding mechanism and impaired inhibitory processes,36 or impairment in selective attention capacities.37

Impairments of quantity processing

A few studies have reported patients with a basic failure in under- standing and processing the quantity indicated by numbers. 24–28,38–45 For example, patient NR with Alzheimer’s disease could no longer understand Arabic numerals, was unable to point to the larger of two Arabic numerals (e.g. ‘34 vs 78’ or ‘26 vs 23’), and had lost the ability to match spoken number names to the correspond- ing Arabic numeral.43

Another very profound acalculic patient with a le parietal lesion due to a stroke (CG) retained the ability to process abstract quan- tities, but completely lost the meaning of all numbers above four. For example, she was unable to say how many days there were in a week or whether 7 or 10 was the bigger number.40 Her de cit was so pervasive that it seriously limited her activities of daily living such that, for instance, she could no longer deal with money or check her change, make phone calls, use a calendar, or read the time, although her intellectual skills, language, memory, and visuospatial abilities were largely preserved.40

A few case studies have recently focused on quantity processing in hemispatial neglect patients,47–51 o en testing whether neglect may a ect the mental ‘number line’, a metaphor used to represent numbers as oriented from the smaller to the larger.52 A way to test

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a) Performance of patient EB, with a selective impairment in arithmetical symbol processing such that he systematically plussed the times.54

48 59 ×67 ×29 115 88

b) Performance of patient MT with a calculation procedure impairment such that he consistently subtracted the smaller from the larger number.21

923 171 –644 –48 321 127

c) Performance of patient BE with impaired arithmetical fact retrieval but preserved conceptual knowledge. When asked to perform arithmetical problems such as 8 × 6, he adopted the strategy below.30

8 × 10 = 80; 80 ÷ 2 = 40; 40 + 8 = 48

d) An example of a semantic dementia patient’s (IH) performance in solving a multi-digit multiplication operation.59 e patient spontaneously developed a series of procedures: rst, number ‘531’ was decomposed into the subparts ‘500’, ‘30’, and ‘1’; the following steps were then used, indicated by numbers in squared brackets. Step [1] is ‘27 × 1’. Steps [2] to [4] show how ‘327 × 30’ was obtained. Step [2] is ‘327 × 5’; [3] is ‘327 × 10’, and [4] is ‘327 × 30’; [5] is ‘327 × 100’ obtained through multiple additions; [6] is ‘327 × 500’, again obtained through multiple additions. Finally, [7] is (327 × 500) + (327 × 30) + (327 × 1). e nal result is correct.

Fig. 17.1 Examples of speci c impairments or preservations of calculation skills. (a) Adapted from Neuropsychologia. 35(3), Laiacona M and Lunghi A. A case of concomitant impairment of operational signs and punctuation marks, pp. 325–32, Copyright (1997), with permission from Elsevier; (b) Adapted from Cortex, 32(3), Girelli L and Delazer M. Subtraction bugs in an acalculic patient, pp. 547–55, Copyright (1996), with permission from Elsevier; (c) Source data from Brain. 117(4), Hittmair-Delazer M, Semenza C, and Denes G. Concepts and facts in calculation, pp. 715–28, Copyright (1994), Oxford University Press; (d) Adapted from Cognitive Neuropsychology. 22(7), Cappelletti M, Morton J, Kopelman M, and Butterworth

B, e progressive loss of numerical knowledge in a semantic dementia patient: A follow-up study, pp. 771–93, Copyright (2005), with permission from Taylor & Francis.

Disorders of arithmetical conceptual knowledge

Delazer and Benke28 described a patient (JG) with a le parietal lesion who had lost arithmetical conceptual knowledge, de ned as ‘an understanding of arithmetical operations and laws pertaining to these operations’ (reference 30 at p. 117). Hence, JC could cor- rectly retrieve the result of operations such as ‘3 × 9’ from memory but was unable to recognize that the same multiplication problem could be transformed in repeated additions (i.e. 3 × 9 also equals 9 + 9 + 9), and she could not use basic principles such as commuta- tivity in multiplication (i.e. 4 × 12 = 12 × 4).28

e opposite side of the dissociation—intact conceptual knowl- edge and impaired fact retrieval—has been reported in a few single- case studies.30,31 For example, a patient who su ered from a le basal ganglia infarct could not solve from memory problems such as ‘8 × 6’ but he could adopt the following strategy: 8 × 10 = 80; 80 ÷ 2 = 40; 40 + 8 = 48 (see Fig. 17.1c).15,23,30 Similarly, a seman- tic dementia patient with le temporal lobe degeneration showed well-preserved understanding of arithmetical concepts despite the severe loss of arithmetical facts (see Fig. 17.1d).59

Selective preservation of number

processing and calculation

It is now well established that numerical and calculation abilities can be largely independent from other cognitive abilities, such as general intellectual skills,60 language,61,62 short-term memory,63 and semantic knowledge.59,64–70 One of the most striking dissocia- tions is observed in patients with semantic dementia who typically present with severe impairment in understanding the meaning of words and the use of objects, but with good understanding of numerical concepts and arithmetical operations.59,64–70

Assessment of acalculia

A list of the main numerical and calculation tasks that can be used for the diagnosis of acalculia is provided in Table 17.2. e diag- nosis of acalculia relies on establishing with appropriate tools the presence of a number processing and/or calculation impairment in a patient who premorbidly had acquired normal numeracy skills. e diagnosis of acalculia can be made only when one can exclude that the de cit in numeracy skills is not a secondary consequence of other cognitive de cits, such as generalized impairments in language, attention, visuospatial functions, or other cognitive skills are not underpinning the failure of number processing and calculation.

A formal assessment of a patient’s numeracy skills can be based on number reading, writing to dictation, and repetition tasks, with numerical stimuli presented as either Arabic numerals (8), written (eight), or spoken number names (‘eight’). Patients can be simply asked to read, write, or repeat the numeral presented. Comprehension of number quantity is usually assessed with a magnitude comparison task, where patients are asked to indicate the larger of two numbers (e.g. 6 vs 9) while response times are recorded. Another test of number comprehension is the ‘number composition task’ whereby subjects have to compose the value of a given number using poker chips ranging in value from 1 to 500 (e.g. number ‘52’ made of tokens 20, 20, 10, 2).

Calculation skills can be assessed by tests exploring knowledge of: arithmetical signs, for example by asking patients to read, point

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CHAPTER 17 acquired calculation disorders 185

186 SECTION 2 cognitive dysfunction
Table 17.2 Suggested numerical and calculation tasks for the diagnosis of acalculia

Function

Task

How?

Sequence

Counting

◆ Reciting numbers forwards or backwards by 1 or 2 from 1 to 20 or 20 to 1

◆ ‘What comes next’? Given a number what comes before or after it

Transcoding

Writing Reading

◆ Numbers to dictation (e.g. from spoken ‘two’ to written TWO or 2)

◆ Numbers from Arabic (2) into alphabetic format (TWO) or vice-versa

◆ Numbers from Arabic (2) or alphabetic (TWO) format

Quantity

Number comparison
Comparison of non-symbolic discrete quantity

Comparison of non-symbolic continuous quantity Number composition task

◆ ‘Which is bigger: 6 or 9’? Both accuracy and RTs to be collected

◆ ‘Which display contains more dots’? To be presented with either few eshed dots or
with many for unlimited time to test enumeration and counting respectively

◆ Space or ‘amount’ discrimination (e.g. which line is longer or which container has more liquid?)

◆ Composing the value of a number using poker chips ranging in value from 1 to 500

Calculation

Arithmetical signs Simple facts Procedures

◆ Read, point, and write the arithmetical signs

◆ Solve single-digit arithmetical problems mentally (e.g. 4 + 2, 3 × 4, or 5 – 2)

◆ Solve multi-digit calculation (e.g. 294 + 12 = 306), either in written form or orally

and write signs; arithmetical facts, by asking patients to solve orally presented single-digit arithmetical problems (e.g. 4 + 2, 3 × 4, or 5 – 2); and arithmetical procedures, by asking them to perform multi-digit calculation, such as 294 + 12 = 306, either in written form or orally.

A few test batteries that evaluate numerical skills in detail are available. One of these is the EC301 composite battery or its shorter form (EC301R),71–73 and a more recent set of numerical and cal- culation tasks have been developed for which normative data have also been provided.74 Standardized tests that evaluates mental cal- culation are the Graded Di culty Arithmetic (GDA) test, which comprises 24 multi-digit addition and subtraction problems.17 and the arithmetic subtest of the WAIS-R.75

Error analyses in reading and writing numerals (lexical or syn- tactical), and in retrieving arithmetical facts (operand, operation, table, and non-table errors) are usually not included in standardized tests but can be very useful additions to the assessment, in so far as they can provide information about the nature of the impairment.

Conclusion

Acalculia is a heterogeneous set of disorders consisting of impair- ments in processing numbers, in calculation or both. Speci c com- ponents of number and calculation have been presented in this chapter in the context of both normal functioning and impaired performance following cerebral damage. is includes disorders in transcoding processing, quantity processing, in calculation, or in their sub-components. A few cases of selective preservation of number processing have also been brie y outlined. A short descrip- tion of lesion localization in number and calculation disorders was provided, which indicates that parietal areas are the most relevant brain regions for numeracy impairments. Finally, some guidelines for the assessment of acalculia have been proposed.

Acknowledgements

is work was supported by a Royal Society Dorothy Hodgkin Fellowship.

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Introduction

and can be mapped directly onto a lexicon of how that word sounds and thus what sounds are required to produce a spoken form of the word. is is also called the ‘direct’ route, as the reader moves straight from the visual word form to the spoken word form with- out any intervening analysis; for example, breaking the word down into components such as syllables. Whether this route interacts with the semantic system in a serial or parallel manner is still debated. When this route is damaged patients have problems with ‘exception words’ such as [pint], misreading it to rhyme with [mint]. is is called surface dyslexia.6

e second route is called the ‘nonlexical’ or ‘sublexical’ route, whereby words are read by breaking down the written form into its constituent parts (graphemes) and applying learned rules as to how these elements sound. ese sounds are assembled in order, and the word is read out. is route is also referred to as ‘indirect’ because the word form has to be dissembled before it can be read aloud. is route allows one to read novel words, and this is tested in adult readers by asking them to read non-words like [mune]. Patients with damage to this route have phonological dyslexia and cannot read non-words normally.7 ere is a more severe form of dyslexia called deep dyslexia which can be thought of as phonologi- cal dyslexia with added impairments.8 Table 18.1 depicts the three canonical types of central alexia and the common error types when reading test words aloud.

We will now deal with each of the three main types of central alexia.

Surface dyslexia

is condition was de ned by Marshall and Newcombe in a land- mark paper as a, ‘partial failure of grapheme-phoneme correspond- ence rules’.6 ey discussed two cases with surface dyslexia, giving examples of errors such as [lace] read as ‘lass’ and [island] read as ‘izland’. e concept of surface alexia has been shaped primarily by patients with degenerative disorders as opposed to those with focal injury such as stroke. Indeed stroke patients with ‘pure’ surface alexia are rare. ere appears to be pathological gradient: dementia > head injury > stroke associated with the condition, which perhaps suggests that multifocal damage is usually required to cause it. We will now consider in chronological order the key reports on this topic, and the related issue of semantic dementia, which have in u- enced our understanding.

In a famous paper in which she described three patients with semantic dementia (SD), Elizabeth Warrington argued they all had a selective impairment of semantic memory.9 She used Tulving’s de nition of semantic memory, ‘that system which processes, stores and retrieves information about the meaning of words, concepts

CHAPTER 18

Disorders of reading and writing

Alexander P. Le

Reading and writing are o en not tested in clinical practice, with speaking and listening much higher up the clinician’s bedside language-testing algorithm. However, perhaps because reading and writing develop later in life and seem to require more e ortful prac- tice to master, they quite o en break down earlier than speaking or listening do and thus can be more sensitive markers of disease, especially in the dementias. Disorders of reading and writing have also shaped how we think about normal brain function. Perhaps more than in any other cognitive domain, the models of how the normal reading system works have been built upon a mass of single cases and case series, all delineating the di erential ways reading breaks down in acquired brain injury.

Classi cation of acquired alexia

First we must distinguish the acquired alexias (the subject of this chapter) from the more common developmental dyslexias. We also note that the terms alexia and dyslexia have come to be used interchangeably, although it is perhaps preferable to use ‘alexia’ for acquired causes (where the normally developing language system has become damaged by an acquired disorder such as stroke or dementia) and ‘dyslexia’ for the developmental disorder, where, for reasons still not fully understood, reading fails to become normally instantiated. e two cannot be completely dissociated as people with developmental dyslexia are in no way protected from the usual causes of acquired alexia. In such cases it can be harder to clas- sify patients behaviourally as the standard clinical tests of reading assume normal pre-existing reading behaviour. ose interested in developmental dyslexia may wish to refer to the following works.1,2

e central alexias

Central alexia is an acquired reading impairment in the context of a generalized language disorder. Dejerine used the short-hand ‘alexia with agraphia’3 to di erentiate from cases of acquired alexia where only reading ability is a ected—‘alexia without agraphia’.4 e lesion site for Dejerine’s rst case (le MCA territory infarct with involvement of the angular gyrus) turned out to be prescient as the vast majority of aphasic, and thus central alexic, patients have lesions a ecting this vascular territory.

e neurological classi cation has not moved on much from Dejerine’s time. However, in the late 1970s neuropsychologists were developing di erent models to explain normal reading behaviour by seeing how the process breaks down in patients with focal dam- age. In their simplest form, all of these models propose two ways that the reading brain can get from the written to the spoken word.5 e rst is a ‘lexical’ route where each word is recognized as a whole

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190 SECTION 2 cognitive dysfunction

Table 18.1 e canonical three types of central alexia (rows) are characterized by the lexical types of words (also known as part of speech) patients make errors on ( rst three columns). Functors are a special class of word (such as a preposition, article, auxiliary, or pronoun) that chie y expresses grammatical relationships, and have little semantic content of their own. e errors themselves (last four columns) are also considered diagnostic. Patients with surface dyslexia regularize irregular words [pint] read to thyme with [mint]. Patients with deep dyslexia often make semantic errors,

for example, [little] read as ‘small’. Morphological errors are formed by the deletion, addition, or substitution of an a x, for example, [govern] read as ‘governor’. Visual errors usually occur when a letter or two has been misperceived, for example, [spy] misread as ‘shy’

* = key element; a = deep dyslexics often show concreteness e ects so highly imageable words are read best, then abstract words, then functors and lastly non-words. Irregular words can be of high or low imageability.

Part of speech/Lexical class e ects

Error types: reading aloud

Subtype

Irregular

Non-words

Functors

Semantic

Morphological

Visual

Regularization

Surface

Errors*

Yes

Yes*

Phonological

Errors*

Yes

Deep

Variablea

Errors

Errors*

Yes*

Yes

and facts’,10 which is di erentiated from episodic memory because it is, ‘a common pool of knowledge not unique to the individual’. Of course semantic memory is built up through experiential memory, but once established, it appears to be largely anatomically dissocia- ble from structures supporting episodic memory.

e main thrust of Warrington’s paper was on amodal semantic de cits, that is, regardless of whether the stimuli were visual or audi- tory in nature the patients had great trouble saying what they were (both naming and description), in the absence of a low-level per- ceptual impairment. Although not directly compared, Warrington noted that spoken and written word were equally a ected in terms of accessing meaning. e patients could correctly read aloud writ- ten words, just not say what they meant, ‘the mechanical aspects of reading were remarkably well preserved; words which were mean- ingless to the patients could be correctly read and written’ (refer- ence 9, p. 654).

Beyond this she also highlighted that irregular words presented a particular problem for these SD cases: ‘ at words which are spelt in a bizarre manner presented di culty for these patients is con- sistent with the notion that the direct graphemic route was inop- erative. at phonetically spelt words could be read with relatively little di culty indicates that reading by the phonetic route alone can be quite e ective.’9 e suggestion being that these patients can ‘read’ aloud words they cannot understand by applying grapheme to phoneme rules. Read is in inverted commas because although sounding correct, the words frequently were meaningless to the patients, and the aim of reading is to comprehend the writer’s message.

Is it possible that only a single class of words is a ected in SD? It seems not, as Patterson and Hodges reported a series of six patients with SD and demonstrated an interaction between irregularity and frequency, with low frequency exception words being considerably harder to read,11 suggesting that the patients were able to correctly read such words if they had been exposed to them enough prior to the onset of their illness. ey ended their paper by speculating over the more common syndrome of Alzheimer’s disease (AD), noting that reading errors seem more variable in this group. As if to answer this call, Arsland et al. published a paper that contained data from 16 patients with AD and an average disease duration of 3.4 years.12 ey tested the lexical (direct) and non-lexical (indirect) routes and showed that AD patients were signi cantly worse than controls for both routes in terms of both accuracy and reaction time. Moreover,

reading performance correlated with severity of dementia as judged by mini-mental state examination (MMSE)13 scores.

What about reading in progressive non- uent aphasia (PNFA), a form of primary progressive aphasia (PPA)? A group study was published in 1997 on an impressive 112 cases.14 ey reported that reading was only mildly a ected, with de cits rarely occur- ring before the 4th or 5th year post-presentation and 80 per cent of patients showing no de cit at all; although they employed clinical reading tests that may be insensitive to early impairments. More recently, Hodges and colleagues compared the neuropsychological pro le of patients with AD, SD and the progressive non- uent form of PPA with 19 cases in each group and patients were matched for age.15 Reading was only assessed with the National Adult Reading Test (NART) which comprises 50 irregular words of varying di – culty.16 As expected, SD patients were signi cantly worse than the other two groups on this test, who in turn were not signi cantly worse than controls. Unfortunately, no other reading tests were included, so this study adds little on the reading front to what was already known.

As an aside the NART is commonly used to provide an estimate of premorbid IQ following brain damage or disease, as the ability to read exception words correlates highly with intelligence measures (also in non-injured individuals). is means, of course, that the ability to read low frequency irregular words varies signi cantly in the normal population, a factor that is very important to take into account when assessing single patients.

e standard explanation for surface dyslexia is that regulariza- tions suggest a lack of semantic knowledge, which begs the ques- tion: are surface dyslexia and semantic impairments inextricably linked? Yes, according to the largest study to date on reading in patients with SD (100 datasets on 51 patients), which was published in 2007.17 ey took longitudinal behavioral measures of reading ability and semantic knowledge and found strong correlations between performance on semantic tests and overall reading abil- ity as well as regularization errors on irregular words. Interestingly, the patients were impaired on non-word reading too, even the rela- tively mildly impaired cases, although these scores did not correlate signi cantly with semantic knowledge. e relationship between composite semantic score and low-frequency exception word read- ing accuracy are impressive with R2 = 0.5 (Fig. 18.1). ey found the results so compelling that they dubbed the association between semantic dementia and surface dyslexia ‘SD-squared’.

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(a) 100
90 90

80 80

70 70

60 60

50 50

40 40

30 30

20 20

10 10

00 100 90 80 70 60 50 40 30 20 10 0

Composite Semantic Score (%)

(b) 100

CHAPTER 18 disorders of reading and writing 191

BC1 MA1 EB1 GC1

MG1

WM1

JP1

y = 0.613x + 26.792 R2 = 0.50

BC1 MA1 GC1

WM1 JP1

EB1

MA2 MA3

MG1

GC2 BC4

EB3 MA4 MA5

JP4

MA6

GC6

WM6
MG3

y = 0.6115x + 27.784 R2 = 0.48

Fig. 18.1 (a) Overall accuracy results for 100 observations of reading performance from 51 semantic dementia patients for low-frequency exception (LE) words according to level of semantic knowledge. e horizontal line represents two standard deviations below control performance on LE words; the vertical line represents two standard deviations below control performance on the composite semantic score. (b) Overall accuracy results for 75 observations of reading performance from 27 semantic dementia patients for low-frequency exception words according to level of semantic knowledge. Repeated observations for each patient are connected by lines to indicate progression over time.
Reproduced from Psychological Review. 114(2), Woollams AM, Ralph MAL, Plaut DC, et al. SD-squared: On the association between semantic dementia and surface dyslexia, pp. 316–39, Copyright (2007), with permission from the American Psychological Association.

Phonological dyslexia

Phonological dyslexia—in its Platonic form—serves as a coun- terpoint to surface dyslexia. e syndrome was comprehensively described in 1983 in a patient who su ered a large le MCA stroke.18 e patient was anomic and had a severe impairment of phonological memory (a digit span of only one) with auditory comprehension of speech also a ected. His single word reading was a ected, but with most grammatical classes of words equally a ected (nouns, adjectives, verbs and functors (a word that chie y expresses grammatical relationships and has little semantic content of its own) all read between 86–93 per cent correct). ere was no e ect of regularity. He was especially poor on non-words, unable to read any (0/20) of the four or ve letter examples correctly. His errors were mainly close phonological non-words, but he did attempt to turn a few into real words (e.g. [sweal] read as ‘sweat’).

He was able to read su xed words as well as the other classes of words, but could not read the su xes alone (e.g. [ly] read as ‘why’). is, combined with his ability to read functors, di erenti- ated his reading behavior from that of patients with deep dyslexia (Table 18.1). In its purest form (an inability to read non-words only) phonological dyslexia looks like a neurological curiosity that should have little, if any, impact on normal reading. However, it means that new words will be hard to acquire and if there is any ‘bleed’ into other classes of word being a ected, then these may be di cult to re-learn.

An important and as yet still unresolved issue is what is the root cause of phonological dyslexia. Is it in fact caused by a generalized phonological impairment? e most illuminating study to have examined this question used data from 31 stroke patients.19 A key analysis investigated the relationship between phonological pro- cessing (here derived as a composite score taken from six tests taken from the PALPA or Psyhcolinguistics Assessments of Language Processing in Aphasia battery)20 and scores on real and non-word

reading and writing (spelling to dictation). ey found strong correlations between the phonological composite score (PC in Fig. 18.2) and non-word reading and writing (r = 0.66 and 0.69 respectively) and even stronger correlations with real word reading and writing (r = 0.80 and 0.78 respectively). Overall, the phonologi- cal composite scores proved to be powerful predictors of written language performance, accounting for 67 per cent of the variance in reading accuracy and 61 per cent of the variance in spelling accu- racy. See Fig. 18.2.

A more recent study reported 16 patients with progressive non- uent aphasia (PNFA).21 Similar methodology was used to the SD squared paper mentioned above: namely, correlating phonological impairment (de ned a little unusually by error rates on spoken word picture naming, rather than on tests of phonological percep- tion) with real and non-word reading ability. All the patients had a central alexia of a pattern in which both low-frequency exception word and non-word reading were comparably compromised. ey found that their phonological error rate signi cantly correlated with reading performance. e strength of this relationship was similar for low-frequency exception words and non-words, suggesting that reading de cits for these two types of items in this disorder shared a common cause: a progressive impairment of phonological pro- cessing. us the majority of the evidence in the literature points towards a ‘central’ phonological de cit in phonological alexia.

Lastly, a nice imaging study in 26 patients with PPA, clearly high- lights the two di erent reading streams.22 is was a voxel-based morphometry study which means that reading behaviour (as a continuous variable) was correlated with grey matter density (as a continuous variable). In this case the correlation was a positive one, that is, the better the patients were on a given reading task, the greater their grey matter density. Exception word reading (irregular words, read via the direct or lexical route) correlated with greater

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100 90 80 70 60 50 40 30 20 10 0 Composite Semantic Score (%)

LE Accuracy (%)

192 SECTION 2

cognitive dysfunction

100 90 80 70 60 50 40 30 20 10 0

(a) Independent Effect of Exception Word Reading

Word Read Word Spell Non-word Read Non-word Spell

<25th

25–50th 50–75th PC Scores (Percentiles)

>75th

(b) Independent Effect of Pseudo-Word Reading

Fig. 18.2 Reading and spelling performance for subgroups of patients with peri-sylvian lesions falling into di erent quartiles based on the distribution of phonological composite (PC) scores for the peri-sylvian cohort (x-axis), plotted against reading and spelling performance (y-axis) across words and non-words. ese graphs can be conceived of as a set of performance/resource curves with the x-axis re ecting the amount of phonological resources available to the di erent patient subgroups.

Reproduced from Cortex. 45(5), Rapcsak SZ, Beeson PM, Henry ML, et al. Phonological dyslexia and dysgraphia: cognitive mechanisms and neural substrates, pp. 575–91, Copyright (2009), with permission from Elsevier.

(more normal) grey matter values in the anterior and lateral tem- poral lobe, while non-word reading performance (read via the indirect or sub-lexical route) correlated with greater (more normal) grey matter values in the inferior parietal regions (Fig. 18.3).

Deep dyslexia

Deep dyslexia is related to phonological dyslexia but in its canonical form is clearly di erent. Patients make semantic errors when read- ing real words which are striking when they occur. From a 1930 account, the patient was shown the word [Cat] and, a er each error, was asked to try again, ‘Mice … Dog … Rat …’.23 Deep dyslexic patients also have particular problems with function words, either being unable to read them at all, making a regularization error, [o ] read as ‘ov’, or producing a di erent functor e.g. ‘on’. e usual pat- tern of increasing di culty that patients with deep dyslexia have, in terms of part-of-speech is: concrete > abstract > functors > non- words. ese phenomena all suggest a problem with the way that the semantic system supports reading in these patients. Despite incorrect oral reading, are these patients able to extract the correct meaning from misread words? e answer appears to be ‘Yes’.8

e majority of studies on deep dyslexia have focused on the semantic system, but such patients o en make morphological errors too, e.g. [swimmer] misread as ‘swim’. It has been proposed that this is actually a type of visual error driven by the target word’s low con- creteness or frequency.24 So at their extremes, while there is overlap in terms of impaired non-word reading, phonological and deep dys- lexia appear separable with deep dyslexics making semantic errors on word reading, being signi cantly worse at functors, and making morphological errors on genuinely su xed words. Or are we seeing the e ects of publication bias where cases that represent two ends of a clinical spectrum get reported, while those ‘messy’ cases that form a possible middle ground are missed out? In other words, do phono- logical dyslexia and deep dyslexia exist on a continuum?

Fig. 18.3 Brain areas showing (a) independent e ect of exception word reading; (b) independent e ect of pseudo-word reading. Maps of signi cant correlation are superimposed the 3D rendering of the Montreal Neurological Institute standard brain.

Reproduced from Neuropsychologia. 47(8–9), Brambati SM, Ogar J, Neuhaus J, et al. Reading disorders in primary progressive aphasia: A behavioral and neuroimaging study, pp. 1893–900, Copyright (2009), with permission from Elsevier.

In almost all of the stroke patients that have been reported in papers discussed in this sub-section, there is little regard paid to where they were in terms of any potential recovery curve at the time of testing. Almost all were in the chronic phase (> 6 months post-stroke). e underlying assumption seems to be that lit- tle change is to be expected in their impairment pro le, but this is unlikely to be the case. Friedman pointed this out when she described ve patients whose reading evolved from deep to pho- nological.25 Crisp and Lambon Ralph examined 12 cases recruited from a local speech and language therapy service. e patients had all su ered a stroke and were recruited on the basis of demonstrat- ing the following when reading aloud: (a) a lexicality e ect, (b) an imageability e ect, or (c) production of semantic paralexias. e rst 12 ful lling these criteria were studied with a large battery (over ten) of psycholinguistic tests, mainly from the PALPA. In short, they could nd no clear cut-o s between phonological and deep dyslexia. ey proposed a two-dimensional space in which acquired dyslexic patients might be found (Fig. 18.4).26 is sug- gests continua between all the main groups.

e peripheral alexias Hemianopic alexia

Hemianopic alexia is the most peripheral of the peripheral alexias. It is also the commonest. In its most simplistic form, it can be thought

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Exception Word Pseudo-Word Age Sex

Mean % Correct

Surface dyslexia

Phonological Degree of phonological impairment

Fig. 18.4 e positioning of the acquired dyslexias within a phonological–semantic space.
Courtesy of Professor Matt Lambon Ralph.

of as a purely visual impairment that impacts upon text reading performance because the visuo-motor system requires visual infor- mation away from the point of xation in order to plan e cient reading eye movements. Patients with homonymous, hemi eld defects that encroach within ve degrees of xation, which the majority do,27 can be expected to have some form of hemianopic alexia; although those with le -sided hemianopias are less likely to be impaired than those with right-sided hemianopias when reading languages that are written (and thus read) from le -to-right. e amount of visual sparing is important as there is a clear, monotonic relationship between this and reading speed.28

erapy for this form of alexia has the strongest evidence base of all acquired alexias. Unlike all the others, visual word form and lin- guistic processes are preserved, so the various therapies are all based around retraining eye movements. ere are at least ve examples of these with e ect sizes ranging from 0.2–1.28–32 Both voluntary and involuntary (optokinetic nystagmus) saccades appear to work, with the latter available on a free-to-use website <http://www.read- right.ucl.ac.uk> that has been shown to be clinically e ective.33

Pure alexia

Pure alexia is a selective disorder of reading, caused by damage to occipito-temporal structures in the dominant hemisphere. e disorder is selective in the sense that other language functions, including writing, are intact. However, subtle visual de cits have been reported to accompany pure alexia in many patients.34–36 For a diagnosis of pure alexia to be made, a reading de cit evi- dent in single word reading should be present, while writing and other language functions (speech production and comprehension) should be intact. Typically, patients read slowly, but can identify most letters, words, and nonwords correctly. In the more severe condition of global alexia, word reading and letter identi cation is very impaired, and most words and nonwords cannot be identi ed. Reaction times in reading are slower than normal even for short words, and many authors also use the presence of a word length e ect (WLE: a linear increase in RT with the number of letters in a word) as a diagnostic criteria.

Pure alexia is in many ways a simple syndrome: it is the result of focal brain injury, a ects only one function (word recognition), and commonly patients have residual function so that reading is not abolished but merely de cient. It would seem, then, that pure alexia should be an easy target for rehabilitation e orts. Unfortunately, it has proven rather di cult to help patients with pure alexia read better. Of course, many patients spontaneously use a letter by let- ter (LBL) strategy to compensate for their de cit, but this strategy does not allow them to read uently, and many patients report that they do not read for pleasure, even years a er their injury, as it is too demanding. ere are a whole host of therapeutic approaches that have been tried with varying success.37 Because the condi- tion is rare, few groups studies have been published, although one cross-modal therapy (using audition to boost visual word form recognition) demonstrated small but signi cant (11 per cent) improvements in reading speed.38

Pure alexia, and indeed all the alexias discussed in this chapter result from damage to the le (‘dominant’) hemisphere. ere are, however, two forms of acquired reading disorders that may result from lesions to the non-dominant hemisphere, or bilateral dam- age: neglect alexia and attentional alexia. As the names imply, these de cits are thought to re ect attentional dysfunctions, rather than being core reading de cits. e reason for mentioning them here, is that these two forms of alexia are not necessarily accompanied by writing de cits, and could thus be included under the heading ‘alexia without agraphia’. ey are, however, diagnostics entities in their own right.

Neglect alexia is seen in patients with damage to occipito-parietal areas, most commonly in the right hemisphere. e core symptom of these patients is that they ignore the contralesional (le ) side of words and/or text. Neglect alexia is commonly seen in the con- text of more generalised unilateral neglect syndrome (inattention to contralesional space), but may in some instances be seen as an isolated symptom.39

Patients with attentional alexia have quite a curious de cit in reading: they may be relatively unimpaired in reading words, but unable to identify the constituent letters,40 quite the opposite of what is seen in pure alexia, where each letter in a word is identi- ed, before the word can be read. e core symptom of attentional alexia, migration errors, is almost never observed in pure alexia e.g. the words [win—fed] may be read ‘ n—fed’ or even ‘ n—wed’. e majority of patients have bilateral parietal damage.41

Posterior cortical atrophy

Patients with posterior cortical atrophy (PCA) o en present with reading problems, but they di er from patients with semantic dementia as their cortical atrophy starts posteriorly in the occipi- tal lobes rather than ventrally in the temporal lobes. Posterior cor- tical atrophy is usually caused by Alzheimer’s disease pathology but tends to present earlier than classical AD, in the 6th decade, with relative preservation of episodic memory.42 Presenting symptoms are usually visual in nature and can a ect any type of stimulus but reading makes such demands on the visual system that it is no great surprise that it is commonly a ected. Initially, errors tend to be visual in nature with crowding e ects, but as the disease process moves anteriorly, the ventral visual stream can be a ected leading to pure alexia-like errors (letter confusability).43 But this rarely pro- gresses to a central alexia, as by that point, patients are so visually disorientated as to preclude reading at all.

Normal reading

Global dyslexia

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CHAPTER 18 disorders of reading and writing 193

Degree of semantic impairment

Deep dyslexia

194 SECTION 2 cognitive dysfunction

Very occasionally, reading ability can be preferentially preserved in the face of quite impaired visuoperceptual and visuospatial func- tion (but central acuity must be spared), presumably via strong top-down in uences.44 If the process moves dorsally, as it o en does, then the parietal lobes become a ected, and this causes an extra set of problems with text reading because the patients suf- fer from visuospatial disorientation and cannot plan reading eye movements.45 Patients sometimes have a hemianopia as well (due to the occipital damage).46 ese multiple hits to posterior cortical regions explain why reading is o en the presenting symptom.

Acquired dysgraphia

e debate over whether writing is carried out using dissociable brain region(s), and thus whether ‘pure’ agraphia can exist a er focal brain damage, very much mirrors the debate over pure read- ing disorders with the same sorts of evidence brought to bear e.g. how can phylogenetically recent skills such as reading and writing become instantiated in designated neuronal networks? e answer, if there is one, is via practice and Cohen and Dehaene have written extensively on their ‘neuronal recycling’ hypothesis which they use to explain this phenomenon for reading and writing. In brief, they propose a form of short-term exaptation47 whereby cultural inven- tions invade evolutionarily older brain circuits and inherit many of their structural constraints.48

e clinical data from stroke patients suggests that acquired dysgraphias are most commonly seen in the context of a general- ized language (aphasic) disorder.49 ere are only a few functional imaging studies of writing in the normal population, and a represen- tative study found much overlap in the cortical networks that sup- port reading and writing.50 e main candidate region for a speci c writing area is named a er the person to rst describe it, Sigmund Exner (1849–1926). Exner’s area is above (dorsal to) Broca’s area in the middle frontal gyrus. Small ischemic lesions of this region have been reported as causing acute, seemingly pure, dysgraphia.51 Interestingly, a recent review of Exner’s original writing showed that the evidence put forward for a speci c ‘writing’ centre of the brain in Exner’s book was rather slim.52 Only four of the 167 case reports in his seminal book ‘Studies on the localisation of functions in the cerebral cortex of humans’ explicitly mention agraphia.53

As with the acquired alexia literature, there are a few cases that claim to demonstrate pure agraphia, that is, only writing a ected with reading and other linguistic skills le unharmed. But one could argue that as well as being linguistically pure, the syndrome must also be di erentiated from a general motor output disorder a ecting the dominant hand (a patient with a recently fractured dominant hand will be partially agraphic, but not in any clinically meaningful way). With this in mind, the most useful classi ca- tion is to borrow that from acquired alexia and think about cen- tral dysgraphias, where linguistic functions are impaired, (such as phoneme-to-grapheme conversion); and peripheral dysgraphias, where the stages of letter selection and the planning and implemen- tation of the motor movements break down.54 ese latter condi- tions are akin to the disorders that a ect speech (but not language) such as speech apraxia and the various dysarthrias.

e central dysgraphias

Central dysgraphias are more common than peripheral dys- graphias and are usually seen in association with other language

impairments. eir classi cation mirrors that for reading and depends on both part-of-speech e ects (which classes of words are more or less a ected), and error types so a patient with phono- logical dysgraphia will be more likely to make errors on low fre- quency words or abstract words. If they also make written semantic errors e.g. writing [wine] for ‘beer’ then they would have deep dys- graphia. One has to be particularly careful in enquiring about pre- morbid spelling ability before reading too much into mild written errors, as there is good evidence to suggest that writing errors may show up sooner than speaking errors in degenerative disorders. Homophone spelling appears to be a particularly sensitive test of mild Alzheimer’s disease with patients making errors confusing [knit] and [nit] when asked to spell one of the words in context.55 Treatment of central dyslexias is somewhat ad-hoc and depends on the patient’s residual capacities; a variety of approaches have been championed.54

e peripheral dysgraphias

When the stages of letter selection or the planning and implemen- tation of the motor movements involved in writing break down in isolation, then the patient is said to have an isolated peripheral alexia. Some patients have well formed letters but these are pro- duced in the wrong order, have extra elements or transpositions, e.g. [ owrer] produced for ‘ ower’, [winow] for ‘window’ or [chiar] for ‘chair’. It has been argued that these rare patients have a prob- lem with their graphemic bu er, so should be better at short words, even very irregular ones.54 Oral spelling should be normal in cases of ‘pure’ agraphia.

e more common peripheral dysgraphias a ect letter form gen- eration and are analogous to dysarthria or dysphonia in speech where the rate, rhythm, force, or amplitude of the writing move- ments are a ected. Neurological diseases of the pyramidal, extra- pyramidal or cerebellar systems can all cause this type of peripheral dysgraphia.

Case History I
Peripheral alexia: Hemianopic alexia

is case demonstrates, in a single subject, how text reading speed depends on the degree of visual sparing there is to the right of xation in le -to-right readers. e patient, a 48 year old right- handed male, was found to have a right-sided visual eld defect. Subsequently, a cystic lesion was demonstrated on MRI, located between the le optic tract and lateral geniculate nucleus (LGN). He had a macular splitting hemianopia in his (dominant) right eye, and a macular sparing hemianopia (with 3-4° of foveal/parafoveal sparing) in his le eye (Fig. 18.5a). is type of eld loss (non- identical defects in both eyes, also known as an incongruous hemi- anopia) happens because full segregation of the visual elds does not occur until bres have synapsed in the LGN. His visual acuity was N6 corrected in both eyes.

He read a 32 word news paragraph spread over 8 lines of text with each eye (Fig. 18.5b). He was ~30 per cent faster when reading with his le eye.

Time is depicted on the x-axis, with the bars indicating 240 ms. Distance is on the y-axis with the le of the stimulus at top and right at bottom. Fixations (horizontal portions of the trace) last- ing between 150 and 350 ms are interrupted by saccades (vertical portions) lasting ~20 ms. e start of the rst xation onto the rst

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(a) Visual Fields

(b) Reading eye movements

Left eye 0.00 s

Right eye

Left eye

Right eye

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Fig. 18.5 Peripheral alexia: hemianopic alexia.
Reproduced from J Neurol Neurosur Ps. 74(10), Upton NJ, Hodgson TL, Plant GT, et al. ‘Bottom- up’ and ‘top-down’ e ects on reading saccades: a case study, pp. 1423–28, Copyright (2003), with permission from BMJ Publishing Group Ltd.

word of the opening line, ‘ ere is a signi cant’, is shown as an open arrow, with the end of the nal xation marked by a closed arrow. Regressive saccades occur in both traces (open arrowheads) but the patient clearly takes longer (12 secs as opposed to 9.1 secs) to get to the last word of the 8th line (closed arrowhead), when reading with his right eye.

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46. Formaglio M, Krolak-Salmon P, Tilikete C, et al. Homonymous

hemianopia and posterior cortical atrophy. Revue neurologique.

2009;165(3):256–62. doi:10.1016/j.neurol.2008.10.010.
47. Gould SJ and Vrba ES. Exaptation—a Missing Term in the Science of

Form. Paleobiology. 1982;8(1):4–15.
48. Dehaene S and Cohen L. Cultural recycling of cortical maps. Neuron.

2007;56(2):384–98. doi:10.1016/j.neuron.2007.10.004.
49. Swinburn K, Porter G, and Howard D. Comprehensive Aphasia Test.

Hove and New York: Psychology Press, Taylor & Francis Group, 2004. 50. Purcell JJ, Napoliello EM, and Eden GF. A combined fMRI study of

typed spelling and reading. Neuroimage. 2011;55(2):750–62. doi: S1053-

8119(10)01520-X [pii] 10.1016/j.neuroimage.2010.11.042.
51. Keller C and Meister IG. Agraphia caused by an infarction in Exner’s

area. J Clin Neurosci. 2013. doi: S0967-5868(13)00159-8 [pii]. 10.1016/

j.jocn.2013.01.014.
52. Roux FE, Draper L, Kopke B, et al. Who actually read Exner? Returning

to the source of the frontal ‘writing centre’ hypothesis. Cortex. 2010;46(9):1204–10. doi: S0010-9452(10)00102-4 [pii] 10.1016/ j.cortex.2010.03.001.

53. Exner S. Untersuchungen über die Lokalisation der Functionen in der Grosshirnrinde des Menschen. Wien: Wilhelm Braunmuller, 1881. 54. Beeson PM. Remediation of written language. Top Stroke Rehabil.

2004;11(1):37–48.
55. Neils J, Roeltgen DP, and Constantinidou F. Decline in homophone

spelling associated with loss of semantic in uence on spelling in Alzheimer’s disease. Brain Lang. 1995;49(1):27–49. doi:S0093- 934X(85)71020-6 [pii] 10.1006/brln.1995.1020.

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CHAPTER 19

Neuropsychiatric aspects of cognitive impairment Dylan Wint and Je rey L. Cummings

Emotional and behavioural dysfunction frequently accompany cogni- tive impairment1–3 and dementia.4,5 e study of these neuropsychi- atric disturbances is critical because behavioural problems adversely a ect quality of life, neurologic outcomes, caregiver burden, and cost of care for patients with cognitive disorders (Fig. 19.1).6–10

Neuropsychiatric pro les can also be used to distinguish between cognitive disorders while providing insights into anatomic, physi- ologic, and pathologic correlates of brain function and dysfunc- tion (Table 19.1).10–13 Unfortunately, medical providers continue to underestimate how common neuropsychiatric problems are and the extent to which they impact on patients’ lives. Recognizing neu- ropsychiatric syndromes requires particular patience and thought- fulness in cognitively disturbed patients, who may be less able to help identify symptoms.

Almost all individuals with Alzheimer’s disease (AD)—the most common and most-studied acquired cognitive disorder—develop neuropsychiatric symptoms at some point during the course of ill- ness. e large number of people with AD (more than 5 million in the United States alone) and the high prevalence of neuropsychi- atric disturbances in this population make it one of the most com- mon causes of mental illness.10 Accordingly, dementia-associated neuropsychiatric symptoms have been best characterized in AD. However, there remain de cits even in the eld of AD-associated neuropsychiatric symptoms. Among them are:

◆ Paucity and inconsistency of studies of neuropsychiatric phe- nomena other than depression14

◆ A lack of consensus de nitions for many neuropsychiatric syndromes

◆ Few studies that have found safe and e ective treatments for the neuropsychiatric aspects of cognitive impairment
e Neuropsychiatric Inventory (NPI)15,16 is the most o en-used tool for quantifying psychopathology associated with cognitive dysfunction. Its scoring system rates the frequency and severity of 12 neuropsychiatric abnormalities that can be grouped into clusters of co-occurring symptoms (Table 19.2).17,18 is classi cation of neuropsychiatric disturbances provides a convenient sca old upon which to build this chapter’s discussion of selected mental distur- bances that occur in cognitive diseases.
Agitation/aggression (hyperactive cluster) Clinical phenomenology and importance
Of the hyperactive symptoms, agitation and aggression are the most serious and the most likely to require clinical attention. In

part, this is because other hyperactive symptoms may go unre- ported unless they are accompanied by agitation or aggression. In addition, agitation and aggression are almost always accompanied by one or more of the other hyperactive symptoms. Agitation is an inappropriate and disruptive increase in activity, and may mani- fest as motoric (pacing, dgeting, picking), verbal/vocal (shouting, cursing, grunting), or a ective (anger, laughing, crying) symptoms. e judgment of someone as ‘agitated’ is necessarily subjective— the phrase ‘inappropriate and disruptive’ is open to interpretation. Nevertheless, assessment of agitation by clinicians and caregivers has demonstrated intra- and inter-test reliability.15,19–21 Cognitive disorders reduce the patient’s ability to communicate distress. erefore, a cognitively impaired individual who appears agitated must be assessed for underlying causes, which may be physical (e.g. moaning because of pain), psychiatric (anxious dgeting), or iatro- genic (pacing because of akathisia).

Although a careful evaluation will sometimes reveal a second- ary cause for these behaviours, agitation can be a primary symp- tom of cognitive disease. It is now recognized that even individuals with mild cognitive impairment (MCI)—cognitive dysfunction not severe enough to cause dementia—exhibit elevated rates of agita- tion in comparison to cognitively intact peers.22 Agitation occurs in more than 20 per cent of patients with AD.23 ere are also high prevalences of agitation in frontotemporal dementia (FTD),24 vas- cular dementia (VaD),25 and dementia with Lewy bodies (DLB).26 Agitation seems to be generally less problematic in progressive supranuclear palsy (PSP)27 but this is not a universal nding.28 In addition to determining the likelihood of agitation, the underly- ing disorder also a ects the longitudinal course of agitation. For example, agitation in AD is increasingly likely as the disease pro- gresses,29,30 while patients with FTD demonstrate increasing agita- tion into the middle stages of disease but lower levels of agitation in advanced illness.24 Compared to patients with AD, those with DLB experience earlier occurrence of agitation but less worsening over time.31

Aggression refers to verbal or physical actions that if carried to completion would result in harm. is may include prom- ised, threatened, or actual physical assault, property damage, or unwanted sexual activity. Self-mutilation and suicidality are forms of self-targeted aggression. Unlike agitation, therefore, aggression always implies violence. Among dementia patients, aggressive behaviours have been associated with depressive symptoms, male gender, and worse cognition.30,32–34 On the other hand, Aarsland and colleagues found that aggression was not correlated with dementia severity or depression, but was highly correlated with

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198 SECTION 2

cognitive dysfunction

Exacerbation of Functional Impairment

Exacerbation of Cognitive Impairment

Acceleration of Cognitive Decline

Fig. 19.1 e impact of neuropsychiatric symptoms.

Residential Placement

Increased Patient Distress

Decreased Patient Quality of Life

Higher Cost of Care

Hospitalization

Psychotropic Medication

Increased Caregiver Distress

Decreased Caregiver Quality of Life

Side Effects

Neuropsychiatric Symptoms

psychotic symptoms.35 Studies generally agree that verbal aggres- sion is more common than physical aggression and that physical actions are generally preceded by verbal indications.33,35–37 e number and type of verbal or motor actions that could signal aggressive intent are limitless, but it is important not to impute aggressive intent to benign actions.

Neurobiology

e neurobiology of agitation and aggression in dementia is not well understood. ere are probably multiple underlying causes for these behaviours, further in uenced by disease type and stage, under- lying psychiatric history, psychosocial circumstances, and other variables. In general, studies have focused on roles of the neuro- transmitters acetylcholine (Ach), serotonin (5-hydroxytryptamine, 5HT), noradrenaline (NA), and dopamine (DA) in modulating aggression in humans.

Many studies have demonstrated that the major metabol- ite of serotonin, 5-HIAA, is reduced in the cerebrospinal uid

Table 19.1 Typical neuropsychiatric symptoms of major dementia syndromes

(suggesting lower central 5HT activity) of individuals who have committed aggressive acts against themselves,38 others,39 or prop- erty.40 ese and other studies indicate that 5HT abnormalities are speci cally associated with impulsive aggression.41,42 However, these ndings are subject to reasonable criticism and more study is needed.43 Furthermore, relationships between neurobiology and behaviour in the cognitively intact brain may not be directly applic- able to brains with abnormalities in cognitive processing.

Nevertheless, several lines of evidence suggest that 5HT dysregu- lation may be involved in aggressiveness of cognitively impaired individuals as well. In samples of temporal cortex from patients with AD, 5HT-1A receptor density was inversely correlated with aggression, suggesting that reduced ability to bind 5HT might mediate aggressive behaviour in AD.44 Temporal 5HT-6 receptor density has also been correlated with both agitation and aggression, as measured by the Present Behavioural Examination.45 Low 5HT levels in frontal cortex are associated with overactivity in AD.46 Another study found a correlation between HVA (metabolite of DA)/5-HIAA ratio in CSF and aggression in FTD, but not in AD.47 Studies investigating 5HT-related genetic predispositions toward AD-associated agitation and aggression have mixed results.48–50

e noradrenergic system has also been a target of investiga- tion as a factor in dementia-related agitation and aggression. e noradrenergic locus coeruleus undergoes signi cant cell loss in AD and DLB,51 although not in VaD.52 e magnitude of noradrener- gic cell loss is correlated with AD-related aggression.53 is seems counterintuitive, as high levels of NA stimulation would be expected to promote agitated and aggressive behaviours, and behavioural hypersensitivity to NA stimulation has been demonstrated in AD patients.54 However, there is evidence that locus coeruleus neuronal loss is compensated (possibly over-compensated) by increased NE production in remaining locus coeruleus neurons and postsyn- aptic NE receptor up-regulation in both AD51,55–58 and DLB.51

Dementia syndrome

Typical neuropsychiatric symptoms

Alzheimer disease

Apathy, irritability, depression, delusions

Dementia with Lewy bodies

Visual hallucinations, aberrant motor behaviour, depression

Vascular dementia

Depression, apathy, agitation/aggression

Frontotemporal dementia

Disinhibition, aberrant motor behaviour apathy, disinhibition

Parkinson’s disease with dementia

Hallucinations, depression, agitation

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Table 19.2 Neuropsychiatric inventory

Symptom cluster

NPI subscale

Representative questions

Hyperactivity

Agitation/Aggression

Is the patient stubborn, having to have things his/her way?

Does the patient get upset with those trying to care for him/her or resist activities such as bathing or changing clothes?

Does the patient shout or curse angrily?

Elation/Euphoria

Does the patient nd humour and laugh at things that others do not nd funny?

Does the patient tell jokes or make remarks that have little humour for others but seem funny to him/her?

Does he/she play childish pranks such as pinching or playing ‘keep away’ for the fun of it?

Irritability/Lability

Does the patient have sudden ashes of anger?

Is the patient impatient, having trouble coping with delays or waiting for planned activities?

Is the patient argumentative and di cult to get along with?

Aberrant Motor

Does the patient pace around the house without apparent purpose?

Does the patient rummage around opening and unpacking drawers or closets?

Does the patient dget excessively, seem unable to sit still, or bounce his/her feet or tap his/her ngers a lot?

Disinhibition

Does the patient act impulsively without appearing to consider the consequences?

Does the patient talk to total strangers as if he/she knew them?

Does the patient take liberties or touch or hug others in a way that is out of character for him/her?

Mood/Apathy

Depression/Dysphoria

Does the patient put him/herself down or say that he/she feels like a failure?

Does the patient express a wish for death or talk about killing him/herself?

Does the patient seem very discouraged or say that he/she has no future?

Apathy/Indi erence

Does the patient seem less spontaneous and less active than usual?

Does the patient seem less interested in the activities and plans of others?

Does the patient show any other signs that he/she doesn’t care about doing new things?

Sleep

Does the patient have di culty falling asleep?

Does the patient wander, pace, or get involved in inappropriate activities at night?

Does the patient awaken at night, dress, and plan to go out thinking that it is morning and time to start the day?

Appetite / eating

Has he/she had a loss of appetite?

Has he/she had an increase in appetite?

Has he/she had a change in the kind of food he/she likes such as eating too many sweets or other speci c types of food?

Psychosis

Delusions

Does the patient believe that others are stealing from him/her?

Does the patient believe that unwelcome guests are living in his/her house?

Does the patient believe that his/her spouse is having an a air?

Hallucinations

Does the patient describe hearing voices or act as if he/she hears voices?

Does the patient talk to people who are not there?

Does the patient report smelling odours not smelled by others?

Anxiety

Does the patient say that he/she is worried about planned events?

Does the patient have periods of (or complain of) shortness of breath, gasping, or sighing for no apparent reason other than nervousness?

Does the patient become nervous and upset when separated from your (or his/her caregiver)?

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Furthermore, alpha-1 adrenoceptor density in post-mortem brain samples is correlated with aggressive behaviour of patients with AD.59 More intriguing evidence for NA overactivity—despite locus coeruleus cell loss—in dementia-associated agitation/aggression is also suggested by treatment studies, which are described below.

Much of the evidence supporting a relationship between dopa- minergic overactivity and agitation/aggression in the cognitively impaired is derived from animal data and DA’s demonstrated role in aggression in cognitively healthy individuals.60 However, DA may be only secondarily related to agitation and aggression, because heightened levels of DA activity are also associated with reward-seeking and motivational aspects of behaviour.61 ere are no studies that directly link DA activity with agitation or aggres- sion,62 although one older study found levels of the DA metabo- lite HVA in spinal uid were lower in impulsive aggressors than in non-impulsive aggressors.63 is seems to con ict with the nd- ing that HVA/5-HIAA ratio in CSF is positively correlated with agitation and aggression in FTD.47,64 In the cognitively impaired, non-signi cant associations between DA receptor and transporter genotypes and aggression have been detected.65,66

Low levels of acetylcholine and choline acetyltransferase activ- ity in postmortem frontal and temporal cortex are correlated with overactivity in AD patients.46,67 Other neurotransmitters such as GABA, glutamate, and acetylcholine are even less studied as media- tors of agitation and aggression, especially in cognitively impaired humans. As with NA and DA, clinical responses to medications that modify these systems suggest a role for these less-studied transmitters.

Treatment

ere are few controlled studies of treatments speci cally for agi- tation/aggression in dementia, and these treatments have been largely unsuccessful.68 ere is increasing evidence that the treat- ments that help non-demented patients are not as likely to achieve measurable therapeutic responses in dementia.69,70

Cholinesterase inhibitors, which are o en used to treat cognitive deterioration, have not shown marked bene t for agitation/aggres- sion.71 However, the glutamate antagonist memantine probably reduces irritability and agitation/aggression in dementia patients.72 Memantine may be a particularly attractive option because its side- e ect burden is relatively low and it can provide cognitive stabiliza- tion in addition to its neuropsychiatric bene ts.71

Selective serotonin reuptake inhibitor (SSRI) antidepressants, which are taken by about one-third of patients with cognitive impairment,73 have not shown robust e cacy for treating agitation or aggression. A large controlled study of citalopram 30 mg daily demonstrated an advantage over placebo in reducing some meas- ures of agitation and caregiver distress at nine weeks.74 However, subjects on citalopram exhibited more cognitive decline (1 point on MMSE) over the same period. In this study and others, citalo- pram treatment also appeared to confer a risk of QTc prolongation greater than that of other SSRI antidepressants.75 Sertraline76,77 may reduce restlessness and psychomotor agitation in AD patients. e heterocyclic antidepressant trazodone demonstrated e ect- iveness in reducing agitation in FTD.78 Comprehensive reviews and meta-analyses of the relevant literature suggest that speci c improvements in agitation/aggression with antidepressants are minimal,79 although these drugs may help to improve general neuropsychiatric status.80

Anti-adrenergic agents may also be useful tools for addressing the problem of agitation/aggression in cognitive disorders. e non-selective beta-adrenergic antagonist propranolol reduced vio- lent behaviours in a series of patients with chronic brain damage,81 and it was signi cantly better than placebo at ameliorating NPI agitation/aggression in nursing home patients with possible and probable AD.82 Prazosin, a selective alpha-1 adrenergic antagonist, reduced overall NPI scores in AD patients with agitation/aggres- sion, but the sample was too small to allow for an analysis of its e ects on speci c NPI items.83 e rate of adverse e ects in stud- ies of anti-adrenergic agents is fairly low, but close monitoring of blood pressure and heart rate is advised when using anti-adrenergic therapies in these o en elderly patients.

e anti-epilepsy medications carbamazepine and valproate may help to reduce agitation/aggression, but valproate is associated with more rapid cerebral atrophy and cognitive decline, and several stud- ies show no bene t of valproate over placebo.84–86 Antipsychotic medications have also been studied for the treatment of dementia- associated agitation/aggression. Because many of these studies included patients with psychotic symptoms, speci c details about the use of antipsychotics are discussed in the section on manage- ment of psychotic symptoms, below.

Depression and apathy (mood cluster) Clinical phenomenology and importance

Most studies estimate the prevalence of major depression episodes in dementia to be between 20 per cent and 40 per cent, rates twice as high as those seen in the cognitively intact population, with even more patients su ering minor or subsyndromal depression,23,87–89 rates twice as high as those seen in the cognitively intact population. Within the dementing disorders, the highest and lowest prevalences of depression have been reported in corticobasal syndrome (CBS) and PSP respectively, but ndings have been quite varied.11,27,90,91 Depression is associated with greater cognitive impairment in dementia and other neurological diseases,92–94 but depression does not necessarily increase in prevalence or intensity as dementia pro- gresses.88 ere is a rapidly enlarging body of evidence implicating depression as a risk factor for developing late-life cognitive disor- ders.95–98 It may be that depressive episodes make limbic and cog- nitive circuits more vulnerable to damage by dementia-associated neuropathology. Alternately, mood symptoms could be the rst signs of intrusions of dementia pathology that will later produce impaired cognition. e underpinnings of the relationship between depression and dementia—like most of what we have learned about each of these illnesses—are likely to be complex.99

Diagnosing depression in dementia is not straightforward. Patients with dementia usually have some degradation of recogni- tion, recollection, and/or communication of emotional states and neurovegetative symptoms (see Box 19.1, case 1).100 Informant reports, mental status examination, and clinical intuition must play the primary roles in gathering history about mood problems in this population. Speci cs about depressive symptoms should be sought whenever possible. For example, the patient who reports her lev- els of interest and energy are ‘good’ should be asked to describe how she spends a typical day. e patient who claims he sleeps well should be asked what time he falls asleep, when he gets up for the day, and whether he feels refreshed in the mornings. Caregivers should be asked about their observations. In addition, agitation,

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Box 19.1 Case 1

e family of a 72-year-old woman with moderate Alzheimer dementia was concerned that the patient might be depressed. In addition to sad mood, behavioural changes included insomnia, poor appetite, depressed a ect (including tearfulness during the examination), disinterest in spending time with her family, and lack of energy. e family noted that she had stopped going for daily walks and did not want to attend her weekly card game. She was diagnosed with major depressive disorder and antide- pressant medication was prescribed. Her cognitive impairments made psychotherapy unsuitable.

When the patient returned three months later, her family reported partial resolution of the depression symptoms. Appetite and sleep had returned to normal. She now appeared happy when her grandchildren visited. However, she still was not going on walks or playing cards. She spent most of her time in her bedroom. When asked whether she was still somewhat sad, she replied ‘I’m the happiest I’ve ever been’. On a more speci c review of the evolution of her depression, the family reported that the patient’s activity level had declined 12 to 18 months before her sleep, appetite, and mood changed. At the time, the family attrib- uted her waning activity level to ‘normal slowing down’ because of ageing. e medical provider educated the family and patient about dementia-related apathy, which all agreed was likely a ect- ing this patient.

e provider o ered a trial of stimulant medication. e patient and family declined, citing their reluctance to change the treatment regimen in the face of her recent improvement. ey decided instead to pursue behavioural management—making a daily schedule of activities for the patient to follow, suggesting that she participate in activities (as opposed to asking whether she wanted to do them), visiting more frequently, and moving recreational supplies (television, bookshelf, radio) from her bed- room to the living room. ey reported that although the patient still did not generate her own ideas about how to spend her day, her level of activity increased considerably over the next few months.

disinhibition, anxiety, irritability, aggression, and psychosis should be taken into account because they occur as atypical depressive symptoms in individuals with dementia.101,102

Apathy, a lack of directed thoughts and behaviour, is one of the most common neuropsychiatric disturbances in cognitive disor- ders, including PDD, FTD, DLB, and particularly AD.103,104 Apathy contributes signi cantly to caregiver distress,105,106 loss of inde- pendence,107 and cognitive dysfunction.108 Lack of consensus cri- teria and imprecise use of terms have sometimes led to con ation of depression (mainly anhedonia) and apathy. However, they are neither indistinguishable nor mutually exclusive.109–112 Whereas anhedonia is a diminished response to agreeable stimulation, apa- thy is a lack of interest, drive, and persistence perhaps best concep- tualized as an ‘absence of will’.113,114 e distinction has important therapeutic implications, as apathy is generally persistent115 and unresponsive to antidepressants, while anhedonia is more likely to be a component of a potentially treatable depression.

Anxiety frequently accompanies depression but can also be pre- sent in non-depressed individuals. Like depression, anxiety impacts

CHAPTER 19 neuropsychiatry of cognitive impairment 201 negatively on quality of life and creates caregiver distress, even at

early stages of cognitive disturbance.116

Neurobiology

Although it is becoming clear that monoamines are not the only neurotransmitters that in uence mood, a long-standing line of evidence links depression to dysfunction in monoamine transmit- ter systems.117 As noted previously, adrenergic, serotonergic, and dopaminergic disruptions are also seen in AD, FTD, and DLB. However, there is much less evidence supporting di erences in monamine activity between depressed and non-depressed dementia patients. Neuropathological examination has demonstrated greater loss of locus coeruleus (NA) and dorsal raphe (5HT) neurons in AD patients with depression than those without.118 Lower levels of NA were also seen in cortical areas of depressed AD patients when compared to their non-depressed peers, but the same study showed no consistent or signi cant di erence in 5HT or DA lev- els.119 PET-measured densities of 5HT transporters (a surrogate for 5HT projections) in midbrain, caudate, and putamen were lower in depressed than non-depressed AD patients.120 Limited studies have implicated the cholinergic system in mood and motivation abnormalities.121 Further study of the relationships between mono- aminergic state and mood in AD and other dementias is needed.

Anatomic changes may also be correlated with depression in dementia. Like AD, depression is associated with atrophy of the hippocampus and other regions that are important in cognitive pro- cessing.122–124 Patients with MCI and depression had more frontal, temporal, and parietal white matter atrophy during two years of observation than did patients with no psychiatric symptoms. e same study did not detect accelerated atrophy in a group of MCI patients with non-depressive psychiatric symptoms, suggesting a speci c neuroanatomical e ect of depression.125 ere seems to be a relationship between the burden of AD-speci c pathology (neuro brillary tangles and neuritic plaques) and the presence of depression in individuals with AD, but not in elderly people with normal cognition.126–128

Apathy is associated neuroanatomical and neurochemical changes in the frontal cortex and regions with which it is extensively networked.129 Several studies have demonstrated reduced cerebral perfusion in anterior temporal,130 prefrontal,130,131 and anterior cingulate131,132 regions in dementia patients with apathy. e lat- ter is also associated with apathy in non-demented patients.132 Patients with apathy are under-responsive to amphetamine chal- lenge, implicating DA and NA systems in its pathogenesis.133 e early onset and persistence of apathy in AD, along with treatment studies using cholinesterase inhibitors, strongly suggest that cho- linergic de cits also contribute to apathy.134

Treatment

Although they are widely used by clinicians, the evidence in favour of SSRI drugs for treating dementia-related depression is inconsist- ent at best.135–138 Studies di er in de nitions of depression, rating scales used to measure depression, and the severity of cognitive dis- turbance in the studied populations.139 Furthermore, depression may be a time-limited phenomenon in patients with Alzheimer dementia, resulting in high rates of placebo response. Nevertheless, experts generally recommend use of SSRI antidepressant medi- cation when a depressive episode is identi ed.140 Although these drugs are generally considered quite safe, low starting doses and

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slow titration should be the overriding principles to reduce the risks of side-e ects. A full therapeutic trial of at least eight weeks is necessary to determine an antidepressant’s e ectiveness.141 Clinicians are particularly cautioned regarding antidepressants that have anticholinergic, antiadrenergic, and/or antihistaminic properties. ese are more likely to cause side-e ects in demented patients, and should be used for dementia-related depression only a er failures of less problematic drugs, if at all.142,143

Electroconvulsive therapy (ECT) may also be of bene t, but it should be administered by an expert in treating the cognitively impaired population, because of speci c and substantial cogni- tive risks.144 Standardized evaluation of cognition and depres- sion symptoms are recommended throughout the ECT course.145 Individuals with better baseline cognition and those who are taking antidementia medications have better cognitive outcomes a er a course of electroconvulsive therapy.146 In addition to the assess- ment prior to starting the course of ECT, each individual stimu- lus should be preceded by a thorough risk/bene t analysis. In the authors’ experience, patients who su er signi cant cognitive decline during a course of ECT bene t from increased recovery time between treatments.

e results of studies evaluating treatments for apathy have been inadequate,129,147 as most have measured apathy as a secondary or post hoc outcome. is evidence, from trials in a large num- ber of patients, supports the use of cholinesterase inhibitors at typ- ical treatment doses. e strongest evidence exists for donepezil in AD,148,149 rivastigmine in DLB150 and mixed AD/VaD,151 and galantamine in mixed AD/VaD.152 Ginkgo biloba extract EGb 761 240 mg daily was well tolerated, and superior to placebo in reduc- ing apathy and other neuropsychiatric symptoms in AD, VaD, and mixed dementia.153 In a study of non-depressed patients with AD and apathy, methylphenidate 20 mg daily was superior to pla- cebo in two of three primary endpoints, with a low rate of adverse e ects.154 ere is mixed evidence for the e ectiveness of meman- tine, and no evidence favouring use of antidepressants or antip- sychotics for AD- and VaD-associated apathy.129 Apathy in FTD has proven even more resistant to treatment, with cholinesterase inhibitors,155 memantine,156 and antidepressants157 showing no appreciable e ect. However, it should be noted that treatment of apathy has not been studied nearly as well in FTD as in the more common dementias.

Delusions and hallucinations Clinical phenomenology and importance

Psychosis—a disruption of one’s connection to reality—is not as common as other neuropsychiatric symptoms, but is extremely dis- ruptive to the lives of patients and caregivers (see Box 19.2, case 2). e overt manifestations of psychosis are hallucinations (aberrant sensory experiences), delusions ( xed false beliefs), and ideations (false beliefs not completely xed). Psychosis may also include less obvious symptoms such as internal preoccupation and illogical/ nonsensical patterns of thinking.158

Hallucinations in dementia, unlike those in schizophrenia or mood disorders, tend to be visual. Some types of delusions are more char- acteristic of dementias than primary psychiatric disorders. Among these are:

◆ In delity: the patient’s romantic partner has been unfaithful

◆ e : someone has stolen important items from the patient

◆ Misidenti cation: a loved one has been replaced by an identical- appearing impostor (Capgras syndrome), or a persecutor is dis- guising him/herself as other people (Fregoli syndrome)

◆ Reduplicative paramnesia: a setting such as the patient’s home has been relocated or duplicated in some other location

◆ Phantom boarder: an unseen, sometimes unwanted, guest is liv- ing in the patient’s home158
Rates of speci c psychotic symptoms di er among the dementias. For example, although delusions and hallucinations are commonly seen in both AD and DLB,12 DLB has much higher rates of hallu- cinations than the other dementias, and includes psychotic symp- toms among its diagnostic features.12,159 Studies of the prevalence of psychosis in VaD have varied results. Psychotic symptoms are more likely in very old patients and appear more frequently in multi- infarct dementia than in Binswanger disease.160–163 Although PSP, CBD, and FTD are by no means immune to psychotic symptoms,

Box 19.2 Case 2

An 80-year-old woman with mild Alzheimer dementia com- plained that a small animal, the likes of which she had never seen before, was living in her house. She had only seen the animal once, when it ‘snuck into my house’ while a suspicious neighbor was moving out a few months ago. It had a body like a very small dog (about the size of a squirrel), with a head that resembled a cat’s, except for long, hanging ears. Although she did not see it again, she knew it was in her house because she could hear it ‘scratching around and knocking things over’ as she tried to go to sleep each night. She also woke each morning with ‘bite marks’ on her skin, which she attributed to the animal’s need to suck her blood. She attempted to demonstrate these marks to the exam- iner, who was unable to see the lesions to which she referred.

She was unable to sleep at night (because ‘I don’t know what it’s gonna do next’). Her appetite was unchanged. She was still read- ing avidly and her mood was ‘pretty good’. e patient’s daughter said the patient appeared to be as sociable, happy, and energetic as before. However, she had stopped gardening and attending a twice-weekly senior breakfast because she spent much of the day catching up on sleep. Two thorough inspections of the patient’s home, one by a rodent exterminator, found no evidence of infes- tation, although the patient pointed out a number of innocuous ndings that signi ed to her that the animal was living there.

e patient did not see her concern about the animal as a medical problem, and did not want antipsychotic medication to reduce her preoccupation and anxiety about the animal. e daughter (who was the medical decision-maker) felt that the patient’s symptoms were not severe enough to risk the serious potential side-e ects of antipsychotics. ey accepted trazodone, which did help the patient sleep better at night, but she discon- tinued it because of excessive daytime drowsiness.

Over the next eight months, the patient’s worry about the ani- mal slowly diminished, although she was convinced it was still roaming her house at night. Eventually the animal stopped biting her, ‘or at least, not hard enough that I notice’. She attributed this to her new habit of leaving out a small bowl of milk each night, of which the animal drank ‘just the tiniest bit, but you can tell’. Her sleep and daytime activities eventually returned to normal, and she continued putting out milk for the animal.

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they occur at lower rates in these disorders than in AD, DLB, and VaD.11,12,27,90,164

In addition to appearing as a consequence of the primary disease, psychotic symptoms can also result from delirium superimposed on dementia. erefore, the sudden appearance or exacerbation of psychotic features should prompt a search for a new acute medical condition, such as infection or stroke. In addition, sensory depriv- ation such as impaired visual acuity or deafness can worsen psych- otic symptoms in dementia patients.165,166 Although it is not clear whether improving sensory de cits eliminates the psychotic phe- nomena, there are manifold reasons to improve sensory perform- ance when possible.

Neurobiology

A core biological feature of both AD and DLB is loss of choliner- gic activity in the brain. e high prevalence of psychosis in AD and DLB suggests that acetylcholine de cit may play a role in the pathogenesis of dementia-related hallucinations.167,168 Indeed, cholinergic mechanisms are implicated by research observations. Psychotic symptoms are associated with cholinergic de ciency in frontal and temporal cortex in AD,46,169 and in temporal and par- ietal cortex in DLB.168 As with other forms of psychosis, limbic DA hyperactivity is also posited to play a role in dementia-related psychosis. Patients with DLB o en experience worsening of psych- otic symptoms when exposed to dopaminergic agents.170 SPECT imaging has demonstrated a high correlation between severity of hallucinations and loss of striatal DA transporters (i.e. DAergic nerve terminals) in DLB patients.171 PET imaging in a group of relatively early-stage AD patients showed increased striatal DA2 and/or DA3 receptor availability in patients with delusions; the study technique was not able to resolve whether this nding was due to decreased endogenous DA binding (which seems paradox- ical) or increased DA receptor density in the patients with delu- sions.172 ere are sometimes contradictory implications about the contributions of glutamate, 5HT, and GABA dysregulation to psychosis in dementia.173

Studies of cerebral perfusion in AD patients with psychosis have found abnormally reduced or asymmetric blood ow in several regions, including striatum and thalamus, and frontal, temporal, and parietal cortex, as compared to cognitively healthy con- trols and AD patients without psychosis.174–176 Parietotemporal hyper- and hypometabolism have both been seen with psychosis in AD.177,178 Delusional misidenti cation syndromes are associ- ated with reduced metabolism (FDG–PET) in orbitofrontal, mesial temporal, and cingulate regions,177 and right temporal atrophy.179 Neuropathological studies suggest that patients with AD and psychotic symptoms actually have greater neuronal preservation in parahippocampus, but higher levels of plaques, tangles, and dys- trophic neurites throughout the rest of the cerebral cortex.173,180 Conversely, visual hallucinations and delusions in DLB were asso- ciated with less neuro brillary tangles and more Lewy bodies.181

Treatment

CHAPTER 19 neuropsychiatry of cognitive impairment 203 him, the most appropriate steps might be education, counselling,

and support for a frustrated caregiver.182 On the other hand, if similar hallucinations interfered with the patient’s sleep and eating, then treatment to reduce the intensity or salience of the hallucina- tions could be in order.

Cholinesterase inhibitors demonstrate modest e ectiveness in reducing dementia-related psychotic symptoms.183 Because patients with AD, DLB, PDD, and VaD can bene t cognitively from cholinesterase inhibitors,184–186 these medications are rea- sonable rst-line agents for treating dementia-related psychosis. Antidepressant medicines may have some utility as well, with some studies demonstrating equal e cacy with lower side-e ects when compared to antipsychotics.79

In the dementia population, antipsychotics have usually been studied in populations of patients who exhibit both psychosis and hyperactivity. e lessons learned from these studies can there- fore be applied to both syndrome clusters. Meta-analytic studies of newer ‘atypical’ (combined 5HT and DA blockade) antipsychotics in dementia patients with agitation/aggression estimate small but signi cant bene ts for using risperidone (1–2 mg daily), but poor support for aripiprazole, olanzapine, or quetiapine. Clinicians gen- erally agree that psychotic symptoms are most e ectively treated by antipsychotic medications, but bene ts and risks can be di cult to balance in demented patients.

All current antipsychotics cause some level of postsynaptic DA blockade, which accounts for their class-speci c side-e ects— extrapyramidal syndromes (akathisia, dystonia, and parkinson- ism), neuroleptic malignant syndrome, and tardive dyskinesia. e pharmacodynamic pro les of antipsychotics also predict potential antiadrenergic, antihistaminic, and anticholinergic side-e ects.187 ese risks occur in all patient populations but the elderly are more sensitive. Importantly, antipsychotics have additional class-speci c risks for the elderly and cognitively impaired. Antipsychotic medi- cations are associated with clinically signi cant increases in short- and long-term rates of cognitive decline, stroke, sudden death, and acute hospitalization.70,188,189 e authors recommend starting with low doses and titrating slowly, as antipsychotics can take some time to show their full therapeutic bene t. As with all pharmaco- therapy, regular assessments of the need for continued medication are necessary. However, it should be noted that relapse rates a er discontinuation are high, particularly in patients with severe symp- toms.190,191 Furthermore, as discussed above, other treatments for psychosis have low rates of e ectiveness.

Pimavanserin, a selective 5HT-2A inverse agonist, is being inves- tigated for the treatment of PD-related psychosis. Its e ective- ness has been demonstrated in a placebo-controlled randomized trial.192 is and other trials seemed to bear out the expectation that pimavanserin’s pharmacodynamic selectivity would yield min- imal motor (anti-DA), cognitive (anti-Ach), and sedative (anti- histamine) side-e ects.193,194 Hopefully, pimavanserin will also be e ective in treating psychosis associated with PDD and other dementias.195

Conclusion

Our understanding of cognitive disorders has been enhanced by study of the behavioural disturbances that so o en accompany them. Although an impressive body of data has been accumulated about these symptoms, any clinician with experience in managing

e issue of treatment of dementia-related psychotic phenomena is not straightforward. Psychotic symptoms are usually uncomfort- able for patients and/or their caregivers, but the individual nature and circumstances of psychotic symptoms should always be taken into account when considering treatment. For example, if a patient has hallucinations of deceased loved ones but they do not bother

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204 SECTION 2 cognitive dysfunction

cognitive disorders will recognize that there is a pressing need for much more study. Increased attention to neuropsychiatric syn- dromes, better diagnostic criteria, and improvements in technology will produce a better understanding of their epidemiology, neuro- biology, and—most importantly—the best ways to treat them.

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149. Holmes C, Wilkinson D, Dean C, et al. e e cacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology. 2004 Jul 27;63(2):214–9.

150. McKeith I, Del Ser T, Spano P, et al. E cacy of rivastigmine in demen- tia with Lewy bodies: A randomised, double-blind, placebo-controlled international study. Lancet. 2000 Dec 16;356(9247):2031–6.

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155. Moretti R, Torre P, Antonello RM, et al. Rivastigmine in frontotempo- ral dementia: An open-label study. Drugs & Aging. 2004;21(14):931–7.

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159. McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the consortium on DLB international workshop. Neurology. 1996 Nov;47(5):1113–24.

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161. Ostling S, Gustafson D, Blennow K, et al. Psychotic symptoms in a population-based sample of 85-year-old individuals with dementia. J Geriatr Psych Neur. 2011 Mar;24(1):3–8.

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164. Engelborghs S, Maertens K, Nagels G, et al. Neuropsychiatric symp- toms of dementia: Cross-sectional analysis from a prospective, longitu- dinal Belgian study. Int J Geriatr Psychiatry. 2005 Nov;20(11):1028–37.

165. Ballard C, Bannister C, Graham C, et al. Associations of psy- chotic symptoms in dementia su erers. Brit J Psychiat. 1995 Oct;167(4):537–40.

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168. Perry EK, Irving D, Kerwin JM, et al. Cholinergic transmitter and neu- rotrophic activities in Lewy body dementia: Similarity to Parkinson’s and distinction from Alzheimer disease. Alzheimer Dis Assoc Disord. 1993 Summer;7(2):69–79.

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CHAPTER 19 neuropsychiatry of cognitive impairment 207

208 SECTION 2 cognitive dysfunction

169. Lai MK, Lai OF, Keene J, et al. Psychosis of Alzheimer’s disease is asso- ciated with elevated muscarinic M2 binding in the cortex. Neurology. 2001 Sep 11;57(5):805–11.

170. Goldman JG, Goetz CG, Brandabur M, et al. E ects of dopaminergic medications on psychosis and motor function in dementia with Lewy bodies. Mov Disord . 2008 Nov 15;23(15):2248–50.

171. Roselli F, Pisciotta NM, Perneczky R, et al. Severity of neuropsy- chiatric symptoms and dopamine transporter levels in dementia with Lewy bodies: A 123I-FP-CIT SPECT study. Mov Disord. 2009 Oct 30;24(14):2097–103.

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174. Kotrla KJ, Chacko RC, Harper RG, et al. Spect ndings on psychosis in Alzheimer’s disease. Am J Psychiat. 1995 Oct;152(10):1470–5.

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181. Ballard CG, Jacoby R, Del Ser T, et al. Neuropathological substrates of psychiatric symptoms in prospectively studied patients with autopsy-con rmed dementia with Lewy bodies. Am J Psychiat. 2004 May;161(5):843–9.

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183. Rozzini L, Chilovi BV, Bertoletti E, et al. Cognitive and psychopatho- logic response to rivastigmine in dementia with Lewy bodies com- pared to Alzheimer’s disease: A case control study. American Journal of Alzheimer’s disease and Other Dementias. 2007 Feb–Mar;22(1):42–7.

184. Passmore AP, Bayer AJ, and Steinhagen- iessen E. Cognitive, global, and functional bene ts of donepezil in Alzheimer’s disease and vas- cular dementia: Results from large-scale clinical trials. Journal of the Neurological Sciences. 2005 Mar 15;229–230:141–6.

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186. Rolinski M, Fox C, Maidment I, et al. Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson’s disease dementia and cogni- tive impairment in Parkinson’s disease. Cochrane Database Syst Rev. 2012;3:CD006504.

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189. Rochon PA, Normand SL, Gomes T, et al. Antipsychotic therapy and short-term serious events in older adults with dementia. Arch Intern Med. 2008 May 26;168(10):1090–6.

190. Devanand DP, Mintzer J, Schultz SK, et al. Relapse risk a er discon- tinuation of risperidone in Alzheimer’s disease. New Engl J Med. 2012 Oct 18;367(16):1497–507.

191. Ballard CG, omas A, Fossey J, et al. A 3-month, randomized, placebo-controlled, neuroleptic discontinuation study in 100 people with dementia: e neuropsychiatric inventory median cuto is a predictor of clinical outcome. J Clin Psychiatry. 2004 Jan;65(1):114–9.

192. Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson’s disease psychosis: A randomised, placebo-controlled phase 3 trial. Lancet. 2014 Feb 8;383(9916):533–40.

193. Meltzer HY, Mills R, Revell S, et al. Pimavanserin, a serotonin(2a) receptor inverse agonist, for the treatment of Parkinson’s disease psy- chosis. Neuropsychopharmacology. 2010 Mar;35(4):881–92.

194. Friedman JH. Pimavanserin for the treatment of Parkinson’s disease psychosis. Expert Opin Pharmacother. [Review]. 2013 Oct;14(14):1969–75.

195. Price DL, Bonhaus DW, and McFarland K. Pimavanserin, a 5- HT2A receptor inverse agonist, reverses psychosis-like behaviors in a rodent model of Alzheimer’s disease. Behav Pharmacol. 2012 Aug;23(4):426–33.

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SECTION 3

Cognitive impairment and dementia

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CHAPTER 20

Epidemiology of dementia

ais Minett and Carol Brayne

Demographic changes, the ageing

population, and future projections costs

Demographic ageing is a major consequence of our success in extending life over the last century. People now live longer than at any other time in history. is is a worldwide process result- ing from the extraordinary reductions in mortality and fertility rates. As population ages, the proportion of the older population (those aged 60 years or over) is growing faster than any other age segments. At the same time, the reductions in the proportion of children (persons under age 15) at the world level means that the balance between proportions of the young and the old is expected to shi for the rst time in 2045, when the absolute number of old persons will exceed the number of children.1

e absolute number of older people has tripled over the last 50 years and will more than triple again over the next 50 years. In 1950, according to the United Nations (UN), there were 205 mil- lion people aged 60 or more worldwide. Only 59 years later, in 2009, this number rocketed to 737 million. It is predicted that in 2050 there will be just fewer than 2 billion people aged 60 or over. is phenomenon was rst experienced by high-income countries (HIC) though it has recently become apparent in many of the low and medium-income countries (LAMIC). By 2050, six countries are forecast to have 55 per cent of all those people aged 80 or over in the world. Each of them will have more than 10 million people in this age group: China (101 million), India (43 million), United Sates of America (32 million), Japan (16 million), Brazil (14 mil- lion), and Indonesia (12 million).1

Fertility rates are now well below 2.1 children per woman, the level considered necessary to ensure the replacement of genera- tions. Total fertility rate in the HIC has dropped from 2.8 children per woman in the period 1950–55 to 1.6 children per woman in 2005–10. Although this decline in the LAMIC has started later, it has progressed faster: from 6.0 children per woman in the period 1950–55 to 2.7 in 2005–10.1

Life expectancy at birth has shown a global increase of 21 years from 1990–95 to 2005–10.1 is improvement is a by-product of epidemiological transition, where pandemics of infection are replaced by degenerative, neoplastic and ‘lifestyle’ driven diseases. is is a fact in the HIC as well as in the LAMIC, where this epide- miologic transition is underway.

In the current panorama, chronic diseases have become the pri- mary causes of not only mortality but also morbidity. As a conse- quence, preventive measures are less e ective, investigations and treatments are more complex and expensive, and life-long interven- tions may be required. e costs associated with these disorders are increasingly less a ordable not only for LAMIC but also for HIC.

While longevity is widely seen as positive and is welcomed, the increase in the older population segment, which is typically more vulnerable to frailty and chronic conditions such as heart disease, dementia, arthritis, and stroke, will prompt a dramatic rise in medi- cal and care costs in the years to come, posing nancial risks for governments as well as pension and health providers.

Under the demographic trends expected by the United Nations, the aggregate pension costs incurred by the older population will roughly double over the period 2010–50.2 Accounting for the likely increases in health and long-term care costs will yet further increase the nancial burden associated with ageing.

e impact of population ageing on society means health- care, retirement, and pensions will extend for longer, as there are increased numbers of potential bene ciaries of healthcare and pen- sions entitlements. On the other hand, there will be relatively less economically active contributors, aged 15–64, to support this grow- ing segment of the population.

e ratio of those more likely to be economically productive (aged 16–64) and those more likely to be dependants (aged 65 or over) is termed the potential support ratio (PSR). In 2009, the PSR was 4.2 in Europe, under 3.5 in Japan, but considerably higher at 16.5, 10.2, and 9.6 in Africa, Asia, and Latin America respectively. Over the next four decades, the PSR is projected to drop substan- tially in Asia, Latin America, and the Caribbean as in those areas the demographic transition is rapidly taking place. By 2050, there will be about two people aged 16–64 per person aged 65 or over in Europe, about three in Latin America and the Caribbean, Northern America, and Oceania; in Japan, it is expected to drop below 1.5.1 e nancial impact of these changes will be particularly felt by the working-age population, who are already seeing retirement ages rise, their pensions under threat, and the requirement to pay more and higher taxes.

It is not di cult to see that these demographic trends will have adverse e ects on economic growth and may lead to intergenera- tional con icts. However, some factors may mitigate this scenario. It is forecast that although the older population labour force has been falling for men, labour force will increase by 1 per cent from 1980 to 2020 as the participation of older woman is expected to increase from 9 per cent to 17 per cent.1

Current impact of dementia: Numbers,

costs, geographical distribution

Mortality

Cause of death statistics derived from civil registration systems are an important source of data for continuous and comprehensive monitoring of public health programmes over time. Yet, despite

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212 SECTION 3 cognitive impairment and dementia

their central role in health development, their usefulness has been restricted because of many systemic di culties ranging from sys- tems that do not generate data at all, to malfunctioning systems that produce poor-quality data.

Country reports to the WHO (World Health Organzation Statistical Information Systems, WHOSIS) are the major source of international cause of death statistics from civil registration systems.3

According to WHO and based on analysis of latest available national information on levels of mortality and cause distributions as at late 2003, neurological disorders constitute 12 per cent of total deaths globally. Within these groups of diseases, Alzheimer’s dis- ease (AD) and other dementias were responsible for 6.3 per cent of the deaths in 2005, a number that is projected to rise to 7.5 per cent by 2030.4

Survival a er estimated onset of dementia among participants aged 65 years or older in the UK’s Medical Research Council’s Cognitive Function and Ageing Study (MRC CFAS) was 4.6 years for women and 4.1 years for men. ose who were functionally impaired, older, and male had predicted shorter survival.5

Aguero-Torres and colleagues calculated a mean survival time of 3.0 years among 75-year-old patients with incident cases of demen- tia in contrast to a mean survival time of 4.2 years for persons with- out dementia.6 Helmer and colleagues reported a mean survival time in incident cases of 4.5 years among 65-year-olds and a relative risk of 1.8 (95 per cent CI = 1.8, 2.7).7

In 2005, AD and other dementias contributed 6 per cent of the mortality within the neurological disorders. is gure is expected to be 8 per cent in 2030, being overridden only by the cerebrovas- cular diseases (85 per cent and 87 per cent, respectively).4

However, when taking into account the estimates for 2030 of years of healthy life lost (YLL) as a result of disability, AD and other dementias are forecast to have higher impact than cerebrovascular diseases, contributing to 18 per cent of the YLL among the neuro- logical disorders in relation to 16 per cent represented by cerebro- vascular diseases.

It is important to note that these estimates are based on all age groups. As dementia mainly a ects older people with only 2 per cent of cases starting before the age of 65 years, dementia is one of the major causes of disability in later life. According to the World Health Organization,8 dementia contributed 11 per cent of all years lived with disability among older people, more than stroke (9 per cent) and all forms of cancer (2 per cent).

Morbidity

e Global Burden of Disease (GBD) framework summarizes the disease burden across diagnostic categories of the International Classi cation of Diseases (ICD), and by adopting the concept of disability-adjusted life years (DALY),9 many conditions which are highly incapacitating but have low mortality are aggregated to pro- vide a single measure of overall population health. is is especially the case of the neuropsychiatric disorders. e DALY provides a measure of years expected to be lived in full health lost as a result of a disease that caused either disability or premature mortality.

is methodology uses vital statistics and epidemiological data, which allows for international comparisons as these now exist for many countries including LAMIC.

DALY is calculated as the sum of the years of life lost due to premature mortality (YLL) in the population and the years lost

due to disability (YLD) for incident cases of the health condition (DALY = YLL + YLD).

According to the WHO, in 2005 AD and other dementias con- tributed for 12 per cent of the DALYs for neurological disorders, with projection suggesting a 66 per cent rise by 2030, that is, to account for 18 per cent of the DALY’s for neurological disorders. is contribution is only surpassed by cerebrovascular diseases, which was 55 per cent in 2005 and is expected to be 59 per cent in 2030.4

Geographical distribution

In 2004, Alzheimer’s Disease International convened an interna- tional group of experts to review all available epidemiological data and generate up-to-date evidence-based estimates for the preva- lence of dementia for every WHO world region.10 As evidence from well-conducted, representative epidemiological surveys was lacking in many regions, the panel used the Delphi consensus method to allow inferences in such regions by deriving quantita- tive estimates through the qualitative assessment of evidence. ey estimated that globally 24 million people had dementia in 2005, with 4.6 million incident cases annually. ey concluded that the prevalence would double every 20 years and that most people with dementia live in developing countries (60 per cent in 2001 rising to 71 per cent by 2040). Seven regions with the largest number of peo- ple with dementia in 2001 were: China (5.0 million), the European Union (5.0 million), US (2.9 million), India (1.5 million), Japan (1.1 million), Russia (1.1 million), and Indonesia (1.0 million).

As very little work had been done on evaluating prevalence and incidence of dementia in LAMIC, the 10/66 Dementia Research Group (http://www.alz.co.uk/1066/), as part of Alzheimer’s Disease International, was formed to carry out population-based research into dementia, non-communicable diseases, and ageing in LAMIC. e name 10/66 refers to the two-thirds (66 per cent) of people with dementia living in LAMIC contrasting to less than 10 per cent of population-based research in the same areas. e prevalence of dementia varied widely, from 0.3 per cent in rural India to 6.3 per cent in Cuba. A er standardization for age and sex, taking Europe as a reference population, the prevalence in all studied regions was less than that reported in Europe: in urban Latin American sites the standardized prevalence was four- hs less than in Europe, in China it was half, and in India and rural Latin America it was a quarter. e interpretation of the group was that according to the adopted methodology, dementia might be underestimated, espe- cially in regions with low awareness of dementia.11

Since these estimates from the Delphi consensus were published, the global evidence base has expanded considerably. ere have been new studies from European countries, US, and the above- mentioned 10/66 Dementia Research Group studies in the LAMIC. In the World Alzheimer Report from 2009, the leaders of the Delphi consensus revisited the literature to summarize the evidence on the prevalence of dementia by carrying out quantitative meta-analyses of the available data, and where data were not available the esti- mates from the Delphi consensus or from recent good quality stud- ies were used.12 e estimates are summarized in Table 20.1.

Prevalence of dementia across time

Increasing vascular risk factors such as physical inactivity, obesity, diabetes, population ageing, and social inequalities might raise the risk of dementia across time. On the other hand, successful primary

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Table 20.1 Estimates for dementia prevalence

CHAPTER 20 epidemiology of dementia 213

Region

Age group

Standardized prevalence for those aged 60 and over

60–64

65–69

70–74

75–79

80–84

85–89

90+

Australasia*

1.8

2.8

4.5

7.5

12.5

20.3

38.3

6.91

Asia Paci c, high income*

1.0

1.7

2.9

5.5

10.3

18.5

40.1

5.57

Asia, East*

0.7

1.2

3.1

4.0

7.4

13.3

28.7

4.19

Asia, South*

1.3

2.1

3.5

6.1

10.6

17.8

35.4

5.78

Asia, South-east*

1.6

2.6

4.2

6.9

11.6

18.7

35.4

6.38

Europe, Western*

1.6

2.6

4.3

7.4

12.9

21.7

43.1

6.92

North America (USA only)*

1.1

1.9

3.4

6.3

11.9

21.7

47.5

6.46

Latin America*

1.3

2.4

4.5

8.4

15.4

28.6

63.9

8.48

Asia, Central

0.9

1.3

3.2

5.8

12.1

24.7

5.75

Oceania

0.6

1.8

3.7

7.0

14.4

26.2

6.46

Europe, Central

0.9

1.3

3.3

5.8

12.2

24.7

5.78

Europe, Eastern

0.9

1.3

3.2

5.8

11.8

24.5

5.70

Caribbean

1.3

2.6

4.9

8.5

16.0

33.2

8.12

North Africa/Middle East

1.0

1.6

3.5

6.0

12.9

23.0

5.85

Sub-Saharan Africa, Central

0.5

0.9

1.8

3.5

6.4

13.8

3.25

Sub-Saharan Africa, East

0.6

1.2

2.3

4.3

8.2

16.3

4.00

Sub-Saharan Africa, Southern

0.5

1.0

1.9

3.8

7.0

14.9

3.51

Sub-Saharan Africa, West

0.3

0.9

2.7

9.6

2.07

*Regions included in the meta-analyses.
Reproduced from World Alzheimer Report, Copyright (2009), with permission from Alzheimer’s Disease International.

prevention of heart diseases and longer early life education might reduce the prevalence of dementia.

In a systematic review designed to gather evidence for intergen- erational changes regarding dementia prevalence, Matthews and colleagues13 found that that in higher-income countries, the preva- lence and inferred or measured incidence of dementia might have decreased over the years. Most of the studies included were subject to di erent diagnostic criteria over time. is, could potentially act in both directions, leading either to a decrease in the gures (with some being classi ed in the mild cognitive impairment categories) or an increase (as a result of investigations showing abnormalities, which in fact might be common in non-demented older people).

To study the changes in prevalence and incidence of dementia over time, the UK CFAS compared data from 2011 to those gath- ered in 1991.13 CFAS, now in its second generation, follows almost identical design and method of its parent study, which is ideal for intergenerational comparisons. Both CFAS I and CFAS II drew on the UK system of primary care registration which provides the most robust population base for sampling by age group for epide- miological studies in the UK. Comparison of standardized preva- lence across time showed a substantial decrease in prevalence of dementia in the older population over two decades (OR(CFAS II vs I) 0.7; 0.6, 0.9). is results in stable estimates for the number of people with dementia on the UK over the last 20 years rather than the anticipated substantial increase. e reduction identi- ed was substantial and might be accounted for societal changes such as improvements in education and prevention and treatment

strategies in recent decades. In the UK, substantial evidence exists for inequality in health, and these ndings suggest that some areas will have bene ted more than others from reduction in risk.

Economic impact of dementia

e economic impact of dementia is considerable and includes not only forma but also informal care costs.

Formal care costs refer to those related to the medical care sys- tem, such as costs of hospital care, medication, and visits to clin- ics, services provided outside of the medical care system including community services such as home care, food supply, and transport, and residential or nursing home care. Informal care costs relate to the care provided by unpaid caregivers, normally family members or close friends who, as a consequence, are prevented from earning their own income.

According to the Alzheimer’s Disease International,14 the total cost of dementia, estimated worldwide, was US$604 billion in 2010, with about 70 per cent of the costs coming from Western Europe and North America. ese costs account for around 1 per cent of the world’s gross domestic product. e cost per person with dementia is more than 50 times higher in the richest world regions (e.g. North America, US$48,605) than in the poorest (e.g. South Asia region, US$903).

In LAMIC, informal care costs predominate, accounting for 58 per cent of all costs in low-income and 65 per cent of all costs in lower-middle-income countries, compared with 40 per cent in

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214 SECTION 3 cognitive impairment and dementia

HIC. Conversely, in HIC, the direct costs of care account for the largest element of costs, as between one-third and one-half of all people with dementia live in resource- and cost-intensive resi- dential or nursing home care facilities. It was estimated that in LAMIC only 6 per cent of people with dementia live in care homes. However, this sector is expanding rapidly, particularly in urban set- tings in middle-income countries, boosted by demographic and social changes that reduce the availability of family members to provide care.

e costs of dementia are estimated to increase by 85 per cent by 2030 worldwide, based only on predicted rise in numbers of peo- ple with dementia. Costs in LAMIC are likely to rise faster than in HIC, due to the shi from informal to formal care as a consequence of economic development, and because of the sharper increase in numbers of people with dementia in those regions.14

In 2010, Alzheimer’s Research Trust (now ARUK), a research charity in Britain, commissioned a report focusing on the economic burden of dementia and other chronic diseases. ey estimated that every patient with dementia cost the economy £27,647 per year, more than the UK median salary (£24,700 at the time). By contrast, patients with cancer cost £5,999, stroke £4,770, and heart disease £3,455 per year. e total cost of dementia to the UK was estimated to be £23 billion, which almost matched those of cancer (£12 bil- lion), heart disease (£8 billion), and stroke (£5 billion) combined. At the time, government and charitable spending on dementia research was 12 times lower than on cancer research: £590 million is spent on cancer research each year, compared to just £50 million in dementia research. For every person with cancer, £295 is spent each year on research, compared to £61 for dementia.15

e key ndings from the 10/66 Dementia research group in LAMIC on the economic impact on dementia care were that a high proportion of caregivers had to reduce their paid work to provide care. Governmental compensatory nancial support was negligi- ble. Families faced the additional expense of paid carers and health services, required in addition to public healthcare, presumably because the latter was insu cient or failed to meet their needs.16

Limitations and problems: Diagnostic

accuracy, ascertainment

Prevalence, incidence, and derived measures are heavily in uenced by the methodological di erences of studies and have restricted worldwide comparisons.

At the most basic level, case de nition is not a straightforward process. Diagnosing exactly when an individual with cognitive impairment crosses over to dementia is, as discussed in other chap- ters, to some extent subjective, particularly in the older population where medical comorbidity, which may independently or concur- rently interfere with normal functioning, is common.

Attempts have been made to address case de nition through development of multiple classi cations. However, depending on the system of diagnostic classi cation used, individuals can be identi ed as being a case according to one system, but not accord- ing to the other.17

Llibre Rodriguez and colleagues11 conducted a study to verify the prevalence of dementia in LAMIC according to two de nitions of dementia. e rst was based on an algorithm derived from three measures:18 the Geriatric Mental State Examination/Automated Geriatric Examination Computer Assisted Taxonomy (GMS/

AGECAT),19 Community Screening Instrument for Dementia, and the modi ed Consortium to Establish a Registry of Alzheimer’s Disease (CERAD) ten-word list-learning task.20 e second de ni- tion used was derived from the diagnostic and statistic manual of mental disorders (DSM-IV).21

Across 10/66 regions dementia prevalence varied between 5.6 per cent and 11.7 per cent using the 10/66 dementia algorithm, and 0.4 per cent and 6.4 per cent when using the DSM-IV crite- ria. Prevalence determined by the DSM-IV criteria was generally half of that estimated by the 10/66 algorithm at every site.11 When Erkinjuntti and colleagues17 examined the e ects of six di erent classi cation schemes for diagnosing dementia in the same popu- lation, they found that the frequency of dementia varied depend- ing on the scheme adopted: 3.1 per cent using the international classi cation of diseases (ICD-10), 4.9 per cent with Cambridge mental disorders of the older population examination (CAMDEX), 5.0 per cent with ICD-9, 13.7 per cent with DSM-IV, 17.3 per cent with DSM-III-R, 20.9 per cent according to the Canadian Study of Health and Aging (CSHA) clinical-consensus method,22 and 29.1 per cent with the DSM-III criteria.

Changes in diagnostic criteria over time also challenge diagno- sis ascertainment, especially when de ning dementia subtypes. Criteria for frontotemporal dementia, vascular cognitive impair- ment and dementia, dementia with Lewy bodies and AD have changed and continue to change with the advent of new neuroim- aging techniques and biomarkers.

Some studies base the diagnosis of dementia on a consensus approach, where a multidisciplinary panel of expert clinicians meet to review detailed information on various aspects of an individ- ual such as clinical examination, informant reports of cognition, behaviour, functional impairment, and neuropsychological diag- nosis.23 However, in such cases, the diagnosis process is inevita- bly in uenced by the clinicians’ philosophy, personality, discipline, and inherent biases. By standardizing data collection, the in uence of between-clinician variability is attenuated, which assists study diagnostic reliability and, potentially, validity.24

Representativeness is also an important issue. Few studies can be considered as truly representative of the whole population (Box 20.1). Studies based on referral of patients can cause popu- lation bias a ecting the results of epidemiological studies.25 It is well known that referral is in uenced not only by the condition itself but may vary according to burden of symptoms, recogni- tion of problems in a given family, access to healthcare, how much attention the media are giving to the condition, and the presence of specialized centres nearby.26 Furthermore, convenience or clini- cal studies may have strict selection criteria; for example, excluding individuals with common comorbidities. Similarly, many studies exclude individuals who live in institutions, potentially leading to underestimation of dementia prevalence, rates of cognitive decline, and mortality.

Studies based on performance on cognitive tests may be in u- enced by factors other than cognition. Educational background, cultural experiences, prior testing experience, emotional and phys- ical states, testing environment, use of medicines, and measure- ment error are hard to control even when the same cognitive test is used.27,28

Another methodological source of bias is missing data. Missing values can be due to non-response at baseline or death or drop- out during the study. Longitudinal and multi-stage studies are

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Box 20.1 Main studies on the epidemiology of dementias (chronological order)

Longitudinal studies

◆ Lundby Study59

◆ Iceland birth cohort60
61

◆ Gothenburg Study62

◆ Cambridge City over-75s Cohort Study (CC75C)63

◆ Framingham64

CHAPTER 20 epidemiology of dementia 215 e causes of dementia in di erent

age groups

Not only does dementia have di erent incidence and prevalence according to age but also the subtypes of dementia di er in terms of incidence and prevalence in di erent age groups.

Regardless of all these methodological issues, the most preva- lent clinically diagnosed dementia subtypes are the neurodegen- erative disorders, Alzheimer’s disease (AD), vascular cognitive impairment/dementia (VaD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB). In this chapter, other types of dementia such as metabolic, due to sleep apnoea, head trauma, dementia plus syndromes, etc., will not be covered.

Although it is generally agreed that AD is the commonest cause of dementia, studies show less agreement regarding the ordering of the other causes. In order to compare such studies, it is relevant to consider the changing pathological/clinical conceptual framework in which these disorders have been diagnosed over the years. us, for many years following Alois Alzheimer’s 1907 seminal descrip- tion,30 linking the presence of neuro brillary tangles and senile plaques with dementia AD was considered a presenile dementia. It was only in the 1960s that Blessed and colleagues31 showed that the brains of patients derived from with senile dementia were associ- ated with this same neuropathology, leading to the broader concept of AD across the age spectrum. Similarly, the presenile dementia with lobar brain atrophy described by Pick32 and named in his honour by Alzheimer is now classi ed clinically within the FTD spectrum.

A further complexity is that although the neuropathological sub- strates of DLB and FTD were rst described at the beginning of the twentieth century, the techniques which are currently used to identify them are relatively recent and are more sensitive than the originally used.33,34 erefore, these diseases have only recently35,36 attracted more attention and have not been investigated in most population-based studies. FTD and DLB are also not fully sup- ported by the DSM and ICD classi cation systems, with consensus guidelines used to de ne them changing over time. As a conse- quence, FTD and DLB have not been included in some population- driven studies of prevalence and incidence, perhaps leading to an overestimation of the incidence and prevalence of AD and VaD.

Two di erent perspectives have been looked at when creating diagnostic systems for dementia subtypes: the clinical manifesta- tion and the underlying neuropathological features. Some classi- cation criteria, such as the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS–ADRDA), rely on histopathological con rmation to diagnose AD as a de nite con- dition.37 Consequently, AD is structured as a neuropathological entity despite the diagnosis of AD in life being made based on clini- cal information.38 Besides, the neuropathological diagnosis is far away from being gold standard as the neuropathological criteria for AD have changed several times over the past 30 years. In this con- text it is important to note that even in the well-established clinical centres when the diagnosis of AD is made during life, it is not unu- sual for it to be discordant with the pathological diagnosis. Beach and colleagues39 reported a sensitivity for AD clinical diagnosis ranging from 71 per cent to 87 per cent, and speci city ranging from 44 per cent to 71 per cent, when non-demented patients were excluded. On the other hand, the Nun Study found substantial AD

◆ Reykjavik Study

◆ Established Populations for Epidemiologic Studies of the Elderly (EPESE)78

◆ Gospel Oak study65

◆ Cognitive Function and Ageing Study (CFAS)66

◆ Rotterdam Study67

◆ Vantaa 85+68

◆ Personnes âgées QUID (Paquid)69

◆ Italian Longitudinal Study of Ageing (ILSA)70

◆ e ree-City study (3C)71

◆ e English Longitudinal Study of Ageing (ELSA)72

◆ Newcastle 85+ study73

◆ Epidemiological Clinicopathological Studies in Europe (EClipSE)74
Combined studies

◆ e EURODEM initiative75

◆ e 10/66 Dementia Research Group76
Synthesis of literature

◆ Delphi consensus study10

◆ Meta-analysis of dementia incidence77

◆ World Alzheimer Report 200912
especially prone to missing data due to death or dropout. However, in those cases, missing data cannot be assumed to be occurring at random as individuals with more severe cognitive impairment are more likely to dropout from a study. Missing data are even more common in retrospective studies when information is o en gath- ered from medical records. ere are no perfect solutions to the problem of missing data. Simply omitting variables or individu- als who do not have complete data o en a ects nal estimations. A number of statistical techiniques based—so-called multiple imputation—where missing values are estimated from that indi- vidual’s available data is increasingly used to handle missing data.29 Following imputation, sensitivity analysis can be run to check for similarity in observed associations in the restricted (e.g. complete case analysis) compared to the imputation derived dataset. Many- study analysis and signi cance reporting do not fully take study design into account and this will increase the report of ndings which are not fully robust.

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216 SECTION 3 cognitive impairment and dementia

lesions in brains of elderly subjects with normal cognition assessed shortly before death, creating the concept of status asymptomatic AD (ASYMAD).40

For extrapolation of results to the population to be valid, research must be conducted on a true population sample or on groups with well-characterized biases. However, paradoxically, the pathological criteria for the dementia subtypes rather than being based on the population, were derived from brains originated from highly selec- tive clinical samples.41 In truly population-based pathological sam- ples, the neuropathological hallmarks of dementias o en coexist, which makes determining dementia subtypes even more complex. us Xuereb JH and colleagues,42 in the rst truly population- based clinical neuropathological correlation study in dementia, demonstrated that participants with probable AD showed less severe AD pathology but more mixed pathologies. In a later publi- cation when more brains were added to the sample,43 these ndings were con rmed: 22 per cent of the brains of participants with clini- cal dementia had mixed pathologies. e Honolulu–Asia Aging study44 and the Hisayama study45 also showed similar ndings with respectively 16 per cent and 34 per cent of participants clini- cally diagnosed as having dementia having mixed pathologies, at post-mortem. e CFAS cohort has similarly reported both a high prevalence of vascular pathology and the co-occurrence of a mix- ture of AD and vascular pathology in populations with dementia.46 Despite this evidence, most studies aiming to verify the distribu- tion of dementia subtypes in the population disregard the possibil- ity of mixed dementias, which is a particular problem in older age groups.

ere is evidence not only that neuropathology is more heteroge- neous than our clinical practice recognizes but also that the classic neuropathological features of AD, which are not pathognomonic of AD, can be seen in brains of people dying without dementia; this is true especially in the older age group. Studies that have included individuals in the oldest age groups consistently show that signi – cant numbers of those who die in their 80s and 90s have pathologi- cal features of AD without a diagnosis of dementia during life.46,47 Savva and colleagues48 explored the e ect of age on the relationship between the classical neuropathological features and clinical mani- festation of dementia in a population-based cohort of older people. e burden of AD-type pathological lesions increased with age in individuals without dementia, in contrast to those with dementia where this burden was either constant or declined with age. is study indicated a convergence of AD-type pathological features in individuals with and without dementia at very advanced ages: the di erence in the burden of AD neuropathology was more marked in the younger old with and without dementia than at older ages.

Besides, Boyle and colleagues49 found that much of late life cog- nitive decline is not due to common neurodegenerative patholo- gies. When examining 856 brains of deceased participants from two longitudinal clinical-pathologic studies, the Rush Memory and Aging project and the Religious Orders Study, they found that although pathological indices of the common causes of dementia are important determinants of cognitive decline in old age, much of the variation in cognitive decline remains unexplained, suggesting that other important determinants of cognitive decline remain to be identi ed.

When studying the e ect of age on dementia it is important to highlight that the other extreme of age, people younger than 65 years, are o en le out of studies investigating dementia. AD

can certainly manifest before this age, and some causes of demen- tia (e.g FTD) may be even more prevalent than in the very old.50 e Lundby study,51 which took into account participants of less than 65 years, found that among those who developed dementia from 1947 to 1972, 46 per cent had ‘senile dementia of Alzheimer type’ (SDAT) and the remaining 54 per cent, ‘multi-infarct demen- tia’ (MID). ere was no mention of mixed dementias. e authors also did not look at FTD or DLB, probably because the collection of their sample pre-dated the formal identi cation of these entities.

e distribution of dementia subtypes according to the age groups is shown in Table 20.2.

More recent population-based studies have considered DLB and FTD diagnosis.

Stevens and colleagues52 reported on the distribution of clini- cal dementia subtypes in a community-based study of people aged 65 years or over. ey found that the prevalence of AD was 31 per cent, VaD 22 per cent, DLB 11 per cent, and FTD 8 per cent. When using the DSM-IV criteria, 57 per cent of patients diagnosed as having DLB according to the consensus criteria53 were shi ed to the AD category and 14 per cent to the VaD. Among the FTD patients (diagnosed according to the FTD consensus),54 50 per cent were re-classi ed as AD and 17 per cent as VaD.

Yamada and colleagues55 studied the prevalence of dement- ing disorders in a rural town of Japan (Amino-cho). Of the 3715 individuals aged 65 years or older, the prevalence for all types of dementia was 4 per cent, and for the subtypes 2 per cent of AD, 1 per cent of VaD, and 0.1 per cent of DLB; no patients with FTD were identi ed. e distribution of dementia subtypes according to age is particularly relevant to those who see patients with young- onset dementia, where the subtypes prevalence and incidence di er from those in the older population.

Ratnavalli56 estimated the prevalence of dementia subtypes in a population at 65 years of age or less, living in Cambridge city or east or south Cambridgeshire in the UK. Case ascertainment was by review of case records and inpatient admissions at a univer- sity hospital and checking with primary care. ey identi ed 108 patients with early-onset dementia, with an overall prevalence of 81 per 100 000 in the 45–64 age-group. e prevalence of early-onset FTD and AD were the same (15.1 per 100 000) and for VaD 8.2 per 100 000. ey identi ed no patients with DLB in that age group.

Similar results were found by Harvey and colleagues50 when determining the prevalence of dementia in population of 65 years of age or less in three London boroughs, with diagnosis and age of onset established from all available health and social care records.

Table 20.2 Number of participants with rst- time dementia diagnosis according to dementia subtype and age groups in the Lundby study from 1947–72

Source data from Neuroepidemiology. 11(Suppl 1), Hagnell O, Ojesjo L, and Rorsman B, Incidence of dementia in the Lundby Study, pp. 61–6, Copyright (1992), S. Karger AG, Basel.

Age group

SDAT

MID

0–59

60–79

80+

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90 80 70 60 50 40 30 20 10

0
40–44 45–49 50–54 55–59 60–64

Age group

dementia (6 per cent), and FTD (3 per cent). Fig. 20.2 discloses the dementia subtypes by age groups, showing that for all, VaD was the most prevalent dementia subtype. Another interesting nding in this study was the high frequency of DLB. One possible explana- tion is that the authors amalgamated DLB patients with those with Parkinson’s disease with dementia.

Studies such as these are, however, dependent on the accuracy of clinical diagnosis, consistent diagnostic criteria being used between studies and over time, and adequate ascertainment. In practice, these factors all prove di cult to identify, perhaps particularly in young-onset dementia where the di erential diagnosis is o en broad.58

Conclusion

e world population is ageing, a phenomenon which is true not only for HIC but also for LAMIC. With ageing, it is expected that the prevalence of dementias will increase considerably, causing huge social and economic impacts on society. Studies designed to verify the impact of dementia and its subtypes in the population have many methodological issues, especially regarding case ascer- tainment. In the population, dementia subtypes are o en mixed, which is not o en taken into account in most clinical studies. In the oldest old, the relationship between neuropathological burden and cognitive impairment is o en less clear as many individuals without dementia have at least some, and sometimes marked, neu- ropathological hallmarks of neurodegenerative disease. In younger people, dementia is rarer and associated with a di erent distribu- tion of causes compared to the older population.

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Fig. 20.1 Prevalence of dementia subtype in the younger in London boroughs of Kensington and Chelsea, Westminster, and Hillingdon, UK.
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AD VD FTD DLB

AD VD FTD

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Prevalence per 100,000

218 SECTION 3 cognitive impairment and dementia

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63. O’Connor DW, Pollitt PA, Hyde JB, et al. e prevalence of demen- tia as measured by the Cambridge Mental Disorders of the Elderly Examination. Acta Psychiatr Scand. 1989 Feb;79(2):190–8. PubMed PMID: 2923012. Epub 1989/02/01.

64. Linn RT, Wolf PA, Bachman DL, et al. e ‘preclinical phase’ of proba- ble Alzheimer’s disease. A 13-year prospective study of the Framingham cohort. Arch Neurol. 1995 May;52(5):485–90. PubMed PMID: 7733843. Epub 1995/05/01.

65. Livingston G, Hawkins A, Graham N, et al. e Gospel Oak
Study: Prevalence rates of dementia, depression and activity limita- tion among elderly residents in inner London. Psychol Med. 1990 Feb;20(1):137–46. PubMed PMID: 2138793. Epub 1990/02/01.

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and Ageing: A EURODEM incidence study in progress. Neuroepidemiology. 1992;11 Suppl 1:37–43. PubMed PMID: 1603246. Epub 1992/01/01.

67. Ott A, Breteler MM, van Harskamp F, et al. Incidence and risk of dementia. e Rotterdam Study. Am J Epidemiol. 1998 Mar 15;147(6):574–80. PubMed PMID: 9521184. Epub 1998/04/01.

68. Polvikoski T, Sulkava R, Haltia M, et al. Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein. N Engl J Med. 1995 Nov 9;333(19):1242–7. PubMed PMID: 7566000. Epub 1995/11/09.

69. Letenneur L, Jacqmin H, Commenges D, et al. Cerebral and functional aging: First results on prevalence and incidence of the Paquid cohort. Methods Inf Med. 1993 Apr;32(3):249–51. PubMed PMID: 8341161. Epub 1993/04/01.

70. Maggi S, Zucchetto M, Grigoletto F, et al. e Italian Longitudinal Study on Aging (ILSA): Design and methods. Aging (Milano). 1994 Dec;6(6):464–73. PubMed PMID: 7748921. Epub 1994/12/01.

71. Alperovitch A, Amouyel P, Dartigues JF, et al. Les études epide- miologiques sur le vieillissement en France: De l’étude Paquid a l’étude des Trois Cites. C R Biol. 2002 Jun;325(6):665–72. PubMed PMID: 12360853. Epub 2002/10/04.

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73. Collerton J, Davies K, Jagger C, et al. Health and disease in 85 year olds: Baseline ndings from the Newcastle 85+ cohort study. BMJ. 2009;339:b4904. PubMed PMID: 20028777. Pubmed Central PMCID: 2797051. Epub 2009/12/24.

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CHAPTER 20 epidemiology of dementia 219

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CHAPTER 21

Assessment and investigation
of the cognitively impaired adult Jonathan M. Schott, Nick C. Fox, and Martin N. Rossor

Introduction

Confronted by a patient with symptoms suggestive of cognitive impairment, the clinician has a number of key questions to address:

. (1) Is there evidence of cognitive impairment representing a decline from previous levels of functioning?

. (2) What is the cause of the cognitive impairment?

. (3) How and to what extent are any impairments impacting on the individual’s ability to function normally, and a ecting those around them?

. (4) What strategies—be they pharmacological or non- pharmacological—may be helpful both to improve the situ- ation for the individual in question and those living with or caring for them?

e assessment of a patient in this setting requires a systematic approach: detailed history-taking remains the mainstay of the diagnostic process, complemented by a focused cognitive assess- ment and physical examination. A number of ‘routine’ investi- gations should be undertaken, supplemented by additional tests depending on the speci c scenario. Once a diagnosis has been reached, appropriate management recommendations can then be made.

In this chapter, we provide an overview of this diagnostic process, with particular reference to the importance of establishing the time course over which impairments have occurred; which cognitive domains are a ected and what cognitive de cits result; and how, taken together with the examination and investigation ndings, a speci c dementia syndrome and the probable underlying disease process can be diagnosed. Whilst for the primary neurodegenera- tive dementias, the cognitive history and examination are o en the most important clues to diagnosis, in other, rarer cases, cognitive impairment may occur in the context of a range of other non-cog- nitive, o en neurological or general features—so called dementia plus.1 In these cases, the non-cognitive features may be more diag- nostically pertinent.

A note on de nitions

According to criteria dating from 1994, a diagnosis of ‘dementia’ requires an individual to have impairments of cognition, involv- ing memory and at least one other cognitive domain su cient to interfere with activities of normal living. is de nition, whilst being

recommended for use by the American Academy of Neurology Guidelines2 does, however, have a number of problems: heavily weighted towards memory impairment and thus Alzheimer’s dis- ease, it may be less relevant to patients with other focal cognitive syndromes, where memory impairment is not the leading syn- drome and indeed may not be present. A diagnosis of dementia says nothing about the cause of the cognitive impairment, and there may be some overlaps with delirium in certain conditions. Finally, the requirement for multiple domain impairments that impact on activities of daily living e ectively precludes patients with early or isolated symptoms (see also chapter 32).

A number of other terms have been introduced to describe indi- viduals with isolated or milder forms of cognitive impairment, the most commonly used of which is mild cognitive impairment (MCI), sometimes further divided into amnestic, non-amnestic, or multi-domain MCI.3 New criteria for DSM–V include new de nitions for delirium but also two new syndromes. Major neu- rocognitive disorder, including what is currently referred to as dementia, and minor cognitive disorder, for individuals with mild cognitive de cits in one or more domains but who are still able to function independently [Table 21.1]. Recognition of a cognitive problem is, however, not an end in itself, and as well as these broad syndromic de nitions, more speci c criteria for individual disor- ders have been proposed, discussed in detail in other chapters.

History-taking

Establishing as detailed a history as possible is a prerequisite for reaching an accurate diagnosis. e cognitively impaired individ- ual may not be in a position to provide a detailed history of their current problems alone, and for this reason, and with the patient’s permission, a collateral history should be taken from an informant— ideally interviewed alone—wherever possible.

e patient’s age is clearly relevant to the likely diagnosis: in general, sporadic neurodegenerative dementias are diseases of the elderly although they can occur in mid-life, whereas metabolic and genetically inherited dementias are more likely to present earlier. Handedness should always be recorded, having potential bearing on the interpretation of cognitive testing. Ascertaining an individual’s prior level of functioning, for example from educational achievement and employment history, provides useful information about previous level of cognitive functioning which might be crucial for interpreta- tion of some cognitive test results.

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222 SECTION 3 cognitive impairment and dementia Table 21.1 Criteria for dementia and cognitive impairment

Dementia (DSM–IV)

◆ Short- and long-term memory impairment

◆ Impairment in abstract thinking, judgment, other higher cortical function or personality change

◆ Cognitive disturbance interferes signi cantly with work, social activities, or relationships

◆ Cognitive changes do not occur exclusively in the setting of delirium

Mild Cognitive Impairment (MCI)

Amnestic MCI

◆ Cognitive complaints from patient

◆ History suggestive of decline from previous level of functioning

◆ Objective memory impairment for age

◆ Preserved functional abilities

◆ Not demented

◆ Memory alone a ected; or memory + other cognitive domains (multi-domain amnestic MCI)
Non-amnestic MCI

◆ Cognitive complaints from patient

◆ History suggestive of decline from previous level of functioning

◆ Evidence for impairment on testing

◆ Preserved functional abilities

◆ Not demented

◆ Single or multiple (multi-domain non-amnestic MCI) non-memory domains a ected

Neurocognitive Disorder (DSM–V)

Major Neurocognitive Disorder

Signi cant cognitive decline from a previous level of performance in one or more of the following:

◆ Complex attention

◆ Executive ability

◆ Learning and memory

◆ Language (expressive, receptive, naming)

◆ Visuoconstructional-perceptual ability

◆ Social cognition
Based on:

1. Reports by the patient or caregiver of clear decline; and

2. Clear de cits (typically <2SDs or <2.5th %-ile) on objective testing

Cognitive de cits are:

◆ Su cient to interfere with independence

◆ Not exclusively in the context of delirium

◆ Not wholly or partially attributable to major psychiatric disease
Minor Neurocognitive Disorder
Minor cognitive decline from a previous level of performance in one or domains above, based on:

1. Reports by patient/caregiver (e.g. greater di culty; using compensatory strategies)

2. Mild de cits (e.g. 1–2SDs below mean or 2.5–16th %-ile) on objective testing or a signi cant decline (e.g. 0.5SD) on serial testing;

Cognitive de cits are:

◆ Not su cient to interfere with independence (but greater e ort/compensation required)

◆ Not exclusively in the context of delirium

◆ Not wholly or partially attributable to major psychiatric disease

Source data from American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM–IV), Copyright (2000), and Fifth Edition (DSM–5), Copyright (2013), American Psychiatric Association; Adapted from J Int Med. 256(3), Petersen RC, et al. Mild cognitive impairment as a diagnostic entity, pp. 183–94, Copyright (2004), with permission from John Wiley and Sons.

Timing and clinical course

e timing of development of any impairments has direct relevance to the diagnosis: whilst there may be considerable overlap in indi- vidual cases, most neurodegenerative dementias and metabolic dis- eases slowly progress over years, whilst prion disease, and infective and in ammatory conditions typically progress much more rapidly. Acute confusional states are more likely to re ect delirium than

dementia and a di erent range of aetiologies, but of course delir- ium can also occur in the context of dementia. It is therefore help- ful to ask the patient and informant to try and identify the timing of the earliest possible symptoms relating to the current problems. e pattern of progression should also be noted: abrupt onset or decline may suggest a vascular cause, although many cases of vas- cular cognitive impairment do not have the step-wise progression

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previously considered a core feature;4 uctuations are commonly seen in cortical Lewy body disease,5 but may also suggest metabolic problems or seizures.

Determining the cognitive domains a ected

e next stage in the history is to determine both the patient and informant’s reports of the speci c cognitive problems. When so doing, it is important to try to determine whether there has been objective decline from a previous level of functioning—a distinc- tion that is important for the diagnosis of a dementia or major/ minor neurocognitive disorder—and thus establishing concrete examples of change and its impact at home and work is important. An initial question to be addressed is which cognitive domains are involved. ‘Memory impairment’ is o en used as a surrogate for cognitive impairment in more general terms, but for some patients presenting at cognitive disorders clinics, memory impairment may not be present, or may not be the major problem.

Where memory is the major issue, the commonest problem encountered will be the insidious erosion of event or episodic mem- ory as seen in the majority of patients with Alzheimer’s disease with, for example, di culties remembering recent events, telephone con- versations, or appointments, re ecting medial temporal lobe com- promise. is, however, should be distinguished from other forms of memory impairment including those for names of common objects (semantic memory) and faces/routes, which suggest di erent ana- tomical localization (le and right temporal lobe respectively).

Symptoms referable to other cognitive domains should be sought: these include problems with spelling, numeracy, or object use (apraxia) that suggest dominant (le ) parietal lobe dysfunc- tion; problems related to vision including visual perception and location of objects in space, as seen in non-dominant (right) pari- etal lobe or occipital lobe dysfunction; or behavioural change, including apathy, socially inappropriate behaviour, impulsiv- ity, loss of sympathy/empathy, ritualistic behaviour or dietary changes, that re ect dysfunction of the frontal lobe or its connec- tions. Very prominent cognitive slowing may suggest subcortical involvement. Where possible, documenting speci c examples of any impairment is o en particularly helpful. In this way, the cli- nician should aim to build up a picture both of the extent of any cognitive problems and the impact they have on the individual and those around him/her, but also which anatomical brain regions are either involved or spared.

Neurological history

It is important to consider a relevant review of a number of neu- rological symptoms, whose presence or absence may both give clues to an underlying diagnosis—particularly in unusual dementia syndromes—and have bearing on management. Visual disturbance may re ect cortically based problems with visual processing (e.g. optic ataxia, ocular apraxia, simultagnosia) but may also be seen in cranial nerve dysfunction, in which case the di erential diagnosis is very di erent. e presence or absence of speech and swallow- ing problems is important both diagnostically and may also have practical management issues. Focal weakness, ataxia, extrapyrami- dal involvement (particularly the emergence of parkinsonian fea- tures or hyperkinetic movements), sensory disturbance, symptoms suggestive of denervation (muscular thinning, weakness, cramps), falls, or gait impairments disturbance can all narrow the di erential diagnosis considerably (Table 21.2).

Psychiatric history

The presence of depression or anxiety may be sufficient to lead to cognitive complaints per se but may also complicate estab- lished dementia and occur as early manifestations of neurode- generative disease. Early behavioural change is a cardinal feature of frontotemporal dementia but can also accompany vascular cognitive impairment and a range of other dementing disorders. Delusions and hallucinations may reflect a primary psychiatric disorder, particularly when long standing. However, the devel- opment of these symptoms later in life should serve as a ‘red flag’ for the possibility of an emerging dementia. In particular, the emergence of well-formed visual hallucinations, particu- larly in the presence of motor parkinsonism is very suggestive of dementia with Lewy bodies; and psychosis can be seen in some forms of frontotemporal dementia (e.g. due to mutations in the c9orf72 gene).6

Past medical history and medications

e presence of signi cant vascular risk factors (hypertension, smoking, diabetes, hypercholesterolaemia, and atrial brilla- tion) may alert the clinician to the possibility of vascular cogni- tive impairment (VCI); conversely, their absence should prompt a reappraisal of this diagnosis. A history of frank epilepsy or symp- toms suggestive of seizures, psychiatric disorders, autoimmunity, signi cant head trauma, cranial surgery, obstructive sleep apnoea, rapid-eye-movement sleep behaviour disturbance (shouting dur- ing sleep, acting-out dreams, and vivid dreams), metabolic dis- turbance, multiple sclerosis, vascular events, or prior malignancy may all be relevant. Similarly, current and past medication use may both cause cognitive impairment or in uence phenotype. Commonly encountered problems in this context include the interpretation of extrapyramidal signs in patients who have been exposed to neuroleptics, the cognitive blunting that can accom- pany sedative or opiate use, and confusion associated with the use of anticholinergic drugs.

Family history

In all patients presenting with a cognitive disorder, detailed fam- ily history-taking is mandatory. A family history suggestive of autosomal dominant inheritance of a similar disorder, particularly but not exclusively at young age, may suggest an underlying single gene disorder (Fig. 21.1). is has implications for both how an individual may be diagnosed, but potentially also for other fam- ily members. Particular care should be taken in the presence of a censored or unknown family history; an absence of family history does not entirely exclude an autosomal dominant dementia due to mis-paternity. e possibility of an autosomal recessive inheritance should also not be discounted: whilst none of the principle neuro- degenerative forms of dementia have yet been shown to be inher- ited in this way, a number of disorders within the ‘dementia plus’ spectrum may be.

Social history

e patient’s social circumstances should be explored, including whom they may live with and what level of support is available at home. In many patients, including those who present with sub- jective memory complaints but do not have a diagnosis of demen- tia, discussing the social network of the individual and stressors

CHAPTER 21 assessment of the cognitively impaired adult 223

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224 SECTION 3 cognitive impairment and dementia Table 21.2 Causes of dementia plus

Dementia plus …

Di erential diagnosis

Ataxia

Spinocerebellar ataxia, paraneoplastic diseases, prion diseases, DRPLA, fragile x-associated tremor ataxia syndrome, familial British and Danish dementias, mitochondrial disorders, super cial siderosis, neuronal ceroid lipofuscinosis, Niemann–Pick disease type C, multiple system atrophy, Alexander’s disease, and multiple sclerosis

Pyramidal signs

Multiple sclerosis, frontotemporal lobar degeneration with motor neuron disease, Alzheimer’s disease (some presenilin mutations), spinocerebellar ataxias, phenylketonuria, familial British and Danish dementias, some forms of hereditary spastic paraparesis, adrenoleukodystrophy, vanishing white matter disease, polyglucosan body disease, polycystic lipomembranous sclerosing leukoencephalopathy (Nasu–Hakola disease)

Dystonia/chorea

Huntington’s disease (and related disorders), Kuf’s disease, Wilson’s disease, neuroacanthocytosis, neurodegeneration with brain iron accumulation, Lesch–Nyhan syndrome, DRPLA, corticobasal degeneration, neuroferritinopathy, anti-NMDA receptor-mediated limbic encephalitis, variant CJD

Bucco-lingual mutilation

Neuroacanthocytosis, Lesch–Nyhan syndrome

Akinetic-rigid syndrome

Lewy body disease, progressive supranuclear palsy, multiple system atrophy Huntington’s disease, corticobasal degeneration, dementia pugilistica, Wilson’s disease, neurodegeneration with brain iron accumulation, frontotemporal lobar degeneration with parkinsonism-17, Alzheimer’s disease (usually advanced)

Peripheral neuropathy

Neuroacanthocytosis, cerebrotendinous xanthomatosis, HIV infection, giant axonal neuropathy, alcohol-related diseases, metachromatic leukodystrophy, porphyria, adrenoleukodystrophy, GM2 gangliosidosis, polyglucosan body disease, Krabbe’s disease, sialidosis, Fabry’s disease, mitochondrial disorders, spinocerebellar ataxias (particularly type 3)

Myoclonus/early seizures

Prion disease, Alzheimer’s disease, Lewy body disease, DRPLA, mitochondrial disorders, Gaucher’s disease, GM2 gangliosidosis, neuroserpinopathy, polycystic lipomembranous sclerosing leukoencephalopathy, subacute sclerosing panencephalitis, progressive myoclonic epilepsy syndromes, Kuf’s disease, Lafora body disease, sialidosis

Gaze palsy

Niemann–Pick disease type C, Gaucher’s disease, progressive supranuclear palsy, mitochondrial disorders, spinocerebellar ataxias (particularly type 2), paraneoplastic disorders, Whipple’s disease

Deafness

Super cial siderosis, mitochondrial disorders, familial Danish dementia, alpha mannosidosis, sialidosis

Dysautonomia

Lewy body disease, multiple system atrophy, prion disease, porphyria, adrenoleukodystrophy, anti-NMDA receptor- mediated limbic encephalitis

Cataracts

Myotonic dystrophy, cerebrotendinous xanthomatosis, mitochondrial disorders, familial Danish dementia

Splenomegaly

Niemann–Pick disease type C, Gaucher’s disease

Tendon xanthomas

Cerebrotendinous xanthomatosis

Bone cysts

Polycystic lipomembranous sclerosing leucoencephalopathy

Paget’s disease/Inclusion body myositis

Valosin-associated frontotemporal lobar degeneration

Renal impairment

Fabry’s disease, Lesch–Nyhan syndrome, mitochondrial disorders

Liver dysfunction

Wilson’s disease, Gaucher’s disease, mitochondrial disorder

Respiratory failure

Frontotemporal lobar degeneration and motor neuron disease, Perry syndrome, mitochondrial disease (e.g. POLG), anti-NMDA receptor-mediated limbic encephalitis

Gastrointestinal dysfunction

Coeliac disease, Whipple’s disease, porphyria

Anaemia

Vitamin B12 de ciency, neuroacanthocytosis (McLeod’s syndrome), Wilson’s disease, Gaucher’s disease

Skin lesions

Behcet’s disease, systemic vasculitides and connective tissue disease, Fabry’s disease

Metabolic/infectious crises

Vanishing white matter disease, Alexander’s disease, ornithine transcarbamylase de ciency, alpha mannosidosis, porphyria

Hyponatraemia

LgI1 antibody associated encephalitis

Adapted from Lancet Neurol. 9(8), Rossor MN, Fox NC, Mummery CJ, Schott JM, and Warren JD, e diagnosis of young-onset dementia, pp. 793–806, Copyright (2010), with permission from Elsevier.

at home and work provides crucial insights into potential factors that might be exacerbating cognitive symptoms. Some patients with cognitive impairment may be very vulnerable, and poor judgment or memory can result in signi cant nancial problems. Ascertaining what the individual in question is able to do around the house, whether they are safe or need supervision, and in the

younger population, whether they are still able to work, has impli- cations for management. Estimating current and past alcohol use is also important, as is obtaining a smoking history. It is o en import- ant to establish whether the patient is driving, and if so, whether there is any evidence to suspect that this is being in uenced by their cognitive problems.

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Fig. 21.1 Family tree in family Alzheimer’s disease due to a presenilin1 mutation. Squares = male; Circles = female; Black centre = gene positive; White centre = gene negative.

Overview

Having taken the history, the clinician should aim to answer a num- ber of key questions:

. (1) Is there clear evidence for cognitive decline from a higher baseline?

. (2) Which cognitive domains appear to be a ected?

. (3) Does the pattern and progression of cognitive impairment combined with the other clinical features suggest a speci c diagnosis?

With these questions in mind, the examination and investiga- tions, whilst needing to be comprehensive, can be focused towards con rming or refuting the putative diagnosis reached at this stage.

Examination Cognitive examination

e bedside cognitive examination is discussed in detail in chapter 10. In brief, such an assessment generally starts with a broad screen- ing tool to establish the level of any cognitive impairment, with the caveat that no single screening tool can reliably assess severity across all dementia syndromes. e assessment then should focus on establishing—in the same way as was done during history- taking—which cognitive domains are a ected or spared, through the use of tests which probe speci c cognitive domains; for exam- ple, implicating dysfunction within one or more lobes of the brain, or where possible more ne-grained neuroanatomical description. In general, it is important to observe the patient’s behaviour and interaction with the environment and those around them. Patients with Alzheimer’s disease usually maintain a preserved social façade at least in the early stages of the disease, but may turn to their partner/ carer when questioned, and become withdrawn and tentative. By contrast, patients with dysexecutive syndromes may be overfamil- iar, withdrawn, or inappropriate, sometimes showing utilization behaviour (inappropriately using objects with speci c functions, e.g. seeing a pen, picking it up, and writing unasked during a con- sultation7). Note should be made about whether a patient engages when tested, and whether their performance is in keeping with their functioning in everyday life.

Physical examination

Patients evaluated for a cognitive problem should have a physical examination. Whilst for most patients with Alzheimer’s disease

this will be normal, there are important physical ndings that can guide a diagnosis for many other forms of dementia. Particularly in the case of young-onset, unusual or rapid dementias, where unlike many of the cortical dementias, the pattern of cognitive impair- ment may not give major clues to the underlying diagnosis, the allied physical (neurological and/or non-neurological) symptoms and signs can provide vital clues to narrow the di erential diagno- sis (Table 21.2).

General examination

e general examination should include a cardiovascular assess- ment (pulse, blood pressure, and the heart sounds), all of which may be very relevant to helping establish a diagnosis of (or contri- bution from) vascular cognitive impairment, and in some instances can help de ne much rarer causes such as endocarditis or arteritis. A note should be made of signi cant weight loss or cachexia: exam- ination of the chest and abdomen may be particularly pertinent in patients who smoke and drink respectively. In the case of patients with young onset or more complex dementia syndromes, a detailed systems review and examination may narrow diagnosis consider- ably (Table 21.2).

Neurological examination

In many of the primary neurodegenerative dementias, the neuro- logical examination will be unremarkable. However, where present, neurological signs may help signi cantly narrow the di erential diagnosis. Examination of the eye movements is o en very reward- ing, allowing for the assessment of cerebellar dysfunction, ocular apraxia (suggestive of parietal lobe dysfunction), or either a nuclear or supranuclar gaze palsy. Speech will have been assessed as part of the cognitive assessment, but it may be relevant to assess the swal- low, alongside fundal appearances and visual elds. e presence of a brisk jaw jerk and myotatic facial re exes (elicited by gently tapping around the mouth) provides evidence for upper motor neurone lesions at brainstem level or above, as does the presence of a pout. By contrast, movement of the lips towards an approaching target or reaction to gentle stroking around the mouth is a frontal release sign.7 Observing the facial appearances may also be very revealing: facial hypomimia is suggestive of extrapyramidal disease; staring facies with frontalis overactivity and decreased blink rate are features of progressive supranuclear palsy;8 facial weakness or asymmetry may be suggestive of prior stroke.

Examination of the limbs may reveal signs of parkinsonism, suggestive of dementia with Lewy bodies, or in the case of an existing diagnosis of Parkinson’s disease, Parkinson’s disease dementia, or a number of other disorders including progres- sive supranuclar palsy, and the corticobasal syndrome classically but by no means invariably accompanied by asymmetric dys- tonia, myoclonus, and cortical sensory impairment. e pres- ence of chorea focuses the di erential diagnosis considerably (Table 21.2). e presence of a cerebellar syndrome is unusual in most of the cortical dementias, raising the possibility of alco- hol, vascular cerebellar/brainstem lesions, or a range of genetic or metabolic disorders depending on the clinical context. Focal upper motor neuron weakness is most commonly due to vascular lesions, although this has a large di erential diagnosis, including in ammatory disorders such as multiple sclerosis or neurodegen- erative disorders such as amyotrophic lateral sclerosis. A poten- tially useful observation is that in vascular cognitive impairment,

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226 SECTION 3 cognitive impairment and dementia

the re exes including jaw jerk are o en brisk, but the plantars exor. Particularly in unusual dementia syndromes, the pres- ence of a peripheral neuropathy may provide clues to diagno- sis, although in the elderly, comorbidities are common, and a mild peripheral neuropathy is not uncommon. Examination of the gait may provide useful clues to a parkinsonian syndrome or cerebellar disorder, the e ects of cerebrovascular disease, or possibly hydrocephalus. e presence of prominent retropulsion is o en seen in parkinsonian disorders, and perhaps particularly progressive supranuclear palsy.

Investigation

Following clinical evaluation, the clinician should have narrowed the di erential diagnosis and can use investigations to try to secure the diagnosis as far as possible. For all patients with cogni- tive impairment, a number of investigations including a panel of blood tests and structural brain imaging are recommended. Where possible, all patients with a possible dementing illness should have a formal neuropsychometric assessment to provide quanti – able measures of cognitive performance against age-related norms both globally and in speci c domains. is is discussed in detail in chapter 21. A range of other investigations may be appropriate depending on the clinical context.

How far to investigate patients in whom primary problems with mood or anxiety are thought to underpin the cognitive complaints will depend on the speci c circumstance and the individual patient. Where possible, obtaining baseline neuropsychometric, blood, and imaging data may help support the hypothesis that there is not a signi cant organic component, provide reassurance to the patient, and act as a baseline against which subsequent testing can be com- pared objectively. Where investigation is either not feasible or wanted by the patient, reassessment a er an interval is o en very helpful in determining whether there is a signi cant and progres- sive cognitive problem.

Blood testing

All patients with possible cognitive impairment should have a range of blood investigations, including a full blood count, blood sugar, liver function, electrolytes, thyroid function, B12, folate, and at least some in ammatory indices (e.g. ESR and/or C-reactive protein).2,9 Whilst principally designed to exclude ‘treatable’ causes of cognitive impairments, in practice, at least in our experiences it is rare for any of these conditions in isolation to be su cient to cause cognitive impairment. However, anaemia, liver and renal failure, recurrent and signi cant hypoglycaemia, vitamin B12 de – ciency, and thyroid dysfunction can certainly all cause cognitive impairment and as signi cant comorbidities, worsen other causes of dementia. Abnormalities in any of these parameters should be investigated and treated as appropriate.

Depending on the clinical setting, a large range of other blood tests may be appropriate. Outlines for the screening of poten- tial metabolic problems are given in chapter 24; for infections in chapter 23; and for autoimmune causes of cognitive impairment in chapter 28. HIV testing may be appropriate both as a treatable cause for dementia in itself10 but in addition, it raises the possibility of other opportunistic infections. In atypical parkinsonism, testing copper, caeruloplasmin, and ferritin, and excluding the presence of acanthocytes on a blood lm may all be appropriate.

Brain imaging

Brain imaging can be usefully divided into structural, functional, and metabolic imaging.

Structural imaging

Structural imaging, with magnetic resonance imaging (MRI) or computed tomography (CT), is recommended for all patients being investigated for dementia.2,9 MRI is the modality of choice, providing high white/grey matter contrast without exposure to ionizing radiation. Modern MRI scanning provides very detailed visualization of brain structure, allowing for an assessment of atrophy, and of signal change typically re ecting the presence of vascular disease or demyelination. A standard dementia sequence including a T1-weighted, T2-weighted/FLAIR ( uid-attenuated inversion recovery) sequence complemented where necessary by susceptibility-weighted imaging (sensitive to iron, and thus blood products) and di usion-weighted imaging (for recent infarcts or spongiosis), and can be performed within half an hour.11 Whilst traditionally undertaken to exclude ‘treatable’ causes (i.e. mass lesions such as tumours), MRI is increasingly being used to aid in the di erential diagnosis of the di erent dementias and is being incorporated into new diagnostic criteria.12

We recommend that examination of MRI images be done in a structured manner.13 T2/FLAIR images should be reviewed for evidence of white matter lesions. In the elderly patient, the most likely explanation for these will be on the basis of vascular disease. It is, however, important not to over-interpret the presence of a few small lesions, which is common with advancing age. However, the presence of multiple and particularly con uent vascular lesions, may be su cient, in the correct clinical context, to support a diag- nosis of either vascular cognitive impairment, or in the presence of medial temporal atrophy, mixed (e.g. VCI and Alzheimer’s dis- ease) pathology. Small focal lesions involving thalamocortical cir- cuitry can be su cient alone to cause memory or other cognitive impairments.14 Similarly, the presence of focal large infarcts dem- onstrating prior large vessel stroke would be expected to produce neuropsychological de cits in the regions a ected. White matter change, however, does not always implicate vascular disease, and in the correct clinical context, may be compatible with the e ects of multiple sclerosis and inherited or genetically determined meta- bolic diseases. Susceptibility-weighted imaging can be very useful in detecting microbleeds which, when present in the brainstem and basal ganglia, typically re ect hypertensive changes, with cortical lesions being more commonly associated with the e ects of amy- loid angiopathy (Fig. 21.2, panel f).15

T1-weighted volumetric imaging, particularly viewed in the cor- onal plane with angulations through medial temporal lobe struc- tures, can provide valuable evidence for focal atrophy, which has predictive value for di erent dementia syndromes (Fig. 21.2).16 Alzheimer’s disease is typically associated with bilateral symmetri- cal hippocampal atrophy in excess to that seen elsewhere in the cor- tex (Fig. 21.2, panel a). Involvement of parietal lobe structures and the cingulate gyrus is very common, with the general pattern usu- ally being of a posterior greater than anterior gradient.17 In some patients with Alzheimer’s disease—the posterior cortical atrophy variant—atrophy may be restricted to the occipitoparietal lobes with sparing of the hippocampi (Fig. 21.2, panel b).18

Dementia with Lewy bodies tends to produce relatively less hip- pocampal atrophy than is seen in Alzheimer’s disease,5 although

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CHAPTER 21 assessment of the cognitively impaired adult 227 (a) (b) (c)

(d) (e) (f)

(g) (h) (i)

Fig. 21.2 Imaging in the investigation of dementia. (a) Coronal MRI scan showing selective hippocampal volume loss in postmortem (PM) con rmed Alzheimer’s disease. (b) Coronal MRI scan showing prominent parietal lobe atrophy in PM con rmed posterior cortical atrophy (due to Alzheimer’s disease). (c) Coronal MRI scan showing right temporal lobe atrophy and right lateral ventricle prominance in PM con rmed frontotemporal dementia. (d) Coronal MRI scan showing very asymmetric left temporal lobe atrophy involving the hippocampus and fusiform gyrus in PM con rmed semantic dementia. (e) Di usion-weighted MRI showing basal ganglia and cortical signal change in sporadic Creutzfeldt–Jakob disease. (f) T2* MRI showing multiple cortical microbleeds in cerebral amyloid angiopathy. (g) Sagittal MRI scan shows pontine atrophy (the ‘Hummingbird sign’) in PM-proven progressive supranuclear palsy. (h) FDG-PET scan shows marked parietal hypometabolism in Alzheimer’s disease. (i) Amyloid PET imaging shows widespread cortical brillar amyloid deposits in Alzheimer’s disease.

this may not necessarily be helpful on an individual basis. Patients with frontotemporal lobar degeneration o en have striking atrophy patterns, with prominent asymmetrical frontal and/or temporal atrophy in some cases of behavioural variant FTD (Fig. 21.2, panel c), focal dominant temporal lobe atrophy particularly involving the temporal pole and fusiform gyrus in semantic dementia (Fig. 21.2, panel d), widening of the dominant Sylvian ssure in progressive non- uent aphasia, marked hemispheric atrophy in patients with progranulin mutations, and symmetrical very focal atrophy of the anterior medial temporal lobes in certain tau mutations.19

Assessments of brainstem and subcortical structures may be help- ful in certain parkinsonian conditions; for example, progressive supranuclear palsy (Fig. 21.2, panel g). Asymmetric hippocampal and medial temporal lobe atrophy particularly with signal change may be suggestive of autoimmune limbic encephalitis. Numerous other rare conditions are associated with o en fairly speci c patterns of imaging abnormality. ese are reviewed in detail in reference 20.

Prion diseases are o en associated with speci c patterns of restricted di usion on di usion-weighted imaging, which has revolutionized the diagnosis of sporadic Creutzfeldt–Jakob dis- ease (CJD) (Fig. 21.2, panel e). Variant CJD typically shows high signal on di usion-weighted or FLAIR imaging within the thala- mus, showing higher signal than that seen within the basal gan- glia. Inherited prion diseases can be associated with focal cerebellar atrophy.21

Metabolic and molecular imaging

Imaging using either 18F-fluoro-deoxyglucose (FDG) posi- tron emission tomogrophy (PET) or single photon computed

tomography (SPECT) allows for in vivo assessment of brain metab- olism, and both are licensed for the investigation of dementia in both the UK and the US. e pattern of hypometabolism (e.g. in temporoparietal regions) has positive predictive value for a diagno- sis of Alzheimer’s disease (Fig. 21.2, panel h).22 Conversely, hypo- metabolism in frontotemporal regions can be very useful in the diagnosis of frontotemporal dementia, particularly in patients with behavioural symptoms in whom a non-degenerative syndrome is possible.23

In patients where dementia with Lewy bodies is suspected, dopa- mine transporter (DAT) imaging, which allows for demonstration of dopamine uptake in vivo, can be very useful, demonstrating cen- tral dopamine depletion.24 A normal DAT scan does not, however, help to distinguish between DLB and Parkinson disease dementia (PDD), and is also o en abnormal in other typical parkinsonian syndromes. It may be particularly valuable in di erentiating cen- tral dopaminergic depletion from the e ects of neuroleptics (where the scan would typically be normal) in patients with combinations of cognitive impairment, movement disorders, and psychiatric disease.25

e development of the amyloid PET binding radiotracer 11C- Pittsburg compound (PIB) allowed for brillar amyloid plaques to be visualized during life for the rst time.26. In recent years, the development of 18F-based amyloid tracers has allowed for the commercialization of this approach. At the time of writing, three compounds, orbetapir (Amyvid), utemetamol (Vizamyl), and orbetaben (Neuraceq) have been licensed for use in both Europe and the US to rule in or out the presence of brillar amyl- oid in the brain. e clinical context in which this new technology

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228 SECTION 3 cognitive impairment and dementia

should best be applied has yet to be fully de ned, but it is poten- tially extremely valuable in di erentiating Alzheimer from non- Alzheimer’s dementias in patients with established cognitive impairment (Fig. 21.2, panel i).

Cerebrospinal uid

Examination of the CSF, at least in the UK and the US, has tradition- ally been used to exclude infection or in ammation as the cause of cognitive decline in young-onset cases.2 is remains very impor- tant for patients with an unusual ‘dementia plus’ or rapidly progres- sive cognitive syndrome. e ability to quantify neuronal speci c proteins in the CSF, however, means that lumbar puncture can now be used to increase the certainty of a diagnosis of AD during life. In established AD, concentrations of Aβ1-42 are reduced, probably re ecting deposition of Aβ1-42 within the brain, and concentrations of tau and phosphorylated tau are increased.27 A combination of low Aβ1-42 and elevation of tau and/or phospho tau (o en expressed as a tau:Aβ1-42 ratio) has good sensitivity and speci city for a diag- nosis of AD, and for predicting which patients with mild memory impairment will go onto develop dementia due to AD.28

ese AD-speci c biomarkers are now being incorporated into new criteria for AD.12,29,30 As evidence suggests that they become abnormal prior to the development of symptoms, they may have utility in de ning individuals with presymptomatic disease for clin- ical trials.31 Performing CSF examination to aid in the diagnosis of dementia varies widely between countries, being very commonly used in some European countries, but less so in the US and the UK. Given the very valuable diagnostic information that can be pro- vided and the ability in the correct clinical context to measure other CSF proteins within the CSF, our practice is increasingly to o er CSF testing to all patients with young-onset dementia, and to more elderly patients when the diagnosis is in doubt. In due course it is likely that CSF markers with high sensitivity/speci city for other neurodegenerative diseases will become available.

Genetic testing

Some conditions causing dementia, including Huntington’s disease and a range of other conditions, occur exclusively on an autosomal dominant basis and genetic testing is necessary for de nitive diag- nosis. In the case of the common neurodegenerative dementias, a minority of cases of Alzheimer’s occur secondary to mutations in either the APP (amyloid precursor protein), PSEN1 (presenilin 1), or PSEN2 genes; up to 40 per cent of patients with frontotem- poral dementia have causative mutations, as will a proportion of patients with prion disease. e decision to undertake genetic test- ing should always be made in consultation with the patient and the family and should follow standard guidelines.32 Predictive, as opposed to diagnostic, genetic testing should always be performed via a clinical genetics department. Request for genetic testing var- ies considerably between clinicians, perhaps re ecting di erences in populations seen. Our practice is to o er genetic testing for patients with clear autosomal dominant family histories, particu- larly although not exclusively, occurring at young ages. As genetic techniques advance and more patients are tested, the phenotypic spectrum of autosomal dominant dementia syndromes is expand- ing. e arrival of next-generation genetic sequencing techniques allows for much wider and cheaper genetic testing,33 undoubtedly increasing both the number of mutations positive individuals iden- ti ed and the associated phenotypic diversity.

Other investigations

Depending on the clinical scenario, and particularly in the case of patients with young-onset disease, rapid progression, or ‘dementia plus’, it may be appropriate to undertake a very wide range of other tests in order to reach a de nitive diagnosis,1 including but not limited to body imaging using CT, FDG-PET, mammography, or ultrasonography with/without biopsy (e.g. for suspected paraneo- plasia, systemic in ammation, or infection); bone marrow biopsy (e.g. for haematological malignancy); neuro-ophthalmological or otological assessment (e.g. for complex eye movements, or in the case of suspected in ammatory disease); neurophysiology, includ- ing electroencephalography (seizures) or (EMG) electromyogram/ nerve conduction studies (myopathy or neuropathy); or sleep studies (e.g. for obstructive sleep apnoea or rapid-eye-movement (REM) sleep behaviour disorder). Ultimately, and particularly if an underlying in ammatory condition, particularly CNS vasculitis which is notoriously di cult to diagnose during life, is considered, it may be necessary to proceed to a brain biopsy. Where possible, a targeted biopsy from a clinically non-eloquent area should be taken. Failing this, a full thickness biopsy involving grey matter, white matter, and dura is usually taken from the non-dominant frontal lobe. Particularly in the case of rapidly progressive demen- tia, the possibility of prion disease should always be considered, and appropriate surgical procedures followed to prevent transmis- sion. In our experience of over 130 cerebral biopsies for dementia, a treatable cause was determined in 10 per cent and an alterna- tive diagnosis in around 60 per cent. ere was some—transient— morbidity in around 10 per cent, but no deaths attributable to the procedure.34

Management

Management of the cognitively impaired patient will clearly depend on the speci c diagnosis, with management issues and speci c treatments for the di erent causes covered in their rele- vant chapters. Generic issues that should always be considered in patients diagnosed with signi cant cognitive impairment or dementia include: treatment of intercurrent mood or sleep prob- lems and other comorbidites; control of vascular risk factors; and appropriate counselling and support for the patient and family. Referral to support services may be appropriate depending on the needs and wishes of the patient and carer, and again depending on the speci c circumstance, the patient should be advised about driving. Accurate diagnosis may not only direct appropriate thera- peutic strategies but also may provide useful prognostic informa- tion in uencing future planning. Importantly however, individual treatments and care plans need to be directed on an individual-by- individual basis, taking into account matters speci c to the disease and the cognitive domains a ected, the individual’s personal cir- cumstances, and their and their carers’ responses to their problems and diagnosis.

References

1. Rossor MN, Fox NC, Mummery CJ, et al. e diagnosis of young-onset dementia. Lancet Neurol. 2010 Aug;9(8):793–806.

2. Knopman DS, DeKosky ST, Cummings JL, et al. Practice param- eter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001. p. 1143–53.

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3. Petersen RC. Clinical practice. Mild cognitive impairment. N Engl J Med. 2011 Jun 9;364(23):2227–34.

4. Bowler JV. Modern concept of vascular cognitive impairment. Br Med Bull. 2007;83:291–305.

5. McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005. p. 1863–72.

6. Snowden JS, Rollinson S, ompson JC, et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain. 2012 Mar;135(Pt 3):693–708.

7. Schott JM and Rossor MN. e grasp and other primitive re exes. J Neurol Neurosur Ps. 2003 May;74(5):558–60.

8. Williams DR and Lees AJ. Progressive supranuclear palsy: clinico- pathological concepts and diagnostic challenges. Lancet Neurol. 2009 Mar;8(3):270–79.

9. Sorbi S, Hort J, Erkinjuntti T, et al. EFNS-ENS Guidelines on the diagnosis and management of disorders associated with dementia. Eur J Neurol. 2012. p. 1159–79.

10. Nightingale S, Michael BD, Defres S, et al. Test them all; an easily diagnosed and readily treatable cause of dementia with life-threatening consequences if missed. Pract Neurol. 2013 Dec;13(6):354–56.

11. Schott JM, Warren JD, Barkhof F, et al. Suspected early dementia. BMJ. 2011;343:d5568.

12. McKhann GM, Knopman DS, Chertkow H, et al. e diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia. 2011 May;7(3):263–69.

13. Harper L, Barkhof F, Scheltens P, et al. An algorithmic approach to structural imaging in dementia. J Neurol Neurosur Ps. 2013 Oct. 16.

14. Carrera E and Bogousslavsky J. e thalamus and behavior: e ects of anatomically distinct strokes. Neurology. 2006 Jun. 27;66(12):1817–23.

15. Greenberg SM, Vernooij MW, Cordonnier C, et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol. 2009 Feb;8(2):165–74.

16. Likeman M, Anderson VM, Stevens JM, et al. Visual assessment of atrophy on magnetic resonance imaging in the diagnosis of patho- logically con rmed young-onset dementias. Arch Neurol. 2005 Sep;62(9):1410–15.

17. Frisoni GB, Fox NC, Jack CR, et al. e clinical use of structural MRI in Alzheimer disease. Nat Rev Neurol. 2010 Feb;6(2):67–77.

18. Crutch SJ, Lehmann M, Schott JM, et al. Posterior cortical atrophy. Lancet Neurol. 2012 Feb;11(2):170–78.

19. Warren JD, Rohrer JD, and Rossor MN. Clinical review. Frontotemporal dementia. BMJ. 2013;347:f4827.

20. Barkhof F, Fox NC, Bastos-Leite AJ, et al. Neuroimaging in Dementia. Berlin: Springer-Verlag, 2011.

21. Macfarlane RG, Wroe SJ, Collinge J, et al. Neuroimaging ndings in human prion disease. J Neurol Neurosur Ps. 2007 Jul;78(7):664–70.

22. Foster NL, Heidebrink JL, Clark CM, et al. FDG-PET improves accur- acy in distinguishing frontotemporal dementia and Alzheimer’s disease. Brain. 2007 Oct;130(Pt 10):2616–35.

23. Kipps CM, Hodges JR, Fryer TD, et al. Combined magnetic reso- nance imaging and positron emission tomography brain imaging in behavioural variant frontotemporal degeneration: re ning the clinical phenotype. Brain. 2009 Sep;132(Pt 9):2566–78.

24. McKeith I, O’Brien J, Walker Z, et al. Sensitivity and speci city of dopamine transporter imaging with 123I-FP-CIT SPECT in dementia with Lewy bodies: A phase III, multicentre study. Lancet Neurol. 2007 Apr;6(4):305–13.

25. Kägi G, Bhatia KP, and Tolosa E. e role of DAT-SPECT in movement disorders. J Neurol Neurosur Ps. 2010 Jan;81(1):5–12.

26. Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol. 2004;55(3):306–19.

27. Blennow K, Hampel H, Weiner M, et al. Cerebrospinal uid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol. 2010 Mar;6(3):131–44.

28. Mattsson N, Zetterberg H, Hansson O, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA. 2009 Jul 22;302(4):385–93.

29. Albert MS, DeKosky ST, Dickson D, et al. e diagnosis of mild cog- nitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia. 2011 May;7(3):270–79.

30. Dubois B, Feldman HH, Jacova C, et al. Revising the de n- ition of Alzheimer’s disease: a new lexicon. Lancet Neurol. 2010 Nov;9(11):1118–27.

31. Sperling RA, Aisen PS, Beckett LA, et al. Toward de ning the preclin- ical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnos- tic guidelines for Alzheimer’s disease. Alzheimers & Dementia. 2011 May;7(3):280–92.

32. Burgunder J-M, Finsterer J, Szolnoki Z, et al. EFNS guidelines on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke, and dementias. Eur J Neurol. 2010 May;17(5):641–48.

33. Beck J, Pittman A, Adamson G, et al. Validation of next-generation sequencing technologies in genetic diagnosis of dementia. Neurobiol Aging. 2014 Jan;35(1):261–65.

34. Schott JM, Reiniger L, om M, et al. Brain biopsy in dementia: clin- ical indications and diagnostic approach. Acta Neuropathol. 2010 Sep;120(3):327–41.

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CHAPTER 22

Delirium, drugs, toxins

Barbara C. van Munster, Sophia E. de Rooij, and Sharon K. Inouye

History

e ancient Greeks described a mental disturbance associated with fever and other serious illnesses. ey distinguished two di erent forms of this mental disturbance: an agitated phrenitis (frenzy) and a quiet lethargus (lethargy). Celsius was the rst who introduced the concept delirium (de lira, o the path) in the rst century, where it was used to distinguish this clinical entity from mania, depression, and hysteria. In sixteenth century Italy, Antonio Guainerio recog- nized the need for a comprehensive examination of the delirious patient, and in 1769, Morgagni replaced the concept of phrenitis by the term febrile delirium.1 In 1959, Engel and Romano developed the concept of delirium as a ‘syndrome of cerebral insu ciency’,2 but it was not until 1980, however, that delirium was standardized for the rst time as a clinical entity in the American Psychiatric Association’s (APA) Diagnostic and Statistical Manual, 3rd edition (DSM–III).

Epidemiology

Delirium is a frequently encountered syndrome with a prevalence of 0.4 per cent in the general population rising to 1 per cent in the population aged 55 years and older.3 In hospital, delirium has been reported in 22 per cent of medical, 11–35 per cent of surgical, and 80 per cent of intensive care unit (ICU) patients.4,5 In nursing homes the reported prevalence varies widely from 1 per cent6 to 72 per cent, mainly explained by the poor reliability of the method used for diagnosis.7 Terminal delirium is also a common symptom a ecting up to 90 per cent in patients with cancer at end of life and is a major cause of distress for patients and their families.8 Alcohol withdrawal delirium (AWD) is reported in 5 per cent of placebo- treated alcohol dependent patients entered into clinical trials of inpatient drug treatment for alcohol withdrawal.9 e consequence of an ageing population (chapter 20) which is at greater risk for delirium is that the absolute number of patients with delirium and associated problems can be expected to rise.

ere is a paucity of information about the incidence, prevalence, and severity of delirium in children, since well-validated instru- ments for diagnosing delirium in children have not been available; such scales are, however, currently being developed.10

Diagnosis

Numbers on prevalence and incidence vary greatly based on the di erent instruments used to diagnose delirium, and di erent

diagnostic criteria for delirium.11 e formal gold standard has been based on the diagnostic criteria of the Diagnostic and Statistical Manual of the APA (DSM version III to DSM–5) or the 9th and 10th edition of the International Classi cation of Diseases and Related Health Problems (ICD) (World Health Organization (WHO) 1992; American Psychiatric Association 1994).12 e syndrome is de ned by an acute disturbance in attention, a change in cognition, or a perceptual derangement (See Box 22.1| case history). In 2013, DSM–5, de ned delirium more restrictively in comparison to the former DSM versions. e disturbance in consciousness (DSM–III to DSM–IV TR) has been replaced by a disturbance in attention, and the inattention or changes in cognition ‘must not be occurring in the context of a severely reduced level of arousal such as coma’.

Box 22.1 Case history

Ms B, 92 years, was admitted to hospital because of dehydration and pneumonia. She lived at home independently and was not known to have previous cognitive impairment. On admission she was confused and could not tell the nurses where she lived. She was treated with antibiotics and stimulated to drink. During the evening she was restless and saw cats sitting on her bed, which made her fearful. Her son was encouraged to stay with her in hospital at night, in an attempt to avoid the need to treat her with antipsychotics with possible associated side-e ects. Also, a calendar was placed on the wall and her son brought pictures to make her feel at home.

A er a relatively good night’s sleep, she felt better but the fol- lowing day she was tired and fell asleep even during conversa- tion. An activity programme was instigated to keep her awake during the day, and she fell asleep in the evening without restless- ness or hallucinations. e following day she remembered hav- ing seen cats at some stage but could not recall anything of her day in hospital. Her son, having been concerned that his mother had developed dementia, reported that she was more or less back to normal. She was discharged home but temporarily needed some additional help at home because of reduced concentration.

Conclusion: Ms B experienced delirium, with mainly hyperactive symptoms during the rst day and hypoactive elements during the second day. Non-medical management and treatment of the underlying condition resolved these problems. It can be expected that her attention level will return to baseline a er a few months.

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232 SECTION 3 cognitive impairment and dementia
By de nition, there is evidence from history, physical, or inves-

tigation that the symptoms are caused by direct physiological consequences of a general medical condition, or substance abuse, or withdrawal. To enable non-psychiatric clinicians to detect delirium quickly, the confusion assessment method (CAM) was developed (see Table 22.1). e CAM has become the most widely used instrument in recent years and it is translated and validated in many languages and in various specialty settings, including the adult and paediatric ICU.10,13 To rate the assessment properly, brief instruments to test cognition such as the the Pfei er short portable mental status questionnaire (SPMSQ),14 Mini-Cog,15 or Montreal cognitive assessment (MOCA) test16 are required.

Before delirium is present in its full form, some prodromal symptoms (e.g. memory impairments, vivid dreams, incoher- ence, disorientation, and symptoms of underlying acute illness) are o en present.17 If patients do not completely full l the cri- teria for delirium but experience changes in sleep–wake cycle, thought process, language, attention, orientation, and visuos- patial processes, the non-DSM term ‘subsyndromal delirium’ is used.18 Delirium in childhood typically has a more acute onset, less circadian variety in symptoms, and less sleep–wake cycle dis- turbances as compared to adults.19 ere are several scales both for screening, diagnosing, and assessing the severity and/or sub- typing delirium (Table 22.2).

Three clinical subtypes of delirium (hyperactive, hypoac- tive, and mixed subtype) can be distinguished based on the pre- dominant clinical symptoms.21 Hyperactive patients are restless, agitated, and hyperalert, and o en show hallucinations and delu- sions. Hypoactive delirium, which is particularly easy to miss in clinical practice, is characterized by sleepiness, lack of interest in activities, slow response to questions, and minimal spontaneous movements.20 Mixed delirous patients can move between the two subtypes. Delirium recognition rates are low (12–43 per cent) and its management remains consequently inadequate in up to 80 per cent of the patients.22 Apart from failure to recognize the symp- toms, misdiagnosis is a considerable problem since depression and dementia (especially vascular dementia) are important di erential diagnoses for hypoactive delirium. Hyperactive and mixed sub- type of delirium may falsely be diagnosed as functional psychosis, dementia (especially Lewy body dementia), (hypo)mania, anxiety disorders, or akathisia.23

In the palliative care setting, it has been shown that subtypes o en remain stable during a given episode.24 Distinguishing the di erent delirium subtypes is important both to guide treatment

Table 22.1 Confusion assessment method (CAM) algorithm

Reproduced from 2003 Hospital Elder Life Program, LLC with permission.

Table 22.2 Available scales for screening, diagnosis severity, and subtype of delirium

Test

Aim

Population

Clinical Assessment Confusion-A

Screening

Hospital ward

Confusion Rating Scale

Screening

Hospital ward

Delirium Observation Screening Scale

Screening

Hospital

Neelon/Champagne Confusion Scale

Screening

Hospital ward

Nursing Delirium Screening Scale

Screening

Hospital ward

Confusion Assessment Method (CAM)

CAM–ICU
pCAM-ICU Nursing-Home CAM Minimum Data Set CAM

Screening/Diagnosis

Hospital ward

Intensive care unit (ICU)

Paediatric ICU Nursing home Nursing home

Delirium Rating Scale–Revised-98

Diagnosis/Severity/ Subtype

Hospital

Delirium Symptom Interview

Diagnosis/Subtype

Hospital ward

Memorial Delirium Assessment Scale

Diagnosis/Severity/ Subtype

Hospital

Cognitieve Test for Delirium

Diagnosis

Hospital ward

RAI–MDS/RAI–LTCF

Diagnosis

Nursing home

Confusional State Evaluation

Severity

Hospital ward

Delirium Index

Severity

Hospital ward

Delirium Severity Scale

Severity

Hospital ward

Delirium motor subtype scale

Subtype

Palliative care

Dublin Delirium Assessment Scale

Subtype

Geriatric ward

Lipowski criteria

Subtype

Neuropsychiatric ward

Source data from JAMA. 304(7), Wong CL, Holroyd-Leduc J, Simel DL, et al. Does this patient have delirium?: value of bedside instruments, pp. 779–86, Copyright (2010), American Medical Association; Int J Geriatr Psychiatry. 20(7), de Rooij SE, Schuurmans MJ, van der Mast RC, et al. Clinical subtypes of delirium and their relevance for daily clinical practice: a systematic review, pp. 609–15, Copyright (2005), John Wiley and Sons; Int

Rev Psychiatry, 21(1), Meagher D, Motor subtypes of delirium: past, present and future, pp. 59–73, Copyright (2009), Informa Healthcare.

(see treatment section below) as well as for research purposes. Lack of a reproducible method to standardize classi cation for delirium subtypes has been an important limitation in the eld.20 Studies using actigraphy, devices that are capable of measuring the 24-hour motor activity patterns by measuring accelerations, have revealed psychomotoric di erences between the subtypes, even in small samples of patients,25 and when used together with a well-validated subtype scale, may yet prove useful in distinguishing the di erent subtypes. Currently, however, there is insu cient evidence linking speci c phenomenology with aetiology, pathophysiology, manage- ment, course, and outcome.26

. (1) acute onset and uctuating course -and-

. (2) inattention -and either-

. (3) disorganized thinking -or-

. (4) altered level of consciousness

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CHAPTER 22 delirium, drugs, toxins 233 MULTIFACTORIAL MODEL OF DELIRIUM IN OLDER PERSONS

High Vulnerability Noxious Insult

Predisposing Factors/Vulnerability

Precipitating Factors/Insults

Low Vulnerability Less Noxious Insult

Fig. 22.1 Relationship between predisposing and precipitating factors.
Adapted from JAMA. 275(11), Inouye SK et al. Precipitating Factors for Delirium in Hospitalized Elderly Persons: Predictive Model and Interrelationship With Baseline Vulnerability, pp. 852–7, Copyright (1996), with permission from American Medical Association.

Predisposing and precipitating factors

Knowledge of the predisposing and precipitating factors is relevant for clinical practice and implementing appropriate prevention and treatment strategies. Fig. 22.1 describes the multiplicative relation- ship between predisposing and precipitating factors underlying the risk for delirium, as proposed by Inouye.27,28 While a person with many predisposing factors will only need a minor trigger to develop delirium (e.g. an old patient with dementia experiencing a mild urinary tract infection), a person without predisposing factors requires a much more severe trigger (e.g. severe sepsis in a younger and otherwise t patient).

is conceptual framework can be of assistance in guiding the search for one or more precipitating factors for the individual patient. us, in a relatively healthy person developing delirium, one rela- tively minor precipitating factor may not be su cient explanation and other perhaps potentially more serious precipitants should be sought. Factors precipitating delirium can include any illness, medi- cation, drug, or surgical procedure, but in a geriatric population infections, metabolic abnormalities, adverse drug e ects, and cardio- vascular events are the most common precipitants.29 e exact under- lying cause or trigger for delirium, however, o en remains unknown and is multifactorial in over 50 per cent of cases.30 Predisposing and precipitating factors overlap, and when investigated in a cross- sectional study design it may not be possible to distinguish causal- ity from association.31 Dehydration, for example, can be considered both a predisposing as well as a precipitating factor.

Recent literature tends to split risks for delirium into modi able and non-modi able factors, which makes sense from the point of view of prevention and (early) treatment. Risk factors identi ed in multiple studies include pre-existing cognitive impairment/ dementia or functional impairment, increasing age, severity of dis- ease, infection, fracture at admission, visual impairment, and the use of physical restraints.31,32 With increasing age, the duration of delirium might be longer and the symptoms more severe.31 Other

factors that are associated with a more serious course of delirium are ICU admission, change of rooms during hospitalization, and absence of help in orientation or provision of appropriate vision/ hearing aids.31 ere are no indications that risk factors in nursing homes di er from those in hospitalized patients.7

With regard to medication, there are some indications that use of benzodiazepines and opioids lead to higher risk for delir- ium.31 Controversy still exists about the exact role of benzodi- azepines since they continue to be prescribed to sedate delirious patients, for instance in intensive care and palliative care.8,33 Lorazepam and (to a lesser extent) midazolam have been shown to be associated with a slightly increased risk of delirium.34 Diphenhydramine administration is associated with an increased risk of delirium with a dose-response relationship due to its anti- cholinergic activity.35,36 All opiates can increase delirium risk, with meperidine a particularly high risk; conversely, the evi- dence implicating fentanyl, morphine and oxycodone is less strong.34,36,37 Anticholinergic medications as a group are associ- ated with a high risk of delirium.38 Di erent scales to assess the anticholinergic burden of medication are available but the cor- relation between serum anticholinergic activity level and risk of delirium is uncertain.39

With respect to delirium in children, infection, use and with- drawal of medication, including anticholinergic agents and opioids, and young age are the most important risk factors.40

Pathophysiology

Despite a growing and widespread interest in delirium in elderly patients, relatively few research studies have attempted to elucidate the pathophysiology of delirium. is is likely to be a re ection of the speci c methodological and ethical issues related to studies of the brain in a uctuating neuropsychiatric disorder in persons with a (temporarily) impaired capacity to consent. Additionally, the underlying pathophysiological mechanisms may di er between

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234 SECTION 3 cognitive impairment and dementia

the diverse subtypes of delirium and di erent aetiologies. Clinical observations in many di erent populations, biomarker studies in blood41 as well as in cerebrospinal uid (CSF)42, and a recently developed rodent model43 have resulted in several hypotheses being advanced to explain the processes.

Taking into account the multiple precipitating and predisposing factors, involvement of a number of interacting systems in the brain, leading to disturbance of a nal common pathway, seems to be the most plausible explanation for the development of delirium.44 e main candidates for this nal common pathway are changes in the relative ratio of acetylcholine (decreased) and dopamine (increased). us, drugs or infections resulting in anticholinergic e ects are well-recognized risk factors for delirium in elderly peo- ple; these e ects may be also mediated via the lower anticholinergic activity associated with cognitive impairment (see chapters 32, 33, and 36) and higher age.45,46

Peripheral in ammation can in uence the central nervous sys- tem (CNS) by a number of routes including the circumventricular organs (structures in the brain that are characterized by their exten- sive vasculature and lack of a normal blood–brain barrier), vagal a erents, and the brain endothelium forming the blood–brain barrier.47 Activation of cerebral microglia is considered pivotal for mediation of the behavioural e ects of systemic infections, and in this context delirium can be considered as an extreme form of sick- ness behaviour.43,48–51 Sickness behaviour is a coordinated set of adaptive behavioural changes that develop in ill individuals during the course of an infection. Rodent studies have shown CNS in am- matory responses to acute in ammatory insults of peripheral ori- gin are exaggerated both in the aged as in the neurodegenerative brain.52,53 Decreasing cholinergic inhibition may cause normally protective microglial responses to become neurotoxic46 and this may cause neuronal damage, re ected by biomarkers like (CSF) S100B.54,55 is cascade could account for the strong association between delirium and its sequelae like long-term cognitive impair- ment, although associations between these markers and long-term outcomes are still lacking.

ere is also growing evidence that dysregulation of the limbic– hypothalamic–pituitary–adrenal axis, with pathologically sus- tained high levels of cortisol occurring with acute stress, can play a mediating role.51 Disruption of the sleep–wake cycle, another important characteristic of delirium, may be evoked by lower levels of tryptophan, serotonin, or melatonin, all hormones involved in the circadian rhythm,56 which might be induced by a higher activ- ity of indoleamine 2,3-dioxygenase.57

e two most important neurochemical systems involved in alcohol withdrawal are gamma-aminobutyric acid and glutamine. It is unknown whether both these neurosystems are involved in the pathophysiology of AWD as well, but it is notable that glutamine plays an important role in hepatic encephalopathy.58

Genetics

Information about heritability or predisposition to delirium is lack- ing. ere are no known families with a high frequency of a ected members nor in whom delirium occurs at younger age without serious precipitating factors. However, it is hypothesized that the heritability rate of delirium might be comparable to the estimated heritability of 30 per cent for the occurrence of any psychotic epi- sode in late-onset Alzheimer’s disease.59 Genetic studies in delirium have been scarce until recently, due to the di culties in establishing

the diagnosis and aetiology of the syndrome, and the pitfalls inher- ent in the design of genetic studies.27,60 In AWD, positive associa- tions were found in three di erent candidate genes involved in the dopamine transmission (dopamine receptor D3 (DRD3), the sol- ute carrier family 6 (SLC6A3), and tyrosine hydroxylase); one gene involved in the glutamate pathway (glutamate receptor ionotropic kainate 3); one neuropeptide gene (brain‐derived neurotrophic fac- tor); and one cannabinoid gene (cannabinoid receptor 1).61 In older patients with delirium, a meta-analysis suggested an association between delirium and possession of an APOE ε4 allele.62 In inde- pendent cohorts, a variation in the SLC6A3 gene and possibly the DRD2 gene were found to be protective against delirium.63 In one population, homozygous carriage of the BclI–TthIIII haplotype of the glucocorticoid receptor gene was associated with a reduced risk (92 per cent) of developing delirium.64

Treatment

Treatment of delirium and its symptoms can be classi ed in four parts, summarized in Table 22.3. e most important and rst steps both for the prevention and treatment of delirium are well-proven non-pharmacological measures. ese multidisciplinary, multicom- ponent interventions have been shown to reduce the incidence and duration of delirium in hospitalized patients and reduce functional decline in older patients.65–69 Such interventions should focus on several domains, including addressing cognitive impairment or dis- orientation, sensory deprivation, sleep disturbance, limited mobil- ity, dehydration, constipation, hypoxia, pain, poor nutrition, and medication use.67,68,70 Optimal management requires implementa- tion throughout the hospital on a 24/7 basis and actively promoting these interventions in patients at increased risk for delirium.68,69

e second step is to identify and treat the underlying disease or factors contributing to the delirium; for example, rectifying dehy- dration or commencing antibiotic therapy for a suspected infection.

ird, and only when patients are severely agitated or when they will not comply with steps one and two should antipsychotic medi- cations be considered. When necessary, these should be started at the lowest possible dose. Evidence for their e cacy in the context of delirium, and speci cally in the target group of vulnerable and o en cognitively impaired patients in which it is most commonly used, is limited.71 Haloperidol is still the rst-choice medication for symp- tom reduction because it can be used orally, intramuscularly, and intravenously, and most experience both in research and in daily practice has been acquired with this antipsychotic. Antipsychotics have important side-e ects such as extrapyramidal e ects, seda- tion, increased risk of cerebrovascular accidents and mortality, and when used in high intravenous doses, torsade des points and other ventricular dysrhythmias have been decribed.72–74 People with Lewy body dementia, Parkinson’s disease, or parkinsonism should not be prescribed typical antipsychotic drugs because they are at particular risk of severe adverse reactions. Atypical antipsy- chotics have never been investigated for delirium, but clozapine has been shown to be e ective for hallucinations in Parkinson’s disease (NICE clinical guideline 35).

Whilst commonly used, the evidence to support the use of ben- zodiazepines in the treatment of non-alcohol withdrawal-related delirium among hospitalized patients is lacking, with some evi- dence of worsening or prolongation of delirium symptoms in HIV patients.75,76 On the other hand, for AWD, benzodiazepines are the rst choice of treatment as well as for prevention.77 For delirium

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Table 22.3 Work-up steps for delirium treatment (steps 1, 2, 3, and 4) and prevention in at-risk patients (primary step 1 and secondary step 4)

CHAPTER 22 delirium, drugs, toxins 235 delirium respond differently to antipsychotics compared to

adults.40 In palliative care, delirium is the most common indication for sedation.81

A er delirium, patients should be followed intensively to counsel them about the episode, diagnose possible cognitive impairment, and limit risk factors for a new episode. A systematic intervention in elderly patients a er a delirious state found that institutionali- zation could be delayed by using rehabilitation periods and case management.82 Case management strives to provide proactive individualized care supported by a multidisciplinary team of pro- viders of elderly care.

Prognosis

Adjusted for age, sex, comorbid illness or illness severity, and baseline dementia, delirium is associated with an increased risk of death compared with controls (hazard ratio (HR): 1.95 [95% con – dence interval (CI), 1.51–2.52]).83 Moreover, patients experiencing delirium are also at increased risk of institutionalization (odds ratio (OR): 2.41 [95% CI, 1.77–3.29]), or dementia (OR: 12.52 [95% CI, 1.86–84.21]),28,83 and patients with Alzheimer’s disease experienc- ing delirium have an increased rate of cognitive decline maintained for up to ve years.84,85

Although patients usually recover a er treatment of the precipi- tating factors, persistent delirium in older hospital patients is fre- quent (exact percentages are highly variable) especially in patients with pre-existing cognitive impairment. is persistence is asso- ciated with adverse outcomes and such individuals have a poor prognosis.86

Summary

Delirium is a serious neuropsychiatric syndrome caused by a vari- ety of factors, with serious e ects on overall outcome. Delirium and dementia overlap in many ways: the symptoms may overlap, delirium is a risk factor for developing dementia, and dementia increases the risk of delirium. Many avenues of future research exist in the delirium eld.87 From a pathophysiological perspective, the potential roles of in ammation and impaired cholinergic neuro- transmission and the interactions between these two factors need further exploration and may provide opportunities for develop- ment of targeted preventive strategies. Determining the underlying pathophysiology and identifying speci c biomarkers may explain the subtypes of delirium presentation and guide speci c therapies. Current data support the use of nonpharmacological treatment protocols and in case of severe agitation antipsychotics. However, further randomized trials are required to evaluate other preven- tion and treatment strategies in populations strati ed according to delirium risk, delirium subtype, or associated comorbid demen- tia, and to investigate whether or not pharmacologic treatments improve long-term outcomes following delirium.

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1. Non-medicalmeasures*

• cognitive impairment or disorientation: appropriate lighting, clear signage, clock and calendar easily visible to the person, reorient verbally, introduce cognitively stimulating activities, facilitate visits from well-known persons

• dehydration: adequate uid intake by encouraging patient to drink (by family)

• constipation: adequate uid, dietary bre, no opiates, laxatives

• hypoxia: optimize oxygen saturation

• limited mobility: mobilize soon as possible, if unable to walk carry out active range-of-motion exercises

• pain: look for (nonverbal) signs of pain, initiate and review appropriate pain management

• poor nutrition: adequate nutrition, ensure that dentures t

• medicationuse:reduceanticholinergicmedications

• sensory deprivation: resolve any reversible cause of the impairment, ensure hearing and visual aids are available and in good working order

• sleep disturbance: promote good sleep patterns and sleep hygiene

2. Identify and treat precipitating factors

• Medical history

• Medication review

• Physical examination (including neurological examination)

• Blood testing (as indicated by clinical judgement): renal function, glucose, infection parameters, haemoglobin

• Urinalysis
If not clari ed by rst screening, do a step-by-step more invasive diagnostic evaluation based on prior probability. Consider calcium, medication level, liver and thyroid function tests, culture, of urine, blood, sputum, EKG, chest X-ray, CT brain, etc.

3. Medical treatment

Only when patients are severely agitated or will interrupt essential medical therapies despite the rst two steps:

antipsychotics ( rst choice haloperidol 0.25–0.50 mgs) in the lowest possible dose

4. Post-deliriumtreatment

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• Limit risk factors as described in step 1

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Medication trials for the above populations did not discriminate in e cacy for the di erent subtypes. Experts doubt the bene t of antipsychotic medication for hypoactive delirium based on lack of evidence and the potential serious side-e ects such as torsades.

Limited evidence is available for the prevention of (severe) delirium with antipsychotics or melatonin and they are not rec- ommended at this time. ere is no evidence that children with

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53. Combrinck MI, Perry VH, and Cunningham C. Peripheral infection evokes exaggerated sickness behaviour in pre-clinical murine prion disease. Neuroscience. 2002;112(1):7–11.

54. van Munster BC, Bisschop PH, Zwinderman AH, et al. Cortisol, interleukins and S100B in delirium in the elderly. Brain Cogn. 2010 Oct;74(1):18–23.

55. van Munster BC, Korse CM, de Rooij SE, et al. Markers of cerebral damage during delirium in elderly patients with hip fracture. BMC Neurol. 2009;9:21.

56. de Jonghe A, Korevaar JC, van Munster BC, et al. E ectiveness of melatonin treatment on circadian rhythm disturbances in dementia. Are there implications for delirium? A systematic review. Int J Geriatr Psychiatry. 2010 Dec;25(12):1201–8.

57. de JA, van Munster BC, Fekkes D, et al. e tryptophan depletion theory in delirium: Not con rmed in elderly hip fracture patients. Psychosomatics. 2012 May;53(3):236–43.

58. Desjardins P, Du T, Jiang W, et al. Pathogenesis of hepatic encephalopa- thy and brain edema in acute liver failure: Role of glutamine rede ned. Neurochem Int. 2012 Jun;60(7):690–6.

59. Bacanu SA, Devlin B, Chowdari KV, et al. Heritability of psychosis in Alzheimer disease. Am J Geriatr Psychiatry. 2005 Jul;13(7):624–7.

60. Adamis D, van Munster BC, and Macdonald AJ. e genetics of deliria. Int Rev Psychiatry. 2009 Feb;21(1):20–9.

61. van Munster BC, Korevaar JC, de Rooij SE, et al. Genetic polymor- phisms related to delirium tremens: A systematic review. Alcohol Clin Exp Res. 2007 Feb;31(2):177–84.

62. van Munster BC, Korevaar JC, Zwinderman AH, et al. e associa- tion between delirium and the apolipoprotein E epsilon 4 allele: New study results and a meta-analysis. Am J Geriatr Psychiatry. 2009 Oct;17(10):856–62.

63. van Munster BC, de Rooij SE, Yazdanpanah M, et al. e association of the dopamine transporter gene and the dopamine receptor 2 gene with delirium, a meta-analysis. Am J Med Genet B Neuropsychiatr Genet. 2010 Mar 5;153B(2):648–55.

64. Manenschijn L, Van Rossum EF, Jetten AM, et al. Glucocorticoid receptor haplotype is associated with a decreased risk of delirium in the elderly. Am J Med Genet B Neuropsychiatr Genet. 2011 Jan 13.

65. Marcantonio ER, Flacker JM, Wright RJ, et al. Reducing delirium a er hip fracture: a randomized trial. J Am Geriatr Soc. 2001 May;49(5):516–22.

66. Bo M, Martini B, Ruatta C, et al. Geriatric ward hospitalization reduced incidence delirium among older medical inpatients. Am J Geriatr Psychiatry. 2009 Sep;17(9):760–8.

67. Vidan MT, Sanchez E, Alonso M, et al. An intervention integrated into daily clinical practice reduces the incidence of delirium during hospitali- zation in elderly patients. J Am Geriatr Soc. 2009 Nov;57(11):2029–36.

68. Inouye SK, Bogardus ST, Jr, Charpentier PA, et al. A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med. 1999 Mar 4;340(9):669–76.

69. Inouye SK, Baker DI, Fugal P, et al. Dissemination of the hospital elder life program: Implementation, adaptation, and successes. J Am Geriatr Soc. 2006 Oct;54(10):1492–9.

70. O’Mahony R, Murthy L, Akunne A, et al. Synopsis of the National Institute for Health and Clinical Excellence guideline for prevention of delirium. Ann Intern Med. 2011 Jun 7;154(11):746–51.

71. Lonergan E, Britton AM, Luxenberg J, et al. Antipsychotics for delirium. Cochrane Database Syst Rev. 2007;(2):CD005594.

72. Recupero PR and Rainey SE. Managing risk when considering the use of atypical antipsychotics for elderly patients with dementia-related psychosis. J Psychiatr Pract. 2007 May;13(3):143–52.

73. Blom MT, Bardai A, van Munster BC, et al. Di erential changes in QTc duration during in-hospital haloperidol use. PLoS One. 2011;6(9):e23728.

74. Mittal V, Kurup L, Williamson D, et al. Risk of cerebrovascular adverse events and death in elderly patients with dementia when treated with antipsychotic medications: A literature review of evidence. Am J Alzheimers Dis Other Demen. 2011 Feb;26(1):10–28.

75. Breitbart W, Marotta R, Platt MM, et al. A double-blind trial of halop- eridol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry. 1996 Feb;153(2):231–7.

76. Lonergan E, Luxenberg J, Areosa SA, et al. Benzodiazepines for delir- ium. Cochrane Database Syst Rev. 2009;(1):CD006379.

77. Amato L, Minozzi S, Vecchi S, et al. Benzodiazepines for alcohol with- drawal. Cochrane Database Syst Rev. 2010;(3):CD005063.

78. Bledowski J and Trutia A. A review of pharmacologic management and prevention strategies for delirium in the intensive care unit. Psychosomatics. 2012 May;53(3):203–11.

79. van Eijk MM, Roes KC, Honing ML, et al. E ect of rivastigmine as an adjunct to usual care with haloperidol on duration of delir- ium and mortality in critically ill patients: A multicentre, double- blind, placebo-controlled randomised trial. Lancet. 2010 Nov 27;376(9755):1829–37.

80. Gamberini M, Bolliger D, Lurati Buse GA, et al. Rivastigmine for the prevention of postoperative delirium in elderly patients undergoing elective cardiac surgery—a randomized controlled trial. Crit Care Med. 2009 May;37(5):1762–8.

81. Maltoni M, Scarpi E, Rosati M, et al. Palliative sedation in end-of- life care and survival: a systematic review. J Clin Oncol. 2012 Apr 20;30(12):1378–83.

82. Rahkonen T, Eloniemi-Sulkava U, Paanila S, et al. Systematic interven- tion for supporting community care of elderly people a er a delirium episode. Int Psychogeriatr. 2001 Mar;13(1):37–49.

83. Witlox J, Eurelings LS, de Jonghe JF, et al. Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and demen- tia: A meta-analysis. JAMA. 2010 Jul 28;304(4):443–51.

84. Weiner MF. Impact of Delirium on the Course of Alzheimer Disease. Arch Neurol. 2012 Sep 17;1–2.

85. Gross AL, Jones RN, Habtemariam D, et al. Delirium and Long-term Cognitive Trajectory Among Persons With Dementia. Arch Intern Med. 2012;In Press.

86. Cole MG, Ciampi A, Belzile E, et al. Persistent delirium in older hos- pital patients: A systematic review of frequency and prognosis. Age Ageing. 2009 Jan;38(1):19–26.

87. Fong TG, Tulebaev SR, and Inouye SK. Delirium in elderly
adults: Diagnosis, prevention and treatment. Nat Rev Neurol. 2009 Apr;5(4):210–20.

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CHAPTER 22 delirium, drugs, toxins 237

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CHAPTER 23

CNS infections

Sam Nightingale, Benedict Daniel Michael, and Tom Solomon

Acute central nervous system infection

Acute central nervous system (CNS) infections can be broadly divided into infections involving the meninges, ‘meningitis’, those a ecting the brain parenchyma, ‘encephalitis’, and those with dis- crete space occupying lesions such as brain abscesses.1 Meningitis and encephalitis are most frequently caused by viral and bacterial infection, but fungi and parasites can occasionally be responsible, particularly in the immunocompromised.1,2 ese pathogens have multiple acute clinical manifestations, o en a ecting various cog- nitive domains. In addition to acute CNS disorders, sequaelae of CNS damage sustained at the time of infection can lead to long- term cognitive dysfunction.

Epidemiology

Common viral infections causing meningitis, include enterovi- ruses, which are acquired by faeco-oral transmission, other viruses acquired by respiratory droplet spread, such as the in uenza family, and those acquired sexually, such as herpes simplex virus (HSV) type 2, which may be recurrent. e most common viral cause of sporadic encephalitis is HSV type 1 reactivation, following acqui- sition early in childhood via droplet spread.2 Globally, the most common cause of epidemic viral encephalitis is currently Japanese encephalitis virus despite ongoing vaccination programmes.3

Bacterial CNS infections are typically limited to the meninges, however there may be some para-meningeal parenchymal in am- mation. In the developed world, these are typically caused by Streptococcus pneumoniae and Haemophilus in uenza which o en follow or co-present with an upper respiratory tract infection.4 e other major bacterial cause of meningitis is Neisseria meningitides, which is a particularly common cause of meningitis across the ‘meningitis belt’ of Africa, from Senegal to Ethiopia.88

Clinical features

Classically, meningitis presents with an acute febrile illness asso- ciated with headache, nausea and vomiting, photophobia, rashes and signs of meningeal irritation, such as neck sti ness, Kernig’s and Brudzinski’s signs.4 In contrast, on admission 10–15 per cent of patients with viral encephalitis will not be febrile, and in febrile cases the fever will be of a lower grade or intermittent.2,3 In addi- tion, patients typically have a headache, which may be severe; nau- sea and vomiting, and signs of meningeal irritation. Whilst there is clearly some clinical overlap, and indeed in some cases there is histological overlap too, clinical features re ecting parenchymal

in ammation are more suggestive of encephalitis than meningitis. ese include focal neurological signs and alterations in conscious- ness, cognition, personality, and/or behaviour.2

Acute cognitive presentations in patients with encephalitis due to HSV type 1 may re ect temporal lobe involvement such as dysphasia, or features re ecting frontal lobe involvement, such as aggressive and socially inappropriate behaviour (Fig. 23.1). In addition, features re ecting involvement of the limbic system such as impaired short-term memory and/or emotional lability may be seen in limbic encephalitis, which may be due to HSV, other viral infections or antibody-mediated disease.2

With the exception of the pathognomonic non-blanching, pete- chial rash of meningococcal septicaemia, there are no clinical features or speci c cognitive syndromes which can de nitively determine the aetiological agent in a patient with meningitis or encephalitis.

Investigation

Whilst there is no established gold-standard tool, initial bedside investigations should include assessment of cognition and con- sciousness. In many cases, even of encephalitis, the Glasgow Coma Score (GCS) may be normal and the clinician must instead actively look for changes in cognition, personality, and behaviour; conse- quently a collateral history is invaluable.2 A travel history is vital as many infections have geographical limitations.3

Investigation involves prompt lumbar puncture with gram stain, culture, and polymerase chain reaction (PCR) of cerebrospinal uid (CSF).2 Neuroimaging may be helpful but should not delay lumbar puncture unless there are clear clinical contraindications, including focal neurological weakness, signi cant reduction in the GCS (<13 or fall of >2), seizures, immunocompromise, or signs of raised intracranial pressure (e.g. papilloedema, Cushing’s re ex).4 National UK guidelines recommend that all patients should be tested for human immunode ciency virus (HIV) as both seroconversion and opportunistic infection can cause acute CNS infection.5

Management

Prompt treatment is essential to limit sequelae. Initial management involves stabilizing the patient; this may necessitate controlling sei- zures and/or airway management. Where possible, antimicrobial treatment should be postponed until the lumbar puncture (LP) has been performed. However, if there will be delays beyond 30 minutes from admission for antibiotics and beyond 6 hours for acyclovir,

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240 SECTION 3 (a)

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(b)

addition, some patients su er with phobic anxiety and compulsive behaviours, which may be present in the absence of signi cant cog- nitive impairment.11

Impairments su ered during the acute insult may subsequently show improvements or may remain static. Children with encephali- tis due to enterovirus infection may more frequently return to base- line levels.12 Progression of symptoms following acute infectious encephalitis is unusual and should prompt investigation into other causes, such antibody-associated encephalitis, neoplastic processes, or a progressive post-infectious phenomena such as subacute scle- rosing panencephalitis (discussed below).13–15

Subacute central nervous system infection

Cognitive impairment forms part of the presentation of several subacute CNS infections. In some cases, cognitive features may be the predominant symptoms at presentation. e most important causes are discussed below. In addition, many of the causes of acute CNS infection can present subacutely in patients with signi cant immunocompromise.2

Tuberculosis

Epidemiology

Approximately one-third of the world’s population has been infected with mycobacterium tuberculosis.16 e disease is endemic to many parts of the world, in particular in developing countries in Africa and Asia.

Pathogenesis

CNS infection occurs in 5–15 per cent of active tuberculosis cases. is is most commonly due to reactivation of latent infection in adults, but may occur as a complication of primary infection, par- ticularly in children.17

Clinical features

Confusion, decreased consciousness, and impairment in a number of cognitive domains may occur in addition to the typical features of fever, headache, and meningism.2 Presentation is highly variable and cognitive features may initially be the predominant feature; fever may only be present in approximately two-thirds of patients.17

Investigation

If tuberculosis is suspected larger volumes of CSF should be collected—ideally at least 6 ml—for there to be su cient sensitivity of staining, extended culture, and PCR.2 Some have also demon- strated the use of CSF lactate levels to distinguish TB meningitis from other causes of meningitis, and in distinguishing bacterial from viral infection, although this may not be routinely avail- able.89–91 In areas with limited available investigations, some have advocated the use of composite scores of clinical and laboratory features, such as the waites criteria,17 to guide management. Magnetic resonance imaging is more sensitive than computed tomography, and may identify meningeal gandolinium enhance- ment, with a predilection for the basal meninges, parenchymal tuberculomas, oedema, and hydrocephalus (Fig. 23.2).

Management

Decisions regarding appropriate antituberculous treatment should be made in conjunction with local microbiological and infec- tious disease teams, but a typical regime would include isoniazid,

Fig. 23.1 (a) Sagittal FLAIR MRI of a patient with encephalitis due to herpes simplex virus 1 demonstrating oedema of the left temporal lobe and medial frontal lobes bilaterally with e acement of the sulci and compression of the lateral ventricles. (b) Coronal FLAIR MRI of a patient with encephalitis due to herpes simplex virus 1 demonstrating asymmetric oedema of both temporal lobes, greater on the right.

Courtesy of Dr Ian Turnbull.

then these treatments should be started before the LP.2,6 Aciclovir has virostatic activity against HSV and, to a lesser extent, varicella zoster virus, and is therefore started empirically whilst the results of the virological investigations are awaited in patients with sus- pected encephalitis. Antibiotics should follow local protocols, but typically involve a third-generation cephalosporin, with the addi- tion of amoxicillin in those aged >50 years, or who are pregnant or alcoholic, to cover listeria monocytogenes.6

Sequelae of infection

Bacterial meningitis continues to be associated with 15 per cent mortality. If there are delays or failure to start treatment in HSV encephalitis, the mortality can be >70 per cent and, whilst this can be reduced to <20–30 per cent if aciclovir is started early, at least 60 per cent of survivors will have signi cant neurological disabil- ity.2 In addition to consequent epilepsy, the most common com- plaints following all causes of encephalitis are short-term memory problems, di culty sustaining concentration, speech disturbance, and behavioural disorders.7 Features most commonly reported in HSV encephalitis include cognitive impairments, such as recep- tive and/or expressive dysphasia, frontal lobe features, such as perseveration, impulsivity, and social disinhibition. If the limbic system is involved, there may be ongoing emotional liability and anterograde amnesia. However, encephalitis can result in any syn- drome of cognitive impairment depending on both aetiology and the region of the brain a ected. Notably, previously acquired skills such as musical ability may be retained, and interestingly there is evidence that some patients who otherwise have anterograde amnesia may be able to learn new music.8 However, whilst oth- ers retain some of their premorbid skill sets, implicit long-term memory may not be coordinated with declarative memory and working memory for them to adjust their existent skills to new scenarios.9

ere is some evidence that the certain markers of global cog- nitive performance may be more severe in patients with HSV encephalitis in comparison to those with other aetiologies.10 ere may be some association between post-encephalitis depression and some aspects of cognitive and interpersonal anxiety, and this may be greatest in those with impaired insight into their condition. In

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Fig. 23.2 Gadolinium enhanced T1 MRI of a patient with tuberculous meningitis showing leptomeningeal enhancement, and enhancing nodules in thalamus, basal ganglia, and sulci.

rifampicin, pyrazinamide, and streptomycin. e patient should be watched closely for signs of hydrocephalus, which may neces- sitate neurosurgical intervention, such as emergency extraventricu- lar shunt insertion.6 e prognosis is worse in those with delayed access to therapy and with comorbid conditions such as alcohol- ism and diabetes.17 Dexomethasone is recommended in the acute phase for those with and without HIV co-infection, although the strongest evidence is in the latter group.92

Subacute sclerosing panencephalitis

Epidemiology

Subacute sclerosing panencephalitis (SSPE) is a rare, late complica- tion of infection with the measles virus typically described in areas with poor vaccine uptake, with an incidence ranging between 0.01 cases per million in the United States (US) and 21 per million in India.2,18 It is estimated that there are 4–11 cases of SSPE for every 100 000 cases of clinical measles infection. e highest incidence is in those who have the primary infection when aged under 5 years, and may be as high as 360 per 100 000 in those aged under 1 year at the time of primary infection.18 ere is also a higher risk of developing SSPE in males.

Pathogenesis

e pathophysiology remains poorly understood but is thought to involve an immune response to primary infection that is predomi- nantly humoral rather than cellular, and results in latent viral infec- tion in neurons and the development of highly mutated viruses.18

Clinical features

Patients usually present between 8–11 years old, approximately 6 years a er primary infection. Symptoms initially begin with intel- lectual decline and consequent poor educational activity, associated with personality and behavioural changes. During this period, or sometimes in the preceding two years, there may be early visual symptoms, such as visuospatial disorientation. Within six months this progresses to include motor features which begin as repetitive and frequent myoclonic jerks, sometimes with abrupt-onset peri- odic dystonic myoclonus, and progress to extrapyramidal features,

including rigidity. During this period, focal and/or generalized seizures o en develop and the patient progresses towards a state of akinetic mutism, autonomic failure, vegetative state, coma and death.18 Nevertheless, approximately 10 per cent will present with a more accelerated phenotype with signi cant neurological de cit within three months and death within six months.

SSPE may also present in adults, usually around 20 years of age, with visual symptoms typically dominating for 2–5 years before motor involvement.

Investigation

e diagnosis requires the presence of an appropriate clinical phenotype with evidence of intrathecal anti-measles antibodies, although MRI and EEG ndings may also be supportive. CSF- serum IgG ratios of anti-measles IgG range from 5–40:1. MRI may be normal in the early stages and does not correlate with the clinical stage but rather the duration of the disease. ere may ini- tially be cortical and subcortical hyperintensities on T2 images, progressing to involve the thalamus and basal ganglia, and then periventricular white matter lesions and cortical atrophy and the progressive atrophy of the brainstem and deep structures. Many EEG features have been described, with the most common being stereotyped bilateral synchronous, but asymmetrical, periodic complexes (Fig. 23.3). ese are highly stereotyped within an indi- vidual but di er between patients. Background cerebral activity between complexes is normal initially, with increasing slow activ- ity and then attenuation in later stages. In cases in which there is diagnostic uncertainty, a brain biopsy may be required for de ni- tive diagnosis.

Management

SSPE is a severe progressive neurological infection resulting in death in 94–95 per cent of patients, with the remaining 5–6 per cent developing spontaneous remission, which is more common in adults. Combination therapy with intrathecal interferon alpha and oral isoprinosine is generally recommended, but well-standardized randomized controlled trials (RCTs) are still needed, as despite current therapy, most patients die within three years. e single

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CHAPTER 23 cns infections 241

242 SECTION 3 cognitive impairment and dementia

(a)
25 μV
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(b)

intervention with greatest impact to reduce the burden of SSPE is improving access to healthcare and comprehensive vaccination programmes.

Progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a demyeli- nating condition due to John Cunningham (JC) virus infection in association with immunosuppression.

Epidemiology

Most cases of PML occur in HIV-positive individuals and PML is an AIDS-de ning condition. Prior to antiretroviral therapy, PML occurred in around 5 per cent of people with HIV prior to death.19 Incidence has decreased in areas where antiretroviral treatment is available, although prevalence has increased with improved sur- vival. PML occurs disproportionately in HIV compared to other forms of immunosuppression,20 but can occur in those with severe immunode ciency such as transplant recipients,21 and is becom- ing an increasingly common complication of monoclonal antibody treatment, and in particular of Natalizumab for multiple sclerosis.22

Pathogenesis

JC virus causes central demyelination through destruction of oli- godendrocytes and myelin processes. Typically this process is char- acterized by lack of in ammation, although in ammatory forms do occur, particularly in association with immune reconstitution.23

Clinical features

Typically there is an insidious onset of focal neurological de cit without headache, fever, or meningism. Cognitive de cits occur in around one-third of cases, usually alongside focal neurology, but may be the sole presenting feature, particularly in those with bifrontal lesions. Seizures occur in 20 per cent.19

Investigation

Demonstration of JC viral DNA in the CSF in those with an appro- priate clinical syndrome is highly speci c for PML. Sensitivity of viral PCR is greater than 70 per cent; this increases with progression

of disease so lumbar puncture should be repeated if initial tests are negative but clinical suspicion remains high.

MRI shows characteristic multifocal white matter lesions cor- responding to the areas of clinical de cits (Fig. 23.4). Typically there is no mass e ect or contrast enhancement. PML lesions can be distinguished from the white matter changes of HIV-associated dementia by the asymmetry, lack of atrophy, and involvement of the subcortical U- bres.

Management

ere is currently no speci c treatment of PML.22 A number of agents with in vitro e ect against JC virus have not proved e ca- cious in clinical trials.24

Treatment involves correcting immunosuppression. Without this, PML is invariably fatal, usually within months of diagno- sis. In those with PML secondary to HIV infection, antiretroviral treatment can stabilize disease, sometimes for months or years.25 Cases of PML secondary to monoclonal antibody treatment should receive plasma exchange, and other causes of immunosuppression should be corrected if possible.22 Rapid improvements in immune function may lead to a paradoxical worsening of clinical disease associated with in ammation and swelling of lesions. is is termed immune reconstitution in ammatory syndrome (IRIS) and can be managed with corticosteroids.

Neuroborreliosis

Epidemiology

Borrelia are zoonotic spirochetes transmitted by the bite of an infected tick. Several species causing Lyme disease are prevalent in woodland and heath areas across Europe, Russia, and parts of Asia and North America. Transmission occurs to a lesser degree in the UK, particularly in the New Forest of Hampshire and the Scottish highlands.

Clinical features

Initial infection produces the typical erythema migrans rash, although this is not invariably present and may have gone unnoticed

LF = 0.5 Hz

HF = 50 Hz

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I T4–T6
I T6–02
I Fp1–F7
I F7–T3
I T3–T5
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2 sec 12:09:12 12:09:14 12:09:16 12:09:18 12:09:20 12:09:22 12:09:24 12:09:26 12:09:28 12:09:30 12:09:32

Fig. 23.3 (a) e characteristic electroencephalograph (EEG) picture in SSPE demonstrating stereotyped high-voltage periodic complexes, here at a frequency of
0.3 hertz. In contrast, EEG (b) shows complexes occurring at around 1 hertz in sporadic Creutzfeldt–Jakob disease.
Reproduced from J Neurol Neurosur Ps. 76(suppl.2), SJ Smith. EEG in the diagnosis, classi cation, and management of patients with epilepsy, pp. ii2–7, Copyright (2005), with permission from BMJ Publishing Group Ltd.

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Fig. 23.4 T1- and T2-weighted MRI demonstrating extensive bifrontal demyelination due to progressive multifocal leukoencephalopathy secondary to immunosuppressive treatment post renal transplant.

by the patient. Neurological involvement occurs in around 35 per cent of European cases, but is less common in American strains of Borrelia. Neurological involvement is typically with subacute men- ingitis with or without facial palsy, painful radiculitis (Bannwarth’s syndrome) or transverse myelitis in the weeks to months following initial infection. Myalgia, arthralgia, fatigue, and malaise are com- mon. Acute encephalitis due to Borellia is uncommon but encepha- lopathy can occur, particularly in those in whom infection has persisted for long periods without treatment. Cognitive problems include de cits in processing speed, visual and verbal memory, and executive/attention functions.26

Investigation

e spirochete is rarely demonstrated in the CSF or other tissues and diagnosis is by the detection of speci c antibodies to Borellia

in the CSF and serum. Relative levels of antibody between the CSF and serum can be used to calculate an antibody index; an index of over 1 suggests intrathecal synthesis of antibodies directed against spirochaetes.

Management

Treatment is with parenteral cephalosporin or oral doxycycline for 2–4 weeks.27

Neurobrucellosis

Epidemiology

Brucellosis is a highly contagious zoonosis endemic to many Mediterranean countries, South and Central America, Eastern Europe, Asia, Africa, the Caribbean, and the Middle East. It is the most common zoonosis in the world accounting for 500 000

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human cases annually.28 Transmission has been described in the UK but is rare and most human cases are acquired abroad. Brucella species are transmitted to humans by ingestion of unsterilized milk or cheese, or by close contact with infected animals.

Clinical features

Clinical features are diverse and include prolonged fever, cough, constitutional symptoms, arthritis, hepatosplenomegaly, and endo- carditis. Neurological involvement occurs in 3–5 per cent of cases, usually a er a period of untreated acute brucellosis.29 e most common presentation is with di use encephalopathy or meningoen- cephalitis occurring in approximately 50 per cent of neurobrucellosis cases. Multiple cortical functions are a ected with varying degrees of headache, meningism, and decreased conciousness. Seizures can occur. Other manifestations of neurobrucellosis include in amma- tory transverse myelitis, polyradiculoneuritis, cranial nerve palsies, cerebral demyelination, and neuropsychiatric syndromes.30

Investigation

Brucella species are slow-growing fastidious organisms and culture of CSF or blood is rarely positive. Serological diagnosis is by ELISA or serum and CSF agglutination (STA) tests. IgM antibody titres rise during the rst one to three weeks following infection and IgG a er four weeks. Endemic areas have relatively high background positivity of Brucella IgG, and in such cases a fourfold rise or fall should be demonstrated.

Management

Treatment for neurological disease is typically with two to four weeks of doxycycline and rifampicin with or without streptomycin or a third-generation cephalosporin.

Chronic central nervous system infection

Some pathogens infect the CNS chronically to cause dementia syndromes. Pathogens such as HIV or treponema pallidum may have infected the CNS for a decade or more before presentation with cognitive impairment. However, it is important to note that although the CNS infection is chronic, presentation of the cognitive syndrome may have a relatively acute onset.

Human immunode ciency virus

HIV-associated dementia describes a syndrome of marked cogni- tive impairment that occurs in advanced disease, usually at CD4 counts less than 200, and is an AIDS-de ning illness. It is due to HIV infection itself rather than the e ect of opportunistic infec- tion. Since combination antiretroviral therapy has been widely available in the West the incidence of HAD has declined, however, more subtle neurocognitive impairments remain prevalent and are discussed separately.

HIV-associated dementia Terminology

e terminology around HIV-associated dementia (HAD) can be confusing.

◆ HIV encephalopathy (HIVE) and AIDS dementia complex describe severe impairment and are synonymous with HAD.

◆ HIV encephalitis is the neuropathological correlate of HAD, but this term is also sometimes used to describe the syndrome.

◆ HIV can cause an acute meningoencephalitis at seroconversion which can be severe, leading to seizures and coma.31 Confusingly, this is also sometimes referred to as ‘HIV encephalitis’ due to clinical similarities with acute viral encephalitis, but it is an entirely di erent syndrome.

In this chapter, we use HAD to describe severe impairment and HIV encephalitis for its neuropathological correlate. Speci c dis- cussion of HIV-meningoencephalitis at seroconversion is beyond the scope of this chapter.

Epidemiology

Approximately 34 million people are infected with human immu- node ciency virus (HIV) type 1 globally.32 In the UK, over 90 000 people are infected, a quarter of whom are unaware of their diag- nosis, and the number of new infections continues to rise.33 Prior to antiretroviral therapy, dementia was common and a ected up to 50 per cent prior to death.34 HAD is now uncommon in those stable on antiretroviral treatment, but occurs in those failing treat- ment, or as the rst presentation of HIV infection in advanced disease. Importantly, HIV frequently presents in its late stages as unexplained cognitive impairment in a young person, with or with- out obvious risk factors, and all such patients should be o ered a HIV test as routine.5

Pathogenesis

HIV enters the brain early in infection via infected macrophages and monocytes. Pathologically, activated macrophages and astro- cytes, sometimes with multinucleated giant cells, are seen in brain parenchyma (Fig. 23.5). Infection persists within the CNS in perivascular macrophages and microglia, although direct neu- ronal infection is rare.35 Pro-in ammatory cytokines and toxic viral products cause blood–brain barrier breakdown, rarefaction of white matter, astrocyte apoptosis, dendritic simpli cation, and neuronal loss.36 Subcortical structures such as basal ganglia and the hippocampus appear to be the most vulnerable.37

Clinical features

HAD is associated with a slowly progressive decline in cognition associated with motor slowing and spasticity. As it primarily affects the subcortical white matter, it classically has a subcor- tical dementia phenotype with a combination of cognitive and motor impairment. Features may include bradykinesia, pyrami- dal signs, predominant apathy, social withdrawal, and emotional blunting.

Early symptoms include forgetfulness and inability to concen- trate, as well as personality changes such as apathy, diminished libido, emotional lability, and depression. Individuals may with- draw from social activities or have di culty managing the nan- cial and administrative aspects of their life. In moderate disease, motor abnormalities become more prominent, particularly slow- ing and impairment of ne movements (e.g. typing, buttoning up). Disturbance of gait, leg weakness, tremor, and ataxia may occur. Late features include psychiatric disturbances, mutism, paraplegia, seizures, incontinence, myoclonus and frontal release signs.

Di erential diagnosis

HAD is a diagnosis of exclusion and multiple CNS pathologies may coexist. In HAD, symptoms typically develop slowly over the course of weeks or months. Rapidly developing symptoms should warrant investigation for a di erent aetiology, particularly if associated with impairment of consciousness, headache, or neck sti ness which are

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(a) (b)

Fig. 23.5 (a) High-power microscopic view of a section of brain from a child with HIV encephalitis. A multinucleate giant cell is arrowed. (b) Parenchymal in ammatory in ltrates in a patient with encephalitis due to herpes simplex virus 1.
(a) Courtesy of the Wellcome Library, reproduced under the Creative Commons CC BY- NC 4.0 License. (b) Courtesy of Daniel Crooks.

not features of HAD. ere should be a low threshold for lumbar puncture to exclude infections such as neurosyphilis, cryptococcal meningitis, tuberculous meningitis, Epstein–Barr virus related pri- mary CNS lymphoma, or encephalitis due to varicella zoster, cyto- megalovirus, or Epstein–Barr virus (see Table 23.1).

Marked generalized weakness and spasticity occurring before cognitive impairment is advanced is unusual and should also prompt investigation for other causes such as HIV-associated vacuolar myelopathy or human T-lymphotropic virus-1 (HTLV- 1) infection causing tropical spastic paraparesis. Focal neuro- logical signs do not occur in HAD and may be related to cerebral toxoplasmosis, primary CNS lymphoma, or progressive multifocal leucoencephalopathy.

Both antiretroviral medications and HIV infection itself can cause endothelial dysfunction and accelerated atherosclerosis. Stroke and vascular dementia are more common in HIV.38 Subcortical arterio- sclerotic encephalopathy can mimic HAD.

Metabolic, endocrine, and nutritional disorders may occur in HIV. Electrolytes, renal and hepatic function, blood count, B12/ folate levels, and thyroid function should be routinely checked.

Mood should always be assessed in any HIV-positive individual presenting with cognitive symptoms. Depression and anxiety are common and may occur in over 50 per cent of those infected with HIV.39 Substance misuse should also be excluded.

Investigation

Neuroimaging

MRI may show large, con uent periventricular lesions, hyperin- tense and relatively symmetrical in the white matter, with atrophy representing leukoencephalopathy. However, none of these nd- ings are speci c for HAD and the disease may be present with a normal MRI. Although there may be some faint symmetrical con- trast enhancement symmetrically in the basal ganglia, oedema, space-occupying lesions and frank asymmetry of the white matter are not typical for HAD and should raise suspicion of other condi- tions (Fig. 23.6).

Lumbar puncture

CSF analysis is normal or shows a mild pleocytosis, rarely exceed- ing 50 × 106/l. Total protein and albumin concentrations may be slightly elevated due to blood–brain barrier disruption. Oligoclonal bands are o en present, matched or unmatched in the serum; how- ever, this is nonspeci c and frequently found in the asymptomatic stages of HIV infection. In the pre-antiretroviral therapy era, greater levels of HIV RNA in the CSF was associated with HAD.40,41

Management

Many individuals with HAD improve when commenced on antiret- roviral medications.42,43 is response can be quite marked and some individuals return to independence following treatment; how- ever, response is variable and some show only modest improvement. Several adjunctive anti-in ammatory treatments have been assessed but none has shown clinical bene t to date. Choice of antiretroviral treatment should be based on clinical factors, side-e ects, e cacy, tolerability, and resistance pro le of the virus. Some antiretroviral drugs achieve higher levels in CSF, however at present there is no strong evidence for bene t of these drugs in patients with HAD.5,44 Opinion varies as to whether to prescribe antiretroviral treatment to patients with HAD on the basis of CNS penetration.93

Mild cognitive impairment in HIV

Milder forms of cognitive impairment that do not meet criteria for HAD occur in HIV infection. e full spectrum of cognitive impairment in HIV has been classi ed under the ‘Frascati crite- ria’ (Fig. 23.7).45 Individuals falling at least one standard devia- tion from norms in at least two cognitive domains are classi ed as impaired. ese patients are further divided into asymptomatic neurocognitive impairment (ANI) or mild neurocognitive impair- ment (MND), depending on whether it has a functional impact on daily activities. Along with HAD, these are referred to collectively as HIV-associated neurocognitive disorders (HANDs). ANI is cur- rently a term used in research studies and the clinical consequences of ANI remain to be de ned.

Epidemiology

Since e ective antiretroviral therapy (ART) has been available, the incidence of HAD has dramatically decreased in countries with access to this treatment.46 However, milder forms of cognitive impairment remain common despite treatment.47 ese milder forms of cognitive impairment may be very common. US and European cohort studies have suggested neurocognitive impair- ment may be present in 20–50 per cent of HIV-infected subjects, even those on stable antiretroviral therapy.48–50 Although mild, these subtle impairments represent a signi cant clinical problem as they have been shown to a ect basic daily activities such as driv- ing, shopping, medication adherence, and nancial management, as well as being associated with unemployment and a poorer qual- ity of life.51 As such, cognitive impairment in HIV is an increasingly concerning limitation of ART.

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CHAPTER 23 cns infections 245

246 SECTION 3 cognitive impairment and dementia Table 23.1 Neurological infections causing cognitive impairment

Disease

Pathogen

Comments

Acute presentation

Viral encephalitis

Herpes simplex virus type 1 or 2, varicella zoster virus, enteroviruses and others

Acute encephalitis with current or antecedent febrile illness with headache, seizures, and/or changes in behaviour, personality, cognition, or consciousness. Neurocognitive sequelae may follow

Bacterial menigitis

Streptococcus pneumonae, Haemophillus in uenza, Neisseria meningitides and others

Acute meningitis with fever, neck sti ness, headache, vomiting, and photophobia. Neurocognitive sequelae may follow

Subacute or chronic presentation

HIV-associated dementia and milder forms of cognitive impairment

Human immunode ciency virus

HIV-associated dementia may be rst presentation. Cognitive impairment remains prevelant despite antiretroviral therapy

Neurosyphilis

Treponema pallidium

CNS can be a ected at any stage of infection. Dementia from general paresis is late complication

Tuberculous meningitis

Mycobacterium tuberculosis

Usually in the context of fever, meningism, and/or cranial neuropathy. Intracerebral lesions may coexist

Subacute sclerosing panencephalitis

Measles virus

Rare late complication of infection with the measles virus

Neuroborreliosis

Borrellia species

May be accompanied by constitutional symptoms, meningism, facial palsy, or painful radicultis

Neurobrucellosis

Brucella species

May be preceded by systemic features of acute brucellosis. Infection typically aquired outside of UK

Whipple’s disease

Tropheryma whipplei

Usually accompanied by diarrhoea, weight loss, abdominal pain, and/or arthralgia.

In patients known to be HIV positive or otherwise immunocompromised

Progressive multifocal leucoencephalopathy

JC virus

Nature of impairment dependant on site of lesions. Focal signs may be present

Cerebral toxoplasmosis

Toxoplasma gondii

Encephalitis can occur with or without focal signs from space occupying lesion

Fungal meningitis

Cryptococcus neoformans

Meningitic features may be minimal or absent. Often associated with raised intracranial pressure

Primary CNS lymphoma/encephalitis

Ebstein Barr virus

Signs related to space occupying lesion from primary CNS lymphoma. Less comonly a subacute encephalitis may occur

Ventricuoencephalitis

Cytomegalovirus

CMV has predeliction to infect ependyma of ventricles. ere may be CMV related disease elsewhere such as retinitis or colitis

In patients with tropical foreign travel

Cerebral malaria

Plasmodium falciparum

Fever and decreased concious level in returning traveller from endemic region

African sleeping sickness

Trypanosoma species

Confusion, disruption of sleep–wake cycle and lymphadenopathy in returning traveller from rural Africa, e.g. game reserves

Arboviral encephalitis

Japanese encephalitis, West Nile, chicungunya, dengue, and other arboviruses

Acute encephalitis and sequelae as described above. Pathogen is dependant on geographical location and exposure

Pathogenesis

Antiretroviral CNS penetration is poor, and in some cases CSF levels donotexceedtheminimalinhibitoryconcentrationforwild-typeHIV, suggesting the virus may not be fully controlled in this compartment.52 Other potential causes of CNS damage in those on antiretroviral treat- ment include low-grade immune reconstitution in ammatory syn- drome (IRIS) directed at the CNS,53 and neurotoxicity of antiretroviral drugs.54 However, it remains unclear to what extent these phenom- ena lead to the high prevalence of HAND in treated populations as

there are multiple other factors contributing to cognitive impairment, including hepatitis C coinfection,55 substance misuse,56 and the sys- temic e ects of HIV on atherosclerosis and cerebrovascular disease.57 Nadir (lowest ever) CD4 is associated with HAND;47,50 this re ects the degree of CNS damage sustained before antiretroviral treatment was commenced, some of which will be irreversible, leaving a legacy e ect.

Clinical features

MCI and ANI may be phenotypically di erent to HIV dementia rather than simply a milder form of the same syndrome. Some have

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reported executive function to be worse in MND in contrast to the classical subcortical pattern in HAD. Motor features that are typical of HAD such as bradykinesia, spasticity, and weakness tend to be absent in ANI and MND.58

Investigation

HIV can be detected in the CSF of some patients who are on treat- ment with undetectable viral load in the plasma.59 It is, however,

unclear to what extent this phenomenon leads to mild cognitive impairment, and CSF HIV viral load has not been shown to con- sistently relate to neurocognitive outcomes.60

HIV isolated from within the CNS and from the plasma may have di erent viral characteristics in the same individual, suggest- ing that the CNS virus is partially independent from the haemato- lymphatic compartment and can evolve separately.61,62 In cases of HAND with grossly discordant CSF and plasma HIV viral loads,

CHAPTER 23 cns infections 247

Fig. 23.6 Magnetic resonance imaging (MRI) appearance of HIV-associated dementia. White matter hyper-intensity on coronal uid-attenuated inversion recovery (FLAIR) and sagittal T2-weighted MRI.

HIV-associated neurocognitive disorder (HAND)

Asymptomatic neuro- cognitive impairment (ANI)

Mild cognitive impairment* which does not interfere with everyday functioning

Mild neurocognitive disorder (MND)

Mild cognitive impairment* which produces at least mild interference in daily functioning

Fig. 23.7 Frascati criteria for HIV-associated neurocognitive disorders.
*Performance on neuropsychological tests of at least one standard deviation below the mean for norms in at least two cognitive domains.
**Performance on neuropsychological tests of at least two standard deviations below the mean for norms in at least two cognitive domains.
Adapted from Clin Infect Dis. 54(10), Mailles A, De Broucker T, Costanzo P, et al. Long-term outcome of patients presenting with acute infectious encephalitis of various causes in France, pp. 1455–64, Copyright (2012), with permission from Oxford University Press.

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HIV-associated dementia (HAD)

Marked cognitive impairment** which produces marked interference with day-to- day functioning

248 SECTION 3 cognitive impairment and dementia Table 23.2 Neurological complications of syphilis

Description

Time to presentation

Proportion a ected*

Neuroinvasion

T pallidum in CSF. Most clear infection from CNS spontaneously

days

?100%

Asymptomatic neurosyphilis

CSF abnormalities due to persistant asymptomatic meningitis

<12 months

13–20%

Meningeal disease

Early meningeal syphilis

Meningism, fever, and cranial nerve palsys

<12 months

Meningovascular syphilis

Menigitis with stroke

5–12 years

5–10%

Parenchymal disease

Tabes dorsalis

Posterial column spinal cord disease

15–25 years

3–9%

General paresis

Dementia with personality change

15–20 years

CNS gumma

Mass lession

late

rare

Acute encephalitis

Can mimic herpes simplex encephalitis

? early

rare

*natural progression, i.e. assumes untreated.

genotypic resistance testing can be performed on virus from the CSF.44

Management

Studies have attempted to determine a hierarchy of CNS penetra- tion between di erent antiretrovirals agents; the CNS penetration e ectiveness (CPE) score is based on drug chemical properties, CSF concentration, and e ectiveness in clinical studies.52 Antiretroviral drug combinations with higher composite CPE scores have been shown to have lower CSF HIV viral loads,63,64 however, to date, no conclusive evidence has shown that higher CPE scores have any bene t on neurocognitive function. Use of this score does not form part of current UK or European guidelines.5,44

Hepatitis C virus co-infection

Hepatitis C virus (HCV) is neurotropic, and replicative forms of HCV have been found in autopsy brain tissue.65 Chronic HCV infection is associated with neurocognitive dysfunction that does not correlate with the severity of liver disease and cannot be accounted for by hepatic encephalopathy or drug abuse.66,67 e e ect of HCV on cognition is compounded by HIV infection; HIV and HCV co-infected patients may be almost twice as likely to have neurocognitive impairment as HIV positive individuals without HCV infection.55,68

Neurosyphilis

Syphilis is due to infection with the spirochete bacterium Treponema pallidum. e CNS can be involved at any stage of infection (Table 23.2). Neurocognitive impairment and psychiatric manifesta- tions occur as a late complication of untreated parenchymal neuro- syphilis, known as general paralysis of the insane, or general paresis.69

Epidemiology

In the pre-antibiotic era, up to 10 per cent of the population in some urban areas were infected with syphilis, and the natural his- tory of untreated disease is well described.69 e incidence declined dramatically following the introduction of penicillin in the 1940s, however, since 2000 there has been an increase in new infec- tions, mainly in homosexual men and those with HIV infection.70

Infection remains common in many parts of the developing world and approximately 12 million people are infected globally.70

Pathogenesis

Treponemes disseminate systemically early and CNS infection is common if not universal following primary infection.71 CNS infec- tion may then be cleared or can progress to an asymptomatic stage where CSF abnormalities can be demonstrated without evidence of CNS disease. In a minority of cases there is further progression to symptomatic neurosyphilis with meningeal or parenchymal mani- festations. ose with HIV are less likely to clear spirochetes fol- lowing initial neuroinvasion, and CNS disease is more common in this group.72

Clinical features

See Table 23.2.

Early meningeal syphilis

Acute syphilitic leptomeningitis occurs within 12 months of pri- mary infection and is more common is association with HIV. Symptoms are of meningeal in ammation with headache, neck sti ness, nausea, and photophobia. Cranial nerve palsies may occur.

Meningovascular syphilis

Endarteritis of vessels results in thrombosis and infarction which is most common in the territory of the middle cerebral artery but can occur anywhere in the CNS. is manifestation tends to occur 5–12 years a er primary infection.

Tabes dorsalis

Late disease, typically 20–25 years a er infection, resulting from degeneration of the posterior column and roots of the spinal cord. Symptoms include ataxic gait, paresthesia, bladder dysfunction, and failing vision due to associated optic atrophy. Signs include impaired vibration sense and proprioception, Argyl Robertson pupils, Charcot’s joints, and extensor plantar responses with absent tendon re exes at the ankle.

CNS gumma

Syphilitic gummas can occur anywhere in the CNS, causing focal signs related to site of the space-occupying lesion. ey are

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uncommon, occurring only rarely in large untreated cohorts from the pre-antibiotic era, but may occur in HIV co-infected patients.73

Acute encephalitis

An acute encephalitic syndrome mimicking herpes simplex encephalitis has been described secondary to neurosyphilis.74,75 Patients are typically younger and present with seizures and altered conscious level in association with parenchymal abnormalities on neuroimaging. Most have a brief history of cognitive impairment leading up to presentation. Electroencephalogram typically dem- onstrates periodic lateralizing epileptiform discharges (PLEDS) or nonconvulsive status epilepticus.76

General paresis/General paralysis of the insane

General paresis is a neuropsychiatric disorder developing 15–20 years a er infection. It occurs in approximately 5 per cent of patients infected with syphilis if untreated. ere is widespread atrophy of the cerebral cortex, most severe in the frontal lobes and becoming less pronounced more posteriorly. Focal neurological signs can occur in the ‘Lissauer’ form of the disease, characterized by focal atrophy and seizures.

Although presentation follows long-term infection, the onset of disease may be relatively rapid. Early symptoms include irritabil- ity, forgetfulness, and personality changes. Progressive cognitive impairment follows with psychiatric manifestations which include depression, mania, delusions, hallucinations, and psychosis. In late stages there may be dysarthria, generalized weakness, and hyper- tonia. Argyl Robertson pupils may be seen but are more o en pre- sent in tabes dorsalis. Optic atrophy and ocular muscle palsies are described.69

Investigation

It is not possible to culture treponemes; they can be visualized by dark eld microscopy of lesions or infected lymph nodes, however this is not useful for the diagnosis of CNS disease. PCR tests have been developed but are not available in all centres. In most cases serological tests are used to con rm the diagnosis.

Serological tests

Serological tests are divided into treponemal speci c and non- treponemal speci c tests:

◆ Non-treponemal-speci c
• VDRL (venereal disease research laboratory) • RPR (rapid plasma reagin)

Non-treponemal tests are quantitative and titres indicate disease severity. Levels fall following successful treatment so they can be used to monitor response. Levels decrease over time even without treatment, and false negatives occur in around 30 per cent of those with late neurosyphilis.

◆ Treponemal-speci c
• FTA-Abs ( uorescent treponemal antibody-absorption) • TPHA (treponema pallidum haemaglutination assay)
• TPPA (treponema pallidum particle agglutination)
• TPI (treponema pallidum immobilization)

Treponemal-speci c tests become positive early in infection and remain reactive inde nitely regardless of treatment. ey are useful for diagnosing the late stages of neurosyphilis but cannot be used for monitoring response to treatment.

CSF tests

A positive VDRL in the CSF is considered diagnostic of neurosyph- ilis in the absence of heavy contamination with blood; however, false negatives may occur in up to 50 per cent of those with symp- tomatic disease.77,78 In this situation, a CSF pleocytosis indicates neurosyphilis, although the level considered abnormal is higher in those with HIV infection particularly if not on antiretroviral treat- ment. Testing RPR is not recommended in CSF as the false negative rate is higher than with VDRL.79 CSF treponemal speci c tests are sensitive however passive transfer from blood causes speci city to be low. is can be improved by looking at the titre of the test or calculating the TPHA index. Although some guidelines suggest a negative treponemal speci c test in CSF rules out neurosyphilis, this may not be the case when clinical suspicion is high (Fig. 23.8).78

All patients diagnosed with neurosyphilis should be tested for other sexually transmitted infections including HIV.

Management

Penicillin remains the mainstay of therapy to treat neurosyphilis. Longer duration of treatment and parenteral route of administra- tion is required for syphilis involving the central nervous system. Current UK treatment guidelines can be found at <http://www. bashh.org/documents/1771>.80

Whipple’s disease

Whipple’s disease is a relapsing, slowly progressive systemic infec- tious disease caused by the bacterium Tropheryma whipplei. It is primarily a gastrointestinal disorder causing malabsorbtion but can a ect multiple other parts of the body including the brain. Although rare, it is important to consider as it is fatal without anti- biotic treatment.81

Epidemiology

Fewer than 1000 cases of Whipple’s disease have been reported, of whom less than half have CNS involvement. is is likely to be an underestimation due to the low index of suspicion and di culties making a diagnosis, however Whipple’s disease remains an uncom- mon infectious cause of cognitive impairment.

Clinical features

Infection is systemic and Whipple’s disease may a ect almost any part of the body. e most common manifestations are diarrhoea, weight loss, abdominal pain, and arthralgia with low-grade fever and lymphadenopathy. ese features may be absent and neuro- logical symptoms can occur in isolation.82,83

Cognitive changes are the most common manifestation of CNS disease occurring in around 75 per cent of cases.84 Around half have concomitant psychiatric features including depres- sion, anxiety, hypomania, and psychosis. Oculomasticatory or oculofacial-skeletal myorhythmia is a pathognomonic sign of neuro-Whipple’s.83,85 It occurs in around 20 per cent of cases and is associated with supranuclear gaze palsy.84 Other CNS fea- tures include seizures and symptoms related to hypothalamic dysfunction such as polydipsia, polyuria, hypogonadism, and hypersomnia.

Investigation

Early diagnosis can be di cult due to the variable clinical features and occasional absence of gastrointestinal symptoms. ere is no

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CHAPTER 23 cns infections 249

250 SECTION 3

cognitive impairment and dementia

CSF treponemal specific tests positive

Serology +ve

yes

CSF VDRL positive

no no

yes

CSF pleocytosis

CSF TPHA titre >320 CSF TPPA titre < 640 TPHA index* >70

Fig. 23.8 Flowchart for the diagnosis of neurosyphilis in a symptomatic patient. *TPHA index = CSF TPHA/albumin quotient (CSF albumin ×103/serum albumin).

speci c serologic test for Tropheryma whipplei and diagnosis is usu- ally based on histopathogical appearances on small bowel biopsy. Patients with only CNS involvement may require stereotactic brain biopsy.83 Characteristic changes of villous atrophy and periodic acid–Schi –positive macrophages can be absent in up to 30 per cent; however, newer PCR techniques have a higher sensitivity.86

86 PCR can also be performed on CSF.

Management

For Whipple’s disease involving the CNS initial treatment with parenteral streptomycin, benzylpenicillin or cephalosporins is fol- lowed by long-term trimethoprim-sulphamethoxazole with folate supplementation for up to two years.87

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61. Soulie C, Fourati S, Lambert-Niclot S, et al. HIV genetic diversity between plasma and cerebrospinal uid in patients with HIV encephali- tis. AIDS. 2010;24(15):2412–4.

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63. Letendre S, Marquie-Beck J, Capparelli E, et al. Validation of the CNS Penetration-Effectiveness rank for quantifying antiretro- viral penetration into the central nervous system. Arch Neurol. 2008;65(1):65–70.

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68. Perry W, Carlson MD, Barakat F, et al. Neuropsychological test perfor- mance in patients co-infected with hepatitis C virus and HIV. AIDS. 2005;19 Suppl 3:S79–84.

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Introduction

CHAPTER 24

Metabolic dementia

Nicholas J.C. Smith and Timothy M. Cox
Table 24.1 Metabolic disorders associated with adult-onset cognitive

decline

In clinical practice, ‘metabolic dementias’ are o en considered as singular diagnostic entities, giving little attention to their complex manifestations and protean causes. De ned as progressive cogni- tive impairment su cient to impair independent function, demen- tia induced by disorders of metabolism may be acquired or the result of inborn errors of cellular function (Table 24.1).

Clinical manifestations may arise from infancy to old age, with presenting features ranging from precipitant encephalopathy to indolent cognitive decline. Variation in clinical presentation is o en explained by the time that cellular decompensation occurs in the brain and the neurodevelopmental stage and cognitive function that has been attained at that age. Indeed, normal devel- opment may at rst mask degenerative pathology in childhood, and deterioration in an intellectually impaired patient might be overlooked. Conversely, onset in utero may be associated with profound disease that is declared in infancy, while delayed pres- entation of inborn metabolic errors is increasingly recognized. Relapsing–remitting patterns of dementing disease are also com- mon; these are typically due to external in uences on cellular homeostasis, including metabolic stressors (e.g. intercurrent ill- ness and relative starvation), de ciencies of enzyme co-factors (e.g. vitamin and mineral de ciencies), or intoxication (e.g. excess protein load) [Fig. 24.1].

Given the importance of identifying genetic diseases in a ected pedigrees, and as some conditions may be treatable, metabolic causes of, or contributions to, cognitive impairment should always be considered and speci c diagnoses sought. Advances in biochem- ical genetics have greatly expanded the opportunities for e ective treatments: these include replacement of cofactors, enzyme replace- ment and augmentation, removal of toxic substrates via scavenging chemical agents, or restriction of dietary substrates. While in some monogenic disorders gene transfer techniques show considerable promise.

Here we restrict discussion to a practical diagnostic framework for primary metabolic dementia: the contribution of disturbed cellular metabolism to the classically de ned dementias and the e ects of systemic metabolic conditions, such as accelerated cer- ebrovascular disease in patients with diabetes are discussed in relevant chapters; dementia resulting from mitochondrial dis- ease is discussed in chapter 31 and is summarized only brie y herein.

Classi cation of the metabolic dementias

Many di erent ways of classi ying the metabolic dementia have been proposed. From a practical perspective, an approach based on clinical phenotype is most relevant for clinicians, with the caveat that the clinical behaviour of some disorders may be confounded by the sheer diversity of potential manifestations—particularly when these come to light at di erent neurodevelopmental ages.

To simplify the diagnostic conspectus for practising clinicians rather than biochemists, here we present a working classi cation which rst distinguishes acquired pathologies from inborn errors of metabolism and subclassi es the given entities on the basis of the principal meta- bolic pathways a ected (Fig. 24.2). In making this pathophysiological distinction, the main presenting phenotypes are set out, with empha- sis on conditions with onset in adult life. For these purposes, dementia is de ned broadly as progressive cognitive impairment, without limi- tation to the classical dementias and includes acute encephalopathy.

Acquired

Nutritional de ciencies
Acid-base and electrolyte disturbances Endocrinopathies
Visceral insu ciency
Hypoxia and hypercapnia
Toxins and medication

Inborn errors of metabolism

Disorders of carbohydrate metabolism
Disorders of mitochondrial energy metabolism
Disorders of amino acid metabolism and transport
Vitamin responsive disorders
Disorders of neurotransmitter metabolism and function
Disorders of purine and pyrimidine metabolism
Disorders of lipid and bile acid metabolism
Disorders of haem metabolism
Disorders of elemental co-factor transport and metalloprotein dysfunction Other disorders of lysosomal macromolecule catabolism

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Childhood

Adolescence

Adulthood

Childhood cognitive regression Early-onset dementia [≤ 65 yrs]

1
2

Acquired metabolic insult

Inborn error of metabolism

Fig. 24.1 Patterns of neurocognitive decline in metabolic dementia. Dementia due to inborn errors of metabolism is usually manifest in infancy or childhood, with adult-onset disease most commonly presenting as early-onset dementia (before 65 years of age). However, both inborn and acquired disease may declare at any age and proceed at variable velocities, dependent upon cause. is gure depicts: neurocognitive development in a healthy individual (solid line, black) with variable age-related cognitive decline (dashed line, black) (1); non-progressive intellectual impairment (solid line, red) (2); pathological neurocognitive decline (multiple dashed lines, red) (3); acute deterioration with a relapsing-remitting course and evident recovery (dotted line, red) (4).

Glycolipid metabolism

Protein

Ammonia

Urea cycle Urea

Haem synthesis

Glycogen

Glucose

Pyruvate Acetyl-CoA

Fructose Galactose

Lactate

Ketones

Lipids

Fatty acids

Sphingolipid metabolism

Co-factor metabolism

Neurotransmitter metabolism

Amino acids Organic acids

Purine & pyrimidine metabolism

TCA cycle

Mevalonate
Cholesterol

isoprenoid synthesis

ATP

NADH

Steroids

ETC

Fig. 24.2 Major pathways of cellular metabolism a ected in metabolic neurocognitive decline. e principal substrate pathways for generating acetyl coenzyme A from carbohydrates, lipids, and proteins are shown; acetyl-CoA is the primary carbon donor to the tricarboxylic acid (TCA) cycle and adenosine triphosphate (ATP) is generated by mitochondrial oxidative phosphorylation. Critical pathways of intermediate and macromolecular metabolism are included: pathological disruption of each of these has been implicated in neurocognitive decline.
ETC: electron transport chain; NADH: reduced nicotinamide adenine dinucleotide; NADPH: reduced nicotinamide adenine dinucleotide phosphate; R5P: ribose-5-phosphate.

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Antenatal

Pentose-phospate pathway

RP NADPH

Autophagy
Macro Micro Chaperone

Proteosomal degradation

e scope of metabolic disorders with cognitive manifestations is vast, and with the increasing use of massive parallel DNA sequenc- ing for diagnostic purposes, rare inherited variants of inborn errors of metabolism are emerging as causes of cognitive decline with onset in adult life. e advent of methods for systematic analysis of whole-exome and even individual genome sequences has enabled numerous ultra-rare disorders to be identi ed within the pool of previously undiagnosed neurodegenerative disorders. ese excit- ing initiatives are improving diagnostic power; moreover, they o er the promise of new insights into potential therapy.

When to suspect metabolic dementia

While some clinical features are highly suggestive of a metabolic cause and, with experience, speci c patterns can o en be recog- nized, there can be few certainties. Nonetheless, several features in the clinical presentation should alert the physician to the possibility of a metabolic disorder in the dementing patient (Box 24.1).

Acquired disease may arise at any age; indeed, it may precipi- tate deterioration in those patients harboring metabolic condi- tions due to underlying genetic defects. However, early-onset dementia—generally accepted as presenting before 65 years of age1—should certainly prompt consideration of a metabolic cause, particularly with onset in adolescence or young adulthood, where suspicion of a metabolic dementia is at the forefront of diagnostic possibility.

In metabolic conditions the cognitive manifestations are usually more varied than in the primary dementias; they may range from developmental intellectual delay to late-onset delirium and pro- gressive dementia. Moreover, global encephalopathy and impaired consciousness are more suggestive of a secondary dementing illness than one of the classic dementias.

Rapid decline, o en at times of metabolic stress (e.g. starvation, in ammation, and surgery), increased catabolic load (e.g. high die- tary protein), or following a closed head injury, strongly suggests an inborn metabolic error—particularly those a ecting intermedi- ate metabolism and cellular energy production. Episodic uctua- tions (sometimes with near-complete recovery) are also common, re ecting interval restitution of metabolic homeostasis upon removal of precipitating factors. Of note, hyperemesis gravidarum places the pregnant woman under considerable metabolic stress, compounded by the risk of micronutrient de ciency; the post- partum period is also a vulnerable period for women with latent inborn errors of metabolism and it is important not to overlook such diagnoses when maternal neuropsychiatric disturbances have occurred. Subacute progressive forms of dementia are typical of disorders of macromolecular biosynthesis and degradation, such as the disorders of lipid breakdown and many of the elemental trans- port disorders; certain mitochondrial cytopathies may also present in this manner.

e presence of additional neurological features and concomitant systemic manifestations may also indicate a metabolic derange- ment; the presence of such features giving rise to the designation of ‘dementia plus’ disorders.1 In the assessment of dementing patients, the pattern of these additional features may provide invaluable diagnostic clues (see chapter 21).

A premorbid history of childhood neurodevelopmental delay, presumed static intellectual impairment (o en re ected in poor scholastic performance), or behavioural disorder might re ect early and previously unrecognized manifestations of disease. Indeed, early con rmation of indolent regressive disease is o en di cult in the absence of formal neurocognitive assessments car- ried out serially, especially when slow regression is ‘masked’ by par- allel neurodevelopmental gains in childhood. A transient illness in childhood may similarly provide clues to the cause neurodegenera- tive disease that comes to light later in life—a history of prolonged neonatal jaundice, for example, raises the possibility of disorders of bile acid and cholesterol metabolism2 as is seen in Niemann–Pick disease type C.3,4

Familial occurrence of disease may suggest a genetic cause and the pattern of inheritance may clarify the di erential diagnosis. However, the absence of disease in any known ancestor or family member cannot exclude an inborn metabolic disorder, particu- larly those inherited as autosomal recessive traits. Consanguinity (immediate, or more typically, in antecedents) o en provides vital clues to inform diagnosis in cases presumed to be sporadic; o en consanguinity may emerge from enquiring as to the geo- graphic origin and birthplace of the parents of an index case. At the same time, the potential for de-novo mutation and confound- ing factors such as non-paternity (o en withheld) are of critical diagnostic value. Phenotypic variability amongst family members with inborn errors of metabolism (e.g. childhood cerebral X-linked

CHAPTER 24 metabolic dementia 255

Box 24.1 Features suggestive of metabolic dementia

◆ Early age of onset

◆ Precipitantonset

◆ Rapidly progressive dementia

◆ Global encephalopathy/impaired conscious state

◆ Episodic course

◆ Risk factors for acquired nutritional de ciency
Malnutrition, malabsorption, alcoholism, metabolic con- sumption (pregnancy, cancer)

◆ Childhood neurocognitive impairment

◆ Family history

◆ Familial consanguinity

◆ Presenceofassociatedfeatures/comorbidpathology(demen- tia plus)
Neurological: seizures, pyramidal, extrapyramidal, cerebellar, neuro-ophthalmological, peripheral neuropathic/neurono- pathic, neuromuscular
Psychiatric: a ective spectrum, personality and behavioural changes, psychosis
Somatic: ophthalmological, visceral, endocrinological, cuta- neous, connective tissue, skeletal

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256 SECTION 3 cognitive impairment and dementia

adrenoleukodystrophy and adult-onset adrenomyelneuropathy) may further confound the true genetic basis for the condition. us, a wider knowledge of familial medical history may prove informative; for example, a history of maternal miscarriage might suggest presentation of disease in utero.

As with all cases of dementia, a thorough review of medication is mandatory—also with consideration of the potential metabolic e ects of prescribed and non-presciption drugs. e o en dramatic triggering of acute porphyria by adverse exposure to drugs and metabolic stress, including surgical operations, is a paradigmatic example. Indeed, the temporal relationship of disease onset and exacerbation, especially in relation to use of medication, may lead to the diagnosis in the metabolic dementias.

Acquired nutritional de ciencies occur frequently in develop- ing and displaced populations; although uncommon in Western populations, the possibility must be considered in the context of alcoholism and in situations of restricted intake as may occur in the chronically ill or anorexic patient, and pregnant women with hyperemesis gravidarum. Indeed, multiple nutritional de ciencies o en coexist. Of note, speci c de ciencies are increasingly evi- dent in those adhering to specialist diets or a er bariatric surgery.5 Patients receiving total parenteral nutrition or cytotoxic chemo- therapy are also at risk and careful attention should be given to the micronutrient and elemental composition of replacement nutrition.

Finally, in a dementing patient with a known inborn error of metabolism, where treatment is expected to attenuate disease the possibility of non-compliance should be considered, particularly given the strict dietary regulation that is o en needed to maintain health in many inborn metabolic disorders. A review of the con- sequences of speci c therapies must also be considered: acquired nutritional de ciencies may occur, as exempli ed by symptomatic cobalamin de ciency in patients with phenylketonuria managed by dietary protein restriction,6 and secondary zinc de ciency in patients with Wilson’s disease receiving copper-chelation therapy without supplementation.7

An approach to the investigation

of suspected metabolic dementia

Given their protean nature and heterogeneity, the approach to diagnosis of neurometabolic disease favours targeted investigation over protocol-driven screening. Investigations should be guided by clinical insight, with clear understanding as to their diagnos- tic value and priority given to the rapid identi cation of treatable pathology. While in certain cases the clinical phenotype is highly suggestive, such as Fabry disease presenting with an acute stroke in a young man with angiokeratoma and a history of acroparaesthesia, or hypothyroidism in a middle-aged woman with confusion and myxoedema, in most cases the clinical features are non-speci c. Where aetiology is uncertain, initial consideration should be given to whether the features of the patient’s condition fall within one or more broad ‘functional’ phenotypes (Table 24.2), at the same time recognizing such distinctions are not concrete. Finally, before deciding upon the likely conditions to investigate, in each case it is prudent to consider whether an acquired or inborn metabolic disorder is the more likely.

Clinical assessment should include detailed neurocognitive, sys- temic, cutaneous, and ophthalmological examinations; metabolic

disorders rarely present as isolated cognitive decline, with adjunct central and peripheral neurological impairment (‘dementia plus’) common and o en proving to be the presenting feature of the ill- ness, while non-neurological features may also inform diagnosis. Attention to biochemical consequences of aberrant metabolism can assist diagnosis, such as dark-red to brown urine re ecting excess porphyrin excretion or the presence of malodorous bio uids (per- spiration and urine) which may occur in the context of substrate accumulation, particularly the disorders of amino acid metabolism.

Formal neuropsychological assessment is helpful in de ning the pattern of cognitive impairment and establishes a baseline level of function which facilitates determination of time-dependent reduc- tion in performance, typical of many inborn errors of metabolism.

Routine haematological and biochemical assays may identify a primary metabolic defect (e.g. thyroid function tests) or provide indirect evidence of underlying pathology (e.g. megaloblastic anae- mia in B12 de ciency or abnormal liver-related tests and acantho- cytosis in Wilson’s disease). However, these ndings are of variable speci city and in many cases remain within healthy reference lim- its, particularly if decompensation is episodic.

Where clinical phenotype and routine laboratory investiga- tions fail to suggest a speci c cause, a general screening algo- rithm, intended to identify the more common consequences of metabolic disruption and several rare but potentially treatable causes of cognitive decline, may prove to be useful. Here, consid- eration is given to a more inclusive screen of cerebrospinal uid (CSF) neurochemistry, rather than a stepwise approach, re ect- ing the more invasive nature of diagnostic lumbar puncture (Fig. 24.3). However, it must be noted that while stratagems of high diagnostic utility may become evident, sensitivitiy and speci – city of these screening investigations are variable and care must be exercised when selecting and interpreting them. Furthermore, consideration to practical constraints of sample collection, trans- port, and processing is essential to avoid metabolite artefact in many cases.

Consideration must also be given to the wider consequences of investigations ordered, including the patient and their family mem- bers, in whom the genetic implications of inborn metabolic disor- ders may have profound implications; as with all genetic diorders, strict con dentiality and attentive pre- and post-test counselling are paramount.

Biochemical laboratory investigations

Generally, biochemical screening assays quantify major biological substrates and products of metabolism that accumulate in vivo or assess speci c enzymatic activity by in vitro assay. While frankly disordered homeostasis is usually evident, diagnostic features may only be present at times of cellular metabolic stress or substrate load (particularly in many of the intermediate metabolism disorders); thus apparently normal results are o en obtained when studies are carried out at times of greater or more compensated metabolic stability. Conversely, a negative result during such an episode has greater value in excluding an inborn metabolic error. Furthermore, in most inborn metabolic disorders, late-onset disease re ects an attenuated variant and the pathological biochemical changes may be barely notable, limiting detection, depending upon assay sen- sitivity. Care must be taken to ensure the appropriate sample is

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Table 24.2 Functional classi cation of metabolic disease presenting with adult-onset neurocognitive decline

Intermediate metabolite (‘small molecule’) disorders

Disorders of cellular energy production

Examples

Disorders of cellular energy production re ect impaired production of ATP or its utilization, a process dependent upon several interacting metabolic pathways. Breakdown of complex carbohydrate to glucose and its glycolytic conversion to pyruvate provides the main substrate for mitochondrial generation of acetyl CoA,the main carbon donor to the tricarboxylic acid (TCA) cycle and oxidative phosphorylation pathway, from which the majority of cellular ATP is derived. In addition, products of protein (amino and organic acids), fatty acid, and ketone body metabolism also generate acetyl CoA and are critical in states of impaired carbohydrate availability or utilization. Inborn defects in energy production therefore include disorders
of carbohydrate metabolism, including defects of glycolysis, gluconeogenesis, and glycogenolysis, primary disorders of pyruvate metabolism, and disorders a ecting the TCA cycle and mitochondrial respiratory chain function. Aberrant organic and amino metabolism may also a ect energy production via reduced substrate availability and secondary dysequilibrium of TCA cycle metabolites. Disordered β-oxidation of fatty acids also impairs acetyl-CoA synthesis and ATP production; fatty oxidation defects induce critical dependence on glycolysis and hence the supply of glucose units, especially in the brain where energy production adapts slowly to ketone bodies generated by the liver. Additionally, dysregulation of purine and pyrimidine metabolism impairs ATP synthesis and generation of TCA cycle intermediates.

In the majority of cases, presentation is acute, precipitated by metabolic stress (e.g. fasting or illness),
often with rapid cognitive decline typical of an encephalopathy; episodic exacerbation with complete
or partial recovery and stroke-like episodes are common. However, chronic dementing disease is also recognized, typi ed by several syndromic mitochondrial cytopathies and characteristic of the cerebral glycogenosis (e.g. adult polyglucosan body disease). Additional neurological features are frequent, including cortical (e.g. seizures and myoclonus) and deep grey matter involvement (e.g. extrapyramidal disease), cerebellar dysfunction, dysautonomic features, and peripheral neuromuscular disease (including optic atrophy, extraocular paresis, polyneuropathy, and primary myopathic disease). Of note, white matter disease and spastic paresis are less common, with the exception of certain co-factor de ciencies (e.g. B12 and copper) and adult Polyglucosan body disease. Systemic disease is frequently present, particularly in

the mitochondrial energy defects (e.g. cardiomyopathy, hepatic disease, gastrointestinal dysmotility, and diabetes mellitus), and re ects involvement of tissues outside the central nervous system with high energy requirements.

Acquired disorder of metabolism

Co-factor de ciencies:

e.g. B group vitamin de ciencies, copper de ciency

Inborn error of metabolism

Disorders of carbohydrate metabolism

e.g. cerebral glycogenosis, glucose transporter de ciency

Disorders of mitochondrial energy metabolism

e.g. mitochondrial cytopathies, disorders of fatty acid β-oxidation

Vitamin responsive disorders

e.g. cobalamin C disease, cerebral folate de ciency, biotin-thiamine-responsive basal ganglia disease

Disorders of amino acid metabolism and transport*

e.g. phenylketonuria, organic acidaemias, urea cycle disorders

Disorders of metabolite intoxication

Disorders of metabolite intoxication can be considered as a broad collective of disparate aetiology, characterized by acute or chronic accumulation of compounds which are toxic in excess—here we consider those resulting from an inherent defect of intermediate metabolism (choosing to exclude the inborn disorders of elemental co-factor metabolism which are categorized as a distinct group in this context).

Typically a symptom-free period is observed before cognitive manifestations of intoxication arise—
indeed rst presentation may be well into adulthood; the intoxication is often acute, usually in the
context of metabolic stress (e.g. fever or illness) or increased substrate load, such as hyperammonaemic encephalopathy after protein ingestion in acquired hepatic insu ciency or urea cycle disorders; more insidious cognitive impairment may occur in late-onset disorders of amino and organic acid metabolism. Interval recovery, between acute episodes of decompensation may occur, such as in the hepatic porphyrias, where psycocognitive impairment, sometimes resembling delirium or acute anxiety may be interpreted

as a primary psychiatric illness or ‘toxic confusional state’. Adjunctive neurological features are common, including cortical manifestations (e.g. seizures) and prominent white matter disease with a progressive leukoencephalomyelopathy seen in several aminoacidopathies (e.g. phenylketonuria and the homocysteine remethylation defects). Cerebellar impairment, extrapyramidal disease, and akinetic parkinsonian

features may also arise. While less common, peripheral neuropathy is often recognized in the disorders
of homocysteine metabolism and constitutes a dominant feature of acute hepatic porphyria, typically
with exuberant autonomic features. Systemic manifestations in this group are less prominent than in the disorders of energy metabolism, although the presence of corneal clouding or cataract formation may suggest metabolite accumulation (e.g. galactosaemia). Features overlap with the disorders of cellular energy production and toxicity may give rise to the latter, exempli ed by secondary impairment of TCA cycle metabolism in the context of many amino and organic acidopathies, as well as the hyperammonaemias.

Acquired

Exogenous toxins and medications

e.g. lead inhibition of aminolevulinate dehydratase

Visceral insu ciency

e.g. uraemic encephalopathy, hepatic encephalopathy

Inborn error of metabolism

Select disorders of carbohydrate metabolism

e.g. Galactosaemia, hereditary fructose intolerance

Disorders of amino acid metabolism and transport

e.g. phenylketonuria, tyrosinaemia type 1, organic acidaemias, urea cycle disorders

Disorders of Haem metabolism

e.g. acute hepatic (neurovisceral) porphyrias

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(continued)

Table 24.2 Continued

Intermediate metabolite (‘small molecule’) disorders

Disorders of neurotransmitter metabolism

Examples

Monogenic disorders of monoamine, gamma aminobutyric acid, and glycine metabolism are typically recognized in infancy and childhood, although late-onset variants occur; however, with the exception of glycine encephalopathy (non-ketotic hyperglycinaemia), late-onset neurocognitive decline and dementia are not characteristic. While, disordered regulation of many neurotransmitters, particularly acetylcholine, are thought to underpin several psychocognitive diseases, the mechanisms by which homeostasis is disturbed are uncertain.

Clinically, monoamine de ciencies re ect the primary neurotransmitters a ected; dopamine (parkinsonism, dystonia, and autonomic features), noradrenalin (ptosis, myosis, and orthostatic hypotension), and serotonin (sleep disturbance, dysthymia, and behavioural change). Adult presentations of glycine encephalopathy more readily resemble intoxication states, with acute confusional encephalopathy precipitated by metabolic stress, often upon a background of intellectual delay and disturbed behaviour, although features are variable and have also included paroxysmal choreoform movement disorders and white matter disease. Also considered among ‘acquired’ disorders of neurotransmission are several of the autoimmune encephalopathies, where autoantibodies target the post-synaptic N-methyl-D-aspartate (NMDA) receptor; subacute cognitive decline is typically associated with headache, behavioural change, prominent neuropsychiatric symptoms, generalized seizures, or myoclonus.

Acquired

Exogenous toxins and medications

e.g. dopamine antagonists, anticholinergics

Co-factor de ciencies:

e.g. copper de ciency

Neurotransmitter receptor antibodies (autoimmune encephalitis)

e.g. autoimmune encephalopathy (anti-NMDA receptor antibodies)

Inborn error of metabolism

Inborn error of glycine metabolism

e.g. glycine encephalopathy

Disorders of elemental co-factor transport and metalloprotein dysfunction

Disorders of elemental co-factor transport and metalloprotein dysfunction are recognized causes of metabolic dementia and neuropsychiatric manifestations; in most cases the consequence of disordered metal tra cking and utilization, resultant tissue accumulation underlies end-organ pathology.

Neurocognitive decline is typically subacute in presentation, often with dominant psychiatric features. Metal accumulation within the basal ganglia prompts diagnostic consideration when demonstrated by neuroimaging; extra-pyramidal manifestations including dystonia (often including orofacial dyskinesia), choreoathetosis, and parkinsonism are characteristic. Cerebellar dysfunction may be prominent. Visceral involvement, such as cirrhosis, cardiomyopathy, renal tubular disease, and endocrine pancreatic failure (diabetes mellitus), should also raise the possibility of elemental tissue deposition in this context and may arise independently from neurological disease.

Acquired

Metal intoxication

e.g. lead, copper, manganese

Elemental de ciency

e.g. copper, iron, iodine, zinc

Inborn error of metabolism

Disorder of copper transport

e.g. Wilson’s disease

Disorder of iron transport

e.g. aceruloplasminaemia, neuroferritinopathy

Disorders of endocrine function

Endocrinopathy-associated cognitive decline represents a unique subgroup of acquired metabolic dementia; diagnosis is rarely mistaken when attention is given to the associated systemic features present.

Acquired

Endocrinopathies

e.g. hyperthyroid encephalopathy, Cushing’s disease, diabetes mellitus

Macromolecule disorders

Disorders of lipid metabolism and transport

Disorders of lipid metabolism and transport are increasingly recognized amongst the late-onset metabolic dementias, encompassing a heterogeneous group of diseases which includes disorders of cholesterol and bile acid synthesis, disordered fatty acid catabolism, aberrant cholesterol tra cking, and the disorders of sphingolipid catabolism.

While clinical features are disease-speci c, general associations hold true; cognitive decline is typically of a slowly progressive nature and neuropsychiatric presentations are common, constituting the presenting feature in many cases. Dysmyelination and leukoencephalopathic disease is frequent and peripheral neuropathy is often a feature; cerebellar ataxia, choreoathetosis, seizures, and retinopathy also occur. Systemic pathology may also prove suggestive; splenomegaly suggesting a disorder of lipid storage, or features of cutaneous deposition such as xanthomata. A history of prolonged neonatal jaundice may suggest a disorder of cholesterol or bile acid metabolism.

Acquired

Acquired dyslipiaemias

e.g. metabolic syndrome

Malabsorption of fat-soluble vitamins

e.g. cystic brosis, pancreatitis, intestinal malabsorptive disease

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CHAPTER 24 metabolic dementia 259

Intermediate metabolite (‘small molecule’) disorders

Table 24.2 Continued

Disorders of lipid metabolism and transport

Examples

Inborn error of metabolism

Hereditary dyslipidaemias

e.g. abetalipoproteinaemia

Disorders of bile acid synthesis

e.g. cerebrotendinosis xanthomatosis, 2-methylacyl- CoA racemase de ciency

Disorders of sphingolipid metabolism

e.g. Gaucher disease, GM1 gangliosidosis, GM2 gangliosidosis, metachromatic leukodystrophy

Disorder of cholesterol transport

e.g. Niemann–Pick disease type C

Disorders of peroxisomal function

e.g. X-linked adrenoleukodystrophy/ adrenomyeloneuropathy

Other disorders of macromolecule catabolism and autophagy

Representing a signi cant proportion of the inborn metabolic dementia spectrum, disorders of lysosomal function re ect anomalous macromolecule catabolism.

Progressive cognitive decline and, at times, neuropsychiatric features, are typical of adult manifesting disease, while adjunct neurological involvement is more variable. Visceral disease may be present with enlargement of viscera and skeletal abnormalities and, in the mucopolysaccharidoses and oligosaccharidoses (glycoproteinoses), dysmorphism and coarsening of facial cutaneous tissues. Skeletal dysplasisa, cutaneous angiokeratoma, and peripheral neuropathy occur in the oligosaccharidoses and are near pathognomic when presenting a comorbid tetrad with central neurological disease. e numerous genetically distinct neuronal ceroid lipofuscinoses are characterized by a central neurological phenotype without systemic features; seizures, ataxia, and parkinsonism often accompany dementia, typically with progressive blindness due to retinal dystrophy and optic nerve atrophy.

Disordered cellular catabolism in the lysosomal compartment includes pathological disruption of autophagy and proteosomal degradation, a feature that appears to be associated with neurodegenerative disease, including the primary dementias. While the pathogenesis is not fully understood, it is of great interest that mutations a ecting several proteins involved in lysosomal metabolism are implicated in parkinsonism— rst noted to occur with increased frequency in patients with Gaucher disease who were homozygous for causal mutations in the GBA1 gene: Notably, heterozygotes for mutations causing Gaucher disease, Niemann–Pick C disease, and neuronal ceroid lipofuscinosis also demonstrate an increased risk of age-related parkinsonism.

Inborn error of metabolism

e mucopolysaccharidoses

e.g. San lippo syndrome (MPSIII)

e oligosaccharidosis (glycoproteinoses)

e.g. mannosidosis, fucosidosis, sialidosis

e neuronal ceroid lipofuscinoses

e.g. adult-onset NCL (Kuf’s disease), cathepsin D (CTSD) de ciency

*Secondary impairment of TCA cycle metabolism and cellular energy production arise in a number of aminoacidopathies (e.g. organic acidurias and disorders of urea cycle metabolism)

obtained (blood, CSF, urine, or tissue); sample collection (timing and methodology), transport, and processing are also critical for avoiding artefactual errors, the details of which are within the ter- ritory of specialist biochemical advice and should be con rmed, if unfamiliar.

Magnetic resonance imaging

Magnetic resonance imaging (MRI) serves as an important diagnos- tic modality in the investigation of suspected neurometabolic disease. While stereotypic patterns may prove diagnostic, imaging features are o en non-speci c and, in many cases normal, particularly amongst attenuated late-onset disease variants. Standard T1 sequences permit regional delineation of structure, including atrophy (best determined with dedicated volumetric acquisitions), while T2 and uid-attenu- ation inversion recovery (FLAIR) sequences re ect white matter integrity and may reveal a typically symmetrical leukodystrophic pro- cess, the pattern of which aids pathological discrimination in many

cases.8–10 Indeed, two broad categories of inborn metabolic disease dominate the metabolic leukoencephalopathies: lipid storage disor- ders, in which involvement is typically restricted to tracts within the deep white matter, sparing the juxtacortical bres (U- bres), and dis- orders of amino acid metabolism, which usually extend to a juxta- cortical distribution.8 Regional involvement, including the presence of peripheral nerve involvement, may provide additional diagnostic clues.9,10 Signal change within the basal ganglia should always pre- cipitate consideration of acquired or inborn disorder of metabolic function, particularly, but not limited to, those impacting cellular energy production (typi ed by the mitochondrial cytopathies) and many of the toxic encephalopathies.11,12 Additional sequences should include di usion-weighted acquisitions (DWI/ADC), as restricted di usion is a sensitive marker of cytotoxic oedema, a pathophysi- ological process present in a number of primary and secondary dis- orders of metabolism. While, susceptibility-weighted images (SWI) utilize ow-compensated gradient-echo imaging to exploit suscepti- bility variations between tissues, allowing de nition of paramagnetic

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Magnetic Resonance Spectroscopy

Blood investigations

Suspected Metabolic Dementia

Full blood cound + film examination
Blood gases, pH & HCO3- (calculate anion gap)
Electrolytes
Ketone bodies (β-hydroxybutyrate, acetoacetate)
Lactate & pyruvate (calculate L:P ratio)1,2
Fasting glucose
Renal function (creatinine/urea/calculate GFR)
Liver function (transaminases/prothrombin time/albumin) Plasma ammonia3,4
Uric acid
Creatine kinase
Thyroid function studies
Cortisol5
Cobalamin (vitamin B12)
Erythrocyte folate (vitamin B9)
Thiamine pyrophosphate (vitamin B1)
α-Tocopherol (vitamin E)
Fasting lipids & triglycerides
Total & free carnitine
Acylcarnitine profile
Copper & caeruloplasmin
Zinc
Iron & ferritin
Plasma amino acids
Total homocysteine
Biotinidase activity
Lysosomal enzyme activity,6 plasma chitotriosidase,7 & plasma oxysterols8
Buffy coat electon microscopy9
Very long chain fatty acids, phytanic acid, & pristinic acid

Characteristic phenotype

Urine investigations

Ocular examination (fundus + slit lamp)

Osmolality
Ketone bodies (β-hydroxybutyrate, acetoacetate) Organic acid screen10
Amino acid screen10
Porphobilinogen & porphyrin panel11
Bile acid metabolites; cholestanol Oligosaccharide/glycoprotein analysis (semi-quantitative)

Cerebrospinal fluid investigations

If clinical suspicion of IEM is high, repeat biochemical assays during
acute presentation

Protein
Glucose12
Lactate & pyruvate12 Amino acids12 Methyltetrahydrofolate

1. Ensure free flowing (non-tourniquet) specimen
2. Fasting & post carbohydrate load
3. Specimen is highly sensitive to processing; transport on ice
4. Fasting & post protein load
5. Timed specimen: 0800 hrs
6. Laboratory panel may vary as to the extent of enzyme coverage

7. Non-specific marker of macrophage activation; positive in Gaucher and Niemann-pick C disease
8. Screening for disordered sterol metabolism e.g. Niemann-Pick C
9. If high suspicion of neuronal ceroid lipofuscinosis consider cutaneous biopsy for electron microscopy 10. Tandem mass spectrometry; sample should be fresh or frozen
11. Sample should be UV light protected; best obtained during active disease
12. Pair with serum/plasma

Fig. 24.3 Screening investigations for cognitive decline attributable to a metabolic defect presenting in adult life.

Metabolic screening investigations

Magnetic resonance imaging

Adjunct screening investigations

PRIORITY EXCLUSION OF TREATABLE AETIOLOGIES

Standard T1/T2
DWI
SWI/BOLD Paramagnetic contrast [Gadolinium]

Electrophysiology Electroencephalogram Nerve conduction Electromyography Evoked potentials

Aetiology uncertain

Laboratory screening investigations

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Tissue histology & ultrastructure

Targeted investigations

Diagnosis confirmed

Other imaging skeletal radiology Abdominal ultrasound

(e.g. deoxyhaemoglobin, ferritin, haemosiderin), diamagnetic (e.g. calcium), and ferromagnetic (e.g. iron and manganese-rich) mol- ecules,13 deposition of which is intrinsic to several neurodegenerative disorders.14,15 Finally, T1 sequences following the administration of a paramagnetic contrast agent (e.g. gadolinium) should be considered, enabling de nition of blood–brain barrier integrity and aiding diag- nosis in some cases (e.g. the in ammatory margins typical of adenole- ukodystrophy and patchy enhancement characteristic of Alexander’s disease).10 Imaging of the entire neuraxis may also be of valuable; pathologic changes in the spinal cord are present in numerous meta- bolic disorders, exempli ed by subacute combined degeneration of cobalamin de ciency and peripheral ndings might come to light (e.g. nerve root enhancement in Krabbe disease).16 As well as provid- ing positive evidence for a metabolic disorder, MRI may also suggest an alternate diagnosis (e.g. multiple sclerosis in a younger patient), or concurrent pathology (e.g. cerebrovascular disease).

Proton magnetic resonance spectroscopy

1
( H-MRS)

non-metabolic causes are also recognized. Epileptiform features, while of limited discriminatory value, are present in several neuro- metabolic dementias, and in some cases, electrographic patterns suggest a speci c aetiology (e.g. prominent occipital potentials and photoparoxysmal discharges in several of the neuronal ceroid lipofus- cinoses).21,22 Similarly, evoked potentials, nerve conduction studies, and electromyography may assist diagnosis.

Tissue biopsies

Histopathological, ultrastructural (electron microscopy), and tissue biochemical studies may prove informative in cases of suspected metabolic dementia. Tissue biopsies allow for histopathological analysis of substrate storage, as evident in the cerebral glycogenosis (e.g. adult polyglucosan body disease) and many of the lysosomal disorders, while transmission electron microscopy may identify disordered ultrastructural pathology (e.g. mitochondrial dysmor- phology) or characteristic intracellular inclusions (e.g. neuronal ceroid lipofuscinoses), the latter o en identi ed upon prepara- tion of bu y coat leucocytes. Fibroblast culture is o en useful, providing an enduring source of tissue for analysis of ubiquitously expressed enzymes, substrate loading studies (e.g. llipin staining a er incubation of Niemann–Pick C broblasts in the presence of cholesterol-loaded low-density lipoprotein), and extraction of genomic DNA for molecular analysis of causal genes, while meta- bolically active tissues such as skeletal muscle and liver are typically utilized for the biochemical analyses of respiratory chain complexes in fresh or snap-frozen samples. Of special note, specimens derived postmortem should always be considered in suspected cases of inborn metabolic disease where inherited pathology has relevance for remaining family members. Appropriate preservation of tissue samples is, of course, critical and advice regarding collection, pro- cessing, and storage of samples should be sought.

Acquired metabolic causes of cognitive

decline

Nutritional de ciency

Critical to nervous system development and cellular biochemi- cal function, nutritional de ciency of macronutrients and essential micronutrients (vitamins and trace elements) remains a dominant contributing factor to neurocognitive health globally, particularly in at-risk populations, where multiple de ciencies are common. Speci c de ciencies, while comparatively rare, are more typical in micronutrient-replete Western diets, encountered in restrictive die- tary regimens, psychiatric eating disorders, and, increasingly, a er bariatric surgery.5 However, multiple de ciencies in the context of self-neglect and the impact of illness upon nutritional state must also be considered, particularly in vulnerable persons such as the itinerant, elderly, and chronic alcohol abusers; pathological restric- tion of intake (e.g. malabsorptive disease), increased utilization (e.g. malignancy), and excessive losses (e.g. renal tubular disease) must not be forgotten. Iatrogenic de ciency (e.g. inappropriate parenteral nutrition) may also occur. It is noteworthy that many inborn errors of metabolism parallel acquired micronutrient de ciencies, empha- sizing the importance of these compounds as co-factors for normal enzyme function.

Nutritional excesses are also recognized in the path genesis of cognitive impairment, either through accumulative consequences

Complementary to standard sequences, proton magnetic resonance spectroscopy (1H-MRS) enables relative metabolite concentrations to be quanti ed within the target region of interest (single voxel spec- troscopy) or averaged over multiple sampling regions (chemical shi imaging), in each case re ecting radiofrequency emissions from the proton nuclei of the present metabolites. ese are expressed as parts per million, by convention relative to creatine.17,18 However, in clini- cal practice, in vivo spectral resolution is limited to compounds pre- sent at minimum concentrations of 0.5–1.0 mM, permitting broad inference only. Pathognomic pro les are limited, including elevated N-acetyl aspartate in aspartoacylase de ciency19 and the absence of creatine in disorders of creatine synthesis;20 nevertheless, non-speci c ndings may prove informative and o en preceed changes in stand- ard sequences, such as the presence of a lactate doublet (an inverted peak at 1.3 ppm in long TE acquisitions), occurring in the context of a suspected mitochondrial cytopathy.12 Moreover, advances in MRS technology, in part due to the availability of high eld magnets are permitting greater spectral resolution and more de nitive metabolite identi cation, with the promise of increased clinical utility.

Positron emission tomography

Positron emission tomography has limited utility in the screening assessment of neurometabolic disorders, although this more accu- rately re ects a current lack of data for this modality amongst the heterogeneous cohort of neurometabolic disorders—for the most part limited to individual case reports and small series.

Neurophysiology

While electrophysiological studies have limited utility in the adjunc- tive assessment of suspected metabolic cognitive decline, they are inexpensive, non-invasive, and may demonstrate functional aberra- tions not evident with neuroimaging. Electroencephalography is o en normal, although background slowing consistent with an encepha- lopathic state is common and temporospatial changes may re ect transient cognitive impairment, a feature of many metabolic diseases. Characteristic ndings may also provide diagnostic clues; triphasic waves are o en considered to indicate a metabolic aetiology, most commonly present in hepatic and renal encephalopathy—although

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CHAPTER 24 metabolic dementia 261

262 SECTION 3 cognitive impairment and dementia
of dietary excess (the metabolic syndrome) or speci c toxicities, as

may occur in heavy metal exposure or alcohol.

Vitamin de ciency

Vitamin de ciencies dominate amongst the acquired causes of neu- rocognitive dysfunction.

B-group vitamin de ciencies22–24 re ect their importance as spe- ci c enzyme co-factors, typically occurring in the context of malnu- trition, pathological malabsorption, or states of increased metabolic demand (e.g. malignancy); alcoholism is a common association. Pharmacological interactions may impair bioavailability (eg. folate analogues, including trimethoprim) and dietary inhibitors can impact absorption. e neurocognitive consequences of B-vitamin de ciency are varied, in many cases re ecting compound losses, although isolated de ciencies with characteristic phenotypes do occur—commonly thiamine, cobalamin, and niacin de ciencies manifesting Wernicke– Korsako syndrome, combined degeneration of the spinal cord and pellagra respectively. Subacute cognitive impairment and psychiatric manifestations dominate, o en associated with apathy. Systemic fea- tures are typically prominent, including anorexia, abdominal pain, glossitis, and a seborrheic-like dermatitis; cardiomyopathy is a feature of thiamine de ciency (wet beriberi). While a role for individual vita- min de ciencies in primary dementia and geriatric cognitive decline has been postulated (e.g. B6, B9, and B12), a clear association remains unproven and the population bene t of widespread supplementation in the non-de cient population remains unsubstantiated.25,26 Early treatment response is usual, although irreversible manifestations occur when replacement is delayed, emphasizing the importance of prompt recognition and diagnosis. Biochemical de ciency is read- ily con rmed via fasting assay in plasma or erythrocytes, although laboratory variability can be wide and acess to specialist assays may be limited. Indeed, clinical response to replacement is o en su cient to con rm a presumptive diagnosis, particularly when rapid intervention is indicated. Urinary organic acids may reveal excretion of characteris- tic metabolites such as methylmalonic acid in the presence of cobala- min de ciency, which must be excluded in any case where elevation is present. Rarely, functional enzyme studies are required to con rm increased activity following co-factor loading. Neurophysiological parameters are non-speci c and may demonstrate an encephalopathic EEG, at times with epileptic features. Imaging is typically non-speci c, with the exception of thiamine (see below) and cobalamin de ciencies, the later presenting subacute combined de ciency of the spinal cord.

Vitamins D and E (α-tocopherol) de ciency, while not primar- ily causing dementia, have also been implicated in neurocognitive decline; the latter, when severe, manifesting a phenotype of cere- bellar and posterior column dysfunction, ophthalmoparesis (typ- ically of upgaze) and axonal neuropathy resembling Friedreich ataxia. Each have been hypothesized to contribute to age-related cognitive decline and primary dementia,27–29 although as with the B-group vitamins, bene ts of replacement within the wider popu- lation remain inconclusive.

as a co-factor in the decarboxylation of α-keto acids—inter- mediaries in the generation of ATP via the tricarboxylic acid cycle—and transketolase in the formation of ribose and dex- oyribose via the pentose monophosphate shunt. Within the central nervous system, thiamine is critical to the processes of myelin formation, axonal conduction, and the synthesis of spe- ci c neurotransmitters (e.g. acetylcholine).

Most commonly arising in states of nutritional de ciency, classically starvation and malabsorption, thiamine depletion may also re ect reduced bioavailability due to dietary antithi- amine factors, and increased metabolic consumption; hepatic stores are limited and clinical manifestations can arise in as little as one to three months.

Cognitive manifestations re ect impairment of cellular energy production resulting in cytotoxic oedema and paren- chymal injury. Disease features range from irritability and mild confusion, o en with an apathetic quality, to frank encepha- lopathy and irreversible deficiencies of anterograde and retrograde amnesia (Korsako psychosis). Acutely, focal neu- rological de cits are common with the triad of ophthalmopa- resis, cerebellar ataxia, and encephalopathy de ning Wernicke’s encephalopathy.

Clinical suspicion is o en con rmed by treatment response; fasting plasma thiamine can be measured, although it is subject to protein binding, and quanti cation of erythrocyte thiamine pyrophosphate levels has largely replaced this assay. Urinary excretion of thiamine and its metabolites can be con rmed by HPLC, typically expressed as a spot ratio relative to creatinine, and organic acid pro les may demonstrate elevated levels of pyruvate, lactate, and α-ketoglutarate, re ecting impairment of thiamine-dependent enzymes. Erythrocyte transketolase activity, measured pre- and post-thiamine load, remains the most sensi- tive indicator, with an increase of enzyme activity in excess of 25 percent indicative of deficiency. Folate deficiency and hypomagnesaemia must also be excluded as both may exacerbate thiamine de ciency.

Neuroimaging lacks sensitivity and may prove normal; how- ever, acute disease may demonstrate symmetrical T2/FLAIR signal hyperintensity, restricted di usion, and gadolinium enhancement within the mamillary bodies, mediodorsal thal- amus, tectal plate, and periaqueductal grey matter. In chronic disease, cerebral and cerebellar volume loss may additionally be seen. Proton spectroscopy may demonstrate increased lac- tate, reduced NAA, and reduced choline, the latter suggested to re ect reduced incorporation of lipids into myelin or dis- ordered acetylcholine production. A length-dependent axonal polyneuropathy is o en prominent in chronic de ciency, and non-neurological features, particularly cardiomyopathy, may result. Variability of clinical phenotype is well documented and polygenic in uences have been suggested with variations in transketolase a nity and the thiamine transporter proteins implicated.30,31

Early recognition is critical as prompt thiamine replacement may e ect symptom resolution, albeit permanent amnestic de – cits are common (100 mg/day parenterally for 1 week followed by 10 mg/day orally until symptom resolution).

Example: iamine (vitamin B1) de ciency

iamine (vitamin B1), a heterocyclic carbine, serves as a criti- cal co-factor in carbohydrate and amino acid metabolism; its active phosphorylated form (thiamine pyrophosphate) serves

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Elemental de ciency

Biologically present in trace amounts, many elements are absolutely required for life: although they are o en fastidiously conserved in the body and recycled through various compartments, they must be obtained from the diet—usually in amounts < 1 mg/day. Trace elements are integral to the structure and function of many proteins (metalloproteins), and when de cient or found in excess, cognitive function is o en impaired; indeed elemental de ciencies including copper, iron, selenium, and zinc, have been implicated in the caus- ation of neuropsychiatric disease, non-speci c cognitive decline and primary dementing illnesses, albeit de nitive mechanisms remain poorly de ned.32–35

With the exception of iodine, where one-third of the global population live in de cient regions,36 isolated losses are rare, more typically occurring in the context of multiple nutritional insuf- ciency, the result of inadequate diet, intestinal malabsorption (copper, o en follows gastric bypass surgery), and renal protein losses (e.g. nephrotic syndrome). Speci c iatrogenic de ciencies may occur, as seen with chelating agents, particularly penicil- lamine which has wider medicinal indications, or other pharma- ceutical actions such as urinary zinc losses secondary to thiazide diuretics. Chronic dialysis and dependence upon unsupplemented pareneteral nutrition are also a risk where strict monitoring is not observed; indeed, rare de ciencies of molybdenum, an essential co-factor of sulphite oxidase, xanthine oxidoreductase, and alde- hyde oxidase, leading to irritability and coma have been reported in this context.37

Recognizable phenotypes may inform diagnosis. Cuproproteins serve important roles in cellular energy production, free-radical scavenging, neurotransmitter metabolism, phospholipid synthe- sis, and iron transport, de ciency of which may also contribute to disturbed cognition and adjunct features including sensory ataxia, proprioceptive loss, and spasticity, re ecting peripheral neuropathy and myelopathic disease. Zinc is an integral component of more than 300 metalloenzymes and transcription factors and serves multiple functions within the central nervous system including synthesis of coenzymes requisite in bioamine metabolism and the modulation of postsynaptic N-methyl-D-aspartate (NMDA) receptors, suggesting a role in the regulation of synaptic plastic- ity.38 Neurological features range from impaired concentration and irritability to neuropsychiatric features and variable cognitive impairment; hypogeusia (decreased taste) may alert the treating physician, while the presence of a concomitant vesiculopustular dermatitis should prompt strong consideration. Secondary exacer- bation of hepatic encephalopathy and hyperammonaemia, result- ing from impaired ornithine transcarbamylase activity (OTC), akin to the inborn error of this enzyme, is also a recognized consequence of zinc de ciency.39,40 e neurocognitive e ects of severe iodine de ciency re ect impaired thyroid hormone synthesis; presenting at at any age, with features ranging from mild sequalae in adults to profound intellectual impairment in the context of congenital de – ciency (cretinism). Adjunct neurological ndings include sensori- neural deafness and spasticity of a characteristic axial and proximal appendicular distribution. Only in severe iodine de ciency does hypothyroidism develop, accompanied by an elevated serum TSH value and decreased T3 and T4 levels.

In most cases neuroimaging is non-speci c, although myelop- athy with increased T2 signal in the dorsal columns is suggestive

of copper de ciency.41 Screening biochemical abnormalities may re ect enzyme dysfunction (e.g. reduced alkaline phosphatase level, a zinc-dependent enzyme); however, diagnosis relies upon quanti- cation of elemental plasma and urinary levels (spot ratios relative to creatinine or 24-hour collection); activity assays of dependent enzymes may also inform diagnosis. In all cases, prompt replace- ment is warranted, as delayed correction may result in permanent neurological sequalae.

Marchiafava–Bignami disease

Marchiafava–Bignami disease (MBD) is an extremely rare condi- tion characterized by dementia with axonal injury and demyelina- tion within the corpus callosum, typically beginning in the corpus and extending to the genu and splenium; involvement of the cen- trum semiovale, brachium pontis, and other white matter tracts may also occur, although sparing of the internal capsule, corona radiata, and subcortical association bres is usual. Gliosis in the frontotemporal regions, predominantly in the third cortical layer (Morel cortical laminar sclerosis), is o en a feature. Commonly, but not absolutely described in patients with chronic alcoholism, aeti- ology has been attributed to non-speci c nutritional de ciency and may re ect a reduction in multiple B-group compounds. A pan- ethnic disease, cases are dominated by men, the majority arising a er 45 years of age. Clinical symptoms vary; onset may be pre- cipitous with lethargy, stupor, and rapid progression to coma, while subacute or chronic dementia, o en with ideomotor apraxia and psychiatric disturbance, is also observed. Progressive corticospinal tract involvement, ataxia, and seizures evolve—with distinction from associated disease and comorbid pathology o en di cult. Diagnosis is made upon clinical and neuroradiological grounds, characteristically manifesting a ‘sandwich sign’ wihin the corpus callosum on saggital T2/FLAIR series due to relative sparing of the ventral and dorsal bres; restricted di usion is evident within acute lesions, and cystic necrosis eventuates. Prognosis is poor, how- ever early detection and supportive management including absti- nence from alcohol and administration of B-complex vitamins has improved outcomes in contemporary practice.

Macronutrient de ciency and excess

Critical for normal neurodevelopmental outcomes, the cognitive e ects of macronutrient insu ciency on the developed brain can be profound, albeit distinction from comorbid micronutrient de – ciency is o en di cult. Macronutrient excess is similarly linked to dementia, largely through secondary consequences of insulin resistance and chronic metabolic dysregulation.

Endocrinopathy-associated cognitive decline

Endocrinopathy-associated cognitive decline is well recognized as a primary consequence of the precipitant disorder (e.g. thyroid, parathyroid, and adrenal disease) or as sequalae of the disordered metabolic state that results—exempli ed by diabetes mellitus, in which multiple factors contribute to cerebral pathology, includ- ing abnormal protein glucosylation, recurrent hypoglycaemic insult, and cerebrovascular disease. Patterns of neurocognitive dysfunction vary from acute encephalopathy and subacute cogni- tive decline to late-onset dementing disease and neuropsychiatric manifestations. Systemic features are o en prominent in thyroid and adrenal disease, with recognizable phenotypes in many cases

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CHAPTER 24 metabolic dementia 263

264 SECTION 3 cognitive impairment and dementia

alerting the diagnosis. Biochemical con rmation is readily deter- mined and early initiation of treatment with sustained endocrino- logical homeostasis the priority.

Whilst not a primary endocrinopathy, the consequence of recur- rent non-diabetic hypoglycaemia should also be considered in the cognitively declining patient, particularly if stepwise deterioration is evident; plasma glucose is con rmatory during an acute episode; however, transient episodes may require pre- and post-prandial sampling to substantiate, with an observed fast (up to 72 hours) most sensitive. Once con rmed, diagnostic investigations must fol- low and the di erential causes of hypoglycaemia investigated.

Visceral insu ciency and

cognitive decline

Disordered metabolic homeostasis, as a result of visceral fail- ure, frequently precipitates acute, recurrent encephalopathy; however, more indolent cognitive dysfunction may also occur. In each case, disease can be considered a consequence of neu- rotoxic metabolite accumulation—chie y ammonia and manga- nese in hepatic disease and multiple renally cleared substrates (urea, phosphates, parathyroid hormone, and amino acids) in the presence of renal failure; iatrogenic neurocognitive decline in the context of long-term dialysis (dialysis dementia) has also been recognized—the result of aluminium toxicity, now rarely observed, with removal of this contaminant from dialysate.42 e pathophysiological basis of pancreatic encephalopathy is more protean, implicating cytokine release and consequences of the acute in ammatory response, microcirculation abnormali- ties, and concomitant bacterial infection. Moreover, in all cases of visceral failure, comorbid electrolyte disturbance and micro- nutrient insufficiency are often present; indeed, co-morbid thiamine de ciency has been implicated in both hepatic- and pancreatic-associated encephalopathies.43,44 e contribution of visceral pathology to other dementia subtypes (e.g. nephrogenic hypertension and multi-infarct dementia) should also be consid- ered. In all cases acute management pertains to reduction of the accumulating toxins, through dietary, pharmacotherapeutic, and other means including dialysis, in addition to treatment of the underling systemic pathology. Attention to minimizing precipi- tants of metabolic decompensation (e.g. increased protein load in hepatic and renal disease) is critical to improving longer-term stability.

Inborn disorders of metabolic function causing

cognitive decline in adulthood

Whilst the inborn errors of metabolism remain individually rare causes of adult-onset dementia, recognition is critical: e ec- tive therapeutic intervention is increasingly available and the genetic implications of inborn metabolic errors require considera- tion. Accurate epidemiological data are lacking—in part due to underdiagnosis—however it is notable that the greatest burden is within young adult presentations and amongst those with adjunct neurological and/or systemic disease.

A contemporary view of inborn metabolic diseases includes other genetic disorders a ecting metabolic function, a premise which could be extended to almost all neurodegenerative pro- cesses. Nevertheless, here we focus on recognition of important

classes of neurometabolic disease presenting with adult-onset cog- nitive dysfunction. Readers are refered to specialist resources for further detail.

Disorders of carbohydrate metabolism

As a primary substrate for energy production, inborn errors of carbohydrate metabolism include defects of glucose production and utilization (e.g. disorders of gluconeogenesis and glycolysis), disorders of transport (e.g. glucose transporter de ciency), and abnormalities of glucose storage and mobilization (e.g. the glycog- enopathies). Neurons do not synthesize glycogen and rely upon mitochondrial oxidation of astrocyte-derived lactate, generated by glycogenolysis, to provide an alternative energy source during neuroglycopaenia. Cognitive involvement ranges from childhood intellectual impairment to acute encephalopathy, classic dementing disease, and episodic decline. Neuroglycopaenic-associated cogni- tive impairment and recurrent hypoglycaemic insult must also be considered in this context. Biochemical identi cation corresponds to the protocols for such diagnoses, excepting the glycogenoses. In several cases e ective therapeutic intervention can be imple- mented, again emphasizing the need so far as possible to con rm diagnosis.

Example: e cerebral glycogenoses

Characterized by the intracellular accumulation of polyglucosan—an abnormal storage form of glycogen—the cer- ebral glycogenoses45,46 are an important consideration in the dementing adult. Two subtypes dominate, adult polyglucosan body disease (APGBD), over-represented in the Ashkenazi Jewish population, is the consequence of an autosomal reces- sive mutation in the GBE1 gene, encoding the 1,4-α-glucan- branching enzyme-1; and Lafora body disease, primarily associated with autosomal recessive mutations in either of two genes: epilepsy, progressive myoclonus 2a and 2b (EPM2A and EPM2B) which encode the complicit glycogen regula- tory proteins, laforin phosphatase and malin ubiquitin ligase, respectively. Disease re ects aberrant glycogen synthesis with deposition of periodic acid–Schi (PAS) positive polyglucosan aggregations in neural tissues; the pathophysiological conse- quences of which remain poorly understood, however a sec- ondary de cit of cellular energy production has been suggested, possibly related to inadequate reserves of normally compacted glycogen.47,48

Adult polyglucosan body disease typically presents a er age 40 years, with progressive neurogenic bladder dysfunction, lower limb weakness, and spasticity of a mixed upper and lower motor neuron pattern; distal sensory de cit, cerebellar dys- function, and cognitive di culties also occur, typi ed by mild de cits in executive function. Lafora disease presents in adoles- cence (12–17 years), with progressive myoclonic epilepsy and mixed semiology seizures; occipital seizures presenting as visual hallucinations are o en striking. Of note, a history of infantile seizures is common. Neurocognitive decline, with a frontal dementia pattern ensues with progression to myoclonic status, and death within 10 years of onset. Clinical diagnosis is sup- ported by neuroimaging in APBD where progressive cerebral, cerebellar, and upper cervical spinal cord atrophy is typical, with

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non-enhancing white matter disease involving the subcortex (periventricular), brainstem, and cerebellum; imaging is nor- mal or reveals non-speci c cerebral atrophy in Lafora disease. Conversley, electroencephalography is non-speci c in APBD, and typically epileptiform in Lafora disease, with photosensi- tivity an early feature and generalized, irregular spike-wave dis- charges of occipital predominance. Histological demonstration of periodic acid–Schi (PAS) positive, diastase resistant, poly- glucosan inclusions strongly suggests the diagnosis; con rma- tion is achieved by molecular analysis. In each case, targeted therapy remains unmet and management is symptomatic; while recent attempts to ameliorate the suspected de cit of cellular energy in APBD (using dietary supplementation of the 7-carbon triglyceride, triheptanoin), may a ord some attenuation of clini- cal deterioration, functional recovery is not expected.47

Disorders of mitochondrial energy

metabolism

e primary mitochondrial cytopathies and related disorders of pyruvate, tricarboxylic acid cycle, and respiratory chain metabolism are an important subclass of metabolic cognitive disease (see chapter 31). Childhood onset dominates but late-onset decline, o en with spe- ci c de cits of visual construction, attention, and abstraction (in the absence of general intellectual deterioration) has been reported in mutations involving both the mitochondrial genome (e.g. MELAS, MERRF, MNGIE) as well nuclear-encoded mitochondrial proteins (e.g. POLG, DDP1). Searching for these mutations should be con- sidered in work-up of early-onset dementing patients.49

Fatty acid oxidation disorders similarly re ect an end-de cit of mitochondrial energy failure; four subgroups are de ned 1) car- nitine cycle disorders, 2) fatty acid ß-oxidation disorders, 3) elec- tron transfer disturbances (e.g. type II glutaric aciduria), and 4) anomalies of ketone body production—in each case resulting in disordered synthesis of acetyl CoA. ese diseases typically occur in childhood, however, adult presenting disease is recognized, o en during periods of metabolic stress, and in many cases preceeded by prolonged periods of normal health. Infantile presentations are dominated by non-ketotic hypoglycaemia and encephalopathy, accompanied by hepatomegaly and ‘Reye-like’ liver dysfunction. Cognitive involvement is rare in adult disease and hypertrophic cardiomyopathy and skeletal muscle involvement, o en with rhab- domyolysis, dominate the clinical picture.

ese disorders are brie y summarized.

Disorders of amino acid metabolism

and transport

Disorders of amino acid metabolism and transport are a large group of intermediate metabolism defects, re ecting the import- ance of amino acids in cellular function. ese diseases occur prin- cipally in infancy and childhood; however, adult-onset variants, typically of an attenuated phenotype, are increasingly recognized. Many of these prove amenable to therapeutic intervention, neces- sitating timely and accurate diagnosis. Disease is largely attributed to toxic accumulation of speci c amino acids, their precursors, and derivatives, including secondary impairment of complicit metabolic pathways such as disruption of the tricarboxylic acid

cycle in many of the organic acidopathies and urea cycle disorders. Porphyria-like decompensation, characteristic of tyrosinemia type 1, is another example, re ecting inhibition of aminolevuli- nate dehydratase, an enzyme in haem biosynthesis, by pathogenic metabolites. Less frequently, disruption of cellular homeostasis is due to de ciency of exogenous amino acids, best exempli ed in Hartnup disease, in which impairment of the neutral amino acid transporter, SLC6A19 results in renal and gastrointestinal losses of the niacin precursor tryptophan, giving rise to frank pellagra.

ese are protean disorders, particularly amongst attenuated, late- onset variants: detailed summaries can be obtained from dedicated texts, nevertheless several common features may inform diagnosis. While dementia occurs, the neurocognitive decline is more o en acute or subacute in nature, o en preceeded by a prolonged asympto- matic period or relapsing–remitting decompensation, usually in the context of interval metabolic stress (e.g. fever or illness) or increased protein loading. Dietary aversion to protein-rich diets may be dis- covered, particularly in phenylketonuria, the organic acidopathies, and urea cycle disorders, which may present following protein load- ing. Mutations in the transporter, citrin (citrullinaemia type 2) are a notable exception; here carbohydrate-rich diets trigger decompensa- tion. Neurocognitive decline in the context of childhood intellectual impairment should also suggest an undiagnosed aminoacidopathy. Insidious cognitive impairment in the context of known diagnoses may also occur, prompting consideration of either lack of compli- ance or iatrogenic restriction of essential nutrients, as a result of inappropriate dietary therapy. In general, psychiatric and neurobe- havioural manifestations are common and additional neurological and systemic features o en occur. Progressive leukoencephalopathy revealed by MRI, extending to involve the subcortical bres, neces- sitates exclusion of disordered amino acid metabolism. Stroke-like episodes may be identi ed, particularly in patients with branched chain aminoacidopathies and urea cycle disorders; while peripheral thromboembolism is a feature of homocystinuria—most commonly due to de ciency of the pyridoxine-dependent enzyme, cystathio- nine β-synthase, which causes disrupted methionine transsulfura- tion (classical homocystinuria). In this condition, unique amongst the aminoacidopathies, there is a prominent Marfanoid phenotype which is a distinguishing feature in hyperhomocysteinaemia. In the case of several aminoacidopathies, a characteristic body odour may be reported, re ecting accumulation of the odiferous compound.

Diagnosis relies upon quanti cation of pathological compounds and their derivatives in biological uids—typically plasma and urine, including ammonia and the aminoacids—detection of the latter has been advanced through contemporary re nement of chromatographic techniques and mass spectrometry. In the case of the organic acidopathies, patterns of aberrant acylcarnitine conjugation may assist diagnosis. Secondary metabolic conse- quences may also provide supportive data (e.g. ketoacidosis in the organic acidemias). Caution should be exercised in the diagnosis of hyperammonaemia in this context, as the presentation of many organic acidemias may suggest a urea cycle anomaly, consequent to accumulation of CoA derivatives which inhibit the formation of N-acetylglutamate, the activator of hepatic carbamoyl phos- phate synthetase. It is important to be aware of assay limitations, including factors which lead to artefactual results and, where pos- sible, sampling should be performed during symptomatic states or under conditions of metabolic stress as this will improve detection of pathogenic metabolites, which may fall below levels of detection

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CHAPTER 24 metabolic dementia 265

266 SECTION 3 cognitive impairment and dementia

(periventricular) distribution and including the subcortical bres is typical (this may reverse with treatment); cerebral and cerebellar atrophy may also occur. An increased phenylalanine peak (7.4 ppm) may resolve on 1H-MRS, however it is not usu- ally prominent on standard clinical spectra.

Management includes implementation of a phenylalanine- (protein) restricted diet and, in responsive cases, adjuvant therapy with tetrahydrobiopterin, which acts to stabilize and augment endogenous PAH activity.56 Consideration must also be given to late-onset neuropsychiatric manifestations in patients, arising in the context of treatment non-compliance, although such outcomes are not absolute and some patients may tolerate a relaxation of phenylalanine restriction. Iatrogenic B12 de ciency may account for the dementing phenylketonuria patient—a consequence of low-protein diet without supplemen- tation of this essential vitamin.57,58

during asymptomatic periods. Given the potential for decompen- sation, timed collections under conditions of substrate load should only be performed under careful clinical observation; while occa- sionally required to con rm diagnoses, the advent of genetic analy- ses has rendered such tests increasingly unnecessary.

Many of the aminoacidopathies are treatable, however, par- ticularly when neurological disease is advanced, not all sequalae are reversible. Interventions are subtype speci c and focus upon removal of accumulated toxic compounds by substrate-restrictive diets (in most cases protein restriction), extracorporeal procedures or target speci c ‘cleansing’ drugs such as carnitine, sodium benzo- ate or phenylacetate and betaine; and through supplementation of critical intermediates such as urea cycle metabolites (e.g. arginine, citrulline), essential co-factors (e.g. pyridoxine in homocystinae- mia), and suppression of disordered biosynthesis, particularly dur- ing periods of metabolic stress.

Example: Phenylketonuria and disordered biopterin metabolism

Phenylketonuria is the most prevalent of the aminoacidopathies and is usually the result of an autosomal recessive de ciency of phenylalanine hydroxylase, which catalyses the conversion of phenylalanine (an essential amino acid) to tyrosine. Functional de ciency of the enzyme may also arise from disordered syn- thesis or recycling of its co-factor, tetrahydrobiopterin (BH4), although such disorders have only been described in childhood- onset disease. Central nervous system pathology ensues when excess phenylalanine accumulates and, while the exact mecha- nism of disease is uncertain, consequences include disruption of synaptogenesis and dendritic arborization, glial cell dysfuncton, and oligodendrocyte toxicity—the latter resulting in dysmyelina- tion and white matter vacuolization. Aberrant equilibria of large neutral amino acids within the brain, as a result of competive transport across the blood-brain barrier and impaired synthesis of biogenic amines (e.g. dopamine and norepinephrine) due to a reduction in their precursor, tyrosine, also contribute.50–52

Classical disease presents with progressive neurocogni- tive impairment in infancy and childhood, typi ed by irre- versible intellectual retardation and spasticity; seizures and parkinsonian features may result. However, rare instances of adult-onset disease have been reported, with progressive leu- koencephalopathy, dementia, optic atrophy, and neuropsychiat- ric decline.53–55 Moreover, asymptomatic cases are recognized. Hypopigmentation, the result of reduced melanin synthesis, and a musty odour, caused by excreted phenylacetic acid may be prominent. Increasingly patients are identi ed through newborn screening programmes, facilitating initiation of pre- symptomatic therapy and ameloriating consequences of chronic hyperphenylalaninaemia.

Hyperphenylalaninaemia is readily con rmed through quan- ti cation of plasma and urinary amino acids; urinary organic acid pro les may also demonstrate increased excretion of phe- nylpyruvic and phenylacetic acid. Cofactor de ciencies (disor- ders of biopterin synthesis or recycling) are excluded via urinary pterin analysis and quanti cation of dihydropteridine reductase activity within erythrocytes, while molecular con rmation is now widely available. Neuroimaging ndings are non-speci c, however a leukodystrophy, predominantly of an occipitoparietal

Vitamin-responsive inborn errors

of metabolism

The vitamin-responsive inborn errors of metabolism include homocysteine remethylation defects, and disorders of cobala- min transport and utilization, methylenetetrahydrofolate reduc- tase deficiency, cerebral folate deficiency, and the disorders of biotin metabolism; familial vitamin E deficiency can also be considered in this context. In most of these conditions, disease resembles that seen in the respective acquired co-factor deficien- cies. Clinical suspicion is reinforced by response to replacement therapy, while diagnostic screening relies on demonstration of specific cofactor deficiencies and their related biochemical consequences, such as elevated homocysteine in disorders of remethylation (cobalamin-C disease and methylenetetrahydro- folate reductase deficiency), in the case of cerebral folate defi- ciency necessitating cerebrospinal fluid analysis as plasma levels are normal. Functional studies of enzyme activity may also be required, for example in biotinidase deficiency where plasma biotin may fall within normal range, while in other cases, such as biotin–thiamine-responsive basal ganglia disease, biochemi- cal parameters are typically normal and molecular diagnosis is required.

Example: Cobalamin C de ciency

e inborn disorders of cobalamin transport and utilization rep- resent defects of intracellular cobalamin metabolism, de ned by biochemical phenotype and genetic complementation analysis. e most common of these is cobalamin-C disease (cblC), which results in disordered homocysteine remethylation secondary to a de ciency of the cobalamin binding protein, Methylmalonic aciduria and homocystinuria type C (MMACHC), responsible for catalysing removal of ligands from alkylcobalamins and cya- nocobalamin. Typically presenting during infancy, a small num- ber of cblC patients present as late as the fourth decade of life with confusion, disorientation, dementia, and neuropsychiatric disease, o en associated with subacute combined degenera- tion of the spinal cord; leukoencephalopathy may also emerge. Systemic features, including macrocytic anaemia, while sug- gestive, are not invariably present and do not preclude consid- eration of B12 de ciency in isolated neurological presentations.

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Biochemical hallmarks of disease include increased plasma total homocysteine with low to normal plasma methionine; homocystinuria and methylmalonic aciduria. Treatment with parenteral hydroxycobalamin and oral betaine may normalize biochemical parameters, however disease reversal may prove incomplete, particularly if instigated late in the course of the illness.59–61

Disorders of neurotransmitter metabolism

and function

Disorders of gamma aminobutyric acid, glycine, and monoam- ine metabolism (including disorders of biopterin synthesis) typi- cally present in infancy and childhood, however in many cases survival to adulthood occurs. Late-onset neurocognitive decline and dementia are not characteristic, although adult presentation of non-ketotic hyperglycinaemia is recognized.62,63 In this auto- somal recessive disorder of glycine cleavage, accumulation of the excitatory neurotransmitter manifests as cognitive decline, which may be triggered by fever or prescription of sodium val- proate (an inhibitor of glycine cleavage), o en on a background of existing intellectual delay. Neurobehavioural lability, seizures, optic atrophy, and paroxysmal choreiform movements may occur, with eventual progression to a vacuolating leukoencephalopa- thy, typically sparing the subcortical U- bres. Diagnosis requires demonstration of an isolated elevation in glycine and increased CSF:plasma ratio; con rmation of the molecular defect usually follows. Treatment response is at most partial; a restricted protein diet with additional sodium benzoate may reduce plasma con- centration of glycine, while more recently, N-methyl D-aspartate (NMDA) receptor antagonists have been employed to minimize NMDA receptor activation.64

Disordered neurotransmitter homeostasis, particularly acetyl- choline, is also implicated in a number of neuroocognitive dis- eases, including Alzheimer’s disease and Lewy body dementias, the mechanisms of which are likely multifactorial. However quanti cation of CSF acetylcholine is technically limited and of little practical use.65 Monoamine metabolites and pterin pro les are increasingly accessible in specialist laboratories, albeit these too have little utility in the context of adult-onset dementia. Nevertheless, the spectrum of neurotransmitter disease remains unde ned and consideration to screening of the CSF biochemical pro le may prove to be decisive.

Brief consideration should also be given to ‘acquired’ dis- orders of neurotransmission; autoantibodies targeting the post-synaptic N-methyl-D-aspartate (NMDA) receptor may contribute to the spectrum of autoimmune encephalitidies, often occurring in the context of an ovarian teratoma or other occult malignancy and manifesting after a prodromal ‘influenza-like’ illness, with behavioural change, prominent neuropsychiatric symptoms, and seizures. This important diagnosis is covered in detail in chapter 28.

Disorders of lipid and bile acid metabolism

Disorders of lipid metabolism and transport are very diverse, but they are increasingly recognized amongst the late-onset disorders of metabolism and prominently represented amongst the metabolic

CHAPTER 24 metabolic dementia 267 dementias. Broadly these can be considered under several main

categories:

. 1) Disorders of cholesterol and bile acid synthesis, cerebrotendi- nous xanthomatosis (sterol 27-hydroxylase de ciency) and α- methylacyl-CoA racemase (AMACR) de ciency, each re ecting disordered oxidation of cholesterol side chains.

. 2) X-linked adrenoleukodystrophy/adrenomyeloneuropathy.

. 3) Disorders of cholesterol tra cking, exempli ed by Niemann– Pick disease type C.

. 4) e sphingolipidoses, each the result of a speci c lysoso- mal hydrolase de ciency that impairs catabolism of complex sphingolipids with resultant accumulation leading to neuronal dysfunction.

While clinical features and diagnostic investigations tend to be disease-speci c, several generalizations apply across to this cohort. Cognitive decline is typically slowly progressive and neuropsychiat- ric presentations are common, while leukoencephalopathic disease and peripheral neuropathy are frequently observed. Cerebellar dys- function, extrapyramidal features, seizures, and retinopathy may also occur. Systemic pathology can inform diagnosis; splenomegaly might suggest a disorder of lipid storage, while tissue deposition of storage material, such as tendon xanthomata, may be evident. A history of prolonged neonatal jaundice in the dementing patient necessitates exclusion of disordered cholesterol metabolism, dis- ordered bile acid metabolism or Niemann–Pick disease type C, a cholesterol-tra cking defect.

Example: Cerebrotendinosus xanthomatosis

Cerebrotendinosus xanthomatosis re ects a recessive defect in the mitochondrial enzyme, sterol 27-hydroxylase, required for the synthesis of bile acids from cholesterol; accumulation of cho- lesterol, bile acid precursors, and their metabolites (including cholestenol) results. A history of infantile cholestatic jaundice is common and should always raise suspicion in the dementing adult. Neurocognitive decline is usual and may occur as early as the rst decade, however it appears more typically from adoles- cence and early adulthood, with concomitant neurobehavioural and psychiatric manifestations. Adjunct neurological features are prominent, including cerebellar dysfunction, spasticity and seizures; axonal neuropathy is frequent. Childhood-onset cata- ract is common and the presence of tendon xanthomas—evident from early to mid adulthood—are highly suggestive. Visceral xanthomata may also occur and focal neurological presenta- tions in the context of cerebral lesions are recognized—most frequently within the cerebellar white matter. Neuroimaging demonstrates leukodystrophic changes within the cerebral and cerebellar white matter, with characteristic involvement of the dentate nuclei. Biochemical diagnosis is con rmed by demon- stration of elevated plasma and urinary cholestanol in the con- text of a reduced plasma cholesterol and bile acids. Treatment with chenodeoxycholic acid e ects a reduction in cholestanol synthesis and neurological improvement by suppression of cho- lesterol 7α-hydroxylase, the rst enzyme within the predominant bile acid synthetic pathway. Adjunct strategies include the use of statins (3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors) and low-density lipoprotein apheresis.66,67

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268 SECTION 3

cognitive impairment and dementia

Example: Disorders of sphingolipid catabolism

e disorders of sphingolipid catabolism are lysosomal disor- ders characterized by the pathological accumulation of sphin- golipids and their derivatives. e diseases result from de cient function of a given lysosomal hydrolase or a cognate activa- tor protein. Panethnic in distribution, inheritance is autosomal recessive, with the exception of Andersen–Fabry disease which is X-linked. Individual disorders usually show a spectrum of neu- rovisceral disease, with attenuated, late-onset, cognitive decline in several (Gaucher disease, GM1 and GM2 gangliosidoses, and metachromatic leukodystrophy), generally of a slowly progressive nature and o en with comorbid neuropsychiatric features, acute decompensation may, however, occur. Symmetrical leukoenceph- alopathy, sparing the subcortical U- bres, suggests metachro- matic leukodystrophy [Fig. 24.4], while cerebellar dysfunction, extrapyramidal disease, and seizures are common, although not invariably present. Systemic features are mostly seen in Gaucher disease (e.g. prominent visceromegaly) and GM1 gangliosido- sis; these are not present in metachromatic leukodystrophy or the GM2 gangliosidoses (aside from mild visceral involvement in Sandho variant disease). With the exception of metachro- matic leukodystrophy, neuroimaging is largely non-speci c and diagnosis relies primarily on the demonstration of low residual enzyme activities – speci c to each disease (typically performed in leucocytes or cultured broblasts); excepting rare cases of acti- vator protein de ciency where in vitro activity assays are normal. Consequently, methods to identify pathogenic substrate accu- mulation via tandem mass spectrometry and molecular screen- ing protocols are increasingly employed. In all cases, treatment of neurological disease remains limited, although attempts to e ect central nervous system delivery of recombinant human enzyme, substrate reduction therapy and gene transfer approaches are in development.66–72

Fig. 24.4 Cerebral MRI in a 23-year-old woman with late-onset metachromatic leukodystrophy: T2 (above) and FLAIR axial images demonstrate frontally predominant white matter volume loss with symmetrically distributed signal hyperintensity and sparing of the subcortical U- bres.

Reproduced from Journal of Inherited Metabolic Disease. 33(Suppl 3), Smith NJ, Marcus RE, Sahakian BJ, et al. Haematopoietic stem cell transplantation does not retard disease progression in the psycho-cognitive variant of late-onset metachromatic leukodystrophy, pp. 471–5, Copyright (2010), with permission from Springer.

Example: Nieman–Pick disease type C

One of the more common of the inborn metabolic dementias, Niemann–Pick type C disease shares many features with the dis- orders of sphingolipid catabolism. is defect of endocytosed cholesterol cellular tra cking, is due to mutations in either of two related proteins, NPC1 (≈ 95 percent) and NPC2 (≈ 5 per- cent). e disease is characterized by pathological accumulation of unesteri ed cholesterol and complex sphingolipids (including GM2 and GM3 ganglioside) within the endosomal–lysosomal system. e spectrum of clinical disease is widely variable, rang- ing from progressive neurovisceral disease in infancy (typically with prominent hepatosplenomegaly and infantile cholestasis) to more indolent adult-onset variants, the latter o en presenting with progressive dystonia, cerebellar dysfunction, and variable cognitive impairmen; neuropsychiatric symptoms and demen- tia tend to be dominant and isolated psychiatric presentations are not uncommon. Movement disorders including myoclonus and action-induced dystonia are frequent and seizures may arise. Gelastic cataplexy and vertical supranuclear gaze palsy, with delayed saccadic initiation, are highly suggestive of the diagno- sis, although less common in late-onset presentations. Similarly, visceral symptoms are less prominent in adult-onset disease. Neuroimaging is initially normal, with progressive cerebral and

cerebellar atrophy (usually involving the cerebellar vermis), and thinning of the corpus callosum, with variable white mat- ter hyperintensity, evident in some cases at late-stages of disease. Diagnostic con rmation is o en complex; traditional demon- stration of lipid storage within tissue samples (e.g. ‘foamy,’ lipid- laden macrophages upon bone marrow biopsy) is rarely utilized in contemporary practice. Elevated serum chitotriosidase (a marker of macrophage activation) is non-speci c; demonstration of reduced cholesterol esteri cation and its pathological accumu- lation a er loading of cultured broblasts with exogenous cho- lesterol (using the uorescent polyene macrolide, lipin) is o en employed, however, reliable interpretation of this assay requires specialist expertise and is subject to normal variation. Molecular analysis is also incomplete, with mutations of the NPC1 and NPC2 genes in approximately 94 percent of cases. More recently, the demonstration of altered serum oxysterol pro les has proved an e ective screening assay and is likely to replace lipin staining in this context. Disease is invariably progressive, and manage- ment remains largely symptomatic although inhibition of gly- cosphingolipid synthesis by the non-selective glucosylceramide synthase inhibitor, n-butyldeoxynojirimycin (miglustat) may, incompletely slow progression of late-onset disease.3,4,73

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Disorders of haem metabolism

e hereditary porphyrias are a group of inborn metabolic errors of haem biosynthesis. Pathological accumulation of toxic path- way intermediates and their derivatives occurs, the majority of which are reduced porphyrins (porphyrinogens) which oxidize upon excretion from the intracellular environment to their cor- responding porphyrins—these pigmented photoactive molecules uoresce when exposed to visible light. Accumulation of the rst committed precursor of haem biosynthesis in the liver, 5- aminolaevulinic acid, is associated with the acute neurovisceral e ects of the disorder. Clinical features vary amongst subtypes, with neurovisceral disease largely restricted to the three acute hepatic porphyrias. Disease typically presents a er puberty and may follow a prolonged period of clinical latency, with episodic decompensation o en manifesting in the context of precipitants such as medication, illness or hormonal factors—especially progestogens formed during the luteal phase of the menstrual cycle—which increase demand for hepatic P450 synthesis and haem biosynthesis. While classic dementia is not usually a fea- ture, neurocognitive symptoms include orid agitation and a ec- tive manifestations, o en with features of sympathetic activation and, at their extreme, frank delirium, in many cases leading to an erroneous diagnosis of psychiatric disease. Visceral symp- toms are prominent and include poorly characterized but o en incapacitating abdominal pain, o en with associated nausea or constipation; other e ects such as tachycardia and arterial hypertension, re ect sympathetic overactivity. Additional fea- tures may include a mixed sensorimotor peripheral neuropathy (motor dominant), characteristically a ecting the upper limbs and progressing to tetraparesis with ventilatory paralysis in some cases. While darkly pigmented urine is strongly suggestive, such ndings are not acutely present in the hepatic porphyrias, due to the slow rate of colourless porphobilinogen oxidation to pigmented porphobilin; 5-aminoleavulinate excretion is also acutely elevated but this metabolite is colourless. Hyponatraemia is common, the result of electrolyte depletion and inappropriate antidiuretic hormone secretion; intractable seizures may result. Diagnosis relies upon detecting elevated urinary porphobilino- gen and in some forms of acute porphyria, raised total porphyrin analyses during symptomatic episodes; while excretion patterns typically normalize upon recovery this is not always the case. Neuroimaging may demonstrate subcortical T2 signal inten- sity, without restricted di usion, suggesting vasogenic oedema which resolves upon clinical recovery; a bioccipital pattern may be evident, resembling changes seen in posterior reversible (hypertensive) encephalopathy; di erentiation of which is aided by the presence of contrast enhancement in porphyric lesions. Prompt treatment of acute decompensation is critical; identi ed triggers should be removed (care must be taken to avoid aggre- vating medications) and supportive measures including uid resuscitation, electrolyte replacement, and analgesia initiated. Intravenous therapy with dextrose should be avoided in the face of rapidly progressive hyponatraenmia which characterizes the acute attack; intravenous haem arginate given daily for several days shortens duration of the acute attack. Long-term manage- ment centres upon the avoidance of triggering factors and con- sideration to hepatic transplantation in patients with frequently relapsing disease.74–76

Disorders of elemental co-factor transport

and metalloprotein dysfunction

Disorders of elemental co-factor transport and metalloprotein dys- function are well recognized causes of dementia and neuropsychi- atric dysfunction, in most cases the consequence of disordered metal tra cking and utilization, with resultant tissue accumu- lation leading to toxic e ects. Disrupted copper and iron metab- olism dominate adult-onset presentations, with o en striking clinicopathological similarities; typi ed by the autosomally reces- sive copper transport disorder, Wilson disease, and abnormali- ties of iron-binding proteins ferritin and careuloplasmin, giving rise to autosomally dominant neuroferritinopathy and recessive acaeruloplasminaemia. ese conditions are members of the het- erogeneous cohort of disorders classi ed as neurodegeneration with brain iron accumulation (NBIA), other members of which may also present in adulthood (e.g. pantothenate kinase-associated neurodegeneration).

In Wilson disease, copper accumulation re ects dysfunction of an ATPase copper transporter, encoded by the ATP7B gene, and responsible for excretion of copper and its incorporation into ceruloplasmin, a ferroxidase enzyme, critical to copper and iron transport. Resultant tissue accumulation of copper is responsible for local injury. By comparison, acaeruloplasminaemia results from a de ciency of caeruloplasmin’s ferroxidase activity, required for iron export, while neuroferritinopathy stems from a mutation in a subunit of the iron storage protein, ferritin. Increasingly, other disorders of elemental metabolism are recognized, including the recent indenti cation of autosomal recessive hypermanganesae- mia, in which a parkinsonian phenotype with hepatic cirrhosis and polycythaemia re ect dysfunction of the manganese transporter, SLC30A10.77

Most o en presenting in late adolescence and throughout adult- hood, metal accumulation within the basal ganglia is prominent across these heterogeneous disorders; extrapyramidal manifesta- tions are characteristic—commonly dystonia, choreoathetosis, and parkinsonism. Tremor and a deterioration in handwriting are o en an early feature of Wilson disease, while speech-induced, orofa- cial dystonia, and frontalis overactivity are common in neurofer- ritnopathy; striking asymmetry of limb dystonia may also feature. Cerebellar dysfunction is o en prominent and isolated psychiatric presentations may arise with progressive neurodegeneration typi- cal. Ocular pathlogy may inform diagnosis—retinal dysfunction suggests acaeruloplasminaemia (particularly if comorbid with dia- betes mellitus), while cataracts are common in Wilson disease and the presence of copper deposition within Descemet’s membrane (Kayser–Fleischer rings) near pathognomic, especially when present in association with neurological disease. Visceral involvement, such as cirrhosis, cardiomyopathy, renal tubular disease, and endocrine pancreatic failure (diabetes mellitus is near universal in acaerulo- plasminaemia) should also raise the possibility of elemental tissue deposition and may arise independently. Clinical consequences of visceral disease are notably absent in both neuroferritinopathy and pantothenate kinase-associated neurodegeneration.

Screening investigations vary: neuroimaging often reveals signal change within the basal ganglia, secondary to metal dep- osition with cytotoxic oedema, often with a subregional pattern that is usually specific.14,78 In late-stage disease, generalized

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CHAPTER 24 metabolic dementia 269

270 SECTION 3 cognitive impairment and dementia

cerebral and cerebellar atrophy occurs. Biochemical screening must include serum copper, iron and manganese levels, fer- ritin, and caeruloplasmin, with careful consideration towards artefactual confounding of ferritin and caeruloplasmin which are acute phase proteins. Wilson disease is characterized by low serum protein-bound copper and ceruloplasmin, with elevated unbound copper and increased urinary excretion (best quan- tified by accumulative 24-hour assay); molecular analysis of the ATP7B gene will usually confirm the diagnosis, although rarely, hepatic biopsy and confirmation of pathogenic copper storage is required. Acaeruloplasminaemia demonstrates low serum copper and iron, reflecting deficient caeruloplasmin function, typically with a marked reduction in ceruloplasmin concentration and plasma ceruloplasmin ferroxidase activity, and increased serum ferritin. Hepatic iron stores are increased, although, as with Wilson disease, biopsy is generally reserved for cases where molecular analysis of the caeruloplasmin gene (CP) is unavailing. Conversely, ferritin is decreased in neuro- ferritinopathy; clinical suspicion is confirmed through molecu- lar analysis of the ferritin light chain (FLT) gene. Biochemical abnormalities are absent in pantothenate kinase-associated neurodegeneration, with diagnosis focusing upon neuroradio- logical features and molecular analysis; the presence of acan- thocytosis on a peripheral blood film and low or absent plasma pre-beta lipoprotein fractions may be evident in certain subsets of this disease.

Treatment is directed to removal of excess metal via chelation therapy and restriction of dietary intake and intestinal absorption, an approach best employed early within the disease course. In Wilson disease, early recognition and aggressive copper reduction strategies greatly improve outcome; chelation typically employs penicillamine, although trientine has a more favourable side- e ect pro le and is increasingly the preferred option. Oral zinc supplementation is also used to induce metallothionein synthesis, a copper binding protein within the small intestinal enterocytes, e ecting increased faecal excretion of copper. In those who fail medical therapy, orthotopic liver transplantation may be consid- ered, although this has marginal e ect upon established neuro- pathology. Similarly, reduction of iron load via regular venesection and the use of high a nity iron chelators (e.g. desferrioxamine) to reduce iron stores and zinc sulphate supplements, which reduce gastrointestinal absorption of ironmay ameliorate diabetes and improve hepatic and neurological symptoms in patients with acaeruloplasminaemia, although such approaches have had min- imal e ect in neuroferritinopathy to date. Trials of adjunct coen- zyme Q10 and anti-oxidant therapy are also under investigation, although unlikely to confer signi cant clinical bene t in any of these disorders.79–83

Other inborn disorders of lysosomal

macromolecule catabolism

In addition to its integral role in sphingolipid catabolism, the endo- somal–lysosomal pathway is critical for the degradation and recy- cling of glycosaminoglycans and complex proteins, disruption of which gives rise to a further group of neurodegenerative disorders. Disease burden is greatest in childhood, however late-onset variants occur. Among these diseases are the adult neuronal ceroid lipofus- cinosis and several of the oligosaccharidoses (glycoproteinoses).

e neuronal ceroid lipofuscinoses are 14 genetically distinct diaseases characterized by pathological accumulation of ceroid pigments (lipofuscin and other proteins such as cytochrome C and saposins) within neurons—inducing an auto uorescent aggregate of oxidized protein and lipid residues, with bound metals including iron, copper, and zinc—believed to interfere with cellular autophagy and sensitize cells to oxidative stress.84 Wide molecular heterogeneity is observed and an increasing number of causative mutations, of both recessive (e.g. CLN6 and PPT1) and dominant (e.g. DNAJC5 and CTSF) inheritance iden- ti ed, the majority involving proteins integral to endosomal– lysosomal processing, albeit, the pathogenic mechanisms remain incompletely understood. Adult-onset disease manifests from adolescence, most frequently in the third to fourth decades and progressing to death within 10 years of onset. Unlike other lyso- somal disorders, ceroid neuronal lipofuschinoses are restricted to a central neurological phenotype; broadly, two overlapping sub- types are de ned: type A, dominated by progressive myoclonic epilepsy, cerebellar disease, and cognitive decline, and type B by the absence of epilepsy, with prominent behavioural disturb- ance and dementia. Pyramidal and extrapyramidal disease o en results; however, unlike childhood variants, retinal dysfunction is less commonly evident. Diagnosis of neuronal ceroid lipofus- cinoses can be very challenging in the early phases of the illness; neuroimaging is o en normal although parietal predominant cortical atrophy and attenuation of T2-signal within the puta- men may be observed. Electroencephalography is typically non- speci c with both encephalopathic and epileptogenic features described; prominent photo-paroxysmal responses, as seen in childhood-onset disease, are uncommon, however, when present should raise the index of suspicion. Screening enzymatic assay (typically performed within leukocytes or cultured broblasts) is limited to palmitoyl-protein thioesterase 1 (PPT-1) and cath- epsin D (CTSD) in adult-onset disease; thus, diagnostic con- rmation relies largely upon molecular analysis of known genes. However, in many cases, no defect in DNA can be identi ed and the diagnosis is made on the basis of ultrastructural examin- ation, demonstrating characteristic intracytoplasmic inclusions within leukocytes (bu y coat analysis) or skin biopsy speci- mens. Treatment remains, largely symptomatic although enzyme replacement for CLN2 as well as gene transfer techniques are under investigation.85–87

e oligosaccharidoses also represent a heterogeneous group, with neurocognitive impairment in adulthood typically restricted to α mannosidosis, galactosialidosis and α-N-acetylgalactosa- minidase de ciency, each the consequence of speci c lysosomal hydrolase dysfunction causing disordered glycoprotein catabolism and accumulation of incompletely degraded oligosaccharides. Inherited in an autosomally recessive fashion, adult-onset variants typically manifest progressive cognitive decline, at times, promi- nent neuropsychiatric features and seizures—o en myoclonic. Visceromegaly is typically prominent although by no means uni- versal, while coarsening of facial cutaneous tissues and corneal clouding, re ecting substrate storage, should raise suspicion. In some cases (e.g. adult-onset galactosialidosis) fundoscopy reveals a macular cherry-red spot, re ecting retinal disease. Skeletal dys- plasisa (dysostosis multiplex), cutaneous angiokeratoma, and peripheral neuropathy are suggestive of many oligosaccharidoses and are highly suggestive of the diagnosis in the context of central

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neurological disease. Late-onset cognitive decline in patents with childhood-onset disease also occurs and disease complicated by communicating hydrocephalus has been reported.88 Diagnosis relies upon detection of urinary oligosaccharide excretion, with con rmation by speci c enzyme activity assays and molecular analysis. As with many of the lysosomal disorders, treatment is symptomatic, although targeted approaches utilizing enzyme replacement therapies and gene transfer techniques are under investigation.89–92

Disordered endosomal–lysosomal function

and dementia

While not strictly constituting a primary ‘metabolic dementia’, the pathogenic role of disordered endosomal–lysosomal function and other autophagic processes is increasingly implicated in the patho- genesis of primary dementias.93 Moreover, heterozygous muta- tions in several genes encoding lysosomal proteins—homozygous mutations in which, give rise to recognized lysosomal diseases— have been identi ed amongst the known genetic risk factors

94–96

In comparison to major neurodegenerative diseases, metabolic causes of dementia are rare. However, recognition is vital as, in many cases, speci c treatments are available and there are o en genetic implications for other family members. In addition, meta- bolic disorders, particularly those that are acquired, may compli- cate other causes of dementia and should not be overlooked as contributing factors. Whilst there are myriad metabolic causes of cognitive impairment, focused investigations based on clinical phenotype, with involvement of clinical biochemists and metabolic specialists as required, allows for a speci c diagnosis to be reached in most cases.

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CHAPTER 24 metabolic dementia 271

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93. Nixon RA. e role of autophagy in neurodegenerative disease. Nat Med. 2013 Aug;19(8):983–97. doi: 10.1038/nm.3232. Epub 2013 Aug 6.

94. Beavan MS and Schapira AH. Glucocerebrosidase mutations and the pathogenesis of Parkinson disease. Ann Med. 2013 Dec;45(8):511–21. doi:10.3109/07853890.2013.849003.

95. Murphy KE and Halliday GM. Glucocerebrosidase de cits in sporadic Parkinson disease. Autophagy. 2014 Jul;10(7):1350–1. doi: 10.4161/ auto.29074. Epub 2014 May 15.

96. Deng H, Xiu X, and Jankovic J. Genetic convergence of Parkinson’s disease and lysosomal storage disorders. Mol Neurobiol. 2015 Jun;51(3):1554–68. doi: 10.1007/s12035-014-8832-4. Epub 2014 Aug 7.

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CHAPTER 24 metabolic dementia 273

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CHAPTER 25

Vascular cognitive impairment

Geert Jan Biessels and Philip Scheltens

Changing concepts: From vascular

dementia to VCI

e di culty in capturing the vascular burden in cognitive dys- function in operational diagnostic criteria is re ected in the evolu- tion such criteria over the past decades. e rst diagnostic criteria that were proposed in the early 1990s focused on vascular demen- tia (VaD).1,2 ese criteria have been widely used, both in clini- cal practice and research, but have also been criticized. A key issue in the critique was the way in which dementia was de ned. First, the de nition of dementia was largely based on clinical features of Alzheimer’s disease and required memory impairment, whereas cognitive impairment due to vascular disease involves multiple other cognitive domains. Second, by focusing on dementia, the diagnosis VaD did not apply to patients with cognitive impairment due to vascular disease with relatively preserved daily functioning. erefore in the mid-1990s, the term vascular cognitive impair- ment (VCI) was introduced to refer to all forms of mild to severe cognitive impairment associated with and presumed to be caused by cerebrovascular disease.3–5 e term covers the whole spectrum of cognitive dysfunction from mild cognitive impairments to severe impairments meeting criteria for dementia, with a presumed vas- cular aetiology, regardless of the pathogenesis (e.g. cardioembolic, atherosclerotic, ischaemic, haemorrhagic, or genetic).4

VCI is thus an umbrella term encompassing all forms of cogni- tive dysfunction associated with cerebrovascular disease. Just like other umbrella terms such as, for example, ‘stroke’ or ‘dementia’, it is not very well suited as a diagnostic label in individual patients due to lack of diagnostic speci city and clear leads for prognosis or treatment. erefore, over the past years, there have been e orts to develop the concept of VCI into diagnostic criteria that are applicable in daily care. e criteria for vascular cognitive impair- ment from the American Heart Association/American Stroke Association (Table 25.1)5 and the criteria for vascular cognitive dis- orders (VCD) from VAS COG6 (Table 25.2) are the most recent and relevant examples. Just like the initial VaD criteria, these VCI (or VCD) criteria rely on three pillars: 1) demonstration of the pres- ence of cognitive dysfunction, 2) demonstration of the presence of cerebrovascular disease, and 3) evidence that the two are causally linked. Although this may seem straightforward, it is unfortunately o en not the case.

Let us rst consider the rst pillar: demonstration of ‘cognitive dysfunction.’ Only in a subset of patients with cerebrovascular disease cognitive dysfunction has an acute onset or stepwise pro- gression. If this stepwise decline co-occurs with a cerebrovascular event cognitive dysfunction is o en easily noted and the causal

relationship with the vascular event readily established. However, in the majority of patients that fall under the concept of VCI, cogni- tive decline is insidious and can evolve over many years. Loss of cog- nitive function in such patients is a continuous process. erefore, making a dichotomy between presence or absence of cognitive dys- function in such cases can be di cult and is to some extent arbi- trary. Nevertheless, for a patient to meet the VCI criteria, cognitive dysfunction must be present and con rmed by formal assessment and may not, by de nition, include episodic memory impairment. Most o en, the de cits include slowing of information processing, executive dysfunction, and memory retrieval impairment.

e second pillar, demonstration of cerebrovascular disease, can be based on a history of clinical stroke but is generally supported by demonstrating vascular lesions on brain imaging (Tables 25.1 and 25.2). Vascular lesions on imaging are heterogeneous and may include di erent manifestations of cerebral small vessel disease (SVD; i.e. white matter hyperintensities, lacunes, microbleeds), but also large infarcts, intracerebral haemorrhage, and subarachnoid haemorrhage. Several of these lesions, like a large cortical infarct, can be easily classi ed as ‘abnormal.’ For the di erent manifesta- tions of SVD, however, it is more di cult to draw the line between normal and abnormal. White matter hyperintensities, for example, are extremely common in people over the age of 60, and also in people without any cognitive complaints. Moreover, in the general population lacunes and microbleeds can be observed in 20–30 per cent of people over the age of 75.7,8 Let us consider two individu- als, one 40 and one 80 years of age. Both have a similar burden of white matter hyperintensities on brain MRI, with bands around the ventricles and several punctate lesions in the deep white matter. is would be considered as perfectly normal in an 80 year old, but would de nitely be classi ed as abnormal in a 40 year old. Hence, the context—patient-related factors—determine whether we clas- sify these lesions as abnormal rather than the lesions themselves. is links to the third pillar: to establish causality between cognitive dysfunction and cerebrovascular disease in an individual patient. If the 40-year-old patient displayed slowed information processing and executive dysfunction on cognitive testing, the white matter hyperintensities would be readily accepted as a probable cause and this would prompt extensive investigations. If the 80-year-old man was a healthy volunteer in a research project, the same white mat- ter hyperintensities would be considered as clinically irrelevant and prompt no further action. If this man presented at a memory clinic with progressive memory loss interfering with daily functioning, the clinical diagnosis would most probably be Alzheimer’s disease and again, the white matter hyperintensities would not automati- cally be considered the cause of his cognitive dysfunction but most

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Table 25.1 Criteria for vascular cognitive impairment: Statement from the American Heart Association/American Stroke Association (2011)

1. e term VCI characterizes all forms of cognitive de cits from vascular dementia (VaD) to MCI of vascular origin (VaMCI).

2. ese criteria cannot be used for subjects who have an active diagnosis of drug or alcohol abuse/dependence. Subjects must be free of any type of substance for at least three months.

3. ese criteria cannot be used for subjects with delirium.

Dementia

1. e diagnosis of dementia should be based on a decline in cognitive function from a prior baseline and a de cit in performance in two cognitive domains that are of su cient severity to a ect the subject’s activities of daily living.

2. e diagnosis of dementia must be based on cognitive testing, and a minimum of four cognitive domains should be assessed: executive/attention, memory, language, and visuospatial functions.

3. e de cits in activities of daily living are independent of the motor/sensory sequelae of the vascular event.

Probable VaD

1. ere is cognitive impairment and imaging evidence of cerebrovascular disease, and

a. ere is a clear temporal relationship between a vascular event (e.g. clinical stroke) and onset of cognitive de cits, or

b. ere is a clear relationship in the severity and pattern of cognitive impairment and the presence of di use, subcortical cerebrovascular disease pathology (e.g. as in CADASIL).

2. ere is no history of gradually progressive cognitive de cits before or after the stroke that suggests the presence of a nonvascular neurodegenerative disorder.

Possible VaD

ere is cognitive impairment and imaging evidence of cerebrovascular disease but

1. ere is no clear relationship (temporal, severity, or cognitive pattern) between the vascular disease (e.g. silent infarcts, subcortical small-vessel disease) and the cognitive impairment.

2. ere is insu cient information for the diagnosis of VaD (e.g. clinical symptoms suggest the presence of vascular disease, but no CT/MRI studies are available).

3. Severity of aphasia precludes proper cognitive assessment. However, patients with documented evidence of normal cognitive function (e.g. annual cognitive evaluations) before the clinical event that caused aphasia could be classi ed as having probable VaD.

4. ere is evidence of other neurodegenerative diseases or conditions in addition to cerebrovascular disease that may a ect cognition, such as:
a. A history of other neurodegenerative disorders (e.g. Parkinson’s disease, progressive supranuclear palsy, dementia with Lewy bodies);
b. e presence of Alzheimer’s disease biology is con rmed by biomarkers (e.g. CSF, PET amyloid ligands) or genetic studies (e.g. PS1 mutation); or c. A history of active cancer or psychiatric or metabolic disorders that may a ect cognitive function.

VaMCI

1. VaMCI includes the four subtypes proposed for the classi cation of MCI: amnestic, amnestic plus other domains, nonamnestic single domain, and nonamnestic multiple domain.

2. e classi cation of VaMCI must be based on cognitive testing, and a minimum of four cognitive domains should be assessed: executive/attention, memory, language, and visuospatial functions. e classi cation should be based on an assumption of decline in cognitive function from a prior baseline and impairment in at least one cognitive domain.

3. Instrumental activities of daily living could be normal or mildly impaired, independent of the presence of motor/sensory symptoms.

Probable VaMCI

1. ere is cognitive impairment and imaging evidence of cerebrovascular disease and

a. ere is a clear temporal relationship between a vascular event (e.g. clinical stroke) and onset of cognitive de cits, or

b. ere is a clear relationship in the severity and pattern of cognitive impairment and the presence of di use, subcortical cerebrovascular disease pathology (e.g. as in CADASIL).

2. ere is no history of gradually progressive cognitive de cits before or after the stroke that suggests the presence of a nonvascular neurodegenerative disorder.

Possible VaMCI

ere is cognitive impairment and imaging evidence of cerebrovascular disease but:

1. ere is no clear relationship (temporal, severity, or cognitive pattern) between the vascular disease (e.g. silent infarcts, subcortical small-vessel disease) and onset of cognitive de cits.

2. ere is insu cient information for the diagnosis of VaMCI (e.g. clinical symptoms suggest the presence of vascular disease, but no CT/MRI studies are available).

4. ere is evidence of other neurodegenerative diseases or conditions in addition to cerebrovascular disease that may a ect cognition, such as:
a. A history of other neurodegenerative disorders (e.g. Parkinson’s disease, progressive supranuclear palsy, dementia with Lewy bodies);
b. e presence of Alzheimer’s disease biology is con rmed by biomarkers (e.g. PET, CSF, amyloid ligands) or genetic studies (e.g. PS1 mutation); or c. A history of active cancer or psychiatric or metabolic disorders that may a ect cognitive function.

Unstable VaMCI

Subjects with the diagnosis of probable or possible VaMCI whose symptoms revert to normal should be classi ed as having ‘unstable VaMCI’.

VCI, vascular cognitive impairment; VaD, vascular dementia; MCI, mild cognitive impairment; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CT/MRI, computed tomography/magnetic resonance imaging; PET, positron emission tomography; CSF, cerebrospinal uid; and VaMCI, vascular mild cognitive impairment.

Reproduced from Stroke. 42(9). Gorelick PB, Scuteri A, Black SE, et al. Vascular Contributions to Cognitive Impairment and Dementia: A Statement for Healthcare Professionals from the American Heart Association/American Stroke Association, pp. 2672–713, Copyright (2011), with permission from Wolters Kluwer Health, Inc.

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Table 25.2 Diagnostic criteria for vascular cognitive disorders: Statement from VASCOG (2014)

Proposed Criteria for Mild Cognitive Disorder and Dementia (or Major Cognitive Disorder)
Mild cognitive disorder
(A) Acquired decline from a documented or inferred previous level of performance in ≥ 1 cognitive domains as evidenced by the following:

(a) Concerns of a patient, knowledgeable informant, or a clinician of mild levels of decline from a previous level of cognitive functioning. Typically, the reports will involve greater di culty in performing the tasks, or the use of compensatory strategies; and

(b) Evidence of modest de cits on objective cognitive assessment based on a validated measure of neurocognitive function (either formal neuropsychological testing or an equivalent clinical evaluation) in ≥ 1 cognitive domains. e test performance is typically in the range between one and two SDs below appropriate norms (or between the 3rd and 16th percentiles) when a formal neuropsychological assessment is available, or an equivalent level as judged by the clinician.

(B) e cognitive de cits are not su cient to interfere with independence (i.e. instrumental activities of daily living are preserved), but greater e ort, compensatory strategies, or accommodation may be required to maintain independence.

Dementia or major cognitive disorder

(A) Evidence of substantial cognitive decline from a documented or inferred previous level of performance in ≥ 1 cognitive domains. Evidence for decline is based on

(a) Concerns of the patient, a knowledgeable informant, or the clinician, of signi cant decline in speci c abilities; and

(b) Clear and signi cant de cits in objective assessment based on a validated objective measure of neurocognitive function (either formal neuropsychological testing or equivalent clinical evaluation) in ≥ one cognitive domain. ese typically fall ≥ two SDs below the mean (or below the 3rd percentile) of people of similar age, sex, education, and sociocultural background, when a formal neuropsychological assessment is available, or an equivalent level as judged by the clinician.

(B) e cognitive de cits are su cient to interfere with independence (e.g. at a minimum requiring assistance with instrumental activities of daily living, i.e. more complex tasks such as managing nances or medications).

Evidence for Predominantly Vascular Aetiology of Cognitive Impairment

(A) One of the following clinical features

(1) e onset of the cognitive de cits is temporally related to ≥ 1 CVEs. (Onset is often abrupt with a stepwise or uctuating course owing to multiple such events, with cognitive de cits persisting beyond three months after the event. However, subcortical ischaemic pathology may produce a picture of gradual onset and slowly progressive course, in which case A2 applies.) e evidence of CVEs is one of the following

(a) Documented history of a stroke, with cognitive decline temporally associated with the event

(b) Physical signs consistent with stroke (e.g. hemiparesis, lower facial weakness, Babinski sign, sensory de cit including visual eld defect, pseudobulbar syndrome—supranuclear weakness of muscles of face, tongue, and pharynx, spastic dysarthria, swallowing di culties, and emotional incontinence)

(2) Evidence for decline is prominent in speed of information processing, complex attention, and/or frontal-executive functioning in the absence of history of a stroke or transient ischaemic attack. One of the following features is additionally present

(a) Early presence of a gait disturbance (small-step gait or marche petits pas, or magnetic, apraxic–ataxic, or parkinsonian gait); this may also manifest as unsteadiness and frequent, unprovoked falls

(b) Early urinary frequency, urgency, and other urinary symptoms not explained by urologic disease

(B) Presence of signi cant neuroimaging (MRI or CT) evidence of cerebrovascular disease (one of the following)

. (1) One large vessel infarct is su cient for mild VCD, and ≥ two large vessel infarcts are generally necessary for VaD (or major VCD)

. (2) An extensive or strategically placed single infarct, typically in the thalamus or basal ganglia may be su cient for VaD (or major VCD)

. (3) Multiple lacunar infarcts (> two) outside the brainstem; one to two lacunes may be su cient if strategically placed or in combination with extensive white matter lesions

. (4) Extensive and con uent white matter lesions

. (5) Strategically placed intracerebral haemorrhage, or ≥ two intracerebral haemorrhages

. (6) Combination of the above

Exclusion criteria (for mild and major VCD) (1) History

(a) Early onset of memory de cit and progressive worsening of memory and other cognitive functions such as language (transcortical sensory aphasia), motor skills (apraxia), and perception (agnosia) in the absence of corresponding focal lesions on brain imaging or history of vascular events

(b) Early and prominent parkinsonian features suggestive of Lewy body disease

(c) History strongly suggestive of another primary neurological disorder such as multiple sclerosis, encephalitis, toxic, or metabolic disorder, etc. su cient to explain the cognitive impairment

(2) Neuroimaging
(a) Absent or minimal cerebrovascular lesions on CT or MRI

(3) Other medical disorders severe enough to account for memory and related symptoms

(4) For research: e presence of biomarkers for Alzheimer disease (cerebrospinal Ab and pTau levels or amyloid imaging at accepted thresholds) exclude diagnosis of probable VCD, and indicate AD with CVD

AD, Alzheimer disease; CT, computed tomography; CVD, cerebrovascular disease; CVE, cerebrovascular event; MRI, magnetic resonance imaging; VaD, vascular dementia; VCD, vascular cognitive disorder.

Reproduced from Alzheimer Dis Assoc Disord. 28(3), Sachdev P, Kalaria R, O’Brien J, et al. Diagnostic criteria for vascular cognitive disorders: A VASCOG statement, pp. 206–18, Copyright

(2014), with permission from Wolters Kluwer Health, Inc.

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278 SECTION 3 cognitive impairment and dementia

likely be considered a comorbidity. e bottom line is that causality is easy to establish for clear-cut cognitive dysfunction that is linked to a speci c vascular process or event but much more di cult in instances of subtle cognitive changes with multiple non-speci c vascular lesions, or in the context of other coexistent disease pro- cesses, such as Alzheimer-type pathology. e majority of patients with VCI fall in the latter categories because the most common vascular lesions, in particular manifestations of SVD, are o en not very strongly linked to cognitive functioning in individual patients, and co-occur with other pathologies, especially in older patients. Nevertheless, at the population level the burden of SVD is consid- erable and as such it is an important and potentially preventable contributor to dementia. e key importance of the concept VCI is that it highlights these latter aspects.

Neuropathology of VCI

e neuropathology of VCI is heterogeneous and can be expressed in the blood vessels themselves or in the parenchyma (see references 9–12 for comprehensive overviews). ese pathologies are summa- rized in Table 25.3. Few patients have a single type of pathology and in most cases cerebrovascular pathology is accompanied by other pathologies, most o en Alzheimer type. Pathological changes in the vessels can a ect the whole arterial tree and, less commonly, also the veins.9 Cerebrovascular disease can be grouped under large- and small-vessel domains. Large ischaemic parenchymal lesions can be due to emboli, from cardiac origin or from large-vessel dis- ease, including atherosclerosis, plaque rupture, thrombotic occlu- sion and dissection, but can also result from haemodynamic events, causing borderzone or watershed lesions.9 Although atheroscle- rotic changes in the large arteries supplying the brain are very com- mon in old age, large parenchymal lesions occur only in a subset

of individuals. At the population level, these large parenchymal lesions are not a major contributor to VCI. By comparison, paren- chymal lesions due to abnormalities in the smallest vessels (i.e. the small arteries, arterioles, venules, and capillaries of the brain) are much more common, some clearly linked to cognitive impairment (Table 25.3). Abnormalities in these vessels include arteriolosclero- sis, lipohyalinosis, brinoid necrosis, microatheromas, and cerebral amyloid angiopathy (CAA). Parenchymal lesions that are associ- ated with these vessel abnormalities include lacunes, di use white matter changes, and microinfarcts (Fig. 25.1).9,12 Abnormalities in the smallest vessels and the parenchymal lesions which they cause are collectively referred to as cerebral SVD.13 Age-related and hypertension-related SVD and cerebral amyloid angiopathy (see also chapter 26) are the most common forms.13

Neuroimaging features of VCI

Brain imaging is a cornerstone in the evaluation of VCI. e pre- ferred imaging modality is magnetic resonance imaging (MRI). Computed tomography (CT) can be used as an alternative but it is much less sensitive to white matter hyperintensities and cannot detect microbleeds.

Vascular lesions on brain imaging can roughly be grouped under large- and small-vessel domains, along the same lines as has been described for neuropathology. Large vessel disease most commonly manifests itself in the form of ischaemic stroke. Cortical or cerebel- lar ischaemic lesions and brainstem or subcortical hemispheric infarcts larger than 1.5 cm in diameter on CT or MRI are generally considered to be of large-artery origin, mostly due to atherosclero- sis, or to be due to an embolus from the heart.14 For large sponta- neous intracerebral haemorrhages the most common cause is SVD, due to arteriolosclerosis or CAA. Particularly for SVD, a major

Table 25.3 Types of vascular and parenchymal neuropathological changes in VCI

Pathological Feature

Predominant Location

Frequency

Association with CI

Atheromas
Atheromatous and occlusive disease

Complete infarctions (macroscopic), arterial territorial infarctions

Lacunar infarcts
Cystic infarcts
Small or microinfarcts
Hyalinosis, lipohyalinosis, broid necrosis Cribriform change, perivascular spacing Demyelination and oligodendrocyte changes Gliosis: astrocytosis and microgliosis Cerebral amyloid angiopathy

Intracerebral haemorrhages Microspongiform change
Laminar necrosis, gliosis
Hippocampal atrophy and sclerosis Alzheimer type of pathology (concomitant)

Carotid artery bifurcation and internal
Circle of Willis, proximal branches of MCA, ACA, PCA Cortical and subcortical regions

WM, basal ganglia, thalamus
WM, basal ganglia, thalamus
Cortical and subcortical
WM, cortical and subcortical grey matter
WM, basal ganglia, internal and external capsules WM

WM, cortical and subcortical Cortical
Cortical, subcortical and lobar Neocortical layer I–II Neocortical ribbon CA1–CA4

Hippocampus, neocortex

High High Moderate

Moderate Moderate High Moderate High High Variable Moderate Low Moderate Low Moderate Low

Weak Moderate Weak

Moderate Unknown Strong Unknown Strong Strong Moderate Moderate Moderate Unknown Unknown Strong Strong

VaD, vascular dementia; CI, cognitive impairment; MCA, middle cerebral artery; ACA, anterior cerebral artery; PCA, posterior cerebral artery; WM, white matter. Reproduced from Kalaria (9), based on a review of the neuropathological literature on VCI.

Reproduced from Stroke. 43(9). Kalaria RN, Cerebrovascular Disease and Mechanisms of Cognitive Impairment: Evidence from Clinicopathological Studies in Humans, pp. 2526–34, Copyright (2012), with permission from Wolters Kluwer Health, Inc.

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Fig. 25.1 Gliotic microinfarct in the upper layers of the cerebral cortex in an 83-year-old male with a neuropathologically con rmed diagnosis of vascular dementia. e microinfarct shows up on GFAP (glial brillary acidic protein) immunohistochemistry staining and has a cystic core.

di erence with neuropathology is that brain imaging does not depict the abnormalities in the small vessels themselves but rather the associated parenchymal lesions. Recently, an international working group has provided de nitions and imaging standards for speci c markers and consequences of SVD, the so-called STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) crite- ria.15 ese standards were developed for use in research studies but use in the clinical setting should also be encouraged to standardize image interpretation, acquisition, and reporting. On brain imaging, the core manifestations of SVD include small subcortical infarcts, white matter MRI hyperintensities (WMH), prominent perivascu- lar spaces (PVS), and cerebral microbleeds (CMBs) (Fig. 25.2) (15). Importantly, cerebral atrophy, which is o en used as an indicator of neurodegeneration, can also be due to vascular disease15

Small subcortical infarcts

On imaging, small subcortical infarcts can be detected in the acute stage, but in the context of VCI these lesions are more commonly detected in the chronic stage. According to the STRIVE criteria acute lesions are termed ‘recent small subcortical infarcts (SSI)’. ese SSI,

Courtesy of SV Veluw and W Spliet, UMC Utrecht.

CHAPTER 25 vascular cognitive impairment 279

Recent small White matter Perivascular

subcortical hyperintensity Lacune space infarct

Cerebral microbleeds

Example image

Schematic

Usual diameter1

DWI

T2*/GRE

increased signal

DWI
≤ 20 mm

FLAIR variable

FLAIR
3–15 mm

T2*/SWI
≤ 10 mm

≤ 2 mm

Comment best identified on located in white usually have DWI matter hyperintense

rim

usually linear without hyperintense rim

detected on GRE seq., round or ovoid, blooming

FLAIR

decreased signal

( if haemorrhage) iso-intense signal

Fig. 25.2 MRI ndings for lesions related to small vessel disease—STRIVE criteria. Examples (upper) and schematic representation (middle) of MRI features for changes related to small vessel disease, with a summary of imaging characteristics (lower) for individual lesions. DWI = di usion-weighted imaging. FLAIR = uid-attenuated inversion recovery. SWI = susceptibility-weighted imaging. GRE = gradient-recalled echo.
Reproduced from Lancet Neurol. 12(8). Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration, pp. 822–38, Copyright (2013), with permission from Elsevier.

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280 SECTION 3 cognitive impairment and dementia

o en referred to clinically as ‘lacunar stroke’ or ‘lacunar syndrome,’ represent about 25 per cent of all ischaemic strokes, but recent SSI are occasionally also found in patients without symptoms of acute stroke. A recent SSI is de ned as ‘imaging evidence of infarction in the territory of a single perforating arteriole with imaging features or correlating clinical symptoms consistent with a lesion occur- ring in the last few weeks’.15 ‘Recent’ is derived from symptoms or imaging features—most commonly a di usion weighted imaging lesion on MRI—suggesting that the SSI occurred within the last few weeks. ‘Small’ indicates a lesion that should generally be less than 20 mm maximum diameter in the axial plane. In the chronic stage, a small subcortical infarct can manifest itself on CT and MRI as a so-called lacune. A lacune of presumed vascular origin is de ned as a round or ovoid, subcortical, uid- lled (similar signal to CSF) cavity between 3 mm and 15 mm in diameter, compatible with a previous acute small deep brain infarct or haemorrhage in the territory of a single perforating arteriole.15 On FLAIR, lacunes of presumed vascular origin usually have central hypointensity with a surrounding rim of hyperintensity. However, in some cases the central uid may not be suppressed on FLAIR such that the entire lesion appears hyperintense, in which case it is o en not possible to distinguish these lesions from WMH. Also, in some cases a rim of hyperintensity is not seen on FLAIR. Lacunes of presumed vascular origin should be distinguished from PVS. Although pathological studies show that there is no absolute cut-o , lesions < 3 mm in diameter are more likely to be PVS than lacunes.

White matter lesions

White matter lesions are a common nding on brain imaging, par- ticularly in older individuals.16 On CT, these white matter lesions appear as periventricular or subcortical areas of hypointensity. On MRI FLAIR and T2/proton density-weighted images these lesions are hyperintense (WMH). e term WMH of presumed vascular origin has been proposed to exclude white matter lesions from other diseases such as multiple sclerosis or leukodystrophies.15 e shape, size, and distribution of white matter lesions provide clues to the di erential diagnosis, but the most likely nature of the lesions is best derived from a combination of these imaging fea- tures, other lesions that may be present, and clinical data, includ- ing age, neurological, psychiatric, medical, and family history and medication use.17 If WMH are found in older people, they are gen- erally considered to be of vascular origin, even more so if other vascular lesions are also present. Below the age of 50, however, particularly if the shape and distribution of WMH are atypical, the di erential diagnosis is long, including many non-vascular causes such as hereditary, in ammatory, infectious, and metabolic-toxic conditions.17

Postmortem studies show that WMH of presumed vascular ori- gin re ect tissue abnormalities that range from slight disentangle- ment of the white matter structure to varying degrees of myelin and axonal loss.18 e aetiology includes ischaemia, hypoperfu- sion, blood–brain barrier leakage, in ammation, degeneration, and amyloid angiopathy.18

MRI classi cations of white matter changes usually distinguish between periventricular and deep/subcortical signal abnormali- ties.16 Periventricular WMH typically include caps around the frontal horns of the lateral ventricles and pencil-thin lining or a smooth halo along the side of the lateral ventricles. Deep/subcorti- cal WMH can occur as punctate changes or beginning con uent or

Fazekas 1

Fazekas 2

Fazekas 3

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Fig. 25.3 Grading white matter hyperintensities (WMH). For clinical purposes, severity of WMH is generally assessed with ordinal visual rating scales. To this end, the Fazekas scale is widely used. Periventricular WMH are rated as 0: absent, 1: ‘caps’ or pencil-thin lining, 2: smooth ‘halo’, and 3: irregular periventricular hyperintensities extending into the deep white matter. Separate deep WMH are rated as 0: absent, 1: punctuate foci, 2: beginning con uence of foci, and 3: large con uent areas.

con uent abnormalities. For clinical purposes severity of WMH is generally assessed with ordinal visual-rating scales (Fig. 25.3). For research purposes (semi)automated volumetric methods are o en used.15

Enlarged perivascular spaces

A perivascular space (PVS) is de ned as a uid- lled space, which follows the typical course of a vessel penetrating/traversing the brain through grey or white matter, with signal intensity similar to CSF on all sequences.15 eir diameter commonly not exceeds 2 mm. PVS tend to be most prominent in the inferior basal gan- glia and can also o en be seen coursing centripetally through the hemispheric white matter. As PVSs are a normal anatomical structure, they are present in all individuals. However, due to their small diameter, normal PVSs are o en below the detection limit of low-resolution MR or CT scans. ey may, however, exhibit focal enlargement particularly enlarged (up to in the inferior basal gan- glia, where it can sometimes be di cult to di erentiate them from lacunes; see Fig. 25.2 for distinguishing features). Although the clinical signi cance of presence of numerous visible PVSs is still controversial, a generalized enlargement of PVS has been associ- ated with other markers of SVD and cognitive dysfunction,15 and may therefore be relevant to VCI.

Cerebral microbleeds

Microbleeds are visualized as small (usually 2–5 mm or sometimes 10 mm in size) areas of signal void with associated ‘blooming’ on T2* or other MR sequences sensitive to paramagnetic material.15 Microbleeds are generally not visualized on CT or on FLAIR, T1w-,

or T2w-MR sequences. ey are well de ned and regular, either round or oval, in shape. Neuropathological studies show that these MR lesions correspond to haemosiderin-laden macrophages con- sistent with vascular leakage of blood cells, that is, a small haem- orrhage.15,19 e underlying vascular pathology most commonly involves hypertensive vasculopathy or cerebral amyloid angiopa- thy.18 Cerebral microbleeds are associated with other forms of SVD. Particularly lobar microbleeds are common in Alzheimer’s disease and can be detected in 10–40 pe cent of patients, depending on the sensitivity of the MR protocol.19.20 Lobar microbleeds are also linked to CAA and are incorporated into research criteria for this condition (see chapter 26).

Clinical evaluation of VCI

As has been noted earlier in this chapter, VCI is an umbrella term and as such is not very well suited as a diagnostic label in an indi- vidual patient because it lacks speci city and does not provide suf- ciently clear leads for prognosis or treatment. Nevertheless, the umbrella term does o er guidance on some general principles in the evaluation and management of patients with cognitive dysfunc- tion presumed to be caused by cerebrovascular disease (see refer- ences 5 and 21 for published recommendations). ere are two main pillars in evaluation that jointly guide management. First, the nature and severity of cognitive, psychiatric, and behavioural symptoms should be assessed. Next, the vascular risk-factor pro le should be evaluated and the nature of the vascular aetiology should be established as accurately as possible. In this respect it is import- ant to note that simply labelling the aetiology as ‘vascular’ is too generic and therefore does not direct patient management. Based on the symptom pro le, symptomatic treatment or support may be o ered. Based on the most likely aetiology, vascular risk manage- ment may be optimized and the risk bene t ratio of, for example, antithrombotic treatment considered.

Cognitive and behavioural symptoms

In essence the clinical evaluation of cognitive and behavioural symptoms of patients suspected of VCI is based on the same prin- ciples as the evaluation of any other patient suspected of cogni- tive impairment as has been presented in earlier chapters of this book. It is important to note, however, that the cognitive pro le of patients with VCI can be quite di erent from that of, for example, Alzheimer’s disease. Cognitive de cits may involve any cognitive domain, but executive dysfunction, with slowed information pro- cessing and impairments in the ability to shi between tasks and to hold and manipulate information (i.e. working memory), is a relatively common manifestation of VCI.21 Neuropsychological protocols should therefore be sensitive to these domains for reliable assessment of cognitive dysfunction due to vascular causes. To this end, di erent test protocols have been proposed, from ve-minute protocols for screening purposes in, for example, primary care, to more extensive protocols that allow breakdown of functional de – cits in the executive/activation, language, visuospatial, and memory domains.21

Behavioural changes that should be addressed include change in personality, apathy or disinhibition, and depressive symptoms. In addition, other symptoms of cerebovascular disease should be sought, including focal neurological de cits, gait and balance prob- lems, and incontinence (see chapter 10).

CHAPTER 25 vascular cognitive impairment 281 Vascular risk pro le

e history and physical examination should provide information about vascular risk factors and clinical manifestations of cardiovas- cular disease. Presence of and duration of exposure to hyperten- sion, hyperlipidaemia, diabetes mellitus, and alcohol or tobacco use should be recorded, as well as physical activity and medications. A family history should be obtained, establishing if there are rst- degree relatives (also record the total number of rst-degree rela- tives) with a history of stroke, vascular disease, or dementia (record age at which these conditions occurred).

Vital signs should be collected, including height, weight, blood pressure (orthostatic), waist circumference, heart rate, vision, and hearing.21

Other clinical manifestations of cardiovascular disease are gener- ally retrieved from medical history or records and include ischaemic heart disease, congestive heart failure, peripheral vascular disease, transient ischaemic attacks or strokes, and carotid endarterectomy.

Establishing the ‘vascular cause’

When there is a clear link between an acute stroke and the onset of a cognitive de cit it is generally straightforward to establish causality. Still, brain imaging will be required to classify the causa- tive vascular lesion as this will guide secondary prevention. In this context the so-called TOAST criteria, that classify acute ischaemic strokes into 1) large-artery atherosclerosis, 2) cardioembolism, 3) small-vessel occlusion, 4) stroke of other determined aetiology, and 5) stroke of undetermined aetiology, are still of use.14 Also, for haemorrhagic stroke it is clear that the aetiological subtype pro- vides essential information with regard to long-term prognosis and risk of stroke recurrence. In all cases, secondary prevention should proceed according to established guidelines for that particular stroke subtype, also taking into account the functional ability of the patient (e.g. other medical problems, independence, risk of falls).

As has been noted in an earlier section of this chapter, causal- ity is more di cult to establish when a clear temporal relation- ship between a vascular event and the onset of cognitive decline is lacking. In such cases, evidence of a possible vascular cause will predominantly be derived from brain-imaging studies. While the relationship between the di erent neuroimaging features of VCI, as reviewed later in this chapter, and cognitive dysfunction at the population level is evident, establishing causality between a certain burden of vascular lesions and cognitive functioning is o en not possible in an individual patient. In such cases, the vascular lesions can merely be considered as either incidental or contributing to the functional loss. Another issue is that vascular brain lesions on MRI have quite limited speci city for underlying aetiology. is issue is probably one of the key factors that hamper the development of treatment that targets speci c aetiological processes in SVD. Hence, classi cation of the possible causative lesions therefore cur- rently predominantly guides general vascular risk-factor manage- ment, which is nonetheless important.

Management of VCI

Due to its heterogeneous nature, there are few generalizable prin- ciples that apply to the treatment of all patients with VCI. As has been noted earlier, an individualized approach is required in which the symptom pro le guides symptomatic treatment and support- ive measures, and the aetiological diagnosis directs vascular risk

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282 SECTION 3 cognitive impairment and dementia

management. In this nal section we will highlight the treatment of two very common VCI subtypes, post-stroke cognitive dysfunc- tion and mixed dementia (i.e. Alzheimer’s disease with vascular lesions). e reader is also referred to other chapters in this book that provide guidance on the clinical management of cerebral amy- loid angiopathy (see chapter 26) and rare genetic causes of VCI, in particular CADASIL (see chapters 30 and 31).

Post-stroke cognitive dysfunction

Cognitive dysfunction commonly occurs after stroke. In population-based studies, 5–10 per cent of patients experiencing a rst-ever stroke, who were without dementia prior to stroke, develop dementia within a year a er the event.22 In hospital- based series, the post-stroke dementia rate in the rst year is 10– 14 per cent in those with rst-ever stroke and 18–23 per cent if patients with recurrent strokes are also considered.22 Even more patients experience cognitive dysfunction not meeting criteria for dementia, and these de cits may involve any cognitive domain, but most commonly involve visual perception and construction and executive functioning.23 As with other, non-cognitive, symp- toms of stroke, cognitive functioning may improve during the rst months, but de cits persist in around one in three patients with acute (i.e. within the rst weeks) post-stroke cognitive impair- ment.23 ere are also a substantial number of patients with per- sisting post-stroke cognitive complaints whose actual level of cognitive functioning does not even meet formal criteria for cog- nitive impairment (i.e. cognitive test scores do not fall below the 5th percentile of normative values) but who are still likely to have experienced a decline from pre-stroke level of performance (see Box 25.1 for case history).

Particularly in patients with a rst stroke, without pre-stroke cognitive de cits, the acute lesion may be the only cause of cogni- tive dysfunction. In the large majority of such cases no further cog- nitive decline will occur in the following years, as long as recurrent strokes can be prevented. In many other patients, however, strokes occur in the context of pre-existent SVD or other pathologies, such as incipient Alzheimer’s disease and the prognosis will be much less favourable.

Apart from acute stroke management and prevention of post- stroke complications, which is not the focus of this chapter, initiat- ing adequate secondary prevention is essential. is may not only protect the patient against recurrent vascular events but may also help to preserve cognition. e selection of the right preventive measures again depends on the accurate aetiological subtyping of the stroke. Because post-stroke cognitive dysfunction is so com- mon, high vigilance for its occurrence is warranted and cognitive functioning should be addressed in follow-up outpatient clinics a er stroke. Even in patients who do return to their pre-stroke activities cognitive complaints may occur. In such patients, brief cognitive rehabilitation programmes that provide the patient with some insight into the source of the complaints and o er tips and tricks on how to deal with the de cits may be of use.

Mixed dementia: Alzheimer’s disease

with vascular lesions

Vascular lesions, in particular various manifestations of SVD, are an extremely common nding in patients who meet the diagnos- tic criteria for Alzheimer’s disease. Data from epidemiological and

community-based pathology studies have indicated that many people with dementia have a combination of Alzheimer-type and vascular pathology, thereby challenging the conventional distinc- tion between Alzheimer’s disease and vascular dementia based on widely used clinical criteria.24,25 Dementia in older people is mostly a heterogeneous condition in which di erent pathologies contrib- ute to the clinical dementia syndrome.

When the burden of CVD is exceeding a presumed threshold, patients may be diagnosed with mixed dementia. ere are no real xed criteria for this threshold and thus clinicians use this label at their own discretion, resulting in a very heterogenous category, unsuitable for comparative research. It is probably better to state that SVD may be a contributor, to a greater or lesser extent, to the development of dementia in almost every patient with Alzheimer’s disease who shows these lesions.

Box 25.1 Case history

A 57-year-old man developed an acute le -sided hemiparesis with dysartria. An initial CT showed no abnormalities, but the MRI three days later showed a small subcortical infarct at the lateral border of the right thalamus (Le image: FLAIR; middle image: di usion-weighted image). He was treated with aspirin and dipyridamol, a statin, and an antihypertensive agent.

One year later he returned to the outpatient clinic because of cognitive complaints. Since the occurrence of the infarct he experienced problems with concentration and keeping oversight at his work as owner of a store for kitchen equipment. He could still perform most of his duties, albeit requiring a greater e ort. His wife corroborated his history. On neuropsychological assess- ment his performance on the domains attention and executive functioning was around the 10th–15th percentile of normative values, whereas he performed above the 50th percentile on other domains. e MRI now showed cavitation of the infarct, which had evolved into a lacune (right image). e MRI did not show any other manifestations of small vessel disease except WMH with Fazekas grade 1 (see also Fig. 25.3).

His level of cognitive functioning did not meet formal crite- ria for cognitive impairment (i.e. cognitive test scores did not fall below the 5th percentile of normative values). He therefore does not meet the formal criteria for VCI (Tables 25.1 and 25.2). Nevertheless, the neuropsychological test pro le clearly matches with his complaints and the temporal relation with the infarct— and its location in the thalamus—make the infarct a very likely cause of the cognitive decrements.

e test results were explained to the patient. Because all nd- ings are indicative of a single aetiology (i.e. the infarct) no rapid cognitive decline is expected as long as no other strokes occur. e patient participated in a brief rehabilitation programme aimed to provide insight into his limitations and to acquire com- pensation strategies.

Studies in MCI patients have shown that vascular lesions are not predictive of progression to Alzheimer’s disease but do contribute to the development of other dementia syndromes.26–28 Apart from cognitive outcomes, vascular changes may a ect mobility (i.e. bal- ance and gait)29 and are linked to mortality in memory clinic pop- ulations, as has been shown for microbleeds.30,31 ese data have fuelled the discussion on optimal management of patients with Alzheimer’s disease and vascular lesions. In the EVA trial, a rand- omized controlled clinical trial in 123 subjects, intensive vascular care was compared with standard care in patients with Alzheimer disease with concomitant cerebrovascular lesions on MRI. Subjects receiving vascular care showed less WMH progression but the number of new lacunes or change in global cortical atrophy or medial temporal lobe atrophy did not di er between groups, nor was there any e ect on clinical function between the intervention and control group.32,33 Of note, treatment with aspirin in the vas- cular care group was associated with an increased risk of intracer- ebral haemorrhage. A subsequent pooled analysis of the EVA data with the Aspirin in Alzheimer’s disease (AD2000) trial indicated that the pooled hazard ratio for an intracerebral haemorrhage in patients with Alzheimer’s disease using aspirin is 7.6 (95% CI, 0.72 to 81; P = 0.09).34 In our view, in light of the current evidence, vas- cular risk-factor management in patients with Alzheimer’s disease and small vessel disease should therefore still be guided by general guidelines for cardiovascular risk management. In patients who have su ered a cardiovascular event, this event will dictate the type and intensity of treatment. In patients with cerebral small vessel disease who have not experienced a clinically manifest cardiovas- cular event, risk-factor management should follow guidelines for primary prevention of cardiovascular disease. In other words, dem- onstration of small vessel disease should not be regarded as a ‘cardi- ovascular event’ when deciding on the appropriate therapy. A nal word of caution concerns the use of anticoagulants in patients with small vessel disease, in particular white matter hyperintensities and microbleeds. Judging the balance of risk and bene t of anticoagu- lant treatment in such patients can be very di cult. If there is an indication for anticoagulants to prevent occlusive vascular events this needs to be weighed against the increased risk of haemorrhage. Unfortunately, the available evidence to guide decisions is limited, and currently mainly relies on expert opinion.

References

1. Roman GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diag- nostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology. 1993;43(2):250–60.

2. Chui HC, Victoro JI, Margolin D, et al. Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer’s Disease Diagnostic and Treatment Centers. Neurology. 1992;42(3 Pt 1):473–80.

3. Hachinski V. Vascular dementia: A radical rede nition. Dementia. 1994;5(3–4):130–2.

4. O’Brien JT, Erkinjuntti T, Reisberg B, et al. Vascular cognitive impair- ment. Lancet Neurol. 2003;2(2):89–98.

5. Gorelick PB, Scuteri A, Black SE, et al. Vascular Contributions to Cognitive Impairment and Dementia: A Statement for Healthcare Professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42(9):2672–713.

6. Sachdev P, Kalaria R, O’Brien J, et al. Diagnostic criteria for vascular cognitive disorders: A VASCOG statement. Alzheimer Dis Assoc Disord. 2014;28(3):206–18.

7. Poels MM, Vernooij MW, Ikram MA, et al. Prevalence and risk factors of cerebral microbleeds: An update of the Rotterdam scan study. Stroke. 2010;41(10 Suppl):S103-S106.

8. Vermeer SE, Longstreth WT, Jr, and Koudstaal PJ. Silent brain infarcts: A systematic review. Lancet Neurol. 2007;6(7):611–9.

9. Kalaria RN. Cerebrovascular Disease and Mechanisms of Cognitive Impairment: Evidence from Clinicopathological Studies in Humans. Stroke. 2012.

10. Kalaria RN, Kenny RA, Ballard CG, et al. Towards de ning the neuropathological substrates of vascular dementia. J Neurol Sci. 2004;226(1–2):75–80.

11. DeramecourtV,SladeJY,OakleyAE,etal.Stagingandnaturalhistoryof cerebrovascular pathology in dementia. Neurology. 2012;78(14):1043–50.

12. Jellinger KA. e enigma of vascular cognitive disorder and vascular dementia. Acta Neuropathol. 2007;113(4):349–88.

13. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9(7):689–701.

14. Adams HP, Jr, Bendixen BH, Kappelle LJ, et al. Classi cation of subtype of acute ischemic stroke. De nitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24(1):35–41.

15. Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12(8):822–38.

16. Schmidt R, Schmidt H, Haybaeck J, et al. Heterogeneity in age-related white matter changes. Acta Neuropathol. 2011;122(2):171–85.

17. Barkhof F and Scheltens P. Imaging of white matter lesions. Cerebrovasc Dis. 2002;13 Suppl 2:21–30.

18. Gouw AA, Seewann A, van der Flier WM, et al. Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correla- tions. J Neurol Neurosur Ps. 2011;82(2):126–35.

19. Greenberg SM, Vernooij MW, Cordonnier C, et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol. 2009;8(2):165–74.

20. Goos JD, van der Flier WM, Knol DL, et al. Clinical relevance of improved microbleed detection by susceptibility-weighted magnetic resonance imaging. Stroke. 2011;42(7):1894–900.

21. Hachinski V, Iadecola C, Petersen RC, et al. National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke. 2006;37(9):2220–41.

22. Pendlebury ST and Rothwell PM. Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis. Lancet Neurol. 2009;8(11):1006–18.

23. Nys GM, Van Zandvoort MJ, de Kort PL, et al. e prognostic value of domain-speci c cognitive abilities in acute rst-ever stroke. Neurology. 2005;64(5):821–7.

24. Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Lancet. 2001;357(9251):169–75.

25. Schneider JA, Arvanitakis Z, Bang W, et al. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007;69(24):2197–204.

26. Staekenborg SS, Koedam EL, Henneman WJ, et al. Progression of mild cognitive impairment to dementia: contribution of cerebrovas- cular disease compared with medial temporal lobe atrophy. Stroke. 2009;40(4):1269–74.

27. van de Pol LA, Korf ES, van der Flier WM, et al. Magnetic resonance imaging predictors of cognition in mild cognitive impairment. Arch Neurol. 2007;64(7):1023–8.

28. DeCarli C, Mungas D, Harvey D, et al. Memory impairment, but not cerebrovascular disease, predicts progression of MCI to dementia. Neurology. 2004;63(2):220–7.

29. Baezner H, Blahak C, Poggesi A, et al. Association of gait and balance disorders with age-related white matter changes: the LADIS study. Neurology. 2008;70(12):935–42.

CHAPTER 25 vascular cognitive impairment 283

284 SECTION 3 cognitive impairment and dementia

30. van der Vlies AE, Goos JD, Barkhof F, et al. Microbleeds do not a ect rate of cognitive decline in Alzheimer disease. Neurology. 2012;79(8):763–9.

31. Henneman WJ, Sluimer JD, Cordonnier C, et al. MRI biomarkers of vascular damage and atrophy predicting mortality in a memory clinic population. Stroke. 2009;40(2):492–8.

32. Richard E, Kuiper R, Dijkgraaf MG, et al. Vascular care in patients with Alzheimer’s disease with cerebrovascular lesions-a randomized clinical trial. J Am Geriatr Soc. 2009;57(5):797–805.

33. Richard E, Gouw AA, Scheltens P, et al. Vascular Care in Patients With Alzheimer Disease With Cerebrovascular Lesions Slows Progression of White Matter Lesions on MRI. e Evaluation of Vascular Care in Alzheimer’s Disease (EVA) Study. Stroke. 2010.

34. oonsen H, Richard E, Bentham P, et al. Aspirin in Alzheimer’s Disease. Increased Risk of Intracerebral Hemorrhage: Cause for Concern? Stroke. 2010.

CHAPTER 26

Cerebral amyloid angiopathy

and CNS vasculitis

Sergi Martinez-Ramirez, Steven M. Greenberg, and Anand Viswanathan

Cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA) refers to a heterogeneous group of entities characterized by the deposit of amyloid pro- teins in the vessel walls of small-sized arteries and capillaries of leptomeninges and cerebral cortex.1,2 CAA can be either occur in the more common sporadic form3 or in more rare hereditary forms.4 e accumulation of amyloid in brain vessels may com- promise their self-regulation, narrow their lumen, and eventually compromise their structural integrity.5,6 Sporadic CAA underlies most lobar intracerebral haemorrhages (ICH) in the elderly7 but its clinical spectrum also includes cerebral ischaemia and cogni- tive decline.8 Furthermore, all magnetic resonance imaging-based markers of small vessel disease are typically found in CAA, espe- cially lobar microbleeds (MB) and white matter hyperintensities (WMH).3 Estimates from autopsy studies suggest that CAA could be present in as many as 57 per cent of asymptomatic ageing sub- jects, and in up to 85 per cent when subjects with dementia are also included.9,10

Pathophysiology

pathology is identi ed in only ~50 per cent of patients who die of CAA-related haemorrhage.20 ese observations suggest that CAA and AD, whilst commonly seen together, can exist as distinct enti- ties, and that this may relate to di erences in Aβ1-40:Aβ1-42 ratio. As yet, the factors in uencing the dominant Aβ moieties produced and the associated clinical phenotype remain poorly understood.

Topographically, it has been shown that CAA largely a ects super cial vessels, especially those in the temporal and occipital lobes.21,22 is may be the consequence of age-related changes of vessel walls, resulting in reduced pulsatility of vessels running through the brain surface compared to those supplying deep regions due to their respective anatomical features.11 As already mentioned, one of the main clearance pathways for Aβ is its drain- age along the arterial perivascular spaces.23 Although the dynamics of interstitial uid and solutes within perivascular spaces are still speculative, pulsations of the arterial walls seem to be the driving force;24,25 thus, vessels with lower pulsatility would be more prone to stasis and accumulation of Aβ along perivascular spaces. In sup- port of this theory, it has been shown that arterial perivascular routes match with the topography of Aβ deposits in CAA.16

Genetics

Hereditary forms of CAA manifest earlier in life and are typically more severe than sporadic CAA. Most of these familiar forms occur due to mutations a ecting the APP gene,4,26–29 although in some cases it is not Aβ but other amyloid peptides that accumulate in the brain (i.e. amyloid forms of transthyretin30 or cystatin C31). Hereditary Aβ-amyloidoses are restricted to the brain and may present with the classic picture of recurrent lobar haemorrhages, with or without accompanying cognitive decline, but they may also present with progressive cognitive decline alone, as seen in indi- viduals harboring the Arctic (Icelandic) APP mutation.28 Non-Aβ amyloidoses tend to a ect both the cerebral and systemic circula- tion and thus are associated with a range of extracerebral clinical manifestations.32

In the sporadic form of CAA, only ApoE ε2 and ε4 alleles have been identi ed as genetic risk factors of the disease.33 ApoE co- localizes and interacts with Aβ in experimental studies,34 but its exact biological role in Aβ accumulation is not clear. Clinical studies have shown that both ApoE ε2 and ε4 are associated with CAA-related ICH, but interestingly, these 2 alleles may act through

In the sporadic form of CAA, it is thought that most of the accu- mulated Aβ is neuronal in origin,11 although a potential role of circulating plasma Aβ is still under debate.12,13 Neurons produce amyloid precursor protein (APP), which undergoes sequential proteolytic cleavage by secretase enzymes. As a consequence, two major amyloid species may be formed: Aβ1-40 and Aβ1-42. In normal conditions Aβ is e ectively removed, both through enzymatic deg- radation14,15 and drainage along arterial perivascular spaces.16,17 However, in pathologic conditions, an imbalance between produc- tion and clearance of Aβ may occur, resulting in aggregation both in vascular and parenchymal tissue. e more soluble Aβ1-40 mainly accumulates in the vessel walls (resulting in CAA) while the less soluble Aβ1-42 polymerizes, aggregates, and forms insoluble com- plexes in the parenchyma. ese latter complexes comprise senile plaques, a pathologic feature of Alzheimer’s disease (AD).18,19

e exact relationship between CAA and AD remains unclear. As CAA shares a common pathogenic mechanism with AD, some degree of CAA is observed in virtually all AD brains.20 However, only ~25 per cent of AD cases harbour advanced CAA, while the remaining show lesser degrees of vascular Aβ.21 Similarly, AD

286 SECTION 3 cognitive impairment and dementia

di erent pathways: ε4 by promoting widespread vascular amy- loid deposition, and ε2 by promoting vasculopathic changes on amyloid-laden vessels.35

Clinical-radiological manifestations

Weakening of vessel walls due to amyloid deposition may lead to their rupture and subsequent bleeding. Location of CAA-related haemorrhages is typically lobar, cortical, or juxta-cortical, and small foci of subarachnoid bleeding may also occur.5,36 ese topographies correlate with the anatomical distribution of amyloid deposits (cortex and leptomeninges).37,38 Depending on the mag- nitude of the bleeding, haemorrhages may be small and subclinical (MB) or large and symptomatic (ICH) (Fig. 26.1).

Lobar ICH in the context of CAA is associated with high mor- bidity and mortality, particularly when recurrent,39,40 and spo- radic CAA is the most common cause of lobar ICH in the elderly.3 e presence of lobar MB is also a common feature among CAA patients, and they may be detected in the presence or absence of lobar ICH. In fact, lobar MB are believed to be at least twice more frequent than large, symptomatic ICH, in CAA patients.41 e clin- ical impact of MB has not been completely ascertained: in patients with lobar ICH, the number of both MB at baseline and incident MB at follow-up predicts a higher risk of ICH recurrence.42 MB have been correlated with a higher mortality in CAA42 and AD cohorts,43,44 though this association seems not to be explained by speed of cognitive decline.45 In population-based autopsy studies, CAA severity has been associated with increased risk of cogni- tive impairment during life and worse cognitive performance in patients with AD, controlling for the severity of AD pathology.46,47 Indeed, a recent study on community-dwelling persons found the presence of CAA to be associated with impairment of selec- tive cognitive domains (i.e. perceptual speed), separately from AD pathology.10 us, even though MB may have a modest or marginal e ect on cognition, this evidence suggests that CAA independently causes cognitive decline.

Loss of normal architecture of vessel walls may lead to impaired vascular reactivity in CAA patients.48,49 is phenomenon, com- bined with progressive narrowing of the lumen, is nally respon- sible for severe hypoperfusion and brain ischaemia. White matter

(a)

hyperintensities (WMH) are the most easily identi able expression of chronic hypoperfusion of white matter on magnetic resonance imaging (MRI) studies, and are common among individuals with CAA.3 Although previous studies had shown contradictory results, a recent work using automated detection of WMH centre of mass showed that WMH in CAA patients have a more posterior pre- dominance (occipital > frontal) than in non-CAA cases, even in the absence of lobar haemorrhages, which is potentially helpful to di erentiate white matter damage by CAA versus other forms of small-vessel disease. e clinical importance of WMH relies on their association with cognitive impairment, independently of the e ects of ICH.51 A further form of ischaemic injury attribut- able to CAA is cortical microinfarcts,52,53 a re ection of capillary occlusion at a cortical level. To date, the clinical impact of cortical microinfarcts in CAA subjects is not well studied. In recent years, dilated perivascular spaces (DPVS) in the white matter have been postulated as potential markers of CAA, as opposed to DPVS in the basal ganglia, which are more associated to hypertension and other vascular risk factors.54,55 It has been hypothesized that corti- cal vascular amyloid spreading into the surrounding perivascular spaces may lead to the blockage of the interstitial uid circulating within, thus causing a retrograde dilation of perivascular spaces in the white matter.56

Finally, another part of the clinical spectrum of CAA refers to transient focal neurological de cits (TFND),57,58 also called ‘amy- loid spells.’ TFND may present as ‘aura-like symptoms’ (positive) or ‘TIA-like symptoms’ (negative). Subarachnoid blood in the convex- ity (cSAH) appears to be the most characteristic feature when com- paring patients with TFND to those without.59 Also, TFND may predict a high early risk of ICH in CAA patients.59 Radiologically, cSAH may evolve into focal, lineal deposits of blood degradation products outlining the brain sulci. is feature, so-called super – cial siderosis (SS), is also considered as another relatively speci c marker of CAA.60,61

Diagnosis Pathological diagnosis

e de nitive diagnosis of CAA still requires the direct examination of the brain. On pathologic specimens, multiple e ects of vascular

(b)

Fig. 26.1 Lobar hemorrhages in two pathologically-con rmed CAA cases: (a) with multiple microbleeds; (b) with a large intracerebral haemorrhage.

amyloid deposition may be observed, though the most characteris- tic feature is the loss of smooth muscle cells with replacement of the media layer by amyloid. Wall thickening, lumen narrowing, split- ting of the vessel wall, microaneurysms, and perivascular haemor- rhages are also frequently reported in CAA.5,62 Amyloid proteins have been traditionally identi ed with Red Congo staining using polarized light.63 Due to the low sensitivity of this method, comple- mentary techniques are used to rule out small amounts of Aβ depo- sition; that is, immunohistochemistry with uorescent antibodies against speci c precursor proteins (Fig. 26.2).64

CAA is characteristically a patchy disease.65,66 In practice, this means that pathologic evaluation should include as much brain tis- sue as possible. Autopsy studies, therefore, represent the best source of documentation of CAA. However, de nitive histological diagno- sis during life is sometimes required, especially when symptoms are rapidly evolving or atypical, and not infrequently when the clinical picture resembles the in ammatory form of CAA (see section on CNS vasculitis, following). In-vivo pathologic diagnosis of CAA requires surgical brain biopsy. Although its sensitivity is not 100 per cent, this is a highly reliable method for CAA detection when cortex is sampled appropriately and contains leptomeninges.66 In terms of grading the severity of CAA, several scales have been pro- posed, such as the Vonsattel scale.66

e Boston criteria

e development of MRI sequences particularly susceptible to blood-degradation products including gradient-recalled echo (GRE) or susceptibility-weighted image (SWI) demonstrates that old haemorrhages, mainly MB, were already present in many patients su ering a rst symptomatic lobar ICH.67 e absence or presence of prior exclusively lobar haemorrhages forms the basis of the Boston criteria for CAA, which have been validated pathologi- cally. e term ‘possible CAA’ referred to cases with a single symp- tomatic lobar ICH without the presence of old lobar haemorrhages on neuroimaging, while ‘probable CAA’ refers to the presence of old lobar haemorrhages in cases with symptomatic lobar ICH. e Boston criteria allow physicians to approach the diagnosis of CAA during life without the need to obtain brain tissue. Two histology- based diagnostic categories complete the Boston criteria: ‘Probable CAA with supporting pathology’ and ‘De nite CAA’ (Table 26.1). Validation studies have shown that the categories of ‘possible CAA’ and ‘probable CAA’ diagnoses predict pathologic evidence of CAA

(a)

in around 60 per cent and 100 per cent of cases, respectively.7 e inclusion of additional CAA radiologic markers in the Boston Criteria, such as SS or DPVS in the white matter, has been shown to increase their sensitivity.68,69

e diagnostic value of lobar MB in the absence of lobar ICH has not yet been determined. Although the Boston criteria do not speci cally refer to the size of lobar haemorrhages, these criteria are based on survivors of lobar ICH and may not apply to patients with asymptomatic haemorrhages. is point is of major impor- tance, as many patients with CAA will not experience major haem- orrhagic complications during life. From population-based studies, it is known that ~8–19 per cent of healthy subjects may harbor incidental, strictly lobar MB.70,71 Although the presence of multi- ple, strictly lobar MB is highly suggestive of CAA, the signi cance of only one or a few MB may be more diagnostically challenging. Furthermore, there is some evidence to suggest the vessel pathol- ogy in underlying symptomatic ICH may be di erent from the ves- sel pathology underlying MB in patients with probable or possible CAA.72 erefore, radiological–pathological correlation studies on patients without lobar ICH are needed in order to ascertain the spe- ci c predictive value of lobar MB for CAA.

Other diagnostic approaches

In recent years, in-vivo positron emission tomography (PET) imag- ing using amyloid speci c tracers, such as Pittsburgh Compound-B (PiB), has been an intensive eld of research, mainly focused on patients with AD.73 Vascular amyloid alone can be detected with PiB as one study has imaged vascular amyloid in a single patient with hereditary CAA.74 Further studies using both MRI and PiB– PET have revealed that the location of lobar MB correlates with the highest concentrations of PiB retention in CAA,37 and that PiB cortical retention positively correlates with WMH burden in subjects with CAA.75 Although these novel imaging techniques are promising their clinical applications are still not de ned and, con- sequently, their use remains con ned to research purposes.

e analysis of the cerebrospinal uid (CSF) has become another focus of interest in CAA as it has been shown to be sensitive and speci c in distinguishing between AD and healthy controls.76 CSF in AD patients is characterized by low levels of Aβ1-42 and high levels of tau, whereas Aβ1-40 is not particularly altered.77 In con- trast, CAA is associated with low levels of Aβ1-42 but also Aβ1-40, which is likely to re ect the depletion of this protein in the CSF

(b)

CHAPTER 26 caa and cns vasculitis 287

Fig. 26.2 Histological images of a vessel a ected by CAA. (a) ickened vessel walls staining by eosin (H&E, 40×). (b) Positivity for anti-Aβ antibodies (anti-Aβ immunohistochemistry, 40×).

288 SECTION 3 cognitive impairment and dementia
Table 26.1 Boston Criteria for diagnosis of CAA-related haemorrhage*

testing the safety and e cacy of ponezumab, a monoclonal anti- body targeting Aβ, on individuals with ‘probable CAA’ without cognitive impairment. is monoclonal antibody is expected to clear vascular amyloid from the blood vessels of patients with CAA. e primary outcome is the change in cerebrovascular reactivity as measured on functional functional MRI (fMRI), based on pre- vious work by Dumas and colleagues;48 the trial will test whether ponezumab can improve vascular reactivity in CAA with no sig- ni cant adverse e ects. Enrollment is expected to be completed by late 2015.

Vasculitis of the central nervous system

e term CNS vasculitis refers generically to the in ammation of cerebral blood vessels. A wide and heterogeneous group of diseases may cause CNS vascular in ammation, either primarily or second- arily. Primary CNS vasculitidies are rare but they deserve major attention for two main reasons. First, they are pure CNS vasculi- tis, implying particular pathophysiologic mechanisms and clinical features. Second, diagnosis is more challenging than in secondary CNS vasculitidies, as in ammation can only be demonstrated in the cerebral tissue. Primary CNS vasculitidies are largely represented by two entities: CAA-related in ammation (CAA-RI) and primary angiitis of the CNS (PACS). CAA-RI is particularly interesting as it establishes a unique link between a deposition disease (CAA) and a primary in ammatory process of the CNS. A summary of causes of CNS vasculitis can be found in Table 26.2.

Cerebral amyloid angiopathy-related in ammation

CAA-related in ammation (CAA-RI) is a vasculitic form of CAA that may occur spontaneously in a subset of patients. A report of meningoencephalitis cases from clinical trials testing active immu- nization against Aβ in AD patients83 provided indirect evidence that vascular amyloid is likely to be responsible for triggering the in ammatory response observed in CAA-RI, but little is known about the factors contributing to it. Well-characterized series of patients with CAA-RI are very limited in the literature. However, available literature clearly shows that CAA-RI is clinically, patho- logically, genetically, and radiographically di erentiated from CAA; importantly, these particular characteristics translate into distinct and e ective therapeutic approaches, which do not apply to the non-in ammatory form of CAA.84

e clinical presentation of CAA-RI also di ers from other forms of CAA. e most commonly reported symptoms of CAA- RI are subacute cognitive decline/behavioural changes, seizures, and headache.84–86 Focal neurological signs are also part of the clinical spectrum, but are seen less frequently. e presence of at least two of these four symptoms is present in almost 80 per cent of the patients described thus far. ‘TIA-like symptoms’, which may represent an acute form of presentation of the disease, have been observed only in a few cases.87 In contrast to the non-in ammatory form of CAA, lobar ICH is a very rare presentation.

Brain imaging with MRI shows abnormalities in virtually all patients with CAA-RI. e nding of extensive and asymmetrical WMH on T2 and FLAIR sequences, which can be either patchy or con uent, is very common (Fig. 26.3). ese WMH have char- acteristics of vasogenic oedema rather than ischaemia, includ- ing swelling and sometimes contrast enhancement. e oedema may be pronounced enough to generate mass e ect, sometimes

1. De nite CAA
Full postmortem examination demonstrating:

◆ Lobar,cortical,orcorticosubcorticalhaemorrhage

◆ Severe CAA with vasculopathy†

◆ Absence of other diagnostic lesion

2. Probable CAA with supporting pathology

Clinical data and pathologic tissue (evacuated haematoma or cortical biopsy) demonstrating:

◆ Lobar,cortical,orcorticosubcorticalhaemorrhage

◆ Some degree of CAA in specimen

◆ Absence of other diagnostic lesion

3. Probable CAA

Clinical data and MRI or CT demonstrating:

◆ Multiple haemorrhages restricted to lobar, cortical, or corticosubcortical regions (cerebellar haemorrhage allowed)

◆ Age > 55 years

◆ Absenceofothercauseofhaemorrhage‡

4. Possible CAA
Clinical data and MRI or CT demonstrating:

◆ Singlelobar,cortical,orcorticosubcorticalhaemorrhage

◆ Age > 55 years

◆ Absenceofothercauseofhaemorrhage‡

*Criteria established by the Boston Cerebral Amyloid Angiopathy Group: Steven M Greenberg, MD, PhD, Daniel S Kanter, MD, Carlos S Kase, MD, and Michael S Pessin, MD.

†As de ned in: Von sattel JP, Myers RH, Hedley–Whyte ET, Ropper AH, Bird ED, Richardson EP Jr. Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study. Ann Neurol. 1991;30:637–49.

‡Other causes of intracerebral haemorrhage: excessive warfarin (INR.3.0); antecedent head trauma or ischaemic stroke; CNS tumour, vascular malformation, or vasculitis; and blood dyscrasia or coagulopathy. (INR.3.0 or other nonspeci c laboratory abnormalities permitted for diagnosis of possible CAA.)

Reproduced from Neurology. 56(4), Knudsen KA, Rosand J, Karluk D, et al. Clinical diagnosis of cerebral amyloid angiopathy: Validation of the Boston Criteria, pp. 537–9, Copyright (2001), with permission from Wolters Kluwer Health, Inc.

pool due to its extensive vascular accumulation.78 us, Aβ1-40 lev- els in CSF may be a good biological marker to di erentiate between AD and CAA.

Management

No e ective treatment currently exists for the acute phase of any kind of spontaneous ICH, including CAA-related lobar ICH. A er lobar ICH, modelling studies have suggested that anticoagulants may place patients at an increased risk of recurrence. It is thus gener- ally recommended to avoid these medications a er lobar ICH.79 In patients with MB but not ICH, the risk:bene t ratio of antithrom- botic drugs is controversial. Although there is no formal contrain- dication, some studies have identi ed MB as an independent risk factor for warfarin-related ICH.80 Even antiplatelet agents, tradition- ally safer than anticoagulants, have been associated with an increased risk of ICH, especially in subjects with a high number of MB.81,82 Considering these ndings, it seems reasonable to individualize deci- sions on antithrombotic therapy in patients with lobar MB only.

Regarding disease-modifying therapies for CAA, a phase-II mul- ticentre, randomized, placebo-controlled clinical trial is currently

Table 26.2 Vasculitides that a ect the central nervous system

CHAPTER 26 caa and cns vasculitis 289

CAA-related in ammation Primary angiitis of the CNS Systemic necrotizing arteritis

Polyarteritis nodosa

Churg–Strauss syndrome Hypersensitivity vasculitis

Henoch–Schönlein purpura Hypocomplementemic vasculitis Cryoglobulinemia

Systemic granulomatous vasculitis Wegener granulomatosis Lymphomatoid granulomatosis Lethal midline granuloma

Giant cell arteritis Temporal arteritis Takayasu arteritis

Connective tissue disorders associated with vasculitis Systemic lupus erythematosus
Scleroderma
Rheumatoid arthritis

Sjögren syndrome
Mixed connective tissue disease Behçet disease

Vasculitis associated with infection Varicella zoster virus Spirochetes

Treponema pallidum

Borrelia burgdorferi Fungi

Rickettsia
Bacterial meningitis Mycobacterium tuberculosis HIV-1

Paraneoplastic vasculitis

su cient to resemble a brain tumour. When hemosiderin-sensitive MRI sequences (e.g. GRE or SWI) are performed on patients with CAA-RI, lobar MB are a highly frequent nding, and even suba- rachnoid haemorrhage can be detected. Cerebral angiography is not routinely indicated when CAA-RI is strongly suspected, but when angiography is performed, typical ndings of vasculitis (such as ‘beading’) may be found.88

Although blood tests typically lack diagnostic value in CAA-RI, the study of CSF may provide further proof of the autoimmune nature of the disease. In a recent small study,89 patients with CAA-RI (n = 10) showed signi cantly higher levels of autologous anti-Aβ antibodies in the CSF compared to patients with the non-in ammatory form of CAA (controls, n = 7). Furthermore, CSF levels of Aβ1-40 and Aβ1-42, as well as markers of axonal injury (tau and P-181 tau), were found increased in CAA-RI. Interestingly, the levels of all these proteins decreased to control levels once the disease had resolved clinically and radiologically, and regardless of the use of immunosupressant agents. In the correct clinical context, genotyping of APOE may also provide

Fig. 26.3 Vasogenic oedema a ecting white matter and cortex (FLAIR sequence) in a con rmed case of CAA-related in ammation. e MRI FLAIR sequence shown above is from a 72-year-old woman with subacute behavioural and cognitive changes.

supportive evidence towards a diagnosis of CAA-RI. In a series of 14 con rmed CAA-RI cases, 10 out of 13 (76.9 per cent) were ApoE ε4 homozygotes.84 In the same study it was reported that the frequency of ε4/ε4 in 39 con rmed cases of non-in ammatory CAA with available APoE genotype was only 5.1 per cent. e marked over-representation of the homozygous form in CAA-RI patients suggest that ε4 may play a role in the immunological response against vascular Aβ.

Pathological evidence of Aβ-related vascular in ammation is needed to con rm the diagnosis of CAA-RI. Although one case has been reported with proven increase of anti-Aβ antibodies in CSF,90 brain biopsy is the only means of de nitively diagnosing the disease during life.

Histological studies of CAA-RI cases have revealed that in am- matory in ltrates may be either perivascular (strictly a non- vasculitic form of CAA-RI) or transmural (a ‘true’ vasculitic form, o en accompanied by the formation of granulomas)88 (Fig. 26.4). Considering that surgical biopsy of the brain is an invasive, poten- tially dangerous exam, several authors have suggested a conserva- tive approach in cases with clinical and neuroimaging ndings highly suggestive of CAA-RI.84,85 A set of diagnostic criteria for CAA-RI have been proposed, which include a ‘probable CAA-RI’ category for those cases without pathological study.85 ese crite- ria, however, still require validation.

Treatment of CAA-RI is not standardized, but typically high- dose corticosteroids are given as initial therapy.84,85,91–95 Most treated patients will show some degree of improvement, both clini- cally and radiologically, within a few weeks of treatment onset.84 Immunosuppressive agents, such as cyclophosphamide, may also be used as the initial treatment, or may be used if there is no rapid clin- ical improvement with corticosteroids. e duration of treatment is not well established and thus must be individualized. ree di er- ent patterns of response to treatment may be observed: improve- ment (persistent over time a er treatment withdrawal); relapsing

290 SECTION 3 cognitive impairment and dementia

Fig. 26.4 CAA-related in ammation. Intracortical vessels have complete replacement of the vessel wall with Aβ, and the left-hand vessel demonstrates a lymphocytic reaction to the deposited Aβ (anti-Aβ immunohistochemistry, 40×).

(initial improvement and relapse a er treatment withdrawal), and stable/progressive (no response at all).84

Primary angiitis of the central nervous system (PACS)

PACS is a rare in ammatory condition of the cerebral blood vessels of unknown origin. PACS is traditionally considered a small-vessel vasculitis but reports of focal neurological signs are not uncom- mon, suggesting that major vessels may be involved as well.96 Two major histological forms have been described: granulomatous and non-granulomatous, the latter being more frequent.97 Untreated, PACS generally leads to progressive neurological dysfunction, with high morbidity and mortality. e in ammatory nature of the dis- ease carries a favourable response to corticosteroids and/or cyto- toxic drugs. However, diagnosis is o en delayed, which may result in a poorer outcome.96–98

PACS mostly a ects middle-aged men.96,97,99 Headache and acute/subacute cognitive impairment or encephalopathy are the most common symptoms, and they present in an insidious, pro- gressive way.96 e insidious progression of the disorder com- bined with the o en nebulous or nonspeci c symptoms mean that the diagnosis is o en very di cult to make in the earliest stages, the mean delay between symptoms onset and diagnosis of PACS being as long as six months.98 Severe complications of PACS, such as TIA/stroke, seizures, and permanent neurologic de cits occur later in the course of the disease;96,100 while they are not helpful to establish an early diagnosis, they can be prevented if treatment is initiated promptly. In contrast to many secondary vasculitidies with central nervous system involvement, fever, night sweats, and other systemic symptoms are not very prevalent in PACS (<20 per cent).96,101

In PACS, peripheral blood tests may occasionally show an increase in the erythrocyte sedimentation rate96 but are o en normal. CSF is abnormal in more than 80 per cent of cases,96,102 typically show- ing protein elevation and/or a raised white cells count. MRI studies show abnormalities in almost 100 per cent of cases.96,103 e most distinctive nding is the presence of bi-hemispheric infarcts a ect- ing the subcortical white matter and even the overlying cortex.96,104 Gadolinium enhancement is only observed in one-third of the patients, with leptomeningeal enhancement even more infrequent

Fig. 26.5 Primary CNS vasculitis. A medium-sized leptomeningeal arteriole demonstrates in ammatory in ltrate throughout the vessel wall, with giant cells as well as a mixed lymphocytic population (H&E, 40×).

(10–15 per cent). However, when leptomeningeal enhancement is present in the non-dominant hemisphere, it may serve as an ideal site for biopsy.96 Cerebral angiography, may demonstrate morpho- logic signs frequently associated with vasculitis. ‘Beading’ (or mul- tiple regions of narrowing in a given vessel, with interposed regions of ectasia or normal luminal architecture) is the most recognized angiographic abnormality.105 Angiography, however, has some limitations that considerably limit its sensitivity and speci city for PACS: inability to detect abnormalities in vessels whose caliber is below the resolution of angiography, even when they are respon- sible for infarcts seen on MRI, and, more importantly, inability to provide a pathologic substrate for those morphologic alterations detected. erefore cerebral biopsy, which remains the only way to con rm the diagnosis in vivo, is recommended in all patients with suspected PACS.98 Biopsy may not only demonstrate vascular in ammation (Fig. 26.5) but also rule out other entities that mimic PACS. It should be noted that brain biopsy may result in false nega- tives, given that PACS may have a patchy distribution.96

No speci c guidelines exist for a standardized treatment of PACS. However, expert consensus suggests treating patients with corti- costeroids and a cytotoxic agent,98 typically cyclophosphamide, However, given the high incidence of long-term adverse e ects of cyclophosphamide,106 switching to azathioprine is encouraged once remission is achieved. e cytotoxic agent should be con- tinued for 2–3 years, while corticosteroid may be tapered o a er 12 months of treatment. Given the powerful and broad immuno- suppressant action of all these drugs, it is crucial to rule out other diagnosis (such as reversible vasoconstriction syndrome and CNS infections) prior to initiating treatment.

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73. Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol. 2004;55:306–19.

74. Greenberg SM, Grabowski T, Gurol ME, et al. Detection of isolated cer- ebrovascular beta-amyloid with Pittsburgh compound B. Ann Neurol. 2008;64:587–91.

75. Gurol ME, Viswanathan A, Gidicsin C, et al. Cerebral amyloid angiopa- thy burden associated with leukoaraiosis: a positron emission tomogra- phy/magnetic resonance imaging study. Ann Neurol. 2013;73:529–36.

76. De Meyer G, Shapiro F, Vanderstichele H, et al. Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people. Arch Neurol. 2010;67:949–56.

77. Sunderland T, Linker G, Mirza N, et al. Decreased beta-amyloid1- 42 and increased tau levels in cerebrospinal uid of patients with Alzheimer disease. JAMA. 2003;289:2094–103.

78. Verbeek MM, Kremer BP, Rikkert MO, et al. Cerebrospinal uid amy- loid beta(40) is decreased in cerebral amyloid angiopathy. Ann Neurol. 2009;66:245–49.

79. Eckman MH, Rosand J, Knudsen KA, et al. Can patients be antico- agulated a er intracerebral hemorrhage? A decision analysis. Stroke. 2003;34:1710–16.

80. Lee SH, Ryu WS, and Roh JK. Cerebral microbleeds are a risk factor for warfarin-related intracerebral hemorrhage. Neurology. 2009;72:171–76.

81. Soo YO, Yang SR, Lam WW, et al. Risk vs bene t of anti-thrombotic therapy in ischaemic stroke patients with cerebral microbleeds. J Neurol. 2008;255:1679–86.

82. Bi A, Halpin A, Tow ghi A, et al. Aspirin and recurrent intrac- erebral hemorrhage in cerebral amyloid angiopathy. Neurology. 2010;75:693–98.

83. Orgogozo JM, Gilman S, Dartigues JF, et al. Subacute meningoen- cephalitis in a subset of patients with AD a er Abeta42 immunization. Neurology. 2003;61:46–54.

84. Kinnecom C, Lev MH, Wendell L, et al. Course of cerebral amyloid angiopathy-related in ammation. Neurology. 2007;68:1411–16.

85. Chung KK, Anderson NE, Hutchinson D, et al. Cerebral amyloid angi- opathy related in ammation: three case reports and a review. J Neurol Neurosur Ps. 2011;82:20–26.

86. Eng JA, Frosch MP, Choi K, et al. Clinical manifestations of cerebral amyloid angiopathy-related in ammation. Ann Neurol. 2004;55:250–56.

87. Amick A, Joseph J, Silvestri N, and Selim M. Amyloid-beta-related angiitis: a rare cause of recurrent transient neurological symptoms. Nat Clin Pract Neurol. 2008;4:279–83.

88. Scolding NJ, Joseph F, Kirby PA, et al. Abeta-related angiitis: primary angiitis of the central nervous system associated with cerebral amyloid angiopathy. Brain. 2005;128:500–15.

89. Piazza F, Greenberg SM, Savoiardo M, et al. Anti-amyloid beta autoantibodies in cerebral amyloid angiopathy-related in amma- tion: implications for amyloid-modifying therapies. Ann Neurol. 2013;73:449–58.

90. DiFrancesco JC, Brioschi M, Brighina L, et al. Anti-Abeta autoanti- bodies in the CSF of a patient with CAA-related in ammation: a case report. Neurology. 2011;76:842–44.

91. Fountain NB and Eberhard DA. Primary angiitis of the central nervous system associated with cerebral amyloid angiopathy: report of two cases and review of the literature. Neurology. 1996;46:190–97.

92. Ginsberg L, Geddes J, and Valentine A. Amyloid angiopathy and granu- lomatous angiitis of the central nervous system: a case responding to corticosteroid treatment. J Neurol. 1988;235:438–40.

93. Harkness KA, Coles A, Pohl U, et al. Rapidly reversible demen- tia in cerebral amyloid in ammatory vasculopathy. Eur J Neurol. 2004;11:59–62.

94. Marotti JD, Savitz SI, Kim WK, et al. Cerebral amyloid angiitis process- ing to generalized angiitis and leucoencephalitis. Neuropathol Appl Neurobiol. 2007;33:475–79.

95. Murphy MN and Sima AA. Cerebral amyloid angiopathy associated with giant cell arteritis: a case report. Stroke. 1985;16:514–17.

96. Salvarani C, Brown RD, Jr, Calamia KT, et al. Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol. 2007;62:442–51.

97. Lie JT. Primary (granulomatous) angiitis of the central nervous sys- tem: a clinicopathologic analysis of 15 new cases and a review of the literature. Hum Pathol. 1992;23:164–71.

98. Birnbaum J and Hellmann DB. Primary angiitis of the central nervous system. Arch Neurol. 2009;66:704–709.

99. Calabrese LH and Mallek JA. Primary angiitis of the central nervous system. Report of 8 new cases, review of the literature, and proposal for diagnostic criteria. Medicine (Baltimore). 1988;67:20–39.

100. Crane R, Kerr LD, and Spiera H. Clinical analysis of isolated angiitis of the central nervous system. A report of 11 cases. Arch Intern Med. 1991;151:2290–94.

101. Vollmer TL, Guarnaccia J, Harrington W, et al. Idiopathic granuloma- tous angiitis of the central nervous system. Diagnostic challenges. Arch Neurol. 1993;50:925–30.

102. Stone JH, Pomper MG, Roubeno R, et al. Sensitivities of noninvasive tests for central nervous system vasculitis: A comparison of lumbar puncture, computed tomography, and magnetic resonance imaging.
J Rheumatol. 1994;21:1277–82.

103. Woolfenden AR, Tong DC, Marks MP, et al. Angiographically de ned primary angiitis of the CNS: Is it really benign? Neurology. 1998;51:183–88.

104. Pomper MG, Miller TJ, Stone JH, et al. CNS vasculitis in autoimmune disease: MR imaging ndings and correlation with angiography. AJNR Am J Neuroradiol. 1999;20:75–85.

105. Alhalabi M and Moore PM. Serial angiography in isolated angiitis of the central nervous system. Neurology. 1994;44:1221–26.

106. Ho man GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116:488–98.

CHAPTER 26 caa and cns vasculitis 293

Introduction

and that they may be triggered by adjacent meningeal in amma- tion. Tissue damage in a particular cortical area also gives rise to anterograde or retrograde neurodegeneration in connected cortical regions.

CHAPTER 27

Cognition in multiple sclerosis

Maria A. Ron

Multiple sclerosis (MS) is the commonest disabling neurological disease a ecting young adults in the UK. MS is two to three times commoner in women. MS is also commoner in white populations and in northern latitudes.1

e cause of MS remains uncertain. e increased incidence in rst-degree relatives and concordance rates in monozygotic twins (30 per cent) point to the relevance of genetic factors. Genome- wide association studies have identi ed more than 50 susceptibil- ity loci, many of them closely mapped to immunological relevant genes.2 Epstein–Barr virus infection, vitamin D de ciency, latitude, and smoking are possible environmental risk factors interacting with a genetic predisposition.

In 85 per cent of patients, MS has a relapse onset with an acute episode of neurological symptoms known as a clinically isolated syndrome or CIS. e course of MS a er a CIS is variable. A er the CIS, half of the patients continue to experience relapses and remis- sions (relapsing and remitting MS or RRMS). One-third of the patients follow a benign course with minimal disability. Permanent disability occurs when relapses fail to recover or when the course of the disease becomes progressive (secondary progressive MS or SPMS). Conversion to SPMS tends to occur 15–20 years a er the initial CIS. Around 15 per cent of patients have a progressive course from the beginning (primary progressive MS or PPMS), although superimposed relapses may occur in up to 25 per cent.1

e diagnosis of MS can be made solely on clinical grounds, but magnetic resonance imaging (MRI) can help to demonstrate dis- semination of typical lesions in time and space and allows for the diagnosis to be made in some patients presenting with a CIS.3

e neuropathology of MS is complex. Active focal in ammatory demyelinating white matter lesions are typical of acute relapses. ese lesions occur preferentially in the optic nerve, periventricular white matter, corpus callosum, brainstem, cerebellar white matter, and cervical cord. In progressive forms of MS the acute in amma- tory reaction is less marked and damage to the normal-appearing white matter with di use axonal injury, microglial activation, and cortical demyelination is more prominent.4 e demyelination and transection of nerve bres interferes with the smooth and rapid conduction of electrical impulses. Opinions vary as to whether the acute in ammatory lesions and the widespread neurodegenera- tive changes observed in progressive disease occur independently or whether the focal in ammatory lesion is the primary event. Demyelinating cortical lesions and cortical atrophy are now recog- nized as important elements of MS pathology and are known to be present in the early stages of the disease. Recent research5 suggests that cortical lesions also have a marked in ammatory component

Cognitive impairment in MS: Prevalence,

pattern, and clinical correlates

Impairment can be detected in a wide range of cognitive func- tions, but speed of information processing, complex attention, long- term memory, and executive functions (i.e. reasoning, planning, uency, and organizational skills) are worst a ected, while simple attention and essential verbal skills (word naming and comprehen- sion) tend to be better preserved.7 A decline in IQ from estimated premorbid levels has also been well documented.8 Decrements in cognitive function tend to be moderate and frank dementia is rare. Decreased information-processing speed and visual memory impairment are the commonest de cits and o en the rst to be detected.9 Slow information processing is o en associated with impaired working and long-term memory, and tests tapping pro- cessing speed (e.g. paced auditory serial addition test or PASAT) are o en used to screen for the presence of cognitive impairment and can predict later cognitive decline. De cits in long-term mem- ory can be detected in 40–60 per cent of MS patients, and impaired initial learning, rather than defective recall or recognition, is considered to responsible for the memory decline. e cognitive de cits detected in MS are closely interrelated and impaired initial learning may be explained, at least in part, by the slow information processing and defective working memory; while impaired learn- ing may in turn result in poor decision-making. Cognitive reserve, as estimated by premorbid IQ and years of education,10 appears to modulate the severity of cognitive impairment and may provide a partial explanation for the variability in the severity and pattern of cognitive impairment in a given patient.

Cognitive impairment in patients presenting with a CIS predicts conversion to MS and hence accumulation of physical disability.11 In cross-sectional studies the correlation between the severity of cognitive impairment and physical disability is only modest, as the

Cognitive impairment occurs in 40–70 per cent of MS patients and adds considerably to their disability, limiting independence, ability to work, adherence to treatment, driving safety, and success- ful rehabilitation. Cognitive impairment can be detected in about one-quarter of patients when they present with a CIS, but its preva- lence increases with age and disease duration and it is more severe in those with a progressive disease course. Long-term follow-up studies have documented the accumulation of cognitive de cits over time.7

296 SECTION 3 cognitive impairment and dementia

latter is o en determined by spinal cord pathology, and in some patients cognitive and behavioural abnormalities are the most prominent symptoms in the absence of signi cant physical dis- ability.12 e pattern and the severity of cognitive impairment are similar in those with PPMS and SPMS.

Fatigue, depression, and cognitive

performance

Cognitive performance may be in uenced by fatigue and depres- sion, both common features of MS. Fatigue is reported by about 90 per cent of patients and its relationship with cognitive per- formance is complex. Some studies, but not all, have reported that patients reporting fatigue performed worse in tests of attention13 and information-processing speed.14 More consistent decrements in cognitive performance have been reported in MS patients com- pared to healthy controls when cognitive fatigue is induced using tests that require sustained attention.15

Depression has a life-time prevalence of around 50 per cent in MS patients. e neuropathological substrate of depression in this context is unclear, but associations have been described with lesions located in medial inferior frontal regions and with le anterior tem- poral atrophy.16 Cortico-subcortical disconnection caused by fron- toparietal white matter lesions has been put forward as a possible mechanism.17 Depression has been linked to poor performance on a variety of cognitive tasks, but the link is particularly strong for tasks that demand large cognitive processing capacity and in par- ticular those that also involve working memory.18

DIR

Cognitive impairment and cerebral

pathology as detected by MRI

Conventional MRI is best at detecting white matter lesions and providing measures of brain atrophy, but it is less sensitive for the detection of grey matter pathology or abnormalities in the normal- appearing white matter (NAWM). ese limitations explain the modest correlations between clinical status, including cognition, and conventional MRI. New sequences such as double inversion recovery (DIR) and in particular phase-sensitive inversion recov- ery (PSIR) have improved the detection of grey matter lesions (Fig. 27.1),19 while di usion and magnetization transfer (MTI) and proton MR spectroscopy (1H-MRS) are able to detect abnormali- ties in the normal appearing brain tissue.

Cognitive impairment in MS is thought to result from damage to cognitively relevant white matter tracts (e.g. cingulum, uncin- ate fasciculus, superior and middle cerebellar peduncles) leading to a multisystem cortico-subcortical disconnection syndrome.20 Disruption of functional connectivity between di erent brain regions leads to cortical thinning,21 although primary cortical pathology also plays a part.

Integrity of white matter tracts as indexed by the presence of lesions and by abnormalities in the NAWM correlate with global measures of cognitive performance.22 Studies using di usion- based tractography, a technique that allows the study of speci c white matter tracts, have provided evidence of how pathology in di erent white matter tracts results in speci c cognitive de – cits. us damage to the corpus callosum and tracts connecting

PSIR

DIR

Fig. 27.1 Double inversion recovery (DIR) and phase-sensitive inversion recovery (PSIR) sequences demonstrating cortical lesions.

CHAPTER 27 cognition in multiple sclerosis 297

Fig. 27.2 Di usion images showing white matter lesion in the corpus callosum that resulted in marked reduction of information processing speed.

prefrontal (Fig. 27.2) regions result in impaired processing speed, attention, and working memory, while damage to the uncinate fasciculus is related to memory impairment.22 Measures of whole brain atrophy, indicative of irreversible neuroaxonal damage and re ecting cortico-subcortical disconnection, are associated with cognitive impairment.23 Lesion metrics and atrophy detected early in the disease have also been found to predict future cognitive impairment.8,10 is is in keeping with the ndings of a recent study using resting state fMRI24 that reported di usely impaired func- tional connectivity involving many large-scale neuronal networks, including the salience, executive, and default mode networks. Changes in functional connectivity were correlated with disability, including poor cognitive performance and with the severity of MS- related pathology.

Changes in brain plasticity in patients with MS have been described using fMRI in conjunction with attention-25 and memory-activation26 paradigms. MS patients with preserved cog- nitive performance showed increased activation in the areas nor- mally activated in healthy controls, and also extensive, usually bilateral, activation in areas commonly silent in normal subjects. e extent of increased activation was correlated with measures of pathology in the normal-appearing white and grey matter.27 ese ndings have been interpreted as indicating compensatory neural activity early in the disease. Another fMRI study28 has reported that patients with greater expression of the default mode network, an index of cognitive reserve, can withstand more severe brain pathology before manifesting cognitive impairment.

Approaches to treatment

Available disease modifying therapies (DMTs) target the in amma- tory process of MS and there is good evidence that they reduce the number of relapses, but there is no clear indication that DMTs pre- vent or delay the onset of SPMS or long-term disability. Few studies have looked at the e ect of DMTs on cognition. A systematic review of available trials29 suggests that interferon β1a may slow down the rate of cognitive impairment and of brain atrophy. ere is also some evidence that interferon β1b may also improve information- processing speed and memory in patients with RRMS and that it may protect against cognitive decline in patients with CIS.30 No bene cial cognitive e ects have been reported in association with glatiramer acetate. e e ects of DMTs in patients with PPMS are uncertain, but recent evidence31 suggests that interferon β1b may

have modest bene cial long-term e ects on cognition and in slow- ing down the rate of atrophy. Short-term trials of the monoclonal antibody natalizumab have also reported cognitive improvement in patients with RRMS.32

Bene cial e ects have also been reported when acetylcholinest- erase inhibitors (AChE) donepezil and rivastigmine were admin- istered in double-blind placebo-controlled trials. Donepezil was found to improve verbal learning and memory33 and rivastigmine has been reported to alter functional connectivity, enhancing pre- frontal function and limiting cognitive failure.34 A recent study35 has reported improvements in speed of information processing and memory in MS patients given lisdexanphetamine dimesylate (LDX) a medication used to treat attention de cit/hyperactivity disorder.

Neuroprotection in MS is still in its infancy, and the e ect of neuroprotective drugs (e.g. glutamate antagonists, sodium chan- nel blockers, and cannabinoids) on cognition remains to be determined.

Cognitive rehabilitation—a systematic review of the 16 avail- able trials of cognitive rehabilitation that met required standards36 found some evidence of success for memory rehabilitation tech- niques that use visual imagery and context. Improved memory per- formance was associated with increased fMRI activation in frontal, temporal, and parietal areas associated with memory, visual pro- cessing, and executive control (i.e. the areas subserving the mne- monic treatment strategies). It remains to be determined whether these e ects are long-lasting.37 Cognitive remediation appears to be more e ective in patients with only mild brain atrophy. ere is no evidence so far to suggest that rehabilitation aimed at attention or executive function is of value.

References

1. Cole A. e bare essentials. Multiple sclerosis. Practical Neurology. 2009;9: 118–26.

2. Lin R, Charlesworth J, and van der Mei I, et al. e Genetics of Multiple Sclerosis. Practical Neurology. 2012;12:279–88.

3. Swanton JK, Rovira A, Tintore M, et al. MRI criteria for multiple sclerosis in patients presenting with clinically isolated syndromes: a multicentre retrospective study. Lancet Neurol. 2007;8:677–86.

4. Kutzelnigg A, Lucchinetti CF, Stadelmann C, et al. Cortical demy- elination and di use white matter injury in multiple sclerosis. Brain. 2005;128:2705–12.

5. Lassman H. Cortical lesions in multiple sclerosis: in ammation versus neurodegeneration. Brain. 2012;136:2904–5.

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6. Chiaravalloti ND and DeLuca J. Cognitive impairment in multiple sclerosis. Lancet Neurol. 2008;12:1139–51.

7. Amato MP, Ponziani G, Siracusa G, et al. Cognitive dysfunction in early-onset multiple sclerosis: a reappraisal a er 10 years. Arch Neurol. 2001;58:1602–6.

8. Summers M, Fisniku L, Anderson V, et al. Cognitive impairment in relapsing-remitting multiple sclerosis can be predicted by imaging performed several years earlier. Mult Scler. 2008 14:197–204.

9. Benedict RH, Cookfair D, Gavett R, et al. Validity of the mini- mal assessment of cognitive function in multiple sclerosis. J Int Neuropsychol Soc 2006; 12: 549–58.

10. Summers M, Swanton J, Fernando K, et al. Cognitive impairment in multiple sclerosis can be predicted by imaging early in the disease.
J Neurol Neurosur Ps. 2008; 79:955–8.

11. Zipoli V, Goretti B, Hakiki B, et al. Cognitive impairment predicts con- version to multiple sclerosis in clinically isolated syndromes. Multiple Sclerosis. 2010;16: 62–67.

12. Zarei M, Chandran S, Compston A, et al. Cognitive presentation of multiple sclerosis: evidence for a cortical variant. J Neurol Neurosur Ps. 2003;74:872–877.

13. Weinges-Evers N, Brandt AU, Bock M, et al. Correlation of self-assessed fatigue and alertness in multiple sclerosis. Mult Scler. 2010; 9:1134–40.

14. Andreasen AK, Spliid PE, Andersen H, et al. Fatigue and processing speed are related in multiple sclerosis. Eur J Neurol. 2010;17:212–8.

15. Schwid SR, Tyler CM, Scheid EA, et al. Cognitive fatigue during a test requiring sustained attention: a pilot study. Mult Scler. 2003;9:503–8.

16. Feinstein A, Roy P, Lobaugh N, et al. Structural brain abnormali- ties in multiple sclerosis patients with major depression. Neurology. 2004;62:586–90.

17. Bakshi R, Czarnecki D, Shaikh ZA, et al. Brain MRI lesions and atrophy are related to depression in multiple sclerosis. Neuroreport. 2000;11:1153–8.

18. Arnett PA, Higginson CI, Voss WD, et al. Depressed mood in multiple sclerosis: relationship to capacity-demanding memory and attentional functioning. Neuropsychology 1999; 13:434–446.

19. Sethi V, Yousry TA, Muhlert N, et al. Improved detection of cortical MS lesions with phase-sensitive inversion recovery MRI. J Neurol Neurosur Ps. 2012;83:877–82.

20. Mesaros S, Rocca MA, Kacar K, et al. Di usion tensor MRI trac- tography and cognitive impairment in multiple sclerosis Neurology. 2012;78;969–975.

21. He Y, Dagher A, Chen Z, et al. Impaired small-world e ciency in structural cortical networks in multiple sclerosis associated with white matter lesion load. Brain. 2009;132:3366–79.

22. Filippi M, Rocca MA, Benedict RH, et al. e contribution of MRI in assessing cognitive impairment in multiple sclerosis. Neurology. 2010;75:2121–8.

23. Lanz M, Hahn HK, and Hildebrandt H. Brain atrophy and cognitive impairment in multiple sclerosis: A review. J Neurol. 2007;254 Suppl 2:II43–8.

24. Rocca MA, Valsasina P, Martinelli V, et al. Large-scale neuronal net- work dysfunction in relapsing-remitting multiple sclerosis. Neurology. 2012;79:1449–57.

25. Sta en W, Mair A, Zauner H, et al. Cognitive function and fMRI in patients with multiple sclerosis: evidence for compensatory cortical activation during an attention task. Brain. 2002; 125:1275–82.

26. Chiaravalloti N, Hillary F, Ricker J, et al. Cerebral activation patterns during working memory performance in multiple sclerosis using FMRI. J Clin Exp Neuropsychol. 2005; 27:33–54.

27. Audoin B, Au Duong MV, Malikova I, et al. Functional magnetic reso- nance imaging and cognition at the very early stage of MS. J Neurol Sci. 2006; 245:87–91.

28. Sumowski JF, Wylie GR, et al. Intellectual enrichment is linked to cerebral e ciency in multiple sclerosis: functional magnetic resonance imaging evidence for cognitive reserve. Brain. 2010;133:362–74.

29. Galetta SL, Markowitz C, and Lee AG. Immunomodulatory agents for the treatment of relapsing multiple sclerosis: a systematic review. Arch Intern Med. 2002;162:2161–9.

30. Patti F, Amato MP, Bastianello S, et al. Subcutaneous interferon beta- 1a has a positive e ect on cognitive performance in mildly disabled patients with relapsing-remitting multiple sclerosis: 2-year results from the cogimus study. er Adv Neurol Disord. 2009;2:67–77.

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32. Ia aldano P, Viterbo RG, Paolicelli D, et al. Impact of natalizumab on cognitive performances and fatigue in relapsing multiple sclerosis: a prospective, open-label, two years observational study. PLoS One. 2012;7(4):e35843.

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CHAPTER 28

Autoimmune encephalitis

Sarosh R. Irani, omas D. Miller, and Angela Vincent

Introduction

e eld of autoimmune encephalitis has grown rapidly over the last decade, an expansion principally driven by the description of a variety of new antibody targets (Fig. 28.1). e detection of novel antibodies has, in turn, led to the recognition of a broader spec- trum of phenotypes, and all appear responsive to immunothera- pies. ese phenotypes show some clear overlaps and also some marked di erences which are o en related to the antibody speci c- ity. e clinical lessons emerging from patients has drawn attention to the prevalence and importance of autoimmune disease a ecting cognition and behaviour, including in those patients who are cur- rently ‘negative’ for known antibodies, in serum and/or CSF.

Various terms have been used to describe the main neurocog- nitive syndrome associated with these autoantibodies, including autoimmune encephalitis, autoimmune encephalopathy, limbic encephalopathy (LE), limbic encephalitis, autoimmune dementia, and rapidly progressive dementia (RPD).4–6 ese terms probably re ect the varied rapidity of disease onset, the disease localization, the paraclinical evidence for in ammation, and the background of the author. Although the term autoimmune encephalopathy is probably the most inclusive, ‘autoimmune encephalitis’ (AE) has been most widely accepted and is the term we will use throughout this chapter.

Although the rst description of AE is o en attributed to Corsellis and Brierley in the 1960s,7,8 von Economo’s description of encephalitis lethargica (EL) in 1910 ts within this entity and he himself disputed the direct relationship between EL and in uenza and suggested the probable immune basis of the disorder.9,10 AE can be considered as a syndrome encompassing a number of more speci c diagnoses. Many patients present with a rapid onset, typi- cally over days or weeks, of amnesia, behavioural change, psycho- sis, disorientation, and seizures. erefore, a number of di erential diagnoses are initially considered including infective encephalitis (especially herpes virus family-related), drug or toxin overdoses, Creutzfeldt–Jakob disease (CJD), Wernicke–Korsako syndrome, non-convulsive status epilepticus, and also the controversial entity of Hashimoto’s encephalopathy.11–13 Because the details of the clinical and paraclinical features vary signi cantly with antibody speci city, each syndrome is discussed based on its antigenic target (Table 28.1).

We begin by discussing the clinical and paraclinical features associated with the voltage-gated potassium channel (VGKC) complex antibody-related disorders, most importantly the condi- tions associated with antibodies to leucine-rich glioma inactivated 1 (LGI1) or contactin-associated protein 2 (CASPR2). We then describe the encephalitis associated with N-methyl D-aspartate

(NMDA)-receptor antibodies. Subsequently, we brie y review the rarer entities associated with antibodies to the glycine, gamma- aminobutyric acid (GABA) and α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) receptors. We illustrate treatment principles, available evidence for immunotherapies, and address pathophysiological hypotheses for both antibody access to the brain and the mechanisms by which CNS-bound antibodies act. Finally, we address these diseases as models to study the neurosci- ence of memory and psychosis.

Location, location, location

e subcellular distribution of the target antigen appears key to determining the likely antibody pathogenicity (Fig. 28.1). e main distinction made in the literature is between cell-surface and intracellular antigens. Traditionally, intracellular antigenic targets (including Hu, Yo, Ri, CV2/CRMP5) were associated

Amphiphysin

PARANEOPLASTIC

Ma2
Hu

CRMP5/CV2

mGluR5

OFTEN PARANEOPLASTIC

GABABR AMPAR

NMDAR

CASPR2

GABAAR

RARELY PARANEOPLASTIC

GAD LGI1

Contactin-2 Glycine R

Cell surface

Intracellular

Fig. 28.1 Subcellular locations and paraneoplastic associations of neural antibodies.162 Antigens with intracellular (blue rectangles) and extracellular (blue circles) localizations. Antibody targets which are ‘classically’ paraneoplastic (blue circle), often paraneoplastic (peach circle), and rarely paraneoplastic (green circle). Adapted with Arq Neuropsiquiatr. 70(10), Machado S, Pinto AN, and Irani SR, What should you know about limbic encephalitis? pp. 817–22, Copyright (2012), with permission from the Brazilian Academy of Neurology, reproduced under the Creative Commons CC BY-NC 4.0 License.

300 SECTION 3 cognitive impairment and dementia
Table 28.1 Additional features of limbic encephalitis associated with the commonest CNS cell-surface directed antibodies

NMDAR

LGI1

CASPR2

AMPAR

Glycine

GABAB

Frequent clinical associations

Di use encephalitis with psychiatric features with cognitive impairment, seizures, movement disorder, dysautonomia, and reduction in consciousness

LE with faciobrachial dystonic seizures, and serum hyponataremia

Morvan’s syndrome
with psychiatric features, insomnia, dysautonomia, and neuromyotonia (often with LGI1-antibodies). Less frequently, LE

LE, PERM but also some SPS-spectrum syndromes

Tumour/Infectious associations

Ovarian teratoma in about 30%; Relapses post-HSV encephalitis with NMDAR antibodies

<10% (various tumours described)

ymoma (~30%)

Lung, breast, thymoma (~50%)

ymoma rarely (<10%)

Lung (~50%)

Expanding phenotypic spectrum

Few cases with purely psychotic features; predominant movement disorder; few with predominant cryptogenic epilepsy syndrome

Cryptogenic epilepsies

Cryptogenic epilepsies; Guillain-Barre-like syndrome

Atypical psychosis

LE, brainstem encephalitis; Cryptogenic epilepsies

Approximate number of reported cases since rst description

>700 in 6 years

~250 in 3 years

~30 in 3 years

~25 in 4 years

~35 in 5 years

~30 in 3 years

Prevalence in clinically-de ned tested cohorts; controls variable but generally <1%

9/48 (19%) with unknown encephalitis

6/62 (10%) with unknown encephalitis

21/27 (78%) with Morvan’s syndrome

15/410 (4%) with suspected autoimmune encephalitis

Mainly seen in PERM; 10/81 (12%) with SPS; 1/48 (2%) of pediatric encephalopathies

10/70 (14%) of LE cases.

Primary cell type/ Antigenic target

Neuron/NR1 subunit

Neuron

Neuron/ GluR1/2

Neuron/α1 receptor

Neuron/ B1 subunit

Limbic encephalitis (LE) produces amnesia, confusion and seizures (additional features noted above within each antibody speci city). Opsoclonus-myoclonus syndrome (OMS); sti – person syndrome (SPS); status epilepticus (SE); rst episode psychosis (FEP); basal ganglia (BG); progressive encephalomyelitis with rigidity and myoclonus (PERM).

Adapted from Ann Neurol. 76(1), Dahm L, Ott C, Steiner J, et al. Seroprevalence of autoantibodies against brain antigens in health and disease, pp. 82–94, Copyright (2014), with permission from John Wiley and Sons; Ann Neurol. 76(2), Irani SR, Gelfand JM, Al-Diwani A, et al. Cell-surface central nervous system autoantibodies: Clinical relevance and emerging paradigms,
pp. 168–84, Copyright (2014), with permission from John Wiley and Sons, reproduced under the Creative Commons CC BY-NC-ND License.

with paraneoplastic diseases, o en with a very poor prognosis, and where the antibody titre was unrelated to the severity of the illness.14–16

By contrast, more contemporary literature discusses antibod- ies against neuronal surface-directed antibody (NSAbs) which are accessible to the circulating antibodies in vivo. ese diseases are associated with a far better prognosis, even up to near-complete recovery, a lower rate of tumours, and a stricter correlation between antibody levels and clinical state. e cell-surface antibody classi- cation appears to be more important in prognostication than the presence of a tumour.1–3 Interestingly, the de ned targets of many of these antibodies are ion channels (NMDA, GABA, AMPAR, gly- cine receptors) or proteins which co-associate with channels (LGI1, CASPR2, contactin-2, and DPPX) but may also have other roles in neuronal biology.17

One antibody target, glutamic acid decarboxylase (GAD), lies in a hinterland. GAD is an intracellular enzyme and its levels do not correlate well with disease activity. However, there are few tumours observed in patients with GAD antibodies and the associated dis- eases may respond to immunotherapies. A partial resolution to this intracellular cell-surface antigen discrepancy may be that many

patients with GAD-antibodies also harbour other NSAbs, as has been shown in a few studies.18–20

Antibody-detection methods

e assays used to detect the autoantibodies are critical to disease de nitions and are increasingly scrutinized (Fig. 28.2). While some of the arguments below have been summarized elsewhere,2,17,21 the assay di erences are so integral to the syndrome de nition that the related controversies are brie y reviewed here. e main contro- versies surround whether antibody detection in cerebrospinal uid (CSF) or serum is more important, the relevance of intrathecal syn- thesis, and the methodological and technical details of the assay itself which include the sample concentrations, possible exposure to intracellular epitopes, and the use of more than one assay to diagnose a single antibody.

ere are con icting reports as to the relative importance of CSF and serum antibodies.21,22 In our experience, the levels of NSAbs are almost always higher in the serum than the CSF. In patients with NMDAR (NMDA receptor) and LGI1 antibodies for instance, absolute antibody levels are between 5 and 100 times higher in absolute terms in serum. is di erence suggests the antibody is

(a)

(b)

bound by patient IgG (d)

Patient IgG bound to CASPR2-EGFP expressing HEK cells

CHAPTER 28 autoimmune encephalitis 301 di usion across the blood–brain barrier, and it is unclear whether

this intrathecally derived IgG is similarly or more pathogenic than serum IgG. is question may be confounded by the likely di er- ences between intraventricular and lumbar CSF constituents.

Methodological assay di erences are also of potential import- ance (Fig. 28.2). Traditionally, rodent brain sections have been stained with patient serum and/or CSF (Fig. 28.2a). is technique allows antibodies access to both intracellular and extracellular epitopes but can show highly distinctive patterns of binding with di erent antibodies. In order to detect only NSAbs, and therefore antibodies with pathogenic potential, live neuronal cultures have been used as they express native neuronal proteins and deny anti- bodies access to intracellular epitopes (Fig. 28.2b). In cell-based assays, cells transfected with the de ned antigen are probed with the patient sera to determine antigenic speci city (Fig. 28.2c-d), but di erent studies use permeabilized or live cells to perform this diagnostic test. Also, some groups use brain sections and/or live hippocampal neuronal binding plus a cell-based assay approach to diagnoses NSAbs,21,23 whereas others rely on the cell-based assay, with absence of binding to a related cell-expressed antigen as a marker of speci city.18,19,24–26

In summary, currently due to unresolved di erences in meth- odological approaches, it is prudent to send both serum and CSF for diagnosis. Nevertheless, critically, the presence of the antibody should be understood in the context of the clinical presentation.

LGI1 and CASPR2: VGKC-complex antigens

e two commonest antibodies found in patients with cognitive and behavioural de cits are directed against LGI1 and the NMDA receptor (Fig. 28.3 and 28.4). e syndrome associated with

(e)

LGI1

MoS NMT (LE)

Rat brain sections bound by patient IgG

Hippocampal neuron

(c)

CASPR2-EGFP-expressing HEK cells

LE FBDS MoS

DTX VGKC

Extracellular

Intracellular

C A S P R 2

C O N T A C T I N 2

Fig. 28.2 (a) Sagittal rat brain section showing binding of patient serum NMDAR antibody (IgG). (b) Hippocampal neuronal cultures labelled with LGI1- IgG antibody (green) and intracellularly stained with MAP2, a neuronal marker (red). (c) Enhanced green uorescent protein (EGFP)-tagged antigen (in this case CASPR2, green) is bound by patient IgG (d red). (e) Depiction of the voltage- gated potassium channel (VGKC)-complex labelled with dendrotoxin (DTX) to show antibodies known to bind the extracellular domains of LGI1 (in patients with limbic encephalitis (LE), faciobrachial dystonic seizures (FBDS), and Morvan syndrome (MoS)), and CASPR2 in patients with MoS more frequently than in neuromyotonia (NMT) or LE. Contactin-2 antibodies are rare. Some antibodies may bind the intracellular domains of some molecules within the VGKC-complex (blue antibody).
Adapted from Ann Neurol. 76(2), Irani SR, Gelfand JM, Al-Diwani A, et al. Cell-surface central nervous system autoantibodies: Clinical relevance and emerging paradigms, pp. 168–84, Copyright (2014), with permission from John Wiley and Sons, reproduced under the Creative Commons CC BY-NC-ND License.

peripherally generated. However, if normalized to total immuno- globulin G (IgG) concentrations, which are around 400 times higher in the serum, the concentration of antigen-speci c antibody in the CSF relative to that in serum, is o en >1, indicating intrathecal synthesis of the antibodies. is is particularly common in patients with NMDAR antibodies. ese ndings indicate secondary gen- eration of the NSAb within the intrathecal space, not due to simple

Kv1.1

LGI1

AMPAR

ADAM ADAM 23 22

Kv1.1

Fig.28.3 IllustrationoftheVGKC-complexes:theassociationofKv1sandLGI1 (leucine-rich glioma-inactivated 1) and other components of the synaptic complex including Kv1s (blue, such as Kv1.1), LGI1 (red) and α-amino-3-hydroxy-5-methyl- 4-isoxazolepropionic acid receptors (AMPAR) and ADAM22/23 (a disintegrin and metalloproteinase 22/23) (brown) anchored at postsynaptic membranes. Reproduced from J Neurol. 262(4), Varley J, Vincent A, and Irani SR, Clinical and experimental studies of potentially pathogenic brain-directed autoantibodies: current knowledge and future directions, pp. 1081–95, Copyright (2014), with permission from Springer, reproduced under the Creative Commons Attribution License.

302 SECTION 3

cognitive impairment and dementia

(a)

VGKC-complex antibodies

Central Nervous System (CNS) Peripheral Nervous System (PNS)

CFS-NMT Morvan Encephalopathy FBDS Other epilepsies

Dysautonomia and insomnia Psychiatric

Pain

Cognitive Movement disorders

Seizures

Tumour frequency

(b)

Fig. 28.4 (a) e phenotype spread of VGKC (voltage-gated potassium channel)-complex, LGI1 and CASPR2 antibodies. e relative proportions of patients with LGI1- and CASPR2-antibodies and those who remain without a known antigenic target (‘seronegative’) are depicted in the gradient bars. Movement disorders include ataxia, chorea, and parkinsonism.55,163,164 A number of patients, especially those with cramp-fasciculation syndrome-neuromyotonia (CFS–NMT; high-frequency discharges shown) and epilepsy (excluding faciobrachial dystonic seizures, FBDS) currently have no de ned antigenic target (‘NSAb negative’) although their sera precipitate VGKC- complexes in the radioimmunoassay. Reproduced with permissions from Irani et al. 2014.2 (b) e temporal progression of patients with NMDAR-antibody encephalitis. e disease usually begins with psychiatric and cognitive features plus seizures and, after a lag of 10–20 days, a movement disorder, dysautonomia, and reduction in consciousness are seen. CSF pleocytosis occurs earlier than CSF oligoclonal bands. In addition, EEG spikes occur prior to di use slowing.

Adapted from Curr Neurol Neurosci Rep. 11(3), Irani SR and Vincent A, NMDA receptor antibody encephalitis, pp. 298–304, Copyright (2011), with permission from Springer.

VGKC-complex antibodies has been serologically and clinically reclassi ed in recent years (Fig. 28.2e and Fig. 28.3). It has become clear that these autoantibodies only rarely target the VGKCs themselves, but that many are directed against proteins which are tightly complexed with the VGKCs, most frequently LGI1 and CASPR2.24 Around 80 per cent of cases with a purely CNS- localized syndrome have LGI1 antibodies,24,27 with a minority having CASPR2-antibodies.24 Antibodies against contactin-2 are rare and tend to coexist with either LGI1 or CASPR2 antibod- ies in patients with AE.24 e original radioimmunoassay detects over 95 per cent of patients with CASPR2 or LGI1 antibodies, but also detects antibodies against uncharacterized antigenic targets of the VGKC-complex.4,24,26,28,29 Some of these are unlikely to be pathogenic antibodies (for detailed discussion see references 2 and 30) but collectively, the term VGKC-complex antibodies is used to describe the detection of these multiple speci cities within a single

diagnostic assay (Fig. 28.2e),24,26,31 although this radioactive test is not widely available except at specialist centres.

e VGKC-complex antibody-associated encephalopathy is now well known to neurologists and consists of the acute to subacute presentation of amnesia, disorientation, and seizures.4,29,32,33 is is usually seen in adults over 50 years of age, with a slight male predominance. e pattern of cognitive impairment is detailed later, but retrograde and anterograde de cits are present in the acute phase, o en with a dense gap around the illness and for sev- eral years prior to illness onset.34–36 Disorientation and frontal dysexecutive features are o en seen acutely. e observation of a more insidious onset amnestic syndrome in association with VGKC-complex/LGI1 antibodies,5,37 without MRI or CSF markers of in ammation, has led to the adoption of the term autoimmune dementia by some authors.38 In addition to an absence of in am- mation, these antibody-associated dementias have been reported

Abnormal MRI/CSF

LGI1

CASPR2

NSAb NEGATIVE

CORTICAL Psychiatric

Cognitive Seizures

SUBCORTICAL
Movement disorder

Dysautonomia

Reduction in consciousness

Lymphocytosis frequently seen Oligoclonal bands uncommon

Lymphocytosis infrequent Oligoclonal bands appear

10–20 days lag

to show a more chronic presentation and a good immunotherapy response. ese should be considered in the di erential diagnosis of more typically neurodegenerative presentations such as CJD and rapid forms of Lewy body dementia and Alzheimer’s disease.5,6,13

Seizures

Seizures are found in 80–90 per cent of patients with VGKC- complex antibodies. While sometimes seen in isolation, they are o en associated with cognitive impairment,37,39–44 and general- ized convulsions rarely pose a clinical problem. e seizures are o en frequent and with focal onset. Abdominal, olfactory and vis- ual auras, limb automatisms and jerking have all been reported. More recently, three distinctive semiologies have been described, the most characteristic of which are faciobrachial dystonic seizures (FBDS).

FBDS are of particular importance as they illustrate paradigms for both prevention and treatment of antibody-mediated CNS dis- ease.31,37,41,45,46 FBDS are short (o en < 3 seconds) dystonic events which usually a ect the arm and ipsilateral face, and occur at a high frequency (median 50 times, but up to 350 times per day). Many patients with FBDS who were refractory to standard antiepileptic drugs (AEDs) showed an excellent, and o en rapid, response to immunotherapy, especially corticosteroids. Retrospective and pro- spective studies suggest that the onset of FBDS is predictive of the occurrence of a more typical LGI1-antibody associated encepha- lopathy, with a median lag of around ve weeks. ese observations led to the hypothesis that successful treatment of the FBDS may prevent an incipient encephalopathy. While this has been substan- tiated in one small prospective study and several case reports, this is yet to be proven in a blinded or randomized manner.37,47,48

Some patients with VGKC-complex antibodies develop ictal bradycardia and pilomotor seizures. e former are present in around 0.5 per cent of seizures on a telemetry unit49 and, when seen in the context of LGI1 antibodies, may precede the onset of cognitive impairment.50 Pilomotor seizures show a high speci- city for the diagnosis of a LE, mostly associated with LGI1 antibodies.51,52

Patients with LGI1 antibodies o en have a serum hyponatrae-

mia,4,29 which can be a diagnostic clue and, along with seizures,

provide two reasons to dissuade from the diagnosis of CJD.53

Hyponatraemia may arise from the modulation of LGI1 expressed in

the ADH-secreting neurons of the hypothalamus.54 Other features

found in association with this encephalopathy include dysautono-

mia (hyperhidrosis, lacrimation, and cardiovascular instability),

sleep rhythm disturbances (including REM sleep-behaviour dis-

order and insomnia), neuropathic pain (o en associated with

CASPR2 antibodies), cerebellar ataxia (also o en CASPR2 anti-

body related), hallucinations, and depression.4,55–57 Many of these

features are more prominent and common in Morvan’s syndrome (MoS).54,58–60

Morvan’s syndrome and peripheral nerve

hyperexcitability

MoS is a rare syndrome, even with the greater recognition over the last few years. e majority have VGKC-complex antibodies, most commonly associated with CASPR2 antibodies but o en with coexistent LGI1 antibodies. Patients with MoS have peripheral

nerve hyperexcitability (PNH)61 but also a number of central nerv- ous system manifestations, most commonly profound insomnia, agitation, delusions, and hallucinations. ese patients also have a multisystem dysautonomia, pronounced neuropathic pain, sig- ni cant weight loss, and o en normal MR imaging and cerebrospi- nal uid examinations. MoS shows an approximately 30 per cent rate of associated thymomas, which are rare in patients with the LE associated with LGI1 or CASPR2 antibodies.54,58 Patients with MoS have a roughly 30 per cent mortality rate, but this is usually related to metastatic thymoma, and those without a malignancy o en respond well to immunotherapy.

It is of interest that patients with ‘isolated’ PNH have tradi- tionally been reported to have a high rate of anxiety and depres- sion,62 suggesting a spectrum of cognitive involvement from very mild changes in traditionally pure peripheral nerve disorders, through to the orid cognitive impairment seen in patients with LE (Fig. 28.4a).

Cognitive sequelae of VGKC-complex

antibody LE

Early clinical studies of VGKC-complex antibody LE performed

cognitive testing in the acute phase of disease and showed global

impairment across several domains including memory, executive

function and language as measured either by formal neuropsy-

chometry4,32,33 or by the Addenbrooke’s Cognitive Examination–

Revised (ACE–R).37,63 Studies that assessed the cognitive pro le

following resolution of the illness usually indicated that the execu-

tive function and language dysfunction had resolved4,32 but that

patients showed residual anterograde or retrograde memory de cits.4,32,33,64,65

Memory has several anatomically and functionally distinct components. Considering retrograde memory, VGKC-complex antibody LE patients were found to have de cits in the recent epi- sodic memories but not personal semantic memories.65 Another study found that three patients with VGKC-complex antibody LE were impaired on measures of famous faces and famous news events, and measures of anterograde paired-associate learning, with some improvement being observed a er immunotherapy.64 Recognition memory and list-learning, however, were almost uni- versally preserved following resolution of the illness.4,64,65 Each of these distinct functions are believed to have separate anatomical localizations. Paired-associate learning,66–68 stimulus requiring association (i.e. the components constituting the narrative of a story)69,70 and recent episodic memories71 are particularly reliant on the hippocampus, whereas list-learning/single-item memory, recognition memory, and semantic memory72–74 depend on extra- hippocampal structures.

However, these studies are either cross-sectional studies or a case series limited to the period of time a er treatment. Frisch and col- leagues75 used standardized measures of anterograde memory (the verbal learning and memory test: free recall and recognition of a learnt word list) and executive function (the Epitrack battery: trail- making tasks, response inhibition, digit span backwards, word u- ency, and a maze test) and showed signi cant de cits in executive functioning and verbal and visual memory at presentation in 15 patients. At follow-up, a er immunotherapies, there was a reso- lution in the dysexecutive features but a signi cant de cit in visual and verbal memory persisted.75

CHAPTER 28 autoimmune encephalitis 303

304 SECTION 3 cognitive impairment and dementia

Using a larger battery of standardized neuropsychological tests in 20 patients, Butler and colleagues demonstrated that acute VGKC- complex antibody LE likewise impaired anterograde verbal and visual memory, but was also associated with impaired processing speed and executive function.35 At follow-up, there was normaliza- tion in processing speed and executive function but enduring de – cits in anterograde memory. A nal study34 described 12 patients with VGKC-complex antibody LE (eight with LGI1 antibody speci- city, four not further classi ed) with tests of anterograde verbal (California verbal learning test, CVLT) and visual (Benson gure) memory, letter uency (D-words), category uency (animals), and visual uency (design uency), working memory (digits backwards), task switching (modi ed trails), inhibition (Stroop inhibition), visual localization and construction (visual object space perception) and naming (Boston naming test), single-word comprehension (Peabody picture vocabulary test, PPVT) and sentence repetition. e authors undertook a cross-sectional and a longitudinal cognitive perfor- mance study. e cross-sectional work revealed that patients had mild to moderate impairment on anterograde memory as de ned by a group average Z score of -1.9, but this was probably driven by ver- bal memory performance. A mild impairment in executive functions and language were found with normal visuospatial function. 83 per cent were impaired on the CVLT, 64 per cent on category uency, 55 per cent on letter uency, whereas very few performed poorly on Stroop inhibition (11 per cent), gure copy (8 per cent), or repetition (18 per cent). is study suggested that the long-term sequelae might include dysexecutive problems. Category uency requires a search through conceptual knowledge store for semantic extensions derived from a target word.76 Some argue that this also requires normal fron- tal lobe functioning77 to organize retrieval strategies, initiate verbal response, to monitor responses, and to inhibit some responses.78 Moreover, functional MRI studies have demonstrated that both measures access temporal lobe semantic memory stores79,80 and a study in amnesic mild cognitive impairment (aMCI) has shown that patients with otherwise normal cognitive pro le su er from de cits on both letter and uency tasks,81 whereas there was a relative pres- ervation of switching tasks. ese results may represent a de cit in the semantic network for problems with uency tasks but suggests switching tasks require a higher executive burden which is ostensibly normal in aMCI patients.81 erefore, the ndings of Bettcher and colleagues34 may be interpreted as MTL dysfunction within the cor- tical network supporting category uency.

ese longitudinal studies are o en limited by the relatively small number of neuropsychological tests administered and by their lack of integration with localized brain atrophy. Nonetheless, these studies consistently demonstrate that in the acute phase of VGKC- complex antibody LE there is evidence of de cits in executive function, language, processing speed, and both verbal and visual memories. In the more chronic phase there is a resolution in those functions without MTL-dependence, and the most conspicuous residual de cits are MTL-dependent associative anterograde and retrograde memories.

Clinical neuroimaging studies

in VGKC-complex antibody LE

e majority of clinical MRI studies undertaken in acute VGKC- complex antibody LE demonstrate an active in ammatory pro- cess (as shown by high signal on T2 sequences and/or swelling)

predominantly con ned to the MTL structures.4,29,82,83 However, as a number of clinically distinctive features are being better char- acterized, there is increasing reported normality of MR imaging.5,37 Longitudinal scanning o en demonstrates focal atrophy of the MTL structures in at least 48 per cent of patients.84 is medial temporal lobe sclerosis may act as a potential focus for subsequent adult-onset epileptogenesis.82–84 In addition, atrophy has been reported outside of the MTL.46,85 Table 28.2 provides a summary of reported longitudinal imaging ndings.

Volumetric MRI analysis in VGKC-complex

antibody encephalitis

Volumetric analyses have also been used to provide a quantitative assessment of cortical and hippocampal volume change during and a er VGKC-complex antibody-related syndromes. Irani and col- leagues imaged eight patients at convalescence who had normal medial temporal lobe imaging on clinical scans (except for one patient with putaminal high signal). Patients were found to have signi cantly smaller combined hippocampal/total intracranial volumes and brain/total intracranial volume ratios than controls. Regression analysis found a signi cant negative association between brain/total intracranial volume and increasing age for both patients and controls, but no association between either hippocampal/total intracranial volume or brain/total intracranial volume with either cognitive impairment or the dosage of corticosteroids received.37 One potential confound in this study is that more than 50 per cent of the patients were older than the oldest control. However, these results are in keeping with an early volumetric study.33 Examples of these imaging abnormalities are shown in Fig. 28.5.

A second study86 quanti ed the longitudinal structural changes in volumes of both the hippocampus and amygdalae following autoimmune encephalitis using a fully automated so ware package. ey imaged 15 patients with VGKC-complex antibody encephali- tis and all had larger amygdalae and hippocampal volumes on their rst MRI. At the second MRI, the patients (n = 13) experienced a 14.0 per cent reduction in amygdala volume and a 6.0 per cent reduction in hippocampal volume. Between rst and third MRIs (n = 8) there was an 18.3 per cent reduction in amygdala and a 10.7 per cent reduction in hippocampal volumes. ere were no di erences in any other cortical or subcortical volumes. e MTL atrophy was in excess of the resolution of swelling and high signal change seen during acute imaging, and this has been corroborated by histopathological studies.4,87,88

NMDAR-antibody encephalitis

e encephalitis associated with IgG directed against the NR1 subunit of the NMDAR has a very di erent phenotype and a ected demographic to VGKC-complex antibody CNS illnesses (Fig. 28.4b). e disease is associated with benign ovarian terato- mas and is especially seen in females between the ages of 12 and 40 years.89,90 However, young and old men are now reported and the frequency of teratomas is, partly consequentially, decreasing.25,91

Patients usually present with a classical sequence of multifocal neurological de cits.25,89 e typical onset is over a few days with psychiatric symptoms; patients develop delusions, psychosis, and hallucinations, usually without a background history of psychiat- ric disease. is may be accompanied by other cognitive features

Table 28.2 Clinical magnetic resonance features in acute and chronic VGKC-complex antibody encephalitis

Reference No. of patients Acute features Chronic features

Buckley et al.32 2 1 × N MTL –

1 × L HPC abnormality –

Vincent et al.4 10 1 × ↑ signal BL HPC –

1 × ↑ signal BL HPC MTL atrophy, ↑ L HPC swelling, ↑ signal R insula

1 × N ↑ signal esp. L HPC

1 × atrophy with ↑ signal R insula ↑ signal normalized

1× N N

1 × N BL HPC atrophy

1 × ↑ signal HPC L > R N

1 × ↑ HPC and anterior TL signal Minimal signal change in HPC

1 × ↑ L MTL sclerosis and R TL HPC change abnormalities

1 × ↑ volume and signal in L HPC and Atrophy and signal change L > R AMYG

Bien et al.83 4 1 × HPC swelling N then atrophy with ↑ signal

Urbach et al.151 3 – 1 × BL MTL atrophy

– 1 × L > R MTL atrophy

– 1 × L HPC atrophy

Chan et al.36 3 1 × ↑ signal BL HPC Mild BL MTL atrophy

1 × ↑ in HPC and AMYG R HPC atrophy

ieben et al.29 7 6 × ↑ signal BL MTL –

1 × ↑ signal L MTL –

Jacobs et al.85 2 – 1 × BL HPC atrophy and ↑ signal R MTL

1 × ↑ signal hypothalamus and MTL –

Sekiguchi et al.152 1 ↑ signal HPC Hypothalamic ↑ signal

Khan et al.88 1 L HPC atrophy –

Chatzikonstantinou 1 ↑ signal and di use swelling of R HPC R HPC atrophy et al.153

Kaymakamzade 1 ↑ signal BL HPC and AMYG – et al.154

Kapina et al.155 1 L HPC lesion –

Kartsounis et al.65 1 ↑ BL HPC signal –

Wong et al.63 7 7 × ↑ signal and oedema BL HPC –

Ballater et al.156 2 2 × ↑ signal BL MTL –

Schott et al.33 1 ↑ signal BL HPC 22.6% L HPC atrophy, 39.6% R HPC atrophy; 11.4% whole-brain volume loss

Harrower et al.157 2 1 × N –

Irani et al.46 3 1 × ↑signal R caudate and putamen 1 × mild R caudate atrophy

1 × N 1× N

1 × ↑ signal in BL HPC 1 × N

Irani et al.37 8 8 × N MTL – 1 ×↑putaminalsignal

AMYG: amygdala; BL: bilateral; HPC: hippocampus; L: left; MTL: medial temporal lobe; N: normal; R: right; ↑: increased.

306 SECTION 3 cognitive impairment and dementia
(a) (b)

(e) (f)

Fig. 28.5 Acute neuroimaging features in VGKC-complex encephalitis. (a & b) Longitudinal imaging from a single patient demonstrating A. Bilateral hippocampal swelling and mild signal change (red boxes). (b) Marked hippocampal atrophy following resolution of the illness (red boxes). (c) Unilateral signal change in the left hippocampus (red arrowhead). (d) Unilateral signal change in the right hippocampus (right arrowhead). E: Bilateral signal change and swelling (red boxes). (f) Caudate head signal change (red arrowhead).

Adapted from Brain. 136(Pt8), Pertzov Y, Miller TD, Gorgoraptis N, et al. Binding de cits in memory following medial temporal lobe damage in patients with voltage-gated potassium channel complex antibody-associated limbic encephalitis, pp. 2474–85, Copyright (2013), with permission from Oxford University Press, reproduced under the Creative Commons CC BY-NC 3.0 License.

such as amnesia, disorientation, behavioural disturbances, and dys- phasia. In a number of patients, particularly males, the presenting symptom can be seizures.91 However, only occasionally are seizures a severe or recurrent problem.

Subsequently, and typically with the lag of 10 to 20 days, patients develop a movement disorder, dysautonomia, and, sometimes, cen- tral hypoventilation.25,89,90 ese are distinctive features, in par- ticular the movement disorder. When hyperkinetic, this movement disorder o en shows prominent orofacial dyskinesias, particularly centred around the lips, and stereotyped, antigravity movements of arms and legs.92 ese movements can persist for several hours per day over a period of many weeks and have been likened to status dissociatus.93 However, the movement disorder can also be hypokinetic, and highly reminiscent of Von Economo’s descrip- tion of one form of EL, with a predominant parkinsonian disorder, bradyphrenia, and bradykinesia.94 e dysautonomia can o en cause tachycardia and labile blood pressure and may be the cause of the uctuating fever. Some patients have required pacemaker

insertion. e central hypoventilation is a less common feature but may necessitate intensive care unit admission which is itself a poor prognostic factor.90

e CSF is usually lymphocytic, especially early on in the ill- ness, and oligoclonal bands develop at later time points. In addi- tion, the EEG appearances usually follow a temporal trend from spikes to di use slowing (Fig. 28.3b). Alongside this, the dichotomy of the timings of lymphocytosis and oligoclonal band appearances lend support to two major stages to the disease process. e rst is characterized by cortical features (neuropsychiatric impairment, seizures, CSF lymphocytosis, and EEG spikes) and the second by a more subcortical process with a movement disorder, dysauto- nomia, and loss of awareness with di use EEG slowing.25 Some patients do not t this model but it does o er a framework to con- sider the biology of the, frequently distinctive, temporal progres- sion of the disease.

More recently, patients have been described with relatively lim- ited presentations. is includes patients with status epilepticus,

a predominant movement disorder, or isolated psychiatric fea- tures.95–97 Indeed one controversial question is how o en patients with early psychosis have NMDAR antibodies.98–100 e literature is divided on this subject, probably partly due to the di erences in assays used to de ne the presence of the antibody described above.2

e NMDAR antibodies are IgG, but a few recent reports have described phenotypes associated with IgA and IgM NMDAR- directed antibodies.101,102 ese appear to be diseases with an indo- lent form of cognitive impairment. While the antibodies may have e ector functions in vitro, clear evidence supporting an immuno- therapy response is lacking. Perhaps these antibodies are generated secondary to an alternative primary CNS pathology and, indeed, NMDAR–IgG or VGKC-complex antibodies have been described in occasional patients with neurodegenerative dementias103 and in a small number (<5%) of patients with proven CJD.104–106

Neuroimaging and cognitive studies in

NMDA-receptor antibody encephalitis

Patients with NMDAR-antibody encephalitis o en have normal MR imaging in the acute phase but 10–20 per cent of patients have hyperintensities on MRI which may localize to the hippocampi (the typical picture of limbic encephalitis), neocortical structures, and/or subcortical regions.25,89 e latter are o en in white matter tracts and appear demyelinating, generating interest in the recently rede ned overlap between demyelination and NMDAR-antibody encephalitis.107,108 Studies reporting imaging from two or more patients are summarized in Table 28.3.

Only two formal studies have been performed to examine the neuropsychological consequences of NMDA-receptor antibody encephalitis. In the rst,109 nine patients were tested at a median time of 43 months (range: 23–69), with ve receiving immu- nomodulatory treatment within three months of symptom onset, three receiving immunomodulation late in the disease, and one patient receiving no treatment. e authors tested attention (dual- task paradigm), working memory (digit span forwards and back- wards), verbal memory (Rey auditory verbal learning test, RAVLT), non-verbal memory (Rey–Osterreith complex gure), executive function (category uency, letter uency, Stroop inhibition test, behavioural assessment of the dysexecutive syndrome, Tower of London task) and a delayed-matching-to-sample (DMTS) task in which patients had to remember the colour, location, or the asso- ciation between the colour and location of visual stimuli across either a 900 ms or a 5000 ms delay. is study found that attention was impaired in four patients, working memory was impaired in four patients, verbal memory in two patients, non-verbal memory in one patient, and executive function in ve patients. Five patients were impaired in up to four tests, mainly a ecting attention or working memory processes, but two patients had extensive neu- ropsychological impairments across a number of neuropsychologi- cal domains (attention, working memory, memory and executive function). Five patients were impaired on the DMTS task, four on the localization aspect of the task, one on the colour aspect, and all patients on the associative component of the task; these were de – cits previously shown to be sensitive to hippocampal lesions.110,111 e authors found a signi cant positive e ect of early treatment on cognitive performance at follow-up and there was also a correlation between the delay in treatment and cognitive outcome.

A second study112 found evidence of executive dysfunction (as measured by the digit span backwards, Stroop inhibition, and word uency) but also anterograde memory impairment (as measured by

Table 28.3 Clinical magnetic resonance imaging ndings in NMDA- receptor antibody encephalitis. Inclusion of studies reporting imaging from two or more patients

CHAPTER 28 autoimmune encephalitis 307

Reference

No. of patients

Acute features

Dalmau et al.158

46 × N

22 × ↑ MTL signal change

22 × cortical change

6 × CBM change

6 × BS change

5 × BG change

14 × contrast enhancement (cortex, meninges, BG)

4 × corpus callosum change 2 × hypothalamic change
1 × pericallosal change
1 × multifocal WM change

Iizuka et al.159

3× N
1 × ↑ signal MTL

Irani et al. 201024

34 × N throughout
6 × WM ↑ signal
4 × ↑ MTL signal change 1 × hippocampal sclerosis

Baumgartner et al.160

1 × ↑ signal BL MTL 1 × ↑ signal Occipt.

Finke et al.109

8× N

1 × ↑ signal L insula, L frontal lobe, and L periventricular regions

Finke et al.112 (at 3-T)

10 × N

5 × frontal WM lesions

2 × L frontal WM lesions

1 × L frontoparietal WM lesion

1 × L insular WM lesions

1 × WM lesions in R palladium, L insula, R frontotemporal regions

1 × R temporal, L trigonal, L frontal horn, L central WM lesions

1 × L frontal and R frontotemporal WM lesions 1 × BL frontobasal WM lesions
1 × L frontal and L temporoparietal WM lesions

Sarkis et al.161

3× N
2 × ↑ signal subcortex

Viaccoz et al.91

6× N
2 × ↑ signal L HPC
1 × ↑ signal BL HPC, and Occipt.
1 × ↑ signal BL HPC, putamen, and CBM

BG: basal ganglia; BL: bilateral; BS: brainstem; CBM: cerebellum; L: left; MTL: medial temporal lobe; N: normal; Occipt.: occipital cortex; WM: white matter; ↑: increased.

the RAVLT sum score, immediate-recall and delayed-recall measures) against age-matched controls. ey also found evidence of bilaterally reduced hippocampal connectivity in the anterior default mode net- work but no changes in the sensorimotor, primary visual, or auditory resting state networks. is suggests that the cognitive sequelae in

308 SECTION 3 cognitive impairment and dementia

NMDA-receptor antibody encephalitis are due to a functional dis- sociation of the hippocampi from this memory network and, sur- prisingly, not due to regional atrophy.113–115 Di usion tensor imaging (DTI) also found evidence of white matter atrophy in the cingulum bilaterally, a nding that correlated with disease severity (as measured by the modi ed Rankin score).112

Rarer antibodies

Recently, a number of less common autoantibodies have been described in the context of a number of central nervous system diseases, typically a limbic encephalitis. ese include antibod- ies to CASPR2 (part of the VGKC complex),24,116 the glycine receptor,18,117 GABAA and GABAB receptors,23,118 the AMPA receptor,119 GAD,120 and, more rarely, AQP4.121 Each antibody- associated syndrome has a few particularly prominent clinical fea- tures and associations (Table 28.1).

Some important features include the presence of small cell lung cancer (SCLC), thymomas, and breast cancers in patients with AMPA receptor antibodies. Patients with GABABR antibodies o en have frequent refractory seizures and SCLC. e encephalopathy associated with glycine receptor antibodies has traditionally been termed PERM (progressive encephalomyelitis with rigidity and myo- clonus). is describes the variable presence of cognitive disturbance with few seizures, but more speci cally oculomotor di culties, ataxia, and a sti -person-like phenotype (o en startle, spasms, and ridgity). An AQP4-antibody associated encephalopathy can occur in children, sometimes with a longitudinally extensive transverse myeli- tis and/or optic neuritis.

Treatments Symptomatic

A number of symptomatic therapies are useful in patients with AE. is is especially relevant to those with NMDAR-antibody enceph- alitis who o en have a protracted clinical course, with agitation or seizures, and require intensive care unit admission.

Atypical antipsychotics, especially olanzapine, quetiapine, and benzodiazepines are used to sedate agitated, psychotic patients. Haloperidol should be avoided if possible as it can worsen parkin- sonism and may precipitate oculogyric crises. Electroconvulsive therapy should be reserved for the most refractory cases.122 Benzodiazepines may also be used for seizure control, as should other antiepileptic agents, but o en immunotherapies are more e ective at achieving seizure control (see following for more details). For those patients admitted to ITU, especially those with NMDAR-antibody encephalitis, long-term ventilation is o en required. A thiopental coma may be induced and empirical thera- pies for control of blood pressure, bradycardia/asystole, and dyski- nesias are o en administered.

Immunotherapies

e mainstay of disease modi cation in patients with AE is immu- notherapies with evidence principally based on expert clinician experience and respective observational data.

e largest dataset exists for patients with NMDAR-antibody encephalitis. is disease is thought to have a natural history show- ing a chronic course, o en over several years with relapses. A retro- spective series of 501 patients with NMDAR-antibody encephalitis has o ered a number of recommendations.90 is series showed

that 53 per cent of patients respond to steroids, IVIG and/or plasma exchange. 57 per cent of the non-responsive patients were subse- quently either treated with additional immunotherapy (cyclophos- phamide and/or rituximab) or no incremental immunotherapies. e group who were o ered further immunosuppressive agents had a better outcome (p = 0.012). Overall, at two years, 394/501 (79 per cent) patients had a good outcome (modi ed Rankin score, mRS < 3). Patients who were not o ered any treatment had a 13 per cent mortality rate compared to 8 per cent in those treated with any immunotherapy. Furthermore, relapse rates were reduced in patients o ered additional immunotherapies. e message is con- sistent with other studies: treat early and upscale immunotherapy if there is a limited response.25,123 A similar message emerges from the literature around patients with LGI1-antibody encephalitis. Data show that time to reach baseline or improved function (meas- ured by mRS) is expedited with early treatment, in particular cor- ticosteroids.4,31,37 However, as for NMDAR-antibody encephalitis, it is not clear whether treatments for VGKC-complex antibody LE alter long-term outcomes. Indeed, a recent retrospective analysis suggested identical outcomes at four years in 64 patients with LGI1- antibodies treated with corticosteroids alone, corticosteroids plus IVIG, or corticosteroids plus IVIG and PLEX.2 As many patients do well with rst-line immunotherapies, data regarding second- line immunotherapies in VGKC-complex antibody LE are limited to two recent retrospective reports which suggest a response to rituximab in a minority of corticosteroid-refractory patients.124,125

Pathophysiological hypotheses

Our understanding of the pathophysiology of these diseases is based upon clinical and serological observations, in addition to recent in vitro and in vivo studies. As discussed earlier, antibodies are likely to be peripherally generated. e cells, and limited amounts of anti- bodies, then migrate across the blood–brain barrier.

Postmortem studies have suggested that sometimes, especially in cases with VGKC-complex antibodies, there is complement xation by bound antibodies.87 In NMDAR-antibody encephalitis, comple- ment appears to play less of a role. In this disease, the receptors are internalized by the divalent antibodies and this appears to be the major pathogenic mechanism.126 ese di erences may explain the atrophy seen in many patients with VGKC-complex antibody disease, and o ers a potential reason for why the patients with NMDAR antibodies may make an almost complete recovery with less brain atrophy.112 Antibodies may also directly a ect channel function although this appears to be a minor mechanism (Fig. 28.6).

However, many questions related to pathophysiology remain unanswered, including why the antibodies modulate hippocampal regions speci cally given the widespread antigen distribution,127 why these diseases di er from those associated with genetic or pharmacological manipulations of the antigenic target,17 how neur- onal plasticity may account for patient recovery from the disease, and the relevance of IgM and IgA subclasses of autoantibodies.

e autoimmune encephalitides as models for the neurobiology of disease

VGKC-complex antibody-associated LE as a model of hippocampal function

Extensive pathological series have not been undertaken in VGKC- complex antibody LE but case reports describe lesions con ned to either the amygdala and/or adjacent hippocampi with only mild

PRESYNAPTIC

LGI1

ADAM 22

C1q

CHAPTER 28 autoimmune encephalitis 309 GLU

GLU GLU

2. Complement GLU

LGI1

ADAM 22

NMDAR

fixation
Ca2+

C9 neo
and C3b MN

D A R

3. Direct effect

on channel kinetics

LGI1

POST-SYNAPTIC ADAM 22

NMDAR
1. Internalization

Fig. 28.6 Potential pathogenic mechanisms of neuronal surface directed antibodies (NSAbs). (1) Internalization of receptors has been demonstrated in vitro using NMDAR (N-methyl-D-aspartate receptor), AMPAR (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor), and GABAAR (γ-aminobutyric acid A receptor) antibodies. Here the LGI1–DAM22 interaction is shown as a possible unit for cointernalization, as is the NMDAR. (2) Antibody-mediated complement xation and complement-mediated membrane receptor disruption is another possible mechanism as is direct alteration of ion channel molecular function (3).

Reproduced from J Neurol. 262(4), Varley J, Vincent A, and Irani SR, Clinical and experimental studies of potentially pathogenic brain-directed autoantibodies: current knowledge and future directions, pp. 1081–95, Copyright (2014), with permission from Springer, reproduced under the Creative Commons Attribution License.

in ltration, if any, of the surrounding MTL structures.88,128,129 One pathological report even describes damage restricted to just the CA4 region of the hippocampus with relative sparing of regions CA1–3.88 Combined with the imaging and behavioural features discussed earlier there is strong evidence to suggest that VGKC- complex antibody encephalopathy is a disease limited to the MTL structures.

One potential implication regarding the apparent restricted MTL pathology following VGKC-complex antibody LE is that these patients could serve as a human model of focal MTL dam- age. Given the retained phylogeny of the mammalian hippocampus across species130 there are several mnemonic71,130–132 and compu- tational accounts133 of the hippocampus that have yet to be studied in humans.

As cited earlier, three VGKC-complex antibody LE patients were studied for evidence of retrograde amnesia for episodic events and faces (i.e. those that occurred as a single event like the fall of the Berlin Wall).36 ese patients were found to have a temporally ungraded amnesia (i.e. extensive for more than 20 years), greater than might otherwise be expected according to current models of memory consolidation.71 However, no measures of episodic mem- ories for personal events were reported, and as such these results can only relate to our understanding of the neural basis of seman- tic memory. e questions asked were highly episodic in nature and so demonstrate the requirement of episodic neural apparatus for semantic recall, especially if relations between object and time are needed.134,135 Hippocampal pathology associated with VGKC- complex antibody LE has also been reported to impair future imagining, a constructional process believed to be reliant upon the hippocampus.136,137

e hippocampus is o en conceptualized as a structure that binds items and their locations or contexts into a single mnemonic entity.132,138 Within this model, focal lesions to the MTL would gen- erate behavioural de cits on tasks requiring associations between several di erent stimuli. A series of VGKC-complex antibody LE patients were found to have de cits on a visual working memory task that required the binding of multiple items in space but not sin- gle items.139 One intriguing possibility will be to investigate whether VGKC-complex antibody LE results in hippocampal sub eld path- ology, especially given that the theoretical models of hippocampal function rely on the functional heterogeneity of these regions.132,133

e glutamate hypofunction theory

of psychosis

Published studies have reported con icting results about the rates of NMDAR-antibodies in schizophrenic patients or those with rst episode psychosis, versus controls. is is probably in part due to discrepancies in assay methodologies, as mentioned earlier. Nevertheless, the close association of psychotic features at the onset of NMDAR-antibody encephalitis lends weight to the importance of glutamate, and the NMDAR, in the pathogenesis of schizophre- nia. Research spanning 50 years supports the similarities between models of human NMDAR dysfunction and schizophrenia. Indeed, the NMDAR hypofunction hypothesis of schizophrenia is a model built around observations that low doses of NMDAR antagonists, like ketamine and phencyclidine, produced psychotic and negative symptoms alongside concomitant cognitive impairments.140,141 Whilst the neurochemical alterations responsible for schizophre- nia are complex and involve several neurotransmitter systems

310 SECTION 3 cognitive impairment and dementia

including dopamine, glutamate, and 5-hydroxytryptamine, the role References

of glutamate appears to be key in this process.142
In vivo, NMDAR antagonism causes an increase in the ring

rate of pyramidal neurons and increased mRNA expression of the immediate-early gene c-fos. In turn, this causes an increased release of other cortical neurotransmitters like glutamate, dopa- mine, and 5-HT143,144 but also of GABA.145 It appears paradoxical that NMDAR blockage would lead to the emergence of the facilita- tory actions of these other neurotransmitter systems and produce the positive symptoms observed in schizophrenia. However, disin- hibition of the GABA-ergic system induces cognitive, behavioural, and dopaminergic alterations commonly seen in schizophrenia,146 and it has been proposed that the NMDAR antibodies are predomi- nantly acting on GABA-ergic neurons. Similarly, the seizures likely to be caused by NMDAR-antibody-induced NMDAR downregu- lation suggest that the NMDAR antibodies may be mediating an e ect via disinhibition of GABAergic systems.

Single photon emission computed tomography (SPECT) studies

with NMDAR ligands have shown a reduction in NMDARs in the

hippocampi of medication-free schizophrenic patients,147 a nding

replicated with ketamine and one that was strongly correlated with

negative symptoms.148 is reduction in NMDARs is also seen in the

few available postmortems of patients with NMDAR antibodies.126

ese converging pieces of evidence suggest there are two phases

to NMDA dysfunction in the emergence of symptoms suggestive of

schizophrenia: an acute phase charaterized by cortical disinhibition

resembling rst-episode psychosis and a sustained phase of NMDA

receptor hypofunction believed to simulate the chronic, negative

symptoms of schizophrenia.149 Maybe the latter can also be respon-

sible for the movement disorder and brainstem dysfunction com-

monly associated with NMDAR-antibody encephalitis. Di usion

tensor imaging (DTI) has demonstrated that chronic administration

of ketamine causes abnormalities in frontal callosal bres in pat-

terns not unlike schizophrenia,150 or indeed in NMDAR-antibody

112
encephalitis. ese changes could underlie the emergence of the

chronic symptoms of schizophrenia142 and could underlie the cog- nitive changes seen secondary to NMDAR-antibody encephalitis.112 While NMDA hypofunction is not the sole cause of schizophre- nia, several related strands of research suggest that glutamate dys- function is an important contributor to the emergence of positive and negative symptoms associated with schizophrenia. e over- laps with NMDAR-antibody encephalitis patients support a shared

pathophysiological mechanism with schizophrenia.

Conclusion

e autoimmune encephalopathies associated with antibodies directed against cell surface neuronal proteins are an expanding group of immunotherapy-responsive conditions with distinctive clinical features and major potential implications for neurobiol- ogy studies. Future studies will o er insights as to how speci c prolonged receptor dysfunction is reversible, the mechanisms of plasticity, and the neuronal networks engaged in the disease pro- cess and recovery. Furthermore, the di ering focality of these dis- eases may o er novel insights into functional localizations. Novel antibody targets are likely to emerge in diseases with cognitive and psychiatric overlaps. Knowledge of their biology will feed into the diseases with known antibody targets and further inform a number of brain neurotransmitter systems and neuronal populations.

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CHAPTER 28 autoimmune encephalitis 313

314 SECTION 3 cognitive impairment and dementia

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CHAPTER 29

Pathology of degenerative dementias
Tamas Revesz, Tammaryn Lashley, and Janice L. Holton

Introduction

e term neurodegenerative disease is used to describe a large group of neurological conditions characterized by relentless clini- cal deterioration due to gradual loss of neuronal function.

e pathological processes underlying neurodegenerative dis- orders o en selectively a ect anatomically interconnected, func- tionally related systems and networks giving rise to characteristic, o en overlapping clinical presentations such as di erent forms of dementia, akinetic or hyperkinetic movement disorders, or cerebel- lar degenerations. As the distribution of the pathological changes determines the clinical presentation, several diseases may result in a similar clinical presentation. e examples include frontotem- poral dementia (FTD) and corticobasal syndrome, which may be caused by one of a number of diverse pathologies.1,2

In order to be able to execute their functions, newly produced pro- teins need to acquire a speci c three-dimensional structure, which is the result of a process that takes place under stringent quality control. Central to the pathomechanism of the neurodegenerative dementias to be discussed in this chapter is that they are charac- terized by age-dependent misfolding, abnormal aggregation and deposition of disease-speci c proteins, hence the o en used terms protein folding or conformational disorders, proteinopathies, or proteopathies.3 e initial phase of the protein aggregation process is the conversion of random-coil secondary structures of soluble native proteins into β-sheet-rich conformations, which initially self- associate into oligomers, consisting of only a few protein molecules, followed by formation of proto brillar intermediate ensembles and, nally, brils.4 ere are several mechanisms, which are known to be able to destabilize the secondary structure of soluble native pro- teins, and these include increased protein concentration and genetic as well as post-translational modi cations of proteins.

Duplication or triplication of genes are associated with increased protein concentration while missense mutations in the coding region of a gene results in an amino acid substitution, which can alter the aggregation potential of a disease protein. Another genetic mechanism is represented by the suprathreshold expansion of an unstable cytosine–adenine–guanine (CAG) repeat region, which takes place in the huntingtin (HTT) gene resulting in the formation of an expanded polyglutamine stretch predisposing the huntingtin protein to aggregation in Huntington’s disease.5

Mutations may also cause disease via haploinsu ciency such as in familial FTD with parkinsonism due to mutations of the GRN gene (FTDP-17GRN), leading to reduced levels of progranulin

protein,6 although the link to the formation of the TAR DNA- binding protein-43 (TDP-43) inclusions is still not clear. Mutations in noncoding intronic sequences may change the process of alter- native splicing of a disease-related protein such as that of the microtubule-associated protein tau, which is the main component of neuro brillary tangles in Alzheimer’s disease and a number of primary tauopathies (see also following).7

Repeat expansion of a GGGGCC hexanucleotide repeat, present in a noncoding region of the C9orf72 gene, has been identi ed as a major cause of familial motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) and also FTD. Data indicate that there is at least 50 per cent loss of at least one of three C9orf72 transcripts. e mechanisms that may be responsible for disease in the C9orf72 cases include haploinsu ciency, RNA gain of function with the formation of nuclear RNA foci, or the expanded non-coding GGGGCC repeats are translated via repeat-associated non-ATG translation process.8

e most common risk factor for sporadic protein-folding disor- ders is age, which is thought to result in altered protein homeosta- sis (proteostasis), possibly due to changes in cellular protein levels and/or failure of cellular machinery responsible for eliminating damaged, misfolded proteins.3 Genome-wide association studies have also demonstrated genetic variants which carry an increased risk for developing sporadic neurodegenerative diseases such as Alzheimer’s disease, frontotemporal lobar degeneration with TDP- 43 inclusions (FTLD-TDP), Parkinson’s disease, and progressive supranuclear palsy.9

As pathologically altered proteins, characteristic for each disease or group of diseases, form extracellular deposits and/or intracel- lular inclusions in neurons and in some instances also in glia, these protein aggregates provide a valuable tool in the everyday neuro- pathological diagnosis. Although the aetiology of the majority of neurodegenerative diseases remains elusive, the signi cant increase in knowledge about genetic background, cellular events, and bio- chemical changes has allowed the introduction of molecular clas- si cations of neurodegenerative diseases, including dementias, which will be followed in this chapter (Table 29.1).

Diseases with extracellular protein

aggregates and neuro brillary degeneration

is group of diseases are all characterized by formation of extracel- lular amyloid plaques composed of di erent disease-speci c amy- loid peptides, accompanied by neuro brillary degeneration. In this

Table 29.1 Molecular classi cation of neurodegenerative dementias

Disease

Type of protein deposit

Toxic protein

Precursor protein

Genes+

Risk factors

Diseases with amyloid plaques and NFT

Alzheimer’s disease

Senile plaques CAA

Aβ

APP

APP, PS1, PS2

Yes*

NFT

tau

Familial British dementia

Amyloid plaques CAA

ABri

ABriPP

BRI2

NFT

tau

Familial Danish dementia

Amyloid plaques CAA

ADan

ADanPP

BRI2

NFT

tau

Prion diseases

Amyloid plaques CAA**

PrP

PRNP

Yes

NFT

tau

Synucleinopathies

Dementia with Lewy bodies

Lewy body

αSyn

SNCA

Yes*

Amyloid plaques

Aβ

APP

Parkinson’s disease with dementia

Lewy body

αSyn

SNCA

Amyloid plaques

Aβ

APP

Frontotemporal lobar degenerations

FTLD-TDP

TypeA

NCI, NII, DN, GI

TDP-43

GRN, C9orf72

Yes*

TypeB

NCI

TDP-43

C9orf72

TypeC

TDP-43

–

TypeD

NII, DN

TDP-43

VCP

FTLD-FUS

aFTLD-U

NCI, NII, GI

FUS

–

NIFID

NCI, NII, GI

FUS

–

BIBD

NCI, NII, GI

FUS

–

FTLD-tau

Pick’s disease

Pick body, GI

tau

–

CBD

NFT, NT, GI-AP

tau

–

MAPT, H1

PSP

NFT, NT, GI-TA

tau

–

MAPT, H1

GGT

NFT, NT, GGI

tau

–

AGD

NFT, NT, GI

tau

–

FTDP-17MAPT

NFT, NT, GI

tau

MAPT

Polyglutamine diseases

Huntington disease

NII, CP

Huntingtin

HTT

αSyn: α-synuclein; Aβ: amyloid-β; APP: amyloid precursor protein; ABri: amyloid-Bri; ABriPP: amyloid-Bri precursor protein; ADan: amyloid-Dan; ADanPP: amyloid-Dan precursor protein; aFTLD-U: atypical FTLD with ubiquitin-positive, tau and TDP-43-negative inclusions; AGD: argyrophilic grain disease; AP: astrocytic plaque, BIBD: basophilic inclusion body disease; CAA: cerebral amyloid angiopathy; CBD: corticobasal degeneration; CP: cytoplasmic positivity; DN: dystrophic neurites; FTDP-17MAPT: frontotemporal dementia with parkinsonism linked to chromose 17 due to mutation of the MAPT gene. FTLD: frontotemporal lobar degeneration; FUS: fused in sarcoma; GGI: globular glial inclusion; GI: glial inclusion; GGT: globular glial tauopathy; NCI: neuronal cytoplasmic inclusion; NIFID: neuronal intermediate lament inclusion disease; NII: neuronal intranuclear inclusion; NFT: neuro brillary tangle; NT: neuropil thread; PrP: prion protein; PSP: progressive supranuclear palsy; TA: tufted astrocyte; TDP-43: TAR DNA-binding protein-43. For gene abbreviations see: <http://www.ncbi.nlm.nih.gov/omim/>; *For review see reference 9; ** CAA is a rare manifestation in prion diseases; for review see reference 4.

group, Alzheimer’s disease and the BRI2 gene-related dementias will be discussed and, although some of the familial prion diseases would also fall into this category, they will be discussed elsewhere.

Alzheimer’s disease

Alzheimer’s disease, by far the most common neurodegenerative disease, is characterized microscopically by two cardinal features: (1) deposition of the amyloid-β peptide (Aβ) in cerebral paren- chyma as senile plaques and in blood vessels as cerebral amyloid angiopathy, and (2) formation of neuro brillary tangles, which are composed of abnormally hyperphosphorylated tau, which is a microtubule-associated protein.

Aβ is produced by multistep processing of the amy- loid precursor protein (APP) with the initial step being a β-secretase cleavage, which releases a 99-amino-acid-long C-terminal fragment (C99). is is followed by a second, intram- embranous cleavage by the γ-secretase complex, which produces 40- or 42-amino-acid-long peptides (Aβ40 and Aβ42).10 Soluble Aβ is considered the precursor of disease-associated Aβ deposited in the brain.

Neuro brillary tangles are due to intraneuronal accumulation of abnormally hyperphosphorylated tau laments in the cell soma of neurons. Tau laments also deposit in dendrites as neuropil threads and in axons surrounding amyloid plaques as plaque-associated neurites.

Macroscopic changes

Based on the investigation of large cohorts of cases at postmortem, an overall reduction in brain weight is a typical feature of Alzheimer’s disease, although in individual cases the severity of substance loss is variable and may overlap with age-matched controls. Brain atrophy is usually most severe in medial temporal lobe structures, includ- ing the hippocampus (Fig. 29.1). It is also prominent in the infer- ior temporal, middle, and superior frontal gyri while the inferior frontal and orbitofrontal gyri and the occipital lobe are preserved.11 In early-onset and familial (autosomal-dominant) cases, brain atro- phy may be more severe. Inspection of coronal slices of the cere- bral hemispheres also demonstrates thinning of the cerebral cortex, reduction in bulk of subcortical white matter, enlargement of the ventricles (Fig. 29.1) and pallor of the locus coeruleus. Data pro- vided by in vivo studies using serial MRI have provided insight into the time course of brain atrophy in Alzheimer’s disease.12

Microscopic changes

e diagnosis of Alzheimer’s disease at postmortem depends on the recognition of senile/neuritic plaques and neuro brillary degeneration in brains of individuals with dementia. Both the Aβ (Fig. 29.1E and 29.1F) and neuro brillary tangle pathologies (Fig. 29.1C and 29.1D) follow a stereotypic progression from early stages of subclinical Alzheimer’s disease to full-blown disease. e Braak and Braak scheme proposes six di erent stages of hierarchical pro- gression, re ected in the distribution and severity of neuro brillary degeneration. According to this, the transentorhinal and entorhinal cortices are a ected in stages I and II, the hippocampus and other limbic structures in stages III and IV, while isocortical areas are involved in stages V and VI.13,14

Aβ plaque accumulation in different brain areas has also been shown to advance in a hierarchical manner and according to

the scheme recommended by Thal and colleagues this can be separated into five distinct phases.15 In phase 1 Aβ deposits are restricted to the neocortex; in phase 2 additional involve- ment of allocortical regions including the hippocampus and entorhinal region is seen; in phase 3 the Aβ pathology extends into diencephalic nuclei, the striatum, and cholinergic nuclei of the basal forebrain; in phase 4 brainstem nuclei are affected, and finally in phase 5 Aβ deposition also takes place in the cerebellum.

The most up-to-date neuropathological diagnostic criteria of Alzheimer’s disease include the establishment of a CERAD (Consortium to Establish a Registry for Alzheimer’s Disease) neur- itic plaque-score (none, sparse, moderate, or frequent), the Braak and Braak neuro brillary pathology stage (0–VI), and al Aβ deposition phase (0–5). Consideration of all three components allows the neuropathologist to establish an ABC score, and nally the level of Alzheimer’s disease neuropathological change (none, low, intermediate, and high levels) is provided.16

Cerebral amyloid angiopathy (CAA)

Amyloid deposition takes place in leptomeningeal and paren- chymal small blood vessels, including arteries, arterioles, and capillaries in over 80 per cent of all Alzheimer’s patients (Fig. 29.1G).17 The ApoE ε4 allele is more prevalent when cap- illary amyloid is also present (type 1) than in cases without capillary Aβ deposition (type 2).18 Hypoperfusion and occlu- sion of capillaries due to cerebral amyloid angiopathy are pos- sible additional mechanisms, which adversely affect the brain in Alzheimer’s disease.19

Other diseases coexisting with Alzheimer’s disease

Lewy body disease, TDP-43 inclusions, argyrophilic grain disease, vascular brain injury, and hippocampal sclerosis are the most com- mon comorbidities in Alzheimer’s disease.20

Alzheimer’s disease neuropathology after Aβ42

immunotherapy

Postmortem examination of brains of Alzheimer patients treated with active Aβ42 immunotherapy showed lower Aβ load with evi- dence that plaques had been removed, a reduced tau burden in neuronal processes, but no evidence of a bene cial e ect on syn- apses. e pathological side-e ects included an increased micro- glial activation and increased CAA.21

Familial British dementia and familial

Danish dementia

Mutations of the BRI2 gene cause the two, closely related rare her- editary, autosomal dominant neurodegenerative diseases, familial British dementia and familial Danish dementia (BRI2 gene-related dementias).22,23 Clinically, patients present with a ‘dementia and spasticity’ syndrome, but cerebellar ataxia is also characteristic.24

Neuropathologically, both familial British dementia (Fig. 29.1H- J) and familial Danish dementia (Fig. 29.1K-M) show a striking resemblance to Alzheimer’s disease as in both there are widespread cerebral parenchymal amyloid plaques, severe CAA and neuro bril- lary tangles, although the ABri and ADan amyloid peptides, have no homology with the Aβ peptide.25,26

CHAPTER 29 pathology of degenerative dementias 317

318 SECTION 3 cognitive impairment and dementia

Fig. 29.1 Pathological features of neurodegenerative diseases with extracellular protein deposition. A: A macroscopic coronal slice from a case with Alzheimer’s disease and B: Brain slice from a matched control case. e Alzheimer case shows enlargement of the lateral ventricle (arrow) and a reduced sized hippocampus (double arrows). Please also note the narrowing of the cortical ribbon and the reduced bulk of the hemispheric deep white matter in Alzheimer’s disease. C: Tau immunohistochemistry shows neuro brillary tangles (arrow) and numerous neuropil threads, and D: Plaque-associated abnormal neurites (arrows) while Aβ immunohistochemistry (E–G) demonstrates di use and mature plaques (E and F), and a blood vessel with cerebral amyloid angiopathy (G) in the cerebral cortex in Alzheimer’s disease (AD).

H–J: Familial British dementia (FBD) is characterized by deposition of the ABri peptide in amyloid and preamyloid plaques (H) and blood vessel walls resulting in severe cerebral amyloid angiopathy (I). J: Neuro brillary tangles (arrow), neuropil threads and ABri plaque-associated neurites (double arrow) are also present. K–M: In familial Danish dementia (FDD), the parenchymal ADan deposits are of the di use, preamyloid type (K) and, as in familial British dementia, the cerebral amyloid angiopathy is widespread and severe (L). M: Tau immunohistochemistry demonstrates neuro brillary tangles (arrow), neuropil threads, and abnormal, tau-positive neurites, which are seen around amyloid-laden blood vessels (double arrow) in this disease.

Frontotemporal dementias

A er Alzheimer’s disease, FTD is the second most common form of dementia in the presenium (disease onset <65 years). e term frontotemporal lobar degeneration (FTLD) is used by neuropathol- ogists for this clinically, genetically, and pathologically diverse group of diseases. A common feature is degeneration of the frontal and temporal lobes with the canonical clinical presentations being behavioural variant FTD (bvFTD), progressive non- uent apha- sia (PNFA), and semantic dementia (SD). An important aspect

of FTLDs is that degeneration of motor neurons may also occur, which highlights the aetiological link between FTLDs and MND)/ ALS (FTLD–ALS spectrum). e major genes currently known to be involved in familial FTDs include the MAPT, GRN, C9orf72, TARDBP, VCP, and CHMP2B genes (see chapter 35).6

Classi cation of frontotemporal lobar degenerations

e discovery of tau, TDP-43, and the fused in sarcoma protein (FUS) as the disease proteins composing pathological inclusions and the identi cation of several genes associated with familial

Table 29.2 FTLD-tau

of Pick’s disease; it is frontotemporal in bvFTD cases, frontoparietal in cases when apraxia is also a feature, and peri-Sylvian in cases with PNFA.32

Pick bodies are particularly common in the granule cells of the dentate fascia and pyramidal neurons of the hippocampus, but they are widespread. Pick bodies are composed mainly of 3R-tau isoforms, which can be con rmed with both biochemical meth- ods33 and immunohistochemistry (Fig. 29.2A).34 Tau-positive glial pathology of variable severity is a feature of PiD and these include oligodendroglial cytoplasmic inclusions (Fig. 29.2C) and astrocytic inclusions (rami ed astrocytes) (Fig. 29.2B). ere is di use tau immunoreactivity in the neuropil of a ected grey matter.

Corticobasal degeneration (CBD)

Corticobasal degeneration (CBD), which is a cause of corticobasal syndrome, is a 4R-tauopathy with neuronal and glial tau inclusions in cerebral cortex, basal ganglia, brainstem, and cerebellar nuclei.35 Macroscopically, there is cortical atrophy a ecting the posterior frontal lobe and the parietal region, with involvement of the pre- central and postcentral gyri in cases presenting with corticobasal syndrome. e atrophy may be asymmetrical with the more severe changes being found contralateral to the most severely a ected limbs.32

e cortical atrophy is more generalized in cases with frontal dementia or primary progressive aphasia.36–38 A ected cerebral cortices show neuronal and glial inclusions, neuronal loss with astrocytosis and super cial spongiosis. Pick cells are a feature of CBD.37 ere is signi cant loss of neurons in the substantia nigra. Neuronal loss, astrocytosis, and occasional swollen neurons are variable in subcortical grey nuclei. e corticospinal tracts may show evidence of degeneration.39,40

4R-tau-positive neuronal inclusions are usually prominent in areas of super cial microvacuolation in moderately a ected cor- tex and are seen in subcortical grey nuclei, substantia nigra, other brainstem nuclei, and cerebellar dentate nucleus.37,41,42 Tau- positive coiled bodies (oligodendroglial inclusions) are widespread in cortices and white matter (Fig. 29.2D).42–44 e characteristic lesion is the ‘astrocytic plaque’, comprising a distinct annular array of short, tau-positive stubby processes (Fig. 29.2E)43,45,46 most easily identi ed in the premotor, prefrontal, and orbital cortical regions and also in the striatum.47 Tau-positive neuropil threads are also frequent,2,35

Progressive supranuclear palsy (PSP)

PSP is the most common primary tauopathy with the common clinical presentation being atypical parkinsonism (Richardson’s syndrome, PSP–RS).48 However, some patients may have a clini- cal presentation, which deviates from that seen in PSP–RS and these include parkinsonism resembling initially Parkinson’s disease (PSP–P), corticobasal syndrome (PSP–CBS),49–51 bvFTD,52,53 or speech and language impairment (PSP–FTD).48,54–57

Atrophy of the subthalamic nucleus, midbrain and pontine teg- mentum and marked pallor of the substantia nigra are charac- teristic in the majority of the PSP cases. Atrophy of the superior cerebellar peduncle is also common. e globus pallidus and cere- bellar dentate nucleus are atrophied in a signi cant proportion of the cases and dilatation of the third and fourth ventricles and the cerebral aqueduct is common. Mild generalized or predominantly

CHAPTER 29 pathology of degenerative dementias 319

Predominant tau isoforms in inclusions

3R-tau

4R-tau

3R-tau and 4R-tau

Pick’s disease

PSP

PART

FTDP-17MAPT

CBD

FTDP-17MAPT

AGD

GGT

FTDP-17MAPT

3R-tau: 3-repeat tau; 4R-tau: 4-repeat tau; AGD: argyrophilic grain disease; CBD: corticobasal degeneration; FTLD: frontotemporal lobar degeneration; FTDP-17MAPT: frontotemporal dementia with parkinsonism linked to chromosome 17 due to mutations in the MAPT gene; FTLD-tau: frontotemporal lobar degeneration with tau-positive inclusions; GGT: globular glial tauopathy; PART: primary age-related tauopathy.

forms of FTLD have provided the foundation of a molecular clas- si cation of FTLDs.27,28 ree of the four major disease groups are characterized by speci c proteinaceous inclusions (FTLD-tau, FTLD-TDP, and FTLD-FUS) while in the fourth group the protein component of the ubiquitin-positive inclusions remains unidenti- ed, hence the term FTLD-UPS. Within each of the three groups in which the proteinaceous nature of the inclusions is known there are several subtypes or separate diseases (Table 29.1).

Tau

Tau is a microtubule-associated protein and its main function is to promote assembly and stabilization of microtubules. In the adult human brain, six tau isoforms are expressed by alternative splicing from the MAPT gene.29 e isoforms are di erent from one another on the basis of the presence or absence of 29- or 58- amino-acid-long N-terminal inserts and whether they possess a fourth 31-amino-acid-long repeat in the microtubule-binding domain of tau. On the basis of presence or absence of this fourth repeat sequence, there are two major classes of tau isoforms. ree isoforms contain three repeats (3R-tau) with the remaining three having four repeats (4R-tau) in the microtubule-binding domain of tau. In some diseases such as progressive supranuclear palsy, corticobasal degeneration, and certain forms of FTDP-17 due to mutations of the MAPT gene (FTDP-17MAPT), the inclusions are predominantly composed of 4R-tau, while in Pick’s disease and some forms of FTDP-17MAPT they are composed of 3R-tau. Both 3R-tau and 4R-tau are present in a third group, which includes Alzheimer’s disease, familial British dementia, familial Danish dementia, and certain forms of FTDP-17MAPT (Table 29.2).30

Frontotemporal lobar degenerations with

tau-positive inclusions (FTLD-tau)

Pick’s disease

Pick’s disease is a rare cause of FTD of all dementia cases (~5 per cent) in large autopsy series.31 It is characterized by severe circum- scribed lobar atrophy with marked neuronal loss with accompa- nying gliosis, presence of swollen achromatic neurons (Pick cells), and compact, rounded, argyrophilic and tau-positive neuronal cytoplasmic inclusions, known as Pick bodies. e distribution of the localized cortical atrophy correlates with the clinical phenotype

320 SECTION 3 cognitive impairment and dementia

Fig. 29.2 Pathological features of FTLD-tau. A: In Pick’s disease the characteristic inclusions, Pick bodies, are composed of 3R-tau. Pick bodies are numerous in the granule cells of the dentate fascia. B and C: Tau-positive glial pathology in the form of rami ed astrocytes (B) and oligodendroglial cytoplasmic inclusions (C) is also characteristic. D: In corticobasal degeneration (CBD), subcortical white matter areas are particularly rich in tau-positive neuritic processes. E: e hallmark lesion is the astrocytic plaque in CBD. F–H: Progressive supranuclear palsy (PSP) is characterized by accumulation of hyperphosphorylated 4R-tau in neurons (F) and glia (G and H). G: e stellate shaped tufted astrocytes are the hallmark lesions in PSP and oligodendroglial, coiled bodies are also common (H). I: Widespread deposition of 4R-tau in a ected grey matter in argyrophilic grain disease. J: In this condition argyrophilic, tau-positive grains are characteristic, which represent tau deposition in neuronal apical dendrites.

frontal atrophy with involvement of the precentral and postcen- tral gyri may be seen. e microscopic pathology of progressive supranuclear palsy is characterized by accumulation of hyper- phosphorylated 4R-tau in neurons and glia, neuronal loss in basal

ganglia, brainstem, and cerebellar nuclei with astrocytosis.41,58 e neuronal tau pathology includes both neuro brillary tangles and pretangles (Fig. 29.2F). e tu ed astrocytes (Fig. 29.2G) or glial brillary tangles, which are tau-positive stellate-shaped astrocytes

possessing ne radiating processes, are highly characteristic for this disease.41,58 Deposition of brillar tau in oligodendroglia gives rise to coiled bodies (Fig. 29.2H).41 Neuropil threads are also present in both grey and white matter. In PSP–RS, the tau burden is usually greater in the basal ganglia and brainstem structures than in neo- cortex. In contrast, PSP–CBS and PSP–FTD variants are associated with an increased neocortical tau load.49–51,54

Argyrophilic grain disease (AGD)

Argyrophilic grain disease (AGD) is a sporadic 4R-tauopathy occurring in the elderly with or without clinical dementia. Young- onset disease has been documented to present clinically as FTD,59 but AGD does not have a consistent phenotype and is therefore not diagnosable during life.

e pathological hallmark lesions are the argyrophilic and tau- positive grains, which are comma- or spindle-shaped small 4–8 micron structures, occurring in apical dendrites (Fig. 29.2I, J). Other tau-positive lesions such as coiled bodies, pretangles, and bushy astrocytes are also features.60 Balloon neurons are also a characteristic, albeit non-speci c feature of the pathology.

e neuropathological changes are mostly restricted to the medial temporal lobe, but structures such as orbitofrontal cortex, insular cortex, hypothalamic lateral tuberal nucleus, and nucleus accum- bens may also be a ected. A di use form, associated with frontal lobe dementia, has been documented.60 Staging of AGD, re ecting progression of the disease, has been proposed.61 AGD is seen to occur in association with other neurodegenerative disease such as Alzheimer’s disease, CBD, PSP, Pick’s disease, and FTDP-17MAPT.

Tangle-predominant dementia

Tangle-predominant dementia or primary age-related tauopathy (PART) also occurs in elderly individuals and neuropathology is characterized by neuro brillary tangles composed of 3R- and 4R- tau with no or mostly di use Aβ plaques. e tangle pathology may be relatively restricted to the medial temporal lobe with ghost, extracellular tangles o en being a feature.

Globular glial tauopathy

A form of sporadic tauopathy has been identi ed in which, in addi- tion to neuronal tau inclusions, there are widespread characteristic ‘globular’ oligodendroglial and astrocytic inclusions composed of 4R-tau. e cases have been described under a number of di er- ent names and have been reported to be associated with a range of clinical presentations including FTD,62 MND/ALS,63 or a combina- tion of both FTD and MND/ALS.64 Recently the overarching term of globular glial tauopathy has been recommended.65

Frontotemporal dementia with parkinsonism linked to chromosome 17 due to mutations of the MAPT gene (FTDP-17MAPT)
ere are over 40 di erent mutations which have been identi ed as a cause of FTDP-17MAPT. A group of mutations a ect alterna- tive splicing of tau pre-mRNA while the primary e ect of others is at protein level, resulting in reduced ability of tau to interact with microtubules.66

Although the severity of the macroscopic changes is dependent on the length of the disease duration, cases with intermediate and late disease stages show frontotemporal atrophy of variable severity,

enlargement of the lateral and third ventricles, reduction in bulk of the white matter of the centrum semiovale and temporal lobes, atrophy of the basal ganglia with pallor of the substantia nigra and locus coeruleus.67

Microscopically there is super cial spongiosis and a variable degree of nerve cell loss in the a ected cortical regions accompa- nied by astrogliosis. Swollen, achromatic neurons may be present. Nerve cell loss is usually seen in a ected basal ganglia and brain- stem nuclei. Tau-positive inclusions are widely distributed in cer- ebral cortex, subcortical grey matter structures, brainstem nuclei, and cerebellum, and may be seen in the spinal cord. e pattern of tau pathology is variable and depends on the type of the MAPT mutation, which also determines whether tau deposition takes place in neurons or in both neurons and glia.

Neuronal inclusions include pretangles, neuro brillary tangles, and Pick body-like inclusions. e spectrum of glial inclusions includes oligodendroglial coiled bodies, tu ed astrocytes, and astrocytic plaques. In some of the mutations such as V337M and R406W, neuro brillary tangles predominate. In these variants the biochemical characteristics of insoluble tau and the ultrastruc- tural features of the tau laments are similar to Alzheimer tau.68,69 A number of mutations such as K257T, G272V, Q336R, and G389R result in a pathological phenotype in which Pick bodies are char- acteristic. As in cases of sporadic Pick’s disease, in these mutants Pick bodies are primarily composed of 3R-tau isoforms, although in some cases inclusions also contain 4R-tau.

e impact of mutations in intron 10 (+3, +11, +12, +13, +14) or exon 10 (N279K, N296N, N296H, and G303V) on alternative splicing of tau is such that 4R-tau is more abundant and forms the inclusions.67 In another group of cases such as those with P301L or P301S mutations, the tau laments are also formed by 4R-tau, but the mutations’ primary e ect is at protein rather than pre-mRNA level. e pathological phenotype in these variants is neuronal and glial, and importantly glial pathology reminiscent of progres- sive supranuclear palsy and corticobasal degeneration has been documented.70

Frontotemporal lobar degenerations with

TDP-43-positive inclusions (FTLD-TDP)

Pathologically, FTLD-TDP is de ned by the presence of inclusions, composed of the disease-associated form of TDP-43.71–73 TDP-43 is a highly conserved RNA/DNA binding protein, which is widely expressed and predominantly found in the nucleus. It shuttles between the cytoplasm and nucleus and its major functions include transcription and splicing regulation, microRNA processing, apop- tosis, cell division, and stabilization of messenger RNA.74

FTLD-TDP includes both sporadic and familial forms and, being responsible for ~50 per cent of all FTLD, is the largest FTLD type.75 e altered TDP-43 protein is N-terminally truncated, hyperphos- phorylated, and ubiquitinated. A further important feature of the pathology is that inclusion-harbouring nerve cells lose the di use nuclear TDP-43 staining, which is seen in normal neuronal nuclei (Fig. 29.3A).71,76 In FTLD-TDP the typical postmortem macro- scopic nding is frontotemporal cerebral atrophy. is is asymmet- rical in some cases such as in those with GRN gene mutations, in which involvement of the parietal lobe is also found. e asymmetry observed by in vivo imaging in cases with SD may not be seen in

CHAPTER 29 pathology of degenerative dementias 321

322 SECTION 3 cognitive impairment and dementia Table 29.3 FTLD-TDP

ALS parkinsonism/dementia complex, and also in cases with hip- pocampal sclerosis.75

Frontotemporal lobar degenerations with

FUS-positive inclusions (FTLD-FUS)

FUS shuttles between the nucleus and cytoplasm and shows both nuclear and cytoplasmic expression. Its functions are poorly char- acterized but they include cell proliferation, DNA repair, transcrip- tion regulation, and RNA and microRNA processing.74

e FTLD-FUS group includes three sporadic entities, atypical FTLD with ubiquitin-positive, tau- and TDP-43-negative inclu- sions (aFTLD-U), neuronal intermediate lament inclusion disease (NIFID), and basophilic inclusion body disease (BIBD).82–84

In aFTLD-U, the major disease protein of the ubiquitin-positive NCIs and NII is FUS (Fig. 29.3G and 29.3H). Inclusions are seen in frontotemporal cortices, hippocampus, striatum, thalamus, and brainstem nuclei, and spinal cord motor neurons.82,85 A character- istic feature of aFTLD-U is the presence of NIIs, which can be of di erent morphological subtypes and may appear as twisted vermi- form, ring-like, straight, or curved structures (Fig. 29.3G).

NIFID, also described as neuro lament inclusion body disease,86 is characterized by the presence of NCIs (Fig. 29.3I and 29.3J), which are o en eosinophilic and display variable immunoreactiv- ity for ubiquitin, but are o en strongly positive for p62. NIIs also occur in NIFID86 (Fig. 29.3J) and a proportion of the FUS-posi- tive inclusions are also positive for α-internexin and neuro lament proteins.86,87

e term BIBD derives from the pathological observation that inclusions appear basophilic on the haematoxylin and eosin preparation and, as in NIFID, they are variably positive for ubiq- uitin, but, unlike in NIFID, they are negative for α-internexin or neuro lament.

FUS belongs to the family of FET proteins, which also includes Ewing’s sarcoma protein (EWS) and TATA-binding protein-associ- ated factor 15 (TAF15). e FUS-positive inclusions in all FTLD- FUS subtypes, but not those in ALS due to mutations in FUS, also contain EWS, TAF15, and transportin, which is responsible for the nuclear transport of the FET proteins.88,89

Frontotemporal lobar degeneration due to

mutation in the CHMP2B (FTLD-UPS)

Mutations in charged multivescicular body protein 2B (CHMP2B) are associated with familial FTLD (90) with bvFTD and extrapy- ramidal symptoms.91 In the Danish pedigree, the neuronal intra- cytoplasmic inclusions are ubiquitin-positive, but negative for TDP-43 and FUS.92 CHMP2B is a component of the endosomal- sorting complex required for transport-III (ESCRT-III), which is involved in the degradation of proteins in the endocytic and autophagic pathways.

Clinicopathological correlations

in frontotemporal dementia

Large clinicopathological series have allowed the identi cation of certain relatively speci c associations.57,80 SD is predominantly associated with the FTLD-TDP type C while FTD and MND/ALS with TDP-43 type B pathology. PNFA is most commonly due to a tauopathy, although can be caused by Alzheimer’s disease. e

TypeA

TypeB

TypeC

TypeD

Neuronal cytoplasmic inclusions

+ ++

Neuronal intranuclear inclusions

0/+ +

++ +

Dystrophic neurites

+ ++

++ +

Major clinical manifestations

bvFTD, CBS, PNFA

FTD with MND/ ALS, bvFTD

IBMPFD

Mutations in genes*

GRN, C9orf72

C9orf72

–

VCP

0 = absent; + = sparse; + + = moderate; + + + = frequent; bvFTD: behavioural
variant frontotemporal dementia; CBS: corticobasal syndrome; FTD: frontotemporal dementia; FTLD-TDP: frontotemporal lobar degeneration with TDP-43-positive inclusions; IBMPFD: inclusion body myopathy with Paget disease of the bone and frontotemporal dementia; MND/ALS: motor neuron disease/amyotrophic lateral sclerosis; PNFA: progressive non- uent aphasia; SD: semantic dementia * for gene mutations see <http://www.ncbi.nlm.nih.gov/omim/>

Adapted from Lancet Neurol. 9(10), Mackenzie IR, Rademakers R, and Neumann M, TDP- 43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia, pp. 995–1007, Copyright (2010), with permission from Elsevier.

end-stage disease at postmortem. Involvement of the basal ganglia may be noted in some cases and the deep white matter of the fronto- temporal area is o en signi cantly reduced in bulk. A marked dilata- tion of the lateral and third ventricles is seen. e major microscopic TDP-43 lesion types are neuronal cytoplasmic inclusions (NCIs) (Fig. 29.3A), neuronal intranuclear inclusions (NIIs) (Fig. 29.3C and 29.3D), and dystrophic neurites (DNs) (Fig. 29.3B), although deli- cate neurites in the CA1 hippocampal subregion and ‘pre-inclusions with a granular staining pattern’ have also been described.77–79

e currently known genes, associated with familial forms of FTLD with TDP-43 pathology, are the progranulin (GRN), valosin- containing protein (VCP), and C9orf72 genes (for a review see reference 6).

On the basis of morphological features and distribution of the TDP-43 inclusions four subtypes of FTLD-TDP are distinguished with some overlap between subtypes. According to a current har- monized classi cation27 ‘type A’ pathology is present in about 40 per cent of all FTLD-TDP cases and consists of a combination of NCIs, rather short and o en comma-shaped DNs and NIIs. ‘Type B’ pathology is responsible for about one-third of all FTLD-TDP with NCIs being characteristic. If present at all, DNs are sparse. In ‘type C’, which occurs in about 25 per cent of FTLD-TDP, there are rather long and thicker DNs characteristic with NCIs being either absent or rare. In the very rare ‘type D’, associated with mutations in the VCP gene, NIIs and DNs predominate and NCIs are rare or entirely absent.27,80 ere is correlation between pathological sub- type, clinical presentation, and genetics in FTLD-TDP (Table 29.3).

An additional pathology is present in FTLD-TDP cases carrying the C9orf72 expansion repeat. P62 positive ‘star-like’ inclusions are found in neurons predominanlty in the hippocampus and cerebel- lum (Fig. 29.3E and 29.3F).81

Concomitant TDP-43 pathology, o en limited to the medial tem- poral lobe, may be seen in a number of neurodegenerative disor- ders such as Alzheimer’s disease, Lewy body disorders, Guamanian

Fig. 29.3 Pathological characteristics of FTLD-TDP, FTLD-FUS, dementia with Lewy bodies, and Huntington’s disease. A: e major microscopic TDP-43 immunoreactive lesion types are neuronal cytoplasmic inclusions (arrows), B: dystrophic neurites and C and D: neuronal intranuclear inclusions occurring in characteristic combinations in the di erent FTLD-TDP subtypes. E and F: In addition to TDP-43 positive inclusions, characteristic p62-positive ‘star-like’ neuronal cytoplasmic inclusions are also present in neurons of the granule cell layer of the dentate fascia (E) and the cerebellar granule cells (F) in cases carrying the C9orf72 expansion repeat mutation. G–J: FTLD-FUS

is characterized by the presence of FUS-positive neuronal cytoplasmic inclusions and neuronal intranuclear inclusions of di erent morphological subtypes (G–J). Please note that some neurons with cytoplasmic inclusions show preserved nuclear expression of the FUS protein (H) while this is lost in others (I). NIIs also show di erent morphological phenotypes (G and J, arrows) including ring-like and vermiform structures (G). K and L: e major microscopic feature of dementia with Lewy bodies and Parkinson’s disease with dementia is the presence of extensive cortical Lewy pathology including Lewy bodies (K, arrows) and Lewy neurites (L). Multiple Lewy bodies are shown in a neuron of the substantia nigra in a case of Parkinson’s disease with dementia (M). N: In Huntington’s disease (HD) the intranuclear inclusions are readily demonstrated with p62 immunohistochemistry (N). e 1C2 antibody, recognizing expanded polyglutamine repeats, labels intranuclear inclusions, the neuronal cytoplasm of a ected neurons (O and P), and dystrophic neurites (not shown) in HD.

bvFTD syndrome is almost equally associated with FTLD-tau and FTLD-TDP;80 very young-onset (apparently sporadic) bvFTD is closely associated with FTLD-FUS.57,80

Of the familial FTLDs (see chapters 34 and 35), patients with a MAPT mutation most frequently present with bvFTD with or with- out associated parkinsonian signs. bvFTD may also be associated with SD in some cases.80 e neuropathological nding in cases with a GRN mutation is FTLD-TPD type A and the clinical presen- tation may be bvFTD, PNFA, or corticobasal syndrome. Cases with VCP mutations present with bvFTD93 as do those with CHMP2B mutations91 or TARDBP mutations.94 ere is substantial clinical heterogeneity in cases with C9orf72 mutation, although bvFTD has been documented in ~50 per cent and MND/ALS in 60 per cent of the cases.95

Dementia with Lewy bodies

and Parkinson’s disease with dementia

These common and closely related diseases are both α- synucleinopathies with widespread Lewy body pathology. Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia in the elderly, and dementia is a common non-motor manifestation of late Parkinson’s disease, for which the term Parkinson’s disease with dementia (PDD) is used (see chapter 36).96 Longitudinal studies indicate that about 50 per cent of Parkinson’s disease patients at 15 years and more than 80 per cent at 20 years follow-up have dementia.97 In PDD and DLB the clinical presentation may be similar; separation of the two dis- orders is arbitrarily based on the one-year rule. e guidelines of

CHAPTER 29 pathology of degenerative dementias 323

324 SECTION 3 cognitive impairment and dementia

the DLB Consensus Consortium for clinical diagnosis have been prospectively validated, which included postmortem con rmation of diagnosis.98

DLB is a sporadic disorder, although the E46K point mutation and triplication of SNCA gene have been described to be associ- ated with a DLB-like picture.99 SNCA gene point mutations such as G51D100 and duplication101 are associated with a PDD clinical phenotype.

dopamine D2 receptor in the striosomal compartment are the most vulnerable. Other basal ganglia structures and the cerebral cortex are also a ected. Antibodies recognizing expanded poly- glutamine stretches highlight widespread neuronal lesions, includ- ing intranuclear inclusions, cytoplasmic and neuritic aggregates (Fig. 29.3N-P).109,111 e density of neocortical intranuclear inclu- sions correlates with the CAG repeat length.112

Conclusion

Identi cation of disease-associated proteins forming intracellular and, in some instances, extracellular aggregates has signi cantly contributed to understanding the pathological changes associated with each disease. Although no disease-modifying therapies are as yet available for neurodegenerative dementias, major aspects of their pathomechanisms have been clari ed. Understanding mechanisms in one disease type may reveal pathways relevant to several disorders such as the novel concept of prion-like spread of α-synuclein pathology in Parkinson’s disease or tau pathology in tauopathies. Clinicopathological studies have identi ed subgroups in some of the conditions such as Parkinson’s disease, progressive supranuclear palsy, and FTLDs, which will be important when e ects of potential disease modifying therapies are to be assessed.

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Neuropathological diagnosis

Di use cerebral atrophy may be seen and pallor of the substantia nigra and locus coeruleus is a feature. Atrophy of medial temporal lobe structures may indicate the presence of associated Alzheimer- type pathology.

e cardinal microscopic feature of both DLB and PDD is the presence of o en widespread, including cortical, Lewy bodies (Fig. 29.3K and 29.3M) and Lewy neurites (Fig. 29.3L). e severity of the Lewy pathology has been found to correlate with the sever- ity of dementia.102,103 ere are Consensus pathological guidelines for the diagnosis of DLB and the revised criteria require that the severity and distribution of Lewy type α-synuclein pathology are assessed in 10 di erent anatomical regions.

A case is nally categorized as belonging to one of three avail- able categories, ‘brainstem-predominant’, limbic (transitional), and neocortical (di use). Aβ parenchymal plaques and neuro brillary tangle tau pathology are consistently found in DLB102 and comor- bid Alzheimer-type pathology is also common in PDD.104–106 is is also recognized by the DLB Consensus guidelines, and the prob- ability that the clinical dementia is caused by Lewy pathology is dependent on the severity of the Alzheimer’s disease-type pathol- ogy.103 In PDD, a combination of cortical Lewy bodies, cortical Aβ plaques, and neuro brillary pathology stages has been found to be the most robust neuropathological substrate of clinical dementia.104 Data indicate that coexistent Lewy body and Alzheimer pathology may promote each other.106,107

A slightly modi ed diagnostic approach has been suggested for neuropathological assessment and clinicopathological correlations by the National Institute on Aging–Alzheimer’s Association recent guidelines for the neuropathological assessment of Alzheimer’s disease.20 ese also recommend that the overarching term ‘Lewy body disease’ is used for DLB and PDD and distinguish the brain- stem, limbic, neocortical, and amygdala predominant categories. is latter is most commonly seen in association with Alzheimer’s disease.

Huntington’s disease

Huntington’s disease is an autosomal dominantly inherited condi- tion caused by an expanded CAG repeat in the N-terminus of the HTT gene resulting in an extended polyglutamine stretch in the huntingtin protein.108

Macroscopically, very early cases may be normal while advanced cases show atrophy of the entire brain and, in particular, of the neostriatum.109 e scheme proposed by Vonsattel and col- leagues is based on the macroscopic and microscopic pathology of the neostriatum and recognizes ve di erent stages of disease progression.110

e most severe microscopic changes are seen in the neostria- tum where the medium spiny neurons expressing encephalin and

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326 SECTION 3 cognitive impairment and dementia

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81. Al-Sarraj S, King A, Troakes C, et al. p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus de ne the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol. 2011;122(6):691–702. Epub 2011/11/22.

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CHAPTER 29 pathology of degenerative dementias 327

CHAPTER 30

Genetics of degenerative dementias
Rita Guerreiro and Jose Bras

Introduction

e adult-onset forms of degenerative dementias are said to be sporadic. In reality these diseases, from which Alzheimer’s disease (AD) is the most common, are complex disorders, most probably resulting from a combination of genetic and environmental factors. A small proportion of dementia cases have a familial basis and early onset. Most of these cases have a well-de ned molecular genetic lesion and pattern of inheritance. However, some atypical situa- tions are known to occur and we are still learning how to interpret genetic variability and how to use genetic risk factors to predict dis- ease (see Box 30.1, Fig. 30.1).

e identi cation of genes associated with di erent forms of dementia, and particularly the identi cation of genes causative for mendelian forms, was an essential rst step for the understanding of the molecular pathological processes underlying these diseases.

Over the past three decades di erent genetic techniques have been used to identify genes associated with dementias. Recently the development and implementation of new genotyping and sequencing technologies have allowed the interrogation of the whole genome with an unprecedented resolution. We are now able to detect more subtle genetic e ects by replacing or complement- ing the more traditional molecular techniques with these recently developed technologies Box 30.2.

e identi cation of dementia-associated genes has also led to an increased interest in the inclusion of genetic information in diag- nosis, clinical evaluation, and management of dementias, which has emphasized the need for a deeper understanding of the mul- tidimensional issues associated with genetic testing for dementias.

In this chapter we will brie y review the molecular techniques used in the eld and the genes and genetic risk factors currently known to be associated with degenerative dementias. We will also discuss the gaps and uncertainties preventing the e ective transla- tion of genetic ndings into the clinical practice.

Overview of recent genetic technologies

In the past decade, many of the advances in our understanding of the molecular aetiology of di erent dementias were tightly linked with the introduction of novel technologies.1 In particular, the last ve years has seen an almost exponential increase in our knowledge of genes involved in these diseases.

e most common type of genetic study prior to the introduc- tion of these advances, were candidate gene case-control association

studies. In these, researchers would select a gene of interest and test a few markers in that gene in a group of cases and a group of controls to determine if there was a di erence in the frequency of those mark- ers. If a marker was more frequently seen in cases than in controls,

Box 30.1 Causative mutations versus risk factors

Mendelian diseases are de ned by the occurrence in families with a pattern (autosomal dominant or recessive and X-linked, see Fig. 30.1) that re ects the inheritance of mutations at an individual locus.

To understand mendelian inheritance one needs to collect detailed information on the family under study by correctly identifying which family members are a ected and which ones are not. It is easier to identify a mendelian pattern of inherit- ance in multigenerational pedigrees than in families with a small number of cases, particularly if the information collected for the extended family is accurate and detailed.

Mendelian diseases are usually caused by mutations occurring in the coding part of the genome, more speci cally in a gene. ese ‘disease genes’ will normally have an important biological function that is abrogated or altered in some way by the mutation leading to the disease status.

Mutations are generally de ned as variants that occur in the population with a frequency of less than 1 per cent, and polymor- phisms as those variants occurring at a frequency greater than 1 per cent. Not all variants with a frequency below 1 per cent are pathogenic and not all polymorphisms are benign. e distinc- tion between pathogenic and benign variants is not always clear. Currently the interpretation and prediction of the e ects of genetic variants is one of the most studied topics in human genetics.

In addition to mendelian diseases, many common disorders have a genetic component. ese disorders are referred to as complex, polygenic, or multifactorial conditions, and result from the combined action of multiple genes and environmental factors. In these cases, genetic variants are not causative of, but rather modulate (either increasing or decreasing) the risk for the development of the diseases.

It is not always easy to determine the type of transmission of a determined phenotype, with several factors such as genetic heterogeneity, variable expressivity, incomplete penetrance, and occurrence of de novo mutations contributing to a more complex evaluation.

(continued)

330 SECTION 3

cognitive impairment and dementia

Fig. 30.1 Examples of inheritance patterns of mendelian diseases.
From top to bottom: Autosomal dominant; autosomal recessive; X-linked recessive. Black symbols represent a ected individuals; white symbols represent healthy family members, and a central dot in a symbol represents carriers.

Top panel: e autosomal dominant pattern of inheritance is the most common pattern for mendelian disorders. e disease occurs in both males and females and often a ects many individuals throughout the pedigree. Inheritance of one copy of the a ected gene is su cient to cause disease and the risk of disease transmission from an a ected individual is 50 per cent.

Middle panel: e autosomal recessive pattern of inheritance is also common and it occurs when two healthy individuals are carriers for the same recessive mutation. Typically, autosomal recessive mutations are rare, and a ected individuals will often not present a family history of the disease, but when they do, all other a ected individuals are in the same generation. e risk of disease transmission is 25 per cent, and half of the una ected o spring will be carriers for the mutation. Given these characteristics, some times families can present with only one a ected member that can be easily mistaken as sporadic.

Lower panel: X-linked recessive conditions usually occur only in males,
while females are carriers (the second X chromosome in females provides a normal allele). Occasionally females can also show a degree of a ectedness. Female carriers will transmit the mutation to all their sons (they inherit only their mother’s X chromosome and will become a ected) and to half their daughters. A ected males will transmit the mutation to all their daughters (all of whom will be carriers). Sons of a ected males receive only their father’s Y chromosome, thus they will not inherit the disease.

Very rare examples also exist of inheritance in X-linked dominant and Y-linked patterns. Also of note, some inherited conditions (non-mendelian) are caused by mutations in the mitochondrial DNA. ese often show maternal inheritance (re ecting the inheritance pattern of mitochondria).

it was said to be a risk factor. e main problem with this approach was the fact that a gene was pre-selected; this is particularly relevant in diseases for which the complete molecular pathobiological events are not fully understood. For the most part, these studies did not yield replicable results and most reports were, in fact, false positive ndings

derived from small cohorts, gene selection bias, and imperfect control selection, based on population genetic background di erences (com- monly referred to as population strati cation) (for a thorough review see reference 2). With the exception of APOE, no other gene was rep- licated by a case-control study to be a bona- de risk factor for AD. e same is true for Parkinson’s disease, where the exception is GBA.3

e introduction of genome-wide genotyping (and the subsequent reduction in cost) completely changed the playing eld for associa- tion studies. With this technology, researchers were able to test the complete genome in an (almost) unbiased manner. A large number of markers (currently > 1 million) was selected from the genome and samples were assayed for all markers in a single experiment. In the rst iterations of these assays, the markers were selected largely based on how much information of the surrounding genetic landscape they could provide (e.g. because markers that are physically close together are generally more likely to be inherited together, a single marker can work as a proxy for others, allowing a researcher to test a single marker and still obtain information on a larger number of nearby genetic positions). e design of these assays was only possible thanks to the e orts of large-scale projects like the HapMap project and, later, the 1000Genomes project, which have created maps of genetic variability in the human population. More recently, and because of the contin- ued development of these projects, it has become possible to design assays that include speci c variants of interest and not only those that are proxies for surrounding markers. One of the most common array that makes use of this type of content is the Illumina ExomeChip that targets markers present almost exclusively in the coding portion of the genome.4. It was through genome-wide genotyping that researchers were able to conduct genome-wide association studies (GWAS). Here, all markers in those assays were tested in large numbers of cases and controls (usually > 2000 each), and the frequency of each one of those markers was compared between the two cohorts. When a marker’s frequency was found to be statistically di erent between groups, the marker was considered to be associated with the development of dis- ease. is approach has been widely used for a variety of diseases and results have allowed for a better understanding of the molecular path- ways involved in those diseases; Alzheimer’s disease is a prime exam- ple of the application of GWAS to improve our understanding of the molecular events involved in this pathology.5–7

e other remarkable advance in genomic technology was mas- sively parallel sequencing (also called next-generation sequencing or sequencing by synthesis). It allowed researchers to move from sequencing ~500–1000 base pairs of the genome in one experiment to being able to sequence an entire human genome. An enormous amount of e ort has been dedicated to applying this technology to the understanding of disease, with great success. However, there are two aspects that still prevent a more widely application of sequenc- ing: the rst is cost—it is currently very expensive to sequence large numbers of genomes; the second is interpretability—although our understanding of the human genome has grown greatly in the last years, we are still not able to interpret the vast majority of genetic variability in the context of human biology. Nevertheless, massively parallel sequencing has been at the basis of the identi cation of many rare causes of disease and this trend is expected to continue over the next few years.

ese two technological advances have allowed us to start creat- ing maps of the genetic architecture of disease: GWAS enabled us to identify common genetic variability that exerts small to moderate e ects on phenotype, while sequencing allowed us to identify rare

Box 30.2 Main genomic approaches currently being used

Genome-wide genotyping: Determines which alleles are present at a large number of pre-speci ed loci across the genome in a single test. Currently it is possible to determine over 5 million markers per sample in a single experiment.

Genome-Wide Association Study: Makes use of genome-wide genotyping to detect alleles in a cohort of cases and a cohort of controls. To determine if any of the markers is associated with disease, the allele frequency at each locus is compared between the two cohorts, incorporating statistical methods to account for the large number of comparisons made.

Next-generation sequencing: Recent technology that allows researchers to sequence (i.e. determine every allele) vastly larger amounts of DNA at a much lower cost than conventional meth- ods (Sanger sequencing) previously allowed. Typically, short fragments of DNA are sequenced in parallel and then assembled into contigs, using the human genome sequence as a reference.

Whole-exome sequencing: Application of next-generation sequencing that targets only the protein-coding portion of the genome. Given that the interpretability of this portion is higher than noncoding regions, whole-exome sequencing has been widely adopted over the last few years.

variants with large e ect sizes. It is likely that the era of GWAS is now coming to an end for many diseases; recently the largest studies for Parkinson’s and Alzheimer’s diseases were published and each con- tained over 70 000 individuals.5,8 Any subsequent studies will face the law of diminishing returns where any large increase in sample size will only identify risk factors with very minute e ects. On the other hand, sequencing of large numbers of individuals is only get- ting started. Over the next 10 years we will witness the identi ca- tion of novel causative mutations and genetic risk factors for a variety of diseases. e issue then will be to understand how these genetic factors impart their e ect on biological pathways and ultimately on disease.

Alzheimer’s disease

Alzheimer’s disease can have an early (when occurring before 65 years of age) or late (a er 65 years) onset. It can also be heredi- tary (when the disease is present in several members of the same family) or sporadic. e most common form of the disease has a late-onset and is sporadic. e genetic study of the rarer familial, early-onset forms of disease has led to the identi cation of the genes currently known to cause mendelian forms of AD. ese ndings have also allowed the development of a hypothesis for the molecular pathogenesis of AD that is thought to apply to all forms of the disease (see following).

APP, PSEN1, and PSEN2

e use of traditional genetic linkage approaches to study multigen- erational families with AD has led to the identi cation, in the early 1990s, of three genes associated with AD. Mutations in the amyloid precursor gene (APP),9 the presenilin 1 (PSEN1),10 and the preseni- lin 2 (PSEN2)11,12 genes are mainly associated with early-onset and familial forms of the disease. e most commonly mutated gene in AD is PSEN1 with over 200 mutations identi ed so far.13 Mutations

in this gene are fully penetrant and present an age at onset ranging from 24–78 years. e second more commonly mutated gene is APP, associated with ages at onset ranging from 30–75 years. Mutations in PSEN2 are rarer when compared with the other two genes. Ages at onset associated with PSEN2 mutations range from 44–80 years of age. Figure 30.2 represents a practical approach for genetic testing of patients with a familial form of AD, noting that next-generation sequencing is emerging as a means of assessing multiple genes con- currently and at far lower costs than conventional sequencing. From a clinical point of view, early-onset AD and late-onset AD are simi- lar entities and alterations in any of these genes may, theoretically, have implications for both forms of the disease.

Mutations in these three genes usually have a typical autosomal dominant pattern of inheritance, however one recessive mutation (p.A673V) in APP has been identi ed with dominant-negative e ect on amyloidogenesis.21 Recently, a rare variant in the same amino acid position (p.A673T) was shown to result in an approximately 40 per cent reduction in the formation of amyloidogenic peptides in vitro and consequently reported as protective for the risk of development of AD.22 e p.A673T protective variant seems to be primarily found in Northern Europe, particularly in the Icelandic and Scandinavian populations, being extremely rare in other populations.23 If indepen- dently replicated, the nding of such a protective e ect has major implications for AD: (1) it links for the rst time both early- and late- onset forms of AD; (2) it provides important evidence to support the amyloid cascade hypothesis of AD; and (3) it has substantial implica- tions for the development of new drug therapies aimed at reducing APP β-cleavage (beta secretase (BACE) activity), thereby reducing production of toxic amyloidogenic Aβ peptides.

All pathogenic point mutations identi ed in APP are located in exons 16 or 17, which correspond to the amyloid beta portion of the full amyloid precursor protein. In addition to early-onset AD, these mutations are known to cause other related phenotypes: cerebral amyloid angiopathy and hereditary cerebral haemorrhage with amy- loidosis.20 In addition to missense mutations, AD has been found to be caused by chromosomal duplications that include the APP locus. ese quantitative changes were also linked to cerebral amyloid angi- opathy and hereditary cerebral haemorrhage with amyloidosis.14

It is important to recognize that not all genetic variants present in these genes will invariably lead to dementia. Several mutations (classi ed as such because they have a frequency of less than 1 per cent in the general population) may be benign, with no del- eterious e ects in the function of the respective protein. Other changes may be frequent enough to be considered polymorphisms. Polymorphisms are usually not pathogenic but may contribute to the risk of developing the disease (either protective or pathologic).17

One of the main factors preventing the inclusion of genetic test- ing in the diagnosis and clinical management of early-onset AD patients is the true pathogenicity of mutations found on these genes. e evaluation of the pathogenicity of these variants is of extreme importance but in some cases very di cult or even impos- sible to accomplish. Several attempts to predict the e ect of these variants have been devised, but still the most precise assessment of pathogenicity comes from the combination of segregation analyses (where several members of the family are tested and the variant is said to be pathogenic if present in a ected and absent in una ected family members) and functional analyses (where the amyloido- genic e ect of the speci c mutation is tested in cell lines, for exam- ple). Pathogenicity has wrongly been attributed to some variants

CHAPTER 30 genetics of degenerative dementias 331

332 SECTION 3 cognitive impairment and dementia

~60%

PSEN1

– Early onset
– Spastic paraparesis (with characteristic histopathology: cotton wool plaques)

– Cerebral amyloid angiopathy with cerebral haemorrhage

– Volga German origin
– Later onset
– Incomplete penetrance

– Cerebral amyloid angiopathy with cerebral haemorrhage

e analyses of AD cases and controls at the whole-genome level has led to the identi cation of other rare variants associated with the disease (in genes: AKAP9, PLD3, UNC5C).30,31 None of these has yet been independently replicated and it is expected that at least some will be deemed as false positives by future analyses.

Molecular pathways identi ed by genetic ndings

e amyloid cascade hypothesis was proposed in 1991 and sug- gested that the alterations caused by mutations in APP to the amy- loid beta metabolism were the initiating events of a series of steps leading to the full development of dementia.32 ese steps include the aggregation of Aβ, formation of neuritic plaques and NFTs, disruption of synaptic connections, neuronal death and demen- tia. Since its proposal, the amyloid cascade hypothesis has been improved, changed, and extended with the inclusion of other fac- tors now known to be part of the molecular signature of AD, and many di erent versions of the amyloid cascade are used today (see Fig. 30.3).33 is is still the main hypothesis forming a framework for AD research, allowing for several new research questions to be formulated. e identi cation of mutations in APP, and later PSEN1 and PSEN2, were the rst and essential observations for the formulation of the rst possible molecular pathway in AD. As discussed, ndings from genome-wide association studies and exome sequencing have identi ed a large number low risk genetic loci which nonetheless provide important clues to pathogenesis, implicating cholesterol and lipid metabolism, immune system and in ammatory responses, and vesicle transport and endocytosis. How these various pathways interact with one another and with environmental factors to cause clinical AD is the subject of intense current research.

Frontotemporal dementia

Frontotemporal dementia (FTD) is an umbrella term used to cover a range of speci c diseases. ese disorders are characterized by progressive degeneration of the frontal and/or temporal lobes. Clinically, FTD is characterized by a progressive degradation in behaviour, speech, or language. Usually, memory and visuospa- tial functions are relatively spared. It can be subdivided into three clinical subtypes: 1) behavioural-variant frontotemporal dementia;

Table 30.1 Di erent genotypes at the rs429358 and rs7412 single nucleotide polymorphisms (SNPs), respective APOE alleles, and odds ratios (OR) for developing AD

~15% APP

~5% PSEN2

~5% dAPP

Fig. 30.2 Strategy for the screening of mutations in the known AD mendelian genes. If a patient/family presents any of the characteristics shown in the right part of the gure, the sequence of genes to be analysed should be adjusted accordingly. When a mutation is found in one of these genes,
it should be determined if it is a novel mutation or if it has been previously described. is can be done by checking the Alzforum mutations database (<http://www.alzforum.org/mutations>). If the mutation found is deemed to be novel, one needs to evaluate its pathogenicity, as it may be a variant with no clinical signi cance. A systematic decision tree can be used to evaluate the probable pathogenicity of such variants.13–20 dAPP:duplication of the APP locus.

identi ed in these genes. Although these variants cannot be consid- ered as the cause of disease in the cases where they are found, they can increase the risk for the development of AD.17

Genetic risk factors in AD

e linkage analyses of multigenerational families used to identify AD causative genes have also identi ed a strong risk factor for the development of the disease. e E4 allele of the apolipoprotein E (APOE) gene is the strongest risk factor for all forms of AD.24,25 is e ect has been consistently replicated by di erent groups in many populations (Table 30.1).

e development of whole-genome genotyping platforms has allowed the identi cation of common genetic variants with low e ects in the risk for the development of the late-onset form of AD (Table 30.2). Although exerting small e ects in the risk for dis- ease, these variants have been essential to uncovering the molecu- lar pathways underlying the aetio-pathogenic processes of the disease. e three main pathways identi ed so far have been the 1) immunological/in ammatory response, 2) endocytosis (clathrin mediated and synaptic), and 3) cholesterol and lipid metabolism.27

More recently the integration of whole-genome sequencing and genotyping techniques allowed the identi cation of a rare variant (p.R47H) in TREM2 that was shown to increase the risk for AD with odds ratio of ~3. In addition to being the strongest risk factor for AD a er APOE, this nding also con rmed the involvement of immunological and in ammatory pathways in the beginning of the pathological processes.28,29

Reproduced from Hum Mol Genet. 19(16), Corneveaux JJ, Myers AJ, Allen AN, et al. Association of CR1, CLU, and PICALM with Alzheimer’s disease in a cohort of clinically characterized and neuropathologically veri ed individuals, pp. 3295–301, Copyright (2010), with permission from Oxford University Press.

APOE genotype

rs429358

rs7412

E2/E2

0.23

E2/E3

0.32

E2/E4

1.23

E3/E3

0.50

E3/E4

1.79

E4/E4

6.90

Particular characteristics associated with mutations in each gene

Frequency in mendelian families

Table 30.2 Genetic risk factors for Alzheimer’s disease

the clinical subtype of FTD is not as strong as the relation with the neuropathology features of the di erent FTD subtypes, with muta- tions in one gene usually leading to one hystopathological subtype but possibly causing a range of di erent clinical phenotypes.37,38

Mutations in several genes are known to cause FTD, with muta- tions in the microtubule-associated tau (MAPT), Progranulin (GRN) and C9orf72 being the most frequent and explaining ~80 per cent of familial FTD cases.39 ere are also several genes known to cause rarer forms of FTD and genes associated with FTD-plus syndromes.

MAPT, GRN, and C9ORF72

MAPT was the rst gene to be discovered in association with FTD by means of positional cloning in families linked to chromosome 17 who presented with frontotemporal dementia and parkinson- ism.40 Currently, over 40 mutations in MAPT are represented in the AD/FTD mutation database.15 Tau is a microtubule-binding protein able to modulate the stability of axonal microtubules and consequently the transport of organelles and other cellular com- ponents. Di erent tau proteins originate from the alternative splicing of the MAPT gene. Six of these isoforms are expressed in human brain and they di er in the number of microtubule-binding domains, which are encoded by the alternative splicing of exons 2, 3, and 10.41 Mutations in MAPT can either cause a disruption in the structure of the tau protein, or they can alter the proportion of the di erent tau isoforms available. ese changes lead to impaired microtubule assembly and impaired axonal transport, promoting pathological tau lament aggregation.42,43

Soon a er the identi cation of MAPT it was recognized that many chromosome-17-linked FTD families did not have mutations in this gene and had a rather di erent neuropathology, presenting ubiquitin abnormalities and not tau-associated changes. ese fam- ilies were later found to carry mutations in GRN. Currently there are close to 70 mutations described in this gene, the vast majority being loss of function mutations associated with nonsense medi- ated decay of the mutant GRN mRNA and consequent reduced expression of the protein.15,44,45 is allows for mutation carriers to be detected by measuring their serum concentration of GRN.46 Although the exact role of progranulin in the neurodegenerative processes occurring in FTD is not clear, granulins are known to be a family of secreted, glycosylated peptides involved in the regula- tion of cell growth. Recently, homozygous mutations in GRN were found to cause neuronal ceroid lipofuscinosis (NCL11).47 Given the well-established link between NCL and proteins a ecting the lyso- somal processing, these results associating GRN mutations with a form of NCL suggest that progranulin has a lysosomal function.48

e last gene harbouring common mutations in FTD to be iden- ti ed was C9ORF72, in several families presenting linkage to chro- mosome 9 and a phenotype of FTD, ALS, or FTD/ALS.49,50 Even though many chromosome 9-linked families were studied for a long period of time, the gene underlying the disease in these cases remained elusive for several years. is happened because the muta- tion found to be the cause of disease in these cases was not a typical coding variant but was instead an intronic GGGGCC hexanucleo- tide repeat expansion. e typical pathogenic C9ORF72 expansions have hundreds of repeats (usually ranging from 400 to more than 4 400 repeats on one allele), with healthy controls usually having less than 30 repeats. Exceptions occur with individuals harbouring more than 30 repeats not presenting any cognitive changes: patho- genicity of the intermediate range (from around 20–100 repeats)

CHAPTER 30 genetics of degenerative dementias 333

Gene o cial symbol

Gene name

Location

Risk genes

APOE

Apolipoprotein E

19q13.2

TREM2

Triggering receptor expressed on myeloid cells 2

6p21.1

Risk loci

CLU

Clusterin

8p21–p12

PICALM

Phosphatidylinositol binding clathrin assembly protein

11q14

CR1

Complement component (3b/4b) receptor 1 (Knops blood group)

1q32

BIN1

Bridging integrator 1

2q14

MS4A6A

Membrane-spanning 4-domains, subfamily A, member 6A

11q12.1

MS4A4E

Membrane-spanning 4-domains, subfamily A, member 4E

11q12.2

CD33

CD33 molecule

19q13.3

ABCA7

ATP-binding cassette, subfamily A (ABC1), member 7

19p13.3

CD2AP

CD2-associated protein

6p12

EPHA1

EPH receptor A1

7q34

HLA-DRB5 and DRB1

Major histocompatibility complex, class II, DR beta 5 and DR beta 1

6p21.3

SORL1

Sortilin-related receptor, L(DLR class) A repeats containing

11q23.2– q24.2

PTK2B

Protein tyrosine kinase 2 beta

8p21.1

SLC24A4

Solute carrier family 24 (sodium/ potassium/calcium exchanger), member 4

14q32.12

ZCWPW1

Zinc nger, CW type with PWWP domain 1

7q22.1

CELF1

CUGBP, Elav-like family member 1

11p11

FERMT2

Fermitin family member 2

14q22.1

CASS4

Cas sca olding protein family member 4

20q13.31

INPP5D

Inositol polyphosphate-5- phosphatase, 145kDa

2q37.1

MEF2C

Myocyte enhancer factor 2C

5q14.3

NME8

NME/NM23 family member 8

7p14.1

2) progressive non- uent aphasia; and 3) semantic dementia. Frontotemporal dementia is not only a heterogeneous syndrome from a clinical perspective, it also presents heterogeneous imaging features, neuropathology, and genetics. Additionally, it can overlap with other neurodegenerative diseases, mainly parkinsonism syn- dromes and motor neuron disease.34,35 Family history of dementia and related disorders can be found in ~40–50 per cent of people with FTD, but only ~10–40 per cent will have an autosomal domi- nant pattern of inheritance.36 e relation between mutations and

334 SECTION 3

cognitive impairment and dementia

Vascular amyloid

APP mutations (including duplications)

PSEN1/2

mutations

Trisomy21

APOE;TREM2

variants Low genetic

risk (CLU, SORL1, etc.)

Environmental factors

APP A673T mutation

Amyloid aggregation

Soluble forms of oligomeric Abeta

Abeta plaques

Tau phosphorylation and aggregation

Inflammation

Soluble forms of oligomeric tau

PHF formation

NFTs

Neuronal

damage, Dementia depletion of

transmitters

Altered APP metabolism

Fig. 30.3 Amyloid cascade hypothesis. is hypothesis supports the idea that amyloid-β (Aβ) peptide plays a central and probably causative role in Alzheimer’s disease. It was originally developed for familial forms of AD, but it is possibly transversal to all forms of the disease (as depicted here). All three AD mendelian genes are involved in amyloid-β production. Other genetic, environmental, vascular, and in ammatory factors probably also play a part in the pathogenesis of Alzheimer’s disease in general. e amyloid peptide is cleaved from its precursor protein and deposited as senile plaques. Brains with AD typically harbour senile plaques consisting of insoluble aggregates of Aβ. Di erent assemblies of Aβ, including brils, soluble dimers, trimers, and dodecamers, may di erentially contribute to AD pathogenesis. Senile plaques trigger oxidative injury and synaptic loss; these, in turn, bring about hyperphosphorylation of tau protein, which leads to formation of tangles, triggering widespread neuronal dysfunction and dementia.

APP: amyloid precursor protein; NFT: neuro brillary tangles; PHF: paired helical laments.

continues unproven and although penetrance is probably high by age 80, partial penetrance has been proposed.51,52 Somatic instabil- ity can cause variability in the expansions sizes in the same tissue between patients and between tissues in one patient.53 Although the function of the C9orf72 protein is still unclear, the results of sensitive homology suggested that it may be related to di erentially expressed in normal and neoplastic (DENN)-like proteins, which act as GDP/GTP exchange factors that activate Rab-GTPases. In this way, C9orf72 is predicted to regulate vesicular tra cking in conjunction with Rab-GTPases.54

Rare genetic causes of FTD

Mutations in MAPT, GRN, and C9ORF72 cause disease asso- ciated with an autosomal dominant pattern of inheritance. Similarly, a mutation in CHMP2B has been found in a large autosomal dominant Danish frontotemporal dementia family. Mutation of this gene is very rare and associate with unusual ubiquitin-positive but TDP-negative and FUS-negative patho- logical abnormalities.55

Recently, mutations in TREM2 have been found to be the cause of FTD in families presenting an autosomal recessive form of disease.56 Mutations in TREM2 were originally found to cause Nasu–Hakola disease, a rare form of dementia characterized by the presence of bone cysts and fractures.57 Several families have now been identi ed with TREM2 mutations but without any bone- related phenotypes, presenting only what resembles behavioural FTD.58,59 Additionally, PRKAR1B was identi ed as the cause of an FTD-like neurodegenerative disorder with a unique neuropatho- logical phenotype, displaying abundant neuronal inclusions by haematoxylin and eosin staining throughout the brain with immu- noreactivity for intermediate laments.60

e presence of linkage in some families with FTD associated with other disorders (mainly motor neuron disease) has also led to the identi cation of mutations in other genes (VCP, CHCHD10, SQSTM1, UBQLN2, and OPTN) in which mutations are rare. Some ALS genes (FUS, TARDBP) have also been found mutated in FTD cases, but the genetic evidence for the segregation of mutations in these genes with FTD is not strong.34

Genetic risk factors in FTD

Genome-wide association studies have recently identi ed two loci associated with FTD (Table 30.3). e rst GWAS was performed on FTD patients with TDP-43 pathology and identi ed a genome-wide associated locus at 7p21 with the strongest associated SNPs lying in or close to TMEM106B.61 e second nding resulted from a two-stage GWAS on clinical FTD where separate association analyses were per- formed for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non- uent aphasia, and FTD overlapping with motor neuron disease) as well as a meta-analysis of the entire data- set. e authors identi ed a genome-wide associated locus at 6p21.3 (HLA locus) in the subtype meta-analysis and a suggestive associa- tion at 11q14 (including RAB38 and CTSC) for the behavioural FTD subtype.62 e use of subphenotypes in this GWAS also allowed the identi cation of a strong association between the C9ORF72 locus and the FTD-MND subgroup.62,63 Ataxin-2 polyglutamine expansions with intermediate repeat sizes (≥ 29 CAG) have also been recently associated with FTD-MND.64 Diekstra and colleagues used GWAS data on ALS and FTD-TDP cases, performed a joint meta-analysis and replicated the most associated hits of one disease in the other to identify the C9ORF72 locus and one SNP in UNC13A (rs12608932, 19p13.11) as shared susceptibility loci between ALS and FTD-TDP.65 Subsequently, rs12608932 in UNC13A was found to be a signi cant

Table 30.3 Genetic risk genes and loci for frontotemporal dementia

complex and thus more di cult to identify than the typical pathogenic mutation (e.g. a mutation similar to those seen in C9ORF72 FTD/ALS would be di cult to identify using standard methodologies).

e gene encoding the protein alpha-synuclein is currently the only replicated genetic cause of DLB. SNCA triplications and the missense mutations p.E46K and p.A53T are associated with clinical and patho- logical phenotypes ranging from PD to PD with dementia to DLB.

Other studies have attempted to identify pathogenic mutations in kindreds presenting with DLB, particularly looking at genes known to be involved in PD or AD, but so far no segregating mutations have been identi ed.75

e search for genetic risk factors of DLB has been slightly more productive. APOE, the strongest risk factor for AD, has also been shown by several groups to be a risk factor for DLB. is has been shown in clinical as well as in pathological con rmed cases.76 It appears as though the association is virtually indistinguishable from that seen in AD, with the ε-4 allele increasing risk and the ε-2 alleles associated with a decreased risk for disease.77

More recently, the gene GBA, encoding the protein glucocerebro- sidase, was also shown to modulate risk for DLB.78 GBA encodes a lysosomal enzyme that is known to be the cause of a recessive lyso- somal storage condition named Gaucher disease, however, when the same mutations are present in a single allele, they increase risk for DLB. is e ect was initially identi ed in PD cases and later replicated in a large multi-centre cohort of DLB cases.

More recently, and through the application of recent genomic technologies, namely genome-wide genotyping, the rst large- scale association in DLB was published.79 In addition to being the largest study in DLB performed to date (700 cases), it also com- prised a large number of neuropathologically diagnosed cases, strengthening the diagnostic accuracy and reducing the potential e ects of mis-diagnosed samples. Here, the authors con rmed the association of APOE with DLB and further identi ed common genetic variability in SNCA to also be involved in disease. A third locus, encompassing the gene SCARB2, was identi ed, show- ing suggestive levels of association. SCARB2, which encodes yet another lysosomal protein, was known as a susceptibility gene for PD but had not been shown to be involved in DLB.

Both associations at SNCA and SCARB2 loci were also seen in PD, however the association pro les in DLB seem to suggest that the associations are, in fact, di erent than the ones previously seen in PD. ese results imply that although the same genes may be involved in both diseases, the manner in which they exert their pathobiological e ect may be di erent. Despite these results, this report is based on a relatively small cohort and further studies are required to replicate these ndings.

e results so far show that APOE is the strongest genetic risk factor for DLB, acting in a way that seems to be independent from amyloid processing. e involvement of GBA and SCARB2 strongly argue for a role of the lysosome in the pathobiology of this disease, and since the protein α-synuclein has been shown to be degraded by the lysosome,80 it is possible that this cellular organelle plays a pivotal role in this disease.

Conclusion

e last decade has seen remarkable advances in the identi cation of novel disease-causing genes and genetic risk factors for neurodegen- erative diseases. ese have largely been due to novel technological approaches and the accompanying reduction in cost for data generation.

CHAPTER 30 genetics of degenerative dementias 335

Gene o cial symbol

Gene name

Location

TMEM106B

Transmembrane protein 106B

7p21.3

HLA

Human leukocyte antigen locus

6p21.3

C9orf72*

Chromosome 9 open reading frame 72

9p21.2

UNC13A/ KCNN1*

Unc-13 homolog A (C. elegans)/potassium channel, calcium-activated intermediate/ small conductance subfamily N alpha, member 1

19p13.11/ 19p13.1

ATXN2*

Ataxin 2

12q24.1

*Loci mainly associated with FTD-MND.

exon-level cis-eQTL for KCNN1 in frontal cortex, with region- speci c eQTL data indicating KCNN1 instead of UNC13A as the most probable relevant gene at this locus.66

A GWAS of plasma GRN levels in a cohort of healthy controls has led to the identi cation of two SNPs in chromosome 1p13.3 (near SORT1) with genome-wide signi cant association with plasma GRN levels. is can be considered a possible risk locus for FTD under the hypothesis that factors associated with reduced levels of plasma GRN can increase the risk of developing FTD.67

A rare variant (p.A152T) in MAPT has also been shown to be a risk factor for frontotemporal dementia spectrum disorders,68 with di erent studies describing carriers with phenotypes comprising progressive supranuclear palsy, bvFTD, non uent variant primary progressive aphasia, corticobasal syndrome, Parkinson’s disease, and clinical Alzheimer’s disease.69,70

Dementia with Lewy bodies

Lewy bodies (LB) are commonly known as the neuropathological hallmark of Parkinson’s disease (PD). ey are protein inclusions, formed of insoluble polymers of alpha-synuclein that are present in the neuronal body, forming round lamellated eosinophilic cyto- plasmic inclusions.71

DLB shares signi cant phenotypical characteristics with PD and AD; additionally, the disease can also present in a very similar fashion to PD with dementia (PDD), di ering only in the earliest symptoms. ere is no molecular data that allows for a distinction between DLB and PDD.72

ere is limited information on the genetic aspects of DLB, mainly because there have been only a few su ciently powered genetic studies performed to date.

DLB is mainly considered to be a sporadic disease. However, as with other neurodegenerative diseases, the fact that disease onset generally occurs late in life means that in many cases, there are no longer living relatives from previous generations which can lead to cases being potentially mislabelled as sporadic.

Rare cases of aggregation of the disease in families have been identi- ed. To date, there has been a single genome-wide linkage study for DLB. Looking at an autosomal dominant family with autopsy-con rmed DLB, the authors identi ed a region on chromosome 2 that segregated with the disease.73 However, follow-up studies searching for pathogenic mutations in the linked locus did not identify a single candidate muta- tion that could be responsible for the phenotype in that family.74 It is not clear if the linkage pointed to the wrong locus or if the causal mutation is

336 SECTION 3 cognitive impairment and dementia

ese advances have allowed for unbiased studies that have linked, on a molecular level, diseases that are very dissimilar from a clinical perspective, suggesting that the current disease classi ca- tion might be improved if these molecular data were to be taken into account. ese results have also brought to light novel biologi- cal pathways involved in disease, which may, in the future, pave the way for new therapeutic approaches.

Over the next few years we will see these technologies mature and be more widely used in a diagnostic setting. is will be tremendously bene cial to the diagnostic process, where a single test—quick and comparatively inexpensive—will provide information for all genes, instead of clinicians having to perform an educated guess about which gene is more likely to be involved in that speci c case. As more data are generated in research and diagnostic settings, we will be able to understand the pathobiology of each syndrome more fully since we will no longer be restricted to analysing only the known genes.

Great strides have also been made in the eld of genetic risk pre- diction. We are now able to estimate the risk a given individual has to develop a neurodegenerative disease over the course of their life based on the genetic make-up of that person. is risk prediction is, however, incomplete, as more information needs to be taken into account to achieve a complete risk pro le. We will need multi-scale biological approaches, integrating DNA, RNA, epigenetics, and envi- ronment to create adequate risk pro les. In this sense, large-scale, longitudinal studies will be key in allowing us to achieve this goal.

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46. Finch N, Baker M, Crook R, et al. Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members. Brain. 2009;132(Pt 3):583–91.

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49. Dejesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-Linked FTD and ALS. Neuron. 2011;72(2):245–56.

50. Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expan- sion in C9ORF72 is the cause of chromosome 9p21-Linked ALS-FTD. Neuron. 2011;72(2):257–68.

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52. Galimberti D, Arosio B, Fenoglio C, et al. Incomplete penetrance of the C9ORF72 hexanucleotide repeat expansions: frequency in a cohort of geriatric non-demented subjects. J Alzheimers Dis. 2014;39(1):19–22.

53. Woollacott IO and Mead S. e C9ORF72 expansion mutation: gene structure, phenotypic and diagnostic issues. Acta Neuropathologica. 2014;127(3):319–32.

54. Levine TP, Daniels RD, Gatta AT, et al. e product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs. Bioinformatics. 2013;29(4):499–503.

55. Skibinski G, Parkinson NJ, Brown JM, et al. Mutations in the endoso- mal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat Genet. 2005;37(8):806–8.

56. Guerreiro RJ, Lohmann E, Bras JM, et al. Using exome sequenc- ing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA Neurol. 2013;70(1):78–84.

57. Paloneva J, Manninen T, Christman G, et al. Mutations in two genes encoding di erent subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet. 2002;71(3):656–62.

58. Guerreiro R, Bilgic B, Guven G, et al. Novel compound heterozygous mutation in TREM2 found in a Turkish frontotemporal dementia-like family. Neurobiol Aging. 2013;34(12):2890 e1–5.

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338 SECTION 3 cognitive impairment and dementia

77. Berge G, Sando SB, Rongve A, et al. Apolipoprotein E epsilon2 geno- type delays onset of dementia with Lewy bodies in a Norwegian cohort. J Neurol Neurosur Ps. 2014;85(11):1227–31.

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CHAPTER 31

Other genetic causes

of cognitive impairment

Davina J. Hensman Moss, Nicholas W. Wood, and Sarah J. Tabrizi

Huntington’s disease Introduction

Huntington’s disease is a devastating progressive neurodegenerative condition characterized by movement, behavioural, and cognition problems. e condition is autosomal dominantly inherited, and while relatively rare, is the most common identi ed genetic cause of cognitive impairment. George Huntington originally described the disease in 18721 in what remains one of the best descriptions of the condition. He noted three ‘marked peculiarities in this disease; (I) its hereditary nature; (II) a tendency to insanity and suicide; and (III) its manifesting itself as a grave disease only in adult life’. Years before Mendel’s work was recognized, Huntington astutely observed the genetic nature of the disorder: ‘If the thread is broken then the grandchildren of the original shakers may be assured that they are free from the disease.’

Prevalence

e prevalence of HD is generally given as 4–10 per 100 000 in pop- ulations of Western European descent;2 prevalence is thought to be lower in Asian, Japanese, Finnish, and South African populations.3,4 However, due to the stigma and complex psychosocial issues sur- rounding the disease this is likely an underestimate: a prevalence of at least 12.4 per 100 000 in the UK population is thought to be more re ective of the true rate.5 e highest prevalence in the world is in Venezuela near Lake Maracaibo: 700 per 100 000, and it is the collaboration of people in this region and an international group of researchers that was crucial in the identi cation of the HD gene.

Genetics of HD

HD is inherited in an autosomal dominant manner, and is caused by a trinucleotide repeat expansion in the huntingtin (HTT) gene on the short arm of chromosome 4 at 4p16.3. e disease is found in individuals with greater than 36 and up to 121 CAG repeats (Table 31.1); the mean repeat number is 40, but there is a marked skew to the right in this distribution. 50–70 per cent of the variabil- ity of age of onset is accounted for by CAG repeat length and age, with higher CAG being associated with more aggressive disease (Table 31.1). e size of CAG repeat can therefore be used to give a prediction of the age of motor onset in premanifest individuals.6,7 and this index is what has been widely used in the research setting.

However, the relationship is not su ciently uniform to predict onset age for a given individual in a clinical context. e onset vari- ability not accounted for by CAG is thought to be partly genetically determined,8 supporting the concept of disease modi ers in HD.9

CAG repeat lengths vary from generation to generation, with both expansion and contraction of the number of repeats occur- ring, but with an overall tendency towards expansion. Large expan- sions are associated with transmission down the male line,10 and there is a familial tendency towards large expansions: 90 per cent of juvenile HD cases inherit the HTT gene through the paternal line. e tendency of the CAG expansion to expand during transmission underlies the phenomenon of anticipation observed in Huntington’s and other neurodegenerative conditions such as SCAs 1, 2, 3, 6, 7, and dentatorubral-pallidoluysian atrophy (DRPLA), in which there is an increased severity of disease in successive generations.

Clinical presentation of adult-onset HD

Typically symptoms develop between 35 and 45 years of age, but onset has been described between 2 and 87 years of age. HD can produce a wide range of phenotypic presentations, and as the dis- ease progresses the signs and symptoms change.

By consensus, disease onset is de ned as the point when a person who carries a CAG-expanded HTT allele develops ‘the unequivocal presence of an otherwise unexplained extrapyramidal movement disorder’ (eg chorea, dystonia, bradykinesia, rigidity).11,12 However, the transition from premanifest to manifest HD is not as abrupt as previously assumed. ere may be more subtle features evident to the careful observer prior to this in the perisymptomatic or pro- dromal phases of HD. ese include delayed initiation of saccades, slower saccades particularly on vertical eye movements, irregular nger tapping, and a generalized restlessness. Psychiatric symp- toms and cognitive changes o en occur before motor onset.13–15

It is thought that neuronal dysfunction starts many years prior to disease onset, but that neural plasticity and compensatory mecha- nisms may be responsible for the lag between neural damage and symptom onset (see Fig. 31.1).

Motor features

e cardinal motor symptoms of HD are chorea and dystonia which are present in 90 per cent2 and 95 per cent16 of symptomatic patients respectively. e ad hoc Committee on Classi cation of the

340 SECTION 3 cognitive impairment and dementia
Table 31.1 Relationship between size of CAG repeat expansion and clinical outcome

CAG repeat length

<27

27–35

36–39

≥40

≥55–60

Clinical manifestation

Normal
Not unstable

Intermediate repeat allele

Not pathogenic

May expand into disease range in future generations in paternal line

Reduced penetrance but pathogenic

Fully penetrant

Usually have juvenile onset

World Federation of Neurology17 de ned chorea as ‘a state of exces- sive, spontaneous movements, irregularly timed, non-repetitive, randomly distributed and abrupt in character. ese movements may vary in severity from restlessness with mild, intermittent exag- geration of gesture and expression, dgeting movements of the hands, unstable dance-like gait to a continuous ow of disabling violent movements.’ Chorea may a ect face, trunk, or limbs, and although the pattern of the movements may di er between patients, they occur in individuals in a stereotyped manner. Choreic move- ments are continuously present during waking hours, and are o en exacerbated by stress.18 Dystonia is characterized by involuntary, sustained or spasmodic and patterned contractions of muscles, frequently causing twisting and posturing19 and may a ect face, trunk, or limbs.

Gait is impaired, not only due to the chorea and dystonia but also due to impairment in motor control and postural re exes, making patients prone to falling. Hypophonia, dysarthria, and dysphagia all cause signi cant morbidity in HD and are important to enquire about and address clinically. Dysphagia with choking episodes is reported even in early disease. At this stage dysphagia is usually

related to impulsive, disordered eating, whilst later disease mechan- ical disintegration of swallowing plays a greater role in disability. Eye movement abnormalities occur early. As the disease progresses, head thrusting is used to initiate gaze shi s, pursuit is impaired with saccadic instructions, and there is gaze impersistence (di – culty in maintaining xation on an item in the visual scene).

Psychiatric features

Psychiatric problems, particularly anxiety and depression, are a major cause of morbidity in HD and may occur many years before symptom onset. A survey of 2835 patients with HD found that 40 per cent had symptoms of depression, and 50 per cent reported having sought treatment for depression at some stage in the past.20 e frequency of psychiatric problems and their potential amena- bility to treatment means that psychiatric symptoms are particu- larly important to address clinically.

Suicide in HD is much higher than the general population both in the manifest and premanifest stages: in a survey of 4171 gene carriers, 17.5 per cent had suicidal thought at or around the time of assessment, and 10 per cent had made at least one suicide attempt in the past.21 Suicidal ideation is highest in gene carriers around the time of diagnosis, with manifest disease, and those beginning to lose independence: risk factors include depression, loneliness, and impulsivity.21,22 Psychosis, despite being relatively well recog- nized in HD, is in fact quite rare. Additional familial factors may predispose to schizophrenia-like symptoms in HD.23 Hypomania and, more rarely, mania are seen.24

Irritability, a mood state characterized by a reduction in con- trol over temper, is common (65.4 per cent)25 and some patients become aggressive. Apathy, which is de ned as a disorder of moti- vation, with diminished goal-directed behaviour, cognition, and emotion26,27 is prevalent in symptomatic HD (55.8 per cent),25,28 and prior to motor onset.29 It should be noted that while apathy may be related to depression, it may also be a feature of HD inde- pendent of mood disturbance. Obsessions and compulsions, for example about bowel habit, food, or in delity of spouse, can be features of HD, and can be challenging for loved ones to cope with.

e combination of low mood, apathy, obsessiveness, and irri- tability can precipitate social isolation, and a negative spiral in the patient’s condition. In addition to addressing these issues and con- sidering pharmacological management, it is also important to pro- vide multidisciplinary support to not only the patient themselves but also to families and carers.

Cognitive features

e severity of cognitive involvement in HD is variable and becomes more prevalent and marked as the disease progresses. Individuals who are many years from predicted motor diagnosis6 show few, if any, overt signs of cognitive decline. ere o en are subtle cogni- tive di erences detectable more than a decade prior to predicted

Clinical status

Early: subtle Late: manifest psychomotor progressive

Neurobiology

dysfunction

disease

Chorea

Neuronal dysfunction

Neuronal cell death

Functional status

Motor impairment

Birth

Motor diagnosis of mainfest Huntington’s disease

Death

Reversible developmental delay

Fig. 31.1 Outline of the clinicopathological progression of HD.
Reproduced from Lancet Neurol. 10(1), Ross CA and Tabrizi SJ. Huntington’s disease: from molecular pathogenesis to clinical treatment, pp. 83–98, Copyright (2011), with permission from Elsevier.

motor onset which gradually decline as motor onsets approaches (Fig. 31.3).30,31 ese presymptomatic changes are likely to relate to abnormalities on MRI such as caudate atrophy which can be seen in cross-sectional studies up to 15 years prior to predicted motor onset, and the increased rates of whole-brain, caudate, and putam- inal atrophy observed up to 15 years before predicted onset and controls (Fig. 31.2).13,15 An important research question is what, if any, compensatory mechanisms exist to minimize cognitive dys- function at this stage. anks to the availability of presymptomatic genetic diagnosis enabling the study of individuals many years from symptom onset, these very early signs of HD are amenable to investigation, and large-scale studies such as TrackOn-HD aim for a better understanding of these mechanisms.

Many of the cognitive changes in HD represent disruption to frontostriatal circuits, evident in the key cognitive abnormalities observed in these patients (see chapters 2, 3, 7, and 8).24 Cognitive de cits are particularly apparent in executive functioning, includ- ing the ability to plan, organize, and monitor behaviour, and to show mental exibility and set-shi ing.32 ere are also impair- ments in attention, verbal uency, psychomotor speed, memory and visuospatial functioning (see reference 24 for a comprehensive review).

ere is no accepted cognitive battery for the cognitive assess- ment of HD although most HD centres rely on the Uni ed Huntington’s Disease Rating Scale (UHDRS) for routine clinical practice, which incorporates the symbol digit modality test, the

(a)

Change in grey matter

CHAPTER 31 other genetic causes of cognitive impairment 341

(b)

Control

Premanifest

0 5 10 15 20 T score

Early HD

Tissue gain Tissue loss

Change in white matter

Fig. 31.2 Imaging changes from the Track-HD study. (a) Parametric maps showing regions with statistically signi cant atrophy in grey matter (top) and white matter (bottom) over 24 months, relative to controls. (b) e brain boundary shift integral, a quanti cation of whole-brain volume change estimated through measurement of shift at the brain–CSF boundary over 12 months within each subject group.
(a) Adapted from Lancet Neurol. 10(1), Tabrizi SJ, Scahill RI, Durr A, et al. Biological and clinical changes in premanifest and early stage Huntington’s disease in the TRACK-HD study: the 12-month longitudinal analysis, pp. 31–42, Copyright (2011), with permission from Elsevier. (b) Adapted from Lancet Neurol, 11(1), Tabrizi SJ, Reilmann R, Roos RA, et al. Potential endpoints for clinical trials in premanifest and early Huntington’s disease in the TRACK-HD study: analysis of 24 month observational data, pp. 42–53, Copyright (2012), with permission from Elsevier.

Boundary shift
integral Early HD PreHD

Baseline groups

Early HD PreHD

342 SECTION 3 cognitive impairment and dementia

Stroop colour word test, and a verbal uency test as part of a com- prehensive examination.33

One of the challenges in interpreting cognitive examination nd- ings in HD is evaluating premorbid intellect.34 Commonly used single-word reading tests such as the Wide Range Achievement Test (WRAT) Reading subset and the National Adult Reading Test (NART)35 test reading ability, which may itself be a ected early in the course of disease, resulting in an underestimation of premorbid IQ. In comparing test-based versus demographic-based estimates of premorbid intellect in mild and moderate HD subjects, O’Rouke and colleagues36 found that demographic-based estimates were less confounded by disease progression and may re ect a more valid indicator of prior cognitive capacity.

e earliest detected cognitive de cit described in premani- fest HD is impairment of emotion recognition, which is signi – cantly di erent from controls in expansion-positive cases more than 15 years from predicted motor onset,34 shows longitudinal change,15 and can cause considerable distress to patients and their families. Timing15,37,38 and speeded tapping15,30 are also a ected early in disease and deteriorate longitudinally making them poten- tial biomarkers for clinical trials. e Track-HD study found cog- nitive decline in 10 out of 12 outcome measures in 116 early-HD subjects relative to controls over 24 months, with greatest sensitiv- ity in symbol digit, circle tracing (direct and indirect), and Stroop word reading tasks,39 see Fig. 31.3.

e concept of mild cognitive impairment (MCI),40 a transitional stage between normal cognition and dementia, is being increasingly used to describe early cognitive changes in HD.34 MCI is opera- tionally de ned by subjective cognitive complaints and objective cognitive de cits, but with the absence of dementia and functional impairment.41,42 Du and colleagues43 tested episodic memory, processing speed, executive functioning, and visuospatial percep- tion in 575 prodromic gene carriers and found the prevalence of MCI was 38 per cent, and this increased as participants approached the estimated age of diagnosis (far = 27.3 per cent, mid = 42.3 per cent, near = 54.1 per cent; p < 0.0001 for trend).

While some argue against the use of the term dementia in HD on the basis that the cognitive changes are more circumscribed

than dementia implies, the term is still widely used. Criteria for HD dementia have been based largely on features of the dementia associated with Alzheimer’s disease (AD), however the pattern of spared and impaired cognitive abilities observed in HD is distinct from that in AD.44,45

Typically, HD patients have a ‘subcortical’ as opposed to cortical cognitive pattern of de cits.46 HD memory performance is a ected by slowed retrieval largely independent of the ability to store infor- mation and motor slowing.47 Peavy and colleagues44 showed that speed of processing, initiation and attention measures de ned the onset of HD dementia better than traditional de nitions created for AD which required memory de cits. In early HD, language is relatively spared with preservation of lexical abilities, however studies show that the application of syntactic movement rules is impaired.48,49 As the disease progresses communication is also compromised by both dysphasia and dysarthria.

Other features of HD

Mutant huntingtin protein is ubiquitously expressed in the body. us Huntington’s disease has peripheral e ects not all of which are secondary to brain dysfunction (reviewed in reference 50). It causes metabolic symptoms, which include catabolic weight loss, skeletal muscle atrophy, endocrine dysfunction, and sleep disturbance. Weight loss, which is thought to be related to the chorea, procata- bolic nature of the condition, xerostomia, and feeding di culties, is associated with poor outcome and is important to recognize and address proactively.18 Sleep is o en disturbed due to disturbed cir- cadian rhythms (reviewed in reference 51) and negatively impacts on quality of life (see Box 31.1).

Juvenile HD

is is also known as the Westphal variant of HD, and is character- ized by onset before 20 years of age, although cases with young- adult onset and a primarily rigid phenotype are also described as having the Westphal variant. e extrapyramidal features of rigid- ity, bradykinesia, and akinesia develop early in these patients, and many have a history of learning impairments at school. Unlike in adult-onset HD, seizures can be a feature and are more common in those with very young onset.

(a) 6.4 Controls HD1 PreHD-A HD2

PreHD-B

6.0 5.6 5.2

4.8 Baseline

(b) 110 100 90 80 70 60 50

50 40 30 20

Baseline

12 24 Months

Months

Fig. 31.3 Longitudinal changes in cognitive measures from the Track-HD study over 24 months. Signi cant change di erences relative to controls over 0–12, 12–24, and 0–24 months are represented by *p < 0.05, **p < 0.01, and ***P < 0.001. Groups determined at start of study; PreHD-A: more than 10.8 years from predicted onset; PreHD-B: less than 10.8 years from predicted onset; HD1: early HD and less symptomatic on total functional capacity scale (TFC); HD2: early HD and more symptomatic on TFC.
Adapted from Lancet Neurol. 11(1), Tabrizi SJ, Reilmann R, Roos RA, et al. Potential endpoints for clinical trials in premanifest and early Huntington’s disease in the TRACK-HD study: analysis of
24 month observational data, pp. 42–53, Copyright (2012), with permission from Elsevier.

Change in

Circle indirect annulus length (log cm)

Stroop word reading (number correct)

Symbol digit modality (number correct)

CHAPTER 31 other genetic causes of cognitive impairment 343 Key features of Huntington’s disease pathogenesis have been con-

sistently described (Fig. 31.4) (reviewed in reference 55):

◆ Mutant HTT has the propensity to form abnormal conforma- tions, including β-sheet structures (although HTT in large inclu- sions is not the primary pathogenic species in HD).

◆ Systems for handling abnormal proteins are impaired in cells and tissues from Huntington’s disease patients and in experimental models.

◆ HTT is truncated and gives rise to toxic N-terminal fragments.

◆ Post-translational modi cations of HTT in uence toxicity, via conformational changes, aggregation propensity, cellular locali- zation, and clearance.

◆ Nuclear translocation of mutant HTT enhances toxic e ects of the protein, in part via transcription-related e ects.

◆ Cellular metabolic pathways are impaired in samples from Huntington’s disease patients and models.
Histologically, there is massive striatal neuronal cell death, with up to 95 per cent loss of GABAergic medium spiny projection neu- rons which project to the globus pallidus and the substantia nigra. ere is relative sparing of large cholinergic interneurons and spe- ci c loss in layers V and VI of the cerebral cortex.56,57 Microglial activation is seen from early in disease.58 From a macroscopic per- spective, there is generalized brain atrophy, particularly involving the caudate nucleus and to a lesser extent the putamen, with atro- phy of the internal segment of the globus pallidus and substrantia nigra pars reticulata.13,57 White matter tracts are a ected in HD from premanifest stages,13–15,59,60 see Fig. 31.2 (also referred to in the cognitive section earlier in this chapter).
Genetic testing in HD
Genetic testing is performed by measuring the CAG repeat length in the HTT gene; a positive test refers to a CAG length in the fully pen- etrant range (see Table 31.1 reference 61 for an overview). Testing may be diagnostic in an individual with symptoms to con rm or refute a diagnosis of HD, or predictive in an individual known to be at risk of disease because of their family history. Most people at risk of HD choose not to undergo predictive testing. Predictive test- ing for HD requires expert counselling; it is performed in special- ist genetic centres and follows internationally agreed guidelines.62 Similar principles are adopted in the genetic testing for the other neurodegenerative diseases covered in this chapter.
Management of HD
e cornerstone of the clinical management of HD is a multidisci- plinary approach since the needs of patients are diverse and change over time (for a detailed overview on management see reference 61). Most HD clinics are run by a combination of clinical geneti- cists, neurologists, neuro-psychiatrists, nurse specialists with sup- port from physiotherapists, speech and language therapists, and dieticians. e role of the general practitioner and sometimes social worker is also important, liaising with the specialist team, and providing regular and local input. HD organizations, such as the Huntington’s disease association in the United Kingdom (HDA; <http://www.hda.org.uk>) provide valuable support via regional care advisors, and also provide a wealth of information on their website and via booklets.

Box 31.1 Case history

A 55-year-old man was brought to see the general practitioner by his wife. She explained that her husband had been healthy and active when younger but that his ability to function inde- pendently had declined over the previous few years to the point where she was now helping him with all activities of daily liv- ing. If she did not help or prompt her husband, he would not wash or dress himself and would sit on the sofa all day doing nothing. Her husband had no history of physical illness but had su ered from recurrent bouts of depression for many years and had developed obsessive–compulsive behaviours over the last 15 years. ese included picking litter up from the street and arranging his belongings in lines. On questioning about illness in the family, the patient explained that he thought that his mother had been diagnosed with Alzheimer’s disease in her 40s.

On examination, the patient had occasional involuntary movements in his arms. Examination of the limbs was otherwise normal. He was fully orientated and scored 26/30 on the mini mental state examination.

A er counselling of the patient and his family at a specialist genetics centre, the patient underwent genetic testing and the diagnosis of Huntington’s disease was con rmed.

A er a full assessment of his care needs, this patient began regularly attending his local day centre; this led to a dramatic improvement in his behaviour and mood. He enjoyed the mental stimulation and social contact of the day centre, and bene ted from the structure and routine of going there every day (having a speci c goal such as leaving the house and going to a day centre is a good way to combat apathy). He also started taking uox- etine; this led to his obsessive–compulsive behaviours improving to a more manageable level. e patient’s wife greatly appreciated the support and time by herself that resulted from her husband’s attendance at the day centre, and she also made contact with, and received support from, the Huntington’s Disease Association (<www.hda.org.uk>), an organization which provides invaluable support for those a ected by Huntington’s disease. e relatives of the patient (those now known to be at risk of carrying the abnormal Huntington’s disease gene themselves) were o ered information and support, including genetic counselling and information about predictive testing for Huntington’s disease for those who wanted it.

Adapted from BMJ. 343, Novak MJ and Tabrizi SJ, A man with deteriorating ability to live independently, Copyright (2011), with permission from the BMJ Publishing Group Ltd.

Molecular pathogenesis of HD

HD is caused by an expanded CAG triplet repeat encoding a polyglu- tamine (polyQ) expansion in exon 1 of the huntingtin (HTT) gene. e protein HTT is large (~350 kDa) and highly conserved, and is necessary for embryonic development.52–54 It is expressed widely in the central nervous system and peripheral tissues and in most intra- cellular compartments. It has been shown to interact with numerous other intracellular proteins. Huntingtin’s exact intracellular functions are incompletely understood but it is known to be involved in vesicu- lar transport, cytoskeletal anchoring, neuronal transport, postsynap- tic signalling, cytoprotection, and transcriptional regulation.55

344 SECTION 3 cognitive impairment and dementia

Proteasome, chaperone, and autophagy inhibition

Accumulation of abnormal proteins

Toxic fragments Oligomerization

Compact β conformation

Abnormal interactions with cellular proteins

ATP ROS

Mitochondrial abnormalities

BDNF

C Cleavage

PGC1α targets

Nucleus

Expanded polyglutamine, abnormal conformation

HAP1 Microtubule

Inclusion C

PGC1α BDNF

N
Expanded polyglutamine, normal confirmation

Neuron

Vesicle

Dynactin p150 glued

Caspase 6 cleavage

C
Mutant HTT

Fig. 31.4 Postulated intracellular pathogenesis of Huntington’s disease. Mutant HTT (shown as a helical structure) with an expanded polyglutamine repeat (shown in green) undergoes a conformational change and interferes with cellular tra cking, especially of BDNF. Mutant HTT is cleaved at several points to generate toxic fragments with abnormal compact β conformation. Pathogenic species can be monomeric or, more likely (and as shown), form small oligomers. Toxic e ects in the cytoplasm include inhibition of chaperones, proteasomes, and autophagy, which can cause accumulation of abnormally folded proteins and other cellular constituents. ere

may be direct interactions between mutant HTT and mitochondria. Other interactions between mutant HTT and cellular proteins in the cytoplasm are still poorly understood. Pathognomonic inclusion bodies are found in the nucleus (and small inclusions are also found in cytoplasmic regions). However, inclusions are not the primary pathogenic species. A major action of mutant HTT is interference with gene transcription, in part via PGC1α, leading to decreased transcription of BDNF and nuclear-encoded mitochondrial proteins. ROS: reactive oxygen species.

Adapted from Lancet Neurol. 10(1), Tabrizi SJ, Scahill RI, Durr A, et al. Biological and clinical changes in premanifest and early stage Huntington’s disease in the TRACK-HD study: the 12-month longitudinal analysis, pp. 31–42, Copyright (2011), with permission from Elsevier.

Management of motor symptoms

ough common, chorea is rarely functionally disabling for patients with HD, however in some cases it causes embarrassment and thereby increases risk of social isolation. e side-e ects of the antichorea medications, and the fact that they are rarely very e – cacious, means that antichoreic medications should be used spar- ingly. Tetrabenazine can be an e ective option63–65 but should be avoided in patients with psychosis, active depression, aggressive behaviours, and non-compliance. Side-e ects include depression, anxiety, sedation, parkinsonism, and cognitive impairment.63 For patients with coexisting psychosis, depression, and aggression, antipsychotic agents such as olanzapine, sulpiride, or rispiridone should be considered as the rst-line option. In some cases aman- tadine or riluzole may be e ective.64 In all cases these medications require careful evaluation prior to initiation of treatment and ongo- ing monitoring of response.

Impairment of voluntary motor function and gait disturbances are challenging to treat but can bene t from physiotherapy assess- ment and exercises. e European Huntington’s Disease Network has some helpful physiotherapy guidelines.66 Walking aids and wheelchairs o en become necessary as symptoms progress, and

involving an occupational therapist to review a patient’s home envi- ronment can prove useful. In the later stages, rigidity and dystonia become more dominant; in some cases antispasticity drugs can assist but o en a ord no functional bene t.

Speech and swallowing can be early and debilitating problems in HD and are important to enquire about; a ected patients should be referred for speech and language therapy input.2 Dysarthria con- tributes to communication di culties, and as the disease progres- sive patients can become mute. Ultimately, feeding via gastrostomy with the option of small amounts of oral feeding for pleasure is sometimes the best option.

Management of psychiatric problems

Much of our current practice is based on anecdotal evidence. e most useful drugs for depression are the serotonin-selective reup- take inhibitors (SSRIs). Anecdotal reports and our own practice suggest that citalopram and mirtazapine are e ective, particularly when anxiety is a co-factor. SSRIs are also the rst-line option for obsessive–compulsive behaviours in HD.67 Irritability, aggres- sion, and impulsivity may be ameliorated by antipsychotic agents such as olanzapine, rispiridone, and quetiapine.68 ese newer

BDNF

CHAPTER 31 other genetic causes of cognitive impairment 345 Table 31.2 Principal causes of Huntington’s disease phenocopy syndromes

Condition

Gene

Protein

Inheritance

Notes

Familial prion disease

PRNP

Prion

Includes HDL1

HDL2

JPH3

Junctophilin 3

African ancestry

HDL3

Unknown

Two pedigrees only

SCA17

TBP

TATA-binding protein

Cerebellar atrophy and ataxia, see below

SCA1

ATXN1

Ataxin 1

SCA2

ATXN2

Ataxin 2

SCA3

ATXN3

Ataxin 3

DRPLA

ATN1

Atrophin 1

Myoclonic epilepsy, see below

PKAN (NBIA1)

PANK2

Pantothenate kinase

MRI ‘eye-of-the tiger sign’; pigmentary retinopathy

Neuroferritinopathy

FTL

Ferritin light chain

Early dysarthria and persistent asymmetry

Chorea-acanthocytosis

CHAC

Chorein

Mutilating orofacial dystonia

Macleod syndrome

Krell antigen

Systemic features

Wilson’s disease

ATP7B

Copper-transporting ATPase

Kayser–Fleischer rings, etc.

Friedreich’s ataxia

FRDA

Frataxin

Rarely resembles HD, see below

Mitochondrial disease

mtDNA or nuclear mitochondrial genes, see below

Benign hereditary chorea

TITF1

yroid transcription factor 1

Non-choreic features rare

Acquired causes

e.g. Sydenham’s chorea, anti-basal ganglia antibodies, neuro-SLE, thyrotoxicosis, vascular disease, and medications

AD: autosomal dominant; AR: autosomal recessive; XR: X-linked recessive.

antipsychotics have an improved side-e ect pro le in terms of extrapyramidal symptoms and are also useful for severe anxiety and motor symptoms. Mood-stabilizing drugs such as valproate and carbamazepine are useful for symptoms of mania. Benzodiazepines can be useful in the short-term treatment of anxiety and long-term agitation in advanced disease. Sleep disturbance is routinely man- aged with sleep hygiene measures and hypnotics; melatonin may also help.

Management of cognitive symptoms

Formal neuropsychometric testing can be useful to quantify impairments and inform optimal management and care of patients with cognitive impairment, particularly when insight is also impaired. ere are no therapeutic agents with proven e cacy for the cognitive impairment in HD. Environmental enrichment, which enhances mental and physical activity levels, has been found to induce bene cial e ects in rodent models of HD,69 and there is some evidence that MCI due to Alzheimer’s disease can respond to cognitive stimulation.70 In our clinical experience there is anecdo- tal support for cognitive stimulation and a strong social network bene ting our patients, and it will be interesting to see whether this is supported experimentally in the future. In the meantime, provid- ing a safe and supportive environment are cornerstones in manag- ing cognitive HD symptoms.

Huntington’s disease phenocopy syndromes

In around 1–3 per cent of cases where Huntington’s disease is sus- pected clinically, patients lack the CAG repeat expansion that causes HD.11,71–73 Such individuals are said to have Huntington’s disease

phenocopy syndromes,74 reviewed in reference 73. e known causes of HD phenocopies are summarized in Table 31.2. In a case series of 285 patients with HD phenocopy syndromes, 8 patients (2.8 per cent) were identi ed as having other inherited neurologi- cal diseases including SCA17, HDL2, PRNP (familial prion dis- ease), and FA (Friedreich’s ataxia).75 Several of these syndromes are described below; Huntington’s disease-like syndrome 1 (HDL1) and Huntington’s disease-like 2 (HDL2) will be discussed here.

Huntington’s disease-like syndrome 1 (HDL1) is a rare autoso- mal dominant condition causing personality change, dementia, and chorea. It is caused by eight extra octapeptide repeats inserted within the prion protein (PrP).74 is and other familial prion dis- eases are described in chapter 38. Huntington’s disease-like syn- drome 2 (HDL2) is caused by GTC/CAG triplet repeat expansions in the JPH3 gene encoding junctophilin-3. e condition is phe- notypically similar to HD with similar cognitive and psychiatric pro le, although dystonia is more marked than chorea. It is more prevalent among populations of African ancestry.76,77

Hereditary cerebellar causes of

cognitive impairment

e role of the cerebellum in motor control is long established, but its role in cognition has been more controversial (see chapter 26). Schmahmann and colleagues78 coined the term ‘cerebellar cogni- tive a ective syndrome’ (CCAS) which is characterized by: dis- turbances of executive functioning, impaired spatial cognition, inappropriate a ect, and linguistic di culties. ere are numer- ous identi ed genetic causes of cerebellar impairment, which we

346 SECTION 3 cognitive impairment and dementia

outline in the following. Known cognitive symptoms will be high- lighted, though it should be noted that for some of the rarer ataxias detailed neuropsychologial studies are limited.

Autosomal recessive ataxias

Friedreich’s ataxia (FRDA)

Friedreich’s ataxia (FRDA) is the most common of the cerebellar ataxias among Indo-Caucasian populations with a prevalence of 2 in 100 000,79 and it is inherited in an autosomal recessive manner. e FRDA gene, on chromosome 9q13, codes for a 210 amino acid protein called frataxin. In more than 97 per cent of cases the condition is caused by a homozygous triplet GAA expansion (> 40 repeats) in the rst intron of the frataxin gene; however, about 3 per cent of such cases are compound heterozygous for the expansion with the second allele carrying a point mutation.80,81 Frataxin is a mitochondrial membrane protein involved in iron distribution. e neuropathological changes of FRDA involve the spinal cord, with degeneration of posterior columns and spi- nocerebellar tracts, the dentate nucleus of the cerebellum, and the heart.79,82

FRDA causes progressive neurological disability and classically presents by 25 years of age. Unsteadiness of gait is the most com- mon presenting symptom;82 there is progressive ataxia (cerebel- lar and sensory),83 limb weakness, spasticity, absent lower limb re exes, extensor plantars, posterior sensory changes, and dysar- thria.82 Systemically, FRDA causes a hypertrophic cardiomyopa- thy, increased risk of diabetes mellitus, and skeletal abnormalities are common; a multidisciplinary approach is therefore key to management.

Although primarily a movement disorder with systemic features, cognitive impairments may be observed in FRDA. ere are reports of slow information-processing speed,84–86 and some suggest ver- bal span and letter uency are impaired.87 Emotional lability and depression have also been recorded.82 e cognitive impairments observed may be due to cerebellar impairment disrupting cerebro- ponto-cerebello-thalamo-cerebral loops, direct cortical pathology, or a combination of the two.88

Autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS)

Autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) is a rare neurodegenerative disorder characterized by early-onset cerebellar ataxia, lower limb spasticity, sensorimotor axonal neuropathy, and atrophy of the superior cerebellar vermis. It has been associated with normal IQ but impaired visuospatial functioning.89 ere are reports of impaired goal directed action, apathy, and impulsivity associated with the condition.90

Autosomal dominant cerebellar ataxias

(spinocerebellar ataxias)

e progressive autosomal dominant cerebellar ataxias are usu- ally labelled spinocerebellar ataxia (SCA), followed by a number to denote the gene locus. ey have an overall prevalence of 1–4 in 100 000.91 Dentatorubral-pallidoluysian atrophy (DRPLA) does not have a SCA designation but bears similarities to the SCAs and so will be included here. e SCAs exhibit many phenotypic sim- ilarities so it can be almost impossible to diagnose the genotype from the phenotype alone,92 although there are features making one or another SCA more likely (see Table 31.3).

Penetrance of the SCAs is generally complete. Patients typically display limb and truncal ataxia, dysarthria, dysphagia, pyramidal signs, extrapyramidal signs (dystonia, rigidity, bradykinesia), and autonomic disorders. Patients may develop other neurological signs that can evolve over the course of years. ere may be non-cerebellar oculomotor features such as slow saccades, oculomotor palsy, blepha- rospasm, an ocular stare, and ptosis. ere may be signs of brainstem disease such as facial atrophy and fasciculations, temporal muscle atro- phy, tongue atrophy and fasciculations, poor cough, and dysphagia.

ere are a variety of mutations responsible for the SCAs; unsta- ble CAG repeat expansions cause SCA1, SCA2, SCA3 (Machado– Joseph Disease), SCA6, SCA7, SCA17, and DRPLA. Analogously to HD, there is an overall tendency for the expansions to expand intergenerationally, age at onset usually has an inverse relation with number of repeats, and earlier onset is generally associated with a more orid phenotype.

Harding93 observed signi cant cognitive impairment in 25 per cent patients with autosomal dominant cerebellar ataxias. As muta- tions have become better characterized, their cognitive attributes have been examined,94 although it is not yet clear to what extent these features are speci c to each disorder, or are more general fea- tures relating to the brain areas damaged. Severity of cognitive de – cit generally correspond with severity of pathological and clinical features.95 Table 31.3 summarizes the autosomal dominant ataxias, with known genetic mutations and well-documented cognitive fea- tures as part of the disease.

ere are currently no e ective curative treatments for the inherited ataxias. As with Huntington’s disease, the manage- ment is supportive and specialist clinics have a multidisciplinary approach involving physical, occupational, and speech therapy. Unfortunately there are currently no medications which help the balance disturbance of cerebellar ataxia. It is, however, important to consider appropriate and targeted symptomatic treatments for the additional features that may arise. ese medications are well reviewed in Ataxia UK’s guidelines, available at: (<http://www. ataxia.org.uk/data/ les/ataxia_guidelines_web.pdf>).

Hereditary vasculopathies

Vascular causes of cognitive impairment are varied, and are the focus of chapter 25. In this section we provide an overview of the hereditary vasculopathies which cause arteriopathy and microvas- cular disintegration leading to vascular cognitive impairment. For more detail, the reader is referred to reference 113.

Cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy (CADASIL)
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) typically presents in youth and adulthood with migraine, subcortical transient ischae- mic attacks or strokes, psychiatric disorders, and subcortical and frontal cognitive impairment.113,114 Systemic involvement with ocular, cardiac, and peripheral nerve features have been reported. e disease is caused by dominant mutations within the NOTCH3 gene115 which is expressed in vascular smooth muscle cells. ere is microangiopathy with granular osmophilic deposits in the base- ment membrane, and abnormal responsiveness to vasoactive agents.116 On MRI there is generalized brain atrophy117 and focal

CHAPTER 31 other genetic causes of cognitive impairment 347 Table 31.3 Autosomal dominant ataxias with known gene loci showing phenotype and cognitive impairment where cognitive features are well

documented

Disease

Gene/locus

Mutation (pathogenic range)

General features in addition to those of cerebellar ataxia

Cognitive features

SCA 1

6p/ataxin 1

CAG expansion (45–83)

Bulbar dysfunction, somatosensory and oculomotor dysfunctions, pyramidal signs, visual impairments, electrophysiological abnormalities92

Executive dysfunction, verbal memory impairment96,97

SCA 2

12q/ataxin 2

CAG expansion33–64 (33–500)

Slowed ocular movements, peripheral neuropathy, postural and action tremor, myoclonus and hypore exia

Dementia in 19–42%97 (higher than SCA1, 3, 6, 7), in those with dementia- impaired attention, memory, frontal executive functions95,98,99

SCA 3

14q/ataxin 3

CAG expansion (52–87)

Pyramidal involvement, opthalmoplegia, peripheral neuropathy, parkinsonism in some

Cognitive dysfunction including attention di culties96,100

SCA 6

19p/CACNA1

CAG expansion (20–33)

Ataxia, occasional extrapyramidal and sensory e ects

Impaired executive function and visual memory95,101,102

SCA 7

3p/ataxin 7

CAG expansion (37–460)

Ataxia, retinal degeneration, opthalmoplegia, seizures

Impaired executive function,95 dementia

SCA 8

13q

CTG expansion (107–127)

Dysarthria with a characteristic drawn- out slowness of speech and gait instability Neuropsychiatric problems

Frequent impairments of attention, information processing and executive functions103,104

SCA 10

22q

ATTCT expansion (1000–4000)

Ataxia, epilepsy
Predominant Latin American origin

Cognitive dysfunction and behavioural disturbances noted105

SCA 12

5q/PPP2R2B

CAG expansion (66–78)

Tremors; common in India

Dementia106

SCA 13

10q/KCNC3

Point mutations

Childhood onset ataxia of slow progression

Mental retardation

SCA 14

19q/PKCγ

Conventional mutations including missense and deletions

Cognitive impairment

SCA 17

6q/TBP

CAG expansion (49–66)

Psychiatric features, extrapyramidal signs, seizures, dementia

Apraxia, dementia107,108

SCA 19

1p/KCND3

Missense mutations

Adult onset ataxia, postural tremor, myoclonus, sensory impairment

Frontal executive dysfunction, global impairment as disease progresses109

SCA 21

Not known

Ataxia, extrapyramidal features

Mild to severe cognitive de cit110

SCA 27

FGF 14

Point mutations

Tremor, dyskinesia

Some cognitive impairment recorded

DRPLA

12p/atrophin

CAG expansion (48–93)

Ataxia, myoclonus, epilepsy, chorea, psychiatric symptoms

Dementia111,112

white matter abnormalities, which can be apparent prior to symp- tom onset.118 Changes are particularly apparent in frontal, parietal, and anterior temporal lobes and the external capsule.113

Cerebral autosomal recessive arterioapthy
with subcortical infarcts and leukoencephalopathy (CARASIL)
CARASIL, also known as Maeda syndrome, is clinically similar to CADASIL but with earlier onset and more systemic features such as arthropathy, lower back pain, spondylosis deformans, disc hernia- tion, and alopecia, and an autosomal recessive rather than domi- nant family history.113 It is more common in Asian regions, and has a male to female predominance of 3:1. e disease has been linked to a mutation in HTRA1. ere is damage to vascular smooth mus- cle bres and arterioscleotic changes.

Small vessel disease associated with COL4A1 mutation

COL4A1 mutations results in a defect of type IV collagen with resulting vascular pathology. Mutations in the COL4A1 gene are

associated with proencephaly and infantile hemiparesis but have more recently been linked to small vessel disease which can present later in life.119 Features include ischaemic stroke, haemorrhage, lacunar infarction, leukariosis, and microbleeds, and systemic involvement of the eye, kidneys, and muscle. Depending on the age of onset, a ected individuals present with infantile hemiparesis, seizures, visual loss, dystonia, strokes, migraine, mental retarda- tion, cognitive impairment, and dementia.113

Other familial amyloid angiopathies

Familial British dementia with amyloid angiopathy (FBD) is an autosomal dominant condition characterized by a dementia, pro- gressive spastic tetraparesis and cerebellar ataxia with onset in the sixth decade. A point mutation in the BRI gene has been shown to be the causative genetic abnormality.120 Familial Danish dementia is an early-onset autosomal dominant disorder due to CHMP2B truncation mutations.121 It is clinically characterized by ataxia and a frontotemporal dementia with early personality change, apathy, hyperorality, early dyscalculia, and stereotyped behaviours; as the

348 SECTION 3 cognitive impairment and dementia
disease manifests, individuals develop a orid motor syndrome

with pyramidal and extrapyramidal features.122

Fabry disease

Myoclonic epilepsy with ragged red bres (MERRF)

ere is progressive myoclonus, focal and generalized epilepsy, cerebellar ataxia, cognitive impairment, and myopathy. Proximal weakness, sensory ataxia, proprioceptive and pyramidal signs abnormalities also occur. In the later stages of the disease, severe cognitive impairment is common and o en exhibits prominent frontal features.128

Conclusion

In this chapter we have provided an overview of a wide range of genetically determined causes of cognitive impairment, and high- lighted their key cognitive features. While curative treatments are not yet available for these conditions, their genetic nature make them amenable to study, and it is hoped that through detailed understanding of the mechanisms by which mutations are linked with disease that therapeutic targets may be identi ed and rational treatments developed.

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Fabry disease is a progressive, X-linked inherited disorder of gly- cosphingolipid metabolism due to a de cient or absent lysosomal α-galactosidase A activity. e classic form of the disease, present- ing in males with no detectable α-Gal A activity, is characterized by angiokeratomas, acroparesthesia, hypohidrosis, corneal opac- ity, and progressive vascular disease of the central nervous system, heart, and kidneys. In contrast, mild forms may manifest only in adulthood with cardiac and renal disease.113 Neurologically it is associated with both peripheral and central nervous system involvement, with large and small vessel ischaemic strokes, and there are reports of mild cognitive de cits.123

Primary mitochondrial disorders

and cognitive impairment

Mitochondria are intracellular organelles whose major function is the generation of the energy carrier ATP. From a clinical genetics perspective, mitochondria are passed only down the female line,124– 126 though in very rare cases there may be paternal transmission.127 Mitochondrial mutations may be present in some (heteroplasmy) or all (homoplasmy) mitochondria within a cell, with correspond- ing variations in severity.

Mitochondrial disorders present as multi-system diseases. Central nervous system manifestations of mitochondrial disor- ders include stroke-like episodes, epilepsy, migraine, ataxia, spas- ticity, movement and psychiatric disorders, cognitive decline, and dementia. Other features include myopathy, deafness, progressive external opthalmoplegia, diabetes, bone marrow involvement. e manifestations of mitochondrial disease are highly variable, and it should be noted that patients may su er from some but not other characteristic features.128 ere have been relatively few neuropsy- chological studies on cognitive impairment in mitochondrial dis- eases but cognitive impairment and dementia are well recognized in these conditions.129,130

Mitochondrial encephalopathy lactic acidosis and

stroke-like episodes (MELAS)

MELAS is characterized by parieto-occipital stroke-like episodes, o en associated with concurrent encephalopathy and elevated plasma and CSF lactate. e stroke-like episodes are not due to thromboembolic disease but respiratory chain dysfunction within cerebral tissues,128,131 consequently the focal de cit o en develops over hours or even days, and they may be associated with head- ache, nausea, and encephalopathic features. Radiological lesions may extend over multiple vascular territories. Seizures commonly accompany the focal episodes. Other symptoms such as deafness, diabetes, myopathy, or a pigmentary retinopathy may be present. In a study of 31 symptomatic MELAS with the m.3243A>G mutation, Kaufmann and colleagues132 found that the global neuropsycho- logical score decreased over annual visits but there was no decline in asymptomatic carrier relatives. Cognitive decline may relate to neurodegeneration rather than just being secondary to stroke-like episodes.133

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CHAPTER 31 other genetic causes of cognitive impairment 349

350 SECTION 3 cognitive impairment and dementia

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131. Yeh HL, Chen YK, Chen WH, et al. Perfusion status of the stroke- like lesion at the hyperacute stage in MELAS. Brain Dev. 2013 Feb;35(2)158–64.

132. Kaufmann P, Engelstad K, Wei Y, et al. Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype. Neurology. 2011;77(22):1965–71. Epub 2011/11/19.

133. Salsano E, Giovagnoli AR, Morandi L, et al. Mitochondrial dementia: a sporadic case of progressive cognitive and behavioral decline with hearing loss due to the rare m.3291T>C MELAS mutation. J Neuro Sci. 2011;300(1–2):165–8. Epub 2010/10/15.

CHAPTER 31 other genetic causes of cognitive impairment 351

CHAPTER 32

Changing concepts
and new de nitions
for Alzheimer’s disease Bruno Dubois and Olga Uspenskaya-Cadoz

Alzheimer’s disease (AD) is a progressive neurodegenerative dis- order with cognitive, behavioural and functional abnormalities. AD is the most prevalent form of dementia: it accounts for approx- imately 70 per cent of cases of progressive cognitive impairment in aged individuals,4 age being the single most important risk fac- tor. e prevalence of AD doubles every 5 years a er the age of 60 and reaches 40 per cent a er 90.5 e disease is linked with ageing but it is not due to ageing, as exempli ed by early-onset cases, usually de ned as symptoms starting before 65.6

e dementia syndrome associated with advanced AD has char- acteristic clinical features usually including various combinations of memory impairment, language abnormalities, impaired ges- tural skills (apraxia), disturbances of visuospatial functions, and executive de cits. ese cognitive and behavioural abnormalities interfere with functional activities of daily living (ADL), with ADL impairment being a marker and core criterion for the diagnosis of a dementia syndrome.7

A number of bedside tests, for example the Mini Mental Status Examination, can be used to provide a global quanti cation of the de cits and is useful for characterizing the stage of cognitive decline.8 However, more detailed neuropsychological testing with standardized assessment of attention, memory, language, executive functions, and visuospatial abilities is required for quantifying the de cits of AD and may aid distinguishing AD from other degenera- tive dementias.

In addition, various neuropsychiatric disturbances can be observed in patients with AD: apathy, dysphoria, and agitation are common during the course of the disease.9 Apathy, characterized by a lack of interest in unusual or interpersonal activities, can occur very early in the course of the disease, in the absence of depression. In contrast, psychosis (delusions or hallucinations), where present, is observed in the more advanced phases of the disease.

e clinical diagnosis of AD has traditionally required exclusion of alternative explanations for cognitive decline using blood test- ing, brain neuroimaging including computerized tomography (CT) or magnetic resonance imaging (MRI), and, on some occasions, cerebrospinal uid (CSF) examination, but has not employed bio- markers to help certify a positive diagnosis.

ere are no established disease-modifying treatments for AD. Cholinesterase inhibitors (ChE-Is) and memantine have proven bene ts in placebo-controlled trials and may be useful

for individual patients, but overall their e ects are limited;10 and trials using potential disease-modifying treatments have not yet demonstrated signi cant e ect, at least on clinical outcomes. Psychotropic agents, including mood-stabilizing anticonvulsants and neuroleptics, should be used with parsimony for behavioural disturbances and neuropsychiatric symptoms, although depres- sion should always be considered and treated as appropriate. Education of and support for caregivers is important for optimal care of the patients.

e historical concept of AD

We have learned—and many still teach—that AD is a clinicopatho- logical entity: the diagnosis of AD cannot be con rmed on clinical grounds alone and de nite diagnosis needs histological con rma- tion based on cerebral biopsy or postmortem examination, the exception being in rare cases where autosomal dominantly inher- ited genetic mutation in the APP, presenilin 1, or presenilin 2 genes identi ed. In the absence of such histological, or genetic, evidence, the clinical diagnosis of AD can only be probable and should only be made when the disease is advanced and reaches the threshold of dementia.

AD as a dementia

Based on the original NINCDS–ADRDA criteria,11 the diagnosis of probable AD requires a two-step procedure. First, a dementia syndrome must be invoked by clinical examination, documented by mental status questionnaire, and con rmed by neuropsychologi- cal testing: there must be de cit in two or more areas of cognition, including memory with a progressive worsening over time respon- sible for a signi cant impact on activities of daily living. ere must be no disturbance of consciousness at the time of the assessment and no evidence of systemic or other brain diseases that could account for a dementia syndrome. Second, a process of exclusion should rule out other possible aetiologies of a dementia syndrome with blood investigations (for excluding infectious, in ammatory, or metabolic diseases), brain neuroimaging—CT scan or MRI (for excluding small vessel disease, strategic lacunar infarcts, large ves- sel infarcts, and/or cerebral haemorrhages, brains tumour, hydro- cephalus, etc.), and where appropriate additional investigations such as CSF examination.

354 SECTION 3 cognitive impairment and dementia e concept of MCI

Considering AD only as a ‘dementia’ has obvious limitations, the most obvious being that it precludes diagnosis of patients with early memory problems that have not yet become disabling. is in turn has led to concept of mild cognitive impairment (MCI), a label that refers to objective memory and/or cognitive impairment not severe enough to impact on daily living activity. e concept of MCI was introduced by Flicker and colleagues12 and the Mayo Clinic group13 to ll the gap between the cognitive changes of normal age- ing and those associated with dementia (be it due to vascular dis- ease, neurodegeneration, or other causes). e mild symptomatic phase of AD, which precedes the fully developed clinical syndrome of dementia, was also included within the MCI spectrum.

Whilst the concept of MCI o ers advantages, it also has several limitations. As used today, MCI is a clinical syndrome syndrome with a number of di erent pathological aetiologies. To decrease the clinical and pathological heterogeneity, subtyping MCI has been proposed (see chapter 21). However, the aetiologic heterogeneity of MCI remains problematic,14 with only ~70 per cent of amnestic MCI cases who progress to dementia actually meet neuropatho- logical criteria for AD.15

From a clinical point of view, in a given patient the most impor- tant thing for the clinician is not just to recognize the syndrome but to identify as far as possible the underlying disease as this may have signi cant impact in terms of prognosis or treatment. An obvious example is the need to distinguish MCI associated with depression and that due to AD, where management (including treatment) and prognosis are very di erent. From a research point of view, the het- erogeneity of MCI may dilute the potential for a signi cant treat- ment e ect and may have contributed to the negative outcomes in several MCI trials aiming to delay time to dementia.16 is is par- ticularly the case as novel approaches or drug compounds currently under development (including immunotherapy, γ- or β-secretase inhibitors, α-secretase activators) are AD-speci c, and would not be expected to alter the disease process in other forms of cognitive impairment.

Revisiting the current concept of AD Considering AD as a dementia is too late

AD pathology is already well advanced by the time patients present with their rst cognitive symptoms, even if these are not su cient to meet current criteria for dementia. ere are a number of reasons for attempting to diagnose AD before dementia, including that:

◆ ere is no reason to link the diagnosis of a disease with a certain threshold of severity and to exclude a large number of patients who are not yet expressing a full-blown dementia from diagnosis and treatment.

◆ ere is no justi cation to anchor the diagnosis of AD to a dementia syndrome. By analogy with Parkinson’s disease, the diagnosis should not hinge on a level of severity (e.g. when the patient is bedridden), but on the presence of the earliest motor symptoms (e.g. a limited resting tremor of one hand). e same should apply for AD.

◆ Earlier diagnosis may allow for earlier therapeutic interven- tions. Selecting patients with functional disability may be too late because at this stage amyloid burden is already extremely

widespread as shown by in vivo amyloid PET studies,17 and there is also considerable irreversible neuronal loss. is may explain why clinical trials of disease-modifying treatments in patients with AD dementia have not proven e ective, at least on meaningful clinical outcomes. ere is therefore considerable interest in using a biomarker-based strategy to identify indi- viduals with prodromal AD in whom therapies might be more e ective, and where there is the potential to prevent the onset of symptoms.

e low speci city of the NINCDS–ADRDA

criteria for AD

Performance of NINCDS–ADRDA criteria is low because at the time (1984) these criteria were established the clinical phenotype of AD was not speci ed and no reference to biomarkers was pro- posed. is explains why AD was frequently misdiagnosed with other neurodegenerative diseases that can ful l the NINCDS– ADRDA criteria.18

Progress since the original NINCDS–ADRDA criteria

e clinical phenotype of AD

In more than 85 per cent of cases, AD presents as a progressive amnestic disorder. Episodic memory de cit is a highly prevalent and reliable neuropsychological marker of AD.14 Early episodic memory impairment in underpinned by postmortem studies of AD patients which typically show that the early disease process appear to a ect medial temporal lobe structures (entorhinal cortex, hippocampal formations, parahippocampal gyrus),19 areas known to be critical for long-term episodic memory.

is pattern explains the typically rather homogeneous clinical presentation of AD, which can be divided into two main stages. e rst consists of a progressive and predominantly amnestic syndrome related to the early involvement of medial temporal structures. e second is characterized by the spread of cognitive symptoms to other domains, including executive (conceptualization, judgment, problem-solving) and instrumental (language, praxis, face or object recognition) functions and of psycho-behavioural changes, due to the progressive spread of neuronal pathology to involve neocortical areas.20 All these symptoms progressively impact on the patient’s ability to continue their ADLs, as required to make a diagnosis of dementia.

A better characterization of other dementias

Diagnostic accuracy of Alzheimer’s disease (AD) has also improved in recent years because of identi cation and de nition of new dementia conditions through speci c criteria, including the fronto- temporal dementias, corticobasal degeneration, and dementia with Lewy bodies (DLB). Individualization of these diseases, which were o en previously confused with AD, has consequently decreased its apparent heterogeneity.

e development of reliable biomarkers

Biomarkers for AD are now available at least in expert centres. ese biomarkers can be divided into those that can demonstrate facets of the underlying pathophysiology, and those that are topo- graphical/downstream markers.2,21,22

Pathophysiological markers. ese target the underlying aetio- logical process that characterizes Alzheimer pathology. ey include increased amyloid-PET imaging and CSF studies.

Amyloid-PET imaging is a very sensitive means of demonstrating Aβ plaque burden in vivo. Several di erent compounds are in various stages of clinical development and use, with one com- pound (Florbetapir) now licensed for the detection of brillar amyloid, and thus as a potential rule in/out of AD in cognitively impaired individuals. Amyloid-PET has shown very high post- mortem validation for the presence of brillar amyloid pathol- ogy,23,24 good predictability for progression to AD dementia,21,25 but low sensitivity to change in the clinical stages.26 An important and as yet unresolved issue is that a signi cant minority of cog- nitively normal elderly individuals are amyloid-PET positive.27

Typical CSF ndings in AD include decreased Aβ1-42 and increased total- and phopho-tau levels, although tau elevation may also be seen in other neurodegenerative diseases.3 ese CSF changes have a good speci city for AD: they signi cantly increase diagnostic accuracy in cases with clinically doubtful diagnoses28 and are highly correlated with postmortem AD changes.29,30 It should be noted that there is a large variability in CSF biomarker levels between techniques31 and centres.32

Topographical/downstream markers. ese evaluate less speci c and downstream brain changes that result from AD pathology. ey include medial temporal lobe atrophy33 and reduced glu- cose metabolism in temporal parietal regions on FDG-PET.34

◆ Medial temporal atrophy, and hippocampal atrophy in particu- lar,35 are the most useful prodromal MRI biomarkers of a further progression to AD dementia. Hippocampal atrophy can be deter- mined either by visual assessment36 or quanti cation (e.g. by manual segmentation or automated so ware). e speci city of hippocampal volume for AD is in uenced by several conditions, such as ageing, and in particular other neurological conditions or dementias which are associated with hippocampal volume loss (e.g. hippocampal sclerosis, Lewy body pathology, argyro- philic grain disease, and frontotemporal dementia). e reliabil- ity of volumetric measures obtained from repeated MRI scans is

high,37 allowing the rate of atrophy over time to be assessed. is measure is a good diagnostic marker for early AD as the progres- sion of hippocampal loss is approximately two to four times faster in AD patients than in age-matched normal controls.38

◆ FDG-PET has also proven to have a good sensitivity to detect brain dysfunction and early changes in AD34 and to follow its evolution over time.39 FDG uptake is reduced, predominantly in temporoparietal association areas including the precuneus and posterior cingulate cortex, and these changes are closely related to cognitive impairment as demonstrated in crosssectional and longitudinal studies.

AD biomarkers therefore demonstrate di erent facets of the dis- ease, and have di erent clinical functions. Some are speci c mark- ers of AD pathology (CSF Aβ1-42 and amyloid-PET) but do not provide useful information about severity. Topographical/down- stream markers (e.g. atrophy) by contrast can be used to show the e ect of neurodegeneration or, when acquired serially, to quantify change over time (i.e. as markers of progression). ey have been shown consistently to predict AD dementia in MCI cohorts and to correlate with disease severity. Recent advances in knowledge, natural history, and time course of these biomarkers have signi – cantly changed our view of the disease. Amyloid markers become dynamic rst before the occurrence of the clinical phase whereas tau markers and structural changes (hippocampal volume) are more linked to the prodromal/dementia phases of the disease. e temporal trajectory of each marker has been illustrated in a hypo- thetical model by Jack and colleagues (see Fig. 32.1).

To conclude this historical perspective, the classical de nition of AD, based on the NINCDS–ADRDA diagnostic criteria,11 had two major limitations: 1) they do not take into account speci c fea- tures of the disease (i.e. the speci c clinical phenotype and positive biomarkers), and 2) they can only be invoked when the demen- tia threshold is reached. e new conceptual framework for the diagnosis of AD recently proposed by the International Working

Abnormal

CHAPTER 32 changing concepts and new definitions for ad 355

Normal

Preclinical AD (Asymptomatic-at-risk of AD)

Prodromal AD

Clinical Disease Stage

AD Dementia

Amyloid-β accumulation (CSF/PET) Synaptic dysfunction (FDG-PET/fMRI)

Tau-mediated neuronal injury (CSF) Brain structure (volumetric MRI) Cognition
Clinical function

Fig. 32.1 Hypothetical model of dynamic biomarkers of Alzheimer’s disease.
Reproduced from Alzheimers Dement. 7(3), Sperling RA, Aisen PS, Beckett LA. et al. Toward de ning the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease, pp. 280–92, Copyright (2011), with permission from Elsevier.

356 SECTION 3 cognitive impairment and dementia Table 32.1 e new concept of Alzheimer’s disease

(see Box 32.1). Adequate memory tests that control for encod- ing and facilitate retrieval processing by the use of semantic cues can qualify the nature of the memory de cit. ey can distinguish genuine memory storage impairment (e.g. failure of information storage and new memory formation as in AD) from attention or retrieval disorders. Memory tests, such the Free and Cued Selective Reminding Test (FCSRT) which controls encoding and retrieval processes,40 can identify the ‘amnesic syndrome of the hippocam- pal type’ observed in AD,14 which is de ned by a very poor free recall (as in any memory disorder) and, crucially, decreased total recall even when given cues (i.e. insu cient e ect of cueing).

Of course, an amnestic presentation may not always be present and other clinical phenotypes can be associated with postmortem evidence of AD pathology.41 erefore, the IWG has highlighted the concept of atypical forms of AD with speci c clinical pheno- types that include non-amnestic focal cortical syndromes, such as logopenic aphasia, bi-parietal atrophy, posterior cortical atrophy, and frontal variant AD (Table 32.3).

◆ Presence of AD biomarkers. Biomarkers are supportive features of a diagnostic framework that is anchored around a core clinical phenotype. e AD diagnosis, evoked in case of a speci c clinical phenotype (either typical or atypical), needs con rmation from the presence of one or several AD biomarkers. Among these, in vivo evidence of AD pathology (CSF changes of Aβ and tau lev- els or positive amyloid-PET) is the most speci c and should be required for research purposes or atypical cases.

For the IWG, the diagnosis of AD is made on the basis of both clinical and biological evidence, with a high level of speci city and predictive validity. e diagnostic algorithm begins with a charac- teristic clinical phenotype (typical or atypical) and then requires supporting biomarkers that re ect the underlying AD process or pathology. e availability of speci c in vivo biomarkers of AD pathology has moved the de nition of AD from a clinicopathologi- cal entity to a clinicobiological entity. As biomarkers can be con- sidered as surrogate markers of the histopathological changes, the clinical diagnosis can now be established in vivo and reference to dementia may no longer be needed.

e NIA/AA criteria

also divide the clinical phase of AD into MCI and AD dementia but employ di erent approaches to the diagnosis in each stage of the illness.

◆ MCI due to AD. e clinical criteria for MCI are the same as those previously published.42 e NIA/AA criteria stratify the diagnosis of MCI with biomarkers to determine the likelihood that the syndrome is due to AD. A single positive biomarker of either amyloid abnormalities or neurodegeneration supports intermediate likelihood of MCI being due to AD, while two biomarkers—one of amyloid type and one of neurodegeneration type—support high likelihood of MCI being due to AD.

◆ AD dementia. e NIA/AA criteria apply an approach to diagno- sis of dementia and AD dementia that di ers from the approach to MCI due to AD.43 Diagnostic standards for all causes of dementia are provided and 10 categories of dementia of the AD type are established including probable AD dementia, possible AD dementia, probable or possible AD dementia with evidence of the AD pathophysiological process.

e NINCDS–ADRA concept of AD diagnosis (1984)

e IWG concept of AD diagnosis (2007)

◆ e diagnosis of AD cannot be certi ed clinically and needs a postmortem con rmation to be ascertained:

◆ erefore, the clinical diagnosis of AD can only be ‘probable’

◆ and can only be made when the disease is advanced and reaches the threshold of dementia

◆ Pathologicalbiomarkerscan be considered as surrogate markers of the underlying AD pathology:

◆ erefore, the clinical diagnosis can be established in vivo

◆ And no more reference to dementia is needed

Group (IWG)1 [and latterly by the NIA/Alzheimer’s Association (NIA/AA)]3 is based on two requirements: (1) to be earlier, and (2) to be more speci c, even at an early stage of the disease. e di erences between the old and new criteria are summarized in Table 32.1.

New concepts of AD

e reliable identi cation of biomarkers of AD is responsible for a major change in the conceptualization and diagnosis of the disease. Importantly, the new diagnostic criteria proposed by the IWG or by the NIA/AA both now use paraclinical investigations (MRI, CSF) not only for excluding other aetiologies of a dementia syndrome but also as part of the diagnostic procedure. However, the NIA/ AA criteria have the advantage of being applicable when no sup- portive biomarkers are available, albeit at the expense of diagnostic speci city.

Considering biomarkers not to be linked to a stage of severity but rather to the disease process, these criteria potentially allow identi- cation of Alzheimer’s disease at a prodromal/MCI stage and even at a preclinical stage of the disease. Both sets of criteria recognize preclinical states of AD necessarily based on pathophysiological biomarkers since cognition remains normal (see Table 32.1 for a summary).

e IWG/Dubois criteria identify these individuals as ‘asymp- tomatic at risk for AD’. is neutral nomenclature was chosen to acknowledge that not all these individuals progress to sympto- matic AD. e NIA/AA criteria describe this state as ‘preclinical AD’. is nomenclature may have more of an implication for pro- gression, suggesting that ‘preclinical’ is the predecessor state for ‘clinical’ AD. e symptomatic phase of AD described in both sets of criteria embraces the same clinical entities, though with di er- ent terminologies and emphases. Di erences in the classi cation of the stages of AD between the two sets of criteria can be found in Table 32.3.

IWG criteria emphasize a single clinical-biological approach that includes all symptomatic phases of AD and they use the same diagnostic algorithm across the spectrum of symptomatic disease consisting of:

◆ A speci c clinical phenotype. As stated earlier, episodic memory disorders are the keystone of the clinical syndrome of typical AD. However, it should be reminded that a free recall de cit is com- mon to many brain diseases. One way to disentangle the di erent diseases is to keep in mind the three stages of episodic memory

CHAPTER 32 changing concepts and new definitions for ad 357 Table 32.2 Di erent stages and classi cation of AD subtypes across NIA–AA and IWG criteria

NIA–AA criteria

IWG criteria

Comments

Preclinical AD

Asymptomatic cerebral amyloidosis (ACA) ACA + evidence of neuronal injury (NI) ACA + NI + subtle cognitive decline

Asymptomatic at risk with AD pathology1

Presymptomatic AD2

1 Normal cognition with a pathophysiological marker

2 Normal cognition with an autosomal dominant AD-causing mutation

MCI due to AD

MCI due to AD high likelihood1
MCI due to AD intermediate likelihood2 MCI possibly due to AD3
MCI unlikely due to AD4

Prodromal AD5

. 1 Biomarkers of amyloidosis and neuronal injury are positive

. 2 Biomarker of amyloidosis positive or biomarker of neuronal injury untested

. 3 Biomarker of amyloidosis positive and biomarker of neuronal injury are untested or give con icting results

. 4 Biomarker of amyloidosis positive and biomarker of neuronal injury are negative

. 5 Episodic memory impairment or atypical AD- compatible syndrome with one pathophysiological marker (CSF or abnormal amyloid imaging)

Dementia caused by AD

Probable AD dementia with increased level of certainty

◆ AD dementia with documented clinical decline

◆ AD dementia with an autosomal dominant AD-causing mutation
Possible AD dementia

◆ AD dementia with an atypical course

◆ AD dementia with evidence of mixed aetiology
Probable AD dementia with evidence of AD pathophysiological process

◆ High likelihood of AD aetiology (biomarkers of amyloid abnormalities and neurodegeneration both present)

◆ Intermediate likelihood of AD aetiology (biomarker of amyloid abnormalities or neurodegeneration is present)
Possible AD dementia with evidence of the AD pathophysiological process

◆ High likelihood of AD aetiology (biomarkers of amyloid abnormalities and neurodegeneration both present)

◆ Intermediate likelihood of AD aetiology (biomarker of amyloid abnormalities or neurodegeneration is present)
Pathophysiologically proved AD dementia (clinical phenotype of probable AD with neuropathology ndings indicative of AD)

AD dementia1

1 Episodic memory impairment or atypical AD phenotype with impaired activities of daily living AND at least one of the following biomarkers:

◆ CSF changes (low Aβ and high tau p-tau)

◆ abnormal amyloid imaging

◆ medial temporal atrophy on MRI

◆ bilateral parietal hypometabolism on FDG–PET

◆ PS1, PS2, APP mutation carrier

Proposal for a new lexicon for AD

e new conceptual framework of AD suggests rede ning a com- mon lexicon2 concerning AD and related entities (see Box 32.2).

Alzheimer’s disease

AD should now be a label de ning the clinical disorder which starts with the onset of the rst speci c clinical symptoms of the disease and which crucially encompasses both the predementia and dementia phases. AD now refers to the whole spectrum of the clini- cal phase of the disease and is not restricted to the dementia syn- drome. e clinical diagnosis can be established in vivo and relies on a dual clinical-biological entity that requires the evidence of an amnestic syndrome of the hippocampal type (de ned by a free recall de cit that is not normalized by cueing) and the presence of pathophysiological markers of AD. Distinguishing prodromal AD and dementia stages within the whole spectrum of AD might be still useful for individual patients, and in the wider socio-economic context.

AD dementia

It is likely to still be meaningful to identify the dementia threshold as a severity milestone in the course of disease. e presence of a dementia adds a set of management issues for the clinician to address includ- ing those related to patient autonomy such as driving and nancial capacity as well as those related to care and daily living. e transition between the two states may be arbitrary when the underlying disease is a continuous process. Individual clinician’s experience in demen- tia diagnosis and quality of information they receive or obtain on the cognitive and functional status of the patient will impact signi cantly on the threshold of detection of the transition to AD.

Prodromal AD

Prodromal AD refers to the early symptomatic predementia phase of the disease, characterized by a speci c clinical phenotype of the amnestic syndrome of the hippocampal type with positive patho- physiological biomarkers. e memory disorders can be isolated or associated with other cognitive or behavioural changes that may

358 SECTION 3 cognitive impairment and dementia

Box 32.1 ree stages of long-term memory

stimulus stimulus

Registration

Consolidation and storage

3) e memory test needs:

. 1) Episodic memory is currently evaluated by the recall of a list of items (words, sentences, drawings) a er a delay (generally around 5–15 minutes).

. 2) To be recalled, the items should go through three successive stages:
a. Registration, which mainly relies on attention resources. is stage is impaired in conditions that interfere with attention pro- cesses: e.g. depression, anxiety, sleep disorders, drugs (anticholinergics, benzodiazepines), ageing.

b. e second stage is storage, i.e. transformation of perceived events into memory traces. is stage mainly relies on the hippocam- pus and related structures. is stage is impaired in Alzheimer’s disease.

c. e last stage is retrieval: this mainly relies on the ability to activate strategic processes to retrieved stored information, con- sidered to be highly dependent on the functioning of the frontal lobes. is stage is impaired in case of frontal lesions/dysfunc- tions (frontotemporal dementias, subcorticofrontal dementias, or even normal ageing where activation of retrieval strategies is decreased and e ortful).

. 3) ere is a need to use memory tests that can dissociate di erent conditions by controlling for registration and by facilitating retrieval. is can be made with semantic cues as in the Free and Cued Selective Reminding Test.40

Retrieval (spontaneous recall)

Attentional ressources (depression)

Hippocampus (Alzheimer)

Activation of strategies (frontal dysfunction, aging)

1) To control that information has been registered (by the use of cueing)

2) To facilitate retrieval of stored information (using semantic cues)

not be severe enough to interfere signi cantly with activities of daily living.

Atypical AD

is refers to less common clinical phenotypes that occur with AD pathology. ere are well-de ned clinical phenotype variant presentations of AD that do not follow the typical pattern of an amnestic syndrome of the hippocampal type. ese include corti- cal syndromes of logopenic aphasia, posterior cortical atrophy, and frontal variants of AD. e diagnosis of atypical AD is established when the well-characterized clinical presentations (Table 32.3) are supported by a positive pathophysiological biomarkers of AD.

Mixed AD

is is de ned by the co-occurrence of Alzheimer’s pathology with other biological causes of cognitive decline, mainly cerebrovascular

disease or Lewy body pathology. Mixed pathologies are highly prevalent in the elderly and account for most dementia cases in the very old.44 e label of ‘mixed AD’ is reserved to cases where both clinical features and diagnostic markers point to a mixed aetiol- ogy. Patients should ful l the diagnostic criteria for typical AD and additionally present with clinical and brain imaging/biological evi- dence of other comorbid disorders such as cerebrovascular disease or Lewy body diseases.

Preclinical states of AD

ere is a growing interest in the long preclinical phase of AD.22 is preclinical phase refers to cognitively normal individuals with biomarker evidence of Alzheimer pathology. Positive retention of amyloid-PET or low Aβ level in the CSF is being reported in up to 30 per cent of older normal controls.45 ese healthy individuals may or may not later convert to prodromal AD. Such evolution to

CHAPTER 32 changing concepts and new definitions for ad 359

Table 32.3 e speci c phenotypes of Alzheimer’s disease biomarker-positive have been de ned as ‘asymptomatic, at risk for AD’ or ‘asymptomatic amyloidosis’ rather than preclinical or pre- symptomatic because a large percentage of them will not progress

Speci c clinical phenotype of typical AD

◆ early, predominant amnestic syndrome of hippocampal type—isolated or associated with other cognitive changes

biparietal variant of AD

◆ impaired limb praxis skills—and features of the Gerstmann syndrome

logopenic variant of AD

◆ impaired single word retrieval—and repetition of sentences

posterior variant of AD

◆ impaired visuospatial functions—and/or of visual identi cation of objects, symbols, or visages

frontal variant of AD

◆ impaired executive functions—with the presence of a primary progressive apathy

a clinical disease may depend on several factors including genetic (such as ApoE genotype), other risk factors (e.g. vascular) or pro- tective factors (diet, cognitive reserve), and comorbidities (e.g. diabetes). In the absence of knowledge about what factors com- bine to in uence conversion, these normal individuals who are

to a symptomatic clinical condition.
is is not the case for cognitively normal individuals sharing

an autosomal dominant monogenic AD mutation46 Because of the full penetrance of the mutations, these individuals will inevitably develop a clinical AD if they live long enough. ey are at a ‘pre- symptomatic state for AD’.

Research versus clinical criteria

Whilst these newer criteria aim both to allow for diagnosis of AD earlier and more accurately, they depend on availability of suit- able biomarkers. According to a report of AD International,47 58 per cent of people with dementia live in low- and middle-income countries. Even in developed countries, there is still a lack of avail- ability of high-tech investigations for biomarkers outside tertiary or research centres. erefore, the diagnostic approach proposed here can be applied only in expert centres with facilities to assess a large spectrum of biomarkers, viable assessment procedures, and with access to normative data. In this context, they may be useful for complex diagnosis such as in case of young-onset AD, poste- rior cortical atrophy, or logopenic aphasias where biomarkers may increase diagnostic accuracy.

When these biomarkers are not a ordable, the older NINCDS– ADRDA criteria can be used in a clinical setting. However, in any case, it is still possible to refer to the new conceptual framework of AD according to which AD refers to the whole spectrum of the clinical phase of the disease, starting with the onset of the rst spe- ci c clinical symptoms and encompassing both the prodromal/pre- dementia and dementia phases.

References

1. Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diag- nosis of Alzheimer’s disease: revising the NINCDS–ADRDA criteria. Lancet Neurol. 2007;6, 734–746.

2. Dubois B, Feldman HH, Jacova C, et al. Revising the de ni- tion of Alzheimer’s disease: a new lexicon. Lancet Neurol. 2010 Nov;9(11):1118–27.

3. Jack CR, Albert MS, Knopman DS, et al. Introduction to the recom- mendations from the National Institute on Aging and the Alzheimer’s Association workgroup on diagnostic guidelines for Alzheimer’s dis- ease. Alzheimers Dement. 2011 May;7(3):257–62.

4. Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Alzheimer’s Disease International. Lancet. 2005 Dec 17;366(9503):2112–7.

5. Brookmeyer R, Evans DA, Hebert L et al. National estimates of the prevalence of Alzheimer’s disease in the United States, Alzheimers Dement. 2011;7(1):61–73.

6. Rossor MN, Fox NC, Mummery CJ et al. e diagnosis of young-onset dementia. Lancet Neurol. 2010 Aug;9(8):793–806.

7. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition—Text Revision (DSM–IV–TR). Washington, DC: American Psychiatric Publishing, Inc., 2000.

8. Folstein MF, Folstein SE, and McHugh PR. ‘Mini-mental state’. A practi- cal method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189–98.

9. Mega MS, Cummings JL, Fiorello T, et al. e spectrum of behavioral changes in Alzheimer’s disease. Neurology. 1996;46 (1):130–135.

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Box 32.2 Terminology

. 1) Alzheimer’s Disease (AD): the whole clinical phase, no longer restricted to the dementia syndrome.

. 2) Prodromal AD: the early symptomatic, predementia phase of AD.

. 3) AD dementia: when cognitive symptoms interfere with activity of daily living.

. 4) Typical AD: the most common clinical phenotype of AD, characterized by an amnestic syndrome of the hippocampal type.

. 5) Atypical AD: less common but well-characterized clini- cal phenotypes that occur with Alzheimer’s pathology. e diagnosis of AD needs in vivo evidence of pathophysiologi- cal markers.

. 6) Mixed AD: patients who ful l the criteria for AD and addi- tionally present with clinical and biomarkers evidence of other comorbid disorders.

. 7) Asymptomatic at risk: cognitively normal individuals with positive pathophysiological biomarkers.

. 8) Presymptomatic AD: cognitively normal individuals with a proven AD autosomal dominant mutation.

. 9) Alzheimer’s pathology: underlying neurobiological changes responsible for AD.

. 10) Pathophysiological markers: biological changes that re ect the underlying AD pathology (CSF changes; PET- amyloid). ey are markers of diagnosis.

. 11) Topographical biomarkers: downstream markers of neu- rodegeneration that can be structural (MRI) or metabolic (FDG-PET). ey are markers of progression.

10) Mild cognitive impairment (MCI): patients for whom there is no disease clearly identi ed.

360 SECTION 3 cognitive impairment and dementia

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