Alzheimer’s Disease

Ll BRARYI

ONL

OXFORD NEUROLOGY LIBRARY

Alzheimer’s Disease

ONL

OXFORD NEUROLOGY LIBRARY

Second edition

Edited by

Gunhild Waldemar

Professor of Clinical Neurology, Faculty of Health and Medical
Sciences, University of Copenhagen, Copenhagen, Denmark;
Director, The Danish Dementia Research Centre, Copenhagen, Denmark

and

Alistair Burns

Professor of Old-Age Psychiatry, University of Manchester, Manchester, UK; Consultant Old Age Psychiatrist, Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK

    

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3

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

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Acknowledgements

Thank you to Kate Freeman for her invaluable administrative support during the editing of Alzheimer’s Disease, second edition.

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Contents

Contributors ix Abbreviations xi

 Dementia disorders: an overview 1 Roland Zahn and Alistair Burns

. 2  Pathophysiology of Alzheimer’s disease 7 Shelley J. Allen

. 3  Epidemiology of Alzheimer’s disease 17 Chengxuan Qiu and Laura Fratiglioni

. 4  Clinical course of Alzheimer’s disease 27 Alberto Lleó and Rafael Blesa

. 5  Atypical presentations of Alzheimer’s disease 35 Matthew Jones and Jennifer Thompson

. 6  Diagnosing Alzheimer’s disease in clinical practice 43 Gunhild Waldemar

. 7  Disclosing the diagnosis of Alzheimer’s disease 55 Anne A. Fetherston and Julian C. Hughes

. 8  Pharmacological treatment of Alzheimer’s disease 61 Krishna Chinthapalli

. 9  Managing behavioural and psychological symptoms in
Alzheimer’s disease 71 Philippe Robert, Elsa Leone, Hélène Amieva, and David Renaud

0 Caring for people with dementia towards and at the end of life 85 Louise Robinson

 Supporting the person with dementia and the caregiver 93 Henry Brodaty and Katrin Seeher

2 Safety, legal issues, and driving 103 Roy W. Jones

           

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3 The planning of appropriate medical and social care in dementia 111 Marcel G.M. Olde Rikkert, Irena Draskovic, and

Myrra Vernooij-Dassen

4 Casevignettes 117 Valeria Manera, Elsa Leone, Jennifer Thompson, Roland Zahn,

Alistair Burns, and Gunhild Waldemar

Index 2

 

Contents

Contributors

Shelley J. Allen

Sigmund Gestetner Senior Research Fellow, Southmead Hospital, Bristol, UK

Hélène Amieva

Professor of Psychogerontology, University of Bordeaux, Bordeaux, France

Rafael Blesa

Director, Hospital de la Sant Pau, Barcelona, Spain

Henry Brodaty

Director, University of New South Wales, Sydney, Australia

Alistair Burns

Professor of Old-Age Psychiatry, University of Manchester, Manchester, UK; Consultant Old Age Psychiatrist, Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK

Krishna Chinthapalli

Clinical Research Fellow, UCL Institute of Neurology, London, UK

Irena Draskovic

Senior Researcher, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Anne A. Fetherston

Academic Clinical Fellow and Specialist Registrar in Old-Age Psychiatry, Newcastle University, Newcastle, UK

Laura Fratiglioni

Professor and Director, Karolinska Institutet, Stockholm, Sweden

Julian C. Hughes

Consultant in Psychiatry of Old Age and Honorary Professor of Philosophy of Ageing, Newcastle University, Newcastle, UK

Matthew Jones

Consultant Neurologist, Salford Royal Foundation NHS Trust, Salford, UK

Roy W. Jones

Director, RICE—The Research Institute for the Care of Older People, Royal United Hospital, Bath, UK; Honorary Professor, University of Bath, Bath, UK; Honorary Professor, University of Bristol, Bristol, UK

Elsa Leone

Neuropsychologist, Centre Hospitalo Universitaire, Institut Claude Pompidou, Nice, France

Alberto Lleó

Clinical Head, Hospital de la Sant Pau, Barcelona, Spain

Valeria Manera

Neuropsychologist, Institut Claude Pompidou, CoBTeK, University of Nice Sophia Antipolis, Nice, France

Marcel G.M. Olde Rikkert

Professor, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Chengxuan Qiu

Associate Professor, Karolinska Institutet, Stockholm, Sweden

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David Renaud

Physician, Centre Hospitalo Universitaire, Institut Claude Pompidou, Nice, France

Louise Robinson

Professor of Primary Care and Ageing and Director, Institute for Ageing, Newcastle University, Newcastle, UK

Philippe Robert

Professor, Institut Claude Pompidou, CoBTeK, University of Nice Sophia Antipolis, Nice, France

Katrin Seeher

Research Associate, University of New South Wales, Sydney, Australia

Jennifer Thompson

Neuropsychologist, Salford Royal NHS Foundation Trust, Salford, UK

Myrra Vernooij-Dassen

Professor, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Gunhild Waldemar

Professor of Clinical Neurology,
Faculty of Health and Medical
Sciences, University of Copenhagen, Copenhagen, Denmark; Director,
The Danish Dementia Research Centre, Copenhagen, Denmark

Roland Zahn

Senior Clinical Lecturer, King’s College London, London, UK

Contributors

Abbreviations

ABAD Amyloid β-peptide binding protein alcohol dehydrogenase ABC ATP-binding cassette
ACP Advance care planning
AD Alzheimer’s disease

ADAS-Cog Alzheimer’s disease Assessment Scale ADI Alzheimer’s Disease International ADRT Advance decision to refuse treatment AICD APP intracellular domain

APh Anterior pharynx-defective phenotype APOE Apolipoprotein
APP Amyloid precursor protein
AT Assistive technology

BACE β-site APP cleaving enzyme
BDNF Brain-derived neurotrophic factor
BPSD Behavioural and psychological symptoms of dementia
BRACE Bristol Research into Alzheimer’s Disease
CCT Cranial computed tomography
CDK Cyclin-dependent kinase
CDRSB Clinical Dementia Rating scale–sum of boxes
ChEI Cholinesterase inhibitor
CIBIC Clinicians Global Impression of Change
CR Complement component receptor
CREB cAMP-response element binding protein
CSF Cerebrospinal uid
DAD Disability Assessment for Dementia
DAT Dopamine transporter scanning
DLB Dementia with Lewy bodies
DSM Diagnostic Statistical Manual of the American Psychiatric Association EEG Electroencephalography
EFNS European Federation of the Neurological Societies
EPA Enduring Power of Attorney
FAD Familial Alzheimer’s disease
FAQ Functional Activities Questionnaire
FCSRT Free and cued selective reminding test

                                 

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FDG-PET Fluoro-deoxy-glucose positron emission tomography FTD Frontotemporal dementia
FTLD Frontotemporal lobar degeneration
GDS Global Deterioration Scale

GFAP Glial brillary acidic protein
GP General practitioner
GSK Glycogen synthase kinase
GWAS Genome Wide Association Studies HDL High-density lipoprotein

ICT Information and communication technologies IDE Insulin-degrading enzyme
IMCA Independent Mental Capacity Advocate iNOS Inducible nitric oxide synthase

LMIC Low- and middle-income countries
LPA Lasting Power of Attorney
LRP Low-density lipoprotein receptor-related protein
LTD Long-term depression
LTP Long-term potentiation
LXR Liver X receptor
lyPPA Logopenic variant progressive aphasia
MCA Mental Capacity Act
MCI Mild cognitive impairment
MMSE Mini-Mental State Examination
MOA Monoamine
MOCA Montreal Cognitive Assessment
mPTP Mitochondrial permeability transition pore
MRCCFA Medical Research Council Study on Cognitive Function and Ageing MRI Magnetic resonance imaging
NDMA N-methyl-D-aspartate
NFT Neuro brillary tangles
NGF Nerve growth factor
NHS National Health Service
NIA–AA National Institute on Aging–Alzheimer’s Association
NICE National Institute for Health and Care Excellence
NO Nitric oxide
NPI Neuropsychiatric Inventory
NSAIDs Non-steroidal anti-in ammatory drugs
PCA Posterior cortical atrophy
PEG Percutaneous endoscopic gastrostomy
PEN Presenilin enhancer

                                      

AbbreviAtions

 

PET Positron emission tomography PHF Paired helical laments
PiB Pittsburgh compound B
POA Power of Attorney

PPA Primary progressive aphasia
PPAR Peroxisome proliferator-activated receptor
RCT Randomized controlled trial
REM Rapid eye movement
ROS Reactive oxygen species
RXR Retinoid X receptor
RYR Ryanodine receptor
sCJD Sporadic Creutzfeldt–Jakob disease
SES Socioeconomic status
SIB Severe Impairment Battery
SORL Sortilin-related receptor
SPECT Single photon emission computed tomography
SSRI Selective serotonin re-uptake inhibitor
TACE Tumour necrosis factor-α converting enzyme
TNF Tumour necrosis factor
TREM Triggering receptor expressed on myeloid cells
VASCOG International Society of Vascular Behavioural and Cognitive Disorders VLDL Very low-density lipoproteins

                    

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AbbreviAtions

70 60 50 40 30 20 10 0

 

Brayne 2006; UK
Prince, et al. 2013; US Chan, et al. 2013; China Anstey, et al. 2010; Australia

                                     

           

65–69

70–74 75–79

80–84 85–89 Age

90–94 95+

Figure 3. Age-speci c prevalence of dementia (per 00 population) across countries.

100

90

80

70

60

50

40

30

20

10

0

The CSHA Group 2000; Canada Matthews & Brayne 2005; UK Plassman, et al. 2011; USA

  

             

65–69

70–74 75–79

80–84 85–89 90+

Age

Figure 3.2 Age-speci c incidence of dementia (per ,000 person years) across countries.

Incidence, per 1000 person-years

Prevalence, per 100 population

(A)

(B)

(C)

Figure 5. Representative examples of MRI and FDG-PET scans in patients with Alzheimer’s disease. Panel A shows left hippocampal atrophy and hypometabolism (red arrows) in a patient with a typical amnesic presentation of AD. Panel B shows left-sided temporoparietal hypometabolism (yellow arrows) in a patient with the language presentation of AD. Panel C shows bi-parietal and occipital atrophy on the MRI and bilateral posterior hypometabolism on the FDG-PET (green arrow) in a patient with posterior cortical atrophy.

Chapter

Dementia disorders: an overview

Roland Zahn and Alistair Burns

Key points

• Dementia is a clinical syndrome which comprises three domains: cognitive impairments, behavioural symptoms, and impairments of activities of daily living

• Dementia may be caused by a wide range of brain disorders and systemic conditions. Alzheimer’s disease (AD) is the most frequent cause of dementia

• Clinical interview, neuropsychological assessments, brain imaging, routine blood tests, and neurological examination are the most important instruments for di erentiating between the causes of dementia

. What is dementia?

Dementia is a clinical syndrome operationally de ned as cognitive impairment in at least two domains interfering with activities of daily living (Diagnostic Statistical Manual of the American Psychiatric Association: DSMIIIR and DSMIV-TR). Dementias are called major neurocognitive disorders in DSM-5, where impairment in only one domain docu- mented by concern of patient or informant and neuropsychological tests, as well as interference with independence in everyday activities, is required. Classically, demen- tias referred to global cognitive impairment and always included prominent memory impairment. With the improvement of treatment, management, and diagnostic proce- dures, dementia disorders are detected at earlier stages and therefore the symptoms can often be focal rather than global. Dementia syndromes can also start with other symptoms than memory, for example language problems.

Although dementia in elderly people has been recognized by clinicians since a long time, it was only at the turn of the twentieth century that di erent causes and forms of dementia became suspected. This was possible due to following up patients with dementia syndromes during the course of their illness until death and then microscopi- cally investigating silver-stained slices of their brains post-mortem.

In 906, Alois Alzheimer described neuro brillary tangles and senile plaques in the brain of patient Auguste D. who had su ered from a progressive dementia, which we now call Alzheimer’s disease (AD) in recognition of this discovery. Despite these early case reports, it was not until the end of the twentieth century that sensitive clinical criteria were formulated that predict a probable post-mortem neuropathological diag- nosis of AD. The sensitivity of clinical criteria for probable AD is very good (sensitivity above 80% with a speci city of about 70%). This means that the clinical diagnosis of AD is correct in most patients but that we may still diagnose somebody with probable

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AD when neuropathology would show a di erent cause. Conversely, there are some patients with atypical symptoms who exhibit AD-typical neuropathological changes post-mortem, however with an atypical regional distribution leading to atypical symp- toms. This di erential diagnostic challenge will become increasingly important in the future when costly disease-modifying treatments become available, especially in case these treatments have serious side-e ects.

.2 How frequent is dementia?

The prevalence of dementia increases with age, doubling with every ve-year increase. Between 65 and 69 years of age the prevalence of dementia is estimated at .3% in the United Kingdom, rising up to 32.5% in people older than 95 years. Estimates of frequency of subtypes of dementia should be interpreted with caution because the clinical information available in large epidemiological studies is often insu cient for accurate di erential diagnosis. Frontotemporal dementia (FTD) may be as likely as AD in patients younger than 65 years, but most people with dementia are late-onset patients (around 98% of all dementia patients in the United Kingdom). At least 60% of dementias are caused by AD and the proportion is higher if cases with additional vascular changes are considered (i.e. ‘mixed dementia’).

.3 Di erent forms of dementia and their diagnosis

One of the most important diagnostic instruments is the interview with a caregiver of the patient. In this interview it is important to ask for the rst and most prominent symptom, the ‘lead’ symptom of the disease which often dates from many years earlier. Further, it is crucial to ask about the course of the problem, whether it started slowly or suddenly and at what pace the progression was noted.

Time course and lead symptoms indicate which diseases one needs to consider and rule out. As a general rule, one should be alarmed when there is a sudden or subacute onset, i.e. if the dementia syndrome has developed within weeks from normal function- ing. Particular diagnostic attention should also be paid to rapidly progressing dementia syndromes in which there is marked decline within three to six months after onset. In both subacute onset or rapid decline, one needs to initiate a more detailed diagnostic assessment. This includes usually an analysis of the cerebrospinal uid (CSF) to deter- mine cell count and 4-3-3 protein sensitive to Creutzfeldt–Jakob disease (CJD) and the exclusion of encephalopathies caused by autoimmune or in ammatory diseases. A magnetic resonance imaging (MRI) examination including axial and coronal T-, T2-, uid-attenuated-inversion-recovery, and di usion-weighted images is needed in these patients. Electroencephalography (EEG) usually shows general slowing in encephalopa- thy patients. In CJD there are often characteristic triphasic complexes.

In the clinical history and blood tests it is also important to look for signs of an occult cancer (e.g. increased blood sedimentation rate) which may in rare cases lead to auto- immune reactions with antibodies directed towards neural tissue, or could cause brain metastases which do not necessarily show up on a cranial computed tomography (CCT) without contrast. In those cases an MRI should be considered. When cognitive impair- ment is slowly progressive, the neurological exam is otherwise normal and routine diag- nostic assessments do not contradict a neurodegenerative disorder, then the diagnosis of a probable cause of dementia is guided by lead symptoms and the neuropsycho- logical test pro le (for an overview see Figure .). In neurodegenerative dementias,

 

CHAPTER  Dementia disorders

Lead symptoms

Lead symptoms of dementia syndromes

If sig. abnormal

If rapidly progressive (3–6 months) or subacute (weeks) onset

 

Neurological examination

Further investigations

  

Past medical history and history of presenting complaint (patient + caregiver)

   

MRI, EEG, CSF to excl. Creutzfeldt–Jakob, autoimmune, or in ammatory encephalopathies

  

Impairment of recent memory

Typical AD?

  

Behavioural changes

Behavioural variant FTD?

   

Impairment of language or speech

Progressive aphasias?

  

Fluctuating confusional states or impairments of attention

Lewy-body dementia?

   

Visuospatial impairments

Posterior cortical atrophy?

Figure . ‘Lead’ symptoms are the most prominent and first symptoms to appear in the course of a dementia syndrome. Lead symptoms differ because neurodegeneration starts in different regions of the brain before spreading to other parts. Often they need to be explored retrospectively. This overview considers progressive cognitive disorders in which neurological symptoms (e.g. rigor, akinesia, muscle fasciculations, gaze palsy, orthostatic dysregulation and bladder incontinence, hyperkinetic movements, abnormal pupillary responses) are not prominent. If such symptoms are present, other forms of dementia need to be considered which are not discussed here. A CCT without contrast is needed in all patients to exclude haematoma, larger tumours, and normal pressure hydrocephalus. The degree of large or small vessel disease needs to be assessed on CCT. Neuropsychological test examination is necessary to identify characteristic profiles of impairment for different forms of dementia and to get objective confirmation of clinical reports. Other causes of dementia syndromes need to be considered if the clinical history or routine laboratory points to complex-partial seizures, chronic alcoholism, autoimmune disorders, signs of occult cancer or renal or liver failure, electrolyte changes, thyroid dysfunction, vitamin B2 and folate deficiencies. ‘Lead’ symptoms point in the direction of possible syndrome diagnoses. A syndrome is a combination of clinical symptoms and/or criteria which is defined in order to correspond most closely to a specific disease (i.e. aetiology). Here, we give an overview of which syndrome diagnoses one needs to consider for slowly progressive cognitive disorders in which the neurological exam and CCT appears normal or only shows atrophy and minor vascular changes. In order to establish a clinical syndrome diagnosis, one needs to check consensus criteria for the particular diagnosis (see suggested readings). As discussed in the text, it is impossible to find a one-to-one correspondence between

a clinical syndrome diagnosis and a neuropathologically defined disease, but there are probabilistic associations.

the non-contrast CCT can appear normal or may show atrophy or small-vessel dis- ease a ecting less than one-quarter of the white matter. Di erential diagnostic speci- city increases when looking at regional distribution of abnormalities on structural T-weighted MRI, di usion tensor-weighted MRI, 8- uoro-deoxy-glucose positron emission tomography (FDG-PET), amyloid-beta (Aβ) biomarkers in CSF or amyloid

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CHAPTER  Dementia disorders

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Typical neuroimaging ndings in AD

Parieto-temporal Posterior cingulate/precuneus

Decreased glucose-metabolism (blue) in one typical AD patient compared with aged controls

Medial temporal

Decreased grey-matter volume (blue) in one typical AD patient compared with aged controls

   

PET. Quantitative analysis of images is more sensitive and speci c but rarely practiced in clinical settings (e.g. see Figure .2). See Chapter 5 for a detailed overview of the diagnosis of AD.

.3. Impairment of recent memory

The lead symptom of impairment of recent memory is characteristic of typical AD. Patients cannot remember important events, such as family gatherings, which happened weeks or days ago. Old memories, such as childhood events, are relatively spared in the beginning of the disease. Impairments of recent memory are associated with the degree of damage to the medial temporal lobe and posterior cingulate cortex which are a ected early in the course of typical AD (see Figure .2).

.3.2 Behavioural changes

The lead symptom of behavioural changes with intact recent memory and visuos- patial skills is characteristic for the behavioural variant of frontotemporal demen- tia. Patients often show socially inappropriate behaviour (e.g. touching strangers), obsessive–compulsive behaviours (e.g. hoarding, repetitive behaviours, clock watch- ing), and changes in food preference (e.g. preference for sweet foods). Neuropathology often shows classic Pick bodies in these patients. In some patients, standard neuropsy- chological tests can be normal, but caution is needed when making a diagnosis without neuropsychological or neuroimaging con rmation.

.3.3 Impairment of language or speech

The lead symptom of language impairment with intact non-verbal memory and visuos- patial skills is characteristic of uent and non- uent forms of progressive aphasia. The uent form is called semantic dementia because patients do not only lose the ability

Figure .2 Brain regions typically involved in patients with mild to moderate stages of AD are depicted: medial temporal lobe, posterior cingulate/precuneus and parieto-temporal cortex.
Data from unpublished single case analysis using Statistical Parametric Mapping Software (<http://www. l.ion.

ucl.ac.uk/spm/>, group results and methods further described in Zahn, et al., Psych. Res.: Neuroimaging (2005), 40: 5–3).

CHAPTER  Dementia disorders

to understand the meaning of words but also of non-verbal material such as pictures. Both forms are classi ed as forms of frontotemporal lobar degeneration, often con- rmed by neuropathology. However, non- uent patients frequently turn out to have AD with atypical distribution on neuropathology. Patients with progressive aphasia usu- ally show intact delayed recall of geometric gures (e.g. a circle) from memory which distinguishes them from patients with typical AD on neuropsychology.

.3.4 Fluctuating confusional states or impairments of attention

Fluctuating confusional states warrant exclusion of autoimmune, in ammatory, para- neoplastic (i.e. antibodies against neural tissue in patients with occult cancer) as well as toxic and metabolic causes. The picture can occur together with visual hallucina- tions and neuroleptic hypersensitivity or Parkinsonian features in Lewy-body dementia. Multiple strokes or small vessel disease within the basilar artery territory also need to be considered.

.3.5 Visuospatial impairments

Some patients show predominantly visuospatial and apraxic di culties due to atrophy of the occipital or parietal lobes (posterior cortical atrophy). Most of these patients show AD-typical neuropathology with atypical distribution.

.3.6 Vascular dementia

The diagnosis of vascular dementia or ‘major vascular cognitive disorder’ according to the International Society of Vascular Behavioural and Cognitive Disorders (VASCOG) criteria can only be made based on neuroimaging showing either multiple large ves- sel disease-related strokes, an extensive single infarct or haemorrhage in critical areas (usually thalamus or basal ganglia), multiple lacunar infarcts or haemorrhages in these areas, or extensive and con uent white matter lesions (more than one-quarter of the total white matter had been previously suggested). Despite these criteria, we have seen patients with extensive haemorrhages to basal ganglia and thalamus on MRI scans who showed mild cognitive impairments but no major changes in functioning after recov- ering from the acute phase. Milder cerebrovascular changes often contribute to the cognitive decline in AD and the distinction between ‘mixed’ dementia versus pure AD is gradual. White matter hypodensities on CCT do not need to be vascular; they can also point to other white matter diseases and should be carefully evaluated in marked cases. CSF analysis may be needed for di erential diagnosis against in ammatory causes of white matter diseases.

References

Alladi S., Xuereb J., Bak T., et al. Focal cortical presentations of Alzheimer’s disease. Brain 2007;30:2636–45.

Knapp M. and Prince M. Dementia UK—The Full Report. London: Alzheimer’s Society, 2007. Maurer K., McKeith I., Cummings J., et al. Has the management of Alzheimer’s disease changed

over the past 00 years? Lancet 2006;368:69–2.
McKeith I.G., Ballard C.G., Perry R.H., et al. Prospective validation of consensus criteria for the

diagnosis of dementia with Lewy bodies. Neurology 2000;54:050–8.
Rascovsky K. and Grossman M. Clinical diagnostic criteria and classi cation controversies in fron-

totemporal lobar degeneration. International Review of Psychiatry 203;25(2):45–58.

Sachdev P., Kalaria R., O’Brien J., et al. Diagnostic Criteria for vascular cognitive disorders: A VASCOG statement. Alzheimer Disease & Associated Disorders 204 Jul-Sep;28(3):206–8.

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Schwarz S., Froelich L., and Burns A. Pharmacological treatment of dementia. Current Opinion in Psychiatry 202 Nov;25(6):542–50.

Sorbi S., Hort J., Erkinjuntti T., et al. EFNS-ENS Guidelines on the diagnosis and management of disorders associated with dementia. European Journal of Neurology 202;9(9):59–79.

Van Straaten E.C.W., Scheltens P., Knol D.L., et al. Operational de nitions for the NINDS-AIREN criteria for vascular dementia – An interobserver study. Stroke 2003;34:907–2.

Vincent A., Bien C.G., Irani S.R., et al. Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurology 20;0(8):759–72.

CHAPTER  Dementia disorders

Chapter 2

Pathophysiology
of Alzheimer’s disease
Shelley J. Allen

Key points

• The neuropathological diagnosis of Alzheimer’s disease (AD), requires the presence of amyloid plaques and neuro brillary tangles, which comprise β-amyloid (Aβ) and tau protein fragments respectively. This diagnosis still relies on post-mortem examination for certainty, although this may change with improved imaging techniques and biomarkers

• Familial AD (FAD), a rare form of dementia with early onset, may result from mutations in one of three genes, APP, PSEN, or PSEN2, each of which is directly related to the increased production of Aβ

• The ‘amyloid hypothesis’ suggests that Aβ is the principal stimulus for AD and that the ensuing disease process results from its overproduction or reduced clearance. This is still considered valid although an earlier role of tau in dementia is currently being given more prominence

• Aβ initiates the pathological process; abnormal phosphorylation of tau may be obligatory in continuing and amplifying this degenerative process. This has important implications for therapeutic strategies

• The relatively selective vulnerability of the projection neurones of the serotonergic, noradrenergic, and cholinergic systems, and the cortical glutamatergic systems provide the rationale for current pharmacological treatment

• The most robust risk, after increased age, for sporadic AD is the presence of the APOE ε4 allele coding for the apolipoprotein E4 (APOE) protein polymorphism. The protein APOE is involved in Aβ clearance and neuronal repair, whereas APOE4 contributes to an unfavourable outcome through a number of pathways. This may prove a challenge with respect to therapeutic approaches

• Symptoms become manifest 5–20 years after the initiation of pathological processes. Even mild cognitive impairment may represent an expression of established disease

2. Alzheimer’s neuropathology

For a de nitive diagnosis of AD, post-mortem microscopic histopathological examina- tion of the brain must reveal the deposition of two types of protein aggregates: paren- chymal deposits of amyloid (Aβ) extracellularly as ‘plaques’, and intraneuronal deposits

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Neuro brillary tangles

Amyloid plaques

Cerebrovascular amyloid

of tau protein fragments as neuro brillary ‘tangles’ (NFT), over and above that which occurs with normal ageing. Tau deposition may also occur as straight or paired helical laments (PHF) surrounding plaques, and as argyrophilic neuropil threads, which are predominantly neuronal dendrites containing tau deposits. Additionally, at least 80 per cent of cases have congophilic angiopathy, with cerebrovascular amyloid deposited in small blood vessel walls of the leptomeninges and cerebral and cerebellar cortex.

All three protein aggregates can be visualized using a uorescent dye, such as Thio avin S (Figure 2.), which binds to proteins which form β-pleated sheets. With disease progression there is an overall reduction in brain size, especially in the hip- pocampus and temporal lobe, where cortical gyri become thinner and sulci wider. Certain neurotransmitter-speci c pathways are particularly vulnerable including the cortical glutamatergic system and also projections from subcortical nuclei such as the serotonergic dorsal raphe, noradrenergic locus coeruleus and the cholinergic basal nucleus. Resultant neurotransmitter de cits may cause symptoms such as depression, aggression, and memory dysfunction, providing the rationale for the symptomatic drugs currently administered. There may be extensive gliosis, including hypertrophic astrocytes which have increased expression of glial brillary acidic protein (GFAP) and neuritic plaques frequently contain GFAP-positive astrocytic bres. Microglial cells are increased in the grey matter near neuritic plaques and NFT. These are enlarged and are activated with increased expression of MHC Class II antigens and complement receptors; they may also express the receptor for advanced glycation endproducts (RAGE) which readily binds Aβ and mediates its e ects. In later stages there is likely to be extensive cell loss with subsequent enlargement of the lateral and third cerebral ventricles. However, motor, sensory, and primary visual areas are generally spared until the end stages of the disease.

Figure 2. Microscopic examination of AD neuropathology in temporal cortex. A section of temporal cortex stained with Thio avin S, a uorescent stain, showing clusters of amyloid plaques and neuro brillary tangles and cerebrovascular amyloid at low magni cation. Insert (top left) shows higher magni cation of an amyloid plaque; the image at top right) shows high magni cation of neuro brillary tangles.

CHAPTER 2 Pathophysiology of Alzheimer’s disease

Dysfunctional axonal transport due to NFT formation will a ect passage of a number of proteins including growth factors. For instance, nerve growth factor (NGF), which is synthesized in the cortex and hippocampus and retrogradely taken to the cholinergic basal nuclei, is known to have impaired transportation.

The importance of NFT as a correlate of dementia severity was reported in 99 by Braak and Braak who described a well-de ned route of deposition of increasing den- sity with progressive stages of dementia. Stages  and 2 of NFT deposition are largely subclinical and this degree of NFT deposition is fairly common in the normal elderly. NFT are largely restricted to the transentorhinal, entorhinal, and CAI regions of the hippocampus. At stages 3 and 4, NFT accumulates in the hippocampus and limbic sys- tem, and at the nal stages, 5 and 6, this spreads to the neocortex. NFT deposition is statistically more closely linked, than amyloid accumulation, with stages of dementia. One reason suggested for this may be because of the extracellular location of amy- loid plaques and the ready availability of clearance enzymes including insulin-degrading enzyme (IDE) and neutral endopeptidase (neprilysin) to remove the plaques. Removal of intracellular NFT may be thought of as more di cult and may result in the extended presence of a trail of neuronal ‘tombstones’. Amyloid plaques are frequently observed at the terminals of neurons which have intracellular NFT which suggests that tangles may form due to retrograde e ects of Aβ actions at the synapse.

We now understand that the disease process is initiated at least 5–20 years before the rst symptoms of cognitive impairment. With the growing availability of early diag- nosis using imaging techniques and new biomarkers, there is hope that by increasing our understanding of the basic mechanisms which underlie the pathology we may actually be able to reverse what has hitherto thought to be an irrevocable process. With this comes a focus on the earliest changes likely to trigger the pathology, such as synaptic withdrawal which marks the loss of communication within neuronal pathways. A num- ber of studies both in human brain and animal transgenic AD models show a signi cant loss of synapses; in mice this is evident very early in the pathology. The focus therefore has moved away from the importance of the amyloid plaques and neuro brillary tangles in the disease process to the soluble Aβ oligomers and phosphorylated tau peptides.

2.2 Genetics of familial Alzheimer’s disease

The amyloid Aβ peptide present in parenchymal plaques or cerebrovascular deposits is a 4 kDa cleavage product of the amyloid precursor protein (APP), coded for by the APP gene. It has three main splice variants, APP770, 75, and 695, of which APP695 is the major neuronal form. APP is a multi-functional protein, important in development and synaptic plasticity. Although Aβ production occurs in normal neurons as well as those from AD, there are much higher brain levels of Aβ in AD, probably due to increased production or reduced clearance.

In autosomal dominant familial forms of AD (FAD), symptoms usually present ear- lier in life (i.e. before 60 years) and are due to mutations in one of three genes: APP, PSEN, or PSEN2 on chromosome 2, 4, or  respectively. According to the Alzforum database <http://www.alzforum.org/mutations&gt;, although many mutations are non-pathogenic, there are at least 25 APP pathogenic mutations, over 200 PSEN, and at least 6 PSEN2 clearly pathogenic mutations which lead to autosomal dominant forms of AD. Familial early-onset AD accounts for less than 5 per cent of cases of AD; however, the underlying mechanisms provide an indication as to how the majority of sporadic (isolated or non-clustering) AD cases may occur. Those living with Down’s syn- drome (trisomy 2) usually develop AD symptoms and pathology by their 40s, and this

9

CHAPTER 2 Pathophysiology of Alzheimer’s disease

Kunitz protease inhibitor (KPI) domain

289 345 364

Membrane

OX2 antigen domain

KM670/671NL (Swedish)

βαγ

V7171 (London)

Non-amyloidogenic pathway

                    

APPβ
+ C99

Amyloidogenic pathway

β-secretase

α-secretase APPα

+ C83 γ-secretase

p3 AICD

Degraded

                   

γ-secretase Aβ AICD

      

Nuclear signalling

10

is thought to be due to the third copy of the APP gene provided by the extra chromo- some 2. Thus gene duplication or the presence of mutations, which facilitate an increase in Aβ, result in AD pathology and consequent symptoms of cognitive dysfunction.

Many of the FAD mutations present in the three aforementioned genes have been shown to result in an increase in total Aβ production or an increase in the Aβ-42:Aβ-40 ratio; that is, the two common forms of Aβ which comprise 42 and 40 amino acids respectively. This lends credence to the ‘amyloid hypothesis’ which suggests that all AD pathology and symptoms are derived from the toxic e ects of Aβ, essentially by its overproduction or lack of clearance. Of the two forms, Aβ-42 has been shown to be more neurotoxic; it is usually found within parenchymal plaques as it has a propensity to aggregate more rapidly. Aβ-40 is found predominantly in the vasculature as it is suf- ciently soluble to be cleared to the blood vessels before being deposited.

2.3 Processing of amyloid precursor protein
The ‘amyloidogenic’ route, by which Aβ is produced during the processing of APP,

is described in Figure 2.2. In the normal brain this constitutes only a small part of

Figure 2.2 The processing of amyloid precursor protein (APP) to form Aβ.This schematic shows the APP770 splice variant, and amino acid residue numbers are derived from this. In the APP695 variant, most commonly found in neurons, the two N-terminal exon insertions are excluded. Cleavage may commonly occur by α-secretase in the plasma membrane or by β-secretase during recycling through the endosomal pathway. In normal neurons, the enzyme α-secretase cleaves APP about 90–95 per cent of the time to form the C-terminal peptide C83 (83 amino acids long), and the N-terminus called APPα
(or soluble sAPPα). α-secretase comprises ADAM 9, 0, or 7. Normally, 5–0 per cent of the time,
the enzyme β-secretase cleaves APP to form C99 and sAPPβ. Subsequently γ-secretase cleaves within the hydrophobic membrane to form the peptide p3 (non-amyloidogenic pathway) or Aβ (amyloidogenic pathway) respectively. The APP intracellular domain (AICD) produced in the non-amyloidogenic pathway is degraded, whereas the identical fragment produced in the amyloidogenic pathway is transferred to the nucleus where it acts as a transcription factor and is stabilized by adaptor proteins such as Fe65. One of the target genes for upregulation includes that for neprilysin.

CHAPTER 2 Pathophysiology of Alzheimer’s disease

the processing of APP protein, the rest is processed by the ‘non-amyloidogenic’ path- way where Aβ is not produced. The enzymes responsible for cleavage of APP are α-, β-, and γ-secretase. α-secretase (comprising three enzymes, known as ADAM 9, 0, and 7) are members of the ADAMs (A disintegrin and metalloprotease) family; ADAM 7 is also known as tumour necrosis factor-α (TNFα) converting enzyme or TACE. β-secretase cleavage is due to the activity of two aspartyl proteases, β-site APP cleaving enzyme (BACE)  and 2, the former of these is most important in the brain. γ-secretase is a complex of four proteins, presenilin  or 2, nicastrin, PEN2 (presenilin enhancer 2), and APha or APhb (anterior pharynx-defective phenotype ). Presenilin is the catalytic component of γ-secretase, responsible for cleaving the APP C-terminal peptide (C99 or C83) to form either Aβ or a non-toxic peptide, p3. This γ-secretase complex has a large number of substrates other than APP, such as Notch, low-density lipoprotein receptor-related protein  (LRP), cadherins, ErbB4, and the cell-surface glycoprotein CD44. Mutations near the C-terminal region of Aβ (such as the ‘London’ mutation V77I) or mutations in PSEN or 2 lead to an increase in the Aβ-42:Aβ-40 ratio as this is the site of cleavage after either 40 or 42 residues. Conversely, the ‘Swedish’ double mutation at the N-terminus of the Aβ peptide results in an increase of both Aβ-40 and Aβ-42. This is because this mutant APP has an approximate hun- dredfold higher a nity for BACE than the normal APP protein.

2.4 The toxicity of Aβ
2.4. Aβ: mitochondrial damage and calcium

Aβ, particularly the Aβ-42 form, has adverse e ects on neurons and the cellular envi- ronment of the brain, and it is suggested that an accumulation of these e ects over a long period of time eventually causes enough neuronal damage to generate symptoms consistent with AD. The brain has a high rate of oxygen consumption yet low levels of protective antioxidant enzymes and therefore is vulnerable to damage from oxidation and the reactive oxygen species (ROS) produced. Aβ accumulates intraneuronally in endosomes and lysosomes and disrupts protein degradation. Mitochondrial dysfunc- tion also occurs early in the disease process and is related to the presence of Aβ. Damage includes decreased mitochondrial membrane potential, loss of respiratory enzyme activity, production of ROS, and calcium dysregulation.

An important aspect of toxicity in the AD degenerative process is the control of calcium homeostasis and there are a number of processes which may facilitate an unde- sirable rise in intraneuronal Ca2+. Extracellular Aβ oligomers, in particular Aβ-42, have been shown to bind to normal cellular prion protein at the plasma membrane to increase entry of Ca2+ into the neurone. The APP intracellular domain (AICD) peptide may also be involved by a ecting the sensitivity of the channels (InsP3 and ryanodine receptors (RYRs)) that cause Ca2+ levels to be released from internal stores. High levels of Ca2+ may also cause the mitochondria to release cytochrome C, with subsequent initiation of caspase cleavage and controlled cell death (apoptosis) and/or synapse reduction via long-term depression (LTD). At the mitochondrial membrane Aβ may also interact with cyclophilin D to form a mitochondrial permeability transition pore (mPTP) which con- tributes to leakage of mitochondrial constituents such as cytochrome C.

2.4.2 Aβ: binding partners and synaptic dysfunction

Aβ is able to bind many proteins and thus interfere with their expression and func- tion. Amyloid β-peptide binding protein alcohol dehydrogenase (ABAD) is a binding

11

CHAPTER 2 Pathophysiology of Alzheimer’s disease

12

partner of Aβ. This enzyme is important in glucose-de cient environments and is able to increase the brain’s ability to use ketones, where it can be protective, as seen after a stroke. However, in the presence of Aβ, this normally protective enzyme is able to facilitate apoptosis. When ABAD is overexpressed in transgenic AD mouse models, the presence of Aβ results in spatial and temporal memory de cits.

Aβ also binds the transcription factor cAMP-response element binding protein (CREB), which is important in formation of memory. CREB controls expression of a number of important proteins including brain-derived neurotrophic factor (BDNF), known to facilitate long-term potentiation (LTP), a correlate of memory formation. Notably, BDNF levels are reduced in AD brain and this fact alone probably contributes signi cantly to synaptic loss and memory dysfunction. Still under examination are the roles of Aβ oligomers and hyperphosphorylated tau in the profound synaptic dysfunc- tion seen early in AD. The presence of Aβ is known to be associated with a decrease in the phosphorylation of glutamate N-methyl-D-aspartate (NMDA) receptor, which is required for LTP and synaptic strengthening. This results in an increase in receptor endocytosis and reduced LTP. Calcineurin (Ca2+-dependent protein phosphatase) is necessary for Aβ-induced spine loss and endocytosis of glutamate receptors. This sup- pression of LTP by Aβ can be prevented by inhibition of caspase-3. Tau appears to be required for some of the Aβ induced synaptic defects as its removal ameliorates some of the synaptic and behavioural de cits seen in animal models of AD.

2.4.3 Aβ: in ammation

The deposition of Aβ into parenchymal plaques acts as a catch-all for other molecules and eventually an in ammatory response may be invoked. As we age, the balance of immune capability shifts from the humoral cell-mediated immune response and anti- body production to rely further on the innate response involving proin ammatory cytokine production. Therefore with continued Aβ production, activated microglia produce proin ammatory mediators, such as the cytokines interleukins and tumour necrosis factor-α (TNFα), upregulate the complement system and produce ROS and excessive amounts of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) which leads to neuronal cell death.

2.4 Tau

Importantly, the production of Aβ is linked with the deposition of tau, thought by many to be the more important of the two peptides in terms of neuronal degeneration and its associated symptoms.

Mutations in the tau gene MAPT have not been shown to be a primary cause of AD. Tau mutations are usually seen in frontotemporal dementias (FTDPs) such as fron- totemporal dementia with parkinsonism associated with chromosome 7 (FTDP-7); chromosome 7 has the MAPT gene within it. Those living with FTDP-7 have tau deposits but rarely amyloid plaques. It seems that Aβ is ‘upstream’ of NFT formation and that tau mutations circumvent this step and do not invoke excessive Aβ production.

The protein tau is a microtubule-binding protein, keeping microtubules in an assem- bled state by stabilizing α- and β-tubulin strands and enabling axonal transport. Tau exists in six isoforms, each with three or four microtubule-binding domains in the middle region of the protein. Microtubules facilitate passage of cargo containing nutri- ents, neurotransmitters, etc., from the cell body to the axon by kinesin protein com- plexes and towards the cell body by dynein protein complexes. Tau prevents cargo

CHAPTER 2 Pathophysiology of Alzheimer’s disease

movement by obstructing its path, whereas phosphorylation of tau causes it to detach from the microtubules allowing regulated cargo movement. Tau may then become de-phosphorylated and return to its position on the microtubule. However, if the tau protein becomes hyperphosphorylated or abnormally phosphorylated, as it does in AD, this results in deposition of tau and production of NFTs. This may occur if kinases are overactivated, and kinases, particularly glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (Cdk5), have been implicated in tau hyperphosphorylation. It is important to have a balance by which phosphorylation is kept optimal. This may occur by dephosphorylation of the tau by phosphatases allowing its reinstatement on the microtubule. Notably however, there is reported to be reduced phosphatase activity in AD brain; in particular, PP-2A (protein phosphatase 2) is reduced by up to 30 per cent.

2.5 Risk factors for sporadic AD 2.5. Age

Age is the greatest risk factor for AD. It is rare to develop dementia before the age of 65 years, yet its prevalence in the UK is given as approximately 7 per cent of people aged 65 years or above. Since AD accounts for an estimated 60–70 per cent of demen- tias this equates to nearly 5 per cent or –20 people in this age range. The prevalence of dementia then almost doubles each subsequent ve years (Dementia UK, 204).

2.5.2 Apolipoprotein E

The second most robust risk factor for AD is the presence of an E4 allele of apolipo- protein E (APOE4), located on chromosome 9. This was shown to be associated with a family with late-onset AD and later, more generally, as a strong risk factor for sporadic AD. There are three common isoforms of the protein APOE: E2, E4, and E3 which is the most frequent in the population. The frequency of the E4 allele in sporadic AD is approximately 40 per cent compared with 6 percent in age-matched normal sub- jects. It is estimated that one E4 allele hastens the theoretical onset of AD by 5 years, and two E4 alleles does so by 0 years. Conversely, the E2 allele is protective. The reason for this striking statistic almost certainly lies in the conformational di erence between the E3 and E4 proteins which is entirely due to one amino acid di erence; whereas APOE3 has the amino acid cysteine at position 2, E4 has an arginine resi- due. APOE is a glycoprotein which enables transport of phospholipids and cholesterol within high-density lipoprotein (HDL) particles to neuronal sites requiring repair and remodelling of synapses. This is especially important after injury. APOE2 and E3 bind to small phospholipids rich in HDL; however, due to its conformation, E4 binds prefer- entially to larger triglyceride-rich very low-density lipoproteins (VLDL). Aβ is formed from within the APP transmembrane region and therefore originally forms an α-helix; all polymorphic forms of APOE catalyse its conversion into a β-strand formation, thus promoting aggregation. APOE4 however is less lipidated than E3 and E2 and therefore tends to promote brillization more readily than the other isoforms. Therefore more plaques are likely to be apparent in the brain of an E4 carrier.

Furthermore, since E4 is less able to bind HDL it is less able to promote neurite outgrowth. There is a reduced capacity for synaptic remodelling which may result in a reduced synapse formation and lower ‘neuronal reserve’. This reserve keeps us above the threshold of cognitive impairment. Thus, in some ways the presence of E4 has been

13

CHAPTER 2 Pathophysiology of Alzheimer’s disease

14

likened to a ‘knockout’ of APOE and is associated with lower synaptic density and a sig- ni cantly reduced repair response after head injury, resulting in a higher mortality rate. Another aspect of APOE is in its facilitation of the removal of Aβ from the brain. When fully lipidated, APOE binds Aβ and can maintain its solubility and promote its clearance from the brain. APOE is mainly produced by glial cells and is lipidated to form lipoprotein particles by means of the lipid transporters ABCA (ATP-binding cas- sette sub-family A member ) and ABCG (sub-family G). APOE4 is less lipidated and is much less e cient in clearing Aβ from the brain. The expression of APOE and the lipid transporters are partly regulated by the retinoid X receptor (RXR), the liver X receptor (LXR), and peroxisome proliferator-activated receptor (PPAR). Further to this, an RXR agonist bexarotene has been shown to upregulate APOE and lipid transporters and to increase phagocytosis by macrophages and microglia, resulting in

increased clearance of Aβ. 2.5.3 Genetic risk factors

Other risk factors have become known due to the Genome Wide Association Studies (GWAS) in which large numbers of individuals are examined for common genetic vari- ants to highlight any associations with the disease. Approximately 30 polymorphisms have been identi ed as signi cantly lowering or increasing the age of onset of sporadic AD. This includes proteins involved in immune function including CR (complement component (3b/4b) receptor ) and TREM2 (triggering receptor expressed on mye- loid cells 2), and cholesterol metabolism and transport such as APOE, clusterin (apoli- poprotein J), and ABCA7. In the light of the link between APOE and other ATP-binding cassette members it is of interest to nd that carriers with inactive forms of ABCA7 have twice the likelihood of developing AD. Additionally, sortilin-related receptor  (SORL) is a sorting receptor which binds APP and APOE. Without SORL present to guide APP, it is directed towards β-secretase. Under these circumstances there would be an increase in Aβ produced. Notably, in blood samples from AD patients, a reduc- tion of approximately 50 per cent in the level of SORL protein was measured in AD compared with normal. Similarly, certain variants of the endothelial cell protein PICALM (phosphatidylinositol-binding clathrin assembly protein) are a signi cant risk factor for AD and it is suggested that these variants may reduce Aβ clearance.

Further studies are underway to provide mechanisms by which these diverse proteins may in uence the course of the disease.

2.6 Conclusion

The consensus is that the initial trigger for commencement of the disease process involves the production of Aβ oligomers which, over time due to unmodulated cellular responses, result in a variety of cellular stresses. Part of this process involves the activa- tion of speci c kinases and abnormal phosphorylation of tau. One of the outcomes is defective neuronal transport but also loss of synaptic and neuronal cell communication. The pathological processes which occur during the onset and progression of AD are now known to occur perhaps 5–20 years before any symptoms appear. This knowl- edge changes the understanding of the disease: if we can develop su ciently sensitive biomarkers of the disease process, with improved imaging we will have more time to identify and slow down the disease and perhaps prevent its appearance completely. This long-term approach also shifts focus somewhat towards diet, exercise, and other environmental factors.

CHAPTER 2 Pathophysiology of Alzheimer’s disease

 

Acknowledgements

SJA is a Sigmund Gestetner Senior Research Fellow. Thanks is given for the support of Bristol Research into Alzheimer’s Disease (BRACE), the Alzheimer’s Society, and the Sigmund Gestetner Trust.

References

Hardy J. and Selkoe D.J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002;297:353–6.

Heneka M.T., Golenbock D.T., and Latz, E. Innate immunity in Alzheimer’s disease Nature Immunology 205;6:229–36.

Sperling R., Mormino E., and Johnson K. The evolution of preclinical Alzheimer’s disease: implica- tions for prevention trials. Neuron 204;84:608–22. doi:0.06/j.neuron. 204.0.038.

Rodríguez-Arellano J.J., Parpura V., Zorec R., et al. Astrocytes in physiological aging and Alzheimer’s disease. Neuroscience 205. doi: 0.06/j.neuroscience.205.0.007.

Spires-Jones, T.L. and Hyman, B.T. The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron 204;82:756-–7.

15

CHAPTER 2 Pathophysiology of Alzheimer’s disease

Chapter 3

Epidemiology of Alzheimer’s disease
Chengxuan Qiu and Laura Fratiglioni

Key points

• More than 44 million people are living with dementia throughout the world, most su ering from Alzheimer’s disease

• In addition to old age and genetic susceptibility (e.g. APOE ε4 allele), current evidence strongly supports the potential role of vascular risk factors and psychosocial factors in the pathogenetic process and clinical manifestation of the dementing disorders, including Alzheimer’s disease

• Intervention towards optimal control of major vascular risk factors and maintenance of a socially integrated lifestyle and mentally stimulating activity may postpone the onset of dementia and Alzheimer’s disease

3. Introduction

Dementia is a disabling syndrome characterized by progressive deterioration in multi- ple cognitive domains that is severe enough to interfere with daily functioning, including social and professional functioning. Alzheimer’s disease is considered the most common form of dementia and accounts for up to 70% of all dementia cases diagnosed accord- ing to current clinical diagnostic criteria, although neuroimaging and autopsy-veri ed studies have revealed that a large majority of dementia cases are attributed to cerebral mixed vascular and neurodegenerative pathology. Epidemiology refers to the study of distribution and determinants of health-related states or events in speci ed populations as well as its application to the control of health problems. In this chapter, we will brie y summarize the major ndings from the recent epidemiologic studies of dementia, and Alzheimer’s disease in particular, concerning global prevalence and incidence, risk and protective factors, and intervention strategies.

3.2 Global prevalence, incidence, and impact

The growing proportion of the ageing population has become a worldwide univer- sal concern. The number of elderly people (65+ years) in the world is projected to increase from 420 million in 2000 to nearly  billion by 2030, with the proportion of elderly people increasing from 7–2%. The most rapid and greatest increase in abso- lute numbers of older persons will occur in low- and middle-income countries (LMIC) such as China, India, and other South Asian nations. As a result, the LMIC share of

17

18

70 60 50 40 30 20 10 0

 

Brayne 2006; UK
Prince, et al. 2013; US Chan, et al. 2013; China Anstey, et al. 2010; Australia

                                    

           

65–69

70–74 75–79

80–84 85–89 Age

90–94 95+

the worldwide ageing population will increase from ~60% to more than 70%. Thus, as a strongly age-dependent disorder, dementia or Alzheimer’s disease will have a huge impact on public health, healthcare, and social service systems in all countries through- out the world.

Alzheimer’s disease or dementia has indeed become a global challenge. The World Health Organization (WHO)/Alzheimer’s Disease International (ADI) estimate that the overall age-standardized prevalence of dementia among people aged 60+ varied from 2.% (West Sub-Saharan Africa) to 8.5% (Latin America), but most of the esti- mated prevalence gures lay between 5% and 7%. For instance, the age-standardized prevalence of dementia in people aged 60 years or older was 5.57% in Asia-Paci c regions, 6.46% in North America (USA), and 6.92% in Western Europe. In 200 nearly 36 million people in the world were a ected by dementia, and the total number of people with dementia was projected to double every 20 years, to 65.7 million in 2030 and 5.4 million in 2050. The global cost of dementia care in 200 was estimated at US$604 billion, which corresponds approximately to % of global gross domestic product. The large proportion of cost (~70%) was spent on informal, social, and direct medical care. As more prevalence data became available in recent years in Eastern Asian (e.g. China) and African (e.g. Sub-Sahara Africa) regions, the updated report from the WHO/ADI estimated that the number of people living with dementia worldwide in 205 was 47.5 million, with 7.7 million new cases occurring every year. It is pro- jected that the total number of people with dementia will reach 75.6 million in 2030 and 35.5 million in 2050. Thus, dementia or Alzheimer’s disease has become a global health priority.

Several meta-analyses and nationwide surveys have yielded roughly similar patterns of age-speci c prevalence of dementia across countries (Figure 3.; see also colour plate section). The age-speci c prevalence of dementia almost doubles every ve years after 65. Overall, approximately one in ten people aged 65–69 years is a ected by

Figure 3. Age-speci c prevalence of dementia (per 00 population) across countries (see also colour plate section).

Prevalence, per 100 population

CHAPTER 3 Epidemiology of Alzheimer’s disease

100

90

80

70

60

50

40

30

20

10

0

The CSHA Group 2000; Canada Matthews & Brayne 2005; UK Plassman, et al. 2011; USA

  

             

65–69

70–74 75–79

80–84 85–89 90+

Age

Figure 3.2 Age-speci c incidence of dementia (per ,000 person years) across countries (see also colour plate section).

dementia, whereas about one-third of people aged over 85 may have dementia-related symptoms. Alzheimer’s disease and vascular dementia are the two main subtypes of dementia, accounting for 50–70% and 5–25%, respectively, of all dementia cases. The distribution pattern of age-speci c prevalence for speci c Alzheimer’s disease is similar to that of dementia in general.

The incidence of dementia or Alzheimer’s disease almost doubles every ve to six years from 65 to 90 years of age (Figure 3.2; see also colour plate section). However, it remains debatable whether the exponential increase in the risk of dementia with increasing age will continue in more advanced ages. The apparent decline in incidence of Alzheimer’s disease among the oldest-olds found in some studies may be due to poor response rates, survival e ects, and nature of population of the oldest-old age group. In addition, several studies from Europe observed a higher incidence of Alzheimer’s disease among women than men, especially among the oldest-old age group, whereas the gender di erence in occurrence of Alzheimer’s disease has been inconsistent from studies in North America. Finally, recent studies have provided evidence suggesting that incidence of dementia and Alzheimer’s disease might have declined in the past decades in high-income countries.

Alzheimer’s disease or dementia deteriorates progressively, which further wors- ens quality of life, increases institutionalization, and shortens life expectancies. First, population-based studies show that more than 50% of mild dementia cases may pro- gress to the severe stage over a three-year period. This progression is due to both cognitive and functional decline. Predictors of a more rapid cognitive decline include initial higher cognitive function, physical disability, and cerebrovascular disease. Second, Alzheimer’s disease and dementia are strongly associated with functional disability. The development of functional dependence over a three-year period on approximately half of all elderly people can be attributed to dementia. In high-income countries, dementia and cognitive impairment are the most common diseases among older adults living in

19

Incidence, per 1000 person-years

CHAPTER 3 Epidemiology of Alzheimer’s disease

20

Table 3. A sum disease by various

Aetiological hypothesis

ary of major risk and protective factors for aetiological hypotheses

Risk and protective (in italic) factors over the lifespan

sporadic Alzheimer’s

Epidemiologic evidence

Genetic susceptibility

APOE ε4 allele and familial aggregation

Strong

Vascular hypothesis

Midlife hypertension, diabetes, smoking, athero- sclerosis, cerebral small vessel disease, alcohol abuse, limited alcohol intake, physical activity, anti- hypertensive therapy, and Mediterranean diets

Moderate or su cient

Psychosocial hypothesis

Low SES, depression, high education, mental activ- ities, social engagement, and rich social network

Moderate or su cient

Others (e.g. oxidative stress, in ammatory, or neurotoxic hypothesis)

Traumatic head injuries, occupational expo- sures to neurotoxic and electromagnetic elds, de ciency in nutrients (vitamins A, E) hormone replacement therapy, and NSAIDs

Insu cient or limited

APOE = apolipoprotein E gene; NSAIDs = non-steroidal anti-in ammatory drugs; SES = socioeconomic status

(Adapted from Fratiglioni and Qiu, Oxford Textbook of Old Age Psychiatry, 2nd edn. Copyright (203) with permission from Oxford University Press)

nursing homes or in institutions. However, the rate of institutionalization of dementia patients depends on age, living region (e.g. urban or rural areas), and other cultural aspects. Finally, epidemiologic studies have revealed that Alzheimer’s disease is a malig- nant condition that could confer an excessive risk of death for elderly people to a similar extent as that of malignant tumours. Several community-based follow-up studies have shown that Alzheimer’s disease was associated with a two- to vefold increased risk of death. The median survival time for people diagnosed with incident Alzheimer’s disease ranges from three to eight years after the initial diagnosis, depending on the age of onset and other demographic features. Older age, male sex, low education, race, multiple comorbidities (e.g. hypertension and diabetes), and functional disability are the most frequently reported indicators of a shorter survival in persons with dementia or Alzheimer’s disease.

3.3 Risk and protective factors

Alzheimer’s dementia is a multi-factorial disease in which older age is the strongest risk factor; up to 80% of all patients with dementia or Alzheimer’s disease occur among people aged 75 years or older. This suggests that the ageing-related biological processes may be implicated in the pathogenesis of the disease. Furthermore, the strong associa- tion of Alzheimer’s disease with increasing age may, at least partially, re ect a lifetime cumulative e ect of di erent risk and protective factors, including e ect of complex interactions of genetic susceptibility, biological factors, and environmental exposures experienced over the life span. Table 3. summarizes the major risk and protective factors following various aetiological hypotheses. Moderate to strong evidence sup- ports the role of genetic, vascular, and psychosocial factors in the development of Alzheimer’s disease. Whereas implementing preventive strategies targeting the genetic

m

CHAPTER 3 Epidemiology of Alzheimer’s disease

component is limited, intervention programmes targeting the pathways indicated in the other two hypotheses may have the potential to reduce the risk or postpone the onset of dementia and Alzheimer’s disease.

3.3. Genetic hypothesis

Mutations in amyloid precursor protein, presenilin-, and presenilin-2 genes cause early-onset familial Alzheimer’s disease that accounts for approximately –3% of all Alzheimer cases. The vast majority of Alzheimer cases are sporadic, caused by genetic susceptibility, environmental factors, and gene–environment interactions. First-degree relatives of patients with Alzheimer’s disease have a higher lifetime risk of developing Alzheimer’s disease than the general population or relatives of non-demented individuals. It is supposed that both genetic and shared environmen- tal factors contribute to the phenomenon of familial aggregation. In addition, some studies suggest that the familial aggregation of Alzheimer’s disease can only be par- tially explained by known genetic components such as APOE ε4 allele, indicating that other susceptibility genes may contribute to the aggregation. The heritability of Alzheimer’s disease is estimated in the twin studies to be approximately 60%, whereas other variance may be due to non-genetic factors. The APOE ε4 allele is the only established genetic factor for both early- and late-onset Alzheimer’s disease; there is a dose-response relation between the number of the ε4 alleles and the risk of Alzheimer’s disease. The risk e ect of APOE ε4 allele on Alzheimer’s disease decreases with increasing age, and after age 75, around 5–20% of Alzheimer cases are attributable to the APOE ε4 allele. Several other candidate genes, such as angio- tensin I-converting enzyme, insulin degrading enzyme, clusterin, and complement component receptor  genes, are suggested to have a weak but signi cant associa- tion with Alzheimer’s disease.

3.3.2 Vascular hypothesis

During the last a couple of decades, moderately strong evidence from the community-based epidemiologic studies has emerged supporting the hypothesis that vascular risk factors and vascular comorbidities are associated with an increased risk of dementia, including Alzheimer’s disease. Cigarette smoking as a risk factor for Alzheimer’s disease has been con rmed in meta-analyses of population-based pro- spective studies. Alcohol abuse is related to alcoholic and vascular dementia, whereas light to moderate alcohol consumption can be associated with a decreased risk of dementia and Alzheimer’s disease in several studies. Elevated blood pressure occur- ring in middle age, especially uncontrolled midlife high blood pressure, has been linked to an increased risk of late-life Alzheimer’s disease in several observational studies. Longitudinal observational studies repeatedly show a protective e ect of use of various antihypertensive drugs against cognitive decline and dementia. The Syst-Eur trials sug- gested that antihypertensive therapy with calcium-channel blockers is associated with an approximately 50% reduction in the risk of dementia, mostly Alzheimer’s disease. However, the randomized clinical trials of antihypertensive therapies with drugs other than calcium-channel blockers among elderly patients with hypertension (e.g. SHEP and SCOPE) have failed to demonstrate such protective e ect. Diabetes and prediabetes are linked to a higher risk of dementia and Alzheimer’s disease in numerous observa- tional studies. Hyperinsulinemia is also associated with Alzheimer’s disease and with decline in memory function. Cerebrovascular disease (e.g. infarcts and cerebral small vessel diseases), even clinically silent, signi cantly increased the risk of not only vascu- lar dementia but also mixed dementia and Alzheimer’s disease. Severe atherosclerosis

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CHAPTER 3 Epidemiology of Alzheimer’s disease

22

and cardiovascular disease, such as atrial brillation and heart failure, are related to dementia and to Alzheimer’s disease as well. There is also evidence that low serum cholesterol, use of cholesterol-lowering drugs, and a dietary pattern of more sh, more vegetables, and low saturated fat (e.g. Mediterranean diet) may be related to a lower risk of Alzheimer’s disease.

Whereas vascular risk factors or comorbidities are expected to cause vascular dementia, several explanations are proposed for the association of vascular risk fac- tors and related comorbidities with Alzheimer-type dementia. Evidence suggests that Alzheimer’s disease may be a disorder of vascular origin. Alternatively, cerebrovascular lesions may contribute to the development and clinical expression of dementia syn- drome by interacting with the neurodegenerative pathology of brain ageing. This is sup- ported by neuroimaging and neuropathological studies, which reveal that coexistence of cerebral vascular and Alzheimer pathologies are fairly common among patients with dementia and Alzheimer’s disease.

3.3.3 Psychosocial hypothesis

Systematic reviews of epidemiologic studies conclude that psychosocial factors and an actively integrated lifestyle over life span may reduce the risk of Alzheimer’s disease and dementia. These factors include early-life high educational attainment, adult-life high work complexity, late-life rich social network, and high levels of social engagement, and more frequently participating in mentally stimulating activity. Although physical exercise may reduce the risk of cerebrovascular damage, the relevance of physical activity itself in reducing the risk of dementia remains in question as most physical activities include also social and mental components. Complex leisure activities with physical, mental, and social components are shown to have the most bene cial e ect against dementia. Long-term follow-up studies support a temporal relationship of depression to subse- quent dementia and Alzheimer’s disease, although it remains debatable whether late-life depression is a preclinical symptom or a causal risk factor for the dementing disorder.

Psychosocial factors may protect against or delay onset of Alzheimer’s disease by increasing neural and cognitive reserve, which may provide compensatory mechanisms to cope with vascular and neurodegenerative pathologies in the brain, and therefore delay the onset of dementia syndrome. Other possible explanations include such as increased premorbid cognitive ability and reduced vascular damage related to psycho- social factors.

3.3.4 Other hypotheses

Evidence had been accumulating that moderate and severe traumatic brain injury is associated with Alzheimer’s disease, especially among carriers of the APOE ε4 allele. The biological mechanism behind this association is that traumatic brain injury increases formation of β-amyloid plaques or reduces brain reserve. Numerous obser- vational studies have found that increasing levels of serum in ammatory markers (e.g. C-reactive protein and interleukin-6) during middle age and late life are associated with an increasing risk of both Alzheimer’s disease and vascular dementia, suggesting that these in ammatory markers may re ect both peripheral disease and cerebral mecha- nisms that are related to dementia. As additional evidence supporting the in amma- tory hypothesis, systematic reviews of observational studies suggested that long-term use of non-steroidal anti-in ammatory drugs for more than two years may have sig- ni cant bene cial e ect against Alzheimer’s disease. However, the major clinical trial of anti-in ammatory prevention on Alzheimer’s disease was suspended due to the increased risk of cardiovascular events and dementia among the treatment group.

CHAPTER 3 Epidemiology of Alzheimer’s disease

Similarly, oestrogen therapy has been linked to a lower risk of Alzheimer’s disease in numerous observational studies, but the large-scale clinical trial of the Women’s Health Initiative Memory Study showed that oestrogen therapy alone did not reduce the incidence of probable dementia and mild cognitive impairment; instead, the active treatments with oestrogen and oestrogen plus progestin were found to be associated with a twofold increased risk for both dementia and mild cognitive impairment. Finally, some follow-up studies have reported a decreased risk of Alzheimer’s disease associ- ated with supplementary intake of antioxidants (e.g. vitamins E and C), suggesting that diets and nutritional factors may play a part in Alzheimer’s disease and dementia.

3.4 Prevention

Dementia or Alzheimer’s disease is the most common mental disorder in our ageing society and has led to enormous public spending on healthcare and social services in both LMICs and high-income countries. Thus, dementia has become one of the global public health priorities. Because there is currently no cure for dementia, implementing intervention programmes targeting manageable risk factors for dementia may be crucial for the reduction of the disease burden and for meeting future challenges resulting from dementia. Current evidence from multidisciplinary research supports the notion that the onset of dementia and Alzheimer’s disease may be postponed by implementing primary (i.e. intervention towards potential aetiological risk and protective factors) and secondary (i.e. early detection) prevention. An ideal intervention program for delay- ing the onset of Alzheimer’s disease should take both the life-course model and the multifactorial nature of this syndrome into consideration. It has been estimated that any intervention measures that delay the onset of Alzheimer’s disease by ve years would halve its prevalence and signi cantly reduce the burden of dementia in the age- ing society.

3.4. Primary prevention

Even if the mechanisms of vascular and psychosocial factors being involved in the patho- genesis of Alzheimer’s disease are still not fully understood, primary prevention sounds possible as most vascular risk factors, psychosocial factors, and lifestyles are modi able or amenable to management. One intervention strategy could be to target the vascular pathway, and includes controlling smoking, midlife high blood pressure, and obesity, and appropriately treating diabetes and lowering blood glucose. This strategy is indirectly supported by evidence from recent studies in high-income countries, which suggests that incidence of dementia might have decreased following the decline of major cardio- vascular diseases owing to improvement in control of major vascular risk factors (e.g. hypertension ad high cholesterol). In addition, to postpone clinical expression of the dementia syndrome, preventing recurrent cerebrovascular disease and maintaining suf- cient cerebral blood perfusion by adequately managing heart failure and avoiding very low blood pressure seem to be critical in very old people. Furthermore, maintaining an active and socially-integrated lifestyle by establishing extensive social networks and frequently participating in social, physical, and intellectually stimulating activities may reduce the risk or delay the onset of Alzheimer’s disease. Theoretically, incidence of dementia and Alzheimer’s disease might be reduced through improved access to edu- cation and use of intervention approaches targeted at reducing the prevalence of major vascular risk factors (e.g. physical inactivity, smoking, midlife hypertension, midlife obe- sity, and diabetes) and depression. Although the most e ective strategy may be to

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CHAPTER 3 Epidemiology of Alzheimer’s disease

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encourage people to practise these preventive measures over the life course, includ- ing childhood, early adulthood, middle age, and later in life, a randomized controlled trial in Finland (FINGER) supports the e ectiveness of a multi-domain intervention programme in delaying cognitive decline among a high-risk group of elderly people by targeting diet, physical exercise, cognitive training, and vascular risk factors.

3.4.2 Secondary prevention

Alzheimer’s disease is characterized by gradual onset of multiple cognitive de cits, and subtle cognitive disturbances may occur years before the clinical diagnosis can be rendered. Studies have suggested that de cits in cognitive domains such as episodic memory and verbal ability can be conceivable up to 0 years before dementia diagno- sis, with a more evident decline occurring over the nal few years. The term amnestic mild cognitive impairment is used in the clinical setting to identify individuals with iso- lated memory loss in cognitive ageing, which might represent the pre-clinical phase of Alzheimer’s disease. Theoretically, detection of mild cognitive impairment may provide an opportunity for implementing early intervention to delay its progression to demen- tia. However, because no e cacious treatment to stop the progression of cognitive impairment to Alzheimer’s disease is currently available, and not all individuals with mild cognitive impairment will progress to dementia, a concern has been raised that a diagnosis of mild cognitive impairment might cause an unnecessary burden on patients and their relatives due to its unclear prognosis. Nevertheless, it is clinically relevant to identify those individuals with cognitive de cits due to treatable and reversible condi- tions such as depression, vitamin B2 de ciency, and use of medications.

3.5 Conclusion

Alzheimer’s disease or dementia, as a growing challenge to public health, has posed a tremendous impact at both individual and societal levels in the ageing society. Alzheimer’s disease is not curable but seems to be preventable. Epidemiologic research has provided su cient evidence that vascular risk factors in middle-aged and older adults play a signi cant role in the development and progression of dementia and Alzheimer’s disease, whereas extensive social network and active engagement in men- tal, social, and physical activities may postpone the onset of the dementing disorders. Community intervention trials are warranted to determine to what extent intervention strategies towards an optimal control of major vascular risk factors and vascular disor- ders as well as the maintenance of an active lifestyle are e ective in delaying onset of dementia and Alzheimer’s disease.

References

Alzheimer’s Disease International. Policy Brief for G8 Heads of Government. The Global Impact of Dementia 2032050. London: Alzheimer’s Disease International, 203.

Chan K.Y., Wang W., Wu J.J., et al. Epidemiology of Alzheimer’s disease and other forms of dementia in China, 990–200: a systematic review and analysis. Lancet 203;38:206–23.

Deckers K., van Boxtel M.P., Schiepers O.J., et al. Target risk factors for dementia prevention: a systematic review and Delphi consensus study on the evidence from observational studies. International Journal of Geriatric Psychiatry 205;30:234–46.

Fratiglioni L., Paillard-Borg S., and Winblad, B. An active and socially integrated lifestyle in late life might protect against dementia. Lancet Neurology 2004;3:343–53.

CHAPTER 3 Epidemiology of Alzheimer’s disease

Fratiglioni L. and Qiu C. Epidemiology of dementia. In: T. Dening and A. Thomas (eds). The Oxford Textbook of Old Age Psychiatry. 2nd edn. New York, NY: Oxford University Press, 203, pp. 389–43.

Ngandu T., Lehtisalo J., Solomon A., et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomized controlled trial. Lancet 205;385:2255–63.

Norton S., Matthews F.E., Barnes D.E., et al. Potential for primary prevention of Alzheimer’s dis- ease: an analysis of population-based data. Lancet Neurology 204;3:788–94.

Prince M., Acosta D., Ferri C.P., et al. Dementia incidence and mortality in middle-income coun- tries, and associations with indicators of cognitive reserve: a 0/66 Dementia Research Group population-based cohort study. Lancet 202;380:50–8.

Prince M., Bryce R., Albanese E., et al. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimer’s and Dementia 203;9:63–75.e2.

Qiu C. Preventing Alzheimer’s disease by targeting vascular risk factors: hope and gap. Journal of Alzheimer’s Disease 202;32:72–3.

Qiu C. and Fratiglioni L. A major role for cardiovascular burden in age-related cognitive decline. Nature Reviews Cardiology 205;2:267–77.

Qiu C., De Ronchi D., and Fratiglioni L. The epidemiology of the dementias: an update. Current Opinion in Psychiatry 2007;20:380–5.

Qiu C.X., Winblad B., and Fratiglioni L. The age-dependent relation of blood pressure to cogni- tive function and dementia. Lancet Neurology 2005;4:487–99.

Wimo A., Jonsson L., Bond J., et al. The worldwide economic impact of dementia 200. Alzheimer’s and Dementia 203;9:–,e3.

World Health Organization. Dementia: a public health priority. Geneva: WHO, Geneva, 202.

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CHAPTER 3 Epidemiology of Alzheimer’s disease

Chapter 4

Clinical course of Alzheimer’s disease
Alberto Lleó and Rafael Blesa

Key points

• Alzheimer’s disease is an age-related neurodegenerative disorder, with onset usually in late life, characterized by cognitive impairment, a variety of behavioural symptoms, and restrictions in the activities of daily living

• The initial symptom is episodic memory loss, in particular in delayed recall of visual and/or verbal material. Immediate and remote memory is usually preserved in early stages

• Behavioural symptoms can be present at early stages, even in pre-clinical phases of the disease, although the frequency increases as the disease progresses

4. Introduction

Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disorder characterized by cognitive impairment, a variety of neuropsychiatric symptoms, and restrictions in the activities of daily living. AD is the most common form of dementia and the prevalence increases exponentially between 65 and 85 years, doubling for each successive 5-year age group. Risk factors for AD include age, family history of AD, female gender, lower education, cerebrovascular disease, vascular risk factors, prior head trauma, and presence of the APOE-ε4 allele, among others.

Although AD can start in any period of adult life, the majority of patients are in their 60s or older. Cases with onset before 50 years are rare and are usually observed with familial aggregation with an autosomal dominant pattern. Mutations in the presenilin ( and 2) and amyloid precursor protein genes have been described in most of these rare families.

4.2 Onset of symptoms

The onset of symptoms is usually so insidious that neither the family nor the patient can date the time of its beginning. Occasionally, it is brought to attention by an unusual degree of confusion in relation to a febrile illness, an operation, or a new medication. In some instances, problems with the sense of direction in certain environments may give the impression that the symptoms are limited in time. Other patients may present with complaints of dizziness, headaches, or other vaguely expressed somatic symptoms. In

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rare instances, patients with AD can present with non-convulsive seizures, which can be di cult to recognize.

4.3 Cognitive symptoms

The cardinal symptom of typical AD is an insidious and progressive loss of episodic memory. The type of memory de cit in AD is speci c and is the manifestation of hippocampal dysfunction: patients have di culty acquiring new information and rap- idly forget the information they were able to learn. Small day-to-day happenings are not remembered. In contrast, older memories are relatively spared, with the oldest memories remaining intact for the longest. Forgetfulness is apparent in everyday life. The patient may forget names (especially seldom-used names), conversations or other recent information, may misplace objects, and may repeat the same questions or sto- ries. Neuropsychological research has consistently shown a failure to store new infor- mation as the rst detectable de cit in AD. Hence, learning and memory tests of new information remain the cornerstone, not only of formal neuropsychological assess- ment, but also of current screening instruments for dementia. Among the di erent memory tests, the free and cued selective reminding test (FCSRT) is speci cally recom- mended by the international guidelines because it controls for a successful encoding and it facilitates retrieval processing. The typical pattern observed in AD is low recall performance despite retrieval facilitation. Other memory tests, such as the Wechsler Memory Scale or the Rey auditory verbal tests can also be useful in the identi cation of the amnestic syndrome.

Even though memory loss is usually the initial and most prominent symptom, de cits in other cognitive domains other than memory can occur in the early stages of the dis- ease. In fewer than 5% of cases of AD, de cits in frontal, occipital, or parietal functions can be the most prominent initial symptoms (see Section 4.7, Atypical clinical variants).

Language is the second most important a ected function in AD. The patient may show word- nding di culties, problems in following a conversation, or simply identify an object as ‘the thing’. Vocabulary becomes restricted and expressive language hesi- tant, stereotyped, and in exible. Comprehension of spoken words can be preserved at rst, but often the patient is unable to follow complex conversations or cannot carry out a complicated request. There may be a tendency to repeat a question before answering it. The same di culties a ect handwriting. Examination may reveal ano- mia, circumlocutions, and paraphasias (e.g. ‘house’ for ‘mouse’ or ‘cat’ for ‘mouse’). Category uency (such as fruits or animals) may be particularly useful in assessing language de cits. The ability to understand gurative expressions (such as metaphors or proverbs) is a ected early, while functional language comprehension is impaired in more advanced stages.

Visuospatial de cits, which re ect right hemisphere dysfunction, are also prominent in the clinical course of AD. Visuospatial orientation may become defective and the patient may feel insecure in unusual places or may take the wrong direction on the way home or get lost. The route from one place to another may not be described or understood. Late in the course of the disease, the patient has di culties in using common objects and tools while retaining motor power and coordination for these activities. The patient can be unable to use utensils properly, eat or dress him or herself. Clinical examination may reveal dyspraxia; most commonly ideational although some- times ideomotor. There may be di culties in drawing a clock or making two simple drawings (Figure 4.).

CHAPTER 4 Clinical course of Alzheimer’s disease

 

Figure 4. Prominent constructive apraxia in a patient with AD.

Executive functions are typically impaired early in the course of AD. Executive functions (often called frontal abilities) refer speci cally to the ability to initiate, plan, sequence, and monitor behaviour required to organize a response and solve a com- plex problem. Patients may show di culties with planning, organizing, and abstract- ing. Previously mastered complex tasks may take much longer to complete that they used to and the patient may be unable to understand conversations with abstract content.

Measurement of executive functions is predictive of functional status in higher activi- ties of daily living such as money engagement, safety, medication administration, and social functioning. De cits in executive functions have also been implicated in driving di culties in AD. The frontal lobes are clearly involved in the successful performance of executive functions but are also involved in executing a wide range of additional cognitive abilities including selective and sustained attention, motor abilities, speech and language, verbal and non-verbal uency, working memory, organization of information, temporal ordering, and spatial orientation.

Patients with AD may show lack of awareness of the cognitive de cits or be una- ble to recognize their magnitude or severity. The actual prevalence of unawareness is debated but may range from 20% to 80% of cases of AD. This may be manifested by a tendency to minimize the signi cance of their symptoms or to positively deny the most obvious de cits. In other patients, the lack of awareness is only apparent from the patient’s actions even if he or she verbally acknowledges the presence of the illness. In practice, the information obtained from patients during the interview should always be contrasted with that of the caregiver. Insight worsens with disease progression and this can be a major source of con ict with the family or caregiver.

4.4 Behavioural symptoms

An estimated 90% of patients with AD develop behavioural disturbances during the course of their illness. These behaviours include aggression, agitation, hallucina- tions, delusions, sleep disturbances, depression, distractibility, apathy, aberrant motor

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CHAPTER 4 Clinical course of Alzheimer’s disease

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behaviour, and wandering. Current evidence indicates that these non-cognitive changes begin in the pre-clinical phases of AD. Behavioural symptoms typically increase with disease progression and their presence is associated with worse prognosis, a decrease in the quality of life for patients and caregivers, and an increase in the likelihood of institutionalization.

Depressive symptoms, such as sadness or anhedonia, are very common in the course of AD and can a ect up to 80% of patients. Major depressive episodes can also occur during the course of dementia and can a ect up to 50% of patients with AD.

Apathy is even more frequent, and it is often a diagnostic challenge to distinguish apathy from true depression. Patients with apathy exhibit a marked decrease in goal-directed behaviour, a lack of motivation accompanied by indi erence, low social engagement, poor persistence, and lack of initiation. Apathy occurs in approximately 70% of cases of AD and has been linked to greater impairments in activities of daily living and a greater degree of functional decline. Apathy is associated with dysfunction of the frontal anterior cingulate-subcortical circuit.

The identi cation and management of behavioural and psychological symptoms in Alzheimer’s disease are described in Chapter 9.

4.5 Physical examination

Physical examination in prodromal or early AD usually reveals normal ndings with the exception of de cits in cognitive function. In contrast, physical examination in patients in the dementia stage of AD may show frontal release signs, olfactory de cits, impaired stereognosis or graphesthesia, gait disorder, or tremor. Usually, corticospinal and corti- cosensory functions, visual acuity, ocular movements, and visual elds remain relatively intact. The presence of focal neurological signs such as hemiplegia or homonymous hemianopia should raise alternative diagnosis (stroke, tumour, or subdural haema- toma). The tendon re exes are little altered and the plantar re exes almost always remain exor until late stages of the disease. There is no true sensory or cerebellar ataxia. As many as 5–0% of patients may have multifocal myoclonus, particularly in the late course of the illness. In advanced stages signs of parkinsonism can be present. Ultimately, the patient loses the ability to stand and walk, being forced to lie in bed, and remains in a vegetative state.

4.6 Course of the disease

AD is a progressive disorder and symptoms tend to worsen gradually over time. Plateaus of one to one-and-a-half years may occur, but progression usually resumes thereafter. The speed of decline varies widely but on average patients in the moderate phase of the disease may lose 3–4 points per year on the Mini-Mental State Examination (MMSE) or 7–9 points on the Alzheimer’s disease Assessment Scale (ADAS-Cog). Eventually, with the patient in a bedfast state, an intercurrent infection such as aspiration pneumo- nia or some other disease mercifully terminates life.

The average duration of the disease between diagnosis and death is 8–2 years. AD cases presenting as a rapidly progressive dementia have been described and the disease duration in these cases can be less than three years.

An estimated 0–22% of patients with AD develop seizures, this being more frequent in familial and early-onset cases. Patients with AD and seizures have a worse prognosis,

 

CHAPTER 4 Clinical course of Alzheimer’s disease

with greater cognitive decline and faster progression. Recent evidence indicates that epileptic activity in the early stages of AD is more prevalent than previously recognized. Epileptiform activity usually occurs in the temporal lobes and cause transient cognitive symptoms that may be di cult to recognize as seizures. The routine electroencepha- logram (EEG) usually shows normal ndings and other techniques, such as long-term video EEG monitoring, may reveal abnormal activity. Treatment with antiepileptic drugs in these cases usually results in cognitive bene t.

4.7 Atypical clinical variants

It is estimated that in 6–4% of AD cases the presentation di ers from the typical amnestic variant, re ecting an atypical distribution of the pathology. These atypical

Box 4. Clinical stages of AD according to the global Deterioration Scale (GDS)

Stage : Normal. Person is free of cognitive or behavioural symptoms.
Stage 2: Subjective complaints. Person experiences the impression that memory and concentration is not as good as it once was but this is not usually noticed by others. Formal testing does not reveal any de cits.
Stage 3: Mild cognitive impairment. Person complains of poor memory, or other cog- nitive functions. Mild behavioural symptoms can coexist. De cits may be evident for others. Person is not demented and activities of daily living are relatively normal.
Stage 4: Mild AD. De cits start to be obvious at this point. Ability to recall recent events or appointments is impaired. Patient may have word- nding di culties or problems with the sense of direction. Patient fails to perform complex activities of daily living, such as handling nances or working. Patient can live independently but may need supervision. Behavioural changes are common.
Stage 5: Moderate AD. The patient cannot live independently for a long time, and the caregiver has taken charge of household chores, nances, and medications. Cognitive de – cits are very evident, patient may not recognize close family members but is still able to retain personal information. Behavioural disturbances are very common and may require urgent attention. Basic activities of daily living such as dressing may start to be impaired. Stage 6. Moderate-severe AD. Basic activities of daily living are impaired and can be divided in ve sub-stages:
• 6a. Patient requires assistance to dress.
• 6b. Patient cannot bathe independently.
• 6c. Patients cannot undertake toileting independently.
• 6d. Patient has urinary incontinence.
• 6e. Patient has double incontinence.
Stage 7: Severe AD. Basic activities of daily living are impaired and the patient needs continuous assistance. This stage can be divided into six sub-stages:
• 7a. Patient’s language has severely deteriorated and is often limited to half a dozen words. • 7b. Language continues to deteriorate and is limited to a single word.
• 7c. Language is completely lost and the patient requires assistance to walk.
• 7d. Patient in unable to sit without lateral support.
• 7e. Patient loses the ability to smile.
• 7f. Patient in unable to keep the head upright. Spasticity and deformities are common.

(Data from The American Journal of Psychiatry, 39, 982, ‘The Global Deterioration Scale for assessment of primary degenerative dementia’, pp. 36–9)

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variants usually present with relative preservation of memory together with de cits in other cognitive domains or behavioural changes. There are at least three proposed variants of atypical AD: a logopenic, a posterior, and a behavioural/dysexecutive vari- ant of AD. The logopenic variant of AD presents as a logopenic primary progressive aphasia characterized by impairment in single-word retrieval and repetition of sen- tences without de cits in semantic storage or motor speech output. The posterior variant of AD typically presents as a posterior cortical atrophy syndrome with impair- ment in visuospatial function. Two subtypes have been described: an occipitotempo- ral variant with de cits in the visual identi cation of objects or faces and a biparietal subtype with features of Gerstmann syndrome, limb apraxia, or neglect. Finally, the behavioural/dysexecutive variant of AD presents as a behavioural syndrome and/or executive dysfunction in formal cognitive tests. The presence of biomarker evidence of the AD pathophysiological process in these atypical variants is particularly impor- tant to support the diagnosis. These atypical presentations are reviewed in more detail in Chapter 5.

4.8 Stages of AD

There are many classical scales to measure in which stage a patient with AD is. One of the most widely used is the Global Deterioration Scale (GDS) developed by Reisberg and colleagues. This scale identi es 7 stages ranging from  (normal) to 7 (severe AD) with some sub-stages (see Box 4.). In addition, recent international criteria have pro- vided a conceptual framework to categorize the prodromal and preclinical phases of AD. In 2007, the International Working Group published the research diagnostic crite- ria of AD which were based on a characteristic amnestic syndrome together with a bio- marker evidence of AD. These criteria were reviewed in 204. In 20, the National Institute on Aging together with the Alzheimer’s Association (NIA–AA) published operational research criteria based on biomarkers to revise the criteria of the mild cognitive impairment (MCI) and preclinical phases of AD. These criteria are reviewed in Chapter 6.

4.9 Conclusion

The clinical picture of AD dementia has been well characterized over the last decades. In the last ten years, the interest has focused in the characterization and detection of the prodromal and preclinical phase of AD. The symptoms and signs in these stages are subtle and the use of biomarkers is key to support the diagnosis.

References

Cummings J.L. Alzheimer’s disease. New England Journal of Medicine 2004;35:56–67.
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CHAPTER 4 Clinical course of Alzheimer’s disease

Reisberg B., Ferris S.H., de Leon M.J., et al. Global Deterioration Scale (GDS). Psychopharmacology Bulletin 988;24(4):66–3.

Sala I., Marquié M., Sánchez-Saudinós M.B., et al. Rapidly progressive dementia: experience in a tertiary care medical center. Alzheimer’s Disease and Associated Disorders 202;26:267–7.

Vossel K.A., Beagle A.J., Rabinovici G.D., et al. Seizures and epileptiform activity in the early stages of Alzheimer’s disease. JAMA Neurology 203;70:58–66.

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CHAPTER 4 Clinical course of Alzheimer’s disease

Chapter 5

Atypical presentations of Alzheimer’s disease Matthew Jones and Jennifer Thompson

Key points

• Alzheimer’s disease usually presents in older age with progressive episodic memory loss

• Alzheimer’s disease may rarely be inherited because of an autosomal dominant mutation in one of three genes (PSEN, PSEN2, and APP)

• Early onset Alzheimer’s disease presents before the age of 65 and typically consists of a constellation of progressive cortical de cits including language disturbance, apraxia, visuospatial de cits, and poor working memory

• Recognition and accurate diagnosis of these atypical forms is vital to ensure patients receive the most appropriate care and treatment

5. Introduction

Alzheimer’s disease usually presents in older age (> 65 years) with gradually progres- sive impairment in episodic memory plus de cits in other cognitive domains such as language, executive function, praxis, and visuospatial skills. However, atypical presenta- tions have long been recognized and in this chapter we aim to summarize the clinical and neuropsychological features of these AD variants.

5.2 Posterior cortical atrophy

Posterior cortical atrophy (PCA) is the syndromic description of a neurodegenerative process that principally a ects the occipital and parietal lobes of the brain. Alzheimer’s disease is the most common cause. It typically occurs in people between the ages of 50 and 65 years. Exact prevalence gures are unavailable, but in some specialist centres PCA accounts for 5% of Alzheimer disease presentations.

The presenting complaint is a higher order disturbance of vision that patients fre- quently nd hard to explain. Patients may describe di culties in reading text or complain of ‘glare’ that makes perceiving visual stimuli troublesome. Some patients complain of problems in judging distances or nding patterned surfaces hard to see clearly. Patients may describe a striking failure to recognize or locate objects visually. Such visual symp- toms frequently result in patients being initially referred to opticians or ophthalmolo- gists. When no ocular abnormality is found there may be a delay before the patient is referred on to an appropriate specialist. Symptoms of anxiety and depression often

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occur which may lead to a patient’s visual symptoms incorrectly being assigned to a mood disorder. In addition to the prominent visual symptoms, direct questioning often reveals other de cits. Many patients have apraxia, acalculia, alexia, and agraphia. A loss of sense of direction is a common nding in patients with PCA. Patients typically do not report symptoms of amnesia. Social behaviour and insight remain intact.

Neurological examination may initially appear strikingly normal given the signi cant dis- ability that patients report. In some instances this results in patients being diagnosed with a ‘functional’ or anxiety-related disorder. However, careful examination often reveals important signs. Optic ataxia describes a problem whereby the patient cannot guide their hand to a visually de ned target (whilst looking straight at the examiner’s face the patient is asked to touch the examiners outstretched hand) yet can locate a target by sound with their eyes closed (the patient is asked to touch some jangling keys with their eyes closed). Optic apraxia describes a patient’s inability to move their eyes to a new visual target. Some patients struggle to copy non-representational hand postures and perform gestures with spatial inaccuracy. Myoclonus of the outstretched limbs is often seen.

On neuropsychological assessment, patients with PCA exhibit prominent de cits in visuoperceptual and visuospatial function. Apperceptive agnosia—impaired object rec- ognition secondary to a failure of perception—is a common feature of PCA. Tasks that require identi cation of degraded or visually complex stimuli (e.g. fragmented letters, overlapping line drawings) are particularly sensitive. However, patients may also have di culty identifying line drawings, such as those used in traditional naming tests, with naming errors indicative of perceptual failure rather than impaired lexical retrieval. When attempting to identify visual stimuli patients may focus on individual elements of a picture rather than the whole, which is a manifestation of simultanagno- sia. Visuospatial impairment is generally present to varying degrees in PCA. Di culties are elicited on tasks involving spatial localization or appreciation of three-dimensional space. In contrast to the ‘typical’ amnestic presentation of AD, episodic memory is relatively preserved, although assessment can be challenging. De cits in immediate or ‘working’ memory are common: patients with PCA often have a reduced digit span and may be easily ‘overloaded’ with information, which limits their ability to assimilate verbal information. Although immediate free recall may therefore be reduced in PCA, patients do not display the rapid forgetting that is a characteristic feature of ‘typical’ amnestic AD.

Magnetic resonance imaging (MRI) scanning of the brain usually reveals atrophy of the occipital and parietal lobes bilaterally. In patients with suggestive early symptoms yet normal structural imaging, brain single photon emission computed tomography (SPECT) or uoro-deoxy-glucose positron emission tomography (FDG-PET) scans usually reveal reduced perfusion or glucose metabolism posteriorly (Figure 5.; see also colour plate section).

The di erential diagnosis of PCA largely rests between AD, dementia with Lewy bodies (DLB) and sporadic Creutzfeldt–Jakob Disease (sCJD). Rapidly progressing cases should be investigated for sCJD; ataxia and myoclonus may be more prominent. The presence of well-formed, non-threatening visual hallucinations, uctuations in cog- nition, and the presence of rapid eye movement (REM)-sleep behaviour disorder sug- gest the diagnosis of DLB.

Management of the condition requires much more than the prescription of cholinest- erase inhibitors. Whilst licensed for AD there is no clear evidence that such drugs have a treatment e ect in PCA, although our practice is to prescribe them. Patients also need management of their mood symptoms and many patients bene t from the input of a low vision service.

CHAPTER 5 Atypical presentations of AD

 

5.3 Logopenic variant progressive aphasia

and the language presentation of AD

Logopenic variant progressive aphasia (lvPPA) is the most recently described of three primary progressive aphasia (PPA) subtypes. ‘Logopenia’, the characteristic feature of lvPPA, is de ned by slowed speech rate due to marked word- nding di culties. This leads to uent speech interspersed with non- uent periods. Patients with lvPPA have impaired repetition of phrases and sentences whilst having spared single word com- prehension, motor speech, and grammar. The majority of lvPPA cases (approximately 60%) that come to autopsy have AD pathology and most patients studied with this syndrome demonstrate positive amyloid positron emission tomography (PET) scans in vivo, however, a signi cant minority of patients ful lling criteria for lvPPA have alterna- tive pathology such as frontotemporal lobar degeneration (FTLD) at autopsy. Thus the clinical diagnosis of lvPPA is not synonymous with an atypical presentation of AD. In part this may be due to the non-speci c features used to de ne lvPPA in the latest classi cation system.

Patients with AD pathology may present with predominantly expressive language symptoms and demonstrate striking word- nding problems in spontaneous speech. They have impaired working memory that results in di culties with repetition of sen- tences and phrases. These patients often ful l criteria for lvPPA but may also have symptoms of poor calculation and evidence of mild apraxia. Patients may develop anxi- ety as a prominent feature of their condition. As with PCA, social behaviour and insight are typically preserved.

The neurological examination is usually normal. Sometimes there may be evidence of mild limb apraxia.

Neuropsychological assessment is particularly helpful in the di erential diagnosis of progressive language disorders. It is important not only to characterize the nature of the language disorder but also to evaluate the extent to which language problems are circumscribed or occur in the context of other cognitive de cits. Language presenta- tions of AD are characterized by a combination of word- nding di culties and working memory impairment. This results in hesitant speech with frequent word- nding pauses and often a tendency to circumlocute in an attempt to describe the searched-for word. Speech is typically grammatically correct but patients may ‘lose the thread’ of what they are saying, leaving sentences un nished. Performance on standard picture-naming tests is typically impaired, with errors consisting of word-retrieval failure (e.g. ‘I know it but I can’t get it’) or descriptions (e.g. ‘what you use when it’s raining’ [umbrella]). Even when Alzheimer’s disease presents as a language syndrome, di culties are rarely totally con ned to the domain of language. Patients typically have a reduced immedi- ate ‘working’ memory as assessed by standard digit and word repetition span tasks. They typically make phonemic errors on repetition tasks, particularly when repeating polysyllabic words or phonologically complex sentences. Assessment of memory is confounded by word- nding and immediate memory di culties. Nevertheless, patients are not typically amnesic. Performance on verbal memory tasks may be compromised by word- nding di culties; moreover, the presence of immediate ‘working’ memory impairment limits patients’ ability to register information. The use of visual recognition memory tasks can be helpful since these do not require assimilating verbal information or producing a verbal response. Visual recognition memory is typically preserved and not generally characterized by accelerated forgetting. Visuoperceptual and visuospatial functions can remain very well preserved although subtle di culties in this domain only

37

CHAPTER 5 Atypical presentations of AD

(A)

(B)

(C)

38

CHAPTER 5 Atypical presentations of AD

Figure 5. Representative examples of MRI and FDG-PET scans in patients with Alzheimer’s disease. Panel A shows left hippocampal atrophy and hypometabolism (red arrows) in a patient with a typical amnesic presentation of AD. Panel B shows left-sided temporoparietal hypometabolism (yellow arrows) in a patient with the language presentation of AD. Panel C shows bi-parietal and occipital atrophy on the MRI and bilateral posterior hypometabolism on the FDG-PET (green arrow) in a patient with posterior cortical atrophy (see also colour plate section).

serve to reinforce the di erential diagnosis of Alzheimer’s disease and patients often develop di culties in this domain as the condition progresses. Certain features would caution against the diagnosis of language Alzheimer’s. Frank agrammatism or apraxia of speech would favour a non-Alzheimer’s non- uent variant primary progressive apha- sia; word- nding di culties together with impaired single-word comprehension and preservation of repetition would favour a non-Alzheimer’s semantic variant primary progressive aphasia.

In group studies, patients with lvPPA or the language presentation of AD have left-sided temporoparietal atrophy and hypometabolism on brain scans. However, at an individual patient level this can be subtle and hard to detect (Figure 5.; see also colour plate section). In patients where there is diagnostic doubt or the syndrome is very mild at presentation clinical follow-up is helpful; patients in whom the language dis- order is due to AD usually go on to develop classical features such as acalculia, apraxia, visuospatial impairment, and amnesia. In patients where the language disorder is due to FTLD, more speci c language features such as agrammatism or apraxia of speech may evolve, and some will develop frontal type behavioural change.

Patients in whom the underlying pathology is thought to be AD are usually o ered cholinesterase inhibitors although, once again, evidence for this practice is lacking.

5.4 Early-onset AD

The majority of AD cases present after the age of 65 years, however, AD still accounts for the greatest proportion of early onset dementia cases. Atypical presentations such as PCA and lvPPA are more common in early-onset AD. Even excluding such syn- dromes, the phenotype of many patients with a young age of onset di ers from that of typical late-onset AD. Whereas late-onset cases are characterized by impaired episodic memory, early-onset cases have relative preservation of this yet show a constellation of temporoparietal cortical de cits. Such patients typically have combinations of lan- guage disturbance, apraxia, visuospatial de cits, and poor working memory. In many ways the phenotype resembles a combination of the features seen in the posterior cortical and language presentations; they demonstrate a greater range of problems without any one being especially severe or prominent. As with PCA and lvPPA there is often a prominent anxiety component to early-onset presentations and this may re ect the preserved insight that patients have. The presence of anxiety may lead to symptoms erroneously being attributed to a mood disorder, which can delay diagnosis.

Neurological examination may be normal although subtle evidence of visuospatial disorientation, apraxia, and myoclonus can be seen. As the illness progresses such physical signs become more prominent.

Cognitive screening instruments typically used in dementia assessments are often heavily weighted towards detecting the episodic memory impairment that is charac- teristic of ‘typical’ late onset AD. Detailed neuropsychological assessment of language, visuospatial, visuoperceptual, praxis, and executive function, in addition to memory, is particularly important in order to characterize the disorder in younger people who present with cognitive symptoms suggestive of a progressive neurodegeneration.

MRI brain scanning may reveal a mild degree of bilateral temporoparietal atrophy with the mesial temporal lobe structures typically spared. Functional imaging can be helpful when the structural scan is normal; posterior cortical hypometabolism or hypoperfusion is frequently seen.

39

CHAPTER 5 Atypical presentations of AD

40

Management involves counselling about the diagnosis, especially as this is a rare con- dition in those under 65 years. There may be an enormous impact on the patient’s ability to work, drive, and care for their dependants. Cholinesterase inhibitors are usu- ally o ered, although once again their utility in this AD subtype is not well understood. Attention must be paid to concomitant mood problems. The support of an early-onset dementia service is invaluable when locally available.

5.6 Frontal variant AD

This is the least well-characterized of the atypical AD presentations and relatively few pathologically con rmed cases are reported. Patients described as having fontal variant AD largely fall in to one of two groups: Many reported cases of ‘frontal AD’ actually describe patients with the typical memory and visuospatial de cits of AD but with additional and prominent executive dysfunction on neuropsychological tests. Rarely, patients with AD pathology may present with a behavioural syndrome akin to fron- totemporal dementia (FTD), lack posterior cortical or memory de cits, and also have frontal changes on brain imaging. Such patients are very challenging to diagnose accu- rately without the use of protein-speci c biomarker technology.

Although evaluation of frontal executive function is an important part of a dementia assessment, it is essential that ndings are interpreted in the context of other cognitive abilities. Neuropsychological tasks of frontal executive function are complex and make demands on multiple cognitive abilities, including language, working memory, and per- ceptuospatial abilities. Impaired performance on such tasks can often occur for reasons other than primary executive dysfunction and probably results in overestimating the prevalence of frontal executive impairment in AD.

5.7 Familial AD

Only –5% of AD cases are associated with an autosomal dominant family history. Mutations in one of three genes are responsible for most of these cases: presenilin  (PSEN), prensenilin 2 (PSEN2), and amyloid precursor protein (APP). Of these, PSEN is the commonest and is associated with a particularly young age of onset. Great phenotypic variability exists between and within families. In addition to typical AD symptoms, patients may have spastic paraparesis, cerebellar ataxia, parkinsonism, and there is a tendency for earlier and more severe myoclonus and seizures than is seen in sporadic AD.

5.8 Conclusion

These atypical presentations of AD represent a broad but partially overlapping spec- trum of cognitive and behavioural symptoms. The cause for such phenotypic variability in AD is currently poorly understood. Recognition and accurate diagnosis of variant forms of AD may be facilitated by protein speci c biomarker technologies, such as amyloid PET and cerebrospinal uid amyloid:tau ratios that are starting to become clinically available. It is hoped that in the future accurate aetiological diagnosis of these atypical syndromes will enable disease speci c treatments to be given to patients.

  

CHAPTER 5 Atypical presentations of AD

References

Crutch S.J., Lehmann M., Schott J.M., et al. Posterior cortical atrophy. Lancet Neurology 202;:70–8.

Henry M.L., Gorno-Tempini M.L. (200) The logopenic variant of primary progressive aphasia. Current Opinion in Neurology 200;23:633–7.

Snowden J.S., Stopford C.S., Julien C., et al. Cognitive phenotypes in Alzheimer’s disease and genetic risk. Cortex 2007;43:835–45.

Stopford C.S., Snowden J.S., Thompson J.C., et al. Variability in cognitive presentation of Alzheimer’s disease. Cortex 2008;44:85–95.

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CHAPTER 5 Atypical presentations of AD

Chapter 6

Diagnosing Alzheimer’s disease in clinical practice
Gunhild Waldemar

Key points

• Diagnosing Alzheimer’s disease (AD) in the early phase may be challenging. The diagnosis is based on characteristic symptoms, typical cognitive impairment, the exclusion of other causes, and the presence of AD biomarkers in uncertain cases

• AD must be di erentiated from cognitive impairment due to depression, delirium, metabolic and toxic conditions, infectious and in ammatory conditions in the brain, substance abuse, and other neurodegenerative or vascular brain diseases

• The basic work-up should include patient and informant interview, physical and neurological examination, cognitive tests, evaluation of psychiatric symptoms and activities of daily living (ADL), a battery of laboratory tests, and structural imaging with cranial computed tomography (CT) or magnetic resonance imaging (MRI) of the brain

• Supplemental investigations may include biomarkers for con rmation of AD pathology and neuronal injury

6. Introduction

Subjective cognitive complaints are frequent in older people in hospital settings, in general practice, and in the general population. While subjective memory impairment may be the rst symptom of a neurodegenerative dementia disorder, there are many other possible causes, and subjective complaints, without other typical signs, may lead to a misdiagnosis of Alzheimer’s disease (AD). In this chapter, patients with cognitive complaints are taken to include not only patients presenting with subjective cognitive complaints but also patients without explicit cognitive complaints in whom caregivers have reported cognitive impairment.

The presence of cognitive complaints should raise the suspicion of a dementia disor- der, but numerous other conditions, including a wide range of neurological, psychiatric, and metabolic disorders may cause reversible, uctuating, persistent or progressive cognitive symptoms.

When planning the diagnostic evaluation of a patient suspected of having AD the diagnostic strategy should include: ) con rming and characterizing the cognitive impairment; 2) checking diagnostic criteria for Alzheimer’s disease; and 3) di erential

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Box 6. ICD-0 criteria for dementia (from WHO, 992)

. There is evidence of the following:

• Decline in memory

• Decline in other cognitive abilities
2. Awareness of the environment is preserved during a period su ciently long to allow the unequivocal demonstration of the symptoms in .
3. Decline in emotional control or motivation, or a change in social behaviour manifest as at least one of the following:

• Emotional lability

• Irritability

• Apathy

• Coarsening of social behavior
4. The symptoms in  should have been present for at least 6 months.
(Data from Geneva: World Health Organization, 992, ‘The ICD-0 Classi cation of Mental and Behavioural Disorders: Diagnostic criteria for research)

diagnosis, ruling out other conditions which could cause cognitive impairment. As for all other conditions, a speci c diagnosis should be established in order for the specialist physician and professional carers to plan the appropriate treatment and care.

Many patients with mild cognitive impairment who do not meet criteria for dementia are referred for diagnostic work-up. With the advent of biomarkers for AD it may be possible to establish an early speci c diagnosis or to con rm an increased risk of pro- gressing to AD dementia. In such cases pre-biomarker counselling and patient consent is essential.

Diagnosing AD may be complex, particularly in the early phase, and is best done in collaboration with multidisciplinary memory clinics (neurologists, psychiatrists, geriatri- cians, neuropsychologists and specialist nurses) where available, and primary healthcare providers.

6.2 Diagnostic criteria
6.2. Dementia and mild cognitive impairment

Traditionally, the diagnosis of AD starts with the diagnosis of a dementia syndrome. Dementia is de ned as signi cant cognitive decline from a previous level of perfor- mance in cognitive domains (such as complex attention, executive functions, learn- ing, memory, language, perceptual motor, or social cognition) which interferes with independence in everyday activities. The ICD-0 (WHO, 992) criteria are shown in Box 6.. Recognizing that a diagnosis of dementia may be associated with stigma, and that the diagnosis of a neurodegenerative disorder may be established in the early phase, the most recent DSM-5 criteria (APA, 203) introduced the new concepts of major and minor neurocognitive disorders. The latter corresponds to the concept of mild cognitive impairment, MCI (Petersen, et al., 999), which is de ned as mild impair- ment of memory (or of another cognitive domain) which does not interfere with activi- ties of daily living.

CHAPTER 6 Diagnosing Alzheimer’s disease

6.2.2 Diagnostic criteria for Alzheimer’s disease

The most recent advances in our understanding of AD and the development of bio- markers have led to a general consensus that AD may be diagnosed prior to the phase where the patients meet criteria for the dementia syndrome, although with the implica- tion that the rate of progression cannot be predicted accurately and that there is no therapy with proven e cacy for very mild stages. Thus, these ethical aspects should be taken into consideration. Furthermore, the availability of advanced biomarker investi- gations varies and biomarkers may not be needed in every case.

Two new sets of diagnostic criteria introduced by the National Institute of Aging (NIA) and Alzheimer’s Association (AA), and the International Working Group (IWG-2), respectively, include the option to increase the certainty of the diagnosis with biomarkers; however, the NIA–AA criteria for AD dementia (McKhann, et al., 20; Box 6.2) and for MCI due to AD (Albert, et al., 20; Box 6.3) allow a diagnosis of AD to be established based on typical clinical features alone (albeit with lower spec- i city). In contrast, the IWG-2 criteria (Dubois, et al., 204; Box 6.4) require in-vivo (biomarker) evidence of Alzheimer’s pathology at any stage. The NIA–AA criteria include typical as well as atypical presentations of AD, while IWG-2 has developed speci c criteria for typical AD (Box 6.4) and for atypical AD. The latter include the following forms:

• Posterior variant of AD with early, predominant, and progressive impairment of either visuoperceptive functions or visual identi cation (occipito-temporal) or visuospatial functions, aspects of Gerstman or Balint syndromes, limb apraxia, or neglect (bi-parietal variant).

Box 6.2 Summary of NIA-AA criteria for dementia due to AD, probable AD

Probable AD dementia, core clinical criteria

General criteria for dementia and the following characteristics (A–D):

A. B.

C.

D.

Insidious onset
History of worsening of cognition by report or observation

Initial and most prominent are evident on history and examination:
• Amnestic presentation OR
• Non-amnestic presentation (with de cits in language, visuospatial, executive

functions)
No other CNS disease/systemic disorders known to cause cognitive impairment.

Probable AD dementia with increased level of certainty

• Probable AD with documented decline or
• Probable AD with evidence of causative genetic mutation (in APP, PSEN, or PSEN2)

Probable AD dementia with evidence of AD pathophysiology

• Positive Aβ biomarker (CSF-Aβ-42 or amyloid-PET)
• Positive biomarker for neuronal injury (CSF-tau or -p-tau; FDG-PET; or medial temporal

lobe atrophy on structural MRI)

The presence of both biomarker criteria indicates a high likelihood that AD pathophysiol- ogy is the underlying cause.

(Adapted from Alzheimer’s & Dementia, 7, McKhann G.M., et al. ‘The 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’, 263–9. Copyright (20) with permission from Elsevier.)

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CHAPTER 6 Diagnosing Alzheimer’s disease

Box 6.3 Summary of NIA-AA criteria for MCI due to AD

Core clinical criteria:

A. Concern regarding a change in cognition

B. Impairment in one or more cognitive domains (typically including episodic memory)

C. Preservation of independence in functional activities D. Not demented

MCI consistent with AD pathophysiology:

• Other causes ruled out
• Evidence of progression
• History of AD genetic factors, where relevant

Biomarkers indicating a high likelihood that the MCI syndrome is due to AD:

• Positive Aβ biomarker (CSF-Aβ-42 or amyloid-PET)

• Positive biomarker for neuronal injury (CSF-tau or -p-tau; FDG-PET; or medial temporal
lobe atrophy on structural MRI)
(Adapted from Alzheimer’s & Dementia, 7, Albert M.S, et al., ‘The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease’, pp. 270–9. Copyright (20) with permission from Elsevier)

46

Box 6.4 Summary of IWG-2 research diagnostic criteria for typical AD

A and B must be met and other potential causes of cognitive impairment excluded.
A. Speci c clinical phenotype
Early and signi cant episodic memory impairment (isolated or associated with other cogni-

tive or behavioural changes) that includes the following features:

• Gradual and progressive change reported by patient or informant over more than six months

• Objective evidence of and amnestic syndrome (episodic memory test)
B. In-vivo evidence of Alzheimer’s pathology (one of the following):

a. Decreased Aβ-42 together with increased T-tau or P-tau in CSF b. Increased tracer retention on amyloid-PET
c. Mutation present (PSEN, PSEN2, APP)

Adapted from The Lancet Neurology, 3, Dubois B., et al., ‘Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria’, 64–29. Copyright (204), with permission from Elsevier)

CHAPTER 6 Diagnosing Alzheimer’s disease

• Logopenic variant of AD with early, predominant, and progressive impairment of single-word retrieval and repetition of sentences

• Frontal variant of AD with early, predominant and progressive behavioural changes including apathy, disinhibition, or executive dysfunction

• Down’s syndrome variant of AD

 

6.3 Di erentiating AD from other causes

of cognitive impairment

Cognitive impairment may occur in a wide range of neurological, psychiatric, and medi- cal conditions, and the di erential diagnosis may be di cult, particularly in patients with mild symptoms. Based on the medical history and the investigations described in the following paragraph, AD should be di erentiated from:

A. Other CNS disorders known to cause cognitive impairment, for example:

• Frontotemporal dementia (FTD)

• Dementia with Lewy bodies

• Vascular dementia

• Parkinson’s disease and Parkinson Plus syndromes

• Huntington’s disease

• Space-occupying lesions

• Normal pressure hydrocephalus

• Neuroinfections

• In ammatory brain disorders.

B. Systemic conditions known to cause cognitive impairment (e.g. hyper- or hypothyreosis, hypercalcemia).

C. Psychiatric disorders known to cause cognitive impairment (e.g. depression, delirium, schizophrenia). Substance abuse (alcohol, drugs).

6.3. Reversible conditions
Particular attention should be paid to identify potentially reversible conditions in

patients presenting with cognitive disorders (see Box 6.5).

6.3.2 Red ags
Particular attention should be paid to the following signs which should lead to a search

for alternative causes of the cognitive symptoms (Kondziella and Waldemar, 203): • rapid progression
• pronounced uctuations

Box 6.5 Potentially reversible causes of cognitive symptoms

Depression
Delirium
Normal pressure hydrocephalus
Meningeoma, subdural hematoma, and other space-occupying intracranial lesions Metabolic conditions (e.g. hypo- and hyperthyroidism, hypercalcemia)
Epilepsy (seizures)
Infectious diseases (e.g. neurosyphilis, neuroborreliosis)
Drug or alcohol abuse
Side-e ects of prescribed drugs

(Adapted from Journal of Neurology, Neurosurgery & Psychiatry, A Hejl, et al., 73, ‘Potentially reversible conditions in 000 consecutive memory clinic patients’. Copyright (2002) with permission from BMJ Publishing Group Ltd)

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CHAPTER 6 Diagnosing Alzheimer’s disease

48

• other neurological signs early in the course of the disease (extrapyramidal signs, focal neurological signs, hallucinations)

• considerable white matter or vascular lesions on MRI.
6.4 Diagnostic procedures: basic work-up

The diagnostic evaluation programme requires a multidisciplinary team and should be individually tailored according to the clinical presentation of the patient.

Evidence-based guidelines for the specialist physician in diagnostic evaluation of Alzheimer’s disease and other dementias have been published by the European Federation of Neurological Societies (EFNS) (Waldemar, et al., 2007; Hort, et al., 200), and by several national authorities. A checklist, based on the most recent EFNS guide- lines (Hort, et al., 200) is presented in Box 6.7.

6.4. Taking the history

The clinical history is a cornerstone of medical practice and serves to focus the exami- nation and investigations for reaching the speci c correct diagnosis. In addition, taking the history also serves to achieve information about everyday life, the social conse- quences of the symptoms, and any relevant legal issues associated with the cognitive impairment. When taking the history, patients with an immediate need for medical or social intervention should be identi ed. The interview also should address caregiver burden and needs. Due both to the presence of cognitive de cit and to the possibility of a person’s inability to recognize their own di culties, it is important to obtain a his- tory from an independent informant as well as from the patient.

During the interview with the patient and the caregiver, the physician will already begin his objective assessment of signs and symptoms. For instance, it is important to pay attention to assessing mood, behaviour, vocabulary, verbal comprehension, and insight. The ‘head-turning sign’ describes the phenomenon where the patient, when confronted with a question from the physician, ‘automatically’ turns his/her head towards the caregiver, as if asking the caregiver to reply.

The interview starts with making the patient feel comfortable—for instance, by talking about his/her background, occupation, and family, or other topics which do not directly confront the patient with the current cognitive impairment. By asking the patient about all or most relevant information concerning past and current symptoms, the physician will get an impression about cognitive function and level of insight.

Following the interview with the patient, the clinical history should be supplemented by an independent informant, where available. Informant reports on cognitive func- tions and their in uence on everyday life may provide an important supplement to brief cognitive screening tests for the detection of dementia. Information about prior diseases, medication, etc., can be checked and supplemented. The caregiver can often contribute with information about the current condition and symptoms, about the con- sequences for activities of daily living (ADL) and about any behavioural and psychologi- cal symptoms. The caregiver has often noticed symptoms in the patient for a very long time, and can describe changes from earlier life. There are, however, some pitfalls in using the caregiver interview to assess the medical history. The result depends on the quantity and quality of the relationship between the patient and the caregiver, and on the emotional state of the caregiver, and it is worth noting that a signi cant number of patients do not have a reliable caregiver. The caregiver interview should also contain

CHAPTER 6 Diagnosing Alzheimer’s disease

Box 6.6 Checklist for taking the history of patients with cognitive complaints

The mode of onset and pattern of progression
The cognitive symptoms (memory, language, insight, executive functions, visuospatial

abilities, perception, praxis, insight)
The impact on ADL, including competency in driving and handling nances
Associated behavioural and psychological symptoms (apathy, agitation, depression, anxi-

ety, sleep disturbance, delusions, misidenti cations, hallucinations, illusions, disinhibition and euphoria, hyperorality, socially inappropriate behaviour, and emotional lability)

Other neurological symptoms (e.g. gait di culty, urinary incontinence, impairment of vision, paresis, speech di culties, tremor or other involuntary movements, sleep disturbance)

Past and current medical history, including any history of drug or alcohol abuse Cardiovascular risk factors
Current comorbidities
Medication

Family history
Educational history
Social network and the use of community services Health status and quality of life of the caregiver

an assessment on the consequences for the caregiver of the cognitive impairment in the patient.

A checklist for taking the history is presented in Box 6.6.

6.4.2 Physical and neurological examination

The neurological examination in early AD is unremarkable apart from the cognitive impairment, however, for many of the other dementia disorders (e.g. dementia with Lewy bodies and prion diseases) the presence of additional neurological features such as an extra pyramidal syndrome or myoclonus is a key component of the diagnostic criteria. Moreover, many of the disorders in which dementia is part of a broader range of neurological dysfunction or in which abnormalities on physical examination such as organomegaly occur, the examination is critical in the diagnostic process. Furthermore, the general physical examination may reveal treatable comorbidities. Thus, a general neurological and physical examination should be performed on all patients presenting with dementia.

6.4.3 Cognitive tests

Cognitive assessment is central to diagnosis and management of dementias and should be performed in all patients. Quantitative neuropsychological testing, ideally performed by someone trained in neuropsychology, should be considered in patients with question- able, prodromal, mild, or moderate dementia. The specialist physician should include a global cognitive measure (e.g. the Mini-Mental State Examination (MMSE), and in addi- tion more detailed ‘bed-side’ testing of the main cognitive domains including memory, executive functions, and instrumental functions (Kondziella and Waldemar, 203). The characteristic nding in patients with early AD is signi cantly impaired episodic memory on testing. This generally consists of recall de cit that does not improve signi cantly or does not normalize with cueing or recognition testing. The episodic memory impairment can be isolated or associated with other cognitive changes at the onset of AD or as AD advances. In atypical presentations of AD, other cognitive de cits may prevail (Box 6.2).

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CHAPTER 6 Diagnosing Alzheimer’s disease

Box 6.7 Checklist for diagnostic work-up

Basic investigations

Taking the history from the patient and an informant Physical and neurological examination
Cognitive tests
Assessment of behavioural and psychiatric symptoms Assessment of activities of daily living

Assessment of comorbidity
Laboratory testing (folate, vitamin B2 complete blood cell count, calcium, glucose, renal

and liver function tests, and thyroid stimulating hormone); more extensive tests will often

be required, e.g. and serological tests for syphilis, HIV, and borrelia, in individual cases Non-contrast cranial CT (or MRI)

Supplemental investigations

MRI
FDG-PET
Amyloid-PET
Lumbar puncture: CSF to be analyzed for cell count, protein, glucose, bands, and Alzheimer

biomarkers: β-amyloid, tau, phospho-tau EEG

Genetic (counselling and) testing in selected patients with a family history

50

CHAPTER 6 Diagnosing Alzheimer’s disease

6.4.4 Assessment of behavioural and psychiatric symptoms (BPSD)

Assessment of BPSD is essential for both diagnosis and management and should be performed in all patients. Symptoms should be actively enquired about from the patient and a closely involved carer using appropriate rating scales, for instance the Neuropsychiatric Inventory (NPI) or the Behave-AD. Comorbidity should always be considered as a possible cause.

6.4.5 Assessment of activities of daily living (ADL)

Impairment of ADL due to cognitive impairment is an essential part of the criteria for dementia and should be assessed in the diagnostic evaluation. Two classical elds measured are basic or general (such as eating, dressing, etc.) and instrumental activities (such as the use of devices, shopping). A semi-structured interview from the caregiver is the most practical way to obtain relevant information, and a panel of validated scales are available, for instance the Alzheimer Disease Cooperative Study (ADCS) ADL Scale, the Functional Activities Questionnaire (FAQ), and the Disability Assessment for Dementia (DAD).

6.4.6 Assessment of comorbidity

There is a strong association between medical comorbidity and cognitive status in AD, and optimal management of medical illnesses may o er potential to improve cognition. Therefore, assessment of co-morbidity is important in the evaluation of the patient with dementia, and should be performed not only at the time of diagnosis but through- out the course of the disease, with particular attention to episodes of sudden worsen- ing of cognitive or behavioural symptoms.

6.4.7 Laboratory testing

Laboratory tests including folate, vitamin B2, complete blood cell count, calcium, glu- cose, renal and liver function tests, and thyroid-stimulating hormone are usually recom- mended in order to screen for metabolic causes of cognitive impairment and to identify comorbidity. More extensive tests may be required (e.g. serological tests for syphilis, HIV, and borrelia) in individual cases.

6.4.8 Structural brain imaging with CT or MRI

Structural imaging using non-contrast computed tomography (CT) or magnetic reso- nance imaging (MRI) should be used in the evaluation of every patient suspected of dementia and serves two purposes: exclusion of other disease and inclusion of speci c ndings for AD. Non-contrast CT can be used to identify surgically treatable lesions and major vascular disease. In patients with AD, CT often will show generalized atrophy. Leucoencephalopathy and single lacunar infarcts do not preclude a diagnosis of AD. The presence of signi cant white matter lesions and vascular lesions should be evalu- ated in the context of the clinical symptoms of the patients and should prompt for fur- ther investigations, in order to identify patients with cardiovascular risk factors, vascular dementia, and other conditions. MRI is more sensitive to subtle vascular changes and to changes which may indicate other speci c conditions (e.g. FTD, multiple sclerosis).

6.4.9 Supplemental investigations

6.4.9. Lumbar puncture

Cerebrospinal uid (CSF) analysis with routine cell count, protein, glucose, and protein electrophoresis is recommended in patients with a clinical suspicion of certain diseases (vasculitis, in ammatory, haematologic, or demyelinating disease), and in patients with atypical clinical presentations. In addition, CSF biomarkers for AD (Aβ-42 indicating AD pathophysiology and total tau, and phospho-tau indicating neuronal injury) may be added in the diagnostic work-up of patients in order to increase the likelihood that AD is the underlying cause, as advised in the diagnostic criteria (Boxes 6.2–6.4). In patients with AD, Aβ-42 is reduced and tau and phospho-tau are elevated. Analysis of 4-3-3 protein may be added when Creutzfeld-Jakob’s disease is suspected.

6.4.9.2 MRI

If a structural MRI was not already part of the basic work-up it should be considered in atypical cases to exclude causes other than AD, for reasons outlined. In addition, MRI may serve as biomarker for neuronal injury in AD by identifying temporal lobe atrophy. Thus, to increase the speci city of the clinical diagnosis, MRI (with a protocol including T, T2, and FLAIR sequences) may be used. The hippocampal volume may be meas- ured using a variety of tracing techniques or linear or visual measurements.

6.4.9.3 PET (regional glucose metabolism)

Assessment of glucose metabolism performed with 8F-FDG-PET may be added to increase the certainty of the AD diagnosis, as described in the diagnostic criteria, A reduction glucose metabolism in parieto-temporal areas indicating neuronal injury, is the most characteristic nding in AD.

6.4.9.4 Amyloid positron emission tomography (PET)

PET imaging with amyloid tracers, including C-labelled Pittsburgh compound B (PiB) and 8F-labelled compounds provides important information about the extent of Aβ

51

CHAPTER 6 Diagnosing Alzheimer’s disease

52

neuritic plaque burden in the brain and may be added when there is a need to increase the certainty of the AD diagnosis as indicated in the diagnostic criteria. However, a pos- itive amyloid PET, also frequently observed in asymptomatic elderly individuals, should not lead to a diagnosis of AD in the absence of clinical core symptoms.

6.4.9.5 Electroencephalography (EEG)

The EEG may be a useful adjunct in diagnostic evaluation of patients with cognitive impairment, and should be included in the diagnostic work up of patients suspected of having Creutzfeldt–Jakob disease or transient epileptic amnesia. In patients with AD, there is a generalized slowing of background rhythm.

6.4.9.6 Genetic (counselling and) testing in selected patients with a family history

Screening for known pathogenic mutations (APP, PSEN, PSEN2) causing AD can be undertaken in patients with appropriate phenotype or a family history of an autosomal dominant dementia. This should only be undertaken in specialist centres with appropri- ate counselling of the patient and family caregivers, and with consent.

6.4.9.7 Other investigations

Single photon emission computed tomography (SPECT) using iso upane (23I), also known as dopamine transporter scanning (DAT scan), can assist in the di erential diag- nosis of AD and dementia with Lewy bodies and parkinsonian disorders. Brain biopsy may be indicated where a treatable disease cannot be excluded by other means.

6.5 Conclusions

When planning the diagnostic evaluation of a patient suspected of having AD, the diag- nostic strategy should include: ) con rming and characterizing the cognitive impair- ment with particular attention to typical (episodic memory impairment) and atypical presentations of AD; 2) checking the diagnostic criteria for AD and considering bio- markers to document AD pathology; and 3) di erential diagnosis: ruling out other con- ditions which could cause cognitive impairment. With the advent of CSF and imaging biomarkers for AD, it may be possible to establish an early speci c diagnosis, or to con rm an increased risk of progressing to AD dementia in patients with mild cognitive symptoms. In such cases pre-biomarker counselling and patient consent is essential.

AD must be di erentiated from cognitive impairment due to depression, delirium, metabolic conditions, substance abuse, and other neurodegenerative or vascular brain diseases. The basic work-up should include patient and informant interview, physical and neurological examination, cognitive tests, evaluation of psychiatric symptoms and ADL, a battery of laboratory tests, and CT (or MRI) of the brain. Supplemental inves- tigations will often be needed, in particular for an early diagnosis of AD based on biomarkers of amyloid pathology and neuronal injury.

References

Albert M.S., DeKosky S.T., Dickson D., et al. The diagnosis of mild cognitive 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 and Dementia 20;7:270–9.

CHAPTER 6 Diagnosing Alzheimer’s disease

American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 5th edn. Washington, DC: APA, 203.

Dubois B., Feldman H.H., Jacova C., et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurology 204;3:64–29.

Hejl A., Hogh P., and Waldemar G. Potentially reversible conditions in 000 consecutive memory clinic patients. Journal of Neurology, Neurosurgery, and Psychiatry 2002;73:390–4.

Hort J., O’Brien J.T., Gainotti G., et al. EFNS Scientist Panel on Dementia. EFNS guidelines for the diagnosis and management of Alzheimer’s disease. European Journal of Neurology 200;7:236–48.

Kondziella D. and Waldemar G. Neurology at the Bedside. London: Springer, 203.

McKhann G.M., Knopman D.S., Chertkow H., et al. The 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 and Dementia 20;5;7:263–9.

Waldemar G., Dubois B., Emre M., et al. Recommendations for the diagnosis and management of Alzheimer’s disease and other disorders associated with dementia: EFNS guideline. European Journal of Neurology 2007;4:e–26.

World Health Organization. The ICD-0 classi cation of mental and behavioural disorders. Clinical descriptions and diagnostic guidelines. Geneva: WHO, 992.

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CHAPTER 6 Diagnosing Alzheimer’s disease

Chapter 7

Disclosing the diagnosis of Alzheimer’s disease Anne A. Fetherston and Julian C. Hughes

Key points

• Diagnostic disclosure of Alzheimer’s disease is generally accepted to be good practice

• There are important factors for clinicians to consider when preparing to impart such a serious diagnosis

• Professionals must be attuned to what the person and family require from them

7. Introduction

The disclosure of a serious, potentially life-limiting diagnosis such as Alzheimer’s disease (AD) is extremely challenging. We shall highlight salient points for clinicians, particularly from an ethical perspective, and suggest ways in which di culties might be approached. We discuss the purpose of disclosure to patients, which is generally desirable, issues around uncertainty, and the question of control.

7.2 Why disclose at all?

Nora is an 87-year-old lady presenting with cognitive and behavioural symptoms of moderate AD. She is living alone but has daily support from her two sons. They are keen not to inform her of the diagnosis lest it frighten her, and they argue that she will not be able to remember the information anyway. Her sons are struggling to cope and want more input from social services. Nora, however, loves her home and wants to stay in it, but she objects to outside help.

Clinicians and family members worry about disclosing the diagnosis of dementia or AD. There are several possible reasons for this: concerns about causing distress, pri- marily to the patient, but also to relatives or carers; worries about social stigma; and the thought that it might cause unnecessary upset if the person does not retain the information anyway. Consequently, professionals may err on the side of giving too little information.

Despite these concerns, opinion nowadays tends to suggest there is a de nite duty to disclose a diagnosis of AD, which re ects the right of the person a ected to know, unless there is a compelling justi cation for not doing so (NICE–SCIE, 2007, p. 24; Nu eld Council on Bioethics, 2009, p. 42).

55

Table 7. Summary of disc et al., 2008)

Category

losure behaviours (adapted from Lecouturier,

Sub-category

Preparing for disclosure

Plan disclosure meeting Arrange post-diagnosis support Establish rapport
Prepare the patient
Elicit preferences for disclosure

Integrating family members

Identify and involve appropriate family members Manage di ering information needs of patient and family Avoid collusion with family members

Exploring the patient’s perspective

Explore patient ideas Elicit patient expectations

Disclosing the diagnosis

Tailor information to patient preferences and ideas Check understanding
Explore the meaning(s) of the diagnosis
Discuss prognosis

Responding to patient’s reactions

Explore the patient’s emotional response
Elicit and address patient questions and concerns

Focusing on quality of life and well-being

Foster hope
Explore coping strategies

Planning for the future

Clarify follow-up arrangements
Discuss support services available Negotiate management plan
Discuss prevention and health promotion

Communicating e ectively

Develop rapport
Use appropriate verbal and non-verbal communication Use active listening skills
Involve the patient
Structure and signpost the consultation
Consider issues of anti-discriminatory practice

56

The literature suggests that although there is a wide range of attitudes and values concerning diagnostic transparency (Bamford et al., 2004), patients mostly favour dis- closure of the diagnosis (van den Dungen et al., 204). In a situation such as Nora’s, careful negotiation with her sons will be required, which means their views must be heard and understood. Part of their objection to the disclosure may stem from general stress so attempts should be made to support them. For Nora herself, gentle explana- tion and gauging of her current insight and understanding will assist the professional to convey information in the right way. Indeed, Nora may have some insight and she may be searching for answers. The more she can understand, the more likely she is to engage with those trying to help.

Table 7. sets out the di erent behaviours which it might be necessary to consider in the complex task of disclosing a diagnosis of dementia.

CHAPTER 7 Disclosing the diagnosis of AD

 

7.3 Uncertainty
7.3. Diagnostic uncertainty

Despite advances in the various techniques used to diagnose AD, there is still an ele- ment of uncertainty. The literature suggests diagnostic sensitivities for AD of between 4 per cent and 00 per cent (median 87 per cent) and speci cities between 37 per cent and 00 per cent (median 58 per cent) (Beach, et al., 200). Thus in some centres diag- nostic certainty is good, though not in all. Further uncertainty is added by diagnoses of pre-clinical AD: what, for instance, does the diagnosis of mild cognitive impairment (MCI) mean for the individual? Potentially, it plunges people into an uncertainty some clinicians, patients, and families would wish to avoid. Clearly there are advantages to making an early diagnosis, particularly in terms of planning for future care, but ques- tions can be raised both about when information should be given and about how to convey any lack of certainty.

7.3.2 When to disclose

There may well be times when it is too early for someone to hear their diagnosis. The decision when to disclose must be guided by the individual situation; professional judge- ment is required to determine what will be acceptable. Some patients will be desperate to hear as soon as possible; others will have poor insight and the presentation to services may be driven more by relatives. In either case, a favoured formulation now is to say the diagnosis should be ‘timely’. The Nu eld Council on Bioethics concluded as follows:

It seems likely that a ‘timely’ diagnosis for most people will be the point when the cognitive and other changes they are experiencing begin to have a signi cant e ect on their lives or on the lives of those close to them. (Nu eld Council on Bioethics, 2009; p. 43)

Patients have a right to refuse input and information. Such decisions should be respected. George is a 72-year-old man with a previous diagnosis of mild cognitive impairment but who has now progressed to AD. He is widowed and lives alone but has a daughter who lives locally. He is unwilling to allow the diagnosis to be disclosed to her, does not want any treatment or input from services, and wants to remain completely independ-

ent ‘until the end’.
At some point George’s daughter will need to know the diagnosis. This would have

to be judged by considering George’s best interests if and when he is no longer able to make decisions for himself (Nu eld Council on Bioethics, 2009, p. 45). On the whole, we would agree with the recommendation that

professionals responsible for communicating a diagnosis of dementia should actively encourage the person with dementia to share this information with their family, making clear that the diag- nosis is of importance to those providing informal care and support, as well as to the individual concerned. (Nu eld Council on Bioethics 2009, p. 45)

This may require time and repeated appointments with familiar sta so that the person builds up therapeutic trust. It might be that as trust increases, diagnostic disclosure becomes easier, the extent or pace of disclosure being led by the person.

7.3.3 Prognostic uncertainty—how long have I got?

Diagnostic disclosure inevitably involves giving information about disease progression. This is fraught with uncertainty too: an accurate prognosis in AD being notoriously dif- cult. Where the literature suggests a life expectancy of 3–0 years post-diagnosis (van den Dungen, et al., 2009), most clinicians know cases where the person has died rapidly

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CHAPTER 7 Disclosing the diagnosis of AD

58

or survived much longer. Yet, uncertainty is di cult to tolerate. Professionals can only be honest and look at people individually.

There may be a temptation to limit the information given with the intention of help- ing those concerned not to lose hope. Albeit well-meaning, this is nonetheless a rather paternalistic view. The crucial factor throughout the process of diagnosis and disclosure is to promote and respect individual autonomy by giving the individual the information available in a manner which accords with the wishes and needs of the person and of his or her family. This emphasizes the importance of good communication. Part of the aim here is to support the person’s ability to make decisions (United Nations, 2006, Art. 2, s. 3).

7.4 Control

Professionals must be attuned to the person and family who are at the heart of the con- sultation and who should, ideally, be given control. How much information the patient requires must be gauged at the time. As well as the risk of giving too little information there is a risk of ‘information overload’, particularly at the beginning of the process of giving a diagnosis. This is an extremely daunting and potentially confusing time.

Professionals must also consider whether information will be understood and retained by the patient, which emphasizes the need for family members to be involved. Information might need to be provided in several forms, including in writing and cer- tainly in the rst language of the patient.

The counsel of perfection, therefore, is to support the person’s autonomous decision-making, but there will be situations in which decision-making capacity, or competence, will need to be assessed formally in accordance with the legislation that governs the particular jurisdiction. Local laws and guidelines will determine how people like Nora and George should be supported in their decision-making. Meanwhile, the important role of family carers must not be overlooked.

7.5 After the diagnosis

Clinicians naturally worry about how patients will react to a diagnosis. There are many possibilities, from elements of a grief reaction to worries about the risk of suicide and self-harm. The risk of suicide in AD is generally considered to be low, however, speci c factors, such as high functional levels and previous suicide attempts (Barak and Aizenberg, 2002) suggest the need for increased vigilance in those caring for the patient. Regular support for the patient and family is essential, including follow-up and screen- ing for signi cant comorbid psychiatric symptoms. The worry about suicide should not necessarily prevent the disclosure of a diagnosis but it should temper the manner in which the diagnosis is given.

Post-diagnostic support is vital and often focuses on future care planning. Patients such as Nora and George may feel helpless when faced with a seemingly bleak progno- sis. Regaining some control—by making advance decisions, for example, or by consid- ering the appointment of an attorney to make decisions for oneself in the future—can be helpful.

 

CHAPTER 7 Disclosing the diagnosis of AD

 

7.6 Conclusion

Giving information about the diagnosis to patients is now generally accepted to be good practice, but this should be tailored to the understanding and needs of the person concerned. Questions about diagnostic certainty, timing of diagnosis, and the amount of information to impart have to be faced.

The truth is that there is no one-size- ts-all solution. Careful communication is key. Honesty, with clear (and often repeated) explanations, is the best way to negotiate di culties. Uncertainties can be shared. The person and his or her family must be sup- ported. Appropriate follow-up, screening for signi cant psychological comorbidities, continuity of care, and signposting regarding future care planning are essential to ensure that the disclosure of the diagnosis of a condition such as AD is made in an optimal fashion.

References

Bamford C., Lamont S., Eccles M., et al. Disclosing a diagnosis of dementia: a systematic review. International Journal of Geriatric Psychiatry 2004;9:5–69.

Barak Y. and Aizenberg D. Suicide amongst Alzheimer’s disease patients: a 0-year survey. Dementia and Geriatric Cognitive Disorders 2002;4:0–3.

Beach T., Monsell S.E., Phillips L.E., et al. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer’s Disease Centers, 2005–200. Journal Neuropathology and Experimental Neurology 202;7:266–73.

Charante E., van der Horst H., and van Hout H. Preferences regarding disclosure of a diagnosis of dementia: a systematic review. International Psychogeriatrics 204;26:603–8.

Lecouturier J., Bamford C., Hughes J.C., et al. Appropriate disclosure of a diagnosis of demen- tia: identifying the key behaviours of ‘best practice’. BMC Health Services Research 2008;8(95):4.

National Institute for Health and Clinical Excellence and Social Care Institute for Excellence (NICE–SCIE). A NICESCIE guideline on supporting people with dementia and their car- ers in health and social care. National Clinical Practice Guideline Number 42. Leicester and London: The British Psychological Society and Gaskill (The Royal College of Psychiatrists), 2007; p. 24.

Nu eld Council on Bioethics. Dementia: ethical issues. London: Nu eld Council on Bioethics, 2009.

United Nations. UN Convention on the rights of persons with disabilities, A/RES/6/06. New York, NT, United Nations, 2006. Available via: <http://www.un.org/disabilities/convention/ conventionfull.shtml> (last accessed 25 April 205).

van den Dungen P., van Kuijk L., van Marwijk H., et al. Life expectancy in Alzheimer’s disease. Archives of Gerontology and Geriatrics 2009;49 (Suppl ):237–43.

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CHAPTER 7 Disclosing the diagnosis of AD

Chapter 8

Pharmacological treatment of Alzheimer’s disease
Krishna Chinthapalli

Key points

• Pharmacological treatment of Alzheimer’s disease is an important part of management of the condition

• There are only four drugs available for treatment of the disease and none halt the disease process

• The choice of drug depends on route of administration, adverse e ects, and medical comorbidities

• There is intensive research into potential treatments, especially those that may stop the underlying disease process

8. Introduction

Pharmacological treatment plays just one part in the management of people with Alzheimer’s disease (AD). Only four drugs are licensed for treatment of AD (see Table 8.), despite over 00 being studied, and even these four do not reverse the disease. At the time of diagnosis, non-pharmacological measures are just as important and may include advice on issues such as driving, nancial help, social services, and advance directives. Drugs have the power to cause harm as well as bene t, especially in people over 65 years in whom 95 per cent of AD occurs. Healthcare professionals should remember this and be vigilant for drugs that could worsen cognitive or behav- ioural symptoms, for example anticholinergic drugs for urinary incontinence or benzo- diazepines for insomnia. Current European guidelines for treatment are summarized in Box 8..

8.2 Outcomes in Alzheimer’s disease

By de nition, AD a ects not just memory but other cognitive and behavioural domains. In addition, it can a ect mood, quality of life, activities of daily living, and care or sup- port needed for a person.

Early trials predominantly focused on cognitive outcomes, especially the MMSE. The MMSE is easy to administer but it is known to lack sensitivity in early dementia and is poor at assessing particular cognitive domains a ected in some dementias (such as visu- ospatial disturbance in posterior cortical atrophy). Also, it is now subject to apparent

61

                                       

62

                                    

   

Table 8. Here Overview of drugs for Alzheimer’s Disease

Mechanism

Acetylcholinesterase inhibitor

NMDA receptor antagonist

Indications
Routes of administration

Mild to severe AD

Moderate to severe AD

Starting dose
Titration
Maximum dose Common adverse e ects

5 mg daily
5 mg per month
0 mg daily
Gastrointestinal: Nausea, vomiting, diarrhoea, anorexia, weight loss Headache, dizziness

Constipation Headache Dizziness

Donepezil

Galantamine

Rivastigmine

Memantine

Tablet Orodispersible tablet

Tablet
Liquid
Modi ed release tablet

Capsule Liquid

Transdermal patch

Tablet Liquid

4 mg twice daily 8 mg per month 2 mg twice daily

.5 mg twice daily 3 mg per 2 weeks 6 mg twice daily

4.6 mg daily
~4 mg per month 3.3 mg daily

5 mg daily
5 mg per week 20 mg daily

CHAPTER 8 Pharmacological treatment of AD

Box 8. European Federation of the Neurological Societies (EFNS) guidelines for the pharmacological management of Alzheimer’s disease

An EFNS taskforce produced international guidelines for Alzheimer’s disease in 200 (Hort, et al., 200). These are summarised below. Current local and national guidelines should also be reviewed before considering pharmacological management.

• There is insu cient evidence to support the use of any drugs purely for the primary pre-
vention of dementia or as treatments for those with mild cognitive impairment.

• In patients with AD, treatment with donepezil, galantamine, or rivastigmine should be considered at the time of diagnosis, taking into account expected therapeutic bene ts and potential safety issues. Bene ts on cognitive and non-cognitive symptoms have been
demonstrated in those with mild, moderate, and severe disease.

• In patients with moderate to severe AD, treatment with memantine should be considered,
taking into account expected therapeutic bene ts and potential safety issues. Bene ts on cognitive and non-cognitive symptoms are apparent, some non-cognitive symptoms (agi- tation, delusions) may respond better than others.

• Realistic expectations for treatment e ects and potential side-e ects should be discussed with the patient and caregivers.

• Regular patient follow-up, which should include scales like the (Mini-Mental State Examination) MMSE to monitor response to treatment and disease progression and should be an integral part of management.

• Aspirin should not be used as a treatment for AD, although it can be used in those with AD who also have other indications for its use (e.g. to prevent cardiovascular events).
Reproduced from European Journal of Neurology, J Hort, et al., EFNS guidelines for the diagnosis and management of Alzheimer’s disease. Copyright (200) with permission from John Wiley and Sons.

copyright enforced by an American organization. Alternatives include the Montreal Cognitive Assessment (MOCA; <http://www.mocatest.org&gt;) and the more detailed Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-COG), scored from 0 (best) to 70 (worst). In people with severe AD, the Severe Impairment Battery (SIB) is a more useful cognitive screening tool and is used in most studies of this sub-population.

Assessment of global function is more di cult but trials have used a number of tools to look at this. All incorporate cognitive function as one component. In the Clinical Dementia Rating scale–sum of boxes (CDRSB) assessment, half of the score is for community a airs, home and hobbies, and personal care. A common problem is the subjective nature of assigning a score to such items and the CDR–SB is relatively crude. Scoring in CDR–SB is from 0–8 with lower scores better. The Clinicians Global Impression of Change (CIBIC-Plus) measures cognition, behaviour, and function with input from carers and is scored –3 for overall improvement, 4 for no change, and 5–7 for worsening. The CIBIC-Plus scale is usually dichotomized to outcomes of ‘worsening or no improvement’ or ‘improvement’.

For each drug listed, any outcomes reported are statistically signi cant compared to placebo unless otherwise stated.

Trials in AD have frequently been too short for a neurodegenerative disorder pro- gressing over years. The longest trials have followed subjects for up to ve years and have usually been open label, with the consequent biases.

One controversial issue has been the health economics of pharmacological treat- ment of AD and studies have looked at the cost of care, stress in carers, or number

63

CHAPTER 8 Pharmacological treatment of AD

64

of hospitalizations and residential care placements. In most countries, all four drugs (except rivastigmine patches) came o patent by 203 and the economic cost dropped markedly after generic versions were introduced.

8.3 Cholinergic hypothesis and acetylcholinesterase inhibitors

In the 980s, the cholinergic hypothesis proposed that acetylcholine depletion in the brain caused AD. The nucleus basalis is rich in neurons using acetylcholine as a neuro- transmitter and projects from the forebrain to most of the cerebral cortex. The nucleus seems to be activated when a new stimulus is presented and so it is suspected to be involved in attention and memory. In AD, the nucleus is known to degenerate with loss of acetylcholine and cholinergic neurons.

The e ect of acetylcholine is ended with breakdown by acetylcholinesterase, an enzyme that is found at the synapses of cholinergic neurons. Reversible acetylcholinest- erase inhibitors, also called anticholinesterases, increase the e ect of acetylcholine by acting on this enzyme.

Acetylcholine is not just common in the central nervous system: it is the main neuro- transmitter used by the parasympathetic nervous system, which decreases heart rate and stimulates the gastrointestinal tract and bladder. Acetylcholinesterase is present here too and a related enzyme, butyrylcholinesterase, is found in the liver. The most common adverse e ects of acetylcholinesterase inhibition can be explained by para- sympathetic activation and include nausea, vomiting, and diarrhoea. Another important adverse e ect is bradycardia and increased risk of syncope. Rivastigmine and tacrine also inhibit butyrlcholinesterase and this may be the reason for increased nausea and vomiting with these drugs.

Of the acetylcholinesterase inhibitors, galantamine alone attaches to nicotinic recep- tors and potentiates the e ect of acetylcholine. This dual cholinergic e ect does not appear to translate to better e cacy than the other anticholinesterases. Donepezil and galantamine are metabolized by the liver, but rivastigmine is excreted by the kidneys.

8.4 Tacrine

Tetrahydroaminoacridine, or tacrine for short, was discovered in the 940s and was used to successfully treat anticholinergic-induced delirium in the following decades. When the cholinergic hypothesis was put forward, tacrine was trialled in patients with dementia. In 993, a multi-centre randomized controlled trial (RCT) of people with AD over just six weeks showed that tacrine led to a decreased decline in cognition of 2.4 points on the ADAS-COG and 0.7 points on the MMSE. However, it had a short half-life, requiring three to four doses per day, and caused liver toxicity. It was discon- tinued in the USA in 203 and never licensed in the UK, but is still available in some countries.

8.5 Donepezil

Donepezil was the second anticholinesterase to be approved for AD in the United States and has been available since 996. Early trials assessed e cacy in mild to moderate

  

CHAPTER 8 Pharmacological treatment of AD

dementia as de ned by baseline MMSE 0–26, but by 2005 trials had also assessed e cacy in severe dementia (MMSE <0). A systematic review of double-blind RCTs in 2006 found that people with mild to severe AD taking 5 mg donepezil at 24 weeks had improved by -2.02 points on ADAS-COG and +.44 points on MMSE compared to placebo. There was a similar e ect with 0 mg donepezil at 24 weeks (+.34 points on MMSE). Global assess- ment, using CDR–SB, found a mean di erence of -0.5 at 24 weeks. Three trials of one- to three-years’ duration suggest donepezil has a sustained longer term bene t.

Adverse e ects on 0 mg daily at 24 weeks in the systematic review included ano- rexia (5 per cent absolute risk increase compared to placebo), diarrhoea (29 per cent), dizziness (3 per cent), hallucinations (5 per cent), muscle cramps (7 per cent), nausea (9 per cent), and vomiting (8 per cent).

No di erences were found in terms of global assessment or MMSE between the 5 mg dose and 0 mg dose, however the 0 mg dose was associated with an increased rate of gastrointestinal adverse e ects and discontinuation of the drug.

In practice, donepezil is started at 5 mg once daily. After four weeks, it can be increased to 0 mg once daily if needed. Adverse e ects are usually mild and tempo- rary. It is available as a standard or orodispersible tablet. There is a liquid solution of donepezil  mp/ml.

8.6 Galantamine

Galantamine is an acetylcholinesterase inhibitor that has been available since 2000. A systematic review of people with mild to moderate AD found that doses of at least 6 mg per day had an odds ratio of .9–2.3 of no worsening in global function at 6 months using CIBIC-Plus compared to placebo. The mean change in ADAS-COG at 6 months was approximately -3.0 points with 6–32 mg galantamine per day. Galantamine also led to improved outcomes when measuring activities of daily living and behavioural symptoms. One longer-term trial suggests that cognitive decline was halved at three years with galantamine and another double-blind trial showed that it is e ective in severe AD.

Adverse e ects are dose-dependent as with other anticholinesterases. At 8 mg daily, no adverse e ects occurred more than in placebo in the systematic review. At doses of 6 mg or higher, nausea, vomiting, and diarrhoea occur more often. Other gastrointes- tinal e ects include abdominal pain, anorexia, and weight loss. Tremor, dizziness, and headache were also reported in trials.

Galantamine is started at 4 mg twice daily as a tablet or liquid. Modi ed-release cap- sules are also available and are given once daily starting at 8 mg. It can be increased in steps of 8 mg every 4 weeks up to 24 mg daily. Slow titration may reduce adverse e ects.

8.7 Rivastigmine

Rivastigmine has been available since 997. A systematic review in 205 showed that at 6 months, 26 per cent of people improved global function (using CIBIC-Plus or a similar scale) with 6–2 mg rivastigmine daily but only 9 per cent with placebo. Cognitive function improves by -.79 points on ADAS-COG and 0.74 points on MMSE at 6 months. Activities of daily living also improved in the rivastigmine group but not behavioural symptoms.

 

65

CHAPTER 8 Pharmacological treatment of AD

66

Signi cant adverse e ects are nausea, vomiting, diarrhoea, and abdominal pain. These seem to occur more often than with donepezil in one double-blind head-to-head trial. Other than gastrointestinal disturbance, dizziness, headache, and syncope also occur more often than with placebo.

Rivastigmine should be started at .5 mg twice daily for both the capsules and liquid preparations. It can be titrated by 3 mg every 2–4 weeks up to a maximum of 6 mg twice daily. There is currently no oral once-daily preparation, although rivastigmine is the only treatment for AD that is available as a 24-hour transdermal patch. This is available in doses of 4.6 mg, 9.5 mg, and 3.3 mg. Patches are associated with fewer gastrointestinal adverse e ects but may cause application-site erythema, oedema, or dermatitis. The 4.6 mg patch should be used for at least 4 weeks before increasing to the 9.5 mg patch. Patients and carers should be warned to ensure removal of the previ- ous patch before applying a new one and not use the same area of skin for two weeks.

8.8 Memantine and glutamate antagonists

Memantine was licensed in 2002 in Europe and 2003 in the US. It is the only glutamate antagonist used for treatment of AD. Glutamate is the major excitatory neurotransmit- ter in the brain but excessive activation of glutamatergic neurons is known to lead to neuronal death (termed excitotoxicity). Memantine acts at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor as a partial antagonist. It acts as a neuropro- tective agent by stopping prolonged in ux of calcium ions into neurons, which is neces- sary for excitotoxicity, yet still allows normal neuronal transmission.

This unique action appears to be underlie memantine’s e cacy as other glutamate antagonists have no bene t in Alzheimer’s disease.

The drug has been shown to have bene t in people with moderate to severe AD in a systematic review. Cognitive function at 6 months improved by 3 points on the 00-point SIB test with 20 mg memantine daily. Global function improves by 0.28 points using the CIBIC-Plus scale. In addition, activities of daily living and behavioural function both improve with memantine at six months. In particular, agitation occurred less often in people taking memantine (2 per cent) than in people taking placebo (8 per cent). These trials mainly enrolled people with MMSE < 4 and memantine does not seem to be e ective in people with MMSE > 20.

Memantine caused no more adverse e ects than placebo in trials and is very well tolerated. The commonest adverse e ects are dizziness and headache. Gastrointestinal adverse e ects include constipation and vomiting. Confusion, hallucinations, and drowsiness also may occur.

Memantine is given as 5 mg once-daily tablets or liquid solution and increased by 5 mg per week up to 20 mg once daily.

8.9 Combination therapy

Con icting results have been obtained in studies of combination therapy of meman- tine and an acetylcholinesterase inhibitor (usually donepezil), with some demonstrating added value of memantine in patients treated with donepezil and other trials show- ing no signi cant e ect when adding memantine. An RCT in 202 concluded that there was no bene t of combination therapy at one year (Howard, et al., 202) but an industry-sponsored trial of extended-release memantine and a recent systematic

 

CHAPTER 8 Pharmacological treatment of AD

Patient is diagnosed with Alzheimer disease
Educate the patient and family about disease process Discuss medicolegal issues
Provide information on support groups
Refer to subspecialist if unable to perform appropriate

follow-up, or if the patient or family requests a referral

Assess baseline functionality, medical and psychiatric state Minimize use of any anticholinergic medication
Review medication options, including potential

e ectiveness, adverse e ects, and cost

    

Patient’s condition is considered mild at diagnosis

Begin treatment with acetylcholinesterase inhibitor

Reevaluate patient two to four weeks after medication initiation; treat serious adverse e ects

Patient’s condition is considered moderate to severe at diagnosis

Begin treatment with acetylcholinesterase inhibitor, with or without memantine

Go to A

        

Patient tolerates medication Patient is not tolerating medication, or and is using stable dose his or her condition deteriorates based

on functionality and caregiver’s input

 

Follow up every three to six months, and contiune treatment while patient’s condition is stable

Change to another acetylcholinesterase inhibitor

 

Reevaluate patient two to four weeks after medication adjustment; treat serious adverse e ects

 

Patient’s condition deteriorates to moderate to severe Alzheimer disease

Add memantine

A Discontinue medications if:
• Patient dose not adhere to treatment
• Deterioration continues
• Patient develops serious comorbid disease or is terminally ill • Patient or caregiver chooses to discontinue treatment

Figure 8. Algorithm for the treatment of Alzheimer’s disease. Used with permission from Winslow BT, Onysko MK, Stob CM, Hazlewood KA. Treatment of Alzheimer disease. Am Fam Physician. 20 Jun 5;83(2):403–2. PubMed PMID: 267540.

67

CHAPTER 8 Pharmacological treatment of AD

68

Box 8.2 Practical advice on drug treatment in people with AD

Before treatment

• Assess severity of AD and other medical conditions including liver and kidney disease.

• Note that cognitive assessment may underdiagnose AD in people with high premorbid intelligence and may over-diagnose AD in people with intellectual disability or neurological
disease.

• Refer to a specialist if in doubt over diagnosis and severity of AD.

• Stop or reduce dose of any anticholinergic drugs if possible.
Drug treatment

• Use the lowest starting dose of an acetylcholinesterase inhibitor. Adjust doses for hepatic and renal function.

• Titrate up slowly to the maximum tolerable dose. If there are adverse e ects then stay at current dose or step down to a lower dose and reassess after an interval.

• If tolerated, then regularly follow up the patient every three to six months to assess its e cacy and the development of late adverse e ects. Memantine could be added in mod- erate to severe AD.

• If not tolerated at the lowest dose, then change to another acetylcholinesterase inhibitor over one day. In moderate to severe AD, memantine may be preferred instead.
Stopping treatment

• Drugs can be stopped gradually over two weeks.

• There are no detailed guidelines for deciding when to stop treatment but four common
indications are:
. Patient or caregiver’s informed decision to stop treatment.
2. Intolerable adverse e ects.
3. Lack of noticeable e ect in slowing disease progression.
4. Severe dementia with, for example, loss of meaningful interaction.

review (Farrimond, et al., 202) concluded that there may be a small bene t at six months of adding memantine to acetylcholinesterase inhibitors. It was again noted that memantine improved behavioural symptoms (see Chapter 9 for a review of the role of memantine in managing behavioural symptoms). The recent ENS-EFNS/EAN evidence-based guidelines for the treatment of moderate to severe AD (Schmidt, et al., 205) recommended combination therapy, but the strength of the recommendation was weak for cognition and ADL.

In people with moderate to severe AD who do not tolerate acetylcholinesterase inhibitors, memantine monotherapy may be used as an alternative treatment.

8.0 Practical issues

Guidelines do not help in clinical decisions about which agent to choose rst or how to start pharmacological treatment. Therapy should rst be individualized taking into account the severity of AD, route of administration, number of doses per day, adverse e ects, and comorbidities (see Table 8.).

Tips based on clinical experience are listed in Box 8.2.

CHAPTER 8 Pharmacological treatment of AD

 

8. Future developments

Over the last two decades, there has been intensive research into new medications for AD with little success. Alzheimer’s disease is now thought to occur due to the formation of insoluble amyloid brils in neurons which then form extracellular plaques. Agents targeting amyloid have included vaccines and monoclonal antibodies, as well as drugs stopping formation of amyloid or increasing its clearance. None of the pro- posed treatments made any di erence in phase 3 trials. Now therapeutic strategies are also focusing on in ammation, insulin resistance, and tau, another pathological protein found in the brains of people with AD.

It may turn out that any disease-modifying treatment for AD needs to be started many years before clinical disease occurs. In inherited forms of AD, increased amy- loid, increased tau and increased brain atrophy are seen at least 5 years before any symptoms begin. For now, prevention is the only cure in AD but available drugs play an important role in slowing cognitive and functional decline.

References

Birks J., Grimley Evans J. Rivastigmine for Alzheimer’s disease. Cochrane Database of Systematic Reviews 205 Apr 0;4:CD009. doi: 0.002/465858.CD009.pub3.

Birks J. and Harvey R.J. Donepezil for dementia due to Alzheimer’s disease. Cochrane Database of Systematic Reviews 2006 Jan 25;:CD0090. Review. PubMed PMID: 6437430.

Chinthapalli K. Alzheimer’s disease: still a perplexing problem. British Medical Journal 204 Jul 8;349:g4433. doi: 0.36/bmj.g4433. PubMed PMID: 25005430.

Farrimond L.E., Roberts E., and McShane R. Memantine and cholinesterase inhibitor combi- nation therapy for Alzheimer’s disease: a systematic review. British Medical Journal Open 202 Jun ;2(3). pii: e00097. doi: 0.36/bmjopen-202-00097. Print 202. PubMed PMID: 22689908; PubMed Central PMCID: PMC3378937.

Hort J., O’Brien J.T., Gainotti G., et al. EFNS Scientist Panel on Dementia. EFNS guidelines for the diagnosis and management of Alzheimer’s disease. European Journal of Neurology 200;7:236–48.

Howard R., McShane R., Lindesay J., et al. Donepezil and memantine for moderate-to-severe Alzheimer’s disease. New England Journal of Medicine 202 Mar 8;366(0):893–903. doi: 0.056/NEJMoa06668. PubMed PMID: 2239765.

Loy C. and Schneider L. Galantamine for Alzheimer’s disease and mild cognitive impairment. Cochrane Database of Systematic Reviews 2006 Jan 25;:CD00747. Review. PubMed PMID: 6437436.

McShane R., Areosa Sastre A., and Minakaran N. Memantine for dementia. Cochrane Database of Systematic Reviews 2006 Apr 9;2:CD00354. Review. PubMed PMID: 6625572.

Schmidt R., Hofer E., Bouwman F.H., et al. EFNS-ENS/EAN Guideline on concomitant use of cho- linesterase inhibitors and memantine in moderate to severe Alzheimer’s disease. European Journal of Neurology 205;22:889–98.

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CHAPTER 8 Pharmacological treatment of AD

Chapter 9

Managing behavioural and psychological symptoms
in Alzheimer’s disease
Philippe Robert, Elsa Leone, Hélène Amieva, and David Renaud

Key points

• The behavioural and psychological symptoms of dementia (BPSD) form an important part of the clinical picture of Alzheimer’s disease (AD)

• Anti-dementia agents may facilitate behavioural management of AD and may decrease the use of psychotropic agents

• Management of BPSD should preferentially be based on non-pharmacologic approaches rst. Pharmacologic treatments should constitute second-line treatment and are to be prescribed only after assessment of the individual risk:bene t ratio. The prescription should be for a limited period and frequently re-assessed

• For patients living in an institution, management of BPSD is part of the institutional plan. It requires initial and continuing training of all care sta involved, the development of appropriate reference practices, and evaluation of professional practice

9. The place of behavioural and psychological symptoms in Alzheimer’s disease

The behavioural and psychological symptoms of dementia (BPSD) also known as neu- ropsychiatric symptoms form part of the clinical picture of Alzheimer’s disease (AD). They are de ned as primary manifestations of cerebral dysfunction and appear spe- ci cally as a result of damage to a system or circuit such as the limbic system or the cortico-subcortical circuits. Neurodegenerative diseases such as Alzheimer’s produce both structural and chemical alterations, and the neuropsychiatric symptoms can be in uenced by one or other of these alterations.

It should, however, be pointed out that these speci c biological modi cations, while necessary, are not su cient alone to produce BPSD. Other factors of a psychological and social nature also have a role to play in determining which patient will manifest behavioural disturbances (Figure 9.).

BPSD in neuropsychiatric diseases are thus abnormal modi cations, with more or less demonstrative clinical expressiveness, which could lead to a variety of signs related to psychosis (delusions, hallucinations), mood (depression, anxiety, euphoria), motor

71

             

72

           

Neurodegeneration associated with dementia

• Changes in ability of the person with dementia to interact with others and the environment

Increased vulnerability to stressors

Behavioural and psychological Symptoms of dementia

• Disruption in neurocircuitry

Patient factors

Caregiver factors

Environmental factors

• Premorbid personality/psychiatric illness
• Acute medical problems
• Unmet needs: pain, sleep problems, fear, …

• Stress, burden, depression
• Lack of education about dementia • Communication issues
• Mismatch of expectations and

• Overstimulation or understimulation • Safety issues
• Lack of activity and structure
• Lack of established routines

dementia severity

Conceptual model describing how interactions between the person with dementia, caregiver, and environmental factors cause behavioural and psychological symptoms of dementia (Kales, et al., 2015)

Figure 9. BPSD aetiological factors.

Reproduced from The BMJ, 350, ‘Assessment and management of behavioral and psychological symptoms of dementia’, Kales H. C. et al., copyright (205) with permission from BMJ Publishing Group Ltd.

CHAPTER 9 Managing BPSD symptoms

and/or disruptive behavior (agitation, aggression, screams, irritability, aberrant motor behaviour), motivation (apathy), appetite, and sleep.

During the progression of AD, the presence of at least one BPSD is common and can vary, depending especially on the severity of the dementia-related syndrome at the time of diagnosis (Karttunen, et al., 20; Youn, et al., 20). This frequency tends to increase with the worsening of the disease (the frequency of at least one BPSD increasing from 50–90% after a 0-year follow up of patients from the same population (Tschanz, et al., 20)).

Irrespective of the severity of the disease, the most frequently encountered symp- tom is apathy followed by depressive symptoms and anxiety (Karttunen, et al., 20; Reynish, et al., 2007; Selbæk, et al., 202; Tschanz, et al., 20). According to recent data, a history of depressive disorders would seem to be considered as a risk factor of AD (Baiyewu, et al., 202; Trivedi, et al., 203). In the pre-dementia phase of the disease, apathy is the earliest neuropsychiatric symptom. In the dementia stage, numer- ous symptoms are present in over 80% of patients, as emphasized by various European studies.

A syndromic grouping (a ective symptoms, apathy, hyperactivity, psychotic symp- toms) could be useful for an understanding of their aetiology and to improve treatment and care.

9.2 Measurement of BPSD

The evaluation of BPSD is indispensable not only at the time of screening but also at diagnosis and during the evolution of the disease (see Figure 9.).

This evaluation must ful ll various conditions:

• As a complement to the reference instrument, the Neuropsychiatric Inventory (NPI) (Cummings, et al., 994), instruments focused on the evaluation of a speci c dimension must be used (apathy, early-stage depression, agitation, hyperactivity, psychosis (moderate to severe stages)).

In most cases, the evaluation is conducted in the form of an interview with a per- son who accompanies the patient and who is aware of his/her behaviour. A patient’s self-evaluation is less often used but is of interest. The clinician’s evaluation must take the answers to the standardized questionnaires into account, but also the direct obser- vation of the patient’s behaviour in the course of the clinical situations (consultation, outpatient hospitalization, taking of neuropsychological tests).

The evaluation must also be accompanied by a search for somatic causes or an iat- rogenicity that could at least partially explain the onset of the disorders. Finally, the evaluation must assess the impact on autonomy and everyday activities.

More recently, use of new technologies, including information and communication technologies (ICT), have shown promising results to improve levels of accuracy and objectivity in the assessment of BPSD. Among them, wearable sensors sensitive to body movement (also called actigraphy) have been used to assess levels of agitation, apathy, and sleep disturbances (David, et al., 202; Robert, et al., 203). Environmental sensors such as automatic video monitoring have been proposed as well for the assess- ment of BPSD (Romdhane, et al., 202).

Several authors have proposed a speci c approach for the management of BPSD (DICE approach) (see Box 9.).

73

CHAPTER 9 Managing BPSD symptoms

Box 9. Summary of the DICE approach

Describe

• Contextualize and characterize the behavior
• Determine wether there are immediate concerns about safety or risk

Investigate

• Examine possible underlying causes of behavior (patient, caregiver, environmental factors)

Create

• Collaborate with caregiver and treatement team ta create and implement a treatment plan to manage the most distressing symptoms

• Key interventions to patient, caregiver and environment
Evaluate

• Were the interventions e ective?

• If psychotropic drugs were used, evaluate for adverse e ects, symptom persistence, and
responsiveness to other interventions
Reproduced from BMJ, 350, Assessment and management of behavioral and psychological symptoms of
dementia’, Kales H. C. et al., copyright (205) with permission from BMJ Publishing Group Ltd. Summary of the DICE (Describe, Investigate, Create, and Evaluate) approach (Kales et al., 205).

74

CHAPTER 9 Managing BPSD symptoms

 

9.3 Pharmacological treatment
From the pharmacological point of view, AD is currently treated symptomatically (and

not curatively). In addition, psychotropic drugs are used for BPSD treatment.

9.3. Anti-dementia drugs

Two classes of medicinal drugs are available. The rst class, named cholinesterase inhibitors, acts on the acetylcholine de cit. It is made up of three molecules: donepezil, rivastigmine, and galantamine. Another medicinal drug, memantine, belongs to the class of antiglutamatergics which seek to reduce the neurotoxic e ects of excessive gluta- mate release.

These drugs have usually been evaluated in therapeutic trials on the strength of four criteria: cognitive deterioration, functional level, global clinical impression, and behav- ioural disorders. Most of the studies have a six-month duration, as recommended by health agencies, in order to identify a symptomatic e ect.

Cholinesterase inhibitors (ChEIs) typically improve behaviour as well as cognition and function in patients with AD.

The total NPI score and the response to treatment of the individual behavioural domains were used when evaluating a drug treatment response in clinical trials. A review from Cummings and colleagues(2008) showed that no behavioural symp- tom responds to ChEIs in all studies. Moreover, the response pro le di ers for the same ChEI in di erent studies. The symptoms that most commonly responded to ChEI therapy were delusions, apathy, and aberrant motor behaviour. Di erences in study design, patient population, and analytic approaches among the trials most likely account for the di erences in outcomes observed.

Usually, ChEI therapy is initiated when a diagnosis of AD is established, whether or not behavioural changes are present. Early initiation of ChEI treatment may defer the emergence of behavioural changes as the disease progresses (Cummings, et al., 2004). ChEIs have a long-term and not acute e ect on BPSD, therefore ChEI therapy may reduce the use of psychotropic agents. Withdrawal of ChEIs has been associated with behavioural deterioration, and patients should be closely monitored for emergence of new behavioural symptoms if ChEIs are withdrawn (Holmes, et al., 2004). A relatively recent treatment-discontinuation study among moderate to severe AD participants (Howard, et al., 202) showed the interest of memantine alone and the association memantine–donepezil to prevent worsening in BPSD for severe stages of the disease. The meta-analysis from Farrimond and colleagues (202) tends also to favour the association memantine–ChEI versus ChEI monotherapy to decrease the level of BPSD. Another recent 2-month randomized controlled trial showed improvement on BPSD with memantine, donepezil, and rivastigmine. Agitation/aggression and anxiety/pho- bias were the mostly improved symptoms (Cumbo, et al., 204).

For memantine, evidence of behavioural e ects has been observed in pivotal stud- ies. A post-hoc analysis (Gauthier, et al., 2005) con rmed a signi cant bene cial e ect of memantine in comparison to placebo treatment in the NPI agitation/aggression domain. Furthermore a dichotomized analysis of the monotherapy study showed that there was signi cantly less agitation/aggression emerging in the memantine-treated group compared to placebo. These results were con rmed by an independent analysis of the add-on study (Cummings, et al., 2006). Pooled analysis of pivotal and follow-on studies indicated statistically signi cant di erences between memantine and placebo for the NPI single items: delusions, hallucinations, agitation/aggression at week 2; delusions, agitation/aggression, irritability/lability at week 24/28. In patients without symptoms at baseline: reduced emergence of agitation/aggression, delusions, disinhibi- tion at week 2; agitation/aggression, irritability/lability, night-time behaviour at week 24/28. Clinical implications of these results indicated that use of memantine may delay the emergence of disruptive behaviours. Memantine could also be used when agitation is present, reducing the need for atypical neuroleptics and other psychotropic drugs, however, memantine has no acute e ect on BPSD.

9.3.2 Psychotropic drugs

Treatment should be initiated in order to attenuate the symptoms which impair the patient’s quality of life or which jeopardize them or those around. Taking into account the characteristics of elderly patients with and without dementia (Table 9.), use of psychotropic treatment should be used with considerable care.

Table 9. Points to be conside in patients with AD

The use of psychotropic agents should be limited in case of:

red before implementation of psychotropic agents

Decreased renal clearance
Slowed hepatic metabolism
Multiple comorbidities take multiple medications

Treatment should not be initi- ated in case of:

Physical origin (e.g. pain), iatrogenic origin (hallucinations due to dopaminergic agonists, anticholinergic drugs, cholinester- ase inhibitors, zolpidem, corticosteroids), su cient response to non-pharmacological intervention, environmental meas- ures, or behavioural therapies

75

CHAPTER 9 Managing BPSD symptoms

76

9.3.2. Antipsychotics

Antipsychotics are predominantly used as the rst-line pharmacological approach to treat agitation and psychosis in people with dementia. These medications showed mod- erate e ect over a brief period of time (3–8 weeks) on severe psychotic symptoms (delusion, hallucinations), and agitation/aggression that cannot be controlled another way (Ballard, et al., 20). Long-term e ect of antipsychotics (> six months) has not been demonstrated so far. Randomized placebo-controlled trials with typical neurolep- tics and with atypical neuroleptics have examined the e cacy of atypical neuroleptics over 6–2 weeks in people with AD (Ballard and Howard, 2006). Best levels of evi- dence have been reported with aripiprazole and risperidone (Schneider, et al., 2006). Results of the CATIE study (Schneider, et al., 2006), a large pragmatic study compar- ing risperidone, olanzapine, and quetiapine to placebo for the treatment of clinically signi cant aggression or agitation in people with AD, suggested that changes observed on speci c rating scales in previous trials may be too modest to be judged as signi cant bene ts by clinicians. That is why prescriptions have been the subject of cautionary notices by the health authorities, the risk:bene t ratio should be assessed and recorded, and the prescription issued only for a limited period and frequently re-evaluated. Antipsychotic are associated with many adverse events including anticholinergic e ects, prolonged QT, extrapyramidal symptoms, metabolic syndrome, seizures, hypotension, hyperprolactinemia, and sexual dysfunction. They are also associated with increased risk of cerebrovascular events (Schneider, et al., 2006; Ballard, et al., 2006) that should encourage physicians to limit their prescriptions.

In daily routine and on failure of other approaches, antipsychotics may be prescribed with respect of the following recommendations (Ballard and Corbett, 200):

• Duration of prescription has to be short (< 2 weeks)
• Start with the lowest posology (e.g. risperidone 0.25– mg/day, aripiprazole 5 mg/day,

olanzapine 2.5–5 md/day)
• Regular re-evaluation (at least every 5 days)

Tolerance has to be the rst selection criterion to determine the choice of a speci c antipsychotic (Alexopoulos, et al., 2004).

9.3.2.2 Antidepressants

Antidepressants have been used in several behavioural targets in dementia such as depression, anxiety, irritability, and agitation. With regard to antidepressants, targeting depression, placebo-controlled studies suggest e cacy, especially for selective seroto- nin re-uptake inhibitors (SSRIs). In comparative trials of antidepressants without pla- cebo, all of which have compared various antidepressants, ndings have consistently suggested comparable e cacy for SSRI and non-SSRI antidepressants. In general, SSRIs appear to be better tolerated, although the monoamine (MAO) inhibitor moclobe- mide has been most promising. Tricyclic antidepressants should not be part of the rst-line treatment due to reported adverse events (orthostatic hypotension, seizures, prolonged QT, glucose dysregulation, anticholinergic e ects, risk of falling). QT prolon- gation has also been reported with SSRIs.

However, more recent data on SSRIs reported a lack of clear bene t of SSRIs for the treatment of depression (Kales, et al., 205).

Regarding placebo-controlled trials of antidepressants, targeting agitation, results have been mixed. One review found evidence for a reduction in agitation with sertra- line and citalopram versus placebo (Seitz, et al., 20). Pollock and colleagues (2007) indicated that no statistical di erence was found in the e cacy of citalopram (SSRI)

CHAPTER 9 Managing BPSD symptoms

and risperidone for the treatment of either agitation or psychotic symptoms in patients with dementia.

9.3.2.3 Other psychotropic drugs

• Mood stabilizers: evidence for the interest of mood stabilizers for BPSD is lacking. Highest levels of evidence are currently available with carbamazepine for which an enzymatic inductor’s e ect might limit the use in daily practice especially among elderly subjects (Kales, et al., 205).

• Benzodiazepines: given serious adverse events (confusion, risk of falling, sedation) as well as increased memory disturbances, benzodiazepines are not recommended for the management of BPSD except for management of an acute crisis. In the latter case, benzodiazepines with short half-time metabolism should be preferred.
9.4 Non-pharmalogical treatment
In view of the fact that AD has an impact on not only the cognitive but also the psy- chological and social functioning of the patient, there is now a broad consensus insist- ing that patient care should not be limited to pharmacological treatment but should also include non-pharmacological approaches. These therapies are widely applied in day centres, day hospitals, physiotherapy departments, memory centres, and speech therapy practices, amounting to a not inconsiderable economic cost.
For several years, many national and international recommendations have been pro- posed concerning good clinical practices, methods to take over BPSD, and the use of non-pharmacological approaches in rst intention (Fossey, et al., 2006; HAS, 20; Galik 200; Giltin, et al., 202). It is acknowledged that BPSD represent the priority target for therapeutic care (ALCOVE, 203). There is in fact today a wide variety of non-medicinal therapies open to patients su ering from dementia. These non-pharmacological treat- ments are multiple but all aim at and reducing, if not eliminating, the occurrences of troublesome behaviours, thus gathering two dimensions, preventive and symptomatic actions. Some of these therapies adopt a psychosocial approach while others belong to the eld of psychotherapy. Some have been developed on the strength of knowledge acquired from cognitive neuropsychology in the eld of AD, and others are based on physical or sensory stimulation. All of these techniques seek to optimize patient care by targeting, according to the therapy applied, di erent aspects of the disease such as cognitive abilities, dependence, mood and behavioural disorders, or patient well-being. These techniques are extremely varied (Table 9.2).
Over the last 20 years, a very large number of articles have been published illus- trating the bene ts of these therapies on AD. According to the studies, the reported improvement concerned di erent measurements. These bene ts could be re ected in a reduction of the depressive symptomatology, a slower decline of certain cognition measurements, preserved autonomy in certain activities of daily living, attenuation of certain behavioural disorders, improvement in quality of life measurements or relative satisfaction reported by caregivers and/or the health care assistants responsible for the daily care of these patients.
These results are encouraging inasmuch as they suggest that a global and multidisci- plinary approach to the disease is likely to attenuate some symptoms and to contribute to a certain well-being for the patient.
Nevertheless, it is noteworthy that the vast majority of these results were derived from studies whose methodology leaves much to be desired; the main weaknesses

77

CHAPTER 9 Managing BPSD symptoms

                                   

Table 9.2 Overview of non-pharmacological approaches to Alzheimer’s disease

Approaches

Techniques

Targeted aspects of disease

References

Environmental intervention

• Therapeutic garden
• Light therapy
• Architectural modi cation and use of

• Anxiety
• Wandering
• Spatio-temporal references • Autonomy
• Quality of life

Adam and Farag, 203; Charras, 203; Zeisel, 203

Sensory stimulation

• Music therapy
• Light therapy
• Aromatherapy
• Snoezelen (multisensory stimulation) • Gymnastics

• Depression
• Agitation/aggression
• Sleep
• Quality of life
• Collaboration during care • Well-being

Andreeva, et al., 20; Fung et al., 202; Monji, et al., 2009; Okahara et al., 200; Ueda, et al., 203

Psychosocial stimulation

• Reminiscence
• Self-maintenance therapy
• Psychotherapy
• Therapy by stimulated presence • Art therapy
• Animal-assisted therapy (dog)
• Geronto-technology

• Depression
• Agitation/aggression
• Apathy
• Quality of life
• Satisfaction of the caregiver

Bernabei, et al., 203; Chalumeau, et al., 20; Sant’anna, et al., 202

colours
• Orientation therapy

                           

Approaches

Techniques

Targeted aspects of disease

References

Motor stimulation

• Motor training • Gymnastics
• Walk

• Balance
• Physical form
• Sleep
• Depression
• Agitation/aggression • Wandering
• Cognition
• Autonomy

Christofoletti, et al., 20; Lowery, et al., 203

Sta and familial training

• Theoretical training • Coaching
• New technologies • Support group

• Agitation/aggression • Apathy
• Autonomy
• Quality of life

Leone, et al., 202, 203; Spector, et al., 203

Cognitive stimulation

• Cognitive stimulation • Cognitive re-education

• Cognition
• Autonomy
• Satisfaction of the caregiver

Aguirre, et al., 203; Fernandez, et al., 200; Mapelli, et al., 203

• Well-being
• Caregiver burden and distress
• Caregiver depression and anxiety

80

of these studies being the absence of a control group, the absence of randomization, the absence of a procedure for evaluating in blind fashion, and insu cient sample size. The scarcity of long-term measurements assessing the continuation of these bene ts beyond the period of intervention is also most unfortunate. For some of these tech- niques, there are very few if any randomized studies. As for the bene ts reported by meta-analyses including only those studies that meet the criteria of randomized con- trolled trials, these tend to be more modest in scope, and in most cases, limited to the duration of the intervention.

One of the points contributing to the lack of credibility concerning the use of these therapies in the context of AD is the failure to respect the uniform application of the same technique on the part of the healthcare assistants. For a given technique, the description of the treatment programmes often varies from one study to another. The outcome is that for most of these techniques, it is di cult to reach a consensus de ning a programme comprising clear indications on such essential points as the qual- ity/training of the professionals likely to apply these techniques, the stage of severity of the patients liable to bene t from the said techniques, the duration of the program, the frequency of the sessions (daily, weekly, etc.), the details (group or individual service, with or without the participation of caregivers, relayed at home or not), or the very content of the sessions to be proposed.

Concerning speci cally BPSD, a total of ,632 studies were identi ed, and 62 satis- ed the inclusion criteria for the review (Livingston, et al., 2005). Speci c types of psy- choeducation for caregivers about managing BPSD were e ective treatments whose bene ts lasted for months. Behavioural management techniques that are centred on individual patients, and possibly cognitive stimulation, appear to have lasting e ective- ness for the management of BPSD. Lack of evidence regarding other therapies is not evi- dence of lack of e cacy. Conclusions are limited because of the paucity of high-quality research. The American Psychiatric Association Practice guideline for the treatment of the treatment of AD and other dementia (APA, 2007) indicated that in addition to the general psychosocial interventions, stimulation-oriented treatments, such as rec- reational activity, art therapy, music therapy, and pet therapy, along with other formal and informal means of maximizing pleasurable activities for patients, have modest sup- port from clinical trials for improving behaviour and mood; however, common sense supports their use as part of the care of patients. Among the emotion-oriented treat- ments, supportive psychotherapy can be employed to address issues of loss in the early stages of dementia.

Recently, a meta-analysis conducted by Kales and colleagues (205) also showed that the non-pharmacologic approaches with the strongest evidence base are those based on family caregiver interventions, which have been shown to have greater e ect than anti- psychotics. These approaches typically provide the caregiver with education and sup- port, training in stress reduction or cognitive reframing techniques (or both), and speci c skills on problem solving to manage behavioural symptoms. They include increasing the activity of the person with dementia, enhancing communication with the person with dementia, reducing the complexity of the physical environment, and simplifying tasks for the person with dementia. Individual non-pharmacologic approaches (such as music and physical activity) may be used within such approaches as tailored activities.

9.5 Management strategy in nursing homes

For patients living in nursing homes, management of BPSD should be part of the institutional plan. It requires initial and continuing training of care sta involved, the

CHAPTER 9 Managing BPSD symptoms

Box 9.2 General principles of management of AD in nursing homes

• Collective management

• Identi cation of the target symptom or symptoms and classi cation by order of impor-
tance: training of carers with this aim in mind should be given greater importance and
tools to aid in identi cation should be more widely di used

• Realistic goals, the drawing-up of a care plan and of its stages

• Encouragement and support of caregivers and of patients

• Reassessment of goals and adjustment of the care plan

development of appropriate reference practices, and evaluation of professional practice.

Care teams have a key role in the evaluation, management, and follow-up of BPSD. Their action also contributes to improve the patients’ quality of life and indirectly ena- bles better functioning of the institution.

The general principles of management are shown in Box 9.2.
Non-pharmacological management and support of the patient and their family should be preferred and should be undertaken in usual practice. They are part of the personal- ized care plan. In this context, the following are particularly important:
• E orts to adapt the living environment in its spatial and temporal context
• The possibility of participation in structured recreational and social activities (walking

groups, painting or cooking workshops) or physical activities
• Training of care teams and assistance o ered to caregivers
Individual management interventions also exist which must be attempted and adapted, even in severe forms of dementia. The absence of scienti c evidence or proof of e – cacy of these methods should not prevent their application. It is essential to promote interventional studies in this eld.

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CHAPTER 9 Managing BPSD symptoms

Chapter 0

Caring for people with dementia towards and at the end of life Louise Robinson

Key points

• Prognostication in people with dementia is di cult; it is useful for professionals to communicate such clinical uncertainty to families

• Future, or advance care planning discussions need to be carried out whilst the person with dementia has capacity to ensure future treatment addresses their wishes

• In people with advanced dementia, common problems such as pain and constipation need to be excluded prior to starting treatment for behavioural problems

• Healthcare professionals should consider people with advanced dementia as having palliative care needs and ensure they have optimum relevant community support (e.g. Macmillan nurses or respite services for carers)

• Many symptoms towards and at end-of-life dementia are similar to
those in older people with any terminal illness and should be managed accordingly: people with dementia, however, are unable to communicate their symptoms, and close observation of agitation and distress is needed with appropriate physical examination

• Family and carers of people with dementia may require more emotional support prior to the person with advanced dementia’s death than
after death

0. Introduction

World-wide dementia care costs are currently estimated to be US$88 billion, with social care and informal care costs comprising 40% of this amount; a considerable pro- portion of the latter cost is accounted for by care in the last year of life. In Europe one in three people aged over 60 years will die with dementia but research shows few die at home or in a hospice; the majority die in either care homes or acute hospi- tals. Evidence has consistently shown that people with advanced dementia experience suboptimal care compared to those dying with cancer, with increased hospitalization, inadequate pain control, and fewer palliative care interventions. This may be explained by the fact that they cannot verbalize their symptoms, so pain and other forms of dis- tress are poorly detected and often untreated. Assessment and management of pain is particularly di cult as there is currently no single assessment tool deemed useful for

85

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Box 0. Outcomes of ACP discussions

• Statement of wishes and preferences: This documents an individual’s wishes for future care and is not legally binding. In the UK this is known as an advance statement.

• Advance directive for refusal of treatment (or ‘living will’): This is a statement of an indi- vidual’s refusal to receive speci c medical treatment in a prede ned clinical situation. It is legally binding and comes into e ect when a person loses mental capacity. In the UK, this is known as an advance decision to refuse treatment (ADRT).

• Power of Attorney (POA) or proxy decision maker: This is a legally binding document whereby the person (‘donor’) nominates another (‘attorney’) to make decisions on their behalf should they lose capacity. In England, following the Mental Capacity Act, this is now known as a Lasting Power of Attorney (LPA); there are two separate aspects to LPA: health and welfare, and property and nancial a airs.

widespread use in practice. Another important area is supporting the family carers of people with advanced dementia. They often need more emotional support prior to the person’s death than afterwards as they experience symptoms of ‘grief’ even though their loved one is still alive; this is called a ‘living bereavement’.

The aim of this chapter is to support professionals to provide good quality end-of- life care to people living with dementia. Although cultural and legal aspects of care can heavily in uence practice (e.g. assisted dying is legally acceptable in some countries such as the Netherlands), many of the basic principles such as planning ahead for the future and treatment of pain and distress are core elements of palliative care. The guidance and recommendations provided are, where possible, grounded in high-quality research evidence; notwithstanding, as the author is a family physician in the UK, practical exam- ples are provided from this country. The key to providing good quality care towards and at end-of-life in dementia is to start at the beginning with open and sensitive discussions whilst the person with dementia has the capacity to discuss their feelings and prefer- ences for future care.

0.2 Discussing the future

Advance care planning (ACP) is a term used to refer to a series of discussions between a patient, their family, and the professionals involved in their care about their future wishes whilst the patient has mental capacity. Following these discussions, patients can formally record their wishes in a number of ways including the completion of an advance directive, or living will as it was previously known, or as other documents (see Box 0.). Guidance in this area will vary from country to country especially if euthana- sia is legal; the example provided is from the UK National End of Life Care Programme whose website provides both advice for patients and professionals about how to start such discussions and also o ers examples of formal documentation <http://www. endo ifecareforadults.nhs.uk/> (last accessed 4 November 205).

In England, the introduction of the Mental Capacity Act (MCA) in 2005 provided a statutory framework for making decisions on behalf of adults who lack the mental capacity to make decisions for themselves. The Act’s ‘code of practice’ acts as good practice guide for professionals in this di cult area, in particular, how to assess mental capacity (see Box 0.2). The Act also established the Independent Mental Capacity

CHAPTER 0 Towards and at end of life care

Box 0.2 Assessment of mental capacity: the two-stage test

. Does patient have an impairment or disturbance of function of brain? If yes, move to question 2

2. Regarding a speci c decision, can the patient carry out the following:

• Understand the decision to be made

• Retain su cient information to make an informed decision

• Use information appropriately

• Communicate their decision
Practical tips for health professionals in the assessment of capacity:

• Information may need to be provided in di erent forms

• The assessment may need to be undertake on several occasions (i.e. when is the best
time of day for the person?)

• Accurately record the two-stage test in the patient’s notes

• Refer to an expert (old-age psychiatry) if in doubt for a specialist assessment.

Advocate (IMCA) Service to represent individuals who lack capacity, but who have no-one to support them when major decisions need to be made about their lives.

The Act has also seen the introduction of a new formal power of attorney, Lasting Power of Attorney (LPA), which replaces the previous Enduring Power of Attorney (EPA); an EPA will, however, remain valid if executed before the implementation of the MCA. LPAs are particularly useful in dementia care and extend the areas in which patients can authorize others to make decisions on their behalf to include personal care and medical treatment, in addition to property and nance. Families need to be advised about seeking an LPA early in the illness, and also that there are two separate aspects for which separate legal fees can be requested.

Advance care planning is particularly important for people with dementia in care homes and can be helpful in reducing inappropriate hospital admissions, especially towards and at the end of life. Hospitals are less than ideal environments for people with dementia and can lead to disorientation and deterioration in their physical health, through falls and acquired infection, as well as being costly. Through discussing patients and their families’ wishes, and completing an advance decision to refuse treatment for speci c interventions such as hospital admission ot resuscitation, unnecessary proce- dures can be avoided.

0.3 Preferred place of care

One of the outcomes of care planning discussions is to assertain where the person with dementia would choose to be cared for as their illness progesses. If they wish to remain at home then a range of support options may exist to facilitate this; however, in some countries, a lack of specialist community resources may not allow this. Aids and adap- tations can make the person’s home a more dementia-friendly environment and help support family carers to continue caring. These include the use of simple picture signs on doors to indicate speci c rooms (e.g. the bathroom), and more advanced technol- ogy such as alarms that indicate the person is wandering in the night. The term ‘assistive technology’ (AT) is used to describe these. Information about AT can be found on a speci c website <http://www.atdementia.org.uk&gt; (last accessed 5 November 205).

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88

In addition, respite care, sitting services, and day centres provide options for carers to have time for themselves.

0.4 Palliative care in dementia: a team approach to symptom management

Palliative care is ‘the active total care of patients whose disease is not responsive to curative treatment’; this encompasses physical symptoms, and psychological, social, and spiritual issues. The goal of palliative care is to achieve the best quality of life for patients and their families. In England, the National Health Service (NHS) End of Life Programme provides guidance and speci c tools (palliative care standards, advance care planning, and care pathways) to facilitate good communication, care, and proac- tive planning.

The National Institute for Health and Care Excellence (NICE) 2006 guidance on dementia care recommends a palliative care approach in the more advanced stages of dementia. The general practitioner (GP) and their primary care team are well placed to facilitate this, particularly as the GP will have probably been involved from the point of diagnosis. To provide coordinated end of life care in dementia, e ective teamwork is essential, with individual members having a good understanding of each other’s roles and responsibilities. The community nurse can provide hands-on nursing care and emo- tional support, organize aids and equipment, and help coordinate and access other services such as respite care. Both the GP and community nurse can liaise closely, if needed, with palliative care services, especially specialist palliative care nurses (often termed Macmillan nurses in recognition of the charity that supports their role), in order to access specialist advice and hospice-based services, such as day care and respite care. In some areas a 24-hours community nursing service is available; a night-sitting service may also be accessed, sometimes provided by Marie Curie nurses. In some areas of the UK, specialist dementia nurses (Admiral nurses) also play a key role especially in sup- porting family carers; see http://www.dementiauk.org (accessed 4 November 205).

In terms of primary care organization and palliative care provision in England, a new General Practice Contract was implemented in 2004 which de ned core primary care services and optional enhanced services. The contract introduced a new concept: the provision of nancial rewards linked to the achievement of clinical and non-clinical qual- ity markers through a Quality and Outcomes Framework derived from evidence-based care. The Quality and Outcomes Framework for palliative care stipulates the develop- ment and maintenance of a GP palliative care register and regular review of all listed patients. Patients eligible for the palliative care register are those whose death would not be unexpected within the next year, consequently patients in the advanced stages of dementia, especially those living in care homes, should be included on the practice palliative care register.

A major di culty for professional carers in advanced dementia, however, is prog- nostication. Due to the slow and prolonged dying trajectory in dementia, it is helpful to discuss honestly such prognostic uncertainty with families to facilitate more realistic expectations. One common area of distress for family carers of people with dementia is the person’s reluctance to eat or drink as the illness progresses. Families should be reassured that this is one of the signs of advancing illness; however, the GP should also exclude depression, swallowing di culties, or other gastrointestinal problems. If the person’s prognosis is short, then good mouth care and oral hygiene is su cient; if

CHAPTER 0 Towards and at end of life care

the patient is expected to live longer, then a discussion around subcutaneous uids or percutaneous endoscopic gastrostomy (PEG) feeding with dietician input may need to be considered, especially if the person is rapidly losing weight.

0.6 Management of common problems in dementia towards, and at, end of life

In the UK, generalized end-of-life care pathways, such as the Liverpool Care Pathway, were used to help doctors and nurses achieve better symptom control and quality of care. Following a national enquiry due to a series of complaints and lack of evidence, however, they have been withdrawn from use in the UK. Individual care planning is now advocated.

Many of the symptoms and problems faced by people with dementia at the end of life are common to older people with any terminal illness; the additional challenge for health professionals is that their communication skills are considerably impaired. Some are prescribed multiple drugs, which may cause side-e ects independently or in combination. It is important to be aware if the person has any renal or liver failure as this will a ect the metabolism and excretion of some drugs. Regular medication review is essential; any non-e ective medication should be discontinued and the num- ber of drugs should be kept to a minimum. In dementia, the patient’s compliance with medication and especially their ability to swallow are often key issues and in uence the form in which drugs should be administered. Transdermal patches, where appropriate, help to ensure patient compliance. Non-drug measures should also be considered; for example, could anxiety be helped by relaxation techniques or aromatherapy rather than benzodiazepine use?

0.7 Management of distress

An assessment of distress must be undertaken by asking carers who know the patient best to report non-verbal signs such as grunting, crying, and moaning. Pain/distress assessment tools exist but there is no one tool that is better than another for use in practice. In terms of treating distress/pain, the normal ‘analgesic ladder’ should be fol- lowed, starting with simple analgesia, such as paracetamol, and moving to second-level analgesia like codeine, and nally opiates as the person moves into the terminal stages of the illness. One-third of opioid naïve patients experience nausea for 7–0 days on commencing morphine; this can be treated with cyclizine or prochlorperazine –2 hours before the opioid, but haloperidol, often recommended in palliative care guidance, should be avoided in people with dementia.Strong opioids will also cause constipation and regular laxatives should be prescribed to prevent this. As swallowing di culties are common in the advanced stages of dementia, opioid patches may be more appropriate; however dose titration should be approached with caution due to the risk of respiratory distress and death.

0.8 Nausea and vomiting

A detailed assessment needs to be made as the choice of antiemetic depends on the likely cause. If the oral route is not e ective, the antiemetic should be given

  

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subcutaneously via a syringe driver for a few days to ensure absorption before being prescribed by the oral route again. At the very end of life when the patient is drowsy, any regular oral antiemetic should be continued subcutaneously via a syringe driver.

0.9 Constipation

Constipation is commonly experienced by people with advanced dementia, exacer- bated by poor appetite and uid intake, immobility, and prescribed drugs, particularly opioids and antimuscarinics. Patients will often need a combination of stimulant (e.g. senna) and softener (e.g. docusate). Combination drugs are available which are more expensive but mean fewer tablets for the patient. If constipation causes discomfort in the dying phase, abdominal colic should be treated with hyoscine butylbromide subcu- taneously (20 mg prn 2-hourly or 60–20 mg via syringe driver over 24 hours).

0.0 Dyspnoea

The cause of the breathlessness needs to be assessed and treated if possible; however, the sensation of breathlessness can be partially relieved by a small dose of opioids given regularly (e.g. morphine solution 5–0 mg prn 4–6 hrly). If the patient is anxious or frightened, this is likely to exacerbate the breathlessness, and can be treated with loraz- epam 0.5 mg sublingually prn hourly. In the dying phase, opioids given subcutaneously (from diamorphine 2.5 mg prn hourly or 0 mg over 24 hours via syringe driver) may help relieve the sensation of dyspnoea.

0. Terminal agitation

This is commonly seen in the last few days or hours. The patient may appear distressed and unable to settle, although not in pain. This usually responds to midazolam given subcutaneously (2.5–5 mg prn hourly or 0–20 mg over 24 hours via syringe driver). If the patient does not settle, higher doses may be needed or, as a second line, levome- promazine may need to be added.

0.2 Conclusion

Research evidence con rms that people dying with dementia receive suboptimal care compared to those with terminal cancer. Good quality end-of-life care in dementia can be achieved. This requires good communication with open and sensitive discussions about future preferences for care; advice about power of attorney, and other practical issues including support services and technology; continuity of care through a named lead GP/care home nurse; detailed observation for signs of distress once communi- cation has been lost and referral to specialist services such as old age psychiatry for behavioural problems, and palliative care for end of life symptom management. Most importantly, the uncertainty of the dying trajectory needs to be understood by health professionals and this uncertainty clearly explained to family carers to enable them to understand the slow and often prolonged pathway to dying and help address unrealistic expectations of care.

   

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References

Brayne C., Gao L., Dewey M., et al. Dementia before death in ageing societies—the promise of prevention and the reality. PLoS Medicine 2006;3:e397.

Houttekier D., Cohen J., Bilsen J., et al. Place of death of older persons with dementia. A study in ve European countries. Journal of American Geriatric Society 200;58(4):75–6.

Mitchell S., Kiely D., and Hamel M. Dying with advanced dementia in the nursing home. Archives of Internal Medicine 2004;64:32–6.

Sampson E.L., Gould V., Lee D., et al. Di erences in care received by patients with and without dementia who died during acute hospital admission: a retrospective case note study. Age and Ageing 2006;35:87–9.

Zwakhalen S.M.G., Hamers J.P.H., Abu-Saad H.H., et al. Pain in elderly people with severe dementia: A systematic review of behavioural pain assessment tools. BMC Geriatrics 2006;6 (3):–5.

van der Steen J.T. Dying with dementia: What we know after more than a decade of research. Journal of Alzheimer’s Disease 200;22():37–55.

Alzheimer’s Disease International. World Alzheimer Report 205. The global impact of demen- tia: an analysis of prevalence, incidence, costs and trends. London: Alzheimer’s Disease International, 205.

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Chapter 

Supporting the person
with dementia and the caregiver
Henry Brodaty and Katrin Seeher

Key points

• The challenges of dementia management evolve throughout the course of the disease

• Support for the person with dementia and the caregiver are crucial and takes many forms

• People with dementia should be o ered continuing support, counselling, and regular appointments

• Caregivers experience psychological distress, physical ill health, social isolation, and nancial hardship

• Training and counselling programmes for caregivers have demonstrated e cacy in reducing caregiver depression and delaying nursing-home admission

• Caregivers should be reminded of the importance of maintaining their own physical, social, and emotional health

. Supporting the person with dementia

The journey of dementia, which starts before diagnosis, is di cult and emotionally fraught; it ensnares the family and friends as well as the person with the condition. Support of the person with dementia can be considered by stages of the disease, group support, and special issues.

.. By stages

... Before diagnosis

Even before diagnosis, awareness in the community can assist people with early symp- toms of memory problems to seek an assessment. Families may be at a loss to under- stand why a loved one has had a change in personality, decreased capacity to cope, altered behaviour, or di culties in relationships. Such symptoms may presage recogni- tion of a dementing process. On the other hand, excessive concern about changes in memory can lead to undue anxiety—‘Alzheimer-phobia’.

...2 At diagnosis

Having received an assessment, people with cognitive complaints have a right to know and a right not to know whether their diagnosis is or is not dementia. The skill of the

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Box . Practical considerations and measures

Legal—enduring or durable Power of Attorney, enduring guardianship, advance directives. Financial—planning for the future.
Life planning—when to take a holiday, whether to change place of residence now while the

person is relatively intact cognitively and can adjust to new surroundings, or later when

it may be more di cult.
Driving—almost always a contentious issue that requires delicate negotiation. Strategies

range from immediate cessation of a driving licence to on-road assessment to gradual end of driving. Some clinicians have a rigid approach and arrange mandatory termination of the patient’s licence; others are more exible.

Work—it is important to ascertain whether it is feasible and safe for patients who are work- ing to continue in their present role. It may be possible for the patient to transfer to a position with more supervision and less responsibility. In general, continuing as normal a life as possible for as long as possible is the aim of management.

clinician is to titrate the level of information to the wishes and needs of the patient and family.

Most patients and almost all accompanying family members want to know what is the diagnosis, how certain it is, what can be done to help them, and what is their outlook or prognosis.

Prescription of cholinesterase inhibitors (donepezil, galantamine, rivastigmine) for Alzheimer’s disease, Lewy body dementia, and mixed Alzheimer’s and vascular demen- tia should be discussed provided that there are no contra indications.

Strategies to compensate for cognitive de cits can be devised. An occupational ther- apy assessment at home, if available, use of a diary, smart phones, automatic remind- ers, GPS monitoring, and other memory aids, clocks with the day and date displayed, use of devices, and establishment of routines can be helpful.

The hope engendered by research and the possibility of disease-modifying treat- ments are frequently seized upon by patients and families, but expectations should be tempered to make them realistic.

A number of practical measures deserve attention and are summarized in Box .. A frequent dilemma that patients and families face is whether to tell family and friends about the diagnosis. Bene ts of informing others include the possibility of gaining more support, the release of stress of trying to hide the problem from others, and the increased potential of arranging compensatory strategies; detriments are the fear of stigma, alienation, and loss of esteem. In practice, most people close to the person with early dementia are aware that something is amiss and are unsure how to handle the increasing di culties.

At diagnosis, the amount of information given to patients and families can be over- whelming. It is useful to provide written feedback of the diagnosis, plan of manage- ment, and prognosis, a telephone number for further contact, and appointments for a second and further follow-up visits.

The overarching aim of management is maintenance of quality of life. It is important to stress to patients and families that imparting a diagnosis does not change a person’s life from one day to the next. The trajectory for most dementias such as Alzheimer’s disease is slow, over a number of years. Loss of short-term memory does not equate to loss of the ability to enjoy life, to receiving and giving love to others, or to having fun.

CHAPTER  Dementia: the person and the caregivers

..2 Early stages

Mild cognitive impairment (MCI), a condition intermediate between normal cognition and dementia, is characterized by subjective cognitive complaints and objective cogni- tive impairment. MCI can be associated with distress for the person with MCI, and the person’s family member often may feel some distress, commonly because of realization or fear that something is wrong but not having a diagnosis.

Once diagnosed with dementia, those a ected should be o ered continuing sup- port and regular appointments. They may want to discuss their frustrations and learn about strategies to cope with their cognitive decline. A meeting with others with similar problems can be helpful. Group support can be o ered but clinicians need to be sensi- tive to individual di erences and be aware that not all patients prefer this type of sup- port. Another option is online support o ered as virtual groups such as the Dementia Alliance International for people with dementia <http://www.dementiaallianceinter- national.org/> (accessed 5 November 205).

Many Alzheimer associations run groups for people with early-stage dementia and courses for people with dementia and their caregivers on how to manage the disease. Some patients accept their diagnosis readily, learn how to live with the disease, and use compensatory strategies as required. Others deny there is a problem and resist help. Attempts to overcome denial generally fail unless there is an attempt to relieve the underlying anxiety about a patient’s condition and their future. For such individuals it is usually more productive to emphasize their strengths and build on strategies to com- pensate for weaknesses rather than insist on acceptance of a diagnosis.

..2. Monitoring

The points brought up at diagnosis should be monitored. Have the legal and nancial matters been attended to? Is the patient still driving? Is the patient still working? How are relationships within the family? Quality of life for the person with dementia and family supporters remains the overarching aim. An occupational therapist or psycholo- gist may help in advising on activities which the patient can maintain. A social worker or Alzheimer’s Association counsellor can help support the family caregiver.

..3 Middle stages

As dementia progresses, increasing dependency begins to overtake the desire for autonomy. In patients, this leads to depression, agitation, or aggression. Loss of con – dence and feelings of insecurity may result in patients hiding valuables, but when their location is forgotten, accusations of theft and frank paranoia may ensue.

The middle stages of dementia are characterized by the emergence of behavioural and psychological symptoms which are potent predictors of stress in family caregivers. Support for the patient requires an understanding of what underlies these behavioural symptoms. Listen to the music not the words is a useful aphorism. Helping those involved with the person with dementia understand the underlying insecurity or other cause driving the behaviour increases the possibility of successful resolution. For example, the person who constantly and repetitively asks to go home will not be quietened by repeated reassurances by a family member, often at increasing volume, that ‘You are home!’ The underlying issue is that the person is feeling insecure, even though in his or her own home. Rather than repeated verbal reassurances, a response at an emotional level such as an a ectionate hug is more likely to make the person feel more secure. Internet-based guides are available to assist caregivers to deal with BPSD (e.g. Burns, et al., 204, or the Care4Dementia app).

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As dementia progresses, relationships change and the balance of power and respon- sibility shift, yet communications should remain on an adult level even though the role of the family caregiver is becoming more parental. When caregivers talk down to their charges as if they were children, the response is often irritability, argumentativeness, or frank aggression.

..4 Late stages

Increasing dependence of the person with dementia often requires support from oth- ers besides the primary caregiver. In some communities this may be an informal net- work of family and friends. In most Western societies community care is available such as community nurses or aged-care workers who can assist with dressing, washing, and toileting, or provide companionship to o er the caregiver some relief. The person with dementia still requires support although continued counselling is usually beyond the capacity of the patient, and support will be in the form of companionship, a ection, and maintaining proper care.

..5 Residential care placement

In western societies, many persons with late-stage dementia are admitted into resi- dential care (e.g. nursing homes). It can be a frightening experience for a person with failing cognition to be placed in a strange environment, cut o from familiar-orientating cues and family and friends. It is desirable to prepare the person for the admission, help familiarize the person with the surroundings by arranging frequent visits before admis- sion, continuing contact with family and friends after admission, providing mementos, photographs, and personal memorabilia in the room in order to give it a sense of familiarity and homeliness. Some nursing homes institute a buddy system whereby a current resident is asked to make a special e ort to support the newly admitted resi- dent. Despite all these measures, many persons with more advanced dementia become agitated or exhibit other behavioural disturbances on admission to nursing homes. Management of these behaviours is discussed in Chapter 9.

Families are often confused about how best to make the transition from home care to residential care. Asking families not to visit until the patient is ‘settled’ is akin to what used to be instructed for parents admitting young children into hospital wards. These children gradually withdrew and developed anaclitic depression. A similar scenario in nursing homes may make the patient more manageable but at a cost of decreasing functioning ability.

.2 Supporting caregivers .2. Who are caregivers?

Caregivers are generally the spouses of the person with dementia or their children. Less frequently they are other relatives or friends but for 0% of people with dementia there is no support, especially for those who live alone. It is useful to divide caregiv- ers into care providers and care managers. Care providers look after the person with dementia directly, supervise dressing, assist with bathing, manage nances, etc. Care managers arrange for others to provide care: a domiciliary nurse to visit and help with medications, showering, and dressing, a companion to provide in-home respite and companionship, Meals-on-Wheels, cleaner, etc. In general, care providers live with the person and tend to be spouses rather than children or other relatives.

CHAPTER  Dementia: the person and the caregivers

.2.2 What is the role of the caregiver?

As well as providing instrumental and practical support, caregivers give emotional support to the person with dementia. The ability of caregivers to provide such support is reduced if they are distressed emotionally or overwhelmed by competing demands. As the inter- generational gap widens with women having children later, many women nd themselves ‘caught in the middle’: sandwiched between caring for children still at home, being a wife, and looking after an ageing parent or parent-in-law. Women in particular may incur sec- ondary role strain whereby their caring duties con ict with their relationships with husband and children resulting in marital or maternal disharmony. In some societies, the wife of the eldest son has the responsibility of providing care for ailing parents with whom they have not built up a lifetime of love and a ection, making the caring role doubly stressful.

.2.3 How does the role of being a caregiver change over time?

There is a gradual alteration in the balance of the relationship between the person with dementia and their primary caregiver, most commonly a spouse. Partners change from having a reciprocal relationship to one of being a caregiver. As behavioural and psychological symptoms complicate the course of the disease in the middle stages, the stress on the caregiver increases.

.2.4 What are the e ects of being a caregiver?

Caregivers experience psychological distress, physical ill health, social isolation, and nancial hardship. Levels of depression, burden, and demoralization are higher than in similarly aged non-caregivers in the general population. Chronic physical condi- tions such as high blood pressure can be exacerbated by the e ects of caring, immune response can be compromised and physical symptoms may develop.

.2.5 What predicts caregiver stress?
High levels of stress in family caregivers are predicted by factors associated with the

following:
• The person with dementia

• behavioural and psychological symptoms of dementia • The caregiver

• lack of knowledge about dementia and its care

• immature coping mechanisms such as denial

• negative stress appraisals and caregiver personality (especially high levels of neuroticism)

• previous poor psychological health

• poor physical health
• The relationship

• poor prior relationship between caregiver and patient

• The context
• Lack of support from family and friends (i.e. informal supports)

.2.6 How to help caregivers

.2.6. Before diagnosis

Even at pre-dementia stages, family members of older people with MCI often report higher levels of burden and more depressive symptoms than relatives of cognitively

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healthy older people. General awareness in the community can help family members identify whether inexplicable changes in their loved one are the prodrome of dementia. As discussed earlier, this needs to be balanced against inciting Alzheimer-phobia in the general population. Targeted and tailored interventions aimed at MCI caregivers who are particularly at risk for experiencing negative mental health outcomes may prepare them for the di cult times ahead.

Frontotemporal dementia in particular may be di cult to diagnose in the early stages since memory is retained as behaviours become erratic. Patients may receive psychi- atric diagnoses, couples may separate, businesses collapse, and children may start to act out because of their parent’s bizarre behaviours, personality changes, and poor judgement.

.2.6.2 At diagnosis

Caregivers frequently complain that they are not given su cient information about what is wrong, how to manage, and what to expect. Caregivers need clear explana- tions, preferably in writing, of what is wrong and what can be done. They should be o ered the opportunity of individual counselling with the specialist making the diagnosis, through the local Alzheimer’s Association, or through social workers or psychologists.

Information provided about practical issues should be made clear to the family.

Frank discussions about possible scenarios, the limitations of existing treatments, and information about genetic risks are often requested. As before, the skill of the clinician is to titrate the amount of information to the needs of the caregiver and other fam- ily members. A follow-up appointment one or two weeks after diagnosis provides a much-appreciated opportunity for family caregivers to discuss other issues they have considered subsequently.

In order for family members to become expert in the care of the person with dementia, they need to learn more about dementia and how best to be supportive. Books, video tapes, links to websites (see list at the end of this chapter), and referral to national Alzheimer associations are all useful strategies.

Training and counselling programmes for caregivers have demonstrated e cacy in reducing caregiver depression and delaying nursing-home admission. Such programmes may be o ered through specialist centres, Alzheimer’s sssociations, or privately.

Mobilizing extended family and friends to provide support to the primary caregiver is more powerful than enlisting professional supports. A session with the extended family can be helpful in galvanizing support for the primary caregiver and working out strate- gies how best to cope now and in the future. Participants in the session can outline how children, family, and friends can help support the primary caregiver in his or her role and can lay the foundations for families to come together in a positive way.

Practical issues including enduring power of attorney, enduring guardianship, advance directives, driving, work and planning life decisions necessarily involve the family caregiver. Caregivers should be reminded of the importance of maintaining their own physical, social, and emotional health. Devoting the whole of one’s life completely to the per- son with dementia makes the caregiver vulnerable to breakdown and later, to severe

bereavement reaction.
Clinicians should make explicit what may be realistically expected from current thera-

pies and what hope there is from future developments and research.

.2.6.3 Early stage

Caregivers can be supported by the o er of continued counselling, meeting with other caregivers (e.g. through Alzheimer associations, virtual groups through online

CHAPTER  Dementia: the person and the caregivers

discussions), or more intensive and specialized treatment if caregivers su ering from a clinical depression. At this stage instrumental support is not usually required and the focus is on planning, legal, and nancial issues.

.2.6.4 Middle stage

In the middle stage, the increasing reliance on the caregiver means that he or she may need further assistance such as arrangements for in-home respite, day centre attend- ance, or residential respite. Caregivers may bene t from continued counselling, atten- tion to their own physical and psychological health, and access to nancial help or welfare bene ts if available.

The emergence of behavioural and psychological symptoms of dementia is particularly stressful for caregivers. Programmes to teach caregivers how to manage these behav- iours have been demonstrated to be successful, though sometimes medications may be required to reduce the level of behavioural disturbance in order to enable caregivers to institute psychosocial strategies. A meta-analysis of caregiver-administered interventions for community-dwelling persons with BPSD showed these were as e ective in reducing these symptoms as drug interventions though without the side-e ects. Online resources (including an app) for caregivers on how to manage BPSD are now available.

.2.6.5 Late stage

Paradoxically, as the person with dementia declines further, care may become easier as the demands are now more physical rather than emotional and many behavioural problems subside. On the other hand, the need for constant supervision, persistent ‘shadowing’, and the lack of opportunity for individual relaxation can be extraordinar- ily taxing. Caregivers can be supported by increasing the amount of community care, more frequent and longer periods of residential respite care, and the possibility of residential care placement.

.2.6.6 Caregivers and institutionalization

Placing a loved one in a nursing home can be very stressful for caregivers. Guilt, family friction, competing advice, nancial hardship, and the reaction of the person with demen- tia compound the emotional turmoil that accompanies the decision to place a partner or parent in a nursing home. However, guilt and distress subside and after some months the levels of depression in caregivers whose dependents have been placed in residential care are signi cantly lower than those who are still providing day-to-day hands-on care.

.2.6.7 Death

After the person with dementia dies, caregivers go through bereavement afresh. ‘The funeral that never ends’ has nally ended. While the caregiver has been going through a continual bereavement process as cherished parts of the person are gradually lost, the nal blow leads to more intense feelings. Spouses, for whom the centre of their world has been the daily care of their partner, suddenly have a deep void in their life. It takes time to mourn the nal passing of the loved one and re-establish life after dementia. Some caregivers will become clinically depressed; most will come through this and will bene t from the opportunity to express their feelings openly. Mobilization of family and friends to provide such support is helpful.

.2.6.8 Caregivers in developing countries

There is a misconception that caregivers in developing countries are less stressed because of larger, extended, often three-generational families. Research from

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Alzheimer’s Disease International 0/66 Group demonstrates that the levels of stress and burden are just as high in family caregivers in developing countries (see World Alzheimer Reports). The predictors of caregiver stress are similar across the world though certain behaviours are more distressing in some countries than others. Support programmes for caregivers in developing countries have been demonstrated to be successful. These take the form of education and counselling by primary healthcare workers.

.2.6.9 Caregivers and GPs

The general practitioner (GP) or primary care physician is the mainstay of continuing care between patient, family, health services, and aged care services. These ‘players’ must develop a partnership for the long haul for the management of dementia. It is prudent for GPs to review people with dementia and their caregivers periodically to determine how they are managing.

.2.6.0 Caregivers and the law

As a ected persons lose competency, caregivers assume greater responsibility and become the legal proxies for their charges. This includes giving informed consent for medications, giving informed consent for participation in research, managing nances, and arranging and agreeing to services. Legal requirements vary by jurisdiction but it is prudent for people with dementia to arrange durable power of attorney, enduring guardianship, and advance directives and attend to their will in the early stage of their condition.

.3 Conclusions

The challenges of dementia management evolve throughout the course of the dis- ease. Support for the person with dementia and the caregiver are crucial and takes many forms.

.4 Websites and apps

Alzheimer’s Disease International <http://www.alz.co.uk&gt;
Alzheimer’s Europe <http://www.alzheimer-europe.org&gt;
Alzheimer’s UK <http://www.alzheimers.org.uk&gt;
Dementias Alliance International (for people with dementia) <http://www.

dementiaallianceinternational.org/>

BPSD—app for clinicians to understand and manage behavioural and psychological symptoms of dementia

Care4Dementia—app for carers to understand and manage behavioural and psychological symptoms of dementia

References

Brodaty H. and Berman K. ‘Interventions for family caregivers of people with dementia’. In: R.T. Woods and L. Clare (eds.) Handbook of Clinical Psychology of Ageing, 2nd edn. Chichester: John Wiley & Sons, 2008, 2, pp. 549–69.

 

CHAPTER  Dementia: the person and the caregivers

Brodaty H. and Arasaratnam C. Meta-analysis of nonpharmacological interventions for neuropsy- chiatric symptoms of dementia. American Journal of Psychiatry 202;69(9):946–53.

Burns K., Eyers K., and Brodaty H. A Guide for Family Carers: Dealing with Behaviours in People with Dementia. 204 <http://www.dementiaresearch.org.au/BPSDGuide&gt; (accessed 5 November 205).

Seeher K. and Brodaty H. ‘Family carers for people with dementia’. In: J. O’Brien, D. Ames and A. Burns (eds). Dementia, 5th edition. Arnold: London, In press.

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Chapter 2

Safety, legal issues, and driving

Roy W. Jones

Key points

• It is important to respect a person with dementia’s autonomy as far as possible and recognize their remaining abilities and rights

• A person with dementia will usually reach a point where they cannot manage their own legal and nancial a airs

• The capacity needed to make a particular decision depends on the nature and complexity of that decision

• Whilst there are many potential safety issues, both inside and outside the home, it is important to balance the need for protection with the continuing independence of the person with dementia

• Driving is a particularly di cult issue; some people with early dementia may remain competent to drive but safety must remain a doctor’s main consideration

2. Introduction

A considerable number of practical and legal issues may be important for people with dementia and their families. Of necessity, they will be discussed in this chapter in a general way; it is important to be aware of the potential di erences from country to country when considering either legal issues such as consent or the rules which apply to drivers with memory problems or dementia. A doctor should be aware of the relevant information and legislation for their country or region; up-to-date advice can usually be obtained through appropriate medical organizations and organizations such as the Driver and Vehicle Licensing Agency (UK) and the Department of Motor Vehicles (US).

2.2 Autonomy

Ethical issues that arise when looking after people with dementia mainly relate to autonomy, which is increasingly compromised as the dementia progresses. However, a diagnosis of dementia is not synonymous with a lack of capacity. It is important to respect a person’s autonomy as far as possible and to recognize and respect a person’s remaining abilities and their human rights.

Human rights legislation within Europe is covered by the Convention for the Protection of Human Rights and Fundamental Freedoms (Council of Europe, 2003) and respect for autonomy is implicit throughout this Convention. On the other hand, strict adherence

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Box 2. Legal and nancial issues

Capacity to deal with nancial a airs
Capacity to make a will
Capacity to make decisions about personal welfare and medical treatment Capacity to participate in research

to the concept of the rights of the person with dementia may compromise the rights of other people such as family care givers, and this can create di culties.

2.3 Legal, nancial, and personal welfare issues

Almost everyone with dementia will eventually reach a point where they cannot man- age their nancial and legal a airs and they are also likely to need help with personal welfare issues such as their medical care. People with dementia show a reduction in memory, intellectual functioning, reasoning ability, insight, and judgement. These prob- lems are likely to impair the capacity of the individual to make certain decisions and this is the usual area of concern (see Box 2.). When making a decision, a person should understand the relevant information and be able to retain this information su ciently to make a decision based on the information given. Clearly the degree of capacity needed will depend on the nature of the decision being made and could also change over time (e.g. if someone is temporarily more confused because of an infection). An adult should be presumed to have capacity until it has been established that this is not the case.

Capacity is a legal concept and it is important, particularly for medical specialists responsible for the care of people with dementia, to be aware of national legislation and guidance relating to the assessment of capacity and other issues such as advance directives.

2.3. Capacity to deal with nancial a airs

2.3.. Power of attorney

A power of attorney allows one person (the donor) to give one or more people (the attorney) the authority to act on behalf of the donor and in their name in relation to issues surrounding property and nancial a airs. An Ordinary Power of Attorney is suitable for this purpose and, for example, would allow someone to act on another’s behalf with their bank account if the donor was going into hospital. An ordinary power ceases to be valid if the donor becomes mentally incapable and is not usually suitable for people with dementia since it ceases to be e ective at the very time when the donor most needs help.

2.3..2 Lasting or durable power of attorney

This type of power of attorney can either continue or come into e ect after the donor has become mentally incapable. It is important that the person has the capacity to understand the nature of a lasting power when they sign the relevant forms, and it may be necessary for a medical practitioner to con rm this at the time. The lasting power needs to be registered with the appropriate authority (the O ce of the Public Guardian in England and Wales: <http://www.gov.uk/o ce-of-public-guardian>) before it becomes active. Lasting Power of Attorney (LPA) in England and Wales was

CHAPTER 2 Safety, legal issues, and driving

created by the Mental Health Capacity Act 2005 and can deal not only with a person’s property and a airs but also with issues of personal welfare (see section 2.3.3.). LPA replaced the previous Enduring Power of Attorney (EPA), which only covered property and a airs. An EPA taken out prior to  October 2007 is still valid and can be used without being registered, but must be registered once the donor becomes unable to make their own decisions about nance and property. When making decisions, the attorney must act in the donor’s best interests and consider the person’s past and present wishes as well as not taking advantage of the donor to bene t themselves, and they must keep the donor’s money separate from their own.

Making an LPA can be reassuring for the donor since they can choose the person that would make a decision on their behalf when they are not able to do so. It can also reduce the likelihood of problems in the future. In the UK, if a person has not created a valid LPA or EPA but lacks the capacity to make a particular decision, then it may be necessary to involve the Court of Protection. The court can potentially make an order relating to the decision and/or appoint a deputy to make the decisions on someone’s behalf; this process can be both lengthy and costly.

2.3.2 Capacity to make a will

A will is a document that appoints someone (the executor) to deal with a person’s nances and a airs when he or she dies. Testamentary capacity describes the level of understanding that a person needs both when giving instructions for preparing the will and at the time of signing. The capacity needed to make a will is likely to be greater than that needed to sign a power of attorney, especially if the details of the will are complex. It is also important when changing a will that a person is aware of the previous will and the e ect of replacing it with an updated document.

Specialists and general practitioners are likely to be asked to advise on whether or not a person has the requisite testamentary capacity, and it is important to make a record of any examination or ndings in case of a future dispute.

2.3.3 Personal welfare, medical treatment, and consent for research

2.3.3. Health and welfare

In England and Wales, a health and welfare LPA came into force in October 2007 which for the rst time gave an attorney the power to make decisions about health and welfare issues such as day-to-day care (e.g. someone’s diet, what they wear, who they should have contact with, and what kind of social activities they should take part in), where the person should live, and medical treatment. This only takes e ect when the donor lacks capacity to make decisions, and the donor can restrict the types of decision the attorney can make on their behalf. They can also authorize the attorney to accept or refuse life-sustaining treatment on their behalf but it is important that the donor realizes that this can potentially overrule any previous advance decisions that they may have made.

2.3.3.2 Advance decisions, advance directives, and living wills

These allow a person to specify particular types of treatment that they do not want should they lack the mental capacity to decide this for themselves in the future. In gen- eral, such advance statements are legally valid but they should preferably be made in writing, and signed and witnessed. Where someone has not made an advance directive then decisions regarding care and treatment for a person who lacks capacity can be

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Box 2.2 Potential safety issues for people with dementia

• Problems within the home Fire, gas, and electrical safety Kitchen safety
Falls
Dangerous substances Medication
Poor judgement and gullibility

• Problems outside the home Getting lost and wandering
Falls Driving

made by someone else, for example by carers or professionals, so long as they try to act in the best interests of the person with dementia.

2.3.3.3 Research and genetic testing

It is important and possible for research to be carried out on people with dementia who lack capacity. There must, however, be safeguards to respect the rights of the person with dementia and to maintain their dignity. For example, the research must be approved by an appropriate body such as an ethics committee; it should relate to the person’s condition and it should be clear that the research would be less e ective or valid if it involved people who had mental capacity. There may be special issues about genetic testing of individuals with Alzheimer’s disease, particularly within the research context. Routine genetic screening is not recommended for people with Alzheimer’s disease; genetic testing may be appropriate in very rare cases (usually with an early age of onset) that are thought to be due to familial Alzheimer’s disease, but this should only be done after genetic counselling.

2.4 Safety

People with conditions like Alzheimer’s disease are prone to accidents and injuries because dementia impairs their ability to function within their normal physical and social environment. Issues concerning safety are frequently raised by members of the family and others and there are natural concerns that someone with dementia, par- ticularly if living alone, is vulnerable and at risk (see Box 2.2). Increasingly, technology is available to o er solutions to some of these issues including safety alarms, remote monitoring, simple phones, and TV remote devices. However, it is important to get the balance right between the need for protection and the person’s continuing inde- pendence. Advice about safety issues and possible solutions can be obtained from the Internet (see references), organizations such as the Alzheimer’s Society, and health professionals such as occupational therapists.

2.4. Problems within the home

Checking the safety of a person’s home may help to reduce the risk of potential problems; adapting the environment may be an easier option than trying to change a

CHAPTER 2 Safety, legal issues, and driving

person’s behaviour. By minimizing danger, it should be possible in many cases to maxi- mize continuing independence.

2.4.. Kitchen safety

It may be necessary to remove items such as sharp knives whilst leaving items for eve- ryday use within easy reach. If there is a tendency to put an empty pan on the stove or leave a pan to boil dry, it may be necessary to remove the cooker or isolate the gas or electrical supply so that it cannot be turned on by people themselves. Removing the knobs on appliances may discourage use except when supervised. The use of a kettle with a cut-o switch is recommended.

The person with dementia is likely to forget items in the fridge or freezer so that they pass their use-by date and are not safe to eat. It is important to check the situation as far as possible and remove mouldy or rotten food.

2.4..2 Fire, gas, and electrical safety

There are risks from re within the kitchen but also elsewhere and smoke alarms should be tted appropriately. Fires or heaters can be a danger so that it is important to use re-guards. Use of automatic timers can help regulate central heating and other devices so that the person does not have to alter anything yet does not become either too hot or too cold. There may be a risk of gas being left on yet unlit and detectors are available for this, or it may be necessary to isolate the supply. All gas and electric appli- ances should be serviced as appropriate.

Smoking may be hazardous and the person’s clothes and furniture should be re-resistant. Any wastepaper basket should be placed well away from where the per- son smokes.

2.4..3 Falls

A person may fall within the home because of frailty but the risk can be reduced. Poorly tting rugs or carpets, trailing exes, and poor lighting may contribute. Grab-rails should be available wherever necessary (e.g. on the stairs and in the bathroom), and a night- light may be advisable.

2.4..4 Dangerous substances

Dangerous substances such as bleach and disinfectants should always be stored in their original containers. Ideally they should be stored out of the reach of anyone at risk or in a locked cupboard.

2.4..5 Medication

Compliance with medication is more di cult for someone with a signi cant memory problem. They may either under- or over-dose, and the risk will depend on the medi- cation. Drugs such as warfarin or digoxin may be particularly dangerous unless the medication can be stored safely or only made available at the time of dosing. Use of weekly or daily dosing boxes may be helpful, making it possible to check what has been taken. It may be necessary for all medication to be supervised; for example, in the case of a diabetic receiving insulin.

2.4..6 Poor judgement and gullibility

People with Alzheimer’s disease may not be fully aware of the risks they take or the consequences of their actions. They may therefore make a mistake when carrying out a task such as using steps to reach a shelf.

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They are also vulnerable to unscrupulous people such as some door-to-door sales- men, to unsolicited mail in the post (e.g. telling them they are a prizewinner in a com- petition), and to cold-callers on the telephone. They should be encouraged to restrict entry into the home to outsiders unless expected (and as far as possible to always check the identity of such a visitor), and to be wary of telephone calls from strangers. It may be necessary to consider issues such as an LPA so that they cannot commit themselves to inappropriate nancial transactions.

2.4.2 Problems outside the home

2.4.2. Getting lost and wandering

People with dementia frequently become lost outside the home, especially in unfamil- iar places. They can end up many miles from home and are potentially vulnerable to becoming victims of crime or violence, or being exposed to severe weather. They are likely to be frightened and cause major concern to their families. It is important for them to carry identi cation including details of someone to contact in the event they become lost; electronic devices, and the use of GPS tracking devices are also possibili- ties to consider.

Wandering is a slightly di erent concept to getting lost and describes a tendency that people, usually with more advanced dementia, have of wanting to go beyond imme- diate surroundings. This is especially di cult if the person starts to wander at night. Wandering also makes someone potentially more vulnerable to crime or weather since they may not be wearing appropriate outdoor clothes. Outside doors should be kept locked and there may be the need to install additional locks or bolts, for example at the top or bottom of the door, or some form of alarm that gives an alert if someone goes outside. Attempts should also be made to understand if there is a reason for the wandering (e.g. an attempt to return to a previous house or searching for the toilet) when strategies can be developed to minimize the person’s desire to roam.

2.4.2.2 Falls

Falls when someone is outside the home may have a di erent aetiology to those within the home but can still cause problems and injury. Older people with dementia will respond more slowly, for example, to tripping on an uneven piece of pavement. They should therefore be encouraged to use a walking stick or other similar means of sup- port to give them increased stability.

2.5 Driving

Driving is a complex activity that requires good reactions, alert senses, and the ability to multitask; it becomes increasingly challenging as a person’s Alzheimer’s disease pro- gresses. Driving safety is a critical issue for people with dementia and may cause di cult issues for the person with dementia, their family and the physician as well as having repercussions for society at large. Concerns about older drivers, especially those with dementia, are increasingly mentioned by politicians and others. Family members often raise concerns about driving with the doctor yet nd di culty in discussing it directly with their relative. It may sometimes be the reason for the initial contact with the fam- ily doctor or the specialist. On the other hand, the patient may regard driving as their right and be unwilling or unaware, through reduced insight, to accept that there are problems. Losing the ability to drive represents a loss of independence and identity and may produce anger and denial and be especially di cult for those living in rural areas or

CHAPTER 2 Safety, legal issues, and driving

where there is little public transport available. There may be particular issues where a patient drives a vehicle for a living especially if it is a large vehicle such as a truck or bus. In such cases, special rules and a di erent type of driving licence may apply.

There are many other reasons why someone, particularly an older person, should not be driving, including visual impairment and reduced mobility, for example, as a result of arthritis. Many older people adopt more conservative driving strategies such as avoiding either the rush hour or night driving, and they may restrict their journeys to well-known routes and local destinations such as the supermarket. They may also decide voluntarily to cease driving at a speci c point such as when they need to buy a new car or following a signi cant period of hospitalization during which they have not driven.

It is always important to ask whether a patient does still drive and, if so, are there any problems or whether there have been any accidents or errors whilst driving. Some people, particularly with early dementia are still competent to drive although patients with AD who continue to drive are at an increased risk for crashes. Assessment within the clinic should take particular note of tests for attention, executive function (judge- ment), praxis, visuospatial and visuoperceptual function. Tests such as the Mini-Mental State Examination are probably not of themselves predictors of the risk of a motor vehicle crash (Joseph, et al., 204).

The patient (and their family) should be advised whether to stop driving or whether they can continue, at least for the time being. In some areas it is possible to arrange a for- mal driving assessment including an on road test, and this may be helpful. Where patients can still drive, it is worth discussing with them and their family that a time will come when they should give up driving to allow them to begin to accept and plan for this.

In all cases the decision of a doctor must conform to the relevant national or state regulations, and it is necessary to be aware of these. The individual may be required to notify national licensing authorities if they have a problem such as signi cant memory problems or dementia that may a ect their driving ability. This may be di cult for a person with cognitive and memory di culties; it may be necessary for the family or the doctor to carry this out, but this should, wherever possible, be carried out with the agreement of the patient. Such a declaration must also take into account any relevant rules about medical con dentiality. In many countries, advice may be obtained from medical assessors employed by the national licensing authority.

References

Useful lea ets and advice concerning legal, nancial, safety, and driving issues are available from national Alzheimer’s organizations, for example: <http://www.alzheimers.org.uk&gt;, and home safety for people with Alzheimer’s disease: <https://www.nia.nih.gov/alzheimers/ publication/home-safety-people-alzheimers-disease/introduction>.

Hort J., O’Brien J.T., Gainotti G., et al. EFNS guidelines for the diagnosis and management of Alzheimer’s disease. European Journal of Neurology 200. doi:0./j.468-33.200.03040.x.

National Collaborating Centre for Mental Health. Dementia: The NICE–SCIE guideline on sup- porting people with dementia and their carers in health and social care. National Clinical Practice Guideline Number 42. Leicester and London: British Psychological Society and Royal College of Psychiatrists 2007 <http://www.nice.org.uk&gt;.

Joseph P.G., O’Donnell M.J., Koon K.T., et al. The Mini-Mental State Examination, Clinical Factors, and Motor Vehicle Crash Risk. Journal of the American Geriatric Society 204;62:49–26.

Champlain Dementia Network and Regional Geriatric Program of Eastern Ontario. The Driving & Dementia Toolkit for Health Professionals, 3rd edn. June 2009. http://www.rgpeo.com/ media/30695/dementia%20toolkit.pdf.

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Chapter 3

The planning of appropriate medical and social care
in dementia
Marcel G.M. Olde Rikkert, Irena Draskovic,

and Myrra Vernooij-Dassen

Key points

• Alzheimer’s disease is probably caused by multiple disease processes that occur simultaneously, have a long pre-clinical history, and together cause a clinically signi cant decline of cognitive reserve

• The cognitive reserve theory is an attractive simple theory that may enable clinicians and researchers to formulate innovative research questions; however, it requires a rmer evidence base

• The diagnostic process in dementia rst consists of diagnosing which disease processes caused the cognitive decline, and next, what problems in care delivery are present and have to be resolved

3. Introduction

Dementia is a global epidemic in our ageing societies. However, both in the scienti c search for its cause and in medical practice we do not have a rm grip on this huge and devastating problem. With regard to the aetiology of dementia, we are currently moving from the classical hypothesis that dementia is caused by a few distinct and well-de ned disease entities (such as Alzheimer’s disease, frontal-lobe dementia, vascular dementia) to another pathogenetic hypothesis, in which each patient’s dementia is caused by a combination of slowly progressing, pathophysiologic processes such as Alzheimer-type pathology (i.e. neuro brillary (β-amyloid) plaques and tangles), tauopathies, synucle- inopathies, and vascular lesions. Consequently, in medical practice we must move from a classical disease model in which symptoms and signs correspond directly to a speci c disease to a model in which the goal is to have a tailor-made disease management programme for each individual patient, in which the diagnostic analysis of the hetero- geneity in both phenomenology and aetiology should be translated into individualized actions. In this way both the patient and the proxies can receive bespoke interventions, from the earliest stage until death. In this chapter we will describe these two transitions, both in pathogenesis and in medical practice, and link them to each other to establish a new model of dementia disease management.

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3.2 Alzheimer’s disease

In the most widely accepted diagnostic criteria for Alzheimer’s disease, the US National Institute on Aging (NIA) workgroups on Alzheimer’s disease, monocausality remains the cornerstone for the diagnosis of probable Alzheimer’s disease: the diagnosis can only be made if other possible explanations of dementia are absent or at least unlikely. These criteria are directed at monocausality—that is, the neurodegenerative cell loss mediated by the β-amyloid plaques and neuro brillary tangles—which is thought to be reliably based on the clinical and biomarker criteria. Comparison of the various clini- cal classi cations of Alzheimer dementia, however, has demonstrated that the some- what arbitrary criteria cause considerable di erences in the number of patients being diagnosed as having Alzheimer’s disease, and that the number of patients with mixed pathology is increasing with age. Nevertheless, for non-scienti c and strategic reasons, the disease concept of monocausality remains the core of the diagnosis of Alzheimer’s disease. Similarly, for the other types of dementia, the leading hypotheses started with the assumption of monocausality, which justi ed calling each of them a separate disease entity. In fact, the leading policy of the most recently published dementia consensus statements remains that each patient ful lling the criteria for the dementia syndrome should be investigated with the aim of establishing a probable or possible single-disease diagnosis. Contrary to this model, we will introduce a new model of multiple causality in dementia, which is supported by a growing amount of evidence, both in neuropatho- logical and imaging studies.

3.3 Mono- or multicausality

The way out of the classical controversies of age versus disease and monocausality ver- sus multicausality in dementia can only be found in research less biased by the classical theoretical framework of single disease classi cations. Several neuropathological land- mark studies have succeeded in circumventing several frequently present biases: bias by selection of speci c cases for necropsy, of speci c parts of the brain to be studied, of speci c staining techniques, and bias by focusing on the pathogenesis of a single type of dementia. The British Medical Research Council Study on Cognitive Function and Ageing (MRCCFA) is such a landmark study: neuropathological examination was carried out with strictly standardized methods, without knowledge of the clinical data, according to the widely accepted CERAD criteria for Alzheimer’s disease, Lewy body dementia, and vascular dementia. More than 80% of the cases, and a non- pathology consisting of small vessel disease (64%), lacunae (20%), infarctions (3%), or haemor- raghes (3%). Modern imaging studies con rm the high prevalence of global vascular pathology in Alzheimer’s disease, and the interaction of vascular pathology with medial temporal lobe atrophy, even in the stage of mild cognitive impairment. These data, con rmed and enforced by recent studies with unrestricted inclusion and complete pathology description (such as the 90+ Study), all argue against the hypothesis of monocausality of dementia and seriously question the nosological system of mutually exclusive, distinct types of dementia. On the contrary, with increasing age, more and more subjects su er from dementia by accumulation of various types of brain dam- age, crossing the borders of the classical diseases, all resulting in a limitation of the available cognitive capacity. The data also show a prominent presence of vascular and other brain pathologies in non-demented persons, suggestive of a slow but universal progression of these pathologies, causing an extremely long pre-clinical stage, which

CHAPTER 3 Medical and social care in dementia

 

Dementia: brain reserve theory
Normal Mild cognitive Impairment Dementia

Repair Compensation

Figure 3. Brain reserve theory: multiple di erent pathological processes (the forms inside the square) diminish the total available cognitive capacity (expressed by the total square surface).

is indistinguishable from normal ageing. In sum, dementia and the preceding stages of cognitive decline cannot be explained by ageing but are the net result of several slowly progressive pathological processes primarily located in the brain, which may be aug- mented by diseases not primarily located in the brain. In the brain the net sum of multiple diseases, compensatory mechanisms, and the premorbid level of cognition
(the maximum brain reserve) together determine the actual cognitive capacity a person
still has. This viewpoint on cognitive decline stems from the ‘cognitive reserve’ or ‘brain 113 reserve’ theory (Figure 3.).

3.4 Descriptive diagnostics

The way out of the monocausality impasse starts with a descriptive diagnostic phase which holds the key to adequate counselling and care. This initial assessment should describe the various domains of cognitive function, and the consequences of the decline in each domain for daily living, behaviour, mood, and thought, as well as the burden it causes to family and other proxies. Impairments in cognition, behaviour, func- tion, and proxy burden should be described and summarized. Key characteristics from this broad assessment of cognitive and behavioural impairments may also be combined in descriptive syndrome labels such as amnestic syndrome, dementia syndrome, apa- thetic syndrome, dysinhibition syndrome, without already referring to a certain cause (e.g. frontal syndrome).

3.5 Explanatory diagnostics

Parallel to this description, the diagnostic process should focus on the elucidation of the factors that cause the cognitive decline (see Table 3.). Neurodegenerative pathology (e.g. by amyloid β protein, tau and/or α-synuclein depositions), medical comorbid- ity (vascular, nutritional, endocrine, in ammatory pathology), psychiatric comorbidity, drugs, and trauma are among the possible causes of decline in brain function, however, interaction between speci c pathological processes complicates such a multicausal model. For example, interaction has been shown for vascular pathology and medial temporal lobe atrophy. Additionally, neuroplasticity (i.e. processes of repair and com- pensation) is present in the human brain.

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    

CHAPTER 3 Medical and social care in dementia

  

Table 3. Two-step cu

Dementia disease model

re and care model of deme

Diagnostic target

tia diagnostics and treatment

Therapeutic targets

st stage: cure- directed

Explanatory diagnostics: disease(s) assessment

Disease modi cation Clarify prognosis

2nd stage: care directed

Descriptive diagnostics: assessment of behaviour, personality, burden, and care

Symptomatic, select and monitor symptoms, arrange care, alleviate caregiver burden, arrange social care

114

n

The search for causal factors starts with a careful medical history, a complete physical and neurological examination, and a psychiatric interview, by indication may be followed by diagnostic investigations, such as laboratory tests (especially cerebrospinal uid test- ing), neurophysiologic tests (especially EEG) and neuroimaging (MRI, PET, SPECT). The aim of these investigations for individual patients is to explain the cognitive decline and to assess possibilities for intervention and secondary prevention. Explanatory diagnos- tics at the stage of pre-dementia or mild cognitive impairment may even give cues for primary prevention.

3.6 Dementia disease model
In sum, the new model of dementia assessment described here is determined by:

. The frequent presence of more than one cause for cognitive decline especially in older persons

2. The interaction between these causes in the overall presentation of symptoms and signs

3. The mechanisms of brain repair and compensation

4. The decline in the speci c domains and the occurrence of behavioural disturbances
Age per se does not play a role in this disease model. Age at onset of dementia only

is the sum of the age at maximum brain reserve and the additional years needed for the often slowly progressing factors to become manifest. This model, in which multiple causes contribute to decline in maximum organ function (cognitive or brain reserve) with increasing age, is also applicable to other degenerative processes often seen in older persons, such as osteoporosis, heart failure, and sarcopenia.

Thus, classical epidemiology methods, originating from the study of infectious dis- eases, have to be complemented by epidemiological methods that are t to study this multicausality model. We argue that in this context, it would be far better to refer to ‘Alzheimer-type pathology’ or ‘Alzheimer syndrome’ instead of the classical disease label of Alzheimer’s disease.

3.7 Multifaceted and personalized disease management

Finally, the two-step diagnostic process should result in state-of-the-art dementia disease management which addresses the problems elucidated in the assessment of cognitive decline and social resources, followed by individualized treatment of all con- tributing factors. This will result in a personalized, multifaceted disease-management programme for the patient and the family. This type of dementia disease management

 

CHAPTER 3 Medical and social care in dementia

is evidence-based, as multifaceted and personalized care has been found to be the most e ective approach for both persons with dementia and their carers. Personalized inter- ventions can be designed if not only the de cits but also the remaining cognitive and psychosocial resources are properly assessed. In addition, by taking into account cogni- tive problems and pathological processes at the same time, the prescription of multiple drugs and the compliance with these regimens will also be optimized. At the time of writing, drug treatment cannot cure or modify the disease course, but medical care by personal disease management, combining optimal drug and non-drug psychosocial therapy, can improve some of the symptoms and activate the remaining capacities.

3.8 Conclusions

Until recent years, the single disease hypothesis has dominated the eld of the demen- tias. It has become clear that the aetiology of dementia often is multi-factorial. Likewise, the complexity and heterogeneity of the clinical and social problems in dementia, requires a multifaceted approach in clinical practice. Therefore, the diagnostic work-up should consist of two stages, a descriptive and an explanatory phase. The descriptive stage will serve to characterize the de cits as well as the remaining capacities, and handle the care needs of the patients, family, and carers. The explanatory stage should support the diagnostic disclosure and the prognosis, assess potential reversible factors, and provide a basis for an individual disease management plan.

It should be made clear to patients and families that dementia is often multicausal or multicomponent disease, parts of which can be elucidated by current diagnostic procedures. In each individual case, the diagnostic work-up has to be agreed on by patient, proxies, and physician. For the patient and proxies, the quest for explanations and therefore the need for diagnostic investigations has to be weighed against other relevant factors such as quality of life, life expectancy, comorbidity, and the perceived burden of diagnostic investigations. For physicians, a priori likelihoods of potential causes and evidence based data on diagnostic validity and accuracy of the di erent tests, together with the patients’ preferences should guide the choice of diagnostic pro- cedures. Next, appropriate modules of treatment, psychosocial care, and counselling of patient and family should be combined in a tailor-made disease-management plan. To make this work, it is essential that the care resources are made coherent and easily accessible, and that di erent dementia care providers work together.

References

Vernooij-Dassen M. and Olde-Rikkert M.G.M. Personal disease management in dementia care. International Journal of Geriatric Psychiatry 2004;9:75–7.

McKhann G.M., Knopman D.S., Chertkow H., et al. The 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 20;7;263–9.

Neuropathology Group. Medical Research Council Cognitive Function and Aging Study. Pathological correlates of late-onset dementia in a multicentre, community-based popu- lation in England and Wales. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Lancet 200;357:69–75.

Snowdon D.A., Nun Study. Healthy aging and dementia: ndings from the Nun Study. Annals of Internal Medicine 2003;39:450–4.

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Doraiswamy P.M., Leon J., Cummings J.L., et al. Prevalence and impact of medical comorbidity in Alzheimer’s disease. Journal of Gerontology A 2002;57:M73–7.

Roe C.M., Xiong C., Miller J.P., et al. Education and Alzheimer disease without dementia: support for the cognitive reserve hypothesis. Neurology 2007;68:223–8.

Kawas C.H., Kim R.C., Sonnen J.A., et al. Multiple pathologies are common and related to demen- tia in the oldest-old: The 90+ Study. Neurology 205;85:535–42.

CHAPTER 3 Medical and social care in dementia

Chapter 4

Case vignettes

Valeria Manera, Elsa Leone, Jennifer Thompson, Roland Zahn, Alistair Burns, and Gunhild Waldemar

Case Managing behavioural and psychological symptoms in AD: apathy

Mr H. received a diagnosis of Alzheimer’s disease four years ago. He has been passion- ate about soccer since his youth, and played in a professional team for some time. He never missed a match on TV, and he used to attend games regularly. He used to read a sports newspaper every day. Now his wife reports that Mr H. spends most of the time sitting in his armchair, completely inactive. He does not spontaneously ask for the sports newspaper but if he sees it on the table he reads it. If someone starts to talk about a picture or an article found in the sports pages, he engages in the conversation. Similarly, when his son asks him to go to the stadium, he accepts and seems satis ed.

Suggestions for non-pharmacological treatment of apathy

• Identify the preserved skills, with a special focus on the responses to external stimulation • Stimulation is important but it is crucial also to maintain resting periods

Lack of initiative

• If the patient does not spontaneously engage in goal-directed behaviours, try to prompt him/her to perform simple everyday activities meeting his/her interests

• Try to work as a ‘starter’

• Start an activity with the patient and then ask him to continue alone

• Propose an activity several times in order to establish a routine so that eventually the patient can start initiating the activity him/herself

Lack of interest

• Identify the patient’s interests, and talk about them

• Talk with the patients about his/her interests and hobbies, or previous work. Try to dig deeper with at least one interest to understand if it is possible to propose an activity that can stimulate this interest

• Don’t hesitate to propose new activities

• Propose an activity meeting the patient’s interests every day; it is important to repeat the activity routinely

• Try to highlight the importance of the activity for everyday life

• Attention should be directed towards the importance of the activity for the everyday family or group functioning

117

118

Emotional blunting

• Try to facilitate emotional expression

• Engage the patient in activities that involve social interactions and exchanges

• Put the accent on experienced emotions (‘This afternoon was really fun, thanks for coming with me’)
• Highlight the importance of the participation to activities of daily living

• Congratulate the patient, and remind him/her the importance of the activities he/she

is doing

Case 2 Posterior cortical atrophy

Sandra, a 57-year-old woman was referred to a specialist early-onset dementia clinic from local adult psychiatric services with a history of anxiety and mild memory prob- lems. She was on long-term sick leave from her role in retail customer services. She attended with her husband. Both reported Sandra had been anxious and low in mood for two years and that her memory was less good than it had been. They did not spontaneously report visual symptoms but when asked speci cally, Sandra said that she needed new glasses because she had been struggling to read and see clearly. Her husband reported that she was slow to nd what was ‘under her nose’ when looking for something. On a recent visit to a department store, she failed to meet her husband at their usual designated place, having been unable to nd her way there. They did not report any problems in speech but said that Sandra could struggle to follow group conversations and had become very anxious and ‘clingy’ in social gatherings. Aside from anxiety and intermittent low mood no personality change was reported. She was generally independent but her husband had gradually taken on more household tasks including most of the cooking. Neurological examination was normal aside from a dif- culty detecting bilaterally presented visual stimuli on visual eld testing, poor tactile localization, and inability to copy hand postures.

During the neuropsychological assessment she had a warm a ect but was highly anxious and became tearful on several occasions. She had di culty ‘taking in’ task instructions and frequently asked for repetition. The assessment revealed di culties predominantly in visuoperceptual and visuospatial function. On standard naming tests she had di culty identifying line drawings; for example, naming handcu s as ‘glasses’ and a shuttlecock as ‘a bunch of owers’. She reported glare when looking at visual stimuli and tilted pages in an attempt to alleviate this. She could read single printed letters and words but was unable to complete a paragraph because she kept losing her place in the text. On speci c assessment of visual perception and spatial function she was unable to identify fragmented letters and made errors in counting dot arrays. She could not complete copies of simple line drawings, producing only isolated fragments. Despite the report of memory problems she was fully orientated in time and place and could provide information about recent personal and current news events. She has a reduced digit span of 4 and, in keeping with this, was easily overloaded with verbal information, often asking for questions or instructions to be repeated. On a verbal memory test her free recall was poor but she retained this limited information over a 30-minute delay.

The clinical picture, with prominent progressive de cits in visuoperceptual and visu- ospatial function, together with impairment of immediate ‘working’ memory, was in keeping with posterior cortical atrophy. A subsequent MR scan showed bilateral

CHAPTER 4 Case vignettes

occipital and posterior parietal atrophy. Of note was that the patient, although insight- ful into cognitive di culties, did not spontaneously report visual di culties and could describe these only in vague terms.

Case 3 The singing lady

The ‘singing lady’ presented to a memory clinic service at age 60 with no previous psychiatric or neurological history and no family history. She had been on sick leave for nine months because of inappropriate social behaviour at work. Her husband recalled the rst signs of her behavioural changes to have occurred insidiously about three to ve years earlier. Her behavioural changes had slowly worsened, with kissing customers at work and singing to them. She had developed a love of Sudoku puzzles and excessive ritualized cleaning. Over the past six months, problems with naming and recognizing objects (e.g. saying ‘cupboard’ instead of ‘fridge’, i.e. semantic paraphasias; and, for example, not recognizing shoe laces: ‘What is that?’). Her memory for recent events was good and she had never been lost. In conversation, she was uent and appeared to understand most things with very mild signs of naming problems.

On neuropsychological examination, she showed a score of 74/00 on the Addenbrooke’s Cognitive Examination with impairments on memory, language, and u- ency subtest scores, but intact attention and visuospatial subtest scores. More detailed neuropsychological test examination revealed mild impairments on naming, non-verbal semantic tests, as well as comprehension (word-to-picture matching). The neurological examination was normal.

According to the Lund–Manchester criteria, we made the diagnosis of a behavioural variant of frontotemporal dementia with secondary features of semantic dementia. Her MRI scan revealed a focal atrophy of the right anterior temporal lobe (see Figure 4.) with intact volumes in the left temporal lobe and frontal lobes, as well as the precuneus and parietal lobes.

This con rmed the diagnosis, although some colleagues would have made the diag- nosis of a right hemispheric variant of semantic dementia, based on the cross-sectional impression and the MRI scan.

 

Figure 4. Coronal MRI section showing focal right anterior temporal atrophy.

119

CHAPTER 4 Case vignettes

120

 

Case 4 Early diagnosis

A 72-year-old retired school teacher was referred to the memory clinic as her husband had noticed a gradual withdrawal from social activities which she had previously enjoyed, such as going to the library and inviting friends for dinner. In addition, she would some- times ask the same questions again and again. Her 73-year-old husband was still active part-time in his profession as an accountant. She performed most activities of daily liv- ing independently, although she had di culties keeping track of her personal accounts and operating her mobile phone. She did not have any subjective complaints but she accepted the referral to the memory clinic. Her neurological examination was normal apart from a clear amnesia and some word- nding di culties. She felt uncomfortable during the interview with lack of insight, but there were no signs of a major depres- sion. The MMSE score was 28/30, and on neuropsychological examination she had pronounced impairment of learning and episodic memory, anomia, and some executive dysfunction. Her blood test screening was unremarkable, and the MRI demonstrated mild bilateral temporal lobe atrophy. It was concluded that she met clinical core criteria for probable AD. Because her symptoms were still relatively mild, the memory clinic physician decided to add CSF analysis and FDG-PET. The CSF had normal cell count, but signi cantly reduced Aβ-42 and elevated phoshpo-tau, with normal total-tau. The FDG-PET demonstrated characteristic bi-temporo-parietal hypometabolism.

The nal diagnosis was Alzheimer’s disease.

CHAPTER 4 Case vignettes

Index

Figures are denoted by f, tables by t and boxes by b after the relevant page number.

A

Aβ peptide 9, 11
in amyloid plaques 9

acalculia 36 accidents 106 acetylcholinesterase

inhibitors see cholinesterase inhibitors

activities of daily living (ADL) 1, 31b

assessment 50

history taking 48 AD see Alzheimer’s disease (AD)

ADAMs enzymes 11 advance care planning

(ACP) 86b–7, 105–6 advance directives

105–6 age

and AD 13 dementia prevalence

18f, 19f ageing, pathological

changes 113 aggression/agitation 8 agnosia 36
agraphia 36
alcohol abuse 4
alexia 36
α-secretase 10f, 11 Alzheimer, Alois 1 Alzheimer associations

95, 98 Alzheimer Disease

Cooperative Study

(ADCS) 50 Alzheimer’s disease

(AD) 112
atypical 31–2, 35–41 clinical course 27–33 criteria 2–5, 44, 45b,

46b
diagnosis 2–5, 43–53 di erential diagnosis

47b–8
disease course 30–1 early-onset 39–40 epidemiology 2,

17–25
familial 9–10, 21, 40 frontal variant 40 lead symptoms 4f neuropathology 2,

7–9
outcomes 61–2 pathophysiology 7–15

pharmacological treatment 61–9, 67f, 68b

prevention 23–4 protective factors

20f–1
risk factors 13–14, 20f–1

Alzheimer’s disease Assessment Scale (ADAS-Cog) 30, 63

amnestic mild cognitive impairment 24, 28 amyloid (Aβ) 3–4, 7, 9

binding partners 11–12

toxicity 11–12
amyloid β-peptide binding

protein alcohol dehydrogenase (ABAD) 11–12 amyloid hypothesis 10

amyloidogenic pathway 10f–11

amyloid PET 51–2 amyloid plaques 7 amyloid precursor

protein (APP) 9,

10f–11, 40 anhedonia 30 anti-dementia drugs

61–9, 67f, 68b, 74,

75t, 76–7 antidepressants 76–7 antihypertensive therapy

21
antioxidants 23 antipsychotics 76 anxiety 118
apathy 30, 117–18 aphasia 4, 5 APOE-epsilon4 allele

21, 27
APOE gene 21 apolipoprotein E 13–14 apperceptive agnosia 36 apraxia 36, 37
assistive technology 87 attention impairment

4, 5, 29
atypical clinical variants

31–2
atypical presentations of

AD 35–41 autoimmune

encephalopathies

3, 4, 5
autonomy 103–4 awareness see attention

impairment; insight

B

Behave-AD 50 behavioural and psychological

symptoms of dementia (BPSD) 4, 5, 29–30, 71–84, 72f

assessment 50 caregiver stress 97 evaluation 50, 73, 74b management 72f, 74b non-pharmacological

treatment 77,

78–9t, 80 pharmacological

treatment 74, 75t,

76–7 benzodiazepines 77

bereavement reaction 86 β-secretase 10f, 11, 14 β-site APP cleaving

enzyme (BACE) 11 biomarkers 3–4, 22, 45b,

46b, 51, 51
blood tests, di erential

diagnosis 2, 3 BPSD see behavioural

and psychological symptoms of dementia

brain-derived neurotrophic factor (BDNF) 12

brain reserve theory 113f

C

calcineurin 12 calcium-channel blockers

21
calcium homeostasis,

dysregulation of 11 cAMP-response element

binding protein

(CREB) 12
cancer, occult 3, 4, 5 capacity as legal concept

86, 87b, 104, 105 carbamazepine 77 caregivers 96

changing role 97 con ict with 97 developing countries

99–100 diagnosis disclosure

55–9 and GPs 100

history from 2–5, 48–9b

legal issues 100 relationship with patient 97

support for 96–100

training 79t
care managers 96
care planning 111–16 care providers 96
case histories 117–20 causal factors 114 cerebral blood perfusion

23
cerebral dysfunction 71 cerebral pathology 2, 7–9 cerebrospinal uid (CSF)

2, 3, 4, 51 cerebrovascular amyloid 8

cerebrovascular disease 21–2

cholesterol levels 22 cholinergic hypothesis 64 cholinesterase inhibitors

(ChEIs) 40, 64 action of 74–5
BPSD treatment 74–5 in consultation 94 galantamine 62, 64, 65 rivastigmine 62, 65–6 withdrawal 75

chromosome cigarette smoking

and dementia 21, 23

safety 107 citalopram 76–7 clinical course of AD

27–33
support needs 93–6

Clinical Dementia Rating scale-sum of boxes (CDRSB) 63

clinical history 2, 3f, 48–9b

clinical practice, AD diagnosis

Clinicians Global Impression of Change (CIBIC-Plus) 63

cognitive decline 1, 5, 19–20

assessment 50 caregiver stress 97 coping strategies 97–9 di erential diagnosis

47b–8
history taking 2–5,

48–9b

121

122

cognitive decline (Cont.) predictors of 19 stages of 113 treatments

antihypertensive drugs 21

ChEIs 61–9, 67f, 68b

non-pharmacological 77, 78–9t, 80

cognitive neuropsychology 77

cognitive stimulation 79t cognitive symptoms

28–9f, 43, 94 di erential diagnosis

47b–8
cognitive tests 49–50b combination therapy

66, 68
community care 96, 99 comorbidity 50
complex leisure activities

22
complex problem

solving 29 compliance with

medication 89, 107,

115
computed tomography

(CT) 2, 3, 4, 51 con dence, loss of 95 con dentiality and

diagnosis in disclosure

55–9
confusional states 4, 5 congophilic angiopathy 8 consent for research 106 consent to medical

treatment, capacity in

86, 87b, 104, 105 constipation 90 constructive apraxia 29f cortical atrophy 4, 5,

32, 35–6
course of disease 30–1 Creutzfeldt-Jakob disease

3, 4, 36
CSF see cerebrospinal

uid
CT see computed

tomography cyclizine 89

D

dangerous substances 107

death 30, 99
delusions 29, 49, 63b, 71,

74, 75
dementia disease model

114
dementia disorders 1–7

behavioural and psychological symptoms of

(BPSD) 50 causal factors 114 diagnosis 2–5, 44b di erential diagnosis

2–7
epidemiology 2, 17–25

management 72f, 74, 74b, 75t, 76–7, 78–9t, 80

support in 93–101 dementia with Lewy

bodies see Lewy-Body

dementia dependency 95, 96 depression 8, 22, 30

in caregivers 97, 98, 99 memory impairment

in 47b
response to medication

76–7
Describe, Investigate,

Create, and Evaluate

(DICE) approach 74b descriptive diagnostics

113
developing countries,

caregivers in 99–100 diabetes

dementia risk 21 medication compliance

107 diagnosis 43–53

criteria 2–5, 44, 45b, 46b

support at 93–4b, 98 Diagnosis and Statistical Manual (DSM-5) 44

diagnostic disclosure 55–9

behaviours 56t
for caregivers 58 reaction to diagnosis 58 support in 58 uncertainty in 57

diagnostic uncertainty 57 di erential diagnosis of

AD 47b–8
di usion tensor-weighted

MRI 3 digoxin 107

Disability Assessment for Dementia (DAD) 50 disclosure see diagnostic

disclosure
distress, management of

89–90
donepezil 62t, 64 dopamine transporter

scanning (DAT

scan) 52
dorsal raphe 8
Down’s syndrome 9 driving 94b, 103, 108–9 drug treatment 61–9,

67f, 68b dyspnoea 90 dyspraxia 28

E

early diagnosis 120 early-onset AD 39–40 early stages dementia

95, 98–9 educational attainment

22, 27
electrical safety 107 electroencephalography

(EEG) 2, 3, 4, 31, 52

emotional blunting 118 emotional lability 44b,

49b
emotional stress of

caregiver 48, 97 emotional support 86, 88 encephalopathies,

di erential diagnosis

2, 3, 4, 5
end of life care 85–91 enduring power of

attorney see Power of

Attorney environmental

intervention 78t epidemiology of

dementia disorders

17–25 episodic memory

impairment 49 ethics

autonomy and 103–4 consent for research

106
diagnosis disclosure

55–9
European Federation of

Neurological Societies

(EFNS) 48, 63 Europe, dementia prevalence 18

executive function impairment 29

explanatory diagnostics 113–14t

F

falls and trips 107, 108 familial Alzheimer’s

disease (FAD) 9–10,

21, 40
family history in AD

9–10, 52 family members

as caregivers 80, 86, 87, 88

diagnostic disclosure 55–9

information needs 67f, 94

training 79t nancial a airs 94b,

104b–5
nancial hardship 97 re safety 107 uctuating confusional

states 4, 5 uid-attenuated-

inversion-recovery (FLAIR) images 2, 3, 51

uoro-deoxy-glucose positron emission tomography (FDG-PET) 36, 38f

frequency of AD 2 frontal abilities,

impairment 29
frontal variant AD 40 frontotemporal dementia

(FTD) 2, 4, 5, 47, 98, 119f

of Parkinson’s type with chromosome (FTDP) 12

frontotemporal lobar degeneration 5, 37

Functional Activities Questionnaire (FAQ) 50

functional decline 19, 30, 69 future care planning 57,

58, 86

G

galantamine 62t, 64, 65 γ-secretase 10f, 11
gas safety 107
genetic hypothesis of

AD 21
genetics of AD 9–10 genetic susceptibility 14 genetic testing 52 Genome Wide

Association Studies

(GWAS) 14 Gerstmann syndrome 32 getting lost 108
glial brillary acidic

protein (GFAP) 8 Global Deterioration

Scale (GDS) 32 global prevalence of dementia 17–20

glucose metabolism 4f, 36, 51

glutamate 8, 66 glutamate antagonists

62, 66
grey matter decrease 4f group support 93, 95, 98 gullibility 108

H

haloperidol 89 handwriting 28
head injuries 22 head-turning sign 48 health care assistants 77 health and welfare 105 high density lipoprotein

(HDL) particles 13 hippocampus 8, 9

atrophy 8
history taking 2–5, 48–9b human rights issues

103–4
Huntington’s disease 47 hyperinsulinaemia 21 hyperphosphorylation of

tau 13 hypertension 21

I

ICD (WHO) on dementia disorders 44b

incidence of AD 17–20 Independent Mental

Capacity Advocate (IMCA) 86–7

Index

in ammation 12 in ammatory

encephalopathies 3, 4 inflammatory markers

22
in ammatory response

to amyloid 12 insecurity, feelings of 95 insight, lack of 29 institutionalization

19–20, 99 insulin-degrading enzyme

(IDE) 9
intellectual stimulation 23 International Working

Group (IWG-2), criteria for dementia 45, 46b

interview, history taking 2–5, 48–9b

K

kinase activity 13 kitchen safety 107

L

laboratory tests in di erential diagnosis 3, 51

lacunar infarcts 51 language impairment 1,

4, 5, 28 logopenic variant

progressive aphasia

37, 39 Lasting Power of

Attorney (LPA) 86b,

87, 104–5
late stage dementia 96

caregivers’ needs 99 lead symptoms 2–5 legal issues 94b, 104b

for caregivers 100 diagnosis disclosure

55–9
history taking 2–5,

48–9b
leisure activities, complex

22 leucoencephalopathy 51 levomepromazine 90 Lewy-body dementia 5

di erential diagnosis 4, 5, 36, 47, 49

treatment 94
life planning 94b lifestyle modi cation in

dementia prevention

23
limbic system 9 Liverpool Care Pathway

89
living bereavement 86 living wills 105–6 locus coeruleus 8 logopenic variant

progressive aphasia

37, 39
lumbar puncture, CSF

analysis 51

M

magnetic resonance imaging (MRI) 3, 4, 5, 36, 38f, 39, 51, 119f

medial temporal lobe atrophy 5

medical codes of ethics see ethics

medical treatment see treatment

medication compliance 89, 107, 115

medicines, safety issues 106b

memantine 62t, 66, 75 memory impairment

1, 8, 28
tests of 28
see also episodic

memory impairment; recent memory impairment

men, AD incidence 19 Mental Health Capacity

Act (2005) 86, 105 microtubule network 12 midazolam 90
middle stage dementia

95–6, 99 mild cognitive

impairment (MCI)

31b, 44, 95 criteria 44b treatment 63b

Mini-Mental State Examination (MMSE) 30, 49

mitochondrial damage 11

mixed dementia 2, 5 moclobemide 76 money management see

nancial a airs monoamine oxidase

inhibitor (MAOI) 76 monocausality 112–13f Montreal Cognitive

Assessment (MOCA)

63
mood stabilizers 77 motor activities, apraxia

36, 37
motor stimulation 79t MRI see magnetic

resonance imaging multicausality 112–13f multifaceted disease,

management 114–15 multiple causality in

dementia 112 myoclonus 49

N

National Institute of Aging, criteria for dementia 45b, 46b

National Institute for Health and Clinical Excellence (NICE) 88

nausea and vomiting 89–90

nerve growth factor (NGF) 9

neuro brillary tangles 2, 8f, 9, 13, 112

neuroimaging 3, 4, 5 neuroleptics 75, 76 neurological examination

49
neurological symptoms 4 neuronal injury,

biomarkers for 45b,

46b, 51 neuropathology in AD

5, 7–9 Neuropsychiatric

Inventory (NPI) 50 neuropsychiatric

symptoms 27 neuropsychological test

pro le 3, 4, 36 neutral endopeptidase

(neprilysin) 9 nitric oxide (NO) 12 nitric oxide synthase,

inducible (iNOS) 12 N-methyl D-aspartate (NMDA) receptor

antagonists 62t non-pharmacological

treatment 77, 78–9t,

80 non-steroidal

anti-in ammatory

drugs (NSAIDs) 22–3 normal pressure

hydrocephalus 4, 47 nursing homes 99

delay in admission to 98 management strategy

80–1b nutrition 4, 23

O

obesity 23
oestrogen therapy 23 olanzapine 76
onset of symptoms 27–8 optic apraxia 36
optic ataxia 36 outcomes in AD 61–2 oxidative stress 20t

P

paired helical laments (PHF) 8

palliative care 85–91 symptom management

88–9 parieto-temporal areas 51 Parkinson’s disease with

dementia (PDD) 5, 47 pathophysiology of

Alzheimer’s disease 7–15 patient-caregiver

relationship 97 patients

diagnosis disclosure 55–9 history taking from 2–5,

48–9b support for 93–6

patients’ rights 103–4 peptide Aβ see

peptide personalized care plan

114–15
PET see positron

emission tomography pharmacotherapy 61–9,

67f, 68b
physical activities 22 physical examination 30, 49 Pick bodies 5
Pick’s disease 2
planning and organisation

29
poor judgement 107 positron emission

tomography (PET) 51 posterior cingulate 5 posterior cortical

atrophy 4, 5, 35–6,

38f, 118–19
Power of Attorney 86b,

94b, 104 pre-diagnosis support

93, 97–8
preferred place of care

87–8 presenilin 40

presenilin gene mutations 40

prevention of AD 23–4 primary prevention 23–4 prochlorperazine 89 prognosis 57–8, 88–9 progressive aphasias 4

logopenic variant 37, 39

protective factors for AD 20f–1

psychological symptoms 71–84

psychosocial hypothesis 22

psychosocial stimulation 78t

psychotherapy 77, 78t, 80

psychotropic drugs 75t, 76–7

public health, dementia prevalence

Q

quality of life 94 non-pharmacological

therapies 77,

78–9t, 80 pharmacotherapy in

61–9, 67f, 68b quetiapine 76

R

rapid decline in ability 3, 4

reactive oxygen species 11, 12

recall de cit 49 recent memory

impairment 4, 5

123

Index

124

receptor for advanced glycation endproducts (RAGE) 8

red ags 47 relationship,

patient-caregiver 97 research, consent for 106 residential care

placement 96 reversible cognitive

symptoms 47b right to know 93 risk factors for AD

13–14, 20t–1 risperidone 76, 77 rivastigmine 62t, 65–6 ryanodine receptors

single photon emission computed tomography (SPECT) 36, 52

sleep disturbance 49b smoking and dementia

21, 23
social functioning 5 speech impairment 4, 5 spouses

diagnosis disclosure 55–9 see also caregivers;

family members stages of AD 32

stigma 44, 55, 94 stress in caregiving 97 strokes, multiple 5 subacute onset of

temporal lobe atrophy 45b, 46b, 51

terminal agitation 90 testamentary capacity

105
thio avin S 8f thyroid dysfunction 4 timing of diagnosis

disclosure 57 treatable mild cognitive

impairment 24,

51, 52 treatment

capacity to consent to 86, 87b, 104, 105 non-pharmacological

V

vascular dementia 5, 19 and alcohol abuse 21 di erential diagnosis

47, 51 treatment 94

vascular hypothesis for AD 21–2

vascular pathology in dementias 112

visitors, unscrupulous 108 visual hallucinations 5 visual perception, agnosia

36
visuospatial impairments

4, 28, 29f, 36 vitamin B12 4

wandering 108
warfarin 107
white matter disorders

5
will making, capacity

in 105
women, AD risk 19 work, cognitive decline

and 94b
written information 94

(RYRs) 11
S 88–9 76 W

safety issues 106b–8 secondary prevention 24 seizures 4, 31
selective serotonin

re-uptake inhibitors

(SSRIs) 76
semantic dementia 4–5 senile plaques 2 sensory stimulation 78t severity of AD 31b

symptom onset 2, 9, 14, 20, 22, 73, 106, 114, 118

synaptic formation, impaired 11–12

T

tacrine 64–5
tau 8, 12–13, 51 temporal cortex 8f

tumour necrosis factor-α converting enzyme (TACE) 11

tumours 4
two-step cure and care

model 114t U

unsolicited mail 108

symptoms 3, 4 subjective complaints 31b symptom management

67f, 68b
tricyclic antidepressants

77, 78–9t, 80 pharmacological 61–9,

Index

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