Non‐Alzheimer’s and Atypical Dementia

Non‐Alzheimer’s and Atypical Dementia

Edited by

Michael D. Geschwind, MD phD

Memory and Aging Center Department of Neurology
University of California, San Francisco San Francisco, CA, USA

Caroline Racine Belkoura, phD

Department of Neurological Surgery University of California, San Francisco San Francisco, CA, USA

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Library of Congress Cataloging‐in‐Publication Data

Non-Alzheimer’s and atypical dementia / edited by Michael D. Geschwind, Caroline Racine Belkoura. p. ; cm.

Includes bibliographical references and index.

ISBN 978-1-4443-3624-5 (cloth)
I. Geschwind, Michael D., editor. II. Belkoura, Caroline Racine, editor.
[DNLM: 1. Dementia. 2. Alzheimer Disease. 3. Neurobehavioral Manifestations. WM 220]

RC521 616.8′3–dc23

2015036764 A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Set in 9.5/12pt Minion by SPi Global, Pondicherry, India

1 2016

Contents

Notes on contributors, vi

. 1 Introduction, 1
Michael D. Geschwind and Caroline Racine Belkoura

. 2 The multidisciplinary evaluation of the atypical dementia patient, 6
Michael D. Geschwind and Caroline Racine Belkoura

. 3 Atypical Alzheimer’s disease, 17 Sharon J. Sha and Gil D. Rabinovici

. 4 Vascular cognitive impairment: Diagnosis and treatment, 30
Helena C. Chui and Liliana Ramirez-Gomez

. 5 Frontotemporal dementia, 49 David C. Perry and Howard J. Rosen

. 6 Lewy body dementias (DLB/PDD), 64 Carol F. Lippa and Katherine L. Possin

. 7 Corticobasal degeneration and progressive supranuclear palsy, 77
Suzee E. Lee and Bruce L. Miller

. 8 Repeat expansion diseases and dementia, 90 Praveen Dayalu, Roger L. Albin and Henry Paulson

9 Prion diseases and rapidly progressive dementias, 103 Leonel T. Takada and Michael D. Geschwind

10 Autoimmune dementias, 123 Andrew McKeon and Sean J. Pittock

11 Toxic and metabolic dementias, 134
Michelle Mattingly, Katie Osborn and Leon Prockop

12 Leukoencephalopathies/leukodystrophies, 150 Gregory M. Pastores and Swati A. Sathe

13 Infectious causes of dementia, 170
Cheryl A. Jay, Emily L. Ho and John Halperin

14 Rheumatologic and other autoimmune dementias, 186 Laura J. Julian and Christopher M. Filley

15 Comprehensive management of the patient with an atypical dementia, 202
Jennifer Merrilees, Cynthia Barton, Amy Kuo and Robin Ketelle

Index, 215

Notes on contributors

Roger L. Albin, MD

Anne B. Young Collegiate Professor of Neurology University of Michigan
and
Chief, Neuroscience Research, VAAAHS GRECC Ann Arbor, MI, USA

Cynthia Barton, RN MSN

Nurse Practitioner
Health Sciences Assistant Clinical Professor Memory and Aging Center
Department of Neurology
University of California, San Francisco
San Francisco, CA, USA

Caroline Racine Belkoura, PhD

Assistant Professor
Clinical Neuropsychologist Department of Neurological Surgery University of California, San Francisco San Francisco, CA, USA

Helena C. Chui, MD

McCarron Professor and Chair Department of Neurology
Keck School of Medicine University of Southern California Los Angeles, CA, USA

Praveen Dayalu, MD

Assistant Professor Department of Neurology University of Michigan Ann Arbor, MI, USA

Christopher M. Filley, MD

Professor of Neurology and Psychiatry Director, Behavioral Neurology Section University of Colorado School of Medicine and

Neurology Service Chief Denver VA Medical Center Denver, CO, USA

Michael D. Geschwind, MD PhD

Professor of Neurology
Michael J. Homer Chair in Neurology Memory and Aging Center Department of Neurology
University of California, San Francisco San Francisco, CA, USA

Liliana Ramirez-Gomez, MD

Adjunct Assistant Professor of Clinical Neurology Department of Neurology
Keck School of Medicine
University of Southern California

Los Angeles, CA, USA

John Halperin, MD FAAN FACP

Medical Director
Atlantic Neuroscience Institute
Summit, NJ, USA
and
Professor of Neurology & Medicine
Sidney Kimmel Medical College of Thomas Jefferson University Philadelphia, PA, USA
and
Chair, Department of Neurosciences
Overlook Medical Center
Summit, NJ, USA

Emily L. Ho, MD PhD

Clinical Instructor in Neurology University of Washington
and
Neurohospitalist

Swedish Neuroscience Institute Seattle, WA, USA

Cheryl A. Jay, MD

Health Sciences Clinical Professor of Neurology University of California, San Francisco
and
Neurology Service

San Francisco General Hospital (SFGH) San Francisco, CA, USA

Laura J. Julian, PhD

Assistant Professor of Medicine University of California, San Francisco San Francisco, CA, USA

Robin Ketelle, RN MS

Clinical Nurse Specialist
Health Sciences Assistant Clinical Professor Memory and Aging Center
Department of Neurology
University of California, San Francisco
San Francisco, CA, USA

Amy Kuo, RN MS GNP‐BC

Nurse Practitioner
On Lok Lifeways
San Francisco, CA, USA

Suzee E. Lee, MD

Assistant Professor of Neurology Memory and Aging Center Department of Neurology
University of California, San Francisco San Francisco, CA, USA

Carol F. Lippa, MD

Professor and Interim Chair
Department of Neurology
Director, Memory and Cognitive Disorders Program Drexel Neurosciences Institute
Drexel University College of Medicine
Philadelphia, PA, USA

Michelle Mattingly, PhD ABPP

Assistant Professor
Departments of Psychiatry and Behavioral Neurosciences and Neurology University of South Florida College of Medicine
Tampa, FL, USA

Andrew McKeon, MD

Associate Professor of Neurology, and Laboratory Medicine and Pathology Neurologist, Department of Neurology
Co‐Director, Neuroimmunology Laboratory
Mayo Clinic

Rochester, MN, USA

Jennifer Merrilees, RN PhD

Clinical Nurse Specialist
Health Sciences Associate Clinical Professor Memory and Aging Center
Department of Neurology
University of California, San Francisco
San Francisco, CA, USA

Bruce L. Miller, MD

A.W and Mary Clausen Distinguished Professor of Neurology Memory and Aging Center
Department of Neurology
University of California, San Francisco

San Francisco, CA, USA

Katie Osborn, MA

Predoctoral Intern
Department of Psychiatry
Geisel School of Medicine at Dartmouth Hanover, NH, USA

Gregory M. Pastores, MD

Consultant
National Center for Inherited Metabolic Diseases Department of Medicine
Mater Misericordiae University Hospital
Dublin, Ireland
and
Visiting Professor
Department of Medicine
Yale University School of Medicine
New Haven, CT, USA

Henry Paulson, MD PhD

Lucile Gross Professor of Neurology University of Michigan
Ann Arbor, MI, USA

David C. Perry, MD

Assistant Professor
Memory and Aging Center Department of Neurology
University of California, San Francisco San Francisco, CA, USA

Sean J. Pittock, MD

Professor of Neurology
Director, Neuroimmunology Laboratory
Director, Center for MS and Autoimmune Neurology Mayo Clinic
Rochester, MN, USA

Katherine L. Possin, PhD

Assistant Professor of Neuropsychology Memory and Aging Center Department of Neurology
University of California, San Francisco San Francisco, CA, USA

Leon Prockop, MD

Department of Neurology University of South Florida Tampa, FL, USA

Gil D. Rabinovici, MD

Associate Professor of Neurology Memory and Aging Center Department of Neurology
University of California, San Francisco San Francisco, CA, USA

Howard J. Rosen, MD

Professor of Neurology
Memory and Aging Center Department of Neurology
University of California, San Francisco San Francisco, CA, USA

Swati A. Sathe, MD MS

Associate Professor
Department of Neurology
Neurological Institute of New Jersey Rutgers, The State University of New Jersey New Jersey Medical School
Newark, NJ, USA

Sharon J. Sha, MD MS

Clinical Assistant Professor
Neurology and Neurological Sciences Stanford Center for Memory Disorders Stanford, CA, USA
and
Memory and Aging Center Department of Neurology
University of California, San Francisco San Francisco, CA, USA

Leonel T. Takada, MD PhD

Neurologist at Hospital das Clinicas Department of Neurology
University of Sao Paulo Medical School Sao Paulo, Brazil

Notes on contributors vii

ChApter 1 Introduction

Michael D. Geschwind and Caroline Racine Belkoura

University of California, San Francisco, San Francisco, CA, USA

This book was developed in order to provide a clinically relevant review of non‐Alzheimer’s and atypical dementia syndromes. Specifically, we felt there was a need for a broad but comprehen sive overview of the differential diagnoses for atypical dementia that could be utilized by health‐care providers who encounter these patients in their clinical practice, including neurologists, primary care providers, psychiatrists, neuropsychologists, nurses, social workers, etc. Where relevant, we have included clinical case studies in each chapter to help illustrate key or unique diag nostic features of each disorder and to provide a “real‐world” view of how each disorder might present in the clinic.

Multidisciplinary evaluation of the atypical dementia patient

In this chapter, the editors review a framework for the clinical evalu ation of the patient with a suspected atypical dementia syndrome. In particular, we focus on the benefits of a multidisciplinary evalua tion with a team that includes a combination of a neurologist, neu ropsychologist, psychiatrist, nurse, and social worker. Each team member brings a unique set of skills to the evaluation, which enables an in‐depth and comprehensive assessment of a variety of domains, including relevant history, neurological function, cognitive abilities, mood and behavior, and daily function. Obtaining information from both the patient and a close family member or friend is essen tial as many atypical syndromes lead to loss of insight, and thus, more accurate reporting might come from someone other than the patient themselves. We have found that a case conference approach, where all team members meet after seeing the patient to review all relevant findings and discuss the case in detail, leads to a more accu rate differential diagnosis, which can then be relayed to the patient and their family members in a timely fashion.

Atypical Alzheimer’s disease

In this chapter, Sharon Sha and Gil Rabinovici review the atypical presentations of Alzheimer’s disease (AD), which by definition present with symptoms other than memory loss and therefore

might not meet most standard diagnostic criteria for AD. These patients tend to be younger than “typical” AD cases and might present with visuospatial complaints, executive dysfunction, behavioral changes, or language impairment. Additionally, often, patients meet diagnostic criteria for posterior cortical atrophy (PCA, a visual dysfunction syndrome), corticobasal syndrome (CBS, executive dysfunction or behavioral syndrome), and/or pri mary progressive aphasia (PPA, language syndrome) disorders that have not historically associated with AD pathology; however, recent research has demonstrated that a significant portion of these clinical syndromes are ultimately found to have AD pathol ogy at autopsy. Neuropsychological testing and atrophy patterns on MRI often are very helpful in the differential diagnosis of the clinical syndrome. PET imaging with amyloid binding agents such as Pittsburgh compound B (PiB) or florbetapir F18 might pro vide additional, if not even more convincing, evidence of underly ing AD pathology. The recognition of AD pathology as a causative factor in these atypical syndromes is important because of availa ble symptomatic treatments and ongoing clinical trials for AD. Future diagnostic criteria for AD will need to incorporate the pos sibility of atypical presentations in order to increase sensitivity.

Vascular cognitive impairment: Diagnosis and treatment

In this comprehensive chapter, Helena Chui and Liliana Ramirez Gomez first review the complex history and terminology of vas cular contributions to cognitive impairment. They postulate that the physiological effects of vascular brain impairment (VBI) lead to variable vascular cognitive impairment (VCI), depending on the location, extent, and severity of injury. White matter imaging methods including structural (i.e., white matter hyperintensities) and functional (diffusion tensor imaging) techniques provide the most useful information regarding the extent of VBI. VCI usually involves slowed processing speed and executive dysfunction but can vary widely depending on the location of pathology. The effect of VBI is additive and might be worsened by the presence of other underlying neuropathological conditions (i.e., AD). Risk factors for VBI/VCI include hypertension, hyperlipidemia,

2 Non-Alzheimer’s and Atypical Dementia

and diabetes, which suggest that the risk profile for cognitive impairment in many individuals could be lowered via lifestyle modifications. Current pharmacological treatments (i.e., cho linesterase inhibitors, NMDA receptor blockers) are symptomatic in nature, and firm evidence regarding their utility is lacking.

Frontotemporal dementia

In this chapter by David Perry and Howard Rosen, the clinical syndrome of frontotemporal dementia (FTD) and its underlying pathological etiologies (frontotemporal lobar degeneration (FTLD)) are reviewed. Newly developed diagnostic criteria for FTD have been developed, which identify three core clinical syndromes: (i) behavioral variant FTD (bvFTD), (ii) semantic variant primary progressive aphasia (svPPA, also called semantic dementia), and (iii) nonfluent variant primary progressive apha sia (nfvPPA). The most common presentation is bvFTD, with initial symptoms that might include apathy, disinhibition, loss of empathy, and other personality changes and MRI revealing rela tive atrophy of the fronto‐insular cortex and underlying white matter. Cognitive testing often reveals relative deficits in execu tive function, although cognition might be relatively preserved early in the disorder. The hallmark features of svPPA include word‐finding deficits and loss of semantic knowledge for words and objects, with MRI usually revealing relative atrophy in the left anterior temporal lobe. Bilateral temporal lobe atrophy becomes more prevalent over the course of the disease with additional frontal lobe involvement and behavioral symptoms including loss of empathy, and compulsions might appear (although they are not usually a presenting feature as in bvFTD). Slow and effortful speech is a classic feature of nfvPPA, with frank mutism being common over the course of the disease. MRI typically reveals asymmetric atrophy of the left inferior frontal cortex. Other clinical syndromes, including motor neu ron disease (i.e., amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS)), can overlap significantly with FTD syndromes and are referred to as FTD spectrum disorders. The underlying neuropathology of FTD is complex, and research in this field is evolving rapidly. As a general guideline, svPPA tends to be associated with TDP‐43 pathology, nfvPPA tends to be associated with tau pathology, and bvFTD is associated with a variety of pathologies (TDP‐43, tau, FUS, PSP, and CBD). Treatments for these disorders are cur rently symptomatic, although clinical trials are in development.

Lewy body dementias

In this chapter, dementia with Lewy bodies (DLB) and Parkinson’s disease with dementia (PDD) are reviewed by Carol Lippa and Katherine Possin. Both disorders feature a parkinsonian motor syndrome (i.e., rigidity, bradykinesia, tremor), cognitive impair ment (visuospatial dysfunction, fluctuations in attention/arousal,

and executive dysfunction), and neuropsychiatric symptoms (depression, anxiety, visual hallucinations). DLB is usually asso ciated with relatively simultaneous onset of cognitive and motor symptoms, while PDD is associated with cognitive impairment in the setting of an established PD diagnosis (usually occur ring >1 year after motor symptoms). Both syndromes are disor ders of alpha‐synuclein and are associated with underlying Lewy body pathology. Concomitant AD pathology is often present. Structural MRI findings are often grossly normal for age, while clinical symptoms associated with alpha‐synuclein disorders (i.e., REM sleep behavior disorder, anosmia, autonomic dysfunc tion) might provide additional confirmation of a suspected DLB or PDD diagnosis. The treatment of the motor symptoms is usually with standard dopaminergic therapies utilized in PD, while acetylcholinesterase inhibitors often improve attention deficits and visual hallucinations. Neuropsychiatric symptoms might require SSRIs or low doses of newer antipsychotic agents such as quetiapine. These patients are susceptible to delirium, and exposure to anesthetics, anticholinergics, and antipsychotics should be closely monitored.

Corticobasal degeneration and progressive supranuclear palsy

Suzee Lee and Bruce Miller define the terms in the title of their chapter as reflecting the neuropathological entities of corticoba sal degeneration (CBD) and progressive supranuclear palsy (PSP), which are both disorders of tau. They move on to discuss the typical clinical presentations of CBD as (i) nonfluent variant PPA (nfvPPA), (ii) an executive motor (EM) syndrome, and (iii) behavioral variant FTD (bvFTD). The clinical syndromes of nfvPPA and bvFTD have been reviewed in Chapter 5. EM syn drome typically presents with early executive dysfunction and motor impairment, often including axial rigidity and dystonia. MRI findings might include relative atrophy in the left frontal cortex. The clinical syndrome associated with pathological PSP is labeled PSP syndrome (PSP‐S), which typically presents with oculomotor abnormalities (reduced saccade velocity and restricted vertical downgaze), axial rigidity and falls, executive dysfunction, and behavioral changes including apathy and disinhibition. Many individuals with PSP‐S during life, however, are found to have other neuropathological disorders at autopsy, such as CBD. Conversely, clinical syndromes other than PSP‐S are sometimes associated with pathological PSP at autopsy (i.e., CBS, bvFTD). Treatment of both CBD and PSP remains symptomatic, but several anti‐tau agents are currently in the early stages of clinical trials.

repeat expansion diseases and dementia

This chapter by Praveen Dayalu, Roger Albin, and Henry Paulson reviews DNA repeat expansion disorders that cause cognitive impairment, the most common of which is Huntington’s disease

(HD). HD is an autosomal dominant, triplet repeat polyglu tamine disorder with motor symptoms (chorea, ataxia, dystonia, rigidity), cognitive dysfunction (early executive dysfunction), and neuropsychiatric features (depression, anxiety, obsessive– compulsive symptoms) that progress to profound dementia and eventual death. A careful family history is critical in determining potential underlying genetic contributions to a clinical syndrome. Genetic testing for the HD mutation ensures accurate diagnosis, but involvement of a genetic counselor in this process is recom mended, as the information has broad implications for family members. The HD mutation affects the protein huntingtin, although how this leads to neurodegeneration is unknown. MRI often shows relative caudate atrophy on visual assessment, and there is disproportionate pathology in the striatum at autopsy, although changes in cortical and white matter are also present. Pharmacological treatments are currently symptomatic in nature, targeting the motor (dopamine receptor blockers) or neuropsy chiatric symptoms (i.e., antidepressants, antipsychotics), whereas social work, physical therapy, speech therapy, and nursing are required as the disease progresses. Other less common triplet repeat disorders that can cause cognitive impairment are pre sented, including spinocerebellar ataxia type 17 (SCA17), which presents with ataxia and prominent cognitive and behavioral symptoms, and fragile X premutation tremor/ataxia syndrome (FXTAS), which develops late in life and often presents with ataxia, tremor, and cognitive impairment and is more common in men.

prion disorders

This chapter, written by Leonel Takada and Michael Geschwind, discusses the three basic forms of human prion disease (PrDs): sporadic (spontaneous), genetic, and acquired. PrDs are uni formly fatal, often rapidly progressive, neurodegenerative dementias. They are caused by the transformation of a normal prion protein into a misshapen form called the prion (pree‐ahn). Prions then act as templates, causing nearby prion proteins to also change shape into the disease‐causing, misshapen form, the prion. As sporadic Creutzfeldt–Jakob disease (sCJD) is by far the most common type of human PrD, much of the chapter focuses on this form, including the importance of diffusion‐weighted brain MRI, and the shortcomings of relying on CSF biomarkers alone for diagnosis. The most common clinical features of sCJD are rapid‐onset (weeks to months) dementia, ataxia, behavioral/ personality changes, and other motor features (parkinsonism, myoclonus, etc.). Although myoclonus sometimes occurs in DLB and CBD, its presence in a patient with rapid progression should suggest CJD. A minority of sCJD patients present with prominent vision and visuospatial abnormalities (Heidenhain variant). Brain MRI should include FLAIR, DWI, and ADC sequences, which have the highest diagnostic utility for sCJD, showing restricted diffusion in the cortex (cortical ribboning) and/or deep nuclei, particularly the striatum. The use of CSF biomarkers, such as 14‐3‐3, neuron‐specific enolase (NSE), and

total tau (t‐tau), is somewhat controversial. Many feel that these are merely markers of rapid neuronal injury and thus not spe cific, but sometimes they can be helpful for CJD diagnosis. Several conditions mimic sporadic CJD, some of which are currently untreatable, such as rapid forms of other more com mon neurodegenerative diseases, such as DLB, AD, CBD, and PSP (discussed in other chapters), and treatable, reversible con ditions, such as autoimmune dementias (Chapter 10). Genetic prion diseases (gPrDs), comprising about 15% of human PrDs, are due to autosomal dominant mutations in the prion gene, PRNP. These forms may present identically to sCJD with a rapid course or present as other neurodegenerative diseases, with pro longed courses of a few years to more than a decade, sometimes with prominent psychiatric features. Often, patients with gPrDs do not have a known positive family history, although further investigation often reveals neuropsychiatric disorders, which likely were misdiagnosed. Although the most notorious, acquired prion diseases are the least common form of PrD. They can occur from iatrogenic exposure, consumption of bovine spongi form encephalopathy (BSE), blood transfusion from variant CJD (vCJD), or other causes. Despite ongoing research, presently there are no cures or disease‐modifying treatments for PrDs.

Autoimmune dementias

This chapter, written by Andrew McKeon and Sean Pittock, reviews autoimmune etiologies of cognitive impairment or encephalopathy. Clinical features suggestive of an autoimmune disorder include acute or subacute presentation with fluctuating symptoms, CSF or laboratory results suggestive of autoimmunity, and positive response to immunotherapy. Past medical and family history is important to review for a history of cancer, familial autoimmune disorders or cancers, smoking history, and consti tutional symptoms. Neuropsychological testing sometimes pro vides evidence of cognitive dysfunction in those with subtle complaints. MRI may demonstrate T2 abnormalities in the mesial temporal lobe, and EEG sometimes demonstrates generalized and/or focal slowing or epileptiform discharges. An elevated CSF protein, oligoclonal bands, and elevated IgG are all potentially suggestive of an autoimmune disorder, although not diagnostic. Antithyroid and antinuclear antibodies (ANA) tend to be non specific but should prompt further autoimmune workup, while neural antibodies (i.e., anti‐Hu, CV2, NMDAR, VGKC) should prompt further evaluation for cancer as a paraneoplastic etiology should be high on the differential. Acute treatment of suspected autoimmune illness usually involves high‐dose corticosteroids, IVIG, or plasma exchange for 6–12 weeks, with subsequent evalu ation to determine improvement. If there is a positive response to treatment, an autoimmune diagnosis is more likely. Maintenance therapy may be required, as many individuals will relapse once treatment is discontinued. Unfortunately, long‐term treatments can be associated with a variety of negative side effects, and the relative risks and benefits should be weighed accordingly.

Introduction 3

4 Non-Alzheimer’s and Atypical Dementia toxic and metabolic dementias

In this chapter, Michelle Mattingly, Katie Osborn and Leon Prockop review toxic and metabolic causes of dementia. Although rare, many of these etiologies are treatable, which emphasizes the need for accurate identification and appropriate intervention. The fluctuating alterations in consciousness asso ciated with delirium can often masquerade as a dementia, but delirium typically is more acute in onset and often associated with toxins or underlying medical illnesses (i.e., cancer, liver disease, thyroid problems). A list of common toxic agents that can cause dementia is provided, with detailed descriptions of the effects of ethanol, carbon monoxide, and lead exposure; these toxins can cause cognitive, neuropsychiatric, and/or movement symptoms that can range from mild to severe with heterogeneous presentations. MRI is not only helpful in some cases of carbon monoxide exposure, with abnormalities in the globus pallidus and white matter, but also may be normal. Treatments include cessation of alcohol intake, hyperbaric oxy gen therapy for carbon monoxide, and chelation therapy for lead exposure. Metabolic causes of dementia are broad, and this chapter reviews three common presentations, including thyroid disease, hepatic dysfunction, and disorders of glucose metabo lism. Both hypo‐ and hyperthyroidism can lead to cognitive impairment and psychiatric symptoms, with resolution of symptoms often observed after appropriate medication is administered and euthyroid laboratory values are obtained. Hepatic encephalopathy can range from mild to severe and may be chronic in individuals with severe hepatic disease; treatment involves the use of nonabsorbable disaccharides and antibiot ics. Both hypo‐ and hyperglycemia can lead to cognitive impairment. Individuals with diabetes are at a higher risk for cognitive decline and dementia, which may be due to secondary effects in the vascular system of the brain or may modify the effects of Alzheimer’s disease pathology. Consideration of potential toxic or metabolic contributions to cognitive and neu ropsychiatric dementia syndromes is important because of the possibility of treatment and reversal of symptoms.

Leukoencephalopathies/leukodystrophies

Authors Gregory Pastores and Swati Sathe review adult‐ onset leukoencephalopathies, a diverse group of disorders of white matter that cause cognitive decline. A distinction bet ween acquired (i.e., inflammatory, vascular, toxic) causes and hereditary forms is made. The chapter largely focuses on these hereditary causes, termed leukodystrophies. Although many of these disorders have onset in childhood, there are also late‐onset presentations that are often misdiagnosed as multiple sclerosis. Symmetric white matter changes on MRI should raise suspicion for leukodystrophy. CADASIL typically presents in the 30s and involves migraine with aura, recurrent strokes, seizures, cogni tive impairment, mood changes, and apathy, with progressive

episodes of decline over decades. It is an autosomal dominant disorder associated with mutations in the Notch3 gene. Treat ment is largely symptomatic for migraine prevention and con trol of vascular risk factors. Adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a term that encompasses other syndromes (hereditary diffuse leukoenceph alopathy (HDLS) and pigmentary orthochromatic leukodys trophy (POLD)), in which individuals present in their 40s with behavioral changes and motor impairment (i.e., parkinsonism, ataxia) and are often suspected to have a frontotemporal demen tia syndrome. In an exciting development, the gene CSF1R has recently been identified as the cause for both POLD and HDLS, further supporting that they are a spectrum of the same disease entity. Several other leukodystrophies are reviewed, including adult‐onset autosomal dominant leukodystrophy with auto nomic dysfunction, adult polyglucosan body disease, and adult‐ onset Alexander disease. Mitochondrial disorders that can have significant white matter involvement and can cause dementia are reviewed, including mitochondrial encephalopathy, lactic acidosis, and strokes (MELAS); myoclonic epilepsy with ragged‐ red fibers (MERRF); Leigh syndrome; Kearns–Sayre syndrome (KSS); neuropathy, ataxia, and retinitis pigmentosa (NARP); Leber hereditary optic neuropathy (LHON); or Muir–Torre syndrome (MTS). Treatment of these disorders may involve ketogenic diet, physiotherapy, metabolite administration, and avoidance of stress. Lysosomal storage disorders are multisys temic, but can have cognitive impairment as a feature, and may include late‐onset forms of metachromatic leukodystrophy (MLD) and globoid cell leukodystrophy (Krabbe disease) and Fabry disease. Treatment may involve hematopoietic stem cell transplant, dietary therapy, enzyme replacement therapy, or adrenal hormone replacement therapy. Although often con fused with multiple sclerosis, identifying the cause of a leukoen cephalopathy or leukodystrophy is important to consider in order to ensure appropriate diagnosis, genetic counseling, and management.

Infectious causes of dementia

This chapter, written by Cheryl Jay, Emily Ho, and John Halperin, reviews the subacute and chronic infections that may leadtoadementiasyndrome.HIV‐associateddementiaisless common in the era of combination antiretroviral therapies (cART) but may involve apathy, slowed thinking, and motor symptoms, along with generalized cognitive dysfunction. The effects of concomitant infections (e.g., hepatitis C, cryptococ cal meningitis), substance abuse, and other associated syn dromes (e.g., primary CNS lymphoma, progressive multifocal leukoencephalopathy) must be ruled out. Treatment with appropriate cART for HIV and appropriate treatment of any other contributing infections or syndromes is recommended. Subacute sclerosing panencephalitis (SSPE) occurs long after an acute measles infection and is relatively rare in locations

with adequate measles vaccination programs. Myoclonus is common, along with cognitive and behavioral impairment and seizures developing over months. Treatment is largely sympto matic with progression to death typically over one to two years from diagnosis. Acute presentations of hepatitis C and viral encephalitis may also cause long‐lasting cognitive impairment. Bacterial causes of dementia include neurosyphilis, Lyme dis ease, and Whipple’s disease. Acute bacterial meningitis may also be associated with cognitive impairment, which continues to stabilize or improve over many years. Fungal infections such as cryptococcal meningitis can cause cognitive impairment, most often in the context of concomitant HIV infection. Intensive antifungal treatment is required. Dementia may also occur in the context of parasitic infection such as neurocysticercosis (NCC), related to tapeworm infection. CNS cysts can be observed on MRI or CT. Seizure and neuropsychiatric symptoms are common presentations. Treatment involves cysticidal drugs and steroids. Although many of these disorders are responsive to therapy, many cognitive deficits will be long‐lasting, and some cases are, unfortunately, fatal.

rheumatologic and other autoimmune dementias

In this chapter by Laura Julian and Christopher Filley, the intersection between neurology and rheumatology is discussed, with a particular focus on systemic lupus erythematosus (SLE). SLE is an autoimmune disease that may affect any organ system and is frequently associated with cognitive and neuropsychiat ric symptoms. MRI findings are often notable for white matter hyperintensities. Antiphospholipid syndrome (APS) can lead to stroke or transient ischemic attack (TIA) and thus secondary cognitive and neuropsychiatric dysfunction. Sneddon’s syn drome also causes early strokes and TIAs that has a more severe clinical course and greater extent of cognitive impairment in comparison to APS. Treatment may involve anticoagulation and immunosuppressive drugs. Sjögren’s syndrome can be associated with a variety of CNS manifestations, although the underlying causes are less well understood. Various vasculitides

(blood vessel inflammation) can also cause CNS symptoms and frequently require blood vessel biopsy for confirmation. These syndromes include Wegener’s granulomatosis, Churg–Strauss syndrome, Behcet’s disease, and giant cell arteritis. Systemic sclerosis or scleroderma may have white matter lesions in the absence of severe neurological symptoms or patient’s cognitive complaints. Sarcoidosis in the CNS is frequently associated with cranial neuropathy but may also be accompanied by cog nitive and behavioral symptoms, depending on brain lesion location. With neurosarcoidosis, there are typically profound MRI abnormalities, often around the brainstem. Immuno suppressive drugs are typically used for treatment. Celiac dis ease, an inflammatory reaction to wheat, may lead to CNS complications in 10–20% of individuals with this disorder, most typically an ataxia. A gluten‐free diet is appropriate for treatment. The link between rheumatological disorders and cognitive impairment is still in its relative infancy, and further studies with large numbers of patients are needed to more fully understand this phenomenon.

Comprehensive management of the patient with an atypical dementia

This chapter, written by Jennifer Merrilees, Cynthia Barton, Robin Ketelle, and Amy Kuo, provides a framework for clinical management of patients with atypical dementia. These patients often have unique challenges relative to older, more typical dementia patients, including younger age, greater behavioral disturbance, inability to work, and increased caregiver strain. These disorders are underrecognized and caregivers and fami lies may have seen multiple health‐care providers before being accurately diagnosed, which can lead to high levels of familial stress. Environmental modifications and behavioral strategies are recommended for a first line of defense in managing mood and personality changes, prior to pharmacological intervention. Caregiver training can be a crucial tool in helping keep the patient at home and delay placement within a facility, which can be difficult as many facilities are not equipped or trained to deal with severe behavioral or motor symptoms.

Introduction 5

CHapTer 2

The multidisciplinary evaluation of the atypical dementia patient

Michael D. Geschwind and Caroline Racine Belkoura

University of California, San Francisco, San Francisco, CA, USA

Introduction

The clinical presentation of atypical dementia varies widely and typically involves more than one symptom domain (e.g., cognition, motor function, behavior, autonomic function). This heterogeneity of presentation, in combination with the relative rarity of these disorders, can make accurate diagnosis difficult even for experienced clinicians. In our experience, the evalua tion of individuals with suspected atypical dementia is optimal when conducted by a multidisciplinary team (e.g., neurology, neuropsychology, nursing, speech therapy, genetic counseling), allowing for a more comprehensive evaluation and the input of experts from several disciplines.

History

Acquiring a thorough history is one of the most critical features of an atypical dementia evaluation. Because these disorders frequently present with symptoms affecting multi ple systems (e.g., gastrointestinal, sleep, autonomic, higher cortical function, etc.), a broad review of systems (ROS) is necessary. A review of previous medical records and the input of family (and sometimes even friends and colleagues) is essential, as patients may not appreciate or be able to accu rately report symptoms secondary to their cognitive deficits or lack of insight. Given that the patient has some cognitive impairment, the presence at the interview of an informant who knows the patient well, such as a family member, a close friend, or a caregiver, is very important. If they cannot be pre sent, then the informant should be interviewed by telephone. When possible, try to leave time to interview the informant separately, such as when the patient is undergoing neuropsy chological (cognitive) testing. This will allow the informant to discuss topics that might upset the patient or they do not feel comfortable discussing in front of the patient. Specific key elements to be included in the history are discussed in the following paragraphs.

First symptoms

Determining the first symptom of a dementia is often the key to making the correct diagnosis. Encouraging family members to describe the earliest atypical behaviors or actions, even if only noted in retrospect, provides important information regarding the initial underlying neuroanatomy of their disease. For example, in a right‐hander, early visuospatial problems might suggest right parietal involvement, early calculation dif ficulties might suggest left parietal dysfunction, and nonfluent speech might suggest left pre‐Broca’s area frontal lobe involve ment. These early symptom clusters can also assist with differ ential diagnosis. For example, profound changes in personality or behavior are seen early in behavioral variant frontotemporal dementia (bvFTD), whereas behavioral changes in the context of early falls are more typical of progressive supranuclear palsy (PSP). New‐onset psychiatric symptoms (i.e., depression, anxi ety, apathy) in someone without a psychiatric history are par ticularly noteworthy, although family members and patients might not realize they are an early symptom of the dementia. A change in employment status is sometimes an early sign that something is wrong but may initially be attributed to outside factors (e.g., downsizing) rather than patient issues. Determining the first symptoms of a disease is a critical step toward earlier detection, correct diagnosis, and, when availa ble, appropriate treatment.

Memory

Irrespective of what cognitive symptoms the patient presents with, a typical complaint might be, “I can’t remember things.” When evaluating a possible memory deficit, it is critical to determine if it is truly a primary memory problem. For exam ple, semantic dementia (SD) patients might report, “I can’t remember words,” which actually reflects semantic loss rather than a primary memory problem. Similarly, posterior cortical atrophy (PCA) patients might describe, “I can’t remember where I put things,” reflecting their visual difficulties rather than impaired memory. Thus, detailed questioning during the history is required to determine the specific nature and

etiology of presenting memory complaints. If it is a memory problem, then one must determine if it is an encoding or a retrieval problem. Many patients with frontal‐executive defi cits, such as due to ischemic vascular disease, report a primary memory problem, but often have problems with retrieval, but not encoding. Patients with frontal‐executive function typi cally are aided in recall when given clues, whereas those with encoding deficits, such as occurs in Alzheimer’s disease (AD), usually are not. Other questions to ask the family and patient include “How are short‐term and/or long‐term memory affected, how long does it take for the patient to forget some thing they were told, and how has this changed over time?” In AD, short‐term memory is often affected early by the illness, and only later is long‐term memory (autobiographical and remote memory) affected.

It is important to note how much of the history the patient can provide and in what level of detail, without relying on clues and hints provided by their family—thus, part of the neurological examination occurs during the history taking. It is sometimes necessary to explicitly tell family members (who might be used to speaking on behalf of the patient) to allow the patient to answer independently, assuring that they will have an opportu nity to provide their input later.

Asking about recent and more remote current major local, regional, national (e.g., “911,” “Hurricane Katrina,” etc.), or world events (e.g., who was the president during, or which countries were involved in, World War II) or family vacations provides additional opportunities to examine the patient’s recall abilities. Additional topics to discuss when asking about for memory difficulties include misplacing objects (e.g., keys, wallet, purse); being overly reliant on lists, post‐it notes, or calendars; missing appointments; getting lost or disoriented in new (or old) envi ronments; repeating oneself in conversation; and forgetting recent events (e.g., dinner with friends, movie recently seen).

Word list learning tasks (e.g., California Verbal Learning Test‐2nd Edition (CVLT‐II) [1], Hopkins Verbal Learning Test‐Revised (HVLT‐R)) [2] are among the most common memory tasks used in neuropsychological testing and require the individual to recall a long series of words across multiple trials (learning) with recall tested again after a 20–30 min delay (delayed recall) followed by yes–no recognition. For younger and relatively high‐functioning individuals, it is necessary to use a longer 16‐item word list rather than a 9‐item list, as ceil ing effects are prominent and often mask subtle deficits. Story learning and recall tasks (e.g., Wechsler Memory Scale–4th Edition (WMS‐IV) Logical Memory [3]) are also helpful tools. Story recall is less dependent on executive function in com parison to word list learning but is often difficult to interpret in the context of semantic and/or auditory comprehension difficulties.

When interpreting the history and neuropsychological test results, it is helpful to think about the pattern of memory defi cits, which suggests underlying neuroanatomy, thereby assisting with the differential diagnosis. A simplified view of memory

deficits is that they are either hippocampal (medial temporal lobe (MTL)) or frontal executive in origin. Each anatomy gener ally has a different clinical pattern. Involvement of the MTL leads to anterograde amnesia (i.e., poor new learning and deficits in encoding) and the rapid forgetting of newly learned information. Associated clinical symptoms often include misplacing objects, repeating self in conversation, forgetting appointments, getting lost or disoriented in new environments, and poor memory for recent events. Neuropsychological testing typically reveals reduced learning, poor recall, and poor recognition (suggesting information was not appropriately stored or consolidated) even when provided with clues. These deficits are common in AD, SD (semantic variant (SV) frontotemporal dementia (FTD)), hip pocampal sclerosis, limbic encephalopathy, and other disorders that affect MTL structures [4].

A frontal‐subcortical pattern of memory loss, on the other hand, is associated with variable learning that is typically due to poor attention, difficulties with self‐initiated recall (which typically improves with cues), and relatively spared recognition (suggesting information has been encoded in the MTL, but self‐ initiated access is difficult). These individuals tend to benefit from multiple learning trials and show progressive learning over time, whereas those with MTL involvement usually have flat learning curves. Clinical symptoms may be more variable (i.e., “he can remember if he pays attention”) and are often seen in combination with frontal‐executive dysfunction on other tasks. Family members often will note that patients will recog nize information when it is presented to them (i.e., “he remem bered that we had gone to the movie as soon as I started talking about the plot”). These deficits are more typical of diseases that affect frontal‐subcortical circuits, such as bvFTD and related disorders, Huntington’s disease (HD), Lewy body disorders, and white matter disorders [4, 5].

Motor

Many atypical dementias have accompanying motor features that help with differential diagnosis. For example, in AD, motor features typically occur very late, although there are motor pres entations of AD, such as corticobasal syndrome (CBS) [6]. If the motor problems occur early, other diagnoses must also be considered. Early parkinsonism is a common feature of demen tia with Lewy bodies (DLB), corticobasal degeneration (CBD), PSP, and Creutzfeldt–Jakob disease (CJD). Some genetic forms of FTD (i.e., FTD‐17) commonly present with parkinsonism. Axial rigidity and early falls are suggestive of PSP, whereas asymmetric progressive apraxia might suggest CBS. Myoclonus is frequently observed in DLB, CBD, CJD, and less commonly in late AD. Ataxia is often present in multiple system atrophy (MSA), fragile X‐associated tremor/ataxia syndrome (FXTAS), spinocerebellar ataxias (SCAs), HD, prion disease, paraneo plastic disorders, and metabolic disorders such as Wernicke’s. Extraocular motor abnormalities occur in many neurodegenera tive conditions and often are nonspecific, but some findings are helpful diagnostically. Gaze‐evoked nystagmus is common in

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8 Non-Alzheimer’s and Atypical Dementia

cerebellar degenerative disorders. Vertical supranuclear gaze palsy (limitations in downgaze) and slowed velocity of saccades are hallmark features of PSP. Breakdown of saccades can be observed in many disorders, particularly those that affect fron tal‐subcortical circuits including the frontal eye fields.

Choreiform movements are commonly seen in HD, several HD‐like syndromes (including some forms of genetic and vari ant prion disease, HDL2 due to junctophilin‐3 gene mutations, and a few SCAs, particularly SCA17), other genetic disorders (e.g., dentatorubral‐pallidoluysian atrophy (DRPLA), neurofer ritinopathy, pantothenate kinase‐associated neurodegeneration (PKAN), and chorea–acanthocytosis), and autoimmune/para neoplastic conditions [7, 8]. Muscle wasting and fasciculations in combination with other upper/lower motor neuron signs are suggestive of amyotrophic lateral sclerosis (ALS) and when seen in combination with behavioral symptoms may suggest a combined FTD–ALS syndrome, although many conditions can mimic features of ALS [9]. Isolated, as well as concomitant, vascular disease is a frequent cause of motor symptoms and should always be considered.

Behavior and neuropsychiatric symptoms

Most atypical dementias have prodromal states involving mood or behavior changes that are often recognized only in retrospect (i.e., depression and anxiety in DLB, depression and irritability in HD, apathy in bvFTD). Early changes in mood or behavior are frequently attributed to a psychiatric disorder or life stressors rather than an underlying neurodegenerative dis ease. A thorough review of the patient’s prior psychiatric history (e.g., depression, anxiety, suicidal ideation/attempt, mania) is essential in order to understand and differentiate new behaviors from those which are exacerbations of previous behaviors. Because patients may have limited insight into their own symp toms and behavior, it is crucial to obtain additional information from a reliable informant (i.e., spouse, relative, or close friend) who knows the person well. Important topics to cover in an interview include depression, anxiety, apathy, hallucinations, delusions, illusions, irritability/agitation, disinhibition, person ality change, obsessions/compulsions, sleep disturbance, and appetite change; using an instrument such as The Neuropsychiatric Inventory can be helpful [10].

Certain conditions have neuropsychiatric symptoms that can greatly assist with differential diagnosis. Well‐formed complex visual hallucinations (i.e., people at the dinner table or small animals) and delusions are common early in DLB but can also occur in late‐stage AD. Depression is common in disorders with basal ganglia involvement (i.e., PSP, CBS, HD, vascular disease, and DLB), whereas anxiety is often seen in many disorders, including DLB, MSA, and HD.

Sleep abnormalities such as REM sleep behavior disorder (RBD), restless legs syndrome (RLS), and periodic limb move ments of sleep (PLMS) are also common in Lewy body disor ders and other synucleinopathies and may predate the onset of the disorder by many years, if not decades [11]. Both central

sleep apnea and obstructive sleep apnea (OSA) are relatively common in the general population and may contribute to cog nitive deficits and depression if left untreated. The presence of sleep abnormalities should prompt a formal sleep evaluation, including polysomnography, to assess and adequately treat any underlying disorders.

Profound personality changes, including early behavioral dis inhibition, early apathy, early loss of empathy, and hyperorality, are hallmark features of bvFTD [12]. Many of these features, par ticularly apathy, increased appetite (particularly for sweets), and disinhibition, are also seen in SV where they are associated with right hemisphere atrophy [13–16]. Compulsions or obsessions (i.e., compulsive recycling, eating the same meal at the same time every day) become common in semantic variant primary pro gressive aphasia (svPPA) as the disease progresses [15]. Apathy is very common in PSP [17, 18], CBD [6], and frontal AD and tends to correlate with medial frontal and anterior cingulate involvement [19–21]. Frontal AD is often misdiagnosed as bvFTD because of prominent executive dysfunction and apathy; frontal AD, however, usually does not have prominent early disinhibi tion and loss of empathy [10, 16, 22].

Behavioral changes and neuropsychiatric symptoms can greatly affect quality of life, including difficulties maintaining employment and caregiver strain. In addition to assisting with diagnosis, the accurate assessment of neuropsychiatric symp toms allows the provider to intervene with appropriate treatment and also to better prepare the family for upcoming changes.

Speech and language

A thorough evaluation of speech and language involves the assessment of motor speech symptoms (i.e., speech apraxia, dys arthria, swallowing) and language (i.e., reading, spelling, com prehension, repetition, fluency). Portions of the Western Aphasia Battery (WAB), the Boston Diagnostic Aphasia Examination (BDAE), the Boston Naming Test (BNT), the Boston Cookie Theft picture description, and the Pyramid and Palm Trees Test are useful in assessing language symptoms [13, 23, 24]. Most language disorders are affected by frequency and regularity effects, with high‐frequency, short, and regular words being preserved until relatively late in the disease. Thus, it is very important to utilize relatively complex, unfamiliar, low‐frequency stimuli in order to maximize the chance of detecting early, subtle language deficits.

Word‐finding difficulties are a common, but nonspecific, symptom associated with several neurodegenerative conditions, particularly progressive aphasias [25]. The types of errors made on naming tasks, however, can provide insight with respect to the underlying anatomy of disease. Patients with frontal deficits may make phonemic paraphasias (i.e., bread for bed) or have frank misarticulation errors but often benefit from phonemic cues and can select the appropriate answer from multiple‐choice cues, whereas those with temporal involvement may make semantic paraphasias (i.e., dog for rhinoceros), do not typically benefit from phonemic cues, and may select incorrect answers

on multiple‐choice testing, suggesting frank semantic loss. Conversational speech should be examined for rate, rhythm, articulation errors, slurring, phonemic substitutions, word‐ finding pauses, circumlocution, and use of syntax. Verbal flu ency tasks, including letter fluency (i.e., “State as many words starting with ‘D’ that you can think of”) and category prompts (i.e., “Tell me all the animals you can think of ”), can be beneficial in determining underlying neuroanatomy, with frontal involve ment usually leading to relative reductions in letter fluency but preserved category fluency (although as speech becomes more impaired, performance for both tasks declines) and temporal involvement leading to relative reduction in category fluency relative to letter fluency. Semantic knowledge can be tested with the Pyramid and Palm Trees Test, as well as asking general knowledge questions in several categories [23, 24].

There are three main subtypes of primary progressive apha sia. The nonfluent variant primary progressive aphasia (nvPPA) is associated with relative declines in left frontal function and presents with early motor speech abnormalities, including decreased speech output and reduced fluency (i.e., fewer words per minute, slow labored speech), dysarthria, and altered pho neme production, and also typically involves altered use of syn tax (i.e., telegraphic speech or writing). Swallowing difficulties may also be present, particularly as the disease progresses, and most often these patients become mute within the first several years of the disorder. Reading, spelling, and comprehension tend to be relatively preserved, while writing may be noteworthy for syntactical errors and reduced output. Repetition may be impaired due to articulation deficits. nfvPPA is most often asso ciated with CBD and PSP at autopsy [23, 26].

The semantic variant primary progressive aphasia (svPPA; formerly called SD) is associated with relative left temporal lobe atrophy and presents with fluent but empty speech, with the fre quent use of generic words (i.e., thing, stuff) and relative omis sion of nouns. Patients may also ask for clarification regarding word meaning (i.e., “what do you mean by banister?”), and they often demonstrate frank difficulties on tasks requiring them to identify body parts (i.e., chin) or choose pictures representing single words (i.e., “primate” on Peabody Picture Vocabulary Test). Errors in the reading and spelling of irregular words (e.g., yacht, gnaw) suggest surface dyslexia, in which a loss of seman tic knowledge associated with temporal lobe involvement results in the application of phonetic rules (e.g., knight = kah‐nih‐ght). Frequency effects are typical, with low‐frequency and irregular words being affected early in the disease, while knowledge about high‐frequency words may be preserved until late in the disease course [23, 26]. The nfvPPA and svPPA are discussed in more detail in Chapter 5.

The logopenic variant primary progressive aphasia (lvPPA) has relative left temporoparietal atrophy and presents with decreased short‐term auditory storage (or echoic memory). These individuals have a reduction in digit span forward, being unable to maintain more than 3–4 bits of information in short‐term storage rather than the 7±2 bits that is typical. This reduction

affects the ability to comprehend lengthy sentences and also results in reduced sentence repetition, particularly for long, unfamiliar phrases. Speech tends to be slow with long pauses, “uh’s and um’s”; frequent word‐finding difficulties; and circum locution. This variant is often misdiagnosed as nfPPA because of these speech symptoms; however, relative to nfPPA, there are less frequent articulation errors (although there may be phone mic substitutions for complex words) and fewer syntactical errors in speech. Decreased reading, poor calculation skills, and left–right confusion are often observed in lvPPA due to left pari etal involvement and help distinguish these individuals from nfPPA [23, 26]. Chapter 5 discusses lvPPA in more detail.

Visuospatial

Early visuospatial abnormalities are common in DLB and PCS (typically AD pathology) [27] as well as the Heidenhain variant of CJD [28]. Common complaints include difficulties finding specific objects among many (i.e., in the refrigerator or a messy desk), changes in driving (i.e., drifting within the lane, difficulties parallel parking, and recent accidents), getting lost or disori ented in unfamiliar environments, and complaints about vision despite adequate visual acuity. Complex visual‐constructional copy tasks (i.e., three‐dimensional cube, Rey–Osterrieth Com plex Figure, Benson Figure) are typically impaired early in these disorders. Decreased interest in reading and difficulty main taining one’s place while reading or working on the computer (especially common in PSP) might be early symptoms. Diffi culties with face or object perception suggest alterations in the ventral visual processing stream within the temporal lobe, whereas difficulties with spatial orientation and location suggest alterations in the dorsal visual processing stream within the parietal lobe [29]. Due to bilateral superior parietal involve ment, individuals with PCA often exhibit some degree of Balint’s syndrome, including optic ataxia (difficulties integrating visual and motor movements, i.e., reaching for a cup), oculomotor apraxia (volitional eye movements), and simultagnosia (ability to pay attention to more than one item in the visual field) [27, 30]. In DLB, in addition to visuospatial difficulties, visual illusions or hallucinations are common [31]. Individuals with PSP may also report early visual difficulties, although upon testing it becomes obvious that this is secondary to restricted eye move ments rather than visual perception per se.

Visuospatial difficulties should prompt an evaluation of driving skills, with appropriate restrictions made (i.e., no night driving, limited freeway use) and, if necessary, early voluntary cessation from driving. In some states, health‐care professionals are mandated to report individuals who are diagnosed with dementia or otherwise thought to be unsafe to drive. A home safety evaluation might also be warranted.

executive function

Executive function is an umbrella term representing many subabilities that allow one to pursue goal‐directed action (i.e., working memory, inhibition, organization, rapid processing,

The multidisciplinary evaluation of the atypical dementia patient 9

10 Non-Alzheimer’s and Atypical Dementia

multitasking, set‐shifting, planning, goal maintenance, and judgment). Patients may have reductions in specific aspects of executive function (i.e., working memory), whereas other aspects remain intact (i.e., inhibition). Executive function is usually associated with the frontal lobe and its links to circuits in the basal ganglia (i.e., frontal‐striatal circuits) [32, 33]. Cere bellar dysfunction, however, can also lead to executive function impairment due to connections between the cerebellum and frontal lobe via the thalamus [34].

Poor executive function is one of the strongest predictors of reduced functional abilities and thus is particularly impor tant to assess during neuropsychological testing. The Mini‐ Mental State Examination (MMSE) is not very sensitive to executive dysfunction [35, 36], whereas the Montreal Cognitive Assessment (MoCA) is a screening measure that is more sensi tive to executive dysfunction and includes a set‐shifting task, verbal fluency, and digit span backwards (www.mocatest.org) [4]. Some other neuropsychological tasks that measure execu tive function include the Wisconsin Card Sorting Test (hypoth esis testing), Category Booklet Test (hypothesis testing), Trail Making Test (set‐shifting), Tower of Hanoi (planning), Digit Span Backwards (working memory), Four Word Short‐Term Memory Test (working memory), Stroop Interference, and the Delis–Kaplan Executive Function System (D‐KEFS Trail Making Test, Design Fluency Test, Color–Word Interference Test, Tower Test, Sorting Test, Verbal Fluency Test) [4].

Poor performance on executive function tasks can occur for several reasons, particularly slowed processing speed (increased time to perform tasks) and/or making errors (i.e., rule viola tions, intrusions, perseverations). Errors are often a better pre dictor of true executive dysfunction than just slowed processing, which can be related to reduced motor function and other more general factors. Qualitative observations of the patient in the clinic, during neuropsychological testing, or in their home/ work environment may also provide evidence of difficulties with executive function (i.e., impulsivity, perseveration, tendencies to make errors, poor problem solving, reduced judgment, poor ability to learn new tasks).

Functional history

A functional history involves identifying what activities of daily living (ADLs) a person is capable of, including such tasks as work, finances, cooking, shopping, medication management, and driving. A functional history is critical for determining if an individual has dementia, because significant functional impair ment usually is required to make this diagnosis.

Important topics to cover during an interview or via a questionnaire include instrumental activities of daily living (often referred to as iADLs), which are higher‐level skills such as management of finances, performance at work, medication management, and driving skills, as well as more basic ADLs such as dressing, bathing, grooming, toileting, and cooking. Detailed questioning regarding each symptom can be particu larly helpful. For example, if a patient stopped driving, knowing

when or why this occurred would be informative. Did they stop driving due to poor depth perception or reduced night vision (suggesting visuospatial issues)? Were they swerving within the lane or scraping the car on one particular side (suggesting pos sible neglect)? Were they stopping abruptly, getting too close to cars in front of them, or speeding around corners (suggesting disinhibition)? Were they getting lost because they were forget ting where they were going or how to get to their destination (suggesting memory loss)? Answers to these types of questions can provide useful clues to which areas of the brain are impacted and enhance differential diagnosis.

The timeline of functional changes may also be helpful in determining when the cognitive decline started. For example, many patients in the early stages of a neurodegenerative illness will begin having troubles at work, particularly if their position changes in some way or they are required to learn a new task or system. Their difficulties may initially be attributed to “normal aging” or issues with management but in retrospect may be an early sign of cognitive decline.

In our clinic, nurses and/or social workers participate in the multidisciplinary evaluation by completing the functional his tory with an informant in a separate interview typically while the patient is undergoing a neuropsychological assessment. Additional functional information is then obtained in the joint patient/informant interview with the physician. There are many questionnaires regarding functional skills that can be utilized either before or during the clinical visit (please see Chapter 15 for a review of these measures).

review of Systems (rOS)

In evaluating atypical dementias, the ROS is critical and should include not only standard medical systems but also items such as behavior, sensory, sleep, motor, and other changes. A focused review of symptoms can help with not only diagnosis but also treatment. For example, patients with an RBD are more likely to have a synucleinopathy such as DLB, PD, or MSA. If dysautono mia is present, MSA and DLB should be considered among the neurodegenerative causes of cognitive impairment. Patients with depression causing memory impairment may have a positive ROS with many somatic complaints. Neuropathies may suggest a more systemic neurologic problem, including metabolic, auto immune, or genetic etiologies.

past medical and surgical history

An examination of the past medical and surgical history can reveal factors that increase the risk of dementia or may exacerbate symptoms, including cardiac issues (e.g., hypertension, coronary artery disease, history of myocardial infarction or arrhythmia or cardiac bypass), metabolic syndromes (e.g., diabetes mellitus, hyperlipidemia, thyroid disease, vitamin B12 deficiency), and previous brain injury (e.g., motor vehicle accidents, concussion, loss of consciousness (LOC), seizures, etc.). When acquiring information on possible LOC, it is important to confirm the LOC and how long the person might have had LOC [37]. Prior

chemotherapy or radiation to the head or neck can have both acute and delayed effects on cognition [38], particularly those who received whole‐brain radiation treatment [39, 40]. Malab sorption syndromes (i.e., celiac disease, B12 or other vitamin deficiencies) may also have effects on cognition.

With respect to past surgical history or hospitalizations, delirium in response to new medicines, including anesthesia, or even hospitalization alone is often observed in Lewy body disor ders [41] but may also be observed in individuals with other dementias as well [42]. Anoxia secondary to extended cardiac or other surgeries may also contribute to cognitive impairment.

Prior and current psychiatric history is also important to obtain in order to determine whether behavioral and personality changes are exacerbations of previous traits or new phenomenon. A subtle enhancement of previous tendencies (i.e., depression, anxiety) is often generally observed in the context of cognitive decline, whereas the onset of new behaviors may be more telling regarding the presence of a specific type of dementia (e.g., compulsions in SD or bvFTD). The development of new‐onset psychiatric symp toms in later life should always raise concerns regarding possible underlying neurodegenerative illness [43, 44]. Many individuals with late‐onset psychiatric or behavioral changes will be referred to psychiatry clinic first and may be relatively impaired by the time they present to a neurology or dementia clinic. If there has been a history of electroconvulsive therapy (ECT) for depression or bipolar disease, this often leads to significant short‐term memory loss, some of which might be transient [45–47], whereas prior treatment with psychiatric medications, particularly first‐ generation antipsychotics, can lead to movement disorders, including tardive dyskinesia, parkinsonism, or dystonia.

Medications

A thorough medication history can best be obtained by having the patient bring in all of the medications that they are taking, as memory impairment may prevent accurate recollection of medications and their doses. By seeing the bottles and examin ing the type and number of pills, the medical provider might be able to discern if a patient has indeed been taking all pre scribed medications. Details regarding when the medication was started, what specific problem it is prescribed for, and any side effects or benefits experienced should be elicited; this should also apply to past medicines as well. It is also critical to obtain similar information about any over‐the‐counter medi cines, including herbal remedies, vitamins, and other nonpre scribed medications; many patients do not consider these “medicines” and might not report these unless specifically questioned about them. Drug allergies or reactions should also be noted. A review of the complete medication list with par ticular attention to medications that may interact and/or are known to have significant effects on cognition (e.g., anticho linergics, pain medications, lithium) is important as cognitive impairment can be observed due to medication side effects alone. This is particularly true in the elderly who generally require lower doses of medications due to decreased metabo

lism and thus are more susceptible to medication side effects. Enhanced susceptibility to the effects of neuroleptic medica tions may be suggestive of underlying DLB, whereas enhanced agitation or delirium in the context of anesthesia or other medi cations affecting the CNS may be more likely in individuals with underlying cognitive impairment, irrespective of etiology. The review of previous medications might also be important due to long‐term side effects; for example, tardive dyskinesia may be secondary to psychotropic use.

Family medical history

The family medical history (FHM) should be relatively compre hensive, generally including information about parents, siblings, grandparents, and children, including age at death, developmen tal delay, mental retardation, neurological disease, psychiatric disease, autoimmune disorders, cardiovascular risk factors, can cer, “odd” behaviors, and “suspicious” early deaths. Based on the differential or any trends for concern, the history might need to be expanded to include cousins, aunts/uncles, and great aunts/ uncles. Issues in younger generations (i.e., autism, polycystic ovary syndrome, mental retardation, spontaneous abortion) may have relevance to older family members (i.e., FXTAS) [48]. If a condition might be genetic in origin, this should prompt consid eration of genetic counseling and testing. It is important to recall that many genetic disorders present heterogeneously, even within the same family, despite a common underlying genetic predisposition (i.e., some family members with tau mutations may have CBS, while others have bvFTD or PSP) [49, 50].

Social history

If relevant, social history should include birth history (prematu rity, anoxic birth injury) and developmental milestones, partic ularly for younger patients. Educational history should include the highest level of education obtained, relative strengths and weaknesses, the need to repeat specific classes or grades, and learning disability/attention difficulties (even if not diagnosed as such). A history of childhood illness, trauma, or seizures should be explored. Occupational history should note frequency of job change and any history of being terminated and the rea sons, as well as any specific difficulties in the workplace. The history of marriages and relationships can provide important information about personality and behavior. Current use and past history of illicit substance use and abuse, including alcohol, should be established. When inquiring about alcohol, it can be important to determine the precise amount being consumed (i.e., how large are the glasses of alcohol being consumed?).

Neurological examination

General appearance

Level of personal hygiene (neglected vs. well groomed) is an important indicator of self‐care abilities. Poor color matching or unusual color/print choice may be seen in bvFTD (particularly

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12 Non-Alzheimer’s and Atypical Dementia

right temporal variants) and related disorders [51]. The accu racy of shaving and applying makeup, improper buttoning, or putting clothes on incorrectly may suggest visual‐perceptual and/or motor deficits.

Cranial nerve examination

The cranial nerve examination should include a thorough examination of ocular motor function (including smoothness of visual pursuit, velocity and latency of saccades, presence of square wave jerks or nystagmus) [52–54], assessment of gag or swal lowing reflex, and an examination of extraneous tongue, palate, or facial movements (for HD, or tongue wasting/fasciculations often observed in ALS). Evidence of asymmetry may suggest focal lesions, such as underlying vascular injury.

Motor examination

The motor examination should include not just strength, but bulk (particularly important for ALS; do not forget to check distal extremities and oropharynx), limb and axial tone (impor tant in PSP and atypical parkinsonian disorders), fine rapid alternating movements, and apraxia testing (both limb (i.e., show me how you would hold a nail in your left hand and hammer with your right), oral buccal (blowing a kiss or out a match), and speech (i.e., repeating multisyllabic words such as “catastrophe” five times and listening for phonemic distortion or frank substitution of syllables)). Slowed rapid movements often suggest pyramidal involvement. Dysdiadochokinesis or irregular movements might suggest cerebellar dysfunction, and small or micro movements are often seen in parkinsonian disor ders. Often, focal motor symptom abnormalities can be elicited on gait exam; reduced arm swing (asymmetric or symmetric) and/or focal limb posturing (particularly with distraction maneuvers by having the patient walk on the outside or lateral aspects of their feet) is often seen with basal ganglia abnormali ties in atypical parkinsonian syndromes. Postural instability should be tested by retropulsion pull testing, making sure there is adequate room behind the examiner for a proper test. Signs of upper and lower motor neuron involvement should be care fully evaluated, particularly in bvFTD syndromes in which ALS might co‐occur; a proper exam for fasciculations should be com pleted with the patient undressed, such as in a gown. Although myoclonus is classically seen in CJD, it also is common in DLB and CBS [55–58], as well as in some autoimmune and metabolic encephalopathies [59].

Sensory examination

Some dementias, particularly genetic etiologies, including SCAs, leukodystrophies, APBD, and certain prion gene muta tions, can be associated with neuropathies. Large fiber neuropa thies should raise concern for a B12 deficiency and should prompt looking for other associated features. The effects of long‐standing diabetes may also contribute to neuropathy, par ticularly involving small fiber nerves.

Cerebellar examination

A standard cerebellar examination is warranted in any atypical dementia patient. Examination should include a thorough assessment of eye movements (looking for any restriction of gaze, nystagmus, etc.); dysdiadochokinesia of hands, feet, or speech; limb dysmetria; and gait and balance. Many genetic dementias, including SCAs, Huntington’s, lysosomal storage diseases, and prion diseases, are associated with cerebellar involvement. The recently described FTD–ALS syndrome due to the hexanucleotide repeat expansion in C9orf72 has been associated with cerebellar atrophy on MRI [60].

Neuropsychological testing

In our experience, neuropsychological testing (whether a brief or extended battery) optimally is conducted within the context of a same‐day clinic visit to allow for integration of a multidisci plinary evaluation including the history, neurological findings, and caregiver assessment, in addition to MRI and laboratory results. Neuropsychological testing provides a quantitative method for assessing the integrity of various cognitive domains (i.e., memory, language, frontal executive, visuospatial, etc.). Results often mirror patient and caregiver complaints but might also suggest additional or more significant impairment that would have been predicted by the history. The pattern of neu ropsychological test results can suggest specific underlying diag noses or at least narrow the differential (i.e., parkinsonism on exam and vague cognitive complaints per history). For example, prominent fluctuations in attention and visuospatial difficulties may suggest DLB, whereas on language assessment, logopenic aphasia might suggest an AD pathology, and a nonfluent aphasia is more suggestive of CBD, PSP, or another tauopathy [23].

Although the scores themselves are important, the behavioral observations associated with performance also are crucial and provide an important source of information regarding the etiol ogy of impairment on a specific test. For example, when perform ing an object naming task, there may be difficulties secondary to speech apraxia, semantic loss, visual difficulties, and/or an inabil ity to focus on the task secondary to behavioral disturbances, with each finding suggestive of a differing underlying neuroanatomy. Thus, knowing the final score is often not sufficient; it is impor tant to know specifically how a patient has done poorly on a task.

There are several brief cognitive screening measures exist that can be utilized in the clinic [61], including the MMSE [62] and the MoCA (www.mocatest.org) [63]. MMSE scores below 26 have historically been used to identify those with cognitive impairment,andmanyuseacutoffoflessthan24fordementia [64]. Unfortunately, the MMSE has reduced sensitivity to subtle cognitive impairment, and many patients with prominent behav ioral or executive dysfunction will perform normally (i.e., bvFTD, PSP, CBD) [65]. Furthermore, as the MMSE is a very language‐ based test, patients with language deficits often do substantially worse on it, making them appear to have more clinical and

functional impairment than they actually have [65]. The MoCA was developed to include more tests of executive function as well as a more difficult memory task (5‐word vs. 3‐word recall). A cut off score below 26 still represents mild cognitive impairment (MCI), and the MoCA has been shown to be more sensitive with less of a ceiling effect than the MMSE particularly for cognitive dysfunction in many disorders, particularly those with prominent frontal‐executive dysfunction [66–68]. Unfortunately, although the MMSE and MoCA are beneficial in clinical settings requiring rapid screening and evaluation, they are necessarily limited in their ability to comprehensively assess cognitive impairment and may not detect more subtle dementia or MCI [67].

In our clinic, typically a 1 h “bedside” neuropsychological evalu ation is conducted by a trained examiner (physician, neuropsy chologist, or even an assistant). This bedside evaluation examines memory using a word list learning task [1] and figure recall, lan guage through naming, verbal fluency, sentence repetition, apraxia of speech and semantic knowledge, visuospatial skills using figure copy and a visual discrimination task, and attention and executive function with the Stroop interference, modified (simplified) trail making tests, design fluency, and digit span forwards and back wards [4]. Mood is assessed with a patient‐reported depression screen (i.e., Geriatric Depression Scale (GDS)) and also via inform ant‐rated questionnaires (i.e., Neuropsychiatric Inventory (NPI)) [10, 69]. Informant‐rated questionnaires such as the Frontal Systems Behavior Scale (FrSBE) can also be useful for quantifying the level of apathy, disinhibition, and executive dysfunction [70], which may be underrecognized by the patient due to loss of insight. The identification of deficits in a specific cognitive arena (i.e., visuospatial) may prompt the administration of other tests in order to more fully characterize the impairment.

Additionally, it may be appropriate at times to refer patients for more comprehensive neuropsychological testing (i.e., 2–6 h), par ticularly if complaints are vague and subtle and/or patients are young, for which screening tests are less sensitive. A demonstra tion of subtle levels of impairment may not be diagnostic early in the course of the disease (i.e., early difficulties with executive func tion can progress to bvFTD, PSP, CBD, PD, or frontal version of AD, among others); however, at the least, a comprehensive evalu ation serves as a useful baseline that can then be used to demon strate stability versus cognitive decline over successive test sessions. This is particularly important in individuals of high premorbid intellect, as “average” performances in these individuals may actu ally represent a significant decline with respect to their premorbid level of performance. Comprehensive neuropsychological evalua tions are also of benefit in assisting with work accommodations, recommendations for intervention, and disability applications.

Laboratory testing

A basic dementia blood screen is recommended. The American Academy of Neurology (AAN) guidelines recommend the following testing in the routine evaluation of a patient with

dementia: complete blood count (CBC), serum electrolytes (we include calcium, magnesium, and phosphorus), creatinine, blood urea nitrogen (BUN), glucose, thyroid function tests (TFTs), liver function tests (LFTs), and vitamin B12 (http:// tools.aan.com/professionals/practice/pdfs/dementia_guideline. pdf). Although screening for syphilis is not recommended by current AAN guidelines because of the low positive rate (unless patient has a specific risk factor, e.g., living in a high‐incidence region), because it is a treatable disorder, we recommend screen ing for syphilis with an nontreponemal test, such as with rapid plasma reagin (RPR), although a treponemal‐specific test is often preferred and cerebrospinal fluid (CSF) must be analyzed when neurosyphilis is suspected (please refer to Chapter 13 for additional details) [71]. If vascular disease is a potential etiol ogy, include a fasting lipid panel, homocysteine, and possibly methylmalonic acid. For rapidly progressive dementias, addi tional lab testing is required [72].

CSF

CSF analysis can be very helpful for diagnosis in certain demen tias. In most typical dementias, CSF is not tested routinely, but there are certain cases in which CSF testing is helpful or even necessary. If inflammatory etiologies, infections, mitochon drial disorders, neoplasms, prion disease, or other rapid dementias are in the differential, CSF analysis is required. If AD is in the differential but the diagnosis is unclear and/or there are some atypical features, CSF testing for abeta amyloid, total tau (t‐tau), and phosphorylated tau (p‐tau) levels can be help ful; in AD, there are often very low abeta amyloid and mild to moderately elevated t‐tau and p‐tau levels. At our center, because of the increasing incidence of autoimmune/inflamma tory etiologies for dementia, we routinely test for IgG index and oligoclonal bands in most patients with atypical dementias. For rapidly progressive dementias, in addition to testing for the aforementioned, we recommend testing for t‐tau, neuron‐ specific enolase, and 14‐3‐3 as markers of rapidly neuronal injury (not because of their utility in diagnosing CJD); as noted in Chapter 9 on prion disease, these CSF biomarkers should be interpreted with caution. A new assay, RT‐QuIC, however, seems to have relatively high specificity (as high as 98%) in CSF for diagnosing sCJD. Although not discussed in this text, if normal pressure hydrocephalus (NPH) is in the differential, a large volume tap (~30 or more cc) is recommended with pre‐ and post‐gait and/or balance assessment.

Genetic testing

A positive FMH suggesting autosomal dominant inheritance or the presence of multiple affected family members may suggest a need for genetic testing for confirmation of genetic status (i.e., mutation and/or relevant polymorphism). As many neu rogenetic dementias present with great variability even within the same family and often not just cognitive symptoms, the cli nician should inquire about a FMH of other symptoms, such as psychiatric illness or peripheral nervous system dysfunction

The multidisciplinary evaluation of the atypical dementia patient 13

14 Non-Alzheimer’s and Atypical Dementia

[73]. For example, a FMH of mental retardation or miscarriage in a patient with cognitive impairment, tremor, and/or ataxia might be indicative of FXTAS [74], or premature ovarian fail ure in a leukodystrophy might indicate mutations in eIF2B causing vanishing white matter disease [75]. As autosomal recessive disorders can also cause atypical dementia, inquiring about any consanguinity and the ethnic backgrounds of both biological parents is important for consideration of genetic etiologies.

Consideration of genetic testing ideally should be performed with the assistance of a genetic counselor or physician with experience in genetic testing, optimally one with expertise in neurological conditions. Counseling regarding the specific genetic tests being performed, the implications of the test, and the desire of each family member to know the results should be performed prior to initiating the testing. Disclosure of the results ideally should take place with the assistance of a genetic counselor or equivalently trained physician [76]. The Genetic Information Nondiscrimination Act (GINA), passed in 2008 in the United States, has made it illegal for bias or discrimination in health insurance or employment on the basis of genetic test ing alone. It is our experience, however, that obtaining specific types of health insurance or long‐term care policies may best be done prior to undergoing genetic testing or receiving genetic results [77]. Please refer to each individual chapter regarding appropriate genetic tests for suspected conditions.

Neuroimaging

Brain MRI has largely supplanted head CT as a critical tool in the evaluation of atypical dementia, as the MRI is more sensitive to focal atrophy, neuroanatomy, white matter abnormalities, and abnormalities not detected at all by CT, such as restricted diffusion. There is no “approved” or standard protocol for MRI in dementia. At our center, we generally recommend acquiring at least the following: T1 (axial, coronal, and sagittal if possible), T2 and FLAIR axial (coronal is also helpful for the evaluation of hippocampal MTL pathology, whereas sagittal is helpful for the evaluation of corpus callosum and demyelinating disease), and a hemosiderin sequence, such as gradient echo (GRE) or susceptibility weighted imaging (SWI). If stroke, intravascular processes, demyelination, thiamine deficiency, or prion disease is on the differential, diffusion weighted imaging (DWI) and attenuation diffusion coefficient (ADC) maps are necessary. If there are focal abnormalities on exam or there is concern for a process involving breakdown of the blood–brain barrier (BBB), at least one sequence with contrast should be done. MRI proto cols as well as findings supportive of certain conditions will be discussed under each chapter.

Brain positron emission tomography (PET) or SPECT scans can be useful to delineate areas of low glucose utilization or hypoperfusion, which is sometimes helpful for diagnosis, particularly if trying to differentiate between conditions with different anatomical involvement. The advent of ligands for ß‐amyloid and tau has increased the clinical utility of PET scans.

Certain ligands are only available in research or not widely available due to short radioactive half‐lives (but F18‐labeled antibodies against ß‐amyloid are now clinically approved in the United States with florbetapir (Amyvid)). Florbetapir can be helpful in early‐onset dementia patients when trying to distin guish between an AD and FTD etiology.

Body imaging

When antibody‐mediated or antibody‐associated syndromes are identified or being considered, a neoplasm workup is often required, as some of these are often paraneoplastic. This typi cally would involve whole‐body CT with contrast and/or whole‐ body PET/CT. More focused examinations such as MRI of the breast, testicular ultrasound, or transvaginal ultrasound might be indicated based on the type of tumor suspected. PET scans may be beneficial in cases in which a paraneoplastic syndrome is suspected and no clear cause (or suspected cause) is identified by other body imaging.

Other tests

Electroencephalogram (EEG) is necessary to rule out seizures or nonconvulsive status epilepticus. EEG also can be helpful in trying to determine if a syndrome is neurological or psychiatric. For example, patients with focal or diffuse cognitive deficits often show commensurate slowing of EEG activity. Electromyogram (EMG) is essential for the diagnosis of motor neuron disease (MND) or other neuromuscular disorders. It is particularly useful when considering FTD syndromes that often have concurrent MND, such as due to the C9orf72 mutations.

putting it all together: Multidisciplinary assessment/review

After the multidisciplinary assessment, including patient/ caregiver interview(s), neurological exam, and neuropsycho logical testing, is complete, it is helpful to have a group meeting among all involved staff to discuss the case, develop a differential, determine the likely diagnosis, additional assessments/testing, and propose a treatment and management plan. We have found that it is best to do the assessment and presentation of findings and conclusions to the patient/caregiver on the same day. It is helpful to provide the patient and caregivers additional reading material or resources (e.g., websites, support groups, etc.) to learn more about the diagnosis on their own time. Depending on the diagnosis and/or clinician preference, one might provide sug gestions and leave management to the referring or primary care physician or plan a follow‐up visit to review any recommended or ordered tests. For detailed description regarding the manage ment of patients with atypical dementia, please refer to Chapter15.Inourclinic,wefindthathavingthefamily/caregivers interviewed separately from the patient at some point is helpful, as they can provide information that might be comfortable or possible to present in front of the patient. When a diagnosis is

made and treatment trials are being considered, a useful website to find out about ongoing studies in the United States (and often internationally) is http://www.clinicaltrials.gov.

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ChAptEr 3
Atypical Alzheimer’s disease

Sharon J. Sha1,2 and Gil D. Rabinovici1

1 University of California, San Francisco, San Francisco, CA, USA 2 Stanford Center for Memory Disorders, Stanford, CA, USA

Introduction

Alzheimer’s disease (AD) is the most common pathologic cause of dementia [1]. Clinically, AD typically presents with early episodic memory loss and visuospatial dysfunction. Less prominent deficits in executive function, attention, and language are common as well. Behavioral disturbances such as psychosis do not typically occur until late disease stages [2]. It is increas‐ ingly recognized, however, that AD pathology can be found in patients with nonamnestic clinical presentations [3–5]. AD is the most common cause of posterior cortical atrophy (PCA) [6, 7] and is found to be the causative pathology in 20–50% of patients with corticobasal syndrome (CBS) [3, 8] and in 20–40% of patients with primary progressive aphasia (PPA) [9, 10], focal cortical syndromes that were initially postulated to be pathologically dis‐ tinct from AD [11–13]. Identifying patients with atypical clinical syndromes who have underlying AD is important clinically as symptomatic therapies are available for AD, but not yet for other degenerative dementias, and disease‐specific therapies for AD are on the horizon [14]. Whereas previous criteria for AD included obligatory decline in memory [15], the new criteria propose to include nonamnestic presentations as well [16, 17].

Epidemiology

AD affects 5.2 million people in the United States and 17 million people worldwide [18, 19]. The prevalence of AD is about 1% at age 60–65 and doubles every 5 years, approaching 40% in 85–90‐year‐olds. The prevalence of atypical presentations of AD is difficult to estimate. Nonamnestic presentations might account for up to 15% of patients seen in dementia referral centers [5]. The average age of onset in patients with atypical syndromes is typically in the 60s [6, 7, 20, 21], and it has been suggested that early age‐of‐onset AD (EOAD) patients (defined in most studies as under age 65 at symptom onset) are more likely to show nonamnestic presentations [22, 23]. It is not known whether patients with atypical presentations

differ from typical patients in disease progression or survival, although rapidly progressive forms of AD recently have been recognized [24].

Diagnosis

In 1984, the National Institute of Neurological Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association (NINCDS‐ADRDA) working group formulated diagnostic criteria that remained in practice through 2011 (Table 3.1) [15]. The NINCDS‐ADRDA criteria had several limitations. First, they were only about 70–80% sensitive and 70% specific compared to pathology [25, 26]. Furthermore, patients with AD who presented with atypical patterns of cognitive impairment often did not meet NINCDS‐ADRDA criteria, which require memory impairment as one of the core features. [5] In addi‐ tion, biomarkers such as molecular, functional, and structural imaging modalities, cerebrospinal fluid (CSF) evaluation, as well as genetic information were not available when these criteria were developed and therefore were not included in the original criteria.

Integrating biomarkers and genetics into diagnostic criteria has been an ongoing process [27]. There are currently two partly overlapping sets of criteria set forth by expert workgroups (Tables 3.1 and 3.2). Both sets of criteria recognize nonamnestic presentations of AD, and both allow the integration of imaging and fluid biomarkers to supplement clinical criteria, but in dif‐ ferent ways. The criteria proposed by the US National Institutes of Health National Institute on Aging (NIA) and the Alzheimer’s Association (AAS) (NIA‐AAS) workgroup allow the diagnosis of probable AD to be made on clinical grounds alone (Table 3.1). If available, biomarkers can be used to supplement the clinical evaluation. Biomarkers are divided into two categories: markers of amyloid beta (Aβ, including CSF Aβ42 levels or amyloid posi‐ tron emission tomography (PET)) and markers of neuronal injury (CSF measures of total or phosphorylated tau, atrophy on MRI or hypometabolism/hypoperfusion on fluorodeoxyglucose

18 Non-Alzheimer’s and Atypical Dementia
Table 3.1 1984 NINCDS‐ADRDA criteria for probable Alzheimer’s disease [15].

1. Insidious onset after age 40 with gradual progression

2. Dementia

3. Deficitinatleast2areasofcognition(onemustincludememory)foratleast
12 months

4. Progressive worsening of cognition

5. No disturbance of consciousness

6. Other systemic disease or brain disorder does not account for the disease

*Possible AD: atypical onset, presentation, or clinical course of dementia without a systemic disease or brain disorder that could account for the disease
*Definite AD: pathological confirmation by biopsy or autopsy + criteria listed for probable AD

2011 updated clinical criteria for AD [16]

1. Insidious onset with gradual progression

2. Clear‐cut history of worsening of cognition by report or observation

3. The initial and most prominent cognitive deficits are evident on history
and examination in one of the following categories.

• Amnestic presentation

• Nonamnestic presentations:
° Language presentation
° Visuospatial presentation ° Executive dysfunction

4. The diagnosis of probable AD dementia should not be applied when there is evidence of

• Substantial concomitant cerebrovascular disease

• Core features of dementia with Lewy bodies

• Prominent features of behavioral variant frontotemporal dementia

• Prominent features of semantic variant primary progressive aphasia or
nonfluent/ agrammatic variant primary progressive aphasia

• Other systemic disease or brain disorder accounting for symptoms
Source: Adapted from McKhann et al. [15]. © 2011 by AAN Enterprises, Inc.
PET (FDG‐PET) or single‐photon emission computed tomog‐ raphy (SPECT)). Various combinations of these markers mod‐ ify the likelihood of underlying AD pathophysiology, for example, from low (if biomarkers from both categories are negative) to high (if there are positive markers in both catego‐ ries) (Table 3.2) [16].
An International Working Group (IWG) has proposed an alternative set of criteria, which require both a suggestive clinical syndrome (“typical” amnestic or “atypical” nonamnestic) and a biomarker evidence of AD pathophysiology by either amyloid PET or CSF Aβ42 and tau measures [17]. MRI and FDG‐PET/ SPECT are conceptualized as “topographical markers” of disease progression, but are not included in the criteria because they are not specific to AD pathophysiology. The IWG criteria are intended to maximize accuracy in research studies but may have limited utility in the clinical setting where access to CSF biomarkers and amyloid PET is limited. Importantly, both sets of criteria also recognize mixed or atypical presentations (which can be distinguished from nonamnestic presentations that are still characteristic of underlying AD, such as PCA or the logopenic variant of PPA).

This case represents a “typical” AD presentation in a patient who developed problems with recent memory in late life. Visuospatial ability, language, and executive function are affected more variably.

Neuropathology

The core neuropathological features of AD are neuritic plaques (NPs) and neurofibrillary tangles (NFTs). NPs are extracellular, florid (flowerlike) appearing structures composed largely of the 42‐amino‐acid amyloid‐beta polypeptide (Aβ1–42), a cleavage product of the amyloid precursor protein (APP). Mature NPs have a dense core surrounded by dystrophic neurites; NPs are more specific for AD than the less fibrillar, diffuse plaques often seen in normal aging [28]. Plaques form seemingly simultaneously

Case 1

Mr. M is a 72‐year‐old right‐handed gentleman who has had memory problems for 4 years. He asks repetitive questions, cannot remember plans for business trips, and forgets conversations. Recently, he has had problems with navigation. Executing complex tasks such as cooking has become more difficult. Functionally, he is no longer able to work or drive. His wife has taken over bill paying and assisted him with cooking. He needs reminders to shower but is able to perform all basic activities of daily living (ADLs). Neurological examination is normal. He scores 22/30 on the Mini‐Mental Status Examination (MMSE). Neuropsychological testing reveals significant deficits in episodic memory and visuospatial and executive functions. Laboratory tests for thyroid function and B12 are normal. An MRI demonstrates cortical atrophy, primarily in temporoparietal regions, and prominent hippocampal atrophy (Figure 3.1). He passed away at age 77. Autopsy diagnosis is high‐likelihood AD (NIA‐Reagan; see neuropathology in the following text).

Figure 3.1 Coronal T1‐weighted MRI of case 1 showing bilateral hippocampal and less severe frontal and temporal cortical atrophy.

Table 3.2 Various criteria for AD incorporating clinical presentation and biomarkers.

Updated AD dementia criteria incorporating biomarkers [16].

Atypical Alzheimer’s disease 19

Diagnostic Category

Probable AD dementia

Based on clinical criteria

With 3 levels of evidence of AD pathophysiological process

Possible AD dementia (atypical clinical presentation)
Based on clinical criteria

With evidence of AD pathophysiological process
Dementia unlikely due to AD

Biomarker probability of AD etiology

Uninformative

Intermediate Intermediate High

Uninformative

High but does not rule out second etiology
Lowest

Aβ (PET or CSF)

Unavailable, conflicting, or indeterminate
Unavailable or indeterminate Positive

Positive

Unavailable, conflicting, or indeterminate
Positive

Negative

Neuronal injury (CSF tau, FDG‐PET, structural MRI)

Unavailable, conflicting, or indeterminate
Positive
Unavailable or indeterminate Positive

Unavailable, conflicting, or indeterminate
Positive

Negative

Proposed criteria for typical AD (must have A and B) [17]

A. Presence of early and significant episodic memory impairment that includes: • Gradual and progressive change in memory function > 6 months
• Objective evidence of an amnestic syndrome of the hippocampal type

B. In vivo evidence of Alzheimer’s pathology (one of the following):
• Decreased Aβ1–42 together with increased t‐tau or p‐tau in CSF
• Increased tracer retention on amyloid PET
• AD autosomal dominant mutation present (in PSEN1, PSEN2, or APP)

Exclusion criteria:

• Sudden onset
• Early occurrence of gait disturbances, seizures, and major and prevalent behavioral changes
• Focal neurological signs
• Early extrapyramidal signs
• Early hallucinations
• Cognitive fluctuations
• Non‐AD dementia
• Major depression
• Cerebrovascular disease
• Toxic, inflammatory, and metabolic disorders
• MRI FLAIR or T2 signal changes in the medial temporal lobe that are consistent with infectious or vascular insults

Proposed criteria for atypical AD (must have A and B) [17]

A. Specific phenotype (one of the following):

• Posterior variant including an occipitotemporal variant defined by the presence of early, predominant, and progressive impairment of visuoperceptive
functions or of visual identification of objects, symbols, words, or faces or a biparietal variant defined by the presence of early, predominant, and
progressive difficulty with visuospatial functions, features of Gerstmann’s syndrome or Balint’s syndrome, limb apraxia, or neglect

• Logopenic variant defined by the presence of early, predominant, and progressive impairment of single‐word retrieval and in repetition of sentences in
the context of spared semantic, syntactic, and motor speech abilities

• Frontal variant defined by the presence of early, predominant, and progressive behavioral changes including association of primary apathy or behavioral
disinhibition or predominant executive dysfunction on cognitive testing

• Down’s syndrome variant defined by occurrence of a dementia characterized by early behavioral changes and executive dysfunction in people with
Down’s syndrome

B. In vivo evidence of Alzheimer’s pathology (as noted above)

Exclusion criteria
• Sudden onset
• Early and prevalent episodic memory disorder
• Major depression
• Cerebrovascular disease
• Toxic, inflammatory, or other metabolic disorders

Source: McKhann et al. [16]. Reproduced with permission of Elsevier.

20 Non-Alzheimer’s and Atypical Dementia

throughout the association isocortex, including parietal, pre‐ frontal, and lateral temporal regions [29, 30]. Primary sensori‐ motor, visual, and auditory cortices, medial temporal cortex, and hippocampus are relatively spared of plaques in AD. NFTs are flame‐shaped, intracellular inclusions composed of hyper‐ phosphorylated species of the microtubule‐associated protein tau (MAPT). NFTs first appear in the entorhinal cortex and then spread to limbic and paralimbic regions and to the tempo‐ ral and parietal neocortex, with later involvement of prefrontal regions. Primary visual and sensorimotor regions are the last to develop pathology [29]. Pathologic criteria for AD include rating the distribution and burden of NPs (using Consortium to Establish a Registry for AD (CERAD) criteria [31]) and NFTs (using Braak staging [29]). Combined CERAD and Braak stag‐ ing is used to establish NIA‐Reagan criteria, which use these pathology ratings to state whether an individual suffered from AD with low, intermediate, or high probability (NIA‐Reagan criteria). In 2012, a new set of neuropathological criteria were proposed by the NIA‐AAS that integrate Thal Aβ plaque score [30] with traditional CERAD and Braak staging [32].

Genetics

Approximately 1–6% of AD patients present under the age of 65, and 60% of these cases have a positive family history with 13% showing an autosomal dominant pattern [33]. Autosomal domi‐ nant AD has been associated with mutations in three genes: ‐presenilin 1 (PS1, chromosome 14), the most common gene associated with familial AD; presenilin 2 (PS2, chromosome 1), and APP (chromosome 21). Both PS1 and PS2 are components of the gamma‐secretase complex that cleaves APP into the toxic species Aβ1–42. Mutations in PS1 have been reported to cause early behavioral changes similar to frontotemporal dementia (FTD) [34] and, in some cases, have been associated with Pick bodies, a pathologic feature of FTLD, in addition to AD pathol‐ ogy. Patients with trisomy 21 (Down’s syndrome) develop AD pathology in the fourth and fifth decade, likely related to the presence of 3 copies of wild‐type APP [35].

APOE, the polymorphic genetic locus for apolipoprotein E on chromosome 19, is the strongest genetic determinant in sporadic AD. There are three allelic variants of APOE: ε3 is the most common, ε2 might decrease the risk of AD, whereas carriers of the ε4 allele are at higher risk for developing the disease [36, 37]. Although the ε3 allele is the most common in the general population, 50–65% of AD patients have at least one ε4 allele [38, 39]. Furthermore, there is a strong gene dose effect, such that ε4 heterozygotes are at approximately three‐ fold greater risk than ε4 noncarriers for developing AD, whereas homozygotes have a 15‐fold greater risk [40]. Each ε4 allele is associated with an approximately 10‐year younger age of onset [40]. The relationship between APOE genotype and AD phenotype (aside from early age of onset) is not clear. One study found that homozygosity for the ε4 allele was present in

17 of 71 patients presenting with an amnestic phenotype com‐ pared to only one patient of 29 patients presenting with nonamnestic phenotype [41]. Another study found a paucity of ε4 carriers (2 out of 10) in patients presenting with PCA [42], but this finding has not been replicated by other groups [6, 43]. A study from our center found no difference in the frequency of APOE ε4 between EOAD patients presenting with typical AD, PCA, or logopenic variant PPA (lvPPA), though the frequency of ε4 carriers was higher in all patient groups compared to controls [20]. Curiously, in European cases of rapidly progressive AD, ε4 carriers were underrepre‐ sented [24]. Additional risk factors for sporadic late‐onset AD are being uncovered via genome‐wide association studies and next‐generation sequencing [44].

Structural and functional neuroimaging: MrI, FDG‐pEt, and SpECt

MRI in typical AD demonstrates atrophy in the areas affected by NFTs, including the hippocampus, medial temporal cortex, lateral temporoparietal cortex, and posterior cingulate/precuneus, with relatively less involvement of dorsolateral prefrontal cortex until advanced disease stages [45, 46]. A similar topographic pattern is seen with FDG‐PET (reflecting hypometabolism) and SPECT (reflecting hypoperfusion) [47]. The degree of atrophy correlates with neurofibrillary pathology [48] and with clinical severity and can be used to track clinical progression [49]. It is increasingly recognized that there is a “hippocampal‐sparing” endophenotype of AD which deviates from traditional Braak staging in that the medial temporal lobes are spared on imaging and at autopsy. Hippocampal‐sparing AD correlates with younger age of onset and a nonamnestic clinical presentation [50, 51].

CSF/amyloid imaging

An exciting recent development in the field has been the emer‐ gence and validation of biomarkers for molecular pathology. Patients with AD show decreased levels of Aβ1–42 and increased levels of total and phosphorylated tau in the CSF, and a ratio of tau/Aβ1–42 can distinguish AD patients from controls with high sensitivity and specificity [52–54]. NPs can be imaged using a variety of PET tracers, including 11C‐PIB [55], 18F‐florbetapir [56], 18F‐flutemetamol [57], 18F‐florbetaben [58], and 18F‐ NAV4694 [59]. Both CSF biomarkers and amyloid PET have been validated against autopsy‐confirmed cases [53, 60, 61]. These biomarkers might be helpful for ruling in AD in patients with atypical clinical presentations [45, 62, 63] as will be dem‐ onstrated in the vignettes below. More recently, PET tracers specific to NFTs have been developed and used in pilot human studies [64–66]. These tracers will allow us for the first time to see in vivo how amyloid and tau interact with each other and with brain structure and function in aging and AD.

Table 3.3 Criteria for primary progressive aphasia.

1. Gradual progression of word finding, naming, or comprehension problems

2. No other cognitive domains affected until 2 years after onset with
language as the primary deficit (apraxia and acalculia may be present)

3. ADLs limited by language only in the first 2 years

4. No other systemic illness or brain disorder (stroke) accountable for the
disease

Source: Adapted from Mesulam [67]. © Wiley.

The patient in case 2 meets Mesulam criteria for PPA as he evolved progressive difficulties with language with relative sparing of other cognitive functions for at least 2 years from symptom onset [67] (Table 3.3). As is often the case, neurode‐ generation appears focal and asymmetric. PPA typically is divided into three distinct clinical variants based on the pattern of aphasia: a nonfluent variant (nfvPPA), also referred to as progressive nonfluent aphasia (PNFA), characterized by motor

speech deficits and agrammatism; a semantic variant (svPPA), previously referred to as semantic dementia, characterized by fluent speech with loss of meaning for single words; and a logopenic variant (lvPPA), defined by anomia and impaired repetition (especially for long sentences with unpredictable content) with intact grammar, motor speech, and single‐word comprehension [69]. Each variant is associated with a selective atrophy pattern with left inferior frontal and perisylvian involve‐ ment in nfvPPA, anterior temporal in svPPA, and left temporo‐ parietal junction in lvPPA [21, 62, 68, 69].

Gorno‐Tempini and colleagues characterized the language and cognitive deficits in lvPPA in depth and have proposed diag‐ nostic criteria [69] (Table 3.4). Mr. D in case 2 meets core criteria and four supportive features for lvPPA. Furthermore, his MRI and PET qualify for an imaging‐supported diagnosis of lvPPA.

Determining the PPA variant can help predict underlying pathology, as AD is frequently the cause of lvPPA, whereas nfvPPA and svPPA are usually associated with FTLD pathology [3, 10].

Atypical Alzheimer’s disease 21

Case 2

Mr. D is a 51‐year‐old right‐handed man with a history of dyslexia who developed word‐finding difficulties over the past 4–5 years. When speaking, he loses phonemes (the speech sound in language of which words are represented) at the end of words and occasionally stutters. He has significant problems producing and comprehending long sentences as well as retaining long strings of numbers. Grammar is intact, but spelling is difficult. Memory has started to decline in the past year. He and his family deny any problems with visuospatial or executive function. He has been anxious and irritable. Functionally, he was forced to stop working but remains independent with all basic ADLs. On exam, his speech is hesitant and deliberate with normal syntax. Repetition is significantly impaired—for example, when asked to repeat “the ship crashed into the

(a) (b)

shore,” he states, “the boat crashed into the sand” (video 1). He has word‐finding difficulties for which he compensates with circumlocutions (video 2). The remainder of his neurological exam is normal. The MMSE score is 26/30, missing points for repetition and orientation to place. Neuropsychological testing shows significant deficits in naming, repetition, echoic memory (i.e., short‐term auditory storage; e.g., digit span forwards), and calculations with only minor deficits in episodic memory and executive functioning. Laboratory studies of vitamin B12 and thyroid function are normal. An MRI demonstrates global atrophy with more prominent atrophy in the left parietal and posterior temporal lobe with normal hippocampal size bilaterally (Figure 3.2). A Pittsburgh compound B PET scan is positive for amyloid. He is started on a trial of donepezil and referred to speech therapy.

(c)

Figure 3.2 (a) Axial T1‐weighted MRI of case 2 showing left parietal atrophy. (b) Coronal T1‐weighted MRI showing normal hippocampal size. (c) PIB‐PET showing cortical PIB binding (yellow to red indicate increasing spectrum of PIB binding). Orientation of MRIs is radiologic (left is right). Orientation of PET scan is neurological (right is right). (See insert for color representation of the figure.)

22 Non-Alzheimer’s and Atypical Dementia Table 3.4 Criteria for logopenic variant PPA.

Clinical diagnosis of lvPPA (both core features must be present)

1. Impaired single‐word retrieval in spontaneous speech and
confrontational naming

2. Impaired repetition of sentences and phrases

At least three of the following other features must be present:
1. Speech (phonological) errors in spontaneous speech and naming 2. Spared single‐word comprehension and object knowledge
3. Spared motor speech
4. Absence of frank agrammatism

Imaging‐supported diagnosis of lvPPA (both criteria must be present)

1. Clinical diagnosis of lvPPA

2. Imaging must show at least one of the following results:

• Predominant left posterior perisylvian or parietal atrophy on MRI

• Predominant left posterior perisylvian or parietal hypoperfusion or
hypometabolism on SPECT or PET
lvPPA with definite pathology (clinical diagnosis of LV and 1 or 2 must be present)

1. Histopathological evidence of a specific neurodegenerative pathology (e.g., AD, FTLD‐tau, FTLD‐TDP, and others)

2. Presence of a known pathogenic mutation

Several studies have shown that the majority of, but not all, lvPPA patients have AD pathology using PIB, autopsy, or CSF biomarkers [62, 70, 71]. Therefore, whereas lvPPA appears to be a marker for AD pathology, the syndrome is pathologically heterogeneous, and both CSF biomarkers and amyloid imaging can be helpful in determining whether AD is the causative pathology. For Mr. D, a positive PIB scan (Figure 3.2) greatly increases the likelihood of AD as the pathologic substrate.

In most studies, PPA patients with pathological AD have been found to have increased NFTs in the left hemisphere [10] compared [72] to the right, though this was not observed in all patients [5]. Results regarding plaque distribution have been more variable, with some studies reporting a left‐sided predominance in PPA [5] and others finding a symmetric distribution of plaques indistinguishable from a typical AD pattern [10, 62].

Ms. S meets criteria for the clinical syndrome PCA [73]. Frank Benson and colleagues coined the term describing five patients with deficits in “high visual function” leading to dementia [12].

Case 3

Ms. S is a 62‐year‐old right‐handed woman with a 5‐year history of visuospatial dysfunction. She began having difficulty driving at night and found several dents on her car. She began bumping into doors and cabinets on her right side and had difficulty deciding whether to push or pull doors to open them. She became unable to read. Writing has also been difficult, as she tends to write letters on top of one another. She does not get lost in familiar environments but has had problems finding public restrooms on her own. She describes difficulty finding her mascara among her other makeup accessories on the dresser which are right in front of her. She needs more time to plan and organize her activities and, in the past 6 months, has had trouble multitasking. She denies memory or language impairment. Her mood is good, but she describes visual hallucinations of cats or a human figure in her room at night. Functionally, she is still able to

(a) (b)

perform instrumental ADLs (IADLs), but for the past 6 months, she has asked her husband to verify her management of finances. She has stopped driving. On exam, her MMSE is 26/30. She has difficulty reading words. She focuses on details but has difficulty appreciating the gestalt when describing a picture (i.e., simultagnosia). She has intact visual acuity, full visual fields, and no extinction to simultaneous bilateral visual stimulation. Neuropsychological testing shows significant impairments in visuospatial function and constructional praxis (Figure 3.3a). An MRI shows significant atrophy in the parietal, posterior temporal, and occipital cortex, right greater than left, with slight hippocampal atrophy and scattered white matter disease (Figure 3.3b and c). FDG‐PET reveals hypometabolism in the parietal, posterior temporal, and lateral occipital cortex. PIB‐PET shows diffuse cortical PIB binding. She is started on donepezil. Occupational therapy for the visually impaired is recommended.

(c)

Figure 3.3 (a) Benson Figure (top) with patient copy (bottom). (b) Axial T1‐weighted MRI showing occipital atrophy. (c) Sagittal T1‐weighted MRI showing parietal and occipital atrophy. Orientation is radiologic.

All patients had problems with visuospatial function but had intact visual acuity and visual fields. Many patients developed agnosia, alexia, agraphia, anomia, and components of Balint’s syndrome (simultanagnosia, optic ataxia, oculomotor apraxia) or Gerstmann’s syndrome (agraphia, finger agnosia, right–left confusion, acalculia). Benson noted that memory and judgment were intact until later in the course of the disease. Insight is typi‐ cally preserved [43, 74]. Later in the course, patients may develop parkinsonism, alien limb, or asymmetric limb apraxia, and these may suggest a non‐AD pathologic substrate. The mean age of onset in PCA is in the late 50s/early 60s in most series, with a mean duration from symptom onset to diagnosis of approximately 4 years [6, 43, 75]. One study found a female predominance in PCA compared to AD [6], but this was not replicated in other series [43, 75]. Neuropsychological testing typically shows impairments in visuospatial tasks, spatial mem‐ ory, alexia, agraphia, and variable performance on construction and calculations compared to AD patients [6, 43, 76]. Memory testing is relatively spared compared to typical AD [43, 75], whereas language function is similar to typical AD patients. There are no consensus clinical criteria for PCA, and we thus list criteria proposed by the two separate groups below (Table 3.5).

In Benson et al.’s original series of five cases, three patients showed PCA on brain imaging as determined by qualitative assess‐ ment [12]. Subsequent imaging studies comparing PCA patients to normal controls have demonstrated right‐sided predominant atrophy and hypometabolism in the posterior parietal, temporal, and lateral occipital cortex and relative sparing of the hippocampus and medial temporal cortex [20, 43, 63, 77, 78]. Compared to typi‐ cal AD patients, PCA patients show more atrophy in primary and

Table 3.5 Two proposed criteria for PCA.

Mendez 2002 [43]

Core features (all must be present)

1. Insidious onset with gradual progression

2. Presentation with visual complaints with intact primary visual function

3. On examination, evidence of predominant complex visual disorder
(Balint’s, visual agnosia, dressing apraxia, environmental disorientation)

4. Proportionally less deficits in memory and verbal fluency

5. Relatively preserved insight

Supportive features

1. Presenile onset

2. Alexia

3. Elements of Gerstmann’s syndrome

4. Ideomotor apraxia

5. Normal physical examination

6. Investigations: neuropsychology (impaired perceptual deficits),
imaging (occipitoparietal abnormality with sparing of frontal and mesiotemporal regions)

McMonagle 2006 [75]

1. Presentation with progressive visual or visuospatial impairment in the absence of ophthalmologic impairment

2. Evidence of complex visual disorder on examination: elements of Balint’s syndrome, visual agnosia, dressing apraxia, or environmental disorientation

3. Proportionately less memory loss or reduced verbal fluency

association visual and right posterior parietal lobe, whereas AD patients have relatively greater left medial and, inferior and middle temporal atrophy and hypometabolism [63, 77].

Although Benson speculated that PCA was likely caused by non‐AD pathology [12], subsequent studies have demonstrated that AD is the most common pathologic substrate, accounting for 67–100% of cases [6, 7, 20]. Additional pathologic causes of PCA include DLB and CBD, suggested by characteristic neu‐ ropsychiatric and motor features [79], and prion disease, sug‐ gested by a rapid course, as well as cortical ribboning on DWI MRI (see Chapter 9). A positive PIB scan supports the notion of underlying AD in Ms. S.’s case, with visual hallucinations sug‐ gesting possible comorbid DLB (although visual hallucinations can also occur in individuals with significant visual impairment, including those with glaucoma or macular degeneration).

Patients with PCA generally have higher counts of NFTs in the occipital cortex, posterior parietal, and posterior cingulate cortex and fewer tangles in the prefrontal cortex and hippocam‐ pus than typically seen in AD [6, 7]. One study found that amy‐ loid plaques were also elevated in visual regions compared to typical AD [80], but most studies have not found a difference in the distribution of plaques in PCA and AD as assessed at autopsy or using PIB‐PET [6, 63, 78].

Atypical Alzheimer’s disease 23

Case 4

Mr. T is a 56‐year‐old left‐handed man presenting with 8 years of progressive behavioral problems. His first symptom was loss of empathy, exemplified by not calling his wife when she was hospitalized for surgery. He developed compulsive recycling and composting, sorting through garbage ritualistically and bagging items for disposal. He began collecting shoes and fruit peels, as well as urine and feces. He became obsessed with having his dog with him at all times and pretended to be blind so that he could bring his dog with him on a train. He became disinhibited, at one point running naked on the beach, inviting a homeless stranger into the home to drink with him, and assisting in the escape of two tenants of a home for cognitively impaired persons. He began overeating and displaying a lack of disgust—eating moldy lemons, apple cores, and sodas left by strangers. Memory problems began 3 years after the onset of behavioral changes, having difficulty remembering his new cell phone number. He became disorganized and developed trouble with household tasks such as making the bed and putting away laundry. He also developed repetitive motor behaviors such as frequent yawning and rubbing the edges of his mouth. Language has been relatively preserved. His navigation skills declined. His personal hygiene worsened, and he had to be encouraged to bathe and change his clothes. On exam, his speech was tangential and perseverative. His behavior was jocular and disinhibited, frequently asking the examiner’s age and marital status and speaking out of context. He was found to be hoarding food under the covers of his hospital bed. On neuropsychological testing, he scored 18 of 30 on the MMSE. Cognitive testing revealed impairment in episodic memory and executive and visuospatial function with relative sparing of language. His initial clinical diagnosis was bvFTD. Brain MRI and FDG‐PET demonstrated atrophy and hypometabolism in both the frontal and parietal cortex, right greater than left, with prominent involvement of the precuneus (Figure 3.4a and b). PIB‐PET scan was positive (Figure 3.4c). Based on his MRI and PIB‐PET scan, his diagnosis was changed to frontal variant EOAD.

24 Non-Alzheimer’s and Atypical Dementia

Mr. T is an example of a patient with very prominent behav‐ ioral symptoms suggestive of behavioral variant frontotempo‐ ral dementia (bvFTD; see Chapter 5 for additional details) but in whom imaging studies supported an AD pathology (bipari‐ etal atrophy and hypometabolism as well as positive PIB). Johnson and colleagues described clinical and pathologic fea‐ tures of three patients with pathological AD who presented with a dysexecutive cognitive profile, coining this presenta‐ tion “frontal variant AD” (fvAD) [81]. Evidence for a behav‐ ioral predominant form of fvAD is provided by the fact that 10–20% of patients clinically diagnosed with bvFTD during life are found to have AD postmortem [3, 82–84]. Differentiating bvFTD due to FTLD and fvAD on clinical grounds often is difficult [85]. Many bvFTD patients met the original NINCDS‐ARDA criteria for AD [86], whereas up to one‐third of AD patients fulfill clinical criteria for bvFTD [87]. Factors that predispose to fvAD are not known, although PS1 mutation carriers in particular may present with a frontal syndrome [34, 74, 88]. Limited studies comparing the distri‐ bution of AD pathology in fvAD and typical AD patients found no difference in the distribution or burden of plaques but greater frontal NFTs in fvAD and greater medial temporal NFTs in typical AD [81]. Notably, Mr. T showed a diffuse pattern of PIB binding, similar to that seen in typical AD (Figure 3.4).

Distinguishing between fvAD and bvFTD based on cogni‐ tive testing can be challenging, as both groups show impair‐ ment on tests of executive function. Episodic memory can be variably affected in bvFTD, such that the presence of amnesia does not assure that AD is the underlying pathology [89, 90]. Rather, the presence of visuospatial dysfunction might be the most predictive of underlying AD [89], whereas the presence of executive dysfunction in the absence of behavioral changes makes underlying FTLD less likely [91]. Conversely, greater behavioral changes are suggestive of bvFTD [92, 93], though, as illustrated in Mr. T’s case, patients with fvAD can have very prominent behavioral disturbances [94–96]. The clinical overlap and distinctions between AD and FTLD are mirrored by neuroimaging studies [97, 98]. Both diseases lead to atro‐ phy in the dorsolateral prefrontal cortex and hippocampus, as suggested by the common findings of executive dysfunction and episodic memory loss. The atrophy patterns diverge in that AD also leads to parietal atrophy, whereas FTLD is associ‐ ated with medial prefrontal atrophy [45]. Temporoparietal and precuneus involvement on imaging suggests that AD is the underlying disease in patients with behavioral or dysexecutive presentations [98].

Mr. T actually fulfilled research criteria for bvFTD [99]. The presence of visuospatial dysfunction and to a lesser degree memory loss relatively early in the course raised suspicion for AD. Prominent parietal involvement on MRI and FDG‐PET supported the diagnosis of fvAD, and this diagnosis was preliminarily confirmed with a positive PIB scan.

(a)

(b)

(c)

Figure 3.4 (a) Sagittal T1‐weighted MRI showing parietal and occipital atrophy. (b) FDG‐PET showing hypometabolism in frontal and parietal cortices. (c) PIB‐PET showing diffuse cortical binding. Orientation is neurological. (See insert for color representation of the figure.)

Atypical Alzheimer’s disease 25

Case 5

Mr. Z is a 65‐year‐old right‐handed man presenting with 5 years of memory and movement problems. His family noted 5 years ago that he was misplacing objects and had difficulty remembering recent events. Three years prior to presentation, he developed problems using his left hand and leg, leading to an abnormal gait. Two years later, he evolved difficulty using tools and noticed a tremor and jerks in the left arm. He began running into walls on the left and developed left–right confusion. He was tried on levodopa without a clear response. Language function was unchanged except for less legible handwriting. Visuospatial function declined, with problems recognizing the faces of his grandchildren and difficulty reading one line to the next. He never became lost, but was involved in a motor vehicle accident in which he was at fault. He began having hallucinations, hearing voices, and seeing lights and on one

(a) (b)

occasion thought a snake was in his bed. He did not act out his dreams nor did he have fluctuations in alertness. He lived in a nursing home for the year prior to presentation. Neurological examination revealed myoclonus in the upper extremities, left greater than right. Tone was increased in the right arm with a tonically contracted left arm. There was extinction on the left with double simultaneous stimulation and ideomotor apraxia of the left arm and leg. His gait was bradykinetic and stooped. His MMSE was 21 of 30. Neuropsychological testing showed deficits in memory, executive function, naming, and visuospatial function. An MRI demonstrated right greater than left parietal and temporal atrophy with some milder atrophy of the bilateral medial perirolandic cortex (Figure 3.5a). PIB‐PET was positive. He died 15 months following the evaluation, 6.5 years after onset. Autopsy revealed high‐likelihood AD (NIA‐Reagan) (Figure 3.5b and c) and intermediate‐likelihood DLB [100b].

(c)

Figure 3.5 (a) Coronal T1‐weighted MRI showing bilateral (right > left) temporal and right parietal (not shown) atrophy; orientation is radiological. (b) His pathology showed AD characteristic amyloid‐beta‐positive plaques (brown) in the middle frontal gyrus (4G8 (anti‐amyloid‐beta) immuno‐ histochemistry; 100x). (c) AD characteristic tau‐positive inclusions in the hippocampus. Neurofibrillary tangles (arrows), neuritic plaques (arrow heads), and neuropil threads (brown background) are present (CP13 (anti‐phosphorylated tau) immunohistochemistry; 40x). DG, dentate gyrus. (See insert for color representation of the figure.)

Mr. Z’s clinical presentation included many features of CBS (see Chapter 7 for additional details). Although CBS is most often associated with FTLD pathology, roughly 15–50% of patients are found to have underlying AD postmortem [8, 98, 100a]. Unfortunately, the core features of CBS do not appear to discriminate patients with underlying AD from those with FTLD [101, 102]. The additional presence of episodic memory loss and visuospatial dysfunction might predict underlying AD, whereas nonfluent aphasia, prominent behavioral symptoms, preferential executive dysfunction, and lower limb apraxia are suggestive of underlying FTLD [101]. Atrophy/ hypometabo‐ lism/hypoperfusion in a perirolandic network that includes the pre‐ and postcentral gyrus, supplementary motor areas, and dorsomedial prefrontal cortex is associated with CBS regardless of underlying neuropathology [46, 103]. Extension of atrophy or hypoperfusion/hypometabolism into the temporoparietal cortex might be a marker for underlying AD, whereas greater frontal or brainstem lesions may indicate FTLD [98, 103]. Mr. Z presented with many of the core features of CBS including cortical sensory loss, ideomotor apraxia, and myoclonus.

Extrapyramidal dysfunction was also present with asymmetric increased tone. Early episodic memory loss, visuospatial dys‐ function, a posterior‐predominant atrophy pattern on MRI, and a positive PIB‐PET suggested AD as the underlying pathology, whereas the episode of visual hallucinations hinted at comorbid DLB. Autopsy demonstrated mixed AD/DLB.

treatment

Two classes of medications are approved in the United States for symptomatic treatment of AD: acetylcholinesterase inhibitors (AChEIs) and memantine, an N‐methyl‐d‐aspartic acid (NMDA) receptor antagonist. Both classes of medications show a symptomatic benefit later, followed by a decline in parallel with placebo, with small but statistically significant treatment benefits at study’s end on cognitive, behavioral, and functional measures [104–107]. These appear to translate into improved patient and caregiver quality of life and delay the need for custodial care [108–110]. The benefit of AChEIs has been established in

26 Non-Alzheimer’s and Atypical Dementia

patients with mild to severe AD, whereas memantine only references

has shown benefit in moderate to severe disease [107, 111]. Combined therapy with AChEI and memantine might provide greater benefit than either medication alone [112, 113]. Selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors are often helpful for treating depression, irri‐ tability, and perhaps apathy associated with AD [114–116].

There is essentially no data to determine whether AChEIs or memantine is effective in patients with atypical presentations, and in fact, a small study suggested that AChEIs are not beneficial in patients with PCA [43]. A trial of dopaminergic therapy should be considered in patients with CBS with prominent parkinsonism, and botulinum toxin might be helpful for dystonia in these patients. Patients with lvPPA often benefit from speech therapy, and PCA patients benefit from rehabilitative services for the visually impaired. Physical and occupational therapies are often helpful for maximizing function, and a structured exercise program is universally recommended in our clinic. A multidisciplinary clinical approach to treatment is critical, emphasizing the needs of the individual patient and providing caregiver education and support specific to the needs of the particular patient (see Chapter 15).

Conclusion

A century following Alois Alzheimer’s initial case report, it has become apparent that AD is the great “mimicker” of other neuro‐ degenerative diseases and can present not only with episodic mem‐ ory loss but also with language, visuospatial, motor, and behavior predominant syndromes. Each syndrome is associated with a dis‐ tinct degenerative pattern apparent on structural and functional imaging, though anatomic overlap across syndromes is found in the precuneus/posterior cingulate and lateral temporoparietal cortex [20]. As is the case in typical AD, the distribution of NFTs correlates more strongly with clinical phenotype and degenerative pattern than the distribution of NPs. Developmental, genetic, envi‐ ronmental, and physiologic mechanisms that contribute to pheno‐ typic heterogeneity in AD are at this point largely unknown.

The clinical heterogeneity of AD poses a challenge for clini‐ cians, as the disease overlaps clinically with syndromes previously associated with other neurodegenerative diseases such as FTLD. Fortunately, sensitive molecular biomarkers such as CSF Aβ1–42, tau, and p‐tau and amyloid imaging have been developed and will likely be adopted into clinical practice to “rule out” AD in patients with atypical clinical presentations. These patients could then be candidates for emerging biologically specific therapies for this devastating illness.

Acknowledgments

The authors would like to thank Michael WEINER for provid‐ ing MRI images, Bill Jagust for providing PET images, and William Seeley for assisting with pathology images.

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Atypical Alzheimer’s disease 29

CHapter 4

Vascular cognitive impairment: Diagnosis and treatment

Helena C. Chui and Liliana Ramirez-Gomez

University of Southern California, Los Angeles, CA, USA

Background

History

During the past century, the estimated contribution of vascular factors to cognitive decline has swung like a pendulum from high to low to high again. In the early twentieth century, pro gressive loss of intellectual function in late life was ascribed to “hardening of the arteries,” so‐called arteriosclerotic dementia. Alzheimer’s disease (AD) was considered a relatively rare early‐ onset dementia associated with neurofibrillary tangles and senile plaques, as first described by Alois Alzheimer in 1907.

When Tomlinson et al. [1] observed identical tangle and plaque lesions in late‐onset dementia cases, AD, not arterioscle rosis, became the ascendant cause. Abrupt onset and stepwise decline in cognition due to cumulative strokes formed the conceptual basis of multi‐infarct dementia (MID). Slowly progressive dementia due to severe arteriopathy and demyelina tion of subcortical white matter, so‐called Binswanger’s syndrome, was regarded as relatively rare.

The landscape shifted once again with the advent of structural imaging in the 1980s. Asymptomatic white matter hyperintensities (WMH) and silent brain infarcts (SBI) were discovered on brain MRI in 20–30% of nondemented, community‐dwelling elderly subjects [2]. The ability to detect early and subclinical vascular dis ease without overt dementia inspired a broader designation, vas cular cognitive impairment (VCI). In the 1990s, epidemiologic studies noted associations between stroke risk factors and cogni tive impairment (absent history of symptomatic stroke). This has led to the notion (still unproven) that vascular factors might pro mote AD, further broadening the saliency of potential adverse downstream effects of hypertension, diabetes, and dyslipidemia.

Concepts

VCI is a syndrome or phenotype, not a disease. At its simplest, VCI embodies the concept that cognitive impairment is due to vascular brain injury (VBI). (See Table 4.1 for terms and abbrevia tions used in this chapter.) Yet the sequence of underlying events

can be incredibly diverse. The pathways leading from risk factors to cerebrovascular disease (CVD) to VBI are widely heterogeneous (Table 4.2). Moreover, the likelihood that VBI contributes to cog nitive impairment is highly variable. Location within cognitive networks and number and size of lesions are considered to be important determinants of cognitive impairment and dementia.

In order to prevent or reduce VCI, efforts must be directed to preventing CVD and VBI. VBI may result from ischemic, hem orrhage, toxic and inflammatory conditions or oxidative stress [3].ThereareseveralformsofCVD,includingatherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy (CAA), cerebral autosomaldominantarteriopathywithsubcorticalinfarctsand leukoencephalopathy (CADASIL), and CARASIL [4]. Risk fac tors for arteriosclerosis are well known, including hyperten sion, diabetes mellitus, and dyslipidemia, whereas risk factors for other types of CVD are less well recognized.

To complicate matters further, pathological overlap between VBI and neurodegenerative disorders is frequent, especially with increasing age. The application of “either‐or” diagnostic criteria in epidemiologic studies fosters a dichotomous view of VCI and AD. Autopsy studies show a more complex reality. Macro‐ and microinfarcts are each found in approximately 30% of elderly persons, often combined with AD pathology [5–7]. Converging evidence indicates that ischemic infarcts and neu rodegenerative lesions combine in an additive fashion to increase the risk of cognitive impairment and dementia [8–12].

G&E → VRF → CVD → VBI → VCI
Genetic and environmental factors → vascular risk factors → cerebrovascular disease → vascular brain injury →vascular cognitive impairment

Aging + AD + VBI + Lewy bodies – cognitive reserve = cognitive impairment

*Lewy bodies

Table 4.1 Terms and abbreviations.

Syndromes

MCI = mild cognitive impairment (cognitive impairment without significant compromise of instrumental or personal activities of daily living)
MCI subtypes: amnestic, amnestic plus other cognitive domain, nonamnestic single domain, nonamnestic plus other cognitive domains
Memory impairment=free recall is below expectations
Amnestic memory impairment = free recall is below expectations and is not attributed to diminished attention or retrieval (i.e., does not improved significantly with cueing)

VCI = vascular cognitive impairment (cognitive impairment ascribed to vascular disease or vascular brain injury) VaD=vascular dementia (dementia ascribed to vascular disease or vascular brain injury)

Alzheimer disease

AD = Alzheimer’s disease (refers to progressive cognitive decline associated with widespread neurofibrillary tangles and neuritic amyloid plaques) Clinically diagnosed AD (mild cognitive impairment or dementia ascribed to AD, without pathological data)

Cerebrovascular disease

CAA=cerebral amyloid angiopathy
CVD=cerebrovascular disease (disease of blood vessels) (e.g., atherosclerosis, arteriolosclerosis) Atherosclerosis=disorder affecting endothelial and elastic lamina of larger arteries Arteriolosclerosis=disorder affecting smooth muscle cell layer of arterioles Arteriosclerosis=includes atherosclerosis and arteriolosclerosis

Vascular risk factors

VRF = vascular risk factors (refers to known risk factors for stroke (e.g., hypertension, hyperlipidemia, diabetes mellitus, atrial fibrillation)) Vascular factors=included VRF and CVD

Vascular brain injury

Stroke=sudden‐onset neurological deficit ascribed to CVD
VBI=vascular brain injury (parenchymal brain injury ascribed to vascular disease)

MRI lesions

MTA=medial temporal atrophy
WMH = white matter hyperintensity on MRI (synonyms include WML (white matter lesion), WMSH (white matter signal hyperintensity), and leukoaraiosis (rarefaction of white matter on CT))
SBI=silent brain infarct on MRI
SI=silent infarct on MRI
SL=silent lacune (may include infarcts and perivascular spaces)

Table 4.2 The pathogenic spectrum of vascular cognitive impairment: RF→ CVD → VBI →VCI.

Risk factors

Modifiable

Hypertension Hyperglycemia

Hyperlipidemia (Apolipoproteins) Smoking

Obesity

Nonmodifiable

Age Gender Race Heredity CADASIL CARASIL HCHWA‐D HCHWA‐I

Vascular phenotype: “Cerebrovascular disease (CVD)”

Cerebrovascular

Atherosclerosis Arteriolosclerosis

Amyloid angiopathy Vasculitis
Tortuosity

Anomaly

Cardiac

Atrial fibrillation Endocarditis Myopathy
Mural thrombus Blood content Hypoglycemia Hypoxemia Hemoglobinopathy Coagulopathy

Vascular distribution

Single artery

Large artery Small arteriole

Capillary

Border zone

Large arteries

Small arterioles Capillaries

Vein

Mechanism of brain injury

Ischemia Acute thrombosis

Embolism

Chronic

hypoperfusion

Hemorrhage Leaky BBB

Anoxia

Brain pathology phenotype: vascular brain injury (VBI)

Complete infarction (Symptomatic or silent) Incomplete infarction

(demyelination;

selective neuronal loss)
Hematoma

Microbleed Neuronal loss with gliosis

Location/neural network

Limbic–diencephalic memory system Multimodal association areas

Corticobasal ganglia‐ thalamocortical loops Deep white matter connections (cingulum, superior frontal occipital fasciculus, superior longitudinal fasciculus)

Clinical phenotype or syndrome: “stroke” or vascular cognitive impairment (VCI)

Multi‐infarct dementia Strategic infarct dementia Lacunar state

Subcortical vascular dementia
Binswanger’s syndrome

Table 4.3 Clinical Criteria for vascular dementia (VaD).

Diagnostic criteria

Dementia

VBI

Evidence of causal relationship

Hachinski Ischemic Score points) [38]:
HIS ≥7 suggests MID
HIS 5–6 suggests MIX HIS ≤4 suggests AD DSM‐IV [39]

(HIS) (0–17

No specific criteria

CVD risk factors (HTN, ASCVD)

Not specifically required

ICD‐10 [42]

Unequal distribution of deficits in higher cognitive functions with some affected and others relatively spared

Evidence from the history, physical examination, or laboratory tests of significant cerebrovascular disease that is judged to be etiologically related to the disturbance
From the history, examination, or test, there is evidence of significant cerebrovascular disease which may reasonably be judged to be etiologically related to the dementia (history of stroke, evidence of cerebral infarction)

ADDTC [41]

Probable Possible Probable

Multifaceted cognitive impairment sufficient to interfere with customary affairs of life

Two infarcts or one infarct with temporal relationship to onset of cognitive impairment
Not required

NINDS‐AIREN [40]

Memory loss
Plus impairment in two other cognitive domains

One infarct outside the cerebellum by imaging OR confluent white matter change
Focal neurological signs
Imaging findings

Abrupt onset
Stepwise progression
Temporal relationship to onset of cognitive impairment

AHA/ASA (2011) [43]

Decline in cognitive function in ≥2 domains sufficient to interfere with ADL
At least 4 domains tested (attention/ executive, memory, language, visuospatial) Decline in ADL is independent from motor/ sensory sequelae of the vascular event Above

Imaging evidence of CVD

Clear temporal relationship between vascular event and cognitive deficit onset
Clear relationship between severity and pattern of cognitive impairment and diffuse subcortical CVD

DSM‐5 [44] Major or mild NCD

Probable

Severe aphasia precludes cognitive assessment
Decline in cognitive function in ≥1 cognitive domains

Imaging findings CT or MRI

Evidence from the history, physical examination, or laboratory tests of significant cerebrovascular disease that is judged to be etiologically related to the neurocognitive deficits

Possible Probable

Either imaging findings, abrupt onset, stepwise, OR temporal relationship

Possible

Imaging findings, but no clear relationship (temporal, severity, or cognitive pattern) with cognitive impairment No imaging available

No history of gradually progressive cognitive deficits before/ after CVA to suggest nonvascular neurodegenerative etiology Evidence of another potential cause for cognitive dysfunction in addition to CVD

Possible

Sufficient to interfere with ADL No clouding of consciousness

Temporal relationship
Prominent decline in attention and executive function
Presence of clinical evidence + genetic disorder
(i.e., CADASIL)
Evidence of VBI without clear temporal relationship to cognitive deficits

Memory loss
Sufficient to interfere
No clouding of consciousness

Sudden onset
Stepwise progression
Focal neurological signs and symptoms
Stepwise deteriorating course and “patchy” distribution of deficits, focal neurologic signs and symptoms
There is evidence of focal brain damage, manifest as at least one of the following: unilateral spastic weakness of the limbs, unilaterally increased tendon reflexes, an extensor plantar response, or pseudobulbar palsy Infarct outside the cerebellum by imaging

ADDTC, State of California Alzheimer’s Disease Diagnostic and Treatment Centers; ASCVD, asymptomatic cardiovascular disease; DSM, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM‐5); HTN, hypertension; MID, multi‐infarct dementia; MIX, mixed dementia (vascular and Alzheimer’s disease (AD); NCD, neurocognitive disorder; NINDS‐AIREN, National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherché et l’Enseignement en Neurosciences; VBI, vascular brain injury.

epidemiology

From a public health perspective, VCI is the second most com mon cause of cognitive impairment in late life after AD. One of three persons meets criteria for dementia following first stroke [13]. Persons with stroke who are not initially demented are twice as likely as normal controls to develop dementia over the next 10 years [14]. The incidence of vascular dementia (VaD) increases exponentially after 65 years of age, ranging from 3 to 19 per 1000 persons/year at age 80 years [15–17], approximately half the rate of AD. In the Canadian Study of Health and Aging of persons older than age 65 years, the preva lence of cognitive impairment no dementia (CIND) was similar to (17%) the number of combined persons with dementia or stroke (8% each) [18]. In this study, the relative contributions of VBI to CIND were believed to be considerable.

To minimize survival bias, cohorts at risk should be established in midlife and followed longitudinally. In the Honolulu Heart Program, history of high systolic blood pressure (SBP) [19] and diabetes mellitus [20] was associated with greater risk of dementia in late life (especially among persons with the apolipoprotein E ε4 allele). In the Framingham Heart Study [21], duration of diabetes was related to poorer cognitive performance. In the CAIDE study, higher midlife cholesterol levels were associated with increased risk of dementia [22, 23]. These epidemiologic studies underscore the importance of managing hypertension, diabetes mellitus, and cholesterol beginning in midlife.

MRI scans in longitudinal population‐based studies reveal SBI and WMH in approximately one‐third of persons over age 65 years [24–26]. These lesions increase with age, are associated with hypertension, and increase the risk of stroke and dementia

Table 4.4 Neurobehavioral approach to diagnosis of VCI, AD, or mixed VCI/AD.

[27, 28]. In the Framingham Offspring Study of middle‐aged adults, SBI and severe WMH were associated with increased risk of stroke and dementia independent of vascular risk factors [29]. These studies identify subclinical VBI on MRI as relevant targets for early detection and primary prevention. Cerebral micro bleeds (CMBs) are also present in one‐third of persons over age 80 years based on population studies and are associated with increased risk of stroke, cognitive decline, and mortality [30].

Genetic epidemiology

Several forms of CVD are associated with genetic mutations or polymorphisms. CADASIL is caused by mutations or deletions in the Notch3 gene (chromosome 19p13) [31, 32]. A similar autoso mal recessive syndrome (CARASIL) results from mutations in the HtrA serine peptidase 1 (HTRA1) [33]. Dutch, Icelandic, and Finnish forms of familial CAA are associated with hereditary cer ebral hemorrhage with amyloidosis (HCHWA) [34]. At the popu lation level, the apolipoprotein E ε4 allele increases vascular deposition of abeta in the sporadic form of CAA [35].

Case presentations

The clinical presentation for VCI is highly heterogeneous, vary ing in onset, progression, and profile of cognitive impairment. In the following case presentations, we illustrate two approaches to diagnosis of VCI: (i) the application of criteria for the clinical diagnosis of VaD (Table 4.3) and (ii) a neurobehavioral approach, which considers location of VBI within memory and cognitive networks (Table 4.4).

Vascular cognitive impairment 33

Feature

Neuropsychological testing

Amnesic memory disorder?
Semantic fluency better than phonemic fluency Executive impairment worse than memory impairment

MRI findings

Moderate to severe hippocampal atrophy Severe WMH (CHS grade ≥7)

Infarction within frontal‐subcortical loops or other strategic locations
Acute stroke with temporal relationship to onset of cognitive impairment

Nonstrategic infarction

Favors VCI

+++ +++ +

Favors AD

+++ ++

+++

+(Can be seen in AD with CAA)

Other Differential

Hippocampal sclerosis Anoxic injury
Herpes simplex Encephalitis Hypertensive angiopathy Cerebral amyloid angiopathy CADASIL

AD, Alzheimer’s disease; CAA, cerebral amyloid angiopathy; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencepha- lopathy; CHS, Cardiovascular Health Study; VCI, vascular cognitive impairment; WMH, white matter hyperintensities.

34 Non-Alzheimer’s and Atypical Dementia

Case 1

Four years prior, a 71‐year‐old Caucasian gentleman sustained a mild stroke with right‐sided weakness and slurred speech. Following this, he became quiet and withdrawn, which the family thought was depression. The family noted a gradually progressive cognitive decline over the past 4 years. He now forgets conversations and, events within a few minutes, offers very little spontaneous speech, shows lack of interest, and is quite apathetic.

Past medical history is significant for a 20‐year history of hypertension and a 15‐year history of type 2 diabetes and hypercholesterolemia, as well as benign prostatic hypertrophy. He takes aspirin, tolazamide, metformin, troglitazone, lisinopril, and lovastatin. He is a retired salesman with
16 years of education.

On physical examination, blood pressure (BP) was 146/92 mmHg. Neurologic examination showed blunted affect, mild right spastic hemiparesis, and bilateral Babinski signs. Mini‐Mental State Examination (MMSE) score was 22/30. He had word‐finding difficulties, concrete thinking, and mild perseveration. Neuropsychological testing revealed severe impairment in all aspects of verbal list learning, including acquisition, immediate and delayed recall, and recognition. He was severely impaired on confrontation naming and semantic and phonemic fluency. Working memory was mildly impaired. Visuospatial skills and abstract reasoning were low average. A self‐reported scale did not suggest depression.

EKG showed left ventricular hypertrophy. MRI revealed cystic infarcts in the right anterior thalamus, left genu of the internal capsule, and left posterior limb of the internal capsule (Figure 4.1). SBI were noted in the

right putamen and left frontal white matter. Periventricular white matter changes were mild (grade 1 on the Cardiovascular Health Study (CHS) white matter scale [25]). Coronal T1 MRI showed moderate medial temporal atrophy (MTA) (2+ on MTA scale [36]) and moderate cerebral atrophy (Figure 4.2).

Comment

This patient has significant risk factors for VaD. His Framingham stroke risk profile [37] is calculated at 19 (+5 age 71; +7 treated systolic blood pressure; +2 diabetes; +5 left ventricular hypertrophy). A Framingham profile of 19 is associated with a 33% 10‐year probability of first stroke. His history of prior right‐sided weakness corresponds with infarct in the left posterior limb of the internal capsule, further increasing the probability of recurrent stroke.

He meets criteria for MID by Hachinski Ischemic Score [38], DSM‐IV criteria for VaD [39], National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherché et l’Enseignement en Neurosciences (NINDS‐AIREN) criteria for possible VaD [40], the State of California Alzheimer’s Disease Diagnostic and Treatment Centers (ADDTC) criteria for probable ischemic VaD [41], ICD‐10 criteria
for VaD [42], American Heart Association/American Stroke Association (AHA/ASA) criteria for possible VaD [43], and DSM‐5 criteria for
possible major vascular neurocognitive disorder [44] (Table 4.3). He meets NINDS‐AIREN criteria for possible but not probable VaD, because there was no temporal relationship between a stroke and his gradual
cognitive decline.

Figure 4.1 Case 1: axial MRI (T1, proton density (PD), and T2 weighted) shows cystic infarcts in the right anterior thalamus and left genu internal capsule. SBI are seen in the right putamen, left posterior limb of the internal capsule (top row), and left frontal white matter (bottom row). Periventricular white matter changes are rated grade 1 on CHS scale.

Vascular cognitive impairment 35

Figure 4.2 Case 1: coronal T1‐weighted MRI shows moderate 2+ hippocampal atrophy on Scheltens’ rating scale [110, 111] and moderate generalized cerebral atrophy.

Apathy, withdrawal, and slowing are typical in SVD. Severe impairment in verbal memory on neuropsychological testing plus moderate atrophy of the hippocampi suggests the possibility of concomitant AD. Two cystic infarcts, however, are observed in strategic locations for memory: the right anterior thalamus and the left genu of the internal capsule. Anterior thalamic lesions are well known to disturb episodic memory [45], and lesions in the genu of the internal capsule disrupt outflow in the anterior thalamic peduncle [46]. The parsimonious clinical diagnosis is VCI.

Neuropathology

Autopsy revealed severe, complicated atheroma in the basal vessels with 55–70% stenosis and multiple lacunar infarcts in the basal ganglia. No significant AD pathology was present (Braak and Braak stage=0; the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) criteria neuritic plaque=none). The final clinicopathologic diagnosis is pure VaD with strategic infarcts.

Case 2

An 85‐year‐old African American gentleman with a history of several old strokes and a combination of stepwise and progressive cognitive decline. The first stroke, 21 years ago, had no significant cognitive or physical sequelae. Eighteen years ago, a more serious stroke caused forgetfulness, mild left hemiparesis, and transient speech disturbance, leading to a right carotid endarterectomy. After this, his memory declined gradually and slowly. He has developed gradual and progressive word‐finding difficulty for 5 years. He still manages his activities of daily living, drives locally, and watches television. He complains of poor memory and decreased interest in socializing but denies depression. Past medical history is significant for hypercholesterolemia. He reports no history of hypertension, diabetes, or heart disease. He takes only aspirin.

On physical examination, BP is 148/94mmHg; pulse is 84 and regular. Spasticity and weakness are present in both upper extremities, left greater than right. Deep tendon reflexes are increased on the left, and Babinski signs are present bilaterally. Snout, glabellar, palmomental, and right grasp reflexes

are present. His gait is wide based and paretic (left‐ greater than right‐sided weakness). His MMSE score is 18 of 30. He is friendly but dysarthric and has significant word‐finding difficulties. Neuropsychological testing reveals severe impairments in verbal memory, naming, and semantic fluency.

MRI shows moderate hyperintensities in bilateral periventricular white matter, SBI in the right anterior limb of the internal capsule, and prominent perivascular spaces plus encephalomalacia in the right putamen (Figure 4.3). WMH are rated 6–7 on the CHS scale [25]. Coronal sections show 3+ MTA [36] and severe cerebral atrophy (Figure 4.4).

Comment

This patient had two strokes and has a Framingham risk profile score [37] of 15 (+10 age 85; +5 untreated SBP). Left‐ greater than right‐sided spastic hemiparesis is consistent with bilateral lesions and worse in the right hemisphere. The left hemiparesis could be related either to the ischemic events involving the right cortical spinal tract in the white matter or in the posterior limb of the internal capsule. The gradual deterioration

36 Non-Alzheimer’s and Atypical Dementia

Figure 4.3 Case 2: axial MRI (T1, PD, and T2 weighted) shows T2‐weighted hyperintensities in bilateral periventricular white matter, SBI in the right anterior limb of the internal capsule, and prominent perivascular spaces plus encephalomalacia in the right putamen. White matter hyperin tensities are rated 6–7 on the CHS scale.

during the past 5 years can be attributed to moderately severe WMH. He meets NINDS‐AIREN criteria and AHA/ASA for probable VaD and DSM‐IV and DSM‐V criteria for VaD (Table 4.3).

The history of two strokes and the presence of infarcts and white matter changes on MRI offer a partial explanation of his cognitive impairment. The second stroke showed a temporal relationship with the onset of forgetfulness. Silent incomplete infarcts (note: incomplete infarct refers to MRI lesions that are hyperintense on T2 or FLAIR and

minimally hypointense on T1‐weighted sequences) in the right anterior limb of the internal capsule disconnect frontal‐subcortical loops and contribute to dysexecutive syndrome and disinhibition. The severity of his verbal memory loss and difficulty with confrontation naming suggests the possibility of a superimposed neurodegenerative process such as AD. This is supported by significant atrophy of the hippocampus and cerebral cortex. Taking a neurobehavioral approach, the clinical diagnosis is mixed dementia due to VCI and possible AD.

Vascular cognitive impairment 37

Figure 4.4 Case 2: coronal T1‐weighted MRI shows 3+ atrophy by Scheltens’ scale [110] of the hippocampus and severe cerebral atrophy.

Neuropathology

Postmortem revealed severe atherosclerosis in the anterior cerebral artery, infarcts in the right putamen and frontal lobe, and deep white matter, with degeneration of the corpus callosum. The white matter

demonstrated spongy changes and gliosis. An infarct was noted in the medulla as well. Widespread AD pathology was present (Braak and Braak stage=VI; CERAD neuritic plaque=moderate). Final clinicopathologic diagnosis is dementia due to mixed AD and CVD.

Case 3

A 78‐year‐old white female gives a 1‐ to 3‐year history of slow decline in memory. She is unable to remember the plots of plays and is using memory aids. For the past year, she has had difficulty with handling her checking account but is otherwise independent in IADL. Her PMH revealed she has a 25‐year history of hypertension which is well controlled and takes aldactazide. Her father died following a stroke. Blood pressure was 110/80, MMSE, 27/30, and blessed memory‐information‐ concentration test, 26/33. She has mild difficulty with tandem gait and slowed alternating movements. Neuropsychological testing shows circumscribed verbal and visual memory deficits. Cholesterol was 225; LDL cholesterol was 156. MRI shows severe confluent deep white matter changes (grade 7–8 on the CHS white matter scale), SBI in the right lateral thalamus, and mineralization of the globus pallidi (Figure 4.5). Coronal

sections show 3+ atrophy of both hippocampi and moderate cerebral atrophy (Figure 4.6).

Comment

She fits criteria for mild cognitive impairment, amnestic type [47], and AHA/ASA criteria for probable VaMCI [43]. She has a long‐standing hypertension. Confluent white matter changes are consistent with small vessel disease, either due to hypertension or to CAA. Neither the WMH nor the SBI in the lateral thalamus explain her amnesic memory impairment.

Neuropathology

The patient died 1 year later at age 79 years. Autopsy showed mild atherosclerosis, moderate arteriolosclerosis, and mild CAA.

38 Non-Alzheimer’s and Atypical Dementia

Figure 4.5 Case 3: MRI (T1, PD, and T2 weighted) shows severe confluent deep white matter changes (grade 7–8), SBI in the right lateral thalamus, and mineralization of the globus pallidi.

Neurofibrillary tangles and neuritic plaques were found in the hippocampus, but not neocortex (Braak and Braak stage IV,
CERAD sparse). Acute infarcts were found in both cortex and white matter. In addition, there were multiple cortical microinfarcts and

diffuse white matter demyelination (better explained by arteriolosclerosis than CAA or Wallerian degeneration). Final pathologic diagnosis is MCI due to mixed SVD and
early AD.

Vascular cognitive impairment 39

Figure 4.6 Case 3: coronal T1‐weighted MRI shows 3+ atrophy by Scheltens’ scale [110] of both hippocampi and moderate cerebral atrophy.

Clinical subtypes of VCI

VCI has been categorized in many ways including heritability (e.g., CADASIL), location (e.g., SVD, strategic), clinical presen tation (poststroke dementia (PSD); Binswanger’s syndrome), or MRI findings (e.g., SBI). We review several common nonmutu ally exclusive syndromes.

pSD

In hospital‐ and community‐based series, it has been shown that stroke doubles the risk of dementia. The incidence of dementia within 6–12 months’ poststroke is about 20%, and the risk of delayed dementia, including AD, is also doubled after stroke [13] (Figure 4.7). In Olmsted County, Minnesota, preva lent dementia was 30% immediately after stroke; incident dementia was 7% 1 year poststroke and rose to 48% 25 years after stroke [48]. Compared to normal controls, history of stroke doubles the risk of dementia over 10 years [14].

Risk factors for dementia at the time of stroke include fewer years of education, older age, diabetes mellitus, atrial fibrillation,

and recurrent stroke [49]. Stroke locations associated with higher likelihood of cognitive impairment include left hemisphere, anterior and posterior cerebral artery distribution, multiple infarcts, and strategic infarcts (see following text) [13]. Neuro imaging variables associated with PSD include SBI, WMH, and global and medial temporal atrophy [13].

Concomitant AD is also a major risk factor for PSD. About 15–30% of persons with PSD have a history of dementia before stroke [50, 51], and approximately one‐third have significant MTA [52]. Case 2 is an example in which severe MTA was shown on MRI (Figure 4.4), and a diagnosis of mixed AD and CVD was confirmed at autopsy.

Strategic infarct dementia

A dementia syndrome might result from a single infarct placed in a strategic location. The left angular gyrus, inferomesial tem poral, and mesial frontal lobe are considered strategic locations perfused by large arteries. Frontal‐subcortical loops are strategic networks for executive function. These networks include the prefrontal cortex, head of the caudate, anterior and dorsomedial

40 Non-Alzheimer’s and Atypical Dementia 50

Tatemichi et al., 1994

Henon et al., 2001

Kokmen et al., 1996

Bornstein et al., 1996

Tatemichi et al., 1994

Kokmen et al., 1996 Kokmen et al., 1996

Inzitari et al., 1998 Ballard et al., 2003

Altieri et al., 2004

Kokmen et al., 1996 0

12 24

Kokmen et al., 1996

36 48 60 Delay after stroke (months)

120 300

Figure 4.7 Incidence of poststroke dementia at different time intervals after stroke onset in hospital‐based studies (gray) and community‐based studies (black). When the reference appears several times, data provided correspond to different assessments at different time intervals in the same cohort of patients. Source: Leys et al. [13]. Reproduced with permission from Elsevier.

Subcortical vascular dementia Prefrontal–subcortical circuits

mutism, dysarthria, pseudobulbar palsy and affect, small‐ stepped gait, and urinary incontinence [57]. Prior to MRI, the distribution of lacunes in subcortical gray matter and white matter, especially of the frontal lobe, was documented by autopsy [57, 58].

The pathological hallmark of Binswanger’s syndrome is prominent demyelination of the deep white matter, ascribed to stenosis of the deep penetrating medullary arteries [59, 60]. A triad of slowly progressive dementia, gait apraxia, and urinary incontinence might be confused clinically with normal pres sure hydrocephalus (NPH). Neuroimaging, however, shows severe cerebral atrophy and widening of the sulci in Binswanger’s syndrome, indicating a secondary ex vacuo type of ventriculomegaly.

CaDaSIL

CADASIL (see Chapter 12) offers a prototypic example of “pure” SVD without concomitant AD. Extracellular domains of NOTCH3 protein accumulate in the smooth muscle walls of small arterioles [61, 62]. CADASIL is associated with migraine, depression, and seizures beginning in early adulthood, followed by recurrent ischemic events and progressive cognitive decline [63, 64]. Prominent slowing and impairment in executive func tion, with relative preservation of recall and receptive language, are noted on neuropsychological testing [65]. Severity of cogni tive impairment correlates better with lacunar infarcts rather than WMH or microbleeds [66, 67].

Subclinical VBI

Symptomatic stroke is the tip of the iceberg of VBI. In the Rotterdam study, the prevalence of SBI was five times greater than symptomatic stroke [26]. SBI should be differentiated from CSF‐filled perivascular spaces (PVS) [68], which are sometimes

Anterior centrum semiovale anterior limb internal capsule

Capsular genu

Prefrontal cortex

Head of caudate

Globus pallidus

Anterior and dorsomedial thalamus

Figure 4.8 Prefrontal‐subcortical circuits important for executive function.

thalamic nuclei, capsular genu, and anterior limb of the internal capsule [53, 54] (Figure 4.8). The dementia syndrome associ ated with thalamic infarcts is characterized by marked apathy, impaired attention and mental control, and anterograde and retrograde amnesia [45, 55, 56]. In case 1, lesions in the right anterior thalamic nucleus and the genu of the left internal capsule demonstrate strategic infarcts.

SVD is defined by VBI confined mainly to subcortical white and gray matter. Small vessel infarcts account for 25% of subjects hospitalized for strokes and make up nearly 60% of asympto matic strokes in community‐based studies [26]. In addition to PSD and strategic infarct dementia due to small vessel disease, lacunar state and Binswanger’s syndrome all fall under the umbrella of SVD.

Lacunar state (etat lacunaire) is an extreme phenotype of SVD, characterized by multiple lacunar infarcts in the basal ganglia, thalamus, and white matter. Clinical features included sudden‐onset hemiparesis, lack of volition, akinetic

Hospital-based study Community-based study

Incidence of dementia (%)

SBI

PVS

Bright

Isointense

Dark

T-2 weighted

Proton density/ FLAIR

T-1 weighted

Figure 4.9 Both SBI and perivascular spaces (PVS) are bright on T2‐weighted sequences. On proton density or fluid‐attenuated inversion recovery (FLAIR) sequences, however, SBI are hyperintense (bright), whereas perivascular spaces (PVS) are isointense, compared to cerebrospinal fluid (CSF). On T1‐weighted sequences, both SBI and PVS are hypointense or dark.

especially prominent in the putamen and infraputaminal regions, as well as near the anterior commissure [69] (Figure 4.9). Rarefaction of the periventricular and deep white matter can be seen as leukoaraiosis (LA) on CT scan [70] and as WMH on FLAIR or T2‐weighted MRI [71]. Semiquantitative white matter intensity scales are useful to communicate the severity of WMH in clinical practice. In cross‐sectional studies, WMH ratings are associated with mild impairment on the Modified Mini‐Mental State (3MS) exam [72]. In longitudinal MRI studies, incident SBI and worsening WMH correlate with cognitive decline, espe cially information processing speed [73–75], supporting the rel evance of SBI and WMH as presymptomatic targets for risk reduction. CMBs are small, round, or ovoid hypointensities, of <10mm in diameter, evident on T2* gradient‐recall echo (T2*GRE) and susceptibility‐weighted (SWI) MRI sequences [30]. The presence of CMBs, which are considered a marker of small vessel pathology due to either hypertensive vasculopathy or CAA, may be an independent contributor to cognitive impairment. Location of CMBs suggests underlying pathology. Deep and lobar CMBs have been associated with hypertensive vasculopathy versus strictly lobar CMBs with CAA. The sensi tivity and specificity of these associations has not yet been stud ied. Cognitive deficits may vary depending on the location of CMBs, mostly affecting executive function, speed of processing, and other nonmemory cognitive domains [76, 77]. Recently, in a Japanese cohort of subjects with vascular risk factors (n = 729), the presence of ≥2 CMBs or mixed lobar and deep CMBs was associated with increased risk of all‐cause dementia, inde pendent of other risk factors (age, sex, education, and APOE ε4 status) [78].

evaluation and diagnosis

Clinical evaluation

The clinical evaluation for VCI follows the established approach to the evaluation of cognitive impairment: a thorough history (from both the patient and a reliable informant); physical exam ination, including screening mental state examination, with emphasis on complete neurologic (focal neurological signs, gait disturbance) and cardiovascular components (funduscopic examination of retinal vessels, carotid bruit, cardiac arrhyth mia); laboratory testing (left ventricular hypertrophy, renal insufficiency); and neuroimaging (brain CT or MRI). At the present time, structural MRI provides the most sensitive and specific measure of VBI [79]. Emphasis is placed on identifica tion by history of vascular risk factors (hypertension, hyperlipi demia, diabetes, heart disease) for risk reduction and on the pattern of cognitive and affective disturbance and functional decline for symptomatic treatment, management, and support.

Neuropsychological testing

There is no single characteristic behavioral profile for VCI. Memory impairment in VCI is variable, tends to be of the dysexecutive rather than amnestic type, and responds better to cueing or recognition formats. WMH and SBI are often associ ated with decreased processing speed and executive function. In contrast to AD in which semantic fluency usually is more affected than phonemic fluency, in VCI, they generally are equally affected [80]. Microinfarcts have been associated with lower perceptual speed and semantic and episodic memory def icits independent of macroscopic infarcts or AD pathology [6].

Vascular cognitive impairment 41

42 Non-Alzheimer’s and Atypical Dementia

Inclusion of Trails B, verbal fluency, clock drawing, digit symbol substitution, episodic memory (including free and cued recall), language, and visuospatial domains has been recommended by a 2005 North American workshop [81].

Clinical diagnosis

A diagnosis of VCI is typically made using one of several diag nostic criteria (Table 4.3). In comparing diagnostic criteria, it is useful to consider (i) evidence of cognitive impairment/demen tia, (ii) evidence of VBI, and (iii) likelihood that VBI is causing VCI. The Hachinski Ischemic Score [38] assigns 1 or 2 points to a list of risk factors, signs, and symptoms associated with stroke. DSM‐IV [39] and ICD‐10 [42] leave assessment of causal rela tionship between VBI and VCI to the judgment of the clinician. For a diagnosis of probable VaD, the California ADDTC criteria [41] allow either a temporal relationship between VBI and VCI or evidence of two or more infarcts on a neuroimaging study. Temporal relationship is required for a diagnosis of probable VaD by NINDS‐AIREN criteria [40], thereby increasing the stringency of these criteria.

More recent clinical criteria were published for the diagnosis of VCI by the AHA/ASA in 2011 [43]. These rely on evidence of VBI present by structural neuroimaging and establish causality based on temporal relationship and correlation between type of VBI and cognitive deficits. In addition, the International Society for Vascular Behavioral and Cognitive Disorders (VASCOG) has recently proposed a new set of criteria [82]. Updated DSM‐5 criteria have been released [44] and propose a change in termi nology from VaD or VCI to major or minor neurocognitive impairment due to CVD.

With the advent of in vivo biomarkers for the detection of amyloid accumulation in the brain, new diagnostic criteria for specific types of VCI are being proposed, that is, the Seoul crite ria for Pittsburgh imaging compound B [PiB]‐negative SVD based on clinical and MRI variables [83]. These criteria are based on the exclusion of coexistent AD pathology by amyloid PET scan and demonstration of VBI on MRI in patients that present with VCI. In their small cohort of patients (n = 77), this criteria had 49% sensitivity and 100% specificity. This needs confirmation and further validation in large clinicopathological cohorts.

Criteria for the SVD subtype of VCI emphasize slowing of cog nition, executive dysfunction (impairment in selective attention, abstract reasoning, and mental flexibility), depression, extrapy ramidal signs, and gait disturbance [84]. In an autopsy‐confirmed study, a “low executive” profile was 67% sensitive and 86% spe cific in distinguishing SVD from AD (positive likelihood ratio = 4.7) [85]. Although the sample size was small, the reference groups were defined by neuropathology, thereby avoiding the circularity that often occurs when comparison groups are defined clinically. The study suggests modest clinical utility of the execu tive dysfunction profile for SVD.

The neurobehavioral approach is illustrated for the three case presentations above and utilizes structure–function correlations

in interpreting neuropsychological and neuroimaging studies (Table 4.4). An advantage is allowance for the dependent assess ment of likelihood of VCI and AD and thus the diagnosis of mixed VCI/AD. The approach is applicable for MCI/CIND as well as dementia syndromes, although validation is needed.

CSF biomarkers

Further studies to determine markers that reflect the health and reactivity of intracerebral blood vessels and blood–brain barrier (BBB) integrity are needed. To date, no validated CSF biomark ers have been established to support the diagnosis of VCI, although a variety of substances have been proposed as measure of BBB dysfunction in CVD, including albumin index and matrix metalloproteinase‐9 (MMP‐9) [86].

Neuropathologic contributions to diagnosis
and understanding
Neuropathologic studies determine the type and severity of CVD and severity and distribution of AD pathology. In contrast to AD, there is no gold standard for the neuropathologic diagnosis of VCI. Typically, the reference standard is based on evidence of infarcts in neocortex, without considering the causal relationship between VBI and VCI. With these caveats, the clinical criteria for VaD show high specificity and moderate sen sitivity [87]. Several longitudinal cohort studies with high autopsy rates (Religious Orders Study, Honolulu‐Asia Aging Study, Baltimore Longitudinal Study of Aging) underscore (i) the high prevalence of mixed vascular and neurodegenerative pathologies in late life and (ii) the additive risk of cerebral infarcts and AD pathology for cognitive impairment [9–11]. They also disclose the importance of microinfarcts [6] and hip pocampal sclerosis [88] for cognitive impairment and memory loss and remind us that these lesions often go undetected or unsuspected until autopsy.

treatment

primary prevention: Identification and
reduction of stroke risk factors
The type of underlying CVD (e.g., arteriosclerosis or CAA) should be considered. It is likely that reduction of vascular risk factors for arteriosclerosis can significantly reduce vascular contributions to pure vascular and mixed dementia. The benefi cial effects of treating hypertension, diabetes mellitus, and dyslipidemia vis‐à‐vis risk of stroke are well established by ran domized clinical trials. Evidence‐based official guidelines have been disseminated [89], but all too often fall short in implemen tation. Primary or secondary prevention trials that include cognitive outcome measures are still limited (Table 4.5), often begin too late in life, and do not include sensitive cognitive out come measures. In a meta‐analysis of several placebo‐controlled trials (SHEP, Sys‐Eur, HYVET, and PROGRESS), treatment of hypertension was associated with reduction in the combined

Table 4.5 Primary and secondary prevention: clinical trials that include a cognition outcome measure.

Vascular cognitive impairment 43

Primary prevention SHEP (1991) N=4736

Syst‐Eur (1998) N=2418

SCOPE (2003) N=4937 HYVET (2008) N=3336

Secondary prevention PROGRESS (2003) N=6104

PRoFESS (2008) N=20332

Antihypertensive

Diuretic (chlorthalidone) and/or beta blocker (atenolol) or reserpine
Ca channel blocker (dihydropyridine) with or without beta blocker (enalapril maleate) and/or diuretic (hydrochlorothiazide)

ARB (candesartan cilexetil) and/or diuretics

Diuretic (indapamide) with or without ACEI (perindopril)

ACEI (perindopril) with or without diuretic (indapamide)
ARB (telmisartan)

Duration of follow‐up (years)

4.5 2.0

3.7 2.2

4.0 2.4

Main results for dementia

16% reduction in dementia

50% (0 to 76%) reduction in dementia

7% increased risk in active arm (but only 3.2/1.6mmHg reduction in BP in treatment vs. control arm)
14% (−9 to 23%) reduction in dementia

Trial stopped early because of significant reduction in stroke and mortality)

12% (−8 to 28%) reduction in dementia
No reduction of the risk of dementia

Significance

n.s. P=0.05

P>0.20 P=0.2

P=0.2 P=0.48

risk ratio (HR 0.87, 0.76–1.00, p = 0.045) [90]. The Syst‐Eur trial [91, 92] suggested that treatment of 1000 patients for 5 years could prevent 20 cases of dementia (95% CI, 7–33). In PROGRESS, a secondary prevention trial among persons with previous stroke or TIA [93], treatment with perindopril plus or minus indapamide showed a 19% relative risk reduction in cog nitive decline and WMH progression over 4 years compared to placebo [94]. The Memory in Diabetes (MIND) substudy of the ACCORD trial will determine whether interventions for type 2 diabetes reduce cognitive decline and structural brain changes [95]. In the PROSPER study, no difference in cognitive decline was found among subjects treated with pravastatin compared to placebo after a mean follow‐up period of 42 months [96]. In the Women’s Antioxidant Cardiovascular Study, antioxidant sup plementation did not slow cognitive change among women with preexisting cardiovascular disease or risk factors [97]. There are several promising prospective cohort studies, but currently, no clinical trials of omega‐3 fatty acids [98] or exercise [99, 100] in the prevention of VCI. Two large trials for primary prevention of VCI are ongoing. The ASPREE trial [101] is a clinical trial evaluating (every 6 months) the prevention of cardiovascular disease and VaD with low‐dose aspirin in the elderly (subjects ≥65 years); the study is expected to be completed in 2017. The Systolic Blood Pressure Intervention Trial: Memory and Cognition in Decreased Hypertension (SPRINT‐MIND) [102] looks to see if tighter blood pressure control parameters over an average of about 5 years reduces the risk of incident dementia, reduces the rate of cognitive decline, and in a subset further decreases the volume of small vessel ischemic vascular disease.

For secondary prevention, a recent paper evaluating out comes of a large community‐based stroke registry from London, United Kingdom, found that “appropriate vascular

risk management,” defined as clinically indicated use of antihy pertensives, antithrombotic agents, and lipid‐lowering drugs, was associated with reduced long‐term risk of cognitive impair ment assessed by the Mini‐Mental State Examination in patients with ischemic strokes without history of atrial fibrilla tion [103]. Independent effects were seen with antihyperten sives, a combination of aspirin and dipyridamole, and statins. No effects on cognition were seen in patients with history of atrial fibrillation or hemorrhagic stroke.

From a population perspective, based on comprehensive reviews of the literature, and assuming a causal relation and intervention at the correct age for prevention of 10% per decade in the prevalence of each of seven risk factors (diabetes, midlife hypertension, midlife obesity, smoking, depression, cognitive inactivity or low educational attainment, and physical inactiv ity), it has been estimated that the prevalence of AD could be reduced by 8.3% worldwide by 2050 [104]. This would translate to 1.1–3.0 million AD cases worldwide and 184,000–492,000 cases in the United States [105]. Five of these risks are vascular risk factors (i.e., midlife hypertension, diabetes mellitus, midlife hyperlipidemia, smoking, sedentary lifestyle, as well as depres sion and low educational attainment). Arguably, the epidemio logical diagnosis of AD may well include cases with subclinical VBIormixedAD/VBI,inwhichcasetheprojectedriskreduc tion in dementia cases may predominantly reflect reduction in VBI contributions to dementia.

treatment of cognitive symptoms

Positive effects of cholinesterase inhibitors and memantine have been reported in randomized, double‐blind, placebo‐controlled trials of VaD. A meta‐analysis showed favorable effects of cho linesterase inhibitors on cognitive outcomes, but not for global

44 Non-Alzheimer’s and Atypical Dementia Drug

307 196
308 199
319 648
Subtotal 1043
Test for heterogeneity: χ2 = 3.37; df2 (p = 0.19); P = 40.70% Test for overall effect: p<0.00001

Donepezil 10 mg vs placebo

307 195
308 194
Subtotal 389
Test for heterogeneity: χ2 = 0.03; df1 (p = 0.86); P = 0% Test for overall effect: p<0.00001

Galantamine 24 mg vs placebo

GAL-INT-6 149
GAL-INT-26 367
Subtotal 516
Test for heterogeneity: χ2 = 0.24; df1 (p = 0.63); P = 0% Test for overall effect: p<0.0001

WMD ( xed) (95% Cl)

Weight (%)

21.09 24.76 54.16

100.00

52.11

47.89 100.00

19.42

80.58 100.00

100.00 100.00

45.77

54.23 100.00

WMD ( xed) (95% Cl)

–1.68 (–2.78 to –0.58) –0.65 (–2.67 to –0.63)

–0.71 (–1.40 to –0.02) –1.15 (–1.65 to –0.64)

–2.24 (–3.37 to –1.11) –2.09 (–3.27 to –0.91) –2.17 (–2.98 to –1.35)

–2.00 (–3.80 to –0.20) –1.50 (–2.38 to –0.62) –1.60 (–2.39 to –0.80)

–1.10 (–2.15 to –0.05) –1.10 (–2.15 to –0.05)

–2.00 (–3.36 to –0.64) –1.75 (–3.00 to –0.50) –1.86 (–2.79 to –0.94)

Placebo

Donepezil 5 mg vs placebo

Mean (SD) n –0.96 (5.49) 194

Mean (SD)

0.72 (5.64) –0.10 (5.36) 0.00 (5.18)

–1.75 (4.70) 180 –0.71 (5.18) 326 700

–1.52 (5.74) –2.19 (6.27)

194 0.72 (5.64) 180 –0.10 (5.36) 374

77 0.00 (6.76) 373 –0.30 (6.32) 450

338 0.40 (6.99)

141 1.60 (6.10) 261 2.28 (7.77) 402

–2.00 (6.10) –1.80 (5.94)

Rivastigmine 12 mg vs placebo

Vantag E 360 Test for overall effect: p=0.04

Memantine 20 mg vs placebo

MMM300 147
MMM500 277
Subtotal 424
Test for heterogeneity: χ2 = 0.07; df1 (p = 0.79); P = 0% Test for overall effect: p<0.0001

–0.70 (7.21)

–0.40 (5.70) 0.53 (7.02)

–4 –2 0 2 4 Favours drug Favours palcebo

Figure 4.10 Meta‐analysis of double‐blind placebo‐controlled trials of cholinesterase inhibitors and memantine for vascular dementia. Cognitive outcomes on the ADAS‐Cog subscale (change from baseline) in vascular dementia patients in cholinesterase inhibitors and memantine trials by drug and dose (last observation carried forward sample); WMD, weighted mean difference. Source: Kavirajan and Schneider [106]. Reproduced with permission from Elsevier.

impressions of change [106] (Figure 4.10). Despite a more rigor ous implementation of diagnostic criteria, it remains difficult to parse contributions of mixed AD. Unlike AD, loss of cholinergic neurons in the basal forebrain is not characteristic of VaD. Disruption of cholinergic pathways by severe WMH in Binswanger’s syndrome [107] and CADASIL [108, 109], how ever, has been demonstrated. In CADASIL, treatment with donepezil was associated with improvement in a secondary measure of executive function [110]. Cholinesterase inhibitors were generally well tolerated, although associated with an increase in gastrointestinal side effects; they should be avoided in patients with heart block. Cholinesterase inhibitors and memantine have been approved for the treatment of VaD in some countries, but not in the United States. At this time, guide lines for VCI should follow guidelines for the prevention and treatment of stroke.

Summary

CVD is the second leading cause of cognitive impairment in late life. The manifestations of VCI are widely heterogeneous in severity, pathophysiology, and neurobehavioral phenotype depending upon site, size, and sum of VBI. MRI might show preclinical evidence of VBI (e.g., SBI and WMH), which is asso ciated with impairment in executive function. One‐third of patients experience PSD and if not initially affected are at twice the risk of developing subsequent cognitive impairment over the ensuing 10 years. Neuropathology studies show that AD and VBI often occur together and exert additive adverse effects on cognition. CADASIL represents the prototype for pure small vessel type of VCI and has greatly advanced our understanding of underlying pathophysiology and brain–behavior correla tions. Many risk factors for sporadic VBI (e.g., hypertension,

diabetes mellitus, dyslipidemia) are modifiable, although double‐ blind placebo‐controlled trials are often inconclusive because they are started too late, are too short in duration, or lack suffi ciently sensitive cognitive outcome measures. Cholinesterase inhibitors and memantine show mild benefits for cognitive, but not global endpoints in trials. They are not currently approved by the US Food and Drug Administration for the symptomatic treatment of VCI, but are approved in some other countries. By and large, the means for early detection and prevention of VCI are known. The major challenge remains one of diligent clinical practice and public health implementation. It has been pro jected that a 10% reduction in seven risk factors (including five vascular risk factors) for 10 years could result in an 8% reduc tion in incident dementia cases.

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ChapTEr 5
Frontotemporal dementia

David C. Perry and Howard J. Rosen

University of California, San Francisco, San Francisco, CA, USA

Introduction and definition of terms

Arnold Pick first described a patient with progressive behavior and language deterioration and left temporal lobe atrophy in 1892. Based upon subsequent cases described by Pick and pathological findings described by Alois Alzheimer, the entity of Pick’s disease was recognized [1, 2]. Although the terminology has changed over time and the term frontotemporal dementia (FTD) has gained favor, the hallmark features of these disorders remain a progressive deterioration in personality and behavior and/or language impair- ment. Rather than being one homogeneous disorder, FTD is now understood as including multiple distinct clinical subtypes that can be caused by several pathological processes.

The nomenclature in the field has been inconsistent and confus- ing. In this chapter, the term FTD will be used to refer to any of the three core clinical syndromes of FTD. These include the behavio- ral variant of FTD (bvFTD), which presents primarily with changes in personality and socioemotional function, and two variants of primary progressive aphasia (PPA), including the semantic variant PPA (svPPA) and the nonfluent/agrammatic variant PPA (nfv‐PPA). The term frontotemporal lobar degeneration (FTLD) will be used to describe the associated pathological entities. This chapter focuses on the clinical features of the FTD syndromes and on FTLD as a whole and its diverse clinical, pathological, and genetic features as well as current treatment approaches. Research in FTD has also identified links between FTD and other neurological syn- dromes, including corticobasal syndrome (CBS), progressive supranuclear palsy (PSP) and motor neuron disease (MND), which are associated with FTLD pathology and are often consid- ered as part of the FTLD spectrum. PSP and CBS are discussed in detail in other chapters of this volume, but the disorders will be reviewed here in order to highlight their relationships with FTD.

Epidemiology

Although FTD was previously felt to be a rare entity, current data indicates that it is the third most common neurodegenerative cause of dementia, behind Alzheimer’s disease (AD) and Lewy body

dementias [3, 4]. Prevalence estimates have varied, but in one study in the Netherlands, it was estimated at 2.7/100 000 [5]. A study con- ducted in Rochester, Minnesota, indicated that in patients whose dementia begins prior to age 60, FTD is as common as AD [6]. Onset is most commonly in the sixth decade but has been described as early as the third decade and as late as the ninth [5].

Survival from disease onset in FTLD is shorter than in AD. The longest survival is in svPPA at 11.9 years from onset, and the shortest is in patients with FTD and coexisting MND (approxi- mately 2 years). Disease durations in bvFTD and nfv‐PPA are intermediate, at 8.7 years and 9.4 years, respectively [7].

Core FTD clinical syndromes

Case 1

A 55 year‐old woman was noted at work to be keeping an inaccurate tally of inventory and 4 years before presentation was fired after making inappropriate comments and gestures about her boss to one of his friends at work. Two years before presentation, her personality gradually changed, and she began to swear more frequently, would burp in public, and would talk to strangers about her sex life. She became less engaged in group activities and was thought to be depressed. She watched more television and when she was unable to figure out the remote control would sit and stare at the blank screen. She seemed indifferent to her family members’ feelings and called her daughter “ugly.” Over time, she started to develop new habits, including collecting artificial flowers and insisting that the clocks in the house be synchronized down to the second. She began craving sweet foods and eating whole bags of cookies in a sitting and gained 30 pounds.

On presentation to the clinic, she was asked why she was visiting the clinic, and said, “I have some problems,” but could not elaborate. She recognized that she had lost her job but said it was because of unreasonable demands from her boss. On examination, she had increased speech output and would use the same phrases repetitively, but her speech was fluent and sensible, and she followed complex commands accurately. She would not persist in following commands, for instance, she would close her eyes when asked by the examiner but repeatedly opened them immediately before the examiner asked her to (motor impersistence). She would stare at the examiner for long periods of time and repeatedly interrupted the examination to tell jokes. The rest of the physical neurological exam was unremarkable.

50 Non-Alzheimer’s and Atypical Dementia

On neuropsychological testing, she scored 27/30 on the Mini‐Mental State Examination (MMSE), had a flat learning curve on a test of verbal memory, and had particular difficulty with tasks of executive function, such as the Stroop interference task (i.e., words for colors printed in different colored ink, and patient must state the color of the ink; if the

(a) (b)

word blue is written in green ink, they must say “green”) and verbal fluency, particularly phonemic fluency as she named only 4 words beginning with the letter D in 1 min with perseveration on one of the words. Her MRI scan showed right greater than left frontotemporal atrophy with particular orbitofrontal and caudate atrophy (Figure 5.1).

Figure 5.1 MRI axial (a), coronal (b), and sagittal (c) T1 showing bifrontal atrophy associated with behavioral variant FTD (bvFTD), greater on the right than left.

(c)

bvFTD

Symptoms in bvFTD

Sometimes referred to as frontal variant or simply as FTD, bvFTD is the most common presentation of FTD, comprising about 50% of cases, with svPPA and nfv‐PPA making up the other 50% [8]. The symptoms begin with insidious changes in behavior and personality. Frequently, these are felt to be either psychiatric in nature or to represent a “midlife crisis” [9]. Typical early symptoms include disinhibition, apathy, loss of empathy, changes in eating behaviors, and compulsive behav- iors. A lack of insight into their symptoms is typical in bvFTD. A distinction between a disinhibited subtype and an apathetic subtype has been proposed [10], though these features tend to be coexistent. The disinhibited acts often include socially inap- propriate behaviors such as touching strangers, lack of manners or appropriate response to social cues, or impulsive or antiso- cial actions such as stealing. Apathy in bvFTD includes a loss of interest or motivation as well as decreased initiation of behav- ior. Affected patients are often described as cold, unfeeling, and indifferent to the emotions of others. This lack of empathy can be illustrated by dramatic examples such as telling jokes at funerals. Typical eating behaviors include both overeating and a change in food preference, with more consumption of sweet or high‐carbohydrate foods, and sometimes development of food fads, such as insisting on foods from certain establish- ments or foods of a certain color. Repetitive motor behaviors are common, including simple stereotypic behaviors such as tapping or rubbing, or compulsive behaviors such as hoarding, checking, cleaning, and arranging.

Curiously, a subset of patients who meet clinical criteria for bvFTD do not progress over time or progress very slowly [11]. Imaging and neuropsychological performance in this group are

normal. This group has been referred to as FTD phenocopy, implying that the etiology in these cases is not FTLD, though this has yet to be established, and the etiology of clinical symp- toms and reason for lack of progression are not known.

Imaging

Both structural and functional brain imaging reveal abnor- malities that can help support a diagnosis of bvFTD. Structural imaging with CT or MRI typically shows a pattern of atrophy that is generally most prominent in the frontal and/or anterior temporal lobes. If there is asymmetry, the right hemisphere is often more affected [12]. The earliest structures affected include the anterior insula, anterior cingulate, and orbitofron- tal cortices [13], which are much less severely affected in AD [14]. The reason for the selective vulnerability of these regions in FTD is not known, but it has been noted that these regions are the only location of large bipolar projection cells called von Economo neurons [15]. These neurons are found only in humans, great apes, certain whales, dolphins, and elephants and are particularly targeted in bvFTD. It has been suggested that the introduction of these phylogenetically new cells into these brain regions might have induced some vulnerability [16]. The significant involvement of these paralimbic struc- tures that are known to be involved in emotional processing [17, 18] explains the prominence of socioemotional dysfunc- tion in bvFTD, as specific symptoms have been correlated with structural atrophy in particular portions of this network, par- ticularly the medial prefrontal and anterior cingulate with apa- thy and right anterior temporal and right medial frontal atrophy with loss of empathy [19, 20]. The eating behavior changes have been correlated with orbitofrontal, right insular, striatal, and most recently hypothalamic atrophy [21–23]. For

repetitive behaviors, simple stereotypies correlate with striatal atrophy[24], and complex compulsions have been variably associated with the orbitofrontal, caudate, and temporal lobe, particularly asymmetric temporal lobe atrophy [25, 26].

Whereas structural imaging usually demonstrates specific patterns of regional atrophy in bvFTD, functional brain imaging such as positron emission tomography using fluorodeoxyglucose (FDG‐PET) and single‐photon emission computed tomography using Tc‐hexamethylpropyleneamine oxime (HMPAO‐SPECT), which images cerebral perfusion, has also been frequently used to demonstrate corresponding frontotemporal abnormalities in bvFTD [27, 28].

Neuropsychological testing

Early in the course of bvFTD, patients typically perform well on traditional neuropsychological measures [29], because most of these tasks assess executive functions mediated by the dorsolat- eral prefrontal cortex, an area spared in early bvFTD, rather than behaviors reliant on the medial and orbital frontal lobe that are affected early in the disease [30]. Degeneration of the regions affected in bvFTD results in deficits in social cognition. Accordingly, studies have demonstrated that bvFTD patients are impaired at recognition of emotion [31], recognition of sarcasm [32], and ability to appreciate another’s point of view (theory of mind) [33]. Efforts are currently underway to develop assess-

Table 5.1 1998 Neary consensus criteria for behavioral variant frontotemporal dementia.

Core diagnostic features (all needed for diagnosis)

Insidious onset and gradual progression
Early decline in social interpersonal conduct
Early impairment in regulation of personal conduct Early emotional blunting
Early loss of insight

Supportive behavioral diagnostic features

Decline in personal hygiene and grooming Mental rigidity and inflexibility Distractibility and impersistence Hyperorality and dietary changes Perseverative and stereotyped behavior Utilization behavior

Supportive speech and language diagnostic features

Altered speech output with economic, aspontaneous or pressed speech Stereotypy of speech
Echolalia
Perseveration

Mutism

Supportive physical diagnostic features

Primitive reflexes Incontinence
Akinesia, rigidity, and tremor Low or labile blood pressure

Investigations

Neuropsychology: impairment on frontal tests in the absence of severe amnesia, aphasia, or perceptual disorder
Brain imaging: predominant frontal or anterior temporal abnormality EEG: normal

ment tools that examine these abilities and can be used in the clinical setting, with appropriate normative data. As bvFTD progresses to involve the more dorsal frontal regions, patients develop deficits in traditional tests of executive functions, such as the Trails B task, which assesses the ability to flexibly switch between two different types of responses [34]; the Stroop interference task, which assesses the ability to inhibit automatic or “prepotent” responses [34]; and phonemic fluency, which assesses the ability to continually generate novel responses [35]. Whereas everyday memory is often relatively spared in bvFTD, performance on tests of verbal and visual memory is variable [36, 37]. Similarly, visuospatial function is relatively spared, though performance on tasks might be affected by poor plan- ning or organization [38].

Diagnosis

Criteria published in 1994 [39] and 1998 [40] were used most commonly for diagnosis, and the 1998 Neary criteria are shown in Table 5.1. These criteria proved difficult to use in clinical practice because not all patients meet the major criteria and many of the minor criteria occur too inconsistently to be clini- cally useful [41]. New, simpler criteria that were proposed by an international consensus panel have shown good reliability and improved sensitivity (Table 5.2) [42, 43]. The new criteria make use of current knowledge about biomarkers to increase the

Table 5.2 Proposed international consensus criteria for bvFTD.
I. Required criterion—progressive deterioration of behavior and/or

cognition by observation or history

II. Possible bvFTD—3 of 6 required
A. Early behavioral disinhibition—socially inappropriate behavior, loss of

manners or decorum, or impulsive actions
B. Early apathy or inertia
C. Early loss of sympathy or empathy
D. Early perseverative, stereotyped, or compulsive/ritualistic behavior
E. Hyperorality and dietary changes
F. Neuropsychological profile: executive/generation deficits with relative

sparing of memory and visuospatial functions

III. Probable bvFTD (all of the following required)

A. Meets criteria for possible bvFTD

B. Significant functional decline

C. Imaging results consistent with bvFTD (frontal and/or anterior
temporal atrophy on CT or MRI or frontal hypoperfusion or hypometabolism on SPECT or PET)

IV. bvFTD with definite FTLD pathology (1 and either 2 or 3 required)

A. Meets criteria for possible or probable bvFTD
B. Histopathological evidence of FTLD on biopsy or at postmortem C. Presence of a known pathogenic mutation

V. Exclusion criteria for bvFTD—criteria A and B must both be answered negatively; criterion C can be positive for possible bvFTD but must be negative for probable bvFTD

A. Pattern of deficits is better accounted for by other nervous system or medical disorders

B. Behavioral disturbance is better accounted for by a psychiatric diagnosis

C. Biomarkers strongly indicative of Alzheimer’s disease or other neurodegenerative processes

Frontotemporal dementia 51

52 Non-Alzheimer’s and Atypical Dementia

certainty of diagnosis. Thus, although clinical features can be used to make a diagnosis of possible bvFTD, imaging findings consistent with bvFTD, such as PET hypometabolism or frontal lobe atrophy, or mutations associated with bvFTD are necessary to increase the certainty to probable. The use of imaging is supported by studies showing that imaging enhances the diag- nostic accuracy [28].

ppa

PPA refers to progressive disorders in which language deteriora- tion is the most prominent symptom and the primary cause of a patient’s impairment for the initial period of the illness [44]. There are three syndromes within this category: svPPA (previ- ously referred to as semantic dementia), nfv‐PPA (also referred to as progressive nonfluent aphasia), and logopenic variant pri- mary progressive aphasia (lvPPA). Whereas svPPA and nfv‐PPA are usually associated with FTLD pathology, lvPPA is usually associated with underlying AD pathology, and because of this relationship, it will be discussed in more detail in the chapter on

atypical AD. Logopenic aphasia, as seen in lvPPA, is character- ized by hesitant speech and profound difficulty with word finding but relatively preserved word comprehension, and brain imaging usually shows left posterior temporal and parietal abnormalities.

svppa

Symptoms in svPPA

svPPA is characterized by progressive deterioration in knowl- edge about words and objects. It begins with word finding and sometimes subtle word recognition difficulties and progresses to involve loss of knowledge about objects. Patients have fluent, empty speech without motor impairment or agrammatism. The disease usually appears to begin in the left temporal pole although patients with right greater than left temporal atrophy are not uncommon, and such patients present with more behavioral symptoms typical of bvFTD in the early phases and more subtle semantic loss [45]. As the disease progresses and involves the left temporal lobe more, typical semantic loss develops. When the

Case 2

A 61‐year‐old right‐handed man presented with symptoms beginning one and a half years ago with trouble remembering the names of people he had known for 15 years. He then began having difficulty coming up with words. He would ask his wife what various words mean, including “what is an éclair?” and “what are immunizations?” When his wife asked him to get a mallet from the garage, he returned with a variety of items, none of which were a mallet. A neighbor came over to borrow an oil filter wrench, and he sent the neighbor to look in his tools because he was not able to identify it himself. More recently, he developed trouble planning and multitasking. He developed a rigid routine regarding eating the exact same

breakfast daily and a fixation on somatic complaints including neck pain and lightheadedness.

Neurologic examination was notable for semantic paraphasias with fluent, tangential speech. Neuropsychological testing was notable for impaired naming, scoring 2/15 on the Boston Naming Test, and he only identified another two pictures with cues and multiple choice. There are some of the objects he was able to describe vaguely, such as a seahorse, which was “an animal in the water somewhere.” On the Peabody Picture Vocabulary Test, which asks patients to point to pictures that match words read by the examiner (i.e., banister), he scored below expectations at 7/16. MRI showed prominent left temporal atrophy (see Figure 5.2). This patient’s history is most consistent with svPPA.

(a) (b)
Figure 5.2 Axial (a) and coronal (b) T1 MRI showing left anterior temporal lobe atrophy associated with semantic variant PPA (svPPA).

disease begins on the right, knowledge about faces also is often an early deficit, for instance, not recognizing very famous faces of politicians or entertainers [46]. Left‐sided predominance is more common than right‐sided predominance by a 3:1 margin [45]. Whether the disease begins on the right or left, svPPA patients usually develop behavioral symptoms typical of bvFTD within 3 or 4 years of onset, presumably because of the spread of the disease from temporal to frontal structures [47].

Imaging

Dramatic anterior temporal atrophy can easily be appreciated on MRI [47], and it is usually remarkably asymmetric, although bilateral [48]. Frontal atrophy may be found at later stages.

Neuropsychological testing

Patients with svPPA will perform poorly on tests of confronta- tional naming, single‐word comprehension (word to picture matching), and category fluency. They often display surface dys- lexia, an inability to correctly pronounce irregular written words (such as knight, yacht, etc.). Those with right temporal involve- ment might also have difficulty on tasks of recognizing famous

faces. Verbal memory is typically impaired above and beyond the language deficits secondary to mesial temporal lobe involvement and in many cases concomitant hippocampal sclerosis. Visuospatial and executive functions tend to be relatively preserved [49].

nfv‐ppa

Symptoms in nfv‐PPA

nfv‐PPA is characterized by slow, effortful speech, apraxia of speech and agrammatism (decreased use of grammatical func- tion words). Nonfluency refers to a reduced rate of speech. Apraxia of speech involves problems with the motor speech production and involves sound distortions. For example, pro- nunciation of a complicated phonological word such as “catas- trophe” by someone with speech apraxia would result in the word sounding different with each attempt, whereas with a cer- ebellar dysarthria the sound errors would be the same or simi- lar each time the word is spoken. Phonological errors with variable substitutions of syllables with each attempt at pronun- ciation of a word are heard. Comprehension is generally spared. Motor signs (typically parkinsonism) are often found on exam- ination, particularly if the underlying pathology is corticobasal

Frontotemporal dementia 53

Case 3

A 74‐year‐old gentleman began to notice difficulty enunciating beginning about 2 years prior to presentation. He says he knows the words he wants to say, but can’t get them out. He stumbles over words, mispronounces them, and must slow his speech down in order to pronounce things better and to find the words he wants to say. Being under stress, such as public speaking, is particularly likely to worsen his difficulties. His wife says sometimes he will use the wrong tense of a verb or will say the wrong word, such as saying “hose” instead of “nose.” He notes no trouble with comprehension. Neither he nor his wife has noted any other areas of thinking difficulty. He is still doing crossword puzzles and paying their bills.

On examination, he was alert and attentive and followed commands quickly and accurately. His speech was slow and effortful, with frequent pauses in between and even within words. He had trouble pronouncing phonemically complex words, making many attempts with varying results. For instance, when asked to pronounce the word anachronistic, he said “acrononistic…ananochronoristic…acronistic….” The remainder of his neurological exam was unremarkable except for slightly decreased arm swing on the right during walking. He scored poorly on verbal fluency but did well on most other cognitive tasks. MRI showed atrophy in the left insular/perisylvian region (Figure 5.3). Based on his clinical history, exam, and MRI, his diagnosis is most consistent nfv‐PPA.

(a)
Figure 5.3 Coronal (a) and axial (b) T1 MRI showing left perisylvian atrophy associated with nfv‐PPA.

(b)

54 Non-Alzheimer’s and Atypical Dementia

degeneration (CBD) or PSP. Depression is common. Although behavioral and personality changes can develop over time in nfv‐PPA, they have less of the dramatic socioemotional dys- function seen in bvFTD and svPPA [50].

Imaging

Asymmetric atrophy and hypometabolism of the left inferior fron- tal/perisylvian area is the characteristic imaging finding [51, 52].

Neuropsychological testing

Nonfluent speech with apraxia of speech and impaired gram- mar are found. Frequently, there are substitutions of incorrect sounds in a word, called phonemic paraphasias. Verbal fluency is typically reduced, and naming may also be impaired. Executive dysfunction is often subtle early in the disease but typically becomes more apparent with progression due to extensive involvement of the left lateral prefrontal cortex. Visuospatial skills and memory abilities are relatively spared early in the course of the disease [51].

Table 5.3 1998 Neary consensus criteria for semantic variant.

Core diagnostic features

Insidious onset and gradual progression Language disorder characterized by:

1. Progressive, fluent, empty spontaneous speech

2. Loss of word meaning, manifest by impaired naming and
comprehension

3. Semantic paraphasias

Perceptual disorder characterized by:
1. Prosopagnosia: impaired recognition of identity of familiar faces and/or 2. Associative agnosia: impaired recognition of object identity
Preserved perceptual matching and drawing reproduction
Preserved single‐word repetition
Preserved ability to read aloud and write to dictation orthographically regular words

Supportive speech and language diagnostic features

Press of speech
Idiosyncratic word usage
Absence of phonemic paraphasias Surface dyslexia and dysgraphia Preserved calculation

Supportive behavior features

Loss of sympathy and empathy Narrowed preoccupations Parsimony

Supportive physical signs

Absent or late primitive reflexes Akinesia, rigidity, and tremor

Investigations

Neuropsychology

1. Profound semantic loss, manifest in failure of word comprehension and
naming and/or face and object recognition

2. Preserved phonology and syntax, elementary perceptual processing,
spatial skills, and day‐to‐day memorizing

Electroencephalography: normal
Brain imaging (structural and/or functional): predominant anterior temporal abnormality (symmetric or asymmetric)

PPA diagnosis

Diagnostic criteria from 1998 have been used until recently for these aphasic syndromes [40] (Tables 5.3 and 5.5). New knowledge about the clinical and imaging features and of PPA has led to new criteria for these disorders (see Tables 5.4 and 5.6) [53].

Table 5.4 Diagnostic criteria for semantic variant PPA.

Core diagnostic features

Insidious onset and gradual progression
Nonfluent spontaneous speech with at least one of the following: agrammatism, phonemic paraphasias, anomia

Supportive speech and language features

Stuttering or oral apraxia
Impaired repetition
Alexia, agraphia
Early preservation of word meaning Late mutism

Supportive behavior features

Early preservation of social skills
Late behavioral changes similar to FTD

Supportive physical signs

Late contralateral primitive reflexes, akinesia, rigidity, and tremor

Investigations

Neuropsychology: nonfluent aphasia in the absence of severe amnesia or perceptuospatial disorder
Electroencephalography: normal or minor asymmetric slowing
Brain imaging (structural and/or functional): asymmetric abnormality predominantly affecting dominant (usually left) hemisphere

Table 5.5 1998 Neary consensus criteria for progressive nonfluent aphasia.

Patients must meet criteria for primary progressive aphasia (modified from Mesulam)
Both of the following core features must be present:
1. Poor confrontation naming

2. Impaired single‐word comprehension
At least three of the following other features must be present:

Poor object knowledge
Surface dyslexia and/or dysgraphia Spared repetition
Spared motor speech and grammar

Imaging‐supported SV‐PPA diagnosis

Both of the following criteria must be present:
Clinical diagnosis of SV‐PPA
Imaging must show one or more of the following results:

Predominant anterior temporal lobe atrophy on MRI
Predominant anterior temporal hypoperfusion or hypometabolism on

SPECT or PET

SV‐PPA with definite pathology

Clinical diagnosis (criterion 1 below) and either criterion 2 or 3 must be present:

Clinical diagnosis of SV‐PPA

Histopathological evidence of a specific pathology Presence of a known pathogenic mutation

Table 5.6 Diagnostic criteria for nonfluent PPA.

Patients must meet criteria for primary progressive aphasia (modified from Mesulam)
At least one of the following core features must be present:

1. Agrammatism in language production

2. Effortful, halting speech with inconsistent sound errors and distortions (apraxia of speech)

At least two of three of the following other features must be present:

1. Impaired comprehension of syntactically complex sentences

2. Spared single‐word comprehension

3. Spared object knowledge

Imaging‐supported nfv‐PPA diagnosis

Both of the following criteria must be present:

1. Clinical diagnosis of nfv‐PPA

2. Imaging must show one or more of the following results:

• Predominant left posterior fronto‐insular atrophy on MRI

• Predominant left posterior fronto‐insular hypoperfusion or
hypometabolism on SPECT or PET
nfv‐PPA with definite pathology
Clinical diagnosis (criterion 1 below) and either criterion 2 or 3 must be present:

1. Clinical diagnosis of nfv‐PPA

2. Histopathological evidence of a specific pathology (e.g., FTLD‐tau,
FTLD‐TDP, AD)

3. Presence of a known pathogenic mutation

Other clinical syndromes associated with FTD

Although bvFTD, svPPA, and nfv‐PPA are the core FTD clinical syndromes, several other neurodegenerative syndromes are associated with FTLD pathology at autopsy and have overlap- ping clinical features. These syndromes are now often included in discussions of FTD as “FTD spectrum” or “FTLD spectrum” and include features of MND and parkinsonism.

Frontotemporal dementia with motor
neuron disease
About 10 to 15% of patients with FTD also develop MND similar to amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) [54], and this combination is associated with the most rapid progression of FTD subtypes and shortest survival [7]. MND is most likely to occur with bvFTD, although it occurs with any of the three core FTD syndromes. MND is characterized by muscular weakness, atrophy, and fasciculations due to degeneration of spinal cord anterior horn cells, as well as pyramidal signs such as spastic tone and hyperreflexia due to degeneration of neurons in the primary motor cortex. Symptoms more frequently involve the bulbar muscles (tongue, face, those associated with swallowing), when MND is associated with FTD. Either cognitive or motor symptoms present first. When FTD is associated with MND, patients sometimes have strong, uncontrollable bursts of laughing or crying, referred to as pseu- dobulbar affect (PBA) [55], and PBA in the setting of FTD should prompt investigations for MND. The behavioral symp- toms in frontotemporal dementia with motor neuron disease

(FTD‐MND) are similar to those occurring in FTD without MND, although psychotic symptoms are more common in FTD‐MND [56]. Imaging in FTD‐MND sometimes is less dramatic than in FTD without MND but can include atrophy around premotor areas extending to the precentral gyrus [57]. Although ALS was traditionally thought to be very rarely associ- ated with dementia, the occurrence of MND in the setting of FTD prompted research to more closely examine the cognition of ALS patients. These studies revealed that approximately 20% of patients presenting to neuromuscular clinics with only motor complaints actually have substantial cognitive and behavioral problems consistent with a diagnosis FTD [58] and up to 50% of ALS patients have more subtle cognitive deficits detectable using psychometric or quantitative assessment—findings which further cemented the link between FTD and ALS [58, 59].

pSp and CBS

PSP and CBS have traditionally been included in neurological texts as atypical forms of parkinsonism. These are discussed in detail in Chapter 7, so will only be briefly mentioned here. Many PSP patients develop cognitive difficulties suggesting frontal lobe dysfunction, and they frequently develop behavioral and/ or language symptoms seen in bvFTD and nfv‐PPA. Some PSP patients initially suffer from these cognitive or behavioral symp- toms, with minimal or very subtle motor difficulties, and later develop the typical motor features of PSP. This symptomatic overlap and association with the pathological features of FTLD has led to its inclusion with FTD‐spectrum disorders.

CBS is also a disorder where the true spectrum of clinical presentation is in flux. Traditionally, CBS (often referred to by the pathological term CBD) was described as a cognitive and motor disorder with markedly asymmetric movement difficul- ties including tremor and myoclonus, rigidity and dystonia, alien limb (tendency for the limb to move on its own and some- times interfere with movements of other limbs), and asymmet- ric sensory problems suggesting somatosensory cortex dysfunction. Studies have also described language difficulties similar to nfv‐PPA or less commonly lvPPA and profound visu- ospatial disturbances and neglect of the left side of space [60, 61]. Recent studies have suggested that many CBS patients, even with asymmetric motor symptoms, have AD pathology [62, 63] and those with AD pathology have more temporoparietal atro- phy [64]. When CBD is found pathologically, patients can pre- sent with the asymmetrical motor symptoms and cognitive and behavioral deficits typical of frontal lobe dysfunction similar to those seen in bvFTD, and they may not have significant motor deficits [65].

Neuropathology

One of the challenges facing clinicians who see patients with neurodegenerative disorders is translating a patient’s presenting clinical syndrome into a prediction of the underlying molecular

Frontotemporal dementia 55

56 Non-Alzheimer’s and Atypical Dementia

and histopathology. These correlations will be more relevant as treatments are developed that target the molecular basis of dis- ease. Unfortunately, this prediction is made more complicated by the fact that the clinical syndromes that comprise FTD are associated with varied underlying pathologies.

All subtypes of FTLD pathology show gross frontal and temporal lobe atrophy as well as neuronal loss, variable glio- sis, and microvacuolation [66]. The different subtypes are dif- ferentiated from each other by the types of neuronal inclusions and other morphological features. The earliest reports of FTLD described Pick bodies [2], which were later recognized to contain hyperphosphorylated tau proteins. Subsequently, many cases of FTLD were described with tau inclusions, but not necessarily Pick bodies; however, this only accounted for about half of cases of FTLD. The pathological descriptions for the other half have evolved over time, having been described for many years as dementia lacking distinctive histopathology (DLDH) [67]. Subsequently, new staining techniques demon- strated that many patients that would have been called DLDH actually show tau‐negative ubiquitinated inclusions, termed FTLD‐U. In 2006, it was discovered that the ubiquitinated protein in most of these cases is the 43 kDa TAR DNA‐bind- ing protein (TDP‐43) [68]. Now, it is recognized that these two pathologies, tau inclusions or TDP‐43 inclusions, are approximately found in equal frequencies in bvFTD and account for the majority of cases [69]. Recently, it was discov- ered that patients showing inclusions with the fused in sar- coma (FUS) protein now explain most of rest of the FTLD‐U cases [70].

Tau

The tau protein, which is also called microtubule‐associated protein tau (MAPT), is coded on chromosome 17 and is important for stabilizing microtubules and thus supports molecular transport within neurons [71]. Tau exists in two forms created by alternative splicing, which leads to a 3‐ amino‐acid sequence repeat form (3R) and a 4 repeat form (4R). Both forms are present in normal cells, but some pathol- ogies are associated predominantly with one form or the other. Pick bodies, the classic histopathology in FTLD, con- tain the 3R form of tau (seen in Figure 5.4). Achromatic bal- looned neurons, or Pick cells, are seen in association with Pick bodies, and many patients have Pick cells without Pick bodies. Other pathological settings with predominant tau pathology include FTDP‐17, a genetic form associated with mutations in the MAPT gene, and this is a mixture of 3R and 4R tau. The rarer tangle‐dominant dementia (TDD) and the Guam ALS parkinsonism–dementia complex are also 3R + 4R mixtures. CBD and PSP are both 4R tau forms. CBD is associated with tau immunoreactive astrocytic plaques and glial threads and coils. PSP is characterized by globose neurofibrillary tangles and tufted astrocytes [72]. Argyrophilic grain disease (AGD) and multiple system tauopathy with dementia are rarer 4R tau pathologies [72].

Figure 5.4 Pick bodies in the left midinsula in a 74‐year‐old woman with nonfluent variant PPA due to Pick’s disease. Immunohistochemistry for 3‐repeat tau, hematoxylin counterstain. Reproduced with permission of W.W. Seeley. (See insert for color representation of the figure.)

TDp‐43

The functions of the TDP‐43 protein are not completely under- stood, but it is a normal constituent of neurons. In these cir- cumstances, staining is limited to the nuclei, which is consistent with data indicating that TDP‐43 is a regulator of DNA tran- scription [73]. In FTLD, TDP‐43 inclusions are found in the cytoplasm, and various patterns of staining have been recog- nized based on whether the TDP‐43 appears to be collecting mostly in cytoplasmic inclusions, neurites, or both. This clas- sification is important because certain pathological subtypes are associated with specific clinical presentations (discussed in the next section). A harmonized classification [74] of the two prior systems [75, 76] recognizes four types of TDP‐43 pathol- ogy. Type A has frequent small dystrophic neurites and neu- ronal cytoplasmic inclusions and might have neuronal intranuclear inclusions. Type B has numerous neuronal cyto- plasmic inclusions in superficial and deep cortical layers with infrequent neurites, and Type C includes long dystrophic neu- rites in superficial layers and few neuronal cytoplasmic inclu- sions. Type D is relatively rare and includes dystrophic neurites and intranuclear inclusions. At the time that the link between TDP‐43 and FTLD was discovered, TDP‐43 was also found to be present in the majority of patients with ALS, which provides a pathological basis for the clinical links between ALS and FTD noted earlier [68, 77].

FUS

FUS pathology was initially discovered in patients with familial ALS and soon thereafter in patients with FTD [78]. Basophilic inclusion body disease (BIBD) [79], neuronal intermediate

filament inclusion disease (NIFID) [80], and atypical FTLD‐U (aFTLD‐U) are rare pathologies in the FTLD spectrum that are now attributed to FUS pathology as well.

Other

There still remain some cases without inclusions in the DLDH category, as well as cases termed FTD‐3 that will be discussed later with the corresponding genetic mutation.

Clinicopathological correlation

Overall, the relationship between the specific clinical presenta- tion and the molecular and histopathology is far from a one‐to‐ one correlation (see Figure 5.5), but some clinical presentations are fairly predictive of specific pathologies.

svPPA usually is caused by TDP‐43 pathology, specifically type C [74, 81], though it can also be caused by AD and very rarely by tau pathology [82]. nfv‐PPA is often caused by tau pathology, usually PSP or CBD [52], though it can be the result of other pathologies as well [83]. FTD‐MND is caused by TDP‐43 type B pathology. Type A pathology is seen in patients with familial FTD associated with progranulin mutations (see following text) and can cause multiple other sporadic FTD syn- dromes. Type D pathology is also associated with familial cases of FTD, inclusion body myositis, and Paget’s disease of bone due to mutations in valosin‐containing protein (VCP) [74, 81].

Clinically, patients with FUS pathology have a young age of onset and often have a psychiatric presentation [70]. Their

imaging is associated with more caudate atrophy than is seen in other FTLD pathologies [84].

Whereas svPPA and nfv‐PPA are strongly associated with spe- cific pathologies, bvFTD is associated about equally with tau or TDP‐43 pathology, and no clinical features are currently recog- nized as predicting the subtype. Some patients with bvFTD have AD pathology at autopsy [85]. In some cases, this is seen in addi- tion to FTLD pathology, but in many of these cases, AD pathol- ogy appears to be the only cause (i.e., frontal variant of AD).

When the supranuclear gaze difficulties characteristic of PSP are present, PSP pathology is highly likely [86]. As noted earlier, the clinical features of CBS can be associated with various pathologies, including AD, and the features predicting CBD pathology are still being resolved.

The development of additional biomarkers to identify the molecular subtype in each case of FTD is currently of great inter- est. For those patients with clinical features of FTD but underly- ing AD pathology, CSF levels of tau and Aβ42 have shown promise for discriminating between FTLD and AD [87]. PET ligands are also available for detecting amyloid plaques in vivo, providing another approach for making this distinction [88], particularly in patients with atypical presentations who are con- sidered diagnostic dilemmas [89]. Recent work has suggested that it might be possible to distinguish FTLD‐tau from FTLD‐ TDP based on assaying multiple specific CSF analytes [90, 91]. Low progranulin levels measured in serum, plasma, and CSF have been found in patients with progranulin mutations [92–94]. One study suggested that elevated serum TDP‐43 levels might be useful [95]. Neurofilament light chains have also been found to be elevated in FTD and to correlate with disease severity [96]. All of these tests, however, must still be considered preliminary.

Genetics

The majority of cases of FTD are sporadic and there is no clear pattern of inheritance. About 10% are associated with an auto- somal dominant inheritance pattern. Forty percent of patients have a family history of dementia or psychiatric conditions but do not necessarily have a clear inheritance pattern [97]. There are two haplotypes of tau, H1 and H2, and the H1/H1 genotype has been associated with an increased risk of developing 4R tau disorders, PSP or CBD [98, 99].

MapT

There are more than 40 different currently recognized disease‐ causing mutations of the MAPT gene, which is found on chromosome 17. Carriers of this gene develop symptoms at a younger age than sporadic or other genetic cases (52 years old compared to 62 years old for PGRN mutations in one series [100]), and imaging reveals a more symmetric pattern of atro- phy with more temporal lobe atrophy than other genetic cases [101]. There is also some suggestion that different mutations are associated with different patterns of atrophy [102].

PSP CBS

FTLD-TAU

bvFTD

FTLD-FUS

FTD-MND

FTLD-TDP AD

svPPA

nfv-PPA

lvPPA

Frontotemporal dementia 57

Figure 5.5 Clinical and pathologic correlates between FTD‐spectrum syndromes and FTLD pathologies. PSP = progressive supranuclear palsy; CBS = corticobasal syndrome; bvFTD = behavioral variant frontotemporal dementia; PPA = primary progressive aphasia; svPPA = semantic variant primary progressive aphasia; nfv‐PPA = nonfluent variant primary progressive aphasia; lvPPA = logopenic variant primary progressive aphasia; FTD‐MND = frontotemporal dementia with motor neuron disease; FTLD‐tau = frontotemporal lobar degeneration with tau pathology; FTLD‐TDP = FTLD with TAR DNA‐binding protein 43 (TDP‐43) pathology; FTLD‐FUS = FTLD with fused in sarcoma (FUS) pathology; AD = Alzheimer’s disease.

PPA

58 Non-Alzheimer’s and Atypical Dementia

pGrN

Mutations in the progranulin gene (also on chromosome 17) cause a wide variety of clinical presentations, including not only symptoms of bvFTD but also parkinsonism, memory impair- ment, hallucinations or delusions, and a nonfluent aphasia (often without apraxia of speech). The atrophy pattern on MRI tends to be more asymmetric and more posterior than other forms of FTLD [103]. The mechanism by which PGRN mutations lead to TDP‐43 pathology is currently unclear, though multiple path- ways have been implicated, including neuroinflammation and impaired lysosomal function [104]. PGRN mutations have been found in patients with AD copathology, suggesting that these mutations may also be an AD risk factor [105]. As opposed to MAPT, mutations in PGRN lead to haploinsufficiency, rather than a toxic gain of function [106].

C9OrF72

A recently discovered hexanucleotide repeat expansion on chromosome 9 (C9ORF72) has been found to be the most com- mon cause of both familial FTD and familial ALS [107, 108]. This expansion may be found in 11–29% of familial FTD, 24% of familial ALS, and 2–4% of sporadic FTD or ALS [107, 109]. The clinical syndrome in these patients is most commonly bvFTD, ALS, or FTD‐MND [110], but PPA subtypes have also been described [111, 112]. Psychosis has been described as a more common feature with C9ORF72 than in nonmutation carriers [111]. Some cases of slowly progressive bvFTD, thought to have been FTD phenocopies, have also been found to carry C9ORF72 mutations [113]. Mutation carriers have been found to have FTLD‐TDP pathology (types A or B), and TDP‐nega- tive p62‐positive inclusions in the cerebellum are a specific pathologic feature [112, 114, 115]. Formation and intracellular accumulation of RNA foci have been proposed as a putative disease mechanism [107]. Dipeptide repeat proteins translated from the hexanucleotide repeat have also been found [116], though it is not clear if these are pathogenic as they do not colo- calize with neurodegenerative findings, with other TDP‐43 pathology, or correspond with the clinical phenotype in these cases [117].

ChMp‐2B

The gene CHMP‐2B (charged multivesicular body protein 2B, also referred to as chromatin‐modifying protein 2B) is found on chromosome 3, encodes a component of the endosomal sorting complex required for transport III, and causes the type of FTLD known as FTD‐3. It is not associated with tau, TDP‐43, or FUS pathology. It is extremely rare and only described in a few families, one Danish [118] and another Belgian.

VCp

Mutations of the VCP on chromosome 9 are associated most commonly with inclusion body myositis and in some affected individuals also with Paget’s disease of bone and FTD. VCP mutations have also been associated with familial ALS [119].

Other

Several studies have looked for additional genes or epigenetic risk factors that might confer risk for development of FTD. Whereas variants in several genes have been found to increase risk in single studies [120, 121], these results have not yet been replicated. Recent genome‐wide association studies (GWAS) in clinical [122] and pathologically confirmed cases [123] of FTD have suggested other genes that confer risk of developing the disease and point to cellular pathways that may be involved in its development. Epigenetic factors, such as methylation or histone modification, may also be relevant and lead to therapeutic targets in FTD [124]. Mutations in the TARDBP and FUS genes have been found and linked mostly to familial ALS, with rare associations with an FTD presentation.

Treatment

There are no US FDA‐approved medications for the treatment of FTD. There is limited evidence regarding symptomatic treatment. Treatments directed at specific molecular targets are currently being developed.

Symptomatic

Nonpharmacologic methods of dealing with behavioral symp- toms are important, particularly given the lack of proven pharma- cologic treatments. Caregiver education is important and can help caregivers to realize that rational debate or argument often is not helpful in modifying the patient’s behavior. (See Chapter 15 regarding patient management.)

The pharmacologic agents used in AD are not necessarily useful in FTD, which affects different neural networks. FTD is not associ- ated with a cholinergic deficit, and there is no strong evidence for the use of cholinesterase inhibitors in FTD. Donepezil showed no beneficial cognitive effect in one open‐label trial and resulted in worsening of behavior [125]. An open‐label study of rivastigmine showed improvement in neuropsychiatric symptoms but not cognition [126], and another study of galantamine showed a non- significant trend toward language improvement in a cohort of PPA patients that might have included some with lvPPA (who likely had underlying AD pathology) [127]. There is no compelling evidence for the use of memantine. Though two open‐label studies showed that the medication is well tolerated [128, 129], a double‐ blind placebo‐controlled trial in France showed no improvement with memantine after 1 year [130], and a subsequent study in the United States confirmed a lack of benefit [131].

Behavioral symptoms can be treated with antidepressants, particularly serotonergic agents. Open‐label studies of fluoxe- tine, fluvoxamine, sertraline, and paroxetine have shown efficacy in controlling behaviors [132, 133]. Paroxetine was effective in a placebo‐controlled study [134], though a separate, very brief randomized study of this drug showed no effect [135]. Trazodone has also been shown effective in one study [136]. There is no evidence for the use of mood‐stabilizing agents. Antipsychotic

medications should be used with caution given the unfavorable side effect profile and US FDA black box warning. Quetiapine has less D2 receptor antagonism, making it a more appealing choice for avoiding extrapyramidal side effects. Some data show benefit for olanzapine [137] (one open‐label study), aripiprazole [138], and risperidone (single case reports) [139].

Disease‐modifying

The ultimate goal of treatment is not only to ameliorate symp- toms but also to cure disease. Current efforts are underway to develop medications to target tau and TDP‐43 pathology. Tau‐active drugs in development include those that prevent tau kinase activity to block phosphorylation, those that clear tau aggregates, microtubule stabilizers, and aggregation inhibitors. The neuroactive peptide davunetide had shown a benefit on microtubule stabilization and decreased tau phosphorylation in preclinical studies, but it was recently shown to be ineffective in PSP [140], although it is not clear that the drug had adequate brain penetration in this study. Progranulin mutations result in their deleterious effect through haploinsufficiency, so treat- ments aimed at this molecular pathology are intended to increase progranulin levels. Many other treatment trials for FTD and related disorders are underway (see http://www.clinicaltrials.gov).

Conclusions

The term FTD encompasses multiple distinct clinical pheno- types with personality, behavior, and language changes, as well as extrapyramidal syndromes and MND. It is caused by multiple distinct pathologies and in some cases genetic mutations. Treatments are currently symptomatic, but molecular‐based treatments are currently in development.

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. 129 Boxer AL, Lipton AM, Womack K, Merrilees J, Neuhaus J, Pavlic D, et al. An open‐label study of memantine treatment in 3 subtypes of frontotemporal lobar degeneration. Alzheimer Dis Assoc Disord 2009 Jul–Sep;23(3):211–217.

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. 131 Boxer AL, Knopman DS, Kaufer DI, Grossman M, Onyike C, Graf‐ Radford N, et al. Memantine in patients with frontotemporal lobar degeneration: a multicentre, randomised, double‐blind, placebo‐ controlled trial. Lancet Neurol 2013 Feb;12(2):149–156.

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Frontotemporal dementia 63

CHaPter 6
Lewy body dementias (DLB/PDD)

Carol F. Lippa1 and Katherine L. Possin2

1 Drexel University College of Medicine, Philadelphia, PA, USA
2 University of California, San Francisco, San Francisco, CA, USA

Introduction

Dementia is characterized by cognitive impairment severe enough to interfere with daily functioning [1]. Alzheimer’s dis ease (AD) is the most common dementia subtype, accounting for more than half of all dementia cases. In AD, memory loss is the most significant aspect of cognitive impairment [2]. Dementia with Lewy bodies (DLB) is probably the second most common dementia, affecting nearly one‐quarter of dementia subjects. In contrast to AD, core diagnostic criteria of DLB include visual hallucinations, parkinsonism, and fluctuations of attention and alertness (see Table 6.1). These symptoms are rare in cognitively normal elderly individuals and early AD patients [4]. Other features in DLB include rapid eye movement (REM) sleep behavior disorder (RBD), other sleep dysfunctions, syn cope, transient impairment in consciousness, delusions, depres sion, and early incontinence [5–7]. The diagnosis of DLB is important to make because treatment specifics differ from those used in other dementias. For example, DLB patients are more susceptible to neuroleptic hypersensitivity than AD patients [8].

Patients with Parkinson’s disease (PD) often develop cognitive decline and up to 80% will progress to dementia (Parkinson’s dis ease with dementia (PDD), [4]). PDD differs from DLB in the temporal sequence of initial symptoms, but with progression, the syndromes and pathology become similar. Both involve progres sive cognitive decline involving visuospatial, attentional, and executive functions. Psychiatric disturbances include visual hal lucinations, anxiety, apathy, and depression. The motor symp toms are similar in PDD and DLB, and both have more axial symptoms, postural instability, and gait difficulty than nonde mented PD [9]. Both are characterized pathologically by intracy toplasmic inclusions containing ubiquitin and alpha‐synuclein called Lewy bodies (LBs). PDD and DLB brains have a loss of the neurotransmitters acetylcholine and dopamine [10].

Nosology

Historical issues/nomenclature

PD was first profiled in 1817 by James Parkinson in “An Essay on the Shaking Palsy.” He described the classic motor symptoms of PD but reported “the senses and intellects being uninjured” [11]. It is now increasingly recognized, however, that many patients newly diagnosed with PD have cognitive impairment associated with their disease and that many of these patients will go on to develop a dementia syndrome.

The initial autopsy descriptions of patients with DLB were written by Dr. Okazaki [12]. They described patients with pro gressive dementia but without the motor symptoms of PD whose brains had cortical LBs. This was followed by detailed clinicopathologic descriptions of DLB cases by Kenji Kosaka [13] who reviewed all available literature cases and noted a characteristic clinical syndrome. Since the original descrip tions, immunohistochemistry with antibodies to components of LBs (antiubiquitin and anti‐alpha‐synuclein antibodies) has made diagnosis easier, and we now realize that DLB is a com mon disorder. In 1996, McKeith et al. established the first con sensus criteria for DLB and formalized the term “dementia with Lewy bodies.”

The discoveries of α‐synuclein mutations in families with autosomal dominant PD [14] and of α‐synuclein as the main component of LBs [15] linked PDD and DLB from a biologic standpoint. The DLB/PDD Working Group recommended the use of a single term and model “Lewy body disorders” (LBD), encompassing these two syndromes and nondemented PD, to study disease pathogenesis, new treatments, and bio markers [16].

Multiple system atrophy (MSA) is a rare neurodegenerative disorder that, as with DLB and PDD, is related to a disturbance of alpha‐synuclein, although, in MSA, inclusions are within glial

Table 6.1 Comparison of DLB and PDD.

Lewy body dementias (DLB/PDD) 65

DLB

Central feature

Dementia: progressive cognitive decline that interferes with social or occupational function. Prominent or persistent memory impairment may not be an early feature but is usually evident with progression. Prominent deficits on tests of attention, executive function, and visuospatial ability

Core features (two sufficient for probable, one for possible) Fluctuating cognition with variations in attention and alertness Recurrent visual hallucinations
Spontaneous parkinsonism

Suggestive features (one or more+in presence of one or more core features sufficient for probable; one or more but without any core features sufficient for possible)
REM sleep behavior disorder

Severe neuroleptic sensitivity
Low dopamine transporter uptake in the basal ganglia (SPECT and PET

imaging)

Supportive features (commonly present, but no diagnostic specificity)
Repeated falls and syncope
Transient loss of consciousness

Severe autonomic dysfunction Hallucinations in other modalities Systematized delusions Depression

Relative preservation of medial temporal lobe volume on CT/MRI Generalized low uptake on SPECT/PET perfusion scan with reduced

occipital activity
Abnormal (low uptake) MIBG myocardial scintigraphy
Prominent slow‐wave activity on EEG with temporal lobe transient

sharp waves

Less likely if

Cerebrovascular disease (focal neurologic signs or on brain imaging) Other physical illnesses or brain disorders sufficient to account for part

or total of the clinical picture
Parkinsonism appears only in severe dementia

Adapted from McKeith [3] and Emre [4].

cells, rather than neurons. An in‐depth description of MSA is outside the scope of this chapter; however, the syndrome is characterized by a combination of autonomic, parkinsonian, and cerebellar features. When parkinsonian features predomi nate, the term MSA‐P is used; when cerebellar features predom inate, the term MSA‐C is used. Dementia is infrequent and in fact is listed as a nonsupportive feature in current consensus criteria [17]. Less severe cognitive impairment is common in MSA, however, and might be intermediate in severity to that of DLB and PD patients of similar disease duration [18].

PDD

Core features (both must be present for probable diagnosis)
1. Diagnosis of PD according to Queen Square Brain Bank criteria 2. Dementia

Insidious onset and slow progression, developing after established PD Impairment in more than one cognitive domain
Decline from the premorbid level
De cits severe enough to impair daily life independent of impairment

ascribable to the motor or autonomic symptoms of PD

Associated clinical features

Cognitive features:
Attention: impairment in spontaneous and focused attention, performance

may uctuate
Executive functions: impairment in tasks requiring initiation, planning,

concept formation, rule‐ nding, set shifting, or set maintenance; impaired

mental speed (bradyphrenia)
Visuospatial function: impairment in tasks requiring visuospatial orientation,

perception, or construction
Memory: impairment in free recall of recent events or in tasks requiring

learning; memory usually improves with cueing; recognition is usually

better than free recall
Language: core functions preserved
Behavioral features:
Apathy
Changes in personality and mood
Hallucinations: mostly visual, formed visions of people and animals Delusions: usually paranoid or phantom boarder
Excessive daytime sleepiness

Less likely if (don’t exclude but diagnosis uncertain)

Coexistence of any other abnormalities which may cause cognitive impairment, but judged not to be the cause of dementia, for example, presence of relevant vascular disease in imaging

Time interval between the development of motor and cognitive symptoms is not known

Features suggesting other conditions (impossible to reliably diagnose PDD)
Cognitive and behavioral symptoms appearing solely in the context of other

conditions including systemic diseases or drug intoxication or major

depression
Features compatible with “probable vascular dementia” criteria according to

NINDS‐AIREN criteria

epidemiology

Approximately 1% of the population over 60 years old suffers from PD, increasing to 4% in older age groups, with slightly higher prevalence in men than women [19, 20]. Approximately 30% of PD patients are estimated to have dementia, which is four to six times higher than controls [21]. Longitudinal PD cohort studies suggest up to 80% of PD patients exhibit dementia before death [22]. About 15–20% of dementia cases involve DLB, whereas approximately 6% are due to PDD [23]. Monogenetic forms of LB disorders represent less than 10% of LBD cases; the

66 Non-Alzheimer’s and Atypical Dementia

majority of cases result from interactions among susceptibility genes and environmental risk factors [24]. A recent case–control study looking at 19 risk factors in 147 DLB subjects compared with cognitively normal controls, as well as an AD cohort, found that compared to controls, DLB subjects were more liked to have depression, history of anxiety, and a family history of PD and to carry ApoE4 alleles, but were less likely to have cancer or use caf feine. Compared to AD subjects, DLB subjects were more likely to be male, about 2 years younger (72.5 vs. 74.9), highly edu cated, have a family history of PD, have no ApoE4 alleles, and have had an oophorectomy before age 45 [25].

Case study

A 74‐year‐old gentleman without significant past medical his tory was referred for neurological consultation for a 2‐year his tory of difficulties concentrating. He lost track of conversations, had trouble reading, and had problems getting lost. His general intellect was intact; he reported no memory loss and had no dif ficulties with specific activities but felt he was less productive. Irritability was his only behavioral symptom. He was on no medications. Family history was notable only for a brother with PD who had a L‐DOPA‐responsive tremor.

General physical examination was normal. Neurological examination disclosed an alert, pleasant patient. His Mini‐ Mental State Examination [26] (MMSE) score was 25/30, losing 1 point for recall, 3 points for spelling WORLD backward, and 1 point for copying the pentagons. Language skills and comprehension were intact, but he had problems with atten tional tasks. Cranial nerve, motor, and gait examination was normal, with the exception of an abnormal glabellar response. Head CT and blood work for reversible causes of dementia was normal. An atypical presentation of early stage of AD was suspected, and an annual follow‐up was recommended.

One year later, he had decreased activities of daily living, sometimes requiring help in cutting his food, needing his clothes laid out for him, occasionally putting on a garment backward or inside out, and often shaving incompletely. He was occasionally visually disoriented at home and had more difficulty with rou tine tasks such as shoveling snow and piling it in illogical places. Once, he walked the dog but returned home without him. He slept more and took daytime naps. Behaviorally, he was mildly depressed, was quieter, and was having well‐formed, usually vis ual and occasionally threatening hallucinations typically involv ing people from his past. He imagined that his (deceased) brother was living with them and insisted on making plans for him to have a bedroom. He stumbled and his gait was slower. He was alert but looked “a little lost.” Vital signs, including orthostatics, and general physical examination remained normal. Neuro logically, he was pleasant and cooperative but hypophonic. His MMSE was 15/30, losing 5 points on orientation—1 for registra tion, 1 for delayed recall, 5 for spelling the WORLD backward, 1 for a 3‐step command, 1 for copying the pentagons, and 1 for repetition. Most language skills and comprehension were intact. Cranial nerve examination was remarkable only for a mild

restriction in upgaze. Motor examination revealed normal strength, bulk but increased muscle tone with mild cogwheel rigidity, and symmetrically brisk reflexes. There was no resting tremor, but a slight postural tremor. Gait testing revealed a mildly stooped posture, shuffling, and reduced stride length. Plantar responses were flexor, but marked frontal release signs developed including a suck, snout, and palmomental responses as well as bilateral grasp reflexes. Sensory examination was intact to pri mary and cortical sensory modalities. He was diagnosed with an extrapyramidal dementia of unclear etiology.

He progressed gradually and died 2 years later, 5 years after onset. His brain weight was normal (1330grams) and showed no focal atrophy with normal ventricle size. The substantia nigra and locus ceruleus were depigmented. LBs were frequent including the amygdala and the adjacent entorhinal cortex/par ahippocampal gyrus and were also present in the cingulate gyrus and lower layers of the frontal, temporal, and parietal lobe cortex. The substantia nigra and locus ceruleus showed neu ronal loss and LBs in some remaining neurons. There were no neurofibrillary tangles (NFTs), but numerous diffuse amyloid plaques were scattered in the cerebral cortex, and moderate amyloid angiopathy was seen. Although there was some Alzheimer’s pathology, as he did not have NFTs, he did not meet NIA‐Reagan or CERAD criteria for AD [27]. His final patho logical diagnosis was DLB.

DLB/PDD clinical features

Diagnostic criteria

Diagnostic criteria specific for dementia associated with PD (PDD) were proposed in 2007 by the Movement Disorder Society Task Force [4]. Diagnosis of PDD requires a dementia syndrome with insidious onset and slow progression, developing with the context of established PD (Table 6.1). The dementia must involve a decline in multiple cognitive domains severe enough to impair daily life. A probable diagnosis requires impairment in at least two of the following: attention, executive functions, visuospatial functions, or memory retrieval. Behavioral features including apathy, changes in personality and mood including depression or anxiety, hallucinations, delusions, or excessive daytime sleepi ness support the diagnosis.

Diagnostic criteria for DLB were proposed in 1996 [28] and refined in 2005 [3] by the DLB Consortium (Table 6.2).

Table 6.2 Bedside tests to evaluate cognitive features in PDD/DLB.

Attention: serial 7 s, months, or days backward
Memory: learning a word list with delayed free recall, recall versus recognition
Executive functions: verbal fluency, trail making, clock drawing Visuospatial functions: copying intersecting pentagons or
a three‐dimensional cube
Language: confrontation naming, understanding complex sentences

According to the original criteria, probable DLB is character ized by dementia associated with any two of the following three core features: (i) fluctuating cognition or level of consciousness, (ii) visual hallucinations, and (iii) spontaneous parkinsonian motor signs. The refined criteria include suggestive features: RBD, neuroleptic sensitivity, and low dopamine transporter uptake in the basal ganglia demonstrated by SPECT or PET imaging. Probable DLB can also be diagnosed if one or more of these suggestive features are present along with one or more core features. The new recommendations contain provisions for a probabilistic basis for the pathologic diagnosis of DLB based on the predominance of cortical and limbic LBs relative to the density of neurofibrillary tangles. Cases with LBs in the setting of extensive AD‐type pathology are classified as having a “low likelihood” of DLB.

Neurological exam and motor features

Motor signs in DLB and PDD include the classic triad of akine sia, rigidity, and tremor, which might be responsive to dopa mine replacement, and axial symptoms, which are considered less responsive [4]. Extrapyramidal motor symptoms are pre sent in about half of DLB patients at presentation, and they eventually occur in most of the remaining patients [29]. In com parison to PD, in DLB, there usually is more axial rigidity and postural instability. Gait is disrupted earlier in DLB than PD, and falls are not uncommon. Although resting tremor is a com mon presenting symptom in PD, DLB patients more typically have an intention or position tremor, if present at all. Their rigidity might lack the classical cogwheel quality that is the hall mark of PD. The gait of DLB patients is similar to PD/PDD and includes postural instability, a stooped posture, and festination [9].

Deep tendon reflexes are generally symmetrical in DLB, and frontal release signs might include palmomental responses and a glabellar response.

In PDD, patients often present with asymmetrical resting tremor and other classical features of PD including cogwheel rigidity. Postural instability and gait disorder is associated with accelerated cognitive decline and subsequent dementia, whereas patients with tremor less commonly develop early dementia [30].

Clinical assessment of motor dysfunction is difficult when dementia is severe; however, a subscale of the Unified PD Rating Scale [31] contains five items (resting tremor, action tremor, bradykinesia, loss of facial expression, and rigidity) that can be reliably assessed independent of dementia severity.

Cognitive features

The neuropsychological phenotype of both DLB and PDD is characterized by impairments in visuospatial and executive functions and also by fluctuations in attention and arousal, with core language functions relatively preserved [32–34]. When matched for dementia severity, the cognitive profiles of PDD and DLB are similar or indistinguishable [35, 36], although some studies suggest greater attentional impairment in DLB [37]. In comparison to AD, LB dementia patients show worse visuospatial, attentional, and executive impairments, whereas AD patients show more severe memory impairment [38]. An absence of visuospatial impairment early in the course of dementia is unusual in LBD and suggests a different etiology [39]. Figure 6.1 presents an example of figure copy performance in DLB that illustrates visuospatial impairment.

PD patients do not evidence dementia at onset; there is, how ever, increasing recognition that milder cognitive impairment is

Lewy body dementias (DLB/PDD) 67

(a)

(c)

(b)

(d)

Figure 6.1 Patients were asked to copy the image exactly. Image (a) is the original figure that patients were asked to copy. Image (b) is the reproduced image from an 80‐year‐old patient with Alzheimer’s disease. Note that the patient struggles with reproducing one of the pentagons but the spatial aspects of the figure are easily identifiable. Image (c) is from a cognitively intact 82‐year‐old elderly individual. Image (d) shows an attempt by an 80‐year‐old patient with probable DLB; although cognitive symptoms were mild, he is unable to reproduce the spatial aspects of the figures.

68 Non-Alzheimer’s and Atypical Dementia

common [40]. Working memory, selective attention, inhibitory processing, cognitive flexibility, and learning are often impacted early and attributed primarily to nigrostriatal dopamine loss causing disruption of frontal‐striatal circuitry function [41], although depletion in noradrenergic and cholinergic neuro transmitter systems have also been implicated [42, 43]. The emergence of impairment on tasks with a more posterior corti cal basis (figure copy or semantic fluency) might signal the tran sition of the disease from the brainstem to the neocortex and indicate that progression to dementia is likely [44].

Bedside cognitive testing is useful to gauge the severity of cognitive impairment and its response to cholinesterase inhibi tors, to diagnose cognitive impairment in PD, and to differenti ate DLB from other diseases. The MMSE [26] is not sensitive to LBD because it emphasizes language and memory over execu tive function and visuospatial skills [45]. The Montreal Cognitive Assessment (MoCA; http://www.mocatest.org) is more sen sitive to LBD; the recommended cutoff for dementia in PD is 20/30 [46]. Suggested methods for brief assessment are listed in Table 6.2. Patients exhibiting cognitive impairment on a brief exam might require more detailed neurocognitive testing.

Neuropsychiatric features

Neuropsychiatric disturbances are common in LBD and con tribute to reduced quality of life [47], caregiver distress [48], and increased risk for nursing home admission [49]. In a study of 537 patients with PDD using the Neuropsychiatric Inventory (NPI), the most common symptoms were depression (58%), apathy (54%), anxiety (49%), and hallucinations (44%).

Depression is more common in LB dementias than in AD [50] and equally common in PD, PDD, and DLB [5]. Depression is listed as a supportive feature in DLB criteria [3]. Anxiety often predates PD by many years [51]. Panic disorder, generalized anxiety disorder, and social phobia are prevalent, and depres sion is often comorbid [52]. Apathy is common in PD and DLB and is associated with cognitive decline [53, 54]. The patho physiology of depression, anxiety, and apathy in LB dementia might involve reductions in dopamine, noradrenaline, and sero tonin [55–58], and depression has been associated with LBs in the amygdala [59].

Although depression, anxiety, and apathy are frequent in other dementias, visual hallucinations are more specific to LBD [60]. Hallucinations occur in 45–65% of PD and 60–80% of DLB patients, with much lower rates in early AD (4–8%) [4]. In patients with PDD or DLB and hallucinations, most experi enced daily complex hallucinations (i.e., people or animals) [61]. Auditory and tactile hallucinations less commonly occur. Hallucinations in DLB are associated with LBs in the temporal cortex [62] and with hypoperfusion on single‐photon emission tomography in the left ventral occipital gyrus and bilateral pari etal areas [63]. Hallucinations are associated with cholinergic deficits [64] and often respond to cholinesterase inhibitors.

Delusions are also common in LB dementia. Capgras syn drome, for example, is characterized by the delusional belief

that a person, usually someone who is closely related, has been replaced by an imposter. For example, a patient might say “she looks like my wife, but she is not my wife.” When occurring early, Capgras syndrome is suggestive of LB dementia; how ever, it also occurs in late‐stage AD. In a study of 47 patients with Capgras syndrome, 38 were clinically diagnosed with a neurodegenerative disease, and of those, 26 had LBD, whereas only 7 had AD (only two subjects were pathology proven, however) [65].

Preclinical symptoms

Recognition of premotor and predementia phases of LBD, which might span 20 years or more, is guiding the search for predictive biomarkers as well as risk factors. RBD is a common early feature of synucleinopathies and has been estimated to precede PD and DLB by a decade on average [66–68], with some patients showing clear RBD up to 50 years before LBD has clini cally manifested [69]. Infrequent bowel movements were associ ated with the development of PD, with a mean 10‐year latency [70], and in a large aging cohort without PD or dementia, infre quent bowel movements were associated with a fourfold risk of incidental LBs at autopsy [71]. Psychiatric symptoms (especially anxiety) might also predate PD [51, 72, 73]. High scores on the composite neuroticism scale of the Minnesota Multiphasic Personality Inventory also predict PD even when administered at ages 20–39 years [73].

Comorbidities

Parasomnias help to distinguish DLB/PDD from nonsynucle inopathies. The most striking is RBD, in which patients act out dreams during REM sleep. Loss of muscle atonia during REM sleep leads to violent vocalizations and thrashing. Individuals diagnosed with RBD have been estimated to have a 41% risk of developing a neurodegenerative disease in 10 years [68], and the presence of RBD in a patient with suspected neurodegenerative disease supports the diagnosis of a synucleinopathy [66]. Considering its specificity for LBD, physicians should be encouraged to ask about RBD during the initial history taking in any dementia patient [74]. Diagnosis can be confirmed by poly somnography [75]. Other sleep disorders in DLB, PDD, and PD include insomnia, sleep apnea, excessive daytime fatigue, and restless legs syndrome [76]. Treating these disorders can improve quality of life. Clonazepam or melatonin at bedtime is often used as first‐line treatment [77].

Another supportive feature of DLB that is uncommon in other dementias is neuroleptic hypersensitivity, which involves an acute worsening of rigidity, psychosis, confusion, and impaired consciousness, following neuroleptic use [8, 78]. This occurs in DLB and PDD and might be life threatening.

Other comorbidities suggestive of DLB/PDD include auto nomic symptoms such as orthostatic hypotension, constipa tion, incontinence, and impotence, which are less common in early AD. Falls, syncope, and transient losses of consciousness also occur.

atypical presentations

When patients present with classical features of LBD, diagnostic specificity is high. Unfortunately, atypical presentations are common [79, 80]. Concurrent pathology (especially neurofi brillary tangles) impacts the symptoms and signs, leading to an amnestic/Alzheimer‐like phenotype. The more plentiful the tau pathology in DLB, the more clinical features mimic AD [81]. The issue of overlap pathology is challenging but needs to be dealt with as over 75% of DLB patients have concurrent pathol ogy. Vascular pathology is common in LBD and might contrib ute to cognitive decline and the severity of motor symptoms [82, 83]. Lastly, in advanced disease, the clinical (cognitive and motor) features of all dementias merge, and diagnosis is almost impossible based on physical examination [84].

Differential diagnosis

Differentiation of DLB from PDD is made on temporal infor mation alone (i.e., cognitive decline within 1 year of motor symptoms is called DLB, otherwise PDD); however, no biologi cally defined differences reliably differentiate these conditions, and treatment is similar.

When cognitive symptoms predominate, differentiation from AD is important. Early memory loss is milder early in the course of DLB and PDD. Attention and alertness fluctuate frequently in DLB, and family members might note that the patient’s cogni tion fluctuates significantly both within and across days, often irrespective of medications or environment, while in AD, cogni tive impairment tends to be more chronic and exacerbated under conditions of increased cognitive demand. Daytime drowsiness, excessive daytime naps, prolonged staring into space, and disorganized speech are also more suggestive of DLB than AD [85].

Employment of standardized criteria for DLB, PDD, and other degenerative conditions will help the physician exclude other dementia diagnoses (Tables 6.1 and 6.3), including pro gressive supranuclear palsy, MSA, Creutzfeldt–Jakob disease, and corticobasal syndrome (CBS). Patients with cerebrovascu lar disease often have extrapyramidal features when ischemic changes involve subcortical regions. Medication effects, tumors, and normal pressure hydrocephalus also might mimic LBD. When the diagnosis remains unclear, functional imaging or cer ebrospinal fluid (CSF) studies (for beta‐amyloid and tau for AD diagnosis) might be of benefit.

Neuroimaging findings

Structural neuroimaging can rule out other diagnoses, but gross structural brain changes in DLB, PD and PDD are nonspecific, so they are of limited diagnostic use [86]. Greater atrophy in the medial temporal lobe occurs in AD [87], whereas putaminal atrophy is sometimes useful to support DLB versus AD [88].

Lewy body dementias (DLB/PDD) 69 Table 6.3 Differential diagnosis of DLB/PDD.

Etiology

Degenerative

Progressive supranuclear palsy

Corticobasal syndrome

Multiple system atrophy

Frontotemporal dementia with parkinsonism

Prion diseases

Secondary parkinsonian syndromes

Vascular parkinsonism

Normal pressure hydrocephalus

Drug/medication induced

Infectious

Structural brain lesions (tumor, trauma)

Distinguishing features

Gait disorder with postural instability; often presents with falls; supranuclear gaze palsy (vertical), poor bulbar control
Alien limb phenomenon, limb apraxia, complex tremor, cortical sensory loss, dystonic features, myoclonus, aphasia
Early autonomic dysfunction; ataxia; cerebellar signs; early speech changes and falls; usually minimal to response to levodopa, and if there is response, it is not sustained
Often early onset; sometimes autosomal dominant inheritance; cognitive profile might show progressive aphasia and deterioration of demeanor in addition to attentional and executive losses
Rapid progression with dementia and ataxia; DWI/ADC brain MRI with cortical ribboning and/or hyperintense deep nuclei

Abrupt onset, stepwise progression (but don’t often occur); vascular risk factors; subcortical infarcts or white matter lesions on MRI, particularly in the brainstem

Classically triad of cognitive impairment, gait apraxia, and urinary incontinence; subacute onset; should have risk factors for hydrocephalus (e.g., prior head trauma, CNS infection or bleed); CT or MRI show enlarged ventricles (out of proportion to cortical tissue loss), transependymal CSF flow
Relevant drug exposure (e.g., dopamine receptor blockers, reserpine, lithium, tetrabenazine, MPTP, carbon monoxide, manganese, mercury, others); often symmetrical, may improve when exposure is eliminated Postencephalitic parkinsonism, neurocysticercosis, syphilis, HIV encephalitis, Whipple’s disease
Focal symptoms and signs; abnormal neuroimaging studies

Presynaptic dopaminergic terminal loss is present in LBD, so functional dopamine transporter imaging often helps distin guish DLB from dementias where the nigrostriatal system remains intact [89]; however, it cannot distinguish DLB from vascular dementia, MSA, and progressive supranuclear palsy because the nigrostriatal tracts might be disrupted.

70 Non-Alzheimer’s and Atypical Dementia Laboratory findings

At present, there is no blood, CSF, or urine test that can establish the diagnosis of DLB or PDD. Routine blood work to assess the patient for B12 deficiency, neurosyphilis, vasculitis, endocrine dysfunction, vitamin deficiency, and organ failure should be done on all patients to rule out medical conditions that cause problems with movement or cognition. Vascular risk factors should be reviewed, and effort should be made to maximize medical management of all vascular risks. CSF studies for beta‐ amyloid and tau might help establish a diagnosis of AD and pre dict cognitive decline in patients with PD [90], but CSF alpha‐synuclein assessments are not currently commercially available.

Pathophysiology and pathology

Neuropathology

The pathological inclusion diagnostic of DLB and PDD is the LB (see Figure 6.2). LBs are round, cytoplasmic inclusions. Nigral LBs, present in all LB disorders, have a distinctive clear halo. Cortical LBs are present in limbic and/or neocortical

(a) (b)

(c) (d)

regions in DLB and are often observed in smaller numbers in PD and PDD. They might compress the nuclei; however, they lack the halo of nigral LBs, and so diagnosis requires a keen, experienced eye. Immunohistochemical stains to ubiquitin and alpha‐synuclein facilitate diagnosis.

Both nigral and cortical LBs are composed of filamentous forms of alpha‐synuclein and ubiquitin fibers. In the substantia nigra, the halo consists of alpha‐synuclein, and the core is com posed of other neurofilaments. Cortical LBs stain diffusely for alpha‐synuclein and ubiquitin. In addition, thinner, elongate alpha‐synuclein aggregates occur in presynaptic terminals (Lewy neurites). Lewy neurites are coupled with the loss of the corresponding (postsynaptic dendritic) spines [91]. The com position of alpha‐synuclein epitopes in LBs and Lewy neurites are indistinguishable in DLB and PDD [92].

The regional distribution of LBs differs between PDD and DLB with greater nigral neuronal loss in PDD than DLB and more alpha‐synuclein pathology in the striatum and cortex in DLB [93]. Although LB burden is only a weak correlate of dis ease severity [94, 95], the regional distribution of pathology might influence neurological features.

Beta‐amyloid plaques are evident in most DLB patients [96, 97]. In PDD, neocortical plaques are less common and most

Figure 6.2 High magnification neuropathology from a DLB case. Cortical (a) and nigral (c) LBs after staining with hematoxylin and eosin. Note that cortical LBs are smaller and lack the halo that typifies LBs within the substantia nigra. Images (b) and (d) are taken after immunostaining DLB tissue with antibodies against alpha‐synuclein. Cortical (b) and nigral LBs (d) both stand out. The entire inclusion stains in the cortex, but only the halo in the substantia nigra contains alpha‐synuclein. Arrows point to the LBs in all images. All images at 60× magnification. Scale bar is 30 μm. (See insert for color representation of the figure.)

often seen in those with early dementia [95]. The greater the neuritic pathology, the more the DLB patient resembles AD clin ically [81]. Additionally, beta‐amyloid plaques and tau aggre gates are associated with LB formation in the amygdala [98].

Pathology of case 1

The pathology of case 1 demonstrates some of the points described earlier. Case 1 had pure DLB and a normal brain size with no atrophy of the hippocampus, parahippocampal gyrus, amygdala, or cortex. Brain size and medial temporal lobe struc tures might be normal in DLB. The more severe the AD pathol ogy, the smaller the volume of the hippocampal complex [99]. Although the number of LBs correlates poorly with the degree of dementia [100], the occurrence of widespread LBs differenti ates LBD from the other dementia subtypes. Those with nigral, limbic, or neocortical LBs are more likely to have symptoms ref erable to motor, behavioral/psychiatric, or cognitive issues, respectively. Case 1 had symptoms related to all three spheres and had LBs in neocortical, limbic, and nigral areas. Cortical LBs account for his disorganization and executive dysfunction (frontal) and visuospatial impairment (temporo‐ and parieto‐ occipital). The visual hallucinations correspond to his LBs in lateral/posterior temporal lobe and parieto‐occipital areas. His mood changes and psychotic symptoms are consistent with his limbic LBs. The substantia nigra was depigmented (with neu ronal dropout), and it showed neuronal loss with classical LBs in remaining neurons, explaining his parkinsonism. The absence of tau aggregates and vascular pathology correlates with his typical DLB phenotype.

Genetic issues and risks

Although PD and its associated dementias are usually sporadic in origin, 5–10% of the patients have monogenic forms of the disease. These cases are more typically early onset and are asso ciated with LRRK2, SNCA, or GBA genes [101]. Tau and pro granulin mutations (chromosome 17) cause frontotemporal dementia but sometimes have clinical features that overlap with DLB or PDD [102]. The majority of patients with early‐onset autosomal dominant forms of AD and half of the elderly indi viduals with trisomy 21 (Down’s syndrome) have LBs and might show extrapyramidal features [103, 104].

The basic pathogenic mechanism underlying LB formation seems to be similar in cases with sporadic and genetic etiologies. The situation is complicated, however, because some patients meeting clinical criteria for DLB do not have LBs or abnormali ties of alpha‐synuclein. For example, LRRK2 abnormalities are sometimes associated with LBs, but other times they are associ ated with tau or ubiquitin pathology [105].

Biochemistry

Alpha‐synuclein is the hallmark pathological protein in the LB disorders. Ubiquitin is also present in LBs, but it also is seen in other pathological inclusions. Normally, alpha‐synuclein is expressed widely in the CNS and in presynaptic nerve terminals.

In LBs, alpha‐synuclein aggregates into insoluble fibrils. Epitope mapping studies of alpha‐synuclein in PD and DLB synucle inopathies show comparable profiles [106].

Over the past few years, it has become increasingly recog nized that alpha‐synuclein can act in a prion‐like manner, spreading from cell to cell in vitro and in vivo, which might help explain the spread of neurodegeneration in the brains of patients with synucleinopathies [107–110]. Some of the earliest indica tions of the potential spread of alpha‐synuclein were discovered in some patients with PD whom had undergone therapeutic fetal tissue transplants; at autopsy, 11–16 years after the trans plant, the fetal neurons had alpha‐synuclein deposits, suggest ing that β‐sheet‐rich alpha‐synuclein prions propagated from the host neurons into the transplanted fetal cells and induced a change in the structure of α‐synuclein and the formation of LBs [111–113]. This led to an explosion of research investigating the potential spread of alpha‐synuclein. In one paper, the Trojanowski and Lee laboratories showed that pathological alpha‐synuclein derived from animals or entirely synthetic alpha‐synuclein preformed fibrils (PFFs) when injected into mice overexpressing alpha‐synuclein greatly accelerated the for mation and propagation of pathological inclusions throughout the mouse nervous system that were highly reminiscent of LBs and Lewy neurites [114]. In a follow‐up paper, they showed that a single injection of synthetic alpha‐synuclein fibrils into the striatum of wild‐type nontransgenic mice caused cell‐to‐cell transmission of pathological alpha‐synuclein and Parkinson’s‐ like Lewy pathology in regions connected anatomically, leading to a disease reminiscent of PD [115]. Thus, there is now a growing body of evidence suggesting that pathological alpha‐synuclein can act in a prion‐like manner, spreading from cell‐to‐cell and inducing the formation of normal alpha‐synuclein into a mis folded, pathologic form [116]. This helps explain the mecha nism of spread of pathological alpha‐synuclein in the brain of PD, PDD, and DLB described by Heiko Braak and colleagues more than a decade ago [117].

Biomarkers

Effective diagnostic biomarkers for DLB/PDD do not currently exist, but are needed to improve differential diagnosis when symptoms are atypical (Table 6.3). Biomarkers are also needed to prognosticate, follow progression, and monitor response an individual’s response to treatment.

In addition to traditional PET scans, which might help to dis tinguish AD from DLB (greater occipital hypoperfusion in DLB), imaging with Pittsburgh compound B (PIB) might help determine beta‐amyloid burden in PDD and DLB [118, 119]. Beta‐amyloid occurs commonly in both conditions, but the bur den is greater in DLB [97]. Cortical cholinergic deficits are more severe in DLB and PDD than other dementias, and thus PET tracers specific for cholinergic function might prove to be useful biomarkers [120, 121]. Dopamine transporter imaging (of stri atal nerve terminals) can also discriminate PDD and DLB from AD, but not always from vascular dementia [122].

Lewy body dementias (DLB/PDD) 71

72 Non-Alzheimer’s and Atypical Dementia

CSF biomarkers are commercially available for AD, but there is need for specific alpha‐synuclein (LB) biomarkers. Serum alpha‐synuclein oligomer assays are under investigation [123]. A SPECT or PET ligand for aggregated alpha‐synuclein would also be beneficial for diagnosis.

treatment and management

Treatment and management of LB dementia includes early diag nosis and treatment or management of cognitive impairment, psychiatric symptoms, and motor symptoms and monitoring and management of autonomic dysfunction and sleep disorders. LB dementia patients can decompensate quickly when faced with infection, metabolic stress, or changes in the environment; these risks should be closely monitored. To avoid adverse reac tions, physicians should carefully monitor medications, intro duce new medications one at a time, and prescribe minimal doses. Medications with anticholinergic effects should be avoided because they can worsen the psychiatric and cognitive syndrome. Nonpharmacological interventions, including physi cal and occupational therapy, community resources, and home care, are discussed in Chapter 15 and should be tried prior to medications when feasible. For example, psychotic symptoms can often be managed more effectively and safely by changes in the patient’s environment.

Cholinesterase inhibitors are the first‐line treatment for cog nitive impairment in LB dementias. DLB and PDD are associated with reduced acetylcholine, which contributes to the attentional and psychiatric symptoms and functional deficits [124, 125]. Several treatment studies have shown positive effects of cho linesterase inhibitors on cognitive impairment (especially atten tion and cognitive fluctuations), neuropsychiatric symptoms (especially visual hallucinations, apathy, and anxiety), sleep dis turbances, and functional domains [126–131]. DLB patients probably are the most responsive to cholinesterase inhibitors of any of the dementias. Gastrointestinal symptoms and/or vivid dreams sometimes occur. Treated patients should be monitored closely for orthostatic hypotension. Due to potential cardiac con duction blocks occurring or worsening with cholinesterase inhibitors, a baseline EKG prior to starting treatment is recom mended. Rivastigmine was approved by the US Food and Drug Administration for treating PDD in 2006. Memantine, an NMDA antagonist, is well tolerated, but its efficacy for cognitive impair ment in PDD and DLB is not clear [132, 133].

Dopaminergic therapy is the mainstay for extrapyramidal symptom treatment in LBD. Clinicians should aim for the low est acceptable dose of levodopa monotherapy to avoid exacer bating psychiatric symptoms and causing delirium [129]; in our experience, DLB patients often respond to carbidopa/levodopa doses in the range of 25/100mg three times per day or less. Levodopa responsiveness in DLB and PDD has not been exten sively studied, but the improvement of symptoms is generally considered to be less than that seen in uncomplicated PD

possibly due to greater intrinsic striatal degeneration [93] and motor symptoms without dopaminergic origin.

Depression and anxiety are common in LBD and can be treated with SSRIs or SNRIs. Tricyclics are also effective but can cause orthostatic hypotension, sedation, and cognitive impair ment. If treatment is required for RBD, clonazepam, melatonin, or low‐dose quetiapine can be tried. For psychotic symptoms, atypical antipsychotic medications must be used cautiously due to the risk of motor and cognitive side effects [78]; consider using atypicals, such as quetiapine, with less extrapyramidal side effects. Traditional neuroleptics should be avoided due to the high rates of neuroleptic hypersensitivity reactions in these patients [8].

For a nice review on pharmacological and nonpharmacologi cal management of DLB, see the article by Boot et al. [134]. The melatonin agonist ramelteon, used to treat sleep disturbances, has been found in a small DLB case series to reduce visual hal lucinations, excessive daytime sleepiness, and even RBD [135].

The symptomatic treatments available do not modify the dis ease course. The current search for disease‐modifying drugs is focused primarily on preventing alpha‐synuclein misfolding and fibril formation and aggregation [16, 136].

Summary

DLB and PDD are particularly challenging disorders to diag nose and treat because of the complexity of cognitive, behavio ral, and motor features involved and because of the frequent presence of overlapping pathology complicating the presenta tion. Diagnostic criteria identify LB dementia patients when presentations are typical. Better biomarkers are needed to clar ify the primary diagnosis when symptoms are not clear‐cut. Several symptomatic treatments are available. There is need for disease‐modifying agents. Agents that impact the aggregation of alpha‐synuclein hold particular promise as future agents for early intervention.

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CHaPtEr 7

Corticobasal degeneration and progressive supranuclear palsy

Suzee E. Lee and Bruce L. Miller

University of California, San Francisco, San Francisco, CA, USA

History and nomenclature

Corticobasal degeneration

In 1968, Rebeiz and colleagues first described three patients with a progressive movement disorder and swollen neurons with poorly staining inclusions found at autopsy, a condition they named “corticodentatonigral degeneration with neuronal achromasia” [1]. Although the authors noted neuropathologi cal overlap with Pick’s disease, they believed that the clinical features of these patients were inconsistent with Pick’s. Subsequent groups emphasized motor features of the disease, including focal reflex myoclonus, alien limb phenomena, apraxia, rigidity and akinesia, postural–action tremor, limb dys tonia, hyperreflexia, and postural instability [2, 3]. Other researchers classified these patients as a subtype of Pick’s dis ease, emphasizing behavioral and cognitive symptoms in addi tion to extrapyramidal features of the condition [4]. Over time, this disorder came to be known as corticobasal degeneration. Neuronal aggregates in CBD were shown to consist of the microtubule‐associated protein tau (MAPT) [5], drawing links to other tau‐associated disorders, including PSP, progressive aphasia [6], and Pick’s disease [7].

Progressive supranuclear palsy

In 1964, Richardson, Olszewski, and Steele observed a syndrome of postural instability, supranuclear gaze palsy with prominent downgaze difficulty, spastic facies, axial rigidity, and dementia with personality changes [9]. Neuropathological studies revealed “cell loss, gliosis, neurofibrillary tangles, granulovacu olar degeneration and demyelination in various regions of the basal ganglia, brainstem and cerebellum”; these pathological changes bore a striking resemblance to postencephalitic parkin sonism and the parkinsonism–dementia complex of Guam [9].

Subsequent studies confirmed the consistency of clinical findings [10, 11], and clinical consensus criteria for PSP were established in 1996 (Table 7.1) [12]. Neuronal aggregates found in PSP consist of tau protein [13], linking PSP to other tau disorders.

Autopsy series highlight the clinical heterogeneity of CBD and PSP. Thus, the terms corticobasal syndrome [14] and progressive supranuclear palsy syndrome distinguish the clinically defined syndrome from the pathological entities, CBDandPSP.Fortheremainderofthischapter,wewilluse the terms CBD and PSP to refer to pathologically defined dis eases and CBS and PSP syndrome to refer to the clinically defined syndromes.

Epidemiology

Typically, symptoms in pathologically proven CBD emerge between the sixth and eighth decades of life [15]. To our knowledge, the youngest patient with pathologically con firmed CBD had symptom onset at age 45 [15]. Both women and men are affected with some studies citing higher rates in women [16]. To date, there have been no population‐based studies of CBD, and CBD is regarded as a rare neurodegen erative disorder, although studies have estimated of 4.9 cases per 100000 people in the United States [17] and 1.7 per 100 000 in Japan [18a]. Mean age at onset in a series of 267 patientswithCBDwas64yearswithadiseasedurationof 6.6 years [18b].

A study from the United Kingdom found that an age‐adjusted prevalence of PSP is approximately 5 per 100000 [19, 20]. Men appear to have a slightly higher incidence of PSP. A study in the United States showed an average annual incidence rate of

78 Non-Alzheimer’s and Atypical Dementia Table 7.1 NINDS–SPSP clinical criteria for PSP (1996).

I. Mandatory inclusion criteria A. PSP possible

1. Gradually progressive disorder

2. Onset at age 40 or later

3. Either vertical (upward or downward gaze) supranuclear palsy or
both slowing of vertical saccades and prominent postural
instability with falls in the first year of disease onset

4. No evidence of other diseases that could explain the foregoing
features, as indicated by mandatory exclusion criteria

B. PSP probable

1. Gradually progressive disorder

2. Onset at age 40 or later

3. Vertical(upwardordownwardgaze)supranuclearpalsyandprominent
postural instability with falls in the first year of disease onset

4. No evidence of other diseases that could explain the foregoing
features, as indicated by mandatory exclusion criteria

C. Definite

1. Clinically probable or possible PSP and histopathologic evidence of typical PSP

II. Mandatory exclusion criteria

A. Recent history of encephalitis

B. Alien limb syndrome, cortical sensory deficits, focal frontal, or
temporoparietal atrophy

C. Hallucinations or delusions unrelated to dopaminergic therapy

D. Cortical dementia of Alzheimer’s type (severe amnesia and aphasia or
agnosia, according to NINCDS‐ADRA criteria)

E. Prominent, early cerebellar symptoms or prominent, early unexplained
dysautonomia (marked hypotension and urinary disturbances)

F. Severe, asymmetric parkinsonian signs (i.e., bradykinesia)

G. Neuroradiologic evidence of relevant structural abnormality (i.e., basal
ganglia or brainstem infarcts, lobar atrophy)

H. Whipple’s disease, confirmed by polymerase chain reaction, if indicated

III. Supportive criteria

A. Symmetric akinesia or rigidity, proximal more than distal

B. Abnormal neck posture, especially retrocollis

C. Poor or absent response of parkinsonism to levodopa therapy

D. Early dysphagia and dysarthria

E. Early onset of cognitive impairment including at least two of the
following: apathy, impairment in abstract thought, decreased verbal fluency, utilization or imitation behavior, or frontal release signs

5.3 per 100 000 person‐years, and incidence was higher in men than women [21]. Most patients with PSP are affected in the sixth decade of life, with ages of presentation ranging from the 50s to the 60s [22, 23].

Studies of the MAPT gene (MAPT) reveal overrepresentation of the H1 MAPT haplotype in both CBD and PSP [24, 25]. Association between the H1/H1 genotypes also occurs with FTD [26, 27] and primary progressive aphasia [28]. H1/H1 is the common genotype found with near 100% prevalence in Japanese and approximately 70% in Caucasians [29, 30]. In one cohort of 64 Caucasian patients with PSP, the prevalence of the H1 haplotype was greater than 90%, with 87.5% H1/H1 and 12.5% H1/H2 [24].

Clinical features of corticobasal syndrome

In the 1980s, clinicians in the movement disorder community suggested that CBD was a progressive neurodegenerative condition characterized by asymmetric parkinsonism, apraxia, myoclonus, dystonia, and alien limb syndrome [1–3]. Clinico pathological studies eventually demonstrated that the CBS clinical syndrome poorly predicts CBD pathology [14]. Despite CBD’s initial characterization as a movement disor der, CBD also manifests frontal lobe degeneration presenting with cognitive and behavioral symptoms [8, 31], with motor symptoms sometimes emerging only during advanced disease stages [8, 32–35]. Thus, the absence of early motor findings does not exclude CBD from the picture. Moreover, features of bvFTD, nfvPPA, and CBS may overlap or evolve within indi vidual patients throughout the disease course [33, 36]. The three main clinical presentations of CBD include a motor syndrome with prominent, early executive dysfunction, nfvPPA, and bvFTD [8]. Case studies are presented below as examples.

Case 1 Executive–motor syndrome

A 68‐year‐old right‐handed woman started having difficulty with balance 4 years prior to presentation. Initially, she tripped on uneven ground, usually with her right foot, although her leg was not weak. Three years before presentation, she noted trouble with organizing and multitasking; memory seemed intact. She noted progressive difficulty controlling her right leg. Once, she tried to step over her grandchild’s toy on the ground, but her right leg remained in the air, and she could not put it down. When seated, she noticed difficulty crossing her right leg over her left. She gradually lost dexterity of her right hand, and her handwriting deterio- rated. About 1 year ago, her right forearm moved suddenly and uncontrollably, knocking over a vase of flowers. Her gait slowed. Six months before presentation, she developed increasing apathy and social withdrawal, slowing losing interest in her grandchildren and ending most of her social relationships.

On exam, affect was sad and facies were masked. On primary gaze, there were no square wave jerks. Saccadic eye movement testing showed

increased latency to initiating saccadic eye movements in all directions, with normal velocity and full excursion of extraocular movements. There was moderate cogwheel rigidity in the upper extremities, more prominent on the right, and hypertonia in the right lower extremity. Mild axial rigidity was present. Strength was full. A mild, high‐frequency bilateral postural hand tremor was present, more prominent on the right. There was no rest tremor. Deep tendon reflexes were symmetric and 2+; plantar response was flexor bilaterally. Sensory exam was intact. Gait revealed diminished arm swing, worse on the right, with mild shuffling and difficulty with turns. She intermittently held her right arm in a flexed posture.

Neuropsychological testing revealed significant deficits in executive function, particularly with verbal fluencies and set‐shifting. Mild deficits in naming and episodic memory were noted. Visuospatial skills were intact. A brain MRI revealed focal atrophy in dorsomedial frontal cortex and insula and bilateral primary motor cortices (see Figure 7.1).

In subsequent evaluations, her gait grew progressively worse, and her memory deteriorated. She developed retrocollis, and severe appendicular rigidity ensued. She had trouble with swallowing and began to choke,

particularly when drinking liquids. She grew nonverbal but remained cooperative on examination. She died 5 years after symptom onset. Autopsy showed CBD.

As described in the case above, the executive–motor syndrome presents with extrapyramidal syndromes including axial or appendicular rigidity,

dystonia, and progressive loss of limb function, findings classically associated with CBS. Poor performance on executive function measures occurs early during the disease course. Perirolandic, supplementary motor area, striatal and insular atrophy are associated with the executive–motor syndrome [8].

Figure 7.1 Brain MRI in executive–motor CBD. T1‐weighted brain MRI of a 68‐year‐old right‐handed woman with pathological‐proven CBD with an executive–motor syndrome. Sagittal MRI (left) shows dorsolateral frontal atrophy, and axial MRI (right) shows bilateral parietal atrophy, particularly in the primary motor cortex. Orientation is radiological (left is right).

Case 2 Nonfluent variant primary progressive aphasia

A 54‐year‐old right‐handed woman first noted difficulty with speaking 3 years prior to evaluation. Initially, she had trouble finding words in conversation, and pauses in her speech evolved into stuttering. Even though she knew what she wanted to say, her speech grew slow and effortful. Her speech was slurred; she made frequent phonemic paraphasic errors, and she occasionally stressed the wrong syllable in pronouncing words. Her speech grew agrammatical and she tended to omit articles and conjunctions. She had no difficulty with comprehension, reading, or spelling. About 1 year prior to evaluation, behavioral symptoms emerged. She compulsively arranged the books on her coffee table with the edges aligned. She also took food from her family members’ plates without permission. Six months prior, she developed difficulty using her right hand and began to use her left hand to pick up objects. Her right arm appeared stiff, and she frequently held it fixed at her side.

On exam, she was cooperative. Speech was effortful, dysarthric, and agrammatical. Apraxia of speech and orobuccal apraxia were noted, but limb apraxia was absent. There were no square wave jerks and saccadic eye movements were normal. There was mild cogwheel rigidity in the right upper extremity, but no axial rigidity. Strength was full. A mild, high‐frequency postural right‐hand tremor was present. Deep tendon reflexes were symmetric and 2+; plantar response was flexor bilaterally. Sensory exam was normal. Gait revealed diminished arm swing on the right with normal stride and turns.

Neuropsychological testing revealed significant deficits in language testing, including naming and repetition. Verbal memory and executive function were impaired, but the prominence of her language impairments rendered the interpretation of other cognitive testing less clear. Visuospatial skills were intact. A brain MRI revealed severe focal left insular and left inferior frontal gyrus atrophy with mild atrophy in bilateral orbitofrontal cortex and medial frontal regions (see Figure 7.2).

Figure 7.2 Brain MRI in nonfluent variant primary progressive aphasia secondary to CBD. Coronal T1‐weighted brain MRI of a 54‐year‐old right‐handed woman showing severe focal left insular and left inferior frontal gyrus atrophy with mild atrophy in bilateral orbitofrontal cortex and medial frontal regions. Orientation is radiological.

80 Non-Alzheimer’s and Atypical Dementia

Over the next few years, she developed severe right‐sided rigidity and grew mute. She had involuntary movements in her right hand
and foot, which also intermittently assumed dystonic postures, and eventually had trouble using utensils in her left hand. On exam, her eye movements were extremely limited, and she had right‐sided visual neglect. She died 7 years after symptom onset; at autopsy, she was diagnosed with CBD.

Features of nfvPPA include agrammatism with effortful, halting speech and impaired comprehension of syntactically complicated sentences, with spared single‐word comprehension and object knowledge [37]. Left frontoinsular atrophy on MRI or hypometabolism on PET might be observed. Some studies suggest that nfvPPA correlates most strongly with FTLD‐tau within the FTLD spectrum [8, 38–40] although FTLD‐TDP pathology [8, 41] has also been found underlying nfvPPA.

Case 3 Behavioral variant frontotemporal dementia

A 64‐year‐old gentleman began to develop personality changes 7 years prior to evaluation. He developed a newfound interest in painting, and began to wear bizarre, brightly colored outfits. Over the next several years, his obsession with painting burgeoned, and he created hundreds of pieces of art. He also became less risk‐averse. Previously conservative with money, he developed an interest in gambling, both winning and losing large amounts of money in casinos. He became a “born‐again” Christian 5 years prior to evaluation and began praying several times a day. He was evaluated by a psychiatrist who diagnosed him with depression and started an SSRI, which did not significantly alleviate his symptoms.

Four years after his personality changes began, he developed short‐term memory difficulty. Word‐finding difficulties emerged and he spoke less. He grew emotionally blunted and withdrawn. In the few months prior to evaluation, his family noted that his gait grew slower and that he had a hand tremor.

On exam, he remained quiet and had a flat affect. Speech was clear and grammatical, but he spoke only in short phrases. Cranial nerve, motor, reflex, and sensory examination appeared normal. Gait exam revealed diminished right arm swing with normal stride and turns.

Neuropsychological testing revealed significant deficits in memory, language, and executive function. Visuospatial skills were intact. A brain MRI revealed bilateral frontoinsular and dorsomedial frontal and dorsolateral prefrontal atrophy, more prominent on the right (see
Figure 7.3).

In follow‐up evaluations, his postural hand tremor worsened. When walking, he developed dystonic posturing of his right arm. He stopped initiating conversations and needed to be monitored and encouraged to perform basic activities of daily living, such as toileting and grooming. His speech grew sparser and he answered questions with single words. He died 12 years after his initial symptoms of personality changes. Autopsy revealed CBD.

The earliest and more salient features of behavioral variant frontotempo- ral dementia (bvFTD) include changes in behavior and personality [42]. bvFTD clinical criteria include early behavioral disinhibition, apathy or inertia, and loss of sympathy or empathy, compulsive behaviors ranging

Figure 7.3 Brain MRI in behavioral variant frontotemporal dementia secondary to CBD. Coronal T1‐weighted brain MRI in a 64‐year‐old gentleman showing bilateral frontoinsular, dorsomedial frontal, and dorsolateral prefrontal atrophy. Orientation is radiological.

from simple repetitive movements to complex, ritualistic behaviors, and hyperorality or dietary changes, such as altered food preferences, binge eating or drinking alcohol, and placing inedible objects in the mouth. Often, behavioral changes are misdiagnosed as psychiatric disease early in the disease course. Typically, visuospatial skills and memory are spared early in bvFTD. Frontal and temporal brain atrophy on MRI brain or hypometabo- lism on PET scans emerges.

Correlation between CBS and CBD

Clinicopathological correlation studies attest to the significant challenges of diagnosing CBD. Autopsy studies demonstrate that the sensitivities of CBS for CBD are poor ranging from 31 to 56% [8, 32, 34, 43]. The pathologies underlying CBS are pro tean and include CBD, tauopathies other than CBD (including PSP, Pick’s disease, frontotemporal dementia, and parkinson ism linked to tau mutations on chromosome 17 (FTDP‐17)),

frontotemporal lobar degeneration with TAR DNA‐binding protein‐43 (TDP‐43) immunoreactive inclusions (FTLD‐ TDP), Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and Creutzfeldt–Jakob disease [38–40, 43–46]. Recent autopsy series have shown that underlying CBD pathology is found in only 35–55% of all patients who present with CBS during life [8, 38, 40, 44, 47, 48]. PSP pathology commonly manifests as CBS with one study citing nearly 50% of 21 CBS patients with PSP at autopsy [40].

Conversely, many patients with autopsy‐confirmed CBD are not suspected of having the disease during life [38, 44, 47, 49, 50]. As described previously, the clinical presentations of CBD are heterogeneous and include bvFTD, nfvPPA, PSP syndrome, Parkinson’s disease (PD), AD, and occasionally posterior cortical atrophy (PCA) [8, 40, 49, 51, 52], rendering diagnosis challeng ing. Based on 267 pathologically confirmed CBD cases, new cri teria for possible and probable CBD have been established [18b]. These 2013 criteria for possible CBD include insidious onset and gradual progression, with symptoms lasting at least 1 year, with one of four clinical syndromes (possible corticobasal syndrome, frontal behavioral–spatial syndrome or nonfluent/agrammatic primary progressive aphasia, PSP syndrome) with an additional feature of CBS. The more stringent criteria for probable CBD include those for possible but also require age at onset to be greater than 50 years and no family history of similar conditions or known tau mutations [18b]. Future studies are necessary to determine the sensitivity and specificity of the new CBD criteria.

Despite attempts to characterize symptoms and signs predic tive of CBD pathology, the overlap of these symptoms and signs with other neurodegenerative diseases makes pathological prediction at the bedside extremely challenging. Although cortical symptoms and signs for CBD have historically included visuospatial deficits, limb apraxia, and cortical sensory loss, these parietal lobe‐associated features are not specific for CBD pathology and are common in AD [8]. Although memory and visuospatial deficits in CBS may suggest underlying AD in group studies, it remains unclear how such deficits improve diagnosis at individual patient level [8]. Motor symptoms in CBD may be absent up to 8 years after symptom onset, and motor symptoms classically associated with CBS are not exclusive to CBD pathology, presenting in similar rates in patients with CBS with underlying AD, PSP, FTLD‐TDP, or mixed pathologies [8]. Quantitative eye movement studies of CBS suggested that saccadic eye movement latency is increased with relatively preserved velocity in CBD [53–57, 57a], although an eye movement study of autopsy‐proven CBD suggests similar saccadic latency and velocity compared with controls, but impairments on an antisaccade task [57b]. This contrasts with the saccadic eye movement changes in PSP, in which the velocity of movements are slowed with relatively preserved latency [53, 54, 57b].

Neuropsychological testing in patients with CBS shows impairments in attention, executive function, and/or language impairments, with memory relatively less affected [8, 32, 34, 50, 58–60]. Although some studies have demonstrated that poorer performance on visual and verbal memory measures suggests underlying AD pathology in CBS [8, 46], the utility of neuropsy chological testing in predicting CBD pathology remains unproven for individual patients.

Although the symptoms, signs, and neuropsychological profile described previously have been associated with CBD, they are variably present in individual patients. In patients with CBS, the presence or absence of any specific clinical sign or symptom does

not reliably predict CBD pathology [8]. Furthermore, although asymmetry has been stressed as a core feature of CBD, several studies have revealed that CBD can emerge with symmetric par kinsonism and with symmetric brain degeneration [8, 61–63].

Clinical features of progressive supranuclear palsy syndrome

Progressive supranuclear palsy was first defined as a neurode generative syndrome consisting of supranuclear vertical gaze palsy, axial dystonia with a hypererect posture, bradykinesia, rigidity, and early falls [9]. In 1996, clinical consensus criteria for PSP syndrome defined core features as a progressive course of impairment beginning after the age of 40, with supranuclear gaze palsy, slowing of vertical saccadic eye movements, and postural instability with falls in the first year of onset (Table 7.1) [12].

Case study: A 63‐year‐old man developed problems with concentration 5 years prior to evaluation. Previously excellent with multitasking, he described significant difficulty keeping track of more than one activity simultaneously. He described his thinking as slowed, although memory remained intact. He grew more outspoken, started telling his coworkers exactly what he thought of them, and became less aware of putting himself and others in uncomfortable situations. Three years prior to evalua tion, he fell when attempting to stand up from a reclining chair. His speech grew softer and slurred, particularly when he was tired. Two years prior to evaluation, he walked more slowly and he developed a shuffling gait. He fell frequently, usually when arising from sitting to standing. One fall resulted in a fractured elbow. Despite awareness of his worsening balance, he could not comply with his family’s pleas to be more cautious when walking. He described difficulty looking downward and seeing objects on the ground. Mild emotional triggers caused him to laugh and cry easily and grew more disinhibited in social situations. Previously outgoing, he became quieter and more passive. He developed urinary frequency at night with occasional urinary incontinence. A trial of levodopa/carbidopa resulted in no improvement in his symptoms.

On exam, he was cooperative. Certain topics, such as his favorite sports team and his dog, invariably provoked uncontrol lable laughter, even when the topics were not amusing to him. Speech was mildly dysarthric and aprosodic. He had masked facies and the procerus sign was present. There were square wave jerks in primary gaze. Vertical saccadic velocity was reduced, with downgaze more affected than upgaze; horizontal saccades appeared normal. Downgaze excursion was limited by about 50%.Severeaxialrigidityandmildsymmetricrigidityappeared in all limbs. Tremor and dysmetria were absent. Repetitive finger, hand, and foot movements were diminutive. Deep tendon reflexes were 2+ in the extremities, and plantar responses were flexor. Sensory exam appeared normal. Gait examination showed diminished left arm swing; a rigid, hypererect posture; and mild

Corticobasal degeneration and progressive supranuclear palsy 81

82 Non-Alzheimer’s and Atypical Dementia

retropulsive instability. Neuropsychological testing revealed deficits only in executive function and indicated that his responses were error prone and impulsive. Memory, language, and visuospatial skills were intact. An MRI brain revealed mild midbrain atrophy (see Figure 7.4). He was given a clinical diagnosis of PSP.

In subsequent evaluations, his falls became increasingly frequent, occurring up to several times per day, despite his family’s efforts to prevent falls. Eventually, he became wheel chair bound. He grew more apathetic and rarely initiated conversations or engaged with others. Downgaze became completely absent, and he could not see food on his plate. He developed severe dysarthria and dysphagia, which required a modified diet to prevent aspiration. He died of pneumonia 5 years after his first symptom. Autopsy confirmed PSP.

The classical PSP syndrome features severe gait and balance impairment with bradykinesia leading to frequent falls, dysar thria and dysphagia, and gaze palsy. In addition to motor and oculomotor abnormalities, patients with PSP syndrome often harbor behavioral changes and executive function deficits show ing clinical overlap with bvFTD [64–66]. A subset of patients with PSP syndrome manifest a predominant behavioral presentation that precedes motor symptoms; in such cases, early falls might not be present [65, 67, 68]. Prominent behavioral changes often emerge, with apathy and disinhibition being the most common [67]. In contrast to bvFTD, neuropsychiatric symptoms such as hyperorality and repetitive motor behaviors occur less commonly. Psychotic symptoms are uncommon in PSP syndrome [69]. Memory difficulties in PSP syndrome are usually mild and usually involve retrieval rather than recognition deficits [59].

Downward gaze palsy is a strong predictor of autopsy‐proven PSP [70], and horizontal square wave jerks on primary gaze may emerge. Oculomotor abnormalities are present in CBS, AD, and FTD spectrum disorders; however, abnormalities in vertical greater than horizontal saccadic velocity and gaze excursion are more typical of PSP [57b]. Although patients with PSP, CBS, and AD have abnormalities in saccadic gain (maintaining accuracy of saccadic eye movements by adjusting saccadic amplitude relative to the target distance) and range of eye movement excursion, patients with PSP have the most prominent decre ments in saccadic gain [53–56]. With supranuclear gaze palsy, the oculocephalic reflex is intact early in the disease course but disappears in later disease stages. Other ocular abnormalities often include square wave jerks, blepharospasm, eyelid opening apraxia, and reduced blink rate [71].

Supportive diagnostic features include symmetric akinesia or rigidity that is proximal more than distal, dysphagia and dysarthria, abnormal neck posture (retrocollis), urinary incon tinence, and cognitive impairment. The procerus sign, caused by contraction of the corrugator and orbicularis oculi muscles leading to wrinkles in the glabellar region and the bridge of the nose, may give a furrowed‐brow appearance [72, 73]. In contrast to PD, tremor is often absent and rigidity is axial rather than appendicular. Postural instability typically is an early symptom, causing frequent falls. Early in the disease course, falls might be provoked by uneven surfaces. As motor symptoms progress, however, falls can be unpredictable, with no known provocation. The etiology of the falls is multifactorial; impaired downgaze, poor postural reflexes and instability, and impulsivity all contribute to fall risk.

Figure 7.4 Brain MRI in progressive supranuclear palsy syndrome secondary to CBD. T1‐weighted brain MRI in a 63‐year‐old gentleman showing mild midbrain atrophy in sagittal (left) and axial (right) planes.

Correlation between PSP syndrome and PSP

About one‐half to two‐thirds of those diagnosed with PSP at autopsy were suspected to have PSP at presentation [44, 68, 70, 74–77]. Other clinical syndromes associated with PSP include PD, CBS, and MSA [43, 75]. In some series, about half of patients with CBS showed PSP pathology [40, 48]. About 80% of patients diagnosed with PSP syndrome during life show PSP at autopsy [68, 74]. Other autopsy diagnoses of those with PSP syndrome include DLB, AD, MSA, CBD, Pick’s disease, and FTDP‐17 [76]. There is substantial clinical overlap between PSP and CBD.

Diagnostic studies

Laboratory tests

Currently, there are no laboratory tests for CBD or PSP, and diagnosis is based on clinical evaluation. In diagnostic evalua tion of patients with cognitive impairment, laboratory tests should be done to rule out medical causes of cognitive decline, including vitamin B12 deficiency, thyroid dysfunction, syphilis, and HIV, if risk factors are suspected in patients. Cerebrospinal

fluid (CSF) diagnostic biomarkers are currently being explored, although none has yet been approved for clinical use (see Pathophysiology and Pathology, “Biomarkers”).

Neuroimaging

Quantitative brain imaging studies reveal distinct atrophy pat terns arising in CBD and PSP, and studies have assessed atrophy patterns in CBS and PSP syndrome in attempts to determine underlying predictors of pathology. Major sites of degeneration in pathologically proven CBD include the frontal lobes, basal ganglia, and brainstem (Figure 7.5) [8, 78]. Although historically CBD was described as a frontoparietal disease [63], voxel‐based morphometry (VBM) studies demonstrate that frontal and striatal degeneration, rather than parietal atrophy, dominates [8, 78]. One study showed that although heterogeneous clinical syndromes such as nfvPPA, bvFTD, and an executive–motor phenotype result from CBD, common regions of atrophy across all three syndromes include bilateral dorsomedial prefrontal cortex, supplementary motor area, perirolandic cortex, and striatum, suggesting that these are the core regions affected by CBD [8].

VBM studies demonstrate that dorsomedial frontal cortex, perirolandic cortex, and dorsal insula atrophy arise in all

CBD by clinical syndrome

z=42 z=10 z=47

z=6

(a)

(b)

z=–10 x=–6 z=–7 y=7

T score = 3.3
p(uncorr.) < 0.001 Cluster size > 50 voxels

x=–12 x=8 bvFTD

EM
PNFA 0.0 0.8 1.6 2.4 3.2

Figure 7.5 Statistical parametric mapping version 5 (SPM5) voxel‐based morphometry (VBM) MRI analysis contrasting gray and white matter volume in (a) a cohort of patients with corticobasal degeneration (CBD) (N = 13) with healthy older controls (NC, N = 44) who had VBM‐compatible 1.5T structural T1 scans and (b) the three main clinical syndromes seen in CBD compared to NC viewed on a DARTEL‐derived template based on 48 healthy controls (voxel resolution: 1 mm). Patients with VBM‐compatible scans in the three CBD clinical syndromes included nfvPPA (N = 4), EM‐CBD (N = 5), and bvFTD‐CBD (N = 3). Source: Lee et al. [8]. Reproduced with permission of Wiley. (See insert for color representation of the figure.)

Corticobasal degeneration and progressive supranuclear palsy 83

All CBD vs. NC

84 Non-Alzheimer’s and Atypical Dementia
CBS-AD <NC CBS-CBD <NC CBS-PSP <NC CBS-TDP <NC CBS by pathology

(a)

(b)

L
z=0 z=6 z=16 z=11

z=9

y=10

y=10 y=11

x=–6 x=–5

T score = 3.2 for all contrasts

y=10 y=10

4 5 6 7 8 9

3.6 4.5 5.4 6.3

3.5 4.2 4.9 5.6

3.2 3.6 4.0 4.4 4.8

CBS-AD<NC CBS-CBD<NC CBS-PSP<NC CBS-TDP<NC

x=5 x=0 x=0

Figure 7.6 SPM5 VBM analysis showing the patterns of gray and white matter volume loss in (a) left panel: each CBS subgroup, all with autopsy studies (CBS‐AD (N = 7), CBS‐CBD (N = 11), CBS‐PSP (N = 4), and CBS‐TDP (N = 3)) relative to healthy controls (NC, N = 44) and (b) right panel: all three CBS subgroups combined relative to NC viewed on a DARTEL‐derived template based on 48 healthy controls (voxel resolution: 1 mm). Source: Lee et al. [8]. Reproduced with permission of Wiley. (See insert for color representation of the figure.)

patients with CBS regardless of underlying pathology (Figure 7.6) [8, 78]. Underlying FTLD histopathology was asso ciated with atrophy extending into frontal cortex and brainstem, whereas extension into precuneus and temporoparietal cortex correlates with underlying AD.

In PSP, dilation of the third ventricle and prominent dorsal midbrain atrophy, with a diminished anteroposterior diameter, appear, although visual inspection of these structures fails to discriminate PSP from other disorders such as CBD, PD, or multiple system atrophy. Studies quantifying the midbrain anteroposterior diameter reveal mixed results, with some show ing complete differentiation between PSP, PD, and MSA [79], while others show overlap between groups [80].

Most imaging studies have examined patients with clini cally defined PSP. On VBM analysis in PSP syndrome, frontal [81], pons, thalamus, and striatal atrophy emerge (Figure 7.7) [82]. Atrophy in the midbrain and cerebral peduncles on VBM distinguishes PSP syndrome from clinical PD [83]. A VBM study of 13 patients with autopsy‐proven PSP showed subcortical and brainstem atrophy, consistent with previous studies, but also atrophy in premotor cortex and supplementary

motorarea[63].Similarly,allimagingstudieswithdiffusion‐ weighted imaging and DTI and magnetic resonance spec troscopy have been performed in PSP syndrome, and the clinical diagnostic utility of such imaging modalities remains uncertain [84a].

Amyloid PET imaging was recently FDA approved by the FDA for clinical use and can help identify AD pathology in patients with CBS. Pilot studies of tau PET ligands in order to detect tau pathology in vivo are underway [84b].

Pathology and pathophysiology

CBD

The gross pathology of CBD reveals narrow cortical gyri, most marked in parasagittal and frequently perirolandic cor tices, and inferior frontal and temporal cortices; atrophy can be asymmetric [85]. The substantia nigra appears pale. According to a working group supported by the Office of Rare Diseases of the National Institutes of Health (ORD NIH), the minimal pathological features for CBD include cortical and

1 P

2
L

1 AP

LR AP

3LR3LR

(a) (b)

Figure 7.7 Regions of brain atrophy in patients with corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome (PSP‐S) relative to controls. VBM‐identified regions of decreased gray and white matter volume in 14 CBS and 15 PSP‐S patients relative to 80 age‐matched control subjects are displayed on a normal adult brain template (P < 0.05, corrected). (a) CBS patients versus controls. (b) PSP patients versus controls. Row 1 shows the regions of significant gray matter loss rendered on a healthy subject’s brain. Row 2 shows regions of significant gray (displayed in red) and white (displayed in yellow) matter loss relative to controls at the following Montreal Neurological Institute (MNI) coordinates: x = −33, y = −4, and z = 49. Row 3 shows regions of significant gray (displayed in red) and white (displayed in yellow) matter loss relative to controls at the following MNI coordinates: x = 5, y = −15, and z = −8. A indicates anterior; P, posterior. Source: Boxer et al. [82]. Reproduced with permission of the American Medical Association.
(See insert for color representation of the figure.)

striatal tau‐positive neuronal and glial lesions, with astrocytic plaques and threadlike lesions present both in gray and white matter and neuronal loss in cortical regions and the substan tia nigra [2, 86]. Swollen (i.e., achromatic or ballooned) corti cal neurons often are present in CBD, but as they are absent in some cases, they were not considered essential for the ORD NIH criteria [86–88]. Coiled bodies, which are tau‐positive oligodendroglial inclusions, are found in CBD and PSP, but at a lower density than astrocytic inclusions [85].

Tau protein has six isoforms which harbor either 3 or 4 tubulin‐binding repeats, referred to as 3R and 4R isoforms, respectively. Tau inclusions in CBD and PSP are hyperphos phorylated and consist of the 4R tau protein. Tau protein assists in microtubule assembly and stability and is highly expressed in axons. Hyperphosphorylation of tau alters its binding affinity for microtubules and increases its aggregation into multimers [89b, c].

PSP

The gross pathology of PSP reveals mild frontal atrophy but prominent midbrain atrophy, with loss of dopaminergic neurons in the substantia nigra and subthalamic nucleus. The cerebellar dentate nucleus and superior cerebellar peduncle show neuronal loss [95]. On microscopy, characteristics of PSP include neu ronal loss, gliosis, and flame‐shaped and globose neurofibrillary tangles in the basal ganglia and brainstem. Mild neuronal loss and gliosis occur in the thalamus and striatum and the nucleus basalis of Meynert [96].

Neurofibrillary tangles are composed of paired helical fila ments and straight filaments of tau protein [97]. The tangles are similar to those seen in AD; however, they consist nearly

entirely of the 4R isoform of the tau protein [13]. Although both CBD and PSP are 4R tauopathies, the biochemical profiles of the tau proteins of each disease have different tau protein cleavage fragments [98, 99]. Gallyas stain and tau immunohis tochemistry reveal NFTs in neurons but also argyrophilic, tau‐ positive inclusions in astrocytes and oligodendrocytes. Tufted astrocytes represent a hallmark of PSP pathology and emerge in the motor cortex and striatum [100, 101]. In oligodendro cytes, tau‐positive, argyrophilic, perinuclear fibers appear as coiled bodies [102].

Quantitative studies of tau burden have been performed in PSP to determine whether clinical PSP variants are associated with variations in pathological features [103–105]. Across all subtypes, the subthalamic nucleus, substantia nigra, and globus pallidus are most severely affected by tau pathology [103, 104, 106].

Biomarkers

Because CBD and PSP pathologies are characterized by tau inclusions, several studies have explored CSF total tau and phosphorylated tau levels. Nearly all of these studies were performed with clinically diagnosed patients without autopsy studies, limiting the scope and power of these analyses.

Studies in CBS are mixed, with studies reporting higher CSF total tau levels in CBS than PSP syndrome and controls [111, 112] and others finding no difference between CBS, PSP syndrome, and controls [113, 114]. For PSP syndrome, two studies reported CSF total tau levels within normal range [111, 115].

Other CSF analytes in CBS and PSP syndrome have been studied. Two studies showed no differences in CSF Abeta42 levels in CBS or PSP syndrome compared with controls

Corticobasal degeneration and progressive supranuclear palsy 85

86 Non-Alzheimer’s and Atypical Dementia

[116, 117], although a subsequent study found that levels are reduced in PSP syndrome and CBS [114]. In one blinded study of 70 patients (21 with PSP syndrome), levels of CSF neurofilament heavy chain, a measure of axonal damage, were significantly higher in PSP syndrome compared with PD and controls [118a].

Genetics

The etiology and pathophysiology of CBD and PSP remain unknown. Although CBD is considered a sporadic disease with most patients reporting no family history, patients with MAPT mutations may present with CBS and also demonstrate pathological overlap with CBD [89–91]. Moreover, mutations in the progranulin gene have been reported to cause familial CBS [92–94]. Studies of the MAPT gene have demonstrated overrepresentation of the H1/H1 MAPT haplotype in both CBD and PSP [24, 25].

For PSP, most cases are sporadic, although familial and genetic factors influencing the development of the disease occur in a subset of patients. One study reported that 33% of patients with PSP have a first‐degree relative with parkinsonism or dementia [107], and there are strong associations with genetic variants in MAPT [24, 108, 109] and chromosome 1q31 [110]. A genome‐wide association study for PSP described several new susceptibility genes associated with PSP, but the functional relevance of these genetic loci to PSP pathology remains to be determined [118b].

treatments

At present, there are no FDA‐approved treatments for CBD or PSP. Anti‐tau agents are under investigation in clinical trials. In CBS, if the suspected underlying pathology is AD, a trial of an acetylcholinesterase inhibitor may be indicated.

Patients with CBD and PSP are typically unresponsive to dopaminergic medications, such as carbidopa/levodopa, although some report mild benefit, even at low doses, that is often transient [119]. Thus, a trial of levodopa is warranted. Neuroleptic medications should be avoided when possible due to their extrapyramidal side effects and the risk of death. Depression occurs frequently; thus, antidepressant medica tions are indicated [120]. Many patients benefit from seroto nin reuptake inhibitors, perhaps because of an underlying dysfunction in the serotonergic system in PSP and related disorders.

Supportive care measures include speech pathology and dys phagia evaluations to prevent aspiration risk. Dystonia and blepharospasm often are ameliorated with botulinum toxin injections [119]. Physical therapy and exercise aid in maintain ing mobility and range of motion; stationary recumbent bicy cling might be useful for those with significant fall risk. Occupational therapy and home safety evaluations can help minimize fall risk.

Summary

Corticobasal degeneration and progressive supranuclear palsy are 4R tauopathies with heterogeneous presentations and considerable clinical and pathological overlap. Though historically CBD was initially defined as a movement disor der and motor symptoms eventually emerge at some point during the CBD disease course, clinicopathological series reveal that CBD predominantly involves frontal degenera tion with the most common syndromes showing executive dysfunction, nonfluent aphasia, and behavioral presenta tions. Neuropathologies presenting as CBS range widely, with clinicopathological studies showing less than 40% of CBS having underlying CBD pathology. Although PSP syn drome usually predicts PSP, early diagnosis remains a chal lenge. As with CBD, early behavioral and cognitive features in PSP are likely underreported. The advent of serological, CSF, and imaging biomarkers such as amyloid and tau PET will be crucial to the diagnosis and monitoring of future treatments.

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Corticobasal degeneration and progressive supranuclear palsy 89

CHapteR 8
Repeat expansion diseases and dementia

Praveen Dayalu1, Roger L. Albin1,2 and Henry Paulson1

1 University of Michigan, Ann Arbor, MI, USA 2 VAAAHS GRECC, Ann Arbor, MI, USA

Introduction

More than 20 neurological disorders are caused by DNA repeat expansions, many of which are associated with neurodegenera tion. Relatively few of these disorders, however, will be consid ered in the patient undergoing evaluation for atypical dementia. The principal reason why these diseases are not high on the dif ferential diagnosis of dementia is that most heritable repeat expansion disorders do not include prominent cortical or sub cortical loss as a primary site of degeneration. The most notable exception to this is Huntington’s disease (HD), in which pro gressive cognitive impairment is a hallmark feature. HD is the most common among the nine diseases known to be caused by polyglutamine‐encoding CAG repeat expansions. The other eight polyglutamine diseases include six dominantly inherited spinocerebellar ataxias (SCAs 1,2,3,6, 7, and 17), dentatorubral‐ pallidoluysian atrophy (DRPLA), and the motor neuron disor der, spinobulbar muscular atrophy (SMA). Of the non‐HD polyglutamine disorders, only SCA17 typically manifests with progressive cognitive impairment that culminates in dementia, although about a third of SCA2 patients develop dementia as well [1–4]. Whereas most patients with SCA17 also have signifi cant ataxia and cerebellar atrophy, the cognitive symptoms often begin early and sometimes dominate the clinical picture before cerebellar or basal ganglionic signs surface. Other SCAs includ ing SCA1, SCA2, SCA3, and SCA8 can also have cognitive defi cits, albeit milder than SCA17, but will not be discussed in this chapter. The other relatively common repeat expansion disease associated with age‐related dementia is fragile X‐associated tremor/ataxia syndrome (FXTAS), which is caused by a modest noncoding CGG expansion.

We begin with a detailed overview of HD because it is an important and readily diagnosed form of atypical dementia associated with basal ganglionic signs and symptoms. In dis cussing the differential diagnosis of HD, we touch on other disorders involving the basal ganglia in which cognitive impair ment can be prominent, including the much rarer Huntington’s

disease‐like 2 (HDL2) disorder, which is caused by a repeat expansion in a different gene (junctophilin‐3). We then briefly discuss SCA17 as the primary SCA in which dementia is a very common, and sometimes presenting, feature. Finally, we dis cuss FXTAS, which displays broad heterogeneity in phenotype, with progressive movement disorder, ataxia, and cognitive impairment being the most common manifestations. When discussing FXTAS, we remind the reader that among sporadic forms of progressive ataxia associated with cognitive impair ment, multiple system atrophy (MSA) is perhaps the most common disorder.

Nosology

History/nomenclature

In 1872, physician George Huntington reported a familial cho rea on Long Island, noted previously by his father and grandfa ther, also physicians [5]. More than a century later, Huntington’s vivid writings are a remarkably complete description of the dis ease that now bears his name. He described chorea as “dancing propensities” in which there “seems to exist some hidden power, something that is playing tricks, as it were, upon the will.” At first, this inherited disease began “as an ordinary chorea might begin, by the irregular and spasmodic action of certain muscles as of the face, arms, etc. These movements gradually increase when muscles hitherto unaffected take on the spasmodic action….” He noted that the disease was “confined to … a few families … hardly ever manifesting itself until adult or middle life, and then coming on gradually but surely, increasing by degrees, and often occupying years in its development, until the hapless sufferer is but a quivering wreck of his former self.” Huntington also commented on the mind, which “becomes more or less impaired, in many amounting to insanity while in others, mind and body both gradually fail until death relieves them of their sufferings.”

Regarding the inheritance pattern, he noted: “When either or both parents have shown manifestations … one or more of the offspring almost invariably suffer from the disease … but if by any chance these children go through a life without it, the thread is broken….” Finally, he noted the relentless, fatal course: “I have never known a recovery … it seems at least to be one of the incurables.”

Epidemiology

HD is the most common polyglutamine neurodegenerative dis ease. In the United States and Canada, approximately 30000 people carry the diagnosis, and an estimated 150 000 more are at risk. HD is most prevalent in those of European descent, approximately 10–15/100 000 [6, 7]. Pockets of particularly high prevalence, probably due to founder effects, include the Lake Maracaibo region of Venezuela and regions of Scotland and Tasmania [8–10]. Prevalence rates are much lower in popula tions of non‐European ancestry [11]. Males and females are equally at risk. Median age of diagnosis approximates 40, with a wide range in age of onset. Onset before age 20 or after age 65 is relatively rare. Death generally occurs 15–20 years after diagno sis [12]. The combination of typical midlife onset and dominant inheritance pulls entire families down the social scale and dev astates the lives of patients, mutation carriers, and unaffected family members alike.

Genetic epidemiology

HD is an autosomal dominant disorder. In the general popula tion, there are on average 17–20 CAG repeats in the HTT gene [13]. With a CAG repeat of 40 or more, a person will develop HD with 100% certainty, but with repeats of 36–39, there is incomplete penetrance. CAG repeat lengths of 6–26 do not cause disease and are thus considered “normal.” The intermedi ate range, from 27 to 35 repeats, does not cause HD with a few reported exceptions [14]. Notably, all alleles of 27 repeats and higher are unstable and prone to expand in future generations, particularly when transmitted by a male parent. Whereas the great majority of HD patients have an affected parent, up to 10% of cases result from new expansions into the disease range [15, 16]. In European populations, there are specific HTT hap lotypes, involving polymorphisms in other regions of the gene, that might promote CAG repeat instability [17]. The appearance of earlier and more severe symptoms in successive generations, known as “anticipation,” reflects CAG instability with further expansions from one generation to the next.

Case presentation

Sonia H, a waitress aged 42, started drinking whiskey every evening. At first, her husband and sons thought this was related to arguments with her coworkers. A year later, her family noted that she often “flew off the handle” at minor issues. Her boss noted a new tendency to drop platters and break dishes. Others suspected her of illegal substance abuse because of her mildly slurred speech and increasing fidgetiness. At age 44, after she

struggled to plan her traditional Thanksgiving dinner, her family brought her to a neurologist.

Sonia’s parents were alive and healthy in their 70s. Her older brother was also well. She knew of no more distant family mem bers with a movement disorder, dementia, or prominent psychi atric problems. Her only medications were citalopram for “moods” and omeprazole. She did not smoke. Other than inter mittently heavy alcohol, she denied substance abuse.

In the office, she was irritable toward her family, offering curt denials of their reports. When her son described her new com pulsion to count cash at home, she snapped, “It isn’t your money, so what do you care!” Her speech was irregular in volume and emphasis. She denied involuntary movements, but her family thought she looked “restless.” Throughout the interview, there were occasional brief random movements: pursing of her lips, raising of her eyebrows, tilting of her head, extending or flexing a finger or wrist, and inverting a foot.

On the Montreal Cognitive Assessment (MoCA), she scored 23/30. She lost 1 point each for trails test, serial 7s, digits back ward, delayed recall, and sentence repetition. She lost 2 points for concrete responses on abstraction. She could not complete the Luria maneuver unless cued verbally: “fist, edge, palm.” On motor examination, her involuntary movements were brought out when she counted backward with hands outstretched; in particular, there were “piano‐playing” finger movements. She blinked and moved her head when initiating saccades. She could not keep her tongue protruded for a full 10s; it flicked briefly back into her mouth at 8 s. Finger tapping was slightly slowed on the left. Hand pronation–supination was clumsy bilaterally. Heel–knee–shin was slightly irregular bilaterally. Her gait was stable and narrow based but with occasional random shoulder, trunk, and hand movements creating a vaguely puppetlike appearance. She sidestepped twice in a 10‐step tandem walk. On pullback testing, she took 3 steps to maintain her balance.

The neurologist concluded that Sonia had chorea, mild ataxia, and cognitive deficits typical of executive dysfunction. Given her change in personality and behavior, he was most concerned about HD. The lack of a family history, however, was puzzling. His differential diagnosis also included other heredodegenera tive diseases (Wilson’s disease, neuroacanthocytosis, DRPLA, SCA17), inflammatory disorders (SLE, antiphospholipid anti body syndrome, demyelinating disease, CNS angiitis), unrecog nized substance abuse with complications, thyroid disease, or chronic CNS infection (e.g., HIV).

Vitamin B12 level, TSH, and a comprehensive metabolic panel had been unremarkable. The neurologist advised the patient and her family that HD was the most common cause of adult‐onset chronic chorea. He informed them that if HD test ing was clearly negative, he would initiate a broader workup including brain MRI. The patient and her family were referred to a genetic counselor to discuss the implications of testing for the HD gene.

Testing revealed 44 CAG repeats in one HTT allele and 17 in the other. Sonia received the diagnosis of HD at a subsequent

Repeat expansion diseases and dementia 91

92 Non-Alzheimer’s and Atypical Dementia

visit, with her family present. Her teenage sons were informed that they, too, were at risk for HD, though they were asympto matic. The neurologist informed them that after reaching age 18, they could receive predictive testing if they so chose. As to why both of Sonia’s elderly parents were unaffected, the neurol ogist explained that one of them might carry an unstable CAG repeat expansion of less than 40 that was not fully penetrant. Other explanations could include nonpaternity.

Sonia’s citalopram was increased to 40mg per day to help with irritability, anxiety, and obsessions. She was referred to occupational therapy to help her compensate for her decline in coordination. Her husband asked for treatment of her “restless ness”; however, the neurologist noted that Sonia herself was not aware of or disabled by her mild chorea, so he persuaded the family that antichorea therapy was not necessary at this time. He informed the family of support and advocacy resources in HD, as well as research opportunities at the nearby academic medical center.

Clinical features

Overview and natural history

The classic clinical triad in HD is (i) a progressive motor disor der, notably with chorea but also with varying degrees of dysto nia, bradykinesia, rigidity, ataxia, dysphagia, and loss of postural reflexes; (ii) progressive cognitive disturbance culminating in dementia; and (iii) various behavioral disturbances including depression, anxiety, apathy, obsessive–compulsive behaviors, outbursts, and occasionally delusions or psychosis. A cognitive or behavioral syndrome is often the first manifestation, a fact that is often clearer in retrospect. Weight loss is another com mon symptom [18].

Motor disorder

Though chorea is only a small part of motor dysfunction in HD, it remains its most recognizable feature. Chorea often begins as fleeting, suppressible random “fidgety” movements, seen best in the distal extremities. With time, chorea becomes insuppressible and more overt, involving larger and more proximal muscles. Chorea might incorporate fragments of complex purposeful movements such as straightening one’s hair. Motor impersis tence is often seen in chorea. The “flycatcher’s tongue,” for example, describes a difficulty in keeping the tongue protruded beyond the lips. Most patients with chorea are not aware of the extent of their involuntary movements; some deny it altogether. Others report that the movements are embarrassing, exhaust ing, or injurious. In many patients, worsening chorea develops the sinuous, writhing quality known as athetosis. The combina tion of athetosis and the more rapid movements of chorea is termed choreoathetosis. Severe chorea–choreoathetosis exhibits violent flinging of the limbs or trunk and can be accompanied by traumatic injuries.

Saccadic eye movement abnormalities occur early and persist throughout the disease. Saccades are slow to initiate, often requiring a head movement or a blink to break fixation. Saccadic

velocities often become slow as the disease progresses [19]. Patients usually do not complain of associated visual problems. Ataxia, manifested by dysmetria and dysrhythmia, is common

in HD, especially as disease advances. Ataxia might be apparent in speech, finger–nose, and heel–knee–shin testing and a broader‐based gait with impaired tandem walking. Dystonia, a more sustained posturing or twisting, is common in HD. Bradykinesia refers to slower and reduced amplitude of move ment: for example, diminished facial expression, reduced spon taneous gesturing, reduced finger tap speed and size, reduced arm swing, and small steps. Well before HD manifests, gene‐positive individuals show increased variability of voluntary motor meas ures such as finger tap and tongue protrusion force [20].

There is considerable motor heterogeneity from patient to patient. In general, younger‐onset patients are more likely to present with bradykinesia, rigidity, and dystonia; juvenile HD patients may lack chorea altogether and look more like they have Parkinson’s disease (PD) (known as the “Westphal variant” of HD). These individuals have a relatively high prevalence of epilepsy [21]. Even within a given HD patient’s disease course, the motor abnormalities evolve across a continuum: chorea early in the disease often progresses to superimposed dystonia as the disease advances [22], culminating often in striking brad ykinesia, rigidity, and poor postural reflexes in late stages. Progressive motor failure is a major cause of life‐ending compli cations; falls and serious injuries become increasingly common. Weight loss in HD occurs even early in the disease, independent of chorea, and might represent a metabolic or homeostatic alter ation due to the disease [23]; dysphagia in late HD only exacer bates this problem.

Cognitive disorder

Dementia is sometimes an underappreciated facet of HD and especially serious because it strikes in the prime of life. Unlike elderly demented adults, HD patients often lack adult children who can assist with planning and care. Marriages and families are disrupted, and children lose an effective parent. With increasing difficulty at work, years of income are lost.

A recent large‐scale prospective observational analysis of pre manifest persons [24] showed declines in several measures, including working memory, attention, and verbal fluency, con sistent with prior studies. These deficits were worse for subjects approaching their expected motor onset. Prediagnosis cognitive impairment, as measured via neuropsychological testing, may serve as an important outcome measure in future clinical trials of potential preventive agents.

By the time of diagnosis, most subjects with HD have cogni tive impairment clearly evident on neuropsychological testing. Patients typically have difficulty with multitasking, focus, short‐ term memory, and learning new skills, although these problems are often first noted by family members. Early in the disease, these difficulties are usually not sufficient to impede most activ ities of daily living, but those with cognitively demanding jobs often find work increasingly difficult.

Over many years, cognitive impairment eventually progresses to frank dementia in most patients with HD. Unlike Alzheimer dementia, HD dementia is largely “subcortical,” marked by slow thought processes, executive dysfunction, and problems with attention and sequencing [25, 26]. Episodic memory, though impaired, is relatively well preserved when compared to Alzheimer’s disease (AD), as is language function. The MMSE is ineffective as a screening instrument in HD; the MoCA is con siderably more sensitive in this population [27] as it contains more items evaluating executive function and attention. The Luria test (fist–edge–palm) requires good motor sequencing and executive function, so it is impaired particularly early in HD.

Individuals with HD often show striking lack of insight into their own cognitive and motor symptoms, even when these are obvious to others [28]. This might reflect dysfunction of striatal neurons receiving prominent frontal lobe inputs.

Psychiatric disorder

For many HD patients and their families, behavioral problems are the most vexing. These range from affective illness to anxiety disorders to delusional behavior and rarely hallucinations [29, 30]. Psychiatric features and their severity vary tremendously and do not correlate with chorea or dementia [29]. Psychiatric problems are especially problematic in juvenile‐onset cases [31].

Most patients experience some behavioral symptoms prior to their diagnosis [32–34]; most common are depression, obsessive– compulsive behaviors, irritability, and outbursts [32, 33]. Per sonality changes may occur for years prior to the diagnosis, though this may be apparent to families only in retrospect.

Up to 50% of patients are depressed at some point in the dis ease [35]. Depression often responds very well to treatment, typically SSRI antidepressants. Apathy is also fairly common, though more difficult to treat. Compulsive behaviors in HD may resemble the cognitive rigidity and perseveration typical of frontal lobe disorders and probably reflect striatal dysfunction.

There is a high rate of suicide in gene‐positive individuals, both after diagnosis and prediagnosis [36, 37]. Factors increas ing suicide risk include being single, lacking children, living alone, being depressed, and showing manifest HD signs [36].

Clinical heterogeneity

There is a remarkable range of ages of onset and symptom fea tures in HD. CAG repeat length is a major factor, correlating inversely with age of onset [38–41]. For the more common smaller repeat lengths (<45), however, there is a much larger variance in age of onset. Other genetic and environmental fac tors, yet unknown, must also contribute to age of onset.

Repeat length also influences motor phenotype, as early‐ onset disease is more likely to present with prominent dystonia and bradykinesia, though this may reflect the impact of the mutant allele on developing brains. It is unclear whether repeat length influences the rate of disease progression; whereas some studies have not [39], other studies have [42] found correlations. Age may have been a confounder; a more recent analysis showed

a stronger correlation between longer repeats and faster decline after adjusting for age [43]. Familial aggregation of certain symptoms (e.g., psychosis) occurs in HD, and this likely reflects genetic modifiers.

Differential diagnosis

Mimics of HD are seen occasionally in clinical practice [44, 45]. The differential diagnosis for chorea alone is extensive and includes acquired entities such as hyperthyroidism, polycythemia vera, lupus, antiphospholipid antibody syndrome, HIV/AIDS, poststreptococcal chorea, anticholinergic and stimulant drug effects, and levodopa‐induced dyskinesias in PD. Most such entities can be excluded by history, physical examination, or simple blood tests.

More difficult to distinguish are a few inherited neurodegen erative diseases that might resemble HD. These include domi nant disorders such as the polyglutamine diseases, SCA17 and DRPLA; Huntington’s disease‐like 1 (HDL1), due to a mutation in the gene for the prion protein; HDL2, which is another expanded repeat disorder that closely resembles HD and is quite rare; and the neurodegeneration with brain iron accumulation (NBIA) disease spectrum. Recessive and X‐linked disorders in the neuroacanthocytosis family might mimic HD. Molecular diagnoses are available for all these diseases. Because it is treat able, Wilson’s disease must be considered in any nonelderly per son (<50 years of age) presenting with a movement and cognitive disorder, though a chorea‐dominant phenotype is uncommon.

Because HD is the most common progressive choreiform disor der, the simplest strategy is to first test for the HD mutation. This should be performed even if there is no apparent family history; there may be a new mutation, early death, or missing information on a parent, nonpaternity, or undisclosed adoption. If HD is excluded, more extensive testing would then be needed. Establishing an accurate diagnosis is crucial for both patient and family; the implications are vastly different for a dominant versus a recessive disorder, and an accurate diagnosis is required for presymptomatic testing of unaffected adult family members over the age of 18.

If there is a confirmed family history of HD (i.e., an affected parent or sibling with an established genetic diagnosis), muta tion testing is generally not required in a patient presenting with motor abnormalities that are unequivocally characteristic of HD. A note of caution, however, is that mild motor anomalies, including subtle chorea, cannot be assumed to be diagnostic of HD simply on the basis of a known family history. Even mutation‐negative relatives sometimes appear hyperkinetic, perhaps from behavioral imprinting.

Neuroimaging findings

Currently, neuroimaging is of limited value in the clinical diag nosis of HD. Individuals with many years of manifest HD typi cally demonstrate obvious caudate atrophy on CT or MRI, altering the contour of and enlarging the lateral ventricles.

Volumetric MRI analyses, performed in ongoing large pro spective studies of at‐risk subjects, reveal that the most clearly

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(a) (b)

Figure 8.1 Coronal T1‐weighted brain MRI in Huntington’s disease. (a) Healthy control. (b) HD carrier with early‐stage (stage 2) disease. MRI shows caudate (white arrow) and putaminal (black arrow) atrophy showing that there is enlargement of the lateral ventricles due to partial degeneration of the caudate nucleus. Source: Mascalchi [48] (TBC). Reproduced with permission of Radiological Society of North America.

measurable and progressive atrophy affects the striatum and global cerebral white matter [46, 47] (see Figure 8.1). These changes occur well before the earliest typical motor features. Cortical atrophy also occurs in asymptomatic subjects [20, 49, 50], changing quantitatively over relatively short intervals (2–3 years), consistent with histopathologic findings of early neocortical degeneration [51]. There is tremendous interest in developing such MRI analyses as biomarkers for use in future clinical trials with premanifest subjects.

PET studies have demonstrated early declines in striatal neu rotransmitter markers, particularly dopamine receptors, that occur even in preclinical HD [52–54].

pathophysiology and pathology

The HTT gene
The HTT gene on chromosome 4 encodes the protein hunting tin [55], a very large protein that is expressed widely in the CNS and in other tissues. In neurons, it is found largely in somato dendritic and axonal cytoplasm and interacts with many other proteins. Huntingtin is essential for early neuronal develop ment, but its precise functions in adults are unclear. It appears to be important in processes as diverse as protein and vesicular transport, signaling, transcriptional regulation, and apoptosis [56]. How mutant huntingtin initiates neurodegeneration is still unknown, though a toxic gain‐of‐function mechanism occur ring primarily at the protein level is very likely.

Biomarkers

There is tremendous interest in identifying reliable biomarkers to pinpoint HD onset, track its progression, and determine response to treatment. Existing markers are useful but clearly not sufficient; the best known is the Unified Huntington’s

Disease Rating Scale (UHDRS) [57]. This standardized clinical instrument has four major components: motor, cognition, behavior, and functional ability; it has been widely used in HD clinical trials and observational studies. A subset of the full UHDRS, perhaps supplemented with specific cognitive assess ments, might someday constitute a straightforward battery of tests that reliably measures disease onset and progression. Other candidate biomarkers might directly measure an aspect of HD pathophysiology; examples include changes in brain imaging (reviewed earlier), metabolic/proteomic profiles [58, 59], or gene expression changes [60].

Neuropathology

Gross CNS pathology

Huntingtin is expressed by neurons throughout the CNS with out dramatic regional differences. Despite this, there is a defi nite regional pattern to HD pathology [51]. Classically, HD is described as a striatal degeneration. This is only partly true; in advanced cases in which HD pathology has been best studied, widespread degeneration is apparent. Gross striatal atrophy is prominent, but thinning of the cortical mantle and low brain weights and volumes are well documented. Careful studies reveal neuronal loss in many regions including the neocortex, cerebellum, hippocampus, substantia nigra, and brainstem nuclei. There is also diffuse loss of cerebral white matter. These findings are consistent with the many clinical deficits in advanced HD, including pyramidal signs, ataxia, dysarthria, dysphagia, incoordination, and dementia.

Early in the disease, however, striatal degeneration occurs nonuniformly and disproportionately to other brain regions [61]; there are even subregional differences in HD pathology in

the striatal complex, with neurodegeneration progressing in caudal to rostral and dorsal to ventral gradients. There is also early degeneration in the neocortex [51].

Striatal pathology

Initial explorations of HD striatal pathology suggested loss of intrinsic GABAergic and cholinergic neurons with relative spar ing of extrinsic dopaminergic terminals.

Intrinsic striatal neurons themselves are differentially affected. There are 2 major populations: (i) aspiny interneu rons whose projection arbors are restricted to the striatum and (ii) GABAergic medium spiny projection neurons whose pri mary axons synapse in targets downstream of the striatum. The best studied aspiny neurons are cholinergic, which are vir tually spared in HD [62]. Striatal choline acetyltransferase (ChAT) levels decline markedly, however, suggesting signifi cant striatal cholinergic interneuron dysfunction, even in the absence of degeneration. At least one other population of striatal interneurons, those cocontaining somatostatin and neuropeptide Y and expressing high levels of nitric oxide synthase, are relatively spared in HD [63–65]. Recent work has identified progressive depletion of parvalbuminergic interneu rons;thisisapossibleexplanationfortheemergenceofdysto nia as HD advances [66].

Subpopulations of medium spiny projection neurons are defined by their primary projection targets, coexpressed neuro peptides, and neurotransmitter receptors. Relatively segregated pools of these neurons project to the external segment of the globus pallidus (GPe), internal segment of the globus pallidus (GPi), substantia nigra dopaminergic pars compacta (SNc), and substantia nigra GABAergic pars reticulata (SNr). Striato‐GPe neurons express enkephalins, dopamine D2 receptors, and adenosine A2a receptors, whereas the other striatal projection neuron pools tend to express tachykinins and dopamine D1 receptors. Examination of postmortem HD material suggests a sequential pattern in degeneration of striatal projection neuron subpopulations. The early changes appear to be loss of striato‐ GPe neurons and perhaps striato‐SNr neurons, whereas striato‐ GPi neurons are relatively spared until late [67–69].

This temporal order of neuronal loss correlates broadly with features of the natural history of HD. As basal ganglia inputs to the superior colliculus come from SNr, the early loss of striato‐ SNr projection neurons correlates nicely with early saccadic abnormalities. The evolution of involuntary movements in HD also has neuropathologic correlates. Initial degeneration of striato‐GPe neurons results in the inhibition of the subthalamic nucleus. Diminished subthalamic activity is associated with chorea. In many patients, disease progression is associated with gradual worsening of chorea, which then peaks in intensity and gradually declines, only to be accompanied by worsening dysto nia and bradykinesia. In these later stages, there is generalized loss of striatal projection neurons and probably neurons within other nuclei of the basal ganglia [70]. The striatum is composed of two chemical compartments: the striosome and the matrix.

One study looked specifically at a marker of striosomal striatal projection neurons in a broad spectrum of HD postmortem specimens; there appeared to be a correlation between disor dered mood and striosomal pathology [71].

Management

HD has no cure. Furthermore, there is no known therapy that slows the degeneration or the rate of clinical decline. This unmet need is a major area of HD research.

Symptomatic pharmacotherapy

HD symptoms respond variably to medications. Psychiatric symptoms, in general, are perhaps the most amenable to phar macotherapy. Of motor symptoms, chorea is the most readily responsive. Cognitive symptoms and dementia are the least responsive.

Many patients with chorea do not notice it or are not impaired by it. In these cases, reassurance and education (especially of family members) are important. When chorea requires treat ment because it affects a patient’s quality of life, function, or safety, it responds best to medications that reduce dopaminergic neurotransmission. In the United States, dopamine receptor blockers have been most commonly prescribed. Examples include haloperidol, risperidone, and olanzapine. These agents have the advantage of augmenting treatment for depression and helping with irritability, outbursts, and psychosis. A disadvan tage is that typical and atypical antipsychotics increase the risk of sudden cardiac death [72]. The other major option for chorea is the dopamine‐depleting agent tetrabenazine, which reduces chorea in a dose‐dependent manner [73]. This medication, however, depletes other catecholamines, including serotonin and norepinephrine, so is best avoided in individuals with sig nificant depression, and it sometimes worsens dysphagia. All of these therapies might worsen gait and bradykinesia or cause somnolence. Other medications, such as amantadine, have been reported as modestly beneficial for chorea [74, 75]. Bradykinesia and rigidity in younger‐onset individuals can respond to dopa minergic agents used in parkinsonism [76]. Myoclonus, which is rare in HD and sometimes mistaken for chorea, can respond to valproic acid [77].

There is a lack of clinical trials for psychiatric treatments in HD specifically [78]. Most experts agree that depression in HD often responds well to antidepressants, most commonly SSRIs. Obsessive–compulsive behaviors, anxiety, and agitation often respond to SSRIs. Mood stabilizers such as valproate and carba mazepine sometimes help with emotional lability and impulsiv ity. Buspirone sometimes helps with anxiety. Antipsychotics, both typical and atypical, are used to treat psychosis, delusions, agitation, and outbursts, but doses should be maintained at a minimum to reduce the risk of extrapyramidal side effects. Apathy is currently the target of an ongoing clinical trial of bupropion [79].

Thus far, limited trials of cognitive‐enhancing agents used pri marily in AD, such as memantine [80], rivastigmine [81], and

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donepezil [82], have shown only questionable benefit. A trial with latrepirdine (also known as dimebon) in HD recently showed no benefit in cognition or other disease aspects [83].

Nonpharmacologic management

Comprehensive care in HD draws from a range of professionals: primary care physicians, neurologists, psychiatrists, geneticists, physical and occupational therapists, speech pathologists, nutri tionists, social workers, and counselors. Nondrug interventions are a critical part of HD management [84].

Physical and occupational therapy are important in HD care. Gait assist devices (such as walkers) and home safety improve ments (hazard removal, grab bars, shower chairs, etc.) are also valuable. Speech therapists can evaluate and palliate dysarthria and dysphagia; options include exercises and food consistency modifications. Distractions should be minimized during meal time so that patients can concentrate on the mechanics of eat ing and swallowing. Dietary consultation can be a valuable adjunct in dealing with weight loss; high‐calorie supplements are often used.

Behavioral symptoms such as apathy and cognitive problems such as executive dysfunction can be ameliorated via structured daily schedules and regular routines. Daytime respite care pro vides a social outlet for some patients and relieves caregiver bur den. Severe dysarthria, rigidity, and bradykinesia can make patients with advanced HD appear more cognitively impaired than they really are. This only adds to frustrations and outbursts from the patient. One should assume that recognition and com prehension are preserved even in advanced HD; clinicians and family members must avoid “talking over” the patient.

The efficacy of nonpharmacologic interventions is often lim ited by the patient’s cognitive and behavioral impairments. As with many aspects of HD, the burden of maximizing benefits from supportive interventions falls on caregivers.

Preventive and neuroprotective approaches

Currently, no therapy is known to delay or prevent the onset of HD or slow its progression. This is a major area of research. High‐dose creatine was well tolerated and attenuated the rate of cortical thinning in premanifest HD subjects [85]. Large multi center clinical trials in manifest HD, for high‐dose creatine and coenzyme Q10, are currently in progress.

The ultimate preventive therapy, of course, would involve suppression of the pathologic gene expression within cells. RNA interference (RNAi) paradigms are currently being developed in animals. In one recent study in HD mice, jugular administration of an RNAi construct, using an adeno‐associated viral vector, reduced mutant huntingtin expression, atrophy, and inclusion formation within the brain [86]. A major concern with RNAi is the off‐target suppression of other normal mRNAs, and work is underway to reduce this risk [87]. Another promising technique uses antisense oligonucleotides (ASO). Infusion of ASO into the cerebrospinal fluid in HD mice reduced huntingtin synthesis and even reversed the disease phenotype [88].

Summary

HD is a relentlessly progressive inherited polyglutamine neuro degeneration causing severe cognitive, motor, and psychiatric disability in the prime of life. It is ultimately fatal in the vast majority of cases. Whereas many of its clinical characteristics can be explained by pathology of the striatum and its connec tions to the frontal lobes, HD is no longer simply considered a basal ganglia disorder. Current treatment is limited to sympto matic pharmacotherapy for behavioral disturbance and chorea and other supportive cares. A major goal of current research is to identify disease‐modifying therapy.

SCa17

Many patients with SCA will admit to cognitive problems, most commonly a slowing of thought processes and difficulty with multitasking [89]. Few, however, develop progressive cognitive impairment culminating in dementia. Among the SCAs, SCA17 is an exception to this general rule [90]. Originally described in Japan, SCA17 was the last of the nine polyglutamine diseases to be discovered [91] and is the rarest among them.

More than any other SCA, SCA17 manifests with widespread cortical, subcortical, and cerebellar dysfunction. Affected persons typically present in young to midadulthood with progressive gait and limb ataxia usually accompanied by significant cognitive impairment, psychiatric symptoms, and various extrapyramidal features including parkinsonism, tremor, dystonia, and occasional chorea [90, 92]; in some cases, SCA17 can be mistaken for HD. More than 80% of SCA17 patients experience significant cognitive deficits, and ataxia is not always a predominant feature. Indeed, behavioral and cognitive symptoms are often the first signs of dis ease, with frontal lobe signs (executive dysfunction, apathy) being most typical. Thus, SCA17 should be considered in patients with atypical dementia, especially when there is any sign of ataxia or a family history consistent with dominantly inherited ataxia.

An individual evaluated by one of us recently illustrates the atypical dementia that can occur in SCA17. A man in his late 40s was referred for apathy and progressive difficulty with exec utive function. He was no longer able to hold down a job due to worsening cognitive difficulties and loss of interest in almost all of his normal activities. A workup had been initiated elsewhere, but no diagnosis had been established. There was a family his tory of unspecified dementia in his deceased father and paternal uncle, but there was no known disease gene in the family.

His mental status exam revealed inattentiveness, depressed affect, bradyphrenia, executive dysfunction, and mild mem ory impairment. The neurological exam showed hypophonic dysarthria, slowed saccadic initiation, slowed finger opposi tion, difficulty with tandem gait, and increased deep tendon reflexes. His affected father, by report, did not have ataxia, but the patient’s MRI showed global brain atrophy with promi nent atrophy of the cerebellum (MRI not available, but please see Figure 8.2 for representative findings). This radiological

Figure 8.2 T1‐weighted brain MRI images from SCA17 patients showing cerebellar atrophy of the vermis and cerebellar hemispheres. Source: Mariotti et al. [93] (TBC). Reproduced with permission of Springer.

finding, together with the slowly progressive limb and gait incoordination and the family history suggestive of a domi nantly inherited disease, prompted us to perform gene testing for the SCA17 mutation. SCA17 gene analysis was the single gene test ordered in light of the patient’s clinical presentation. The diagnosis of SCA17 was established by finding a CAG expansion of 46 repeats in the TBP gene (pathological repeats are greater than 42 CAGs in length). The patient and his mother were informed of this diagnosis and told that his affected father and uncle, in retrospect, must also have suf fered from SCA17.

If the SCA17 gene test had instead been negative, we would have considered testing for another polyglutamine disease, DRPLA, because this disease rarely also can manifest in later adulthood with progressive cognitive impairment and cerebel lar degeneration [94]. Other testable SCAs were not considered because they are unlikely to cause this patient’s constellation of profound cognitive symptoms. The examination and MRI also did not strongly suggest HD as a potential cause. Thus, HD was not highest on the differential diagnosis, though it should be noted that rarely HD is associated with significant cerebellar atrophy.

As seen in many other repeat expansion diseases, SCA17 can show intrafamilial heterogeneity even between individuals with similar or identical repeat lengths. With few exceptions [95], the SCA17 expanded repeat is stably transmitted, thus most affected individuals within a family will share the same repeat length. We later evaluated the patient’s affected cousin, who was similar in age and had an identical repeat number. He was also 6–7 years into the course of the disease with prominent limb dystonia but demonstrated far fewer cognitive difficulties.

The treatment of SCA17, a relentlessly progressive and fatal disease, is purely symptomatic at this point. Patients with depression or other psychiatric symptoms often respond to appropriate medications. In the case described previously, his depressive symptoms responded to an SSRI antidepressant, but he continued to display apathy and other frontal lobe features.

Because dystonia and parkinsonism are frequent in SCA17, physicians should use caution in prescribing antipsychotics due to the increased potential for serious extrapyramidal side effects.

Fragile X‐associated tremor/ataxia syndrome (FXtaS)

FXTAS can be considered the late‐onset “cousin” to fragile X mental retardation syndrome, the most common heritable form of mental retardation. In fragile X syndrome, affected males have mental retardation because a fully expanded repeat (>200 repeats) mutation in a noncoding region of the FMR1 gene silences expression (transcriptional inactivation) of a critical neurodevelopmental protein, FMRP. An intriguing observation made a decade ago is that the grandfathers of males with fragile X syndrome can develop a late‐life neurodegenerative syn drome, FXTAS, characterized by progressive tremor, ataxia, and cognitive impairment [96–98]. Because of the particular genet ics of fragile X, in which the disease‐causing expansion enlarges over three generations, these affected males with FXTAS have a “premutation”‐sized repeat (55–200 repeats) at the FMR1 locus. Until FXTAS was described, premutations were thought not to cause disease.

For several reasons, FXTAS probably remains underrecog nized: it was only recently discovered, is highly variable in pres entation, and manifests late in life when other confounding neurological symptoms might obscure the recognition of FXTAS as a distinct syndrome. As its name suggests, most affected individuals develop a progressive ataxic gait distur bance with tremor and clumsiness accompanied by cognitive impairment. The cognitive deficits often, but not always, pro gress to subcortical dementia [99–101]. Because of its X‐linked inheritance, FXTAS is more common in men than women. Because women carry two copies of the FMR1 gene, female pre mutation carriers are less likely to develop the disease than are male carriers, who only have the premutation allele [102].

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Approximately 45% of male carriers will develop FXTAS but only 10–15% of female carriers [103].

FXTAS should be considered as the cause of progressive cog nitive impairment in elderly men who also have ataxia, with or without tremor, particularly if there is a family history of mental retardation. In a woman with these same symptoms, FXTAS should be considered if she has a history of a mentally retarded child and/or premature ovarian failure, which is also associated with the FMR1 premutation. The most common features of dis ease are gait ataxia, action tremor, and executive dysfunction, with other frequent findings being parkinsonism, psychiatric symptoms (particularly mood and anxiety disorder), peripheral neuropathy, and autonomic dysfunction [96, 97]. The range of symptoms in FXTAS is quite wide, and more severe disease and more profound cognitive disturbance are associated with longer premutation repeats. There is a continuum from unaffected car riers to those with subtle subclinical involvement to those with full‐blown dementia and movement disorder [104, 105].

A typical FXTAS case might be a man in his 60s who develops progressive unsteadiness accompanied by a shaking, clumsy hand when he attempts to write, hold a cup, or fasten buttons [106]. The kinetic tremor usually resembles benign essential tremor, but the accompanying ataxia is unusual for essential tremor. The ataxia and tremor are typically accompanied by cognitive disturbances and in some cases by parkinsonism or features reminiscent of the cerebellar form of multiple system atrophy (gait imbalance and mild autonomic dysfunction). The cognitive impairment in FXTAS is primarily frontal and subcor tical, with prominent executive dysfunction being a hallmark [99, 100]. It has been described as similar to the frontal compo nent of frontotemporal lobar degeneration, and indeed behavio ral symptoms can occur in FXTAS. The brain MRI typically

shows global brain atrophy, often with characteristic T2 hyper intensities in the middle cerebellar peduncles (the “MCP sign”; see Figure 8.3). Although the MCP sign suggests FXTAS, it is only seen in approximately 60% of cases and is more common in affected males [107]. Mood and anxiety disorders are higher in individuals with FXTAS than in “nonaffected” premutation car riers and higher in such carriers than in age‐matched controls [108]. “Nonaffected” premutation carriers tend to show subtle, subclinical impairment in executive cognitive function, suggest ing a forme fruste of the full‐blown FXTAS disorder [99, 104].

The reader is reminded that the identification of a premuta tion in an elderly person has profound implications for his/her family. Because fragile X premutations in an affected male tend to expand into the full range upon transmission through his daughter to the next generation, the male grandsons of a premu tation carrier are at high risk for having fragile X mental retar dation syndrome.

The FMR1 premutation occurs at a relatively high frequency in the population. Thus, the discovery that the premutation leads to a neurodegenerative disease characterized by tremor and gait ataxia led to speculation that individuals with benign essential tremor, progressive supranuclear palsy, or MSA might prove to have the premutation as the cause of disease. Studies have shown, however, that the FXTAS premutation is not a common cause of essential tremor, PSP, or MSA [96, 97, 109]. In individuals with these disorders who do not have radiographic features suggestive of FXTAS or a family history of mental retardation, testing for the FXTAS mutation is of low yield and probably not warranted. The most common cause of slowly progressive ataxia in the absence of a family history of similar disease is the cerebellar subtype of mul tiple system atrophy (MSA‐C). Unlike FXTAS, most individuals with MSA‐C do not develop profound cognitive dysfunction

Figure 8.3 FLAIR MRI brain images of a 59‐year‐old asymptomatic male with the FXTAS premutation. Consecutive images of the posterior fossa highlight the characteristic bilateral signal abnormality of the middle cerebellar peduncles extending into cerebellar white matter. In addition, high FLAIR signal abnormalities are observed in the cerebri and in the splenium of the corpus callosum.

qualifying as dementia. In the elderly patient with clinical features consistent with MSA‐C, no family history of mental retardation, and radiographic findings more suggestive of MSA than FXTAS (e.g., the presence of a pontine “hot cross bun” sign and absence of the MCP sign), we would not order genetic testing for the FXTAS premutation.

The pathophysiological mechanism by which the FMR1 pre mutation causes disease is still uncertain. Full expansion of the FMR1 CGG repeat silences expression of the FMR1 protein. By contrast, the FMR1 premutation actually leads to increased lev els of the FMR1 transcript and is thought to cause disease pri marily at the RNA level [98]. FXTAS is one of several repeat expansion diseases in which the expanded repeat generates a toxic RNA species [110]. Nevertheless, FXTAS is distinct from other putative toxic RNA diseases in that brains examined at autopsy show prominent, widespread ubiquitin‐positive inclu sions, suggesting a superimposed proteinopathy as in polyglu tamine diseases, PD, AD, and frontotemporal dementia (FTD) [111]. More research is needed to determine the precise patho physiology in FXTAS and to determine the best approach toward preventive therapy.

Currently, treatment of FXTAS is purely symptomatic. Therapy for mood and anxiety with standard psychoactive medications can be effective, and the parkinsonism sometimes responds to dopaminergic therapy, though less robustly than in idiopathic PD. There is no effective therapy yet for the ataxia, and the action tremor often does not respond to standard treat ment for essential tremor.

Summary

DNA repeat expansions cause a variety of neurologic disorders with motor problems, especially ataxia. Relatively few, however, result in cerebral degeneration that is widespread enough to cause progressive cognitive loss resulting in dementia. HD, SCA17, and FXTAS are the most notable exceptions. All three cause a movement disorder, a dementia with frontal/“subcortical” characteristics, and behavioral symptoms. HD and SCA17 pre sent in the prime of life, devastating affected individuals and their families; HD, however, is much more common than SCA17. FXTAS is a disease of middle‐aged to older men. Psychiatric symptoms due to these disorders often respond to pharmacotherapy, but the dementia lacks effective therapy. Ataxia is also difficult to treat, but chorea in HD does respond to medications. Genetic testing for each of these disorders is read ily available and is highly sensitive and specific.

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ChaPteR 9
Prion diseases and rapidly progressive dementias

Leonel T. Takada1 and Michael D. Geschwind2

1 University of Sao Paulo Medical School, Sao Paulo, Brazil
2 University of California, San Francisco, San Francisco, CA, USA

Rapidly progressive dementias

Rapidly progressive dementias (RPDs) often are defined as disorders that cause progressive cognitive decline (usually with other signs and/or symptoms), in which the interval between the first symptom to the onset of dementia is typically over weeks to months, but almost always less than 2 years [1–6]. Some have defined rapidly progressive neurodegenerative diseases as those in which survival is less than 3 years [3, 4] as opposed to the 9–12 years typical for most neurodegenerative diseases, such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD) [7]. RPDs might also be thought of as conditions in which Jakob–Creutzfeldt disease (CJD), the prototypical RPD, is considered in the differential diagnosis.

CJD is the most frequent form of prion disease (PrD) and one of the most common etiologies of RPD [1, 3, 8, 9]. CJD and other PrDs therefore will be the primary focus of this chapter. RPDs can also be caused by a myriad of conditions, many of which are treatable, and thus the evaluation of RPDs is challeng- ing not only for the variety of differential diagnoses but also for the sense of urgency to find a reversible or treatable cause. Potentially reversible conditions that cause RPDs are not infre- quent, even at PrD centers [1, 8]. In our UCSF RPD program, whereas PrDs were diagnosed in 62% of the suspected CJD referrals, about 16% had potentially treatable causes (autoim- mune, infectious, psychiatric, neoplastic/paraneoplastic, or toxic‐metabolic) [1]. At the US National Prion Disease Pathology Surveillance Center (NPDPSC), although 68% of the 1106 autopsied cases were positive for PrDs, 6.1% had poten- tially treatable conditions (immune mediated, infectious, toxic‐ metabolic, or neoplastic) [8].

Many of the possible differential diagnoses for RPDs have been discussed in other chapters within this volume; thus, in this chapter, we will briefly discuss the diagnoses not previously covered and provide an algorithm for the clinical evaluation and diagnosis of RPDs.

Prion diseases

Introduction

PrDs are a group of neurodegenerative disorders caused by infectious proteins called prions. The term prion is derived from “proteinaceous infectious particle” and was coined by Stanley Prusiner [10], the 1997 Nobel Prize in Physiology or Medicine laureate for his work on identifying it as the causa- tive agent of transmissible spongiform encephalopathies (TSE). PrD may occur in many species (viz., scrapie in sheep and goat, bovine spongiform encephalopathy [BSE] in cattle, chronic wasting disease in cervids, transmissible mink encephalopathy in minks, feline spongiform encephalopathy in cats, and exotic ungulate encephalopathy in greater kudu, nyala, and oryx) [11], but this chapter will focus on the human forms—for which we will use the single eponym, CJD, when referring to human prion diseases (hPrDs) in general.

CJD was first described in 1921 by the German neurologist and neuropathologist Alfons Jakob [12, 13], who felt his five cases resembled the one published by Hans Creutzfeldt 1 year prior. It is now known that Creutzfeldt’s case was not PrD (only two of Jakob’s cases are what we now consider CJD) [14]. For years, the disease was referred to as Jakob–Creutzfeldt or Jakob’s disease. A prominent PrD researcher, C.J. Gibbs preferred to have the eponym match his own initials, so he began to call the disease Creutzfeldt–Jakob disease (CJD) [15], and the name has largelystuck,althoughitishistoricallyinaccurate.Inthischapter, we will use the eponym Jakob–Creutzfeldt disease but still keep the acronym CJD to avoid often and erroneous associations with the JC virus, causative agent of progressive multifocal leukoencephalopathy.

Currently, hPrDs are classified in three groups: sporadic (85–90% of cases), genetic (10–15%), and acquired (1–3%) [16, 17]. The sporadic forms are called sporadic CJD (sCJD). The genetic forms historically are subdivided into three categories—familial CJD (fCJD), Gerstmann–Sträussler–Scheinker (GSS) disease,

103

104 Non-Alzheimer’s and Atypical Dementia

and fatal familial insomnia (FFI)—and the acquired forms include kuru, iatrogenic CJD (iCJD), and variant CJD (vCJD).

The incidence (which in this case is comparable to mortality rate, because of the short disease duration in CJD) of sCJD is about 1–1.5 per million per year in most developed countries, with some variability from year to year and between countries [17, 18]. The mortality of genetic prion diseases (gPrDs) was calculated in a pooled data from the European countries, Canada, and Australia to be 0.17 per million per year, but with a wide range (0.01–1.07) [17]. The peak age of onset of sCJD occurs around a unimodal relatively narrow peak of about 68 years [19], with an age‐of‐onset range of 12–98 years [20, 21] (Geschwind, personal communication). CJD is rare in individu- als younger than 30 years, and most of those cases are either acquired or genetic [18, 22]. There is no gender preference in sCJD, although there might be a female preponderance, possibly due to females living longer than men, creating a survival bias [18]. In the United States, an incidence 2.5 times higher in Caucasians compared to African Americans was found [18], but other interethnic comparison data is still lacking.

Pathophysiology

Prions

Gajdusek and colleagues were the first to demonstrate that human spongiform encephalopathies were transmissible [23] and, for a long time, slow viruses were thought to be the infective agents. Alper, Pattison, Griffith, and others postulated that the agent caus- ing scrapie did not contain nucleic acid and actually might be a protein [24–27]. Prusiner and colleagues’ groundbreaking work helped prove the concept that proteins could act as infections agents [10]. It is now generally accepted that PrDs are caused by the propagation of abnormally conformed infectious proteins called prions (also named PrPSc, for prion‐related protein in which “Sc” comes from scrapie). The normal cellular prion‐related protein (PrPC, in which “C” stands for the normal cellular form) is a membrane‐bound protein that is predominantly expressed in nervous tissue, but its physiologic function is not entirely known (although it probably plays a role in neuronal development and function) [28, 29]. Interestingly, recently, PrPC has also been impli- cated in the metabolism of the amyloid‐β peptide, one of the main proteins involved in AD pathogenesis [30]. Prion infectivity occurs through a mechanism in which the pathogenic PrPSc act as a tem- plate to convert PrPC into PrPSc [11, 31], such that when PrPSc, which has mostly beta‐pleated sheet structure, comes in contact with PrPC, which has mostly alpha‐helical structure, PrPC is mis- folded into the proteinase K‐resistant PrPSc. This new PrPSc then becomes a template for the conversion of existing PrPC, initiating an exponential, cascade reaction, which leads to neuronal injury and death.

PrDs are unique, as they can occur as sporadic, genetic, and infectious diseases [11]. Though the initial pathogenic step is not clear, sporadic PrD is thought to occur by spontaneous folding of PrPC into PrPSc (or maybe through a somatic mutation in the PRNP gene) [10, 32]. In gPrD, it is believed that mutations

in PRNP gene make PrPC more susceptible to changing confor- mation into PrPSc [33]. In the orally acquired forms of PrD (such as kuru and vCJD), a currently accepted mechanism of neuroinvasion starts with the uptake of prions through the intestinal epithelium. Prions then accumulate in the lymphoid tissue before being transported via sympathetic and parasympa- thetic nerves to the central nervous system (CNS) [34].

Human PrPSc often is subclassified based on the fragment properties resulting from digestion by proteinase K and running on a Western blot into type 1 and type 2 [35]. Type 1 PrPSc frag- ments are approximately 21kDa and type 2 are approximately 19kDa in unglycosylated forms. Brains of patients with sCJD can have either or both types [36]. This has implications on clinical and pathological features, as will be briefly discussed below.

Genetics

In humans, the prion‐related protein gene (PRNP) is located in chromosome 20p13 and is considerably conserved among mammals. Some interspecies sequence variation occurs, how- ever, and might be responsible for the species barrier seen in some experiments on PrD transmissibility, as the differences between the infectious PrPSc and the host’s PrPC appear to influ- ence infectivity and incubation period [32]. For example, the bank vole is very susceptible to prions from many species. Transgenic mice containing bank vole Prnp are much more sus- ceptible than wild‐type mice to prions from other species [37].

Only mutations in PRNP are known to cause gPrD [38, 39], and there are currently more than 40 known mutations in this gene [32, 40]. The majority of mutations are missense mutations, with the most common mutations being E200K (the most common worldwide), D178N, P102L, and V210I [41–43]. Stop codons, insertions (usually octapeptide repeat insertion (OPRI) mutations), and deletions of PRNP are less common causes of gPrD. The pattern of inheritance of gPrD is autosomal dominant and penetrance is usually 100%. Some mutations causing gPrD [44–46] do not have 100% pene- trance, however [42]. Among E200K mutation carriers, for example, penetrance appears to be age dependent (i.e., 1% at age 40, close to 100% after the ninth decade of life); as such, it is not uncommon to find older asymptomatic mutation carriers [47, 48].

It is also known that variations (polymorphisms) in PRNP influence an individual’s susceptibility to develop disease. The most acknowledged and important polymorphism is located in codon 129, which can have either valine (V) or methionine (M) as alleles (and so the three possible combinations are MM, MV, and VV). There is a clear overrepresentation of homozygotes (MM or VV) among PrD patients. Whereas in a normal Caucasian population about 50% are heterozygous (MV), 40% are MM, and <10% VV [49]; in every form of PrD, more than 65% of the patients are either MM or VV [17]. The particulari- ties of codon 129 polymorphisms in each form of PrD will be discussed in the appropriate sections.

Sporadic Jakob–Creutzfeldt disease

Clinical features

The clinical presentation of sCJD is highly variable. In most cases, onset is subacute, although in a few cases onset may be acute or stroke‐like [50]. In Mr. F’s case, the first symptom was unspecific sensory changes, followed by cerebellar symptoma- tology. Cerebellar symptoms are the initial manifestation in about 20% of cases, as are constitutional symptoms (such as dizziness, headaches, sleep or eating changes, or fatigue) and behavioral symptoms (e.g., depression, irritability) [51]. In about 40% of patients, the initial symptom is cognitive (most com- monly presenting as memory problems, executive dysfunction,

and/or language impairment) [19, 51]. Visual changes (blurred vision, diplopia, oculomotor changes, visual hallucinations) occur as a first symptom in 10–15% of cases [19, 51, 52]. Extrapyramidal (i.e., parkinsonism, dystonia, myoclonus, chorea) and pyramidal motor symptoms are less frequently seen as the early or pre- senting manifestation but are more likely to be seen as the disease progresses. Parkinsonism in sCJD might manifest with supra- nuclear gaze palsy, early gait problems, and/or alien limb, sometimes resembling atypical parkinsonism [53]. Dystonia is rare in AD and dementia with Lewy bodies (DLB) but has been reported to be seen in as many as 20% of sCJD cases [54].

Prion diseases and rapidly progressive dementias 105

Case 1

Mr. F was a 62‐year‐old right‐handed man who started to complain of right foot numbness, and after about a month, he began having balance problems. Three months after onset, his family noticed he was more irritable, and he soon started to have memory problems. His gait continued to worsen and was accompanied by right hand cramps; his cognition also declined with time. During neurological examination (performed 6 months after onset), he was alert and cooperative, and his Mini‐Mental State Examination score was 21/30. Neuropsychological testing revealed global cognitive impairment, with relative preservation of visuospatial functions. Neurological exam showed axial and appendicular ataxia, worse on the right. His gait was wide based, with mild postural instability. No involuntary movements were seen, and tone was increased in the upper limbs (right worse than left) only with activation. Motor and sensory examinations were

otherwise unremarkable. Past medical history consisted of hypertension and hyperlipidemia. His family history was unremarkable and negative for dementia; his father died at the age of 58 from stroke and his mother had a sudden death at the age of 85. He had three siblings (one brother and two sisters) who were in good health. CSF analysis showed mildly increased protein levels (54mg/dl; normal 14–45), 14‐3‐3 protein by Western blot was “ambiguous,” and total tau protein level was normal. EEG showed diffuse slowing, but worse on left frontal region. MRI (Figure 9.1) showed restricted diffusion on the DWI and ADC map sequences in caudate nuclei and thalamus. No cortical ribboning was observed in repeated MRIs. Other ancillary testing was unremarkable. He died after 9 months after the onset of symptoms, and autopsy confirmed the diagnosis of probable CJD. It was presumed sporadic, although antemortem PRNP testing was done and the results were pending at the time of autopsy.

(a)

(b)

Figure 9.1 Axial brain MRI of case 1. (a) DWI and (b) ADC MRI scans showing striatal (solid arrows) and medial-dorsal thalamic (dotted arrows) hyperintensities on DWI imaging, with corresponding ADC hypointensities (arrows) in a patient with probable sCJD.

106 Non-Alzheimer’s and Atypical Dementia

Myoclonus is rarely a presenting symptom but is seen during the clinical course in almost 90% of cases per one large retro- spective study [19]. Myoclonus usually starts in a limb and eventually becomes generalized; sometimes, it is associated with periodic sharp wave complexes (PSWCs) on EEG [53]. Seizures (or even status epilepticus) are rarely described as an initial manifestation of sCJD but can occur, usually later, in the disease in a minority (~8–9%) of cases [19, 52, 55]. Clinically evident peripheral neuropathy (including cranial neuropathy) is uncommon in sCJD [56], even though PrP deposits may occasionally be found in the peripheral nerves [56, 57]; certain gPrDs, such as E200K among Libyan Jews, more commonly have neuropathy [58–60].

Symptoms usually follow a rapidly progressive course, and different manifestations are added to the symptomatology throughout the course of the disease. In Mr. F’s case, cerebellar ataxia was soon followed by cognitive and behavioral changes, and the neurological examination revealed subtle extrapyramidal signs. The common final pathway of sCJD in most cases is the development of akinetic mutism, the terminal extrapyramidal manifestation [53]. Patients with sCJD and other PrDs usually die from aspiration pneumonia.

Median duration of disease is reported to be around 4–6 months (mean 7 months), and death occurs within 1 year in 90% of cases, with another 5% of patients dying in the second year of disease [19, 61]. Younger age of onset, female gender, and heterozygosity at PRNP codon 129 have been associated with longer survival in sCJD [61].

sCJD has been divided into six molecular subtypes based on the polymorphisms at codon 129 in the prion gene (MM, MV, or VV) and the type of protease‐resistant prion (type 1 or 2) [35]. This classification, to some extent, separates sCJD cases based on their clinicopathological features. The MM1 and MV1 variants are the most frequent type (60–70% of cases) and are characterized by sCJD with a faster course, with a reported median survival of about 4 months. The VV2 type is characterized by ataxia with a later age of onset and short disease duration (about 6.5 months); the MV2 type is similar to the VV2 but has longer disease duration (17.1 vs. 6.5 months). The VV1 type is the less frequent variant and associated with the earliest age of onset. The MM2 type is fur- ther divided into cortical and thalamic type; the MM2 tha- lamic type is considered by some as the sporadic form of fatal insomnia. Since this classification scheme was established, it later was reported that type 1 and 2 prions often coexist in the same patient, so this classification scheme will need some revision. Preliminary analysis suggested that MM1/2 type phenotypically falls in between MM1 and MM2 subtypes [35, 36, 62, 63].

Amidst the great variability in clinical presentation, a few sCJD variants are recognized: the Heidenhain variant (less than 10% of sCJD cases; it is characterized by visual symptoms at presentation, such as visual hallucinations or distortions, corti- cal visual deficits, and/or oculomotor impairment; mostly MM1 [48, 64]), the Brownell–Oppenheimer variant (with ataxia as the

presenting and dominant symptom, and lack of EEG PSWCs and deep nuclei hyperintensities [64]), a thalamic variant (sometimes referred to as sporadic fatal insomnia [sFI]; linked to MM2 [65, 66]), the panencephalopathic form (with signifi- cant or primary involvement of white matter; described primar- ily in Japan and only rarely seen in Caucasians [see following text, in neuroimaging] [67, 68]), and an amyotrophic form (with motor neuron disease findings) [69].

More recently, a new form of PrD was described, based on the finding that in a group of cases with similar clinical and neuropathological features, the PrPSc was more sensitive to proteinase K digestion. Those cases were termed as having variable proteinase‐sensitive proteinopathy (VPSP) and are clinically characterized by having aphasia, ataxia, and parkin- sonism as prominent manifestations and a longer disease course than sCJD [63, 70, 71].

Diagnostic criteria

The most commonly used diagnostic criteria are the ones pro- posed by the World Health Organization (WHO) in 1998 [72]. Those criteria do not take into consideration MRI findings (which are the most sensitive diagnostic test for PrD), and so, more recently, two other criteria have been published (see Table 9.1 for a review of all three).

Diagnostic criteria for sCJD are developed primarily for research purposes and aim to obtain the highest accuracy in predicting neuropathologically confirmed CJD. Because of that, the criteria are not particularly sensitive early in the disease course, and most cases will only fulfill diagnostic criteria later in the illness (e.g., akinetic mutism is one of the clinical criteria, despite being a late occurrence). The UCSF criteria for sCJD were first proposed in 2007, and they modified the WHO symp- tom criteria by substituting MRI for the CSF 14‐3‐3 protein [2, 73], separating visual and cerebellar symptoms from one another and adding the symptom of higher focal cortical signs. The UCSF CJD MRI criteria were updated in 2011 and are detailed in Table 9.2 [74].

Neuroimaging

Brain MRI is currently the most accurate method for the diag- nosis of sCJD, with approximate sensitivity of 92–96% and spec- ificity of 92–94% using diffusion‐weighted imaging (DWI) [74, 75]. MRI changes can also be seen very early in the disease course (even though in some cases MRI abnormalities will only appear with repeated MRIs) [75], further enhancing its value for the diagnosis. MRI used for the diagnosis of CJD should always include DWI and apparent diffusion coefficient (ADC) sequences, as DWI findings are far more sensitive than FLAIR and/or T2 sequence abnormalities [74, 75].

There are three major patterns of DWI MRI hyperintensities in sCJD (Figure 9.2): cortical and deep nuclei (68% of cases), predominantly neocortical (24%), and predominantly deep nuclei (primarily the striatum; with or without thalamic changes—the pattern seen in Mr. F’s case, Case 1) (5%) [74, 76]. The molecular classification of PrD seems to affect the pattern of MRI

Table 9.1 Diagnostic criteria for sporadic Jakob–Creutzfeldt disease.

WHO 1998 revised criteria [72]

1. Progressive dementia

2. At least 2 of the following four features:
a) Myoclonus
b) Visual or cerebellar disturbance

c) Pyramidal/ extrapyramidal signs d) Akinetic mutism

3. PSWCs on the EEG and/or a positive 14‐3‐3 CSF assay and a clinical duration to death < 2 years

4. No alternative diagnosis on routine investigations

UCSF 2007 criteria [73]

1. Rapidly progressive dementia with at least 2 of the following:
a) Myoclonus
b) Pyramidal/ extrapyramidal dysfunction

c) Visual disturbance
d) Cerebellar signs
e) Akinetic mutism
f) Other higher focal cortical sign†

2. Typical EEG or MRI
3. Routine investigations should not suggest an

alternative diagnosis

European criteria 2009* [188]

1. Progressive dementia
2. At least 2 of the following four features:

a) Myoclonus
b) Visual or cerebellar disturbance c) Pyramidal or extrapyramidal signs d) Akinetic mutism

3. One of more of the following:

Prion diseases and rapidly progressive dementias 107

a) b)

Periodic discharges on the EEG
A positive 14‐3‐3 CSF assay and a clinical duration to death < 2 years
High signal abnormalities in caudate nucleus and putamen or at least two cortical regions (temporal/ parietal/occipital, but not frontal, cingulate, insular, or hippocampal) either in DWI or FLAIR MRI
No alternative diagnosis on routine investigations

* Clinical criteria as originally printed in [188] were erroneous, leaving out myoclonus and putting dementia
† Higher focal cortical signs include such findings or symptoms as apraxia, neglect, acalculia, aphasia, etc.
CSF, cerebrospinal fluid; DWI, diffusion‐weighted imaging; EEG, electroencephalogram; FLAIR, fluid‐attenuated inversion recovery; MRI, magnetic resonance imaging; PSWCs, periodic sharp wave complexes.

Table 9.2 UCSF 2011 MRI criteria for sCJD.

as one of the four possible features.

MRI definitely CJD

MRI probably CJD MRI probably not CJD

MRI definitely not CJD Other MRI Issues

DWI>FLAIR hyperintensities in:
1. Classic pathognomonic: cingulate, striatum, and >1 neocortical gyrus (often the precuneus, angular, superior, or middle

frontal gyrus).
Supportive for deep nuclei involvement:
• Striatum with anterior‐posterior gradient
• Subcortical ADC hypointensity
Supportive for cortical involvement:
• Asymmetric involvement of midline neocortex or cingulate • Sparing of the precentral gyrus
• ADC cortical ribboning hypointensity

2. Cortex only (>3 gyri); see supportive for cortex (above)

1. Unilateral striatum or cortex ≤3 gyri; see supportive for deep nuclei (above); see supportive for cortex (above) 2. Bilateral striatum or posteromesial thalamus; see supportive for deep nuclei (above)

1. Only FLAIR/DWI abnormalities in limbic areas, where hyperintensity can be normal (e.g., insula, anterior cingulate, hippocampi) and ADC map does not show restricted diffusion in these areas

2. DWI hyperintensities due to artifact (signal distortion); see other MRI issues (below) 3. FLAIR>DWI hyperintensities; see other MRI issues (below)

1. Normal
2. Abnormalities not consistent with CJD

1. In prolonged courses of sCJD (approximately >1 year), brain MRI might show significant atrophy with loss of DWI hyperintensity, particularly in areas previously with restricted diffusion

2. To help distinguish abnormality from artifact and obtain sequences in multiple directions (e.g., axial and coronal)

Source: Vitali et al. [74]. Reproduced with permission of Wolters Kluwer Health, Inc.
ADC, apparent diffusion coefficient; CJD, Creutzfeldt–Jakob disease; DWI, diffusion‐weighted imaging; FLAIR, fluid‐attenuated inversion recovery; sCJD, sporadic Creutzfeldt–Jakob disease

involvement [77]. Cortical hyperintensities (or cortical ribbon- ing) can be seen in almost any neocortical region but with rela- tive sparing of the precentral cortex [74]. Figure 9.2b shows an example of a predominantly cortical DWI in sCJD. Deep nuclei hyperintensities usually involve the striatum, often with an anterior‐posterior gradient (i.e., the anterior caudate being more hyperintense than the posterior putamen) [74]. Involvement on MRI may be bilateral and symmetric, bilateral but asymmetric, and even completely unilateral. Limbic (i.e., insula, anterior cingulate, hippocampus) hyperintensities may

be seen as an additional finding in up to 90% of sCJD cases (with the caveat that these regions are more frequently associ- ated with artifacts and/or false‐positive abnormalities), but pre- dominant or isolated limbic abnormalities generally are not characteristic of sCJD and should make one consider a nonp- rion diagnosis (particularly infectious or autoimmune encepha- litis and seizures) [74]. Whenever an area of hyperintensity is questioned to be false positive, adding coronal and sagittal acquisitioned images to the evaluation, as well as searching for correspondent ADC map hypointensities, may be helpful [74].

108 Non-Alzheimer’s and Atypical Dementia

(a)

(b)

(c)

(d)

FLAIR

DWI ADC

Figure 9.2 Axial brain MRI in sporadic CJD and variant CJD. (a-c) Each show a FLAIR, DWI and ADC sequences, whereas d shows only a FLAIR and DWI sequence. (a) Neocortical (solid arrow), limbic (dashed arrow) and subcortical (dotted arrow) DWI and FLAIR hyperintensities with corresponding ADC hypointensities in sporadic CJD. (b) Neocortical (solid arrow) and limbic (dashed arrow) DWI hyperintensities with corresponding ADC hypointensities in sporadic CJD. (c) Subcortical (dotted arrows) DWI and FLAIR hyperintensities, with corresponding ADC hypointensities in sporadic CJD. (d) Pulvinar sign (arrow) in variant CJD. ADC, apparent diffusion coefficient; CJD, Creutzfeldt–Jakob disease; DWI, diffusion‐weighted imaging; FLAIR, fluid‐attenuated inversion recovery; MRI, magnetic resonance imaging. Source: Adapted from Vitali et al. [74, 189]. Reproduced with permission of Wolters Kluwer Health, Inc.

The DWI hyperintensities have a pattern of water diffusion restriction (probably caused by vacuolation [78]), with corre- sponding hypointensities in the ADC maps. The ADC hypoin- tensities are more easily identified in the deep nuclei but may also be found in cortical regions [74]. Cortical ribboning on DWI can also be seen in viral encephalitis, seizures, status epi- lepticus, hypo‐ and hyperglycemia (often with seizures), Wernicke’s encephalopathy due to thiamine deficiency, and

acute stroke (though usually associated with concomitant white matter abnormalities). Striatal or thalamic DWI hyperintensities with ADC hypointensities have also been described in extrapon- tine myelinolysis, Wilson’s disease, Wernicke’s encephalopathy, Bartonella infection, and hyperglycemia with seizures (as reviewed by Vitali et al. [74]) [79–81]. Mitochondrial disease, vasculitis, acute phase of hypoxic ischemic encephalopathy, posterior reversible leukoencephalopathy, and lymphoma may

also be considered in the differential diagnosis of DWI hyperin- tensities [75, 82]. White matter abnormalities are typically absent in sCJD, except in the rare panencephalopathic form of CJD, which is associated with major white matter hyperintensi- ties in T2‐weighted MRI [83]. Many feel that the panencephalo- pathic form of sCJD merely occurs in patients with prolonged courses, often due to life‐extending measures such as feeding tubes or intubation, and is due to Wallerian degeneration [67]. With the progression of disease, particularly in patients with disease duration of over 1 year, as atrophy progresses, DWI hyperintensities might fade away and be absent on later MRI scans [74].

Laboratory and EEG findings

Blood tests

There are no currently available clinical blood tests for the diagnosis of CJD. Blood tests, however, are always necessary to exclude other causes of RPD, as will be discussed in the following.

Cerebrospinal fluid

General cerebrospinal fluid (CSF) analysis is typically nor- mal in sCJD, except mildly elevated protein (typically less than 75 mg/dl) is not uncommon. Although elevated protein (>75, <100 mg/dl), pleocytosis (>5 WBC cells), elevated IgG index, or the presence of oligoclonal bands rarely do occur in sCJD [84], their presence should lead to considering other conditions, particularly infectious or autoimmune disorders.

The most common CSF markers used in clinical practice are 14‐3‐3 protein, total tau (t‐tau), and neuron‐specific enolase (NSE) (S100β is used primarily in the United Kingdom [85]), but due to great variability in accuracy across studies, the clini- cal value of each marker is still not entirely clear. A large European study has found the sensitivity and specificity of the 14‐3‐3 to be 85 and 84%, t‐tau (cutoff >1300 pg/ml) 86 and 88%, NSE 73 and 95%, and S100β 82 and 76%, respectively [86], and CSF markers collected later in the disease course seemed to be more sensitive than those collected earlier [87]. Among these three more common biomarkers, t‐tau might be the best CSF diagnostic marker for sCJD, although there is still no complete agreement over its cutoff value, which tends to vary between 1150 and 1300 pg/ml. Combining markers also seem to increase their diagnostic value [85, 86].

The 14‐3‐3 protein is a nonspecific marker for neuronal injury and can be increased in non‐PrD, such as cerebrovascular disease, metabolic and hypoxic encephalopathies, brain metas- tases and CNS infections, or even other neurodegenerative dementias [85, 88]. Overall, the 14‐3‐3 is not a very specific test; one large study found it to have about 40% specificity for CJD [63]. Among PrDs, 14‐3‐3 protein is not consistently elevated in genetic and iatrogenic forms [89]. A new assay for detecting prions, called real‐time quaking‐induced conversion (RT‐QuIC), can detect very minute amounts of PrPSc by using in vitro conversion of PrPC as a substrate [90]. The test is based on a

combination of two methods for prion detection—a PCR‐like method of amplifying prions called protein misfolding cyclic amplification (PMCA) [91] and an amyloid seeding assay [92]. The sensitivity and specificity of this assay in CSF for sCJD appear to be around 87 and 98%, respectively, based on prelimi- nary studies [93, 94].

Electroencephalogram

A typical EEG in sCJD has sharp, or triphasic, waves (PSWCs) occurring about once every second. This EEG finding, how- ever, is found in only about two‐thirds of sCJD patients and usually only after serial EEGs and/or not until later stages of the illness [95]. Often, the only finding is focal or generalized slowing. PSWCs are relatively specific, but they can also be seen in other conditions, including toxic‐metabolic and anoxic encephalopathies, progressive multifocal leukoencephalopathy, AD, Lewy body dementia, and Hashimoto’s encephalopathy [96, 97].

Neuropathology

Mild atrophy usually is the only gross neuropathological finding in sCJD brains, and it is not always present. The typi- cal neuropathological findings are neuronal loss, gliosis, and vacuolation (or spongiform changes), without inflammatory signs (Figure 9.3). Current diagnostic criteria for definite sCJD also require positive PrPSc tissue immunoreactivity [98, 99]. PrP amyloid plaques (or kuru plaques) are found in 5–10% of sCJD cases, particularly MV2 [65, 99]. These plaques are more char- acteristic of GSS, as will be discussed in the following section.

Genetic prion disease

Prion diseases and rapidly progressive dementias 109

Case 1 (continued)

Even though Mr. F’s case was clinically and by brain pathology considered consistent with sporadic CJD, PRNP testing by blood test (and later from frozen brain tissue) later revealed an E200K–129M mutation. Upon receiving this information, his siblings requested to be tested for PRNP mutations. His older brother was found to carry the E200K mutation, but was asymptomatic at the age of 65, which is not that unexpected as the E200K mutation has approximately 60–96% penetrance, unlike most other PRNP mutations which have 100% penetrance [46, 47, 100].

Introduction to gPrD

gPrDs historically have been divided according to clinical and pathological characteristics into three forms: fCJD, GSS, and FFI. Identifying the prion gene, PRNP, has helped classify gPrDs more precisely by specific mutations, which include mostly point mutations, but also insertions (octapeptide repeats) and deletions [101]. A caveat to classifying patients by their PRNP mutation is that a single PRNP mutation can be associated with different phenotypes (and great variability even within a single family) [102]. Some of this variability depends on the codon 129 polymorphism but other unidentified factors as well.

110 Non-Alzheimer’s and Atypical Dementia

(a)

(b)

Another fundamental issue is that gPrDs are sometimes referred to as familial, but considering that up to 60% of the gPrD cases do not have a positive family history [42], the term “familial” can be misleading. We prefer not to use the term fCJD, as many patients with gCJD or gPrD, a family history of PrD is not known; this can be due to several reasons, including reduced penetrance or misdiagnosis [42, 46]. In those cases of negative family history, often there is a history of family members being (mis) diagnosed with more common neurodegenerative diseases such as AD or Parkinson’s disease [42]. Other possibili- ties are incomplete or age‐dependent penetrance [46, 103] (such as in case 1’s, Mr. F’s, brother and possibly his father, whose death from stroke may have occurred before he would develop CJD symptoms) or incomplete family history (the disease may even be kept secret from younger members of a family; M. Geschwind, personal experience).

Genetic Jakob–Creutzfeldt disease

The clinical features of gCJD are highly variable, and inter‐ and intrafamiliar variations may be seen (not only the muta- tion but also codon 129 polymorphism may affect presentation) [65]. As a group and in comparison to sCJD, gCJD is associ- ated with a younger age of onset (typically <55 years; but onset may occur as late as the ninth decade) and longer clinical course [41, 48, 61]. Also, ancillary testing including CSF, EEG, and MRI may not be as sensitive or specific as in sCJD [41, 65, 104].

The E200K mutation is the most frequent PRNP mutation worldwide, and higher frequency of this mutation has been found among Libyan Jews and in Slovakia [105]. The clinical features (and neuropathological features) are highly variable, but in general comparable to sCJD, including age of onset and duration of disease [41]. Dementia and ataxia are the most fre- quently described symptoms, but vertical gaze palsy, polyneu- ropathy, and sleep changes have also been reported [60].

GSS

Mr. D (Case 2) had the prototypical GSS, which typically pre- sents as a subacute progressive ataxic and/or parkinsonian dis- order with later onset of cognitive impairment, and onset most commonly occurs in the fourth to sixth decades (but can occur as early as the twenties [41]). Because it is usually slower than sCJD or many other gPrDs, often with duration of about 5 years (range 3–8 or more years), the differential diagnoses of GSS are ataxic and/or parkinsonian conditions, such as multiple system atrophy, other atypical parkinsonian disorders, idiopathic Parkinson’s disease, as well as ataxic disorders such as spinocer- ebellar ataxias or Huntington’s disease. Pyramidal signs may also be found, and lower limb dysesthesia and areflexia may be other associated clinical features, especially in the P102L muta- tion [106, 107].

There is considerable phenotypic variability within and between mutations and families, and some cases may not even have ataxia as a main characteristic and rather present with early

(c)

(d)

Figure 9.3 Neuropathological findings in prion diseases. (a) In sporadic CJD, some brain areas may have no (hippocampal end plate, left), mild (subiculum, middle), or severe (temporal cortex, right) spongiform change. Hematoxylin and eosin (H&E) stain. (b) Cortical sections immunostained for PrPSc in sporadic CJD: synaptic (left), patchy/ perivacuolar (middle), or plaque type (right) patterns of PrPSc deposition. (c) Large kuru‐type plaque, H&E stain. (d) Typical “florid” plaques in vCJD, H&E stain. Source: Adapted from Budka [98]. Reproduced with permission of Oxford University Press. (See insert for color representation of the figure.)

Prion diseases and rapidly progressive dementias 111

Case 2

Mr. D. started complaining of balance problems at the age of 57. Symptom onset was gradual, and after a few months, his wife also started noticing an action tremor in his left hand. His gait problems progressed, and he also noticed a change in his voice (as if he had something in his mouth), as well as his handwriting. A neurological exam performed 2 years after symptom onset showed cerebellar ataxia (axial worse than appendicular) and preserved cognition. No pyramidal signs or other

involuntary movements were appreciated at that time. An MRI done
2 years after onset was normal (Figure 9.4), and PRNP sequencing revealed a P102L mutation. Three years after symptom onset, he was wheelchair bound, and 4 years after onset, cognitive decline ensued. His father and paternal grandfather had progressive gait problems starting in their fifties. One of his four siblings was also affected by similar symptoms at the age of 48. Mr. D died after 5 years of disease, and his autopsy confirmed the diagnosis of GSS.

(b)

(a)

Figure 9.4 Axial brain MRI of case 2 with GSS due to a P102L mutation in PRNP. (a) FLAIR and (b) DWI MRI scans show no clear abnormality. There is a suspicion of DWI hyperintensity in the bilateral posterior insula and posterior limb of bilateral hippocampi, which were not, however, hypointense on the ADC map (not shown). Cerebellum was also normal (not shown).

dementia and/or behavioral abnormalities [41, 48]. At least 15 PRNP mutations have been shown to cause GSS [102]. EEG in most cases does not show typical CJD findings, and CSF protein 14‐3‐3 is increased in about 50% of cases [42]. MRI scans are usually normal, and some degree of brain and cerebellar atrophy may be seen with the progression of disease [106]. Cortical rib- boning or deep nuclei (striatal or thalamic) hyperintensities on T2/FLAIR or DWI are uncommon findings in GSS but have been reported [106, 108, 109]. Our own study found that limbic DWI or FLAIR hyperintensities can be found in some cases, but it was not clear that these were true diffusion restricted [74].

Classic neuropathological findings of GSS are its distinct large PrPSc amyloid plaques, called kuru plaques (Figure 9.3c), in association with pyramidal tract degeneration [48, 98, 99]. PrPSc amyloid plaques rarely are seen in other prion disorders, but their presence should make one consider PRNP testing. There is often gliosis but less vacuolation than classic sCJD [41]. GSS symptoms usually begin in the second to eighth decades (typically 20s–60s) with a mean duration of about 5 years [102],

although a 15‐year‐old with a progressive motor and cognitive disorder beginning at age 10 was recently found by whole exome sequencing to have a de novo GSS mutation.

FFI

FFI is a rare disorder that usually begins with progressive, severe intractable insomnia that is present for several months before onset of other symptoms, such as dysautonomia, ataxia, or other motor symptoms, with cognitive problems appearing later in the course. Progressive insomnia is eventually associ- ated with hallucinations. Onset usually occurs in the fifth and sixth decade with duration of around 12–18 months [48, 61]. Although brain MRI is usually normal, FDG‐PET imaging reveals thalamic and cingulate hypometabolism, often even before disease onset. FFI is caused by a single PRNP point mutation, D178N, with codon 129 M on the same chromo- some (cis) (patients with D178N‐129V usually present with fCJD) [110]. The neuropathology of FFI is primarily charac- terized by thalamic gliosis and neuronal loss [48, 98].

112 Non-Alzheimer’s and Atypical Dementia

acquired prion disease

Kuru

Kuru (“to shake or tremble” in the Fore language) [111] was a form of PrD confined to the Fore ethnic group of Papua New Guinea and was transmitted through a practice in which deceased relatives were honored by ritualized cannibalism. The clinical presentation was of pure cerebellar ataxia (and relatively preserved cognition) and an illness duration of 6–36 months [112]. The practice of cannibalism stopped in the late 50s, and since then, the incidence of kuru decreased dramatically (from the more than 2700 cases identified between 1957 and 2004, only 11 occurred after 1996) [113]. The mean incubation period was estimated to be around 12 years, but with a wide range from 5 to 56 years (particularly longer in those heterozygous at codon 129) [113].

Iatrogenic Jakob–Creutzfeldt disease

More than 400 cases of iCJD have been reported, either from the use of cadaveric‐derived human pituitary hormones, dura mater grafts, and corneal transplants, reuse of EEG implanted depth electrodes, and other neurosurgical equipments [114, 115]. The number of iCJD cases has been decreasing over the past years, probably due to increased surveillance and use of effective decontamination measures, but continuing surveillance is still necessary [114, 116].

The first recognized human‐to‐human transmission of CJD was reported in 1974, when a 55‐year‐old woman developed CJD 18 months after having inadvertently received a corneal transplant from a donor with CJD [117]. A second case associ- ated with corneal transplant was reported years later, with an incubation period of 30 years [118]. In 1977, a report described two cases of iCJD caused by contaminated implanted stereotactic EEG electrodes that had been previously used in a CJD patient (incubation time of 16 and 18 months) [119]. Other neurosurgi- cal instruments have also been implicated in iCJD cases [112], thus reinforcing the need of preventive measures when dealing with prions (see decontamination measures in the following).

Cadaveric human pituitary hormones (human growth hormones [hGH] and human pituitary gonadotropic [hPG] hormones) were used for medical treatment from the late 1950s until mid‐1985, and more than 30000 patients are thought to have received them. In 1985, a report first mentioned the association between CJD and hGH, leading to the suspension of human pituitary hormone. The cases of hGH iCJD (~200 world- wide) occurred mainly in France, the United Kingdom, and the United States, and the incubation period was calculated to be around 15 years (range 4–36 years) [114]. The clinical pres- entation usually was of pure cerebellar ataxia, with dementia occurring only late (if at all) in the disease progression [112]. As in other forms of iCJD, PRNP codon 129 homozygosity is a risk factor of hGH iCJD [120]. hGH iCJD risk varies from country to country; in the United States, no cases were reported from individuals that received hormones after 1977 (when purifica- tion methods were changed), whereas in France there was a

strong clustering of cases that received hormone between 1982 and 1985 [121, 122]. In the early 1990s, four cases of iCJD associated with hPG were identified in Australia, in women who had received the hormone in the 1970s as an infertility treat- ment [114, 121, 123]. No cases of hPG iCJD have been reported in other countries.

The last major group of iCJD are those associated with cadaveric dura mater grafts, which was first recognized in 1987 [124]. Around 200 cases have been reported worldwide, and more than 60% occurred in Japan (but also in France, Spain, Germany, United Kingdom, and other countries) [114]. Lyodura© was the brand implicated in more than 90% of the cases, and no iCJD cases have been reported in patients who received the first dural graft in 1993 [112, 125]. The incubation period was calculated in the Japanese sample to range from 1.2 to 24.8 years, and the mean age of onset of symptoms was 55 years (range 15–80) [126]. Homozygosity at codon 129 (particularly M) is also a risk factor for this form of iCJD [114, 126].

Variant Jakob–Creutzfeldt disease

vCJD was first recognized in 1995 in the United Kingdom [127] and soon received worldwide attention for its association with BSE, or mad cow disease. As of June 2014, approximately 225 vCJD cases have been identified, most in the United Kingdom and France [128]. BSE is the only non‐hPrD currently believed to be transmissible to humans, and it is thought that BSE occurred from the practice of feeding scrapie‐infected sheep products to cattle. More than 180000 cattle suffered from BSE, the vast majority in the United Kingdom [129]. Although the incidence of BSE has dramatically declined since 1992, a few isolated cases have still been reported over the past few years [129].

But how was BSE diseased cattle’s meat consumption associated with vCJD? Since the first report of vCJD [127], a possible asso- ciation between with BSE was raised due to the epidemiological temporal relationship between the two diseases. Compelling evidence soon came from experimental studies, in which similarities were found between BSE and vCJD PrP strains in mouse transmission studies, leading to the conclusion that they were caused by the same agent [130, 131].

It was later found out that vCJD could not only be acquired through contaminated beef consumption but also from blood product transfusion and there have been five cases reported so far with this association [132–136]. Four of those patients acquired vCJD from nonleukodepleted blood transfusions received before 1999, and one was a hemophiliac patient who received factor VIII in the 1990s from a contaminated batch. The incubation period ranged from 6 to 9 years in the three 129MM patients that died with definite vCJD. The other two patients (one acquired via blood transfusion, the other via factor VIII) were 129MV and died of nonneurological causes but had posi- tive prion testing in their lymphoreticular system; it is not known whether they ever would have developed neurologi- cal PrD, although they were likely carriers. Because of this,

additional measures were taken to prevent transmission of vCJD through blood products. Aside from donor selection and efforts toward developing methods to detect PrP in the blood, one of the main measures taken was universal leukoreduction of donated blood (which is being done since 1999 in the United Kingdom and later in the rest of Europe) [129]. In one study with hamsters, leukoreduction was shown to reduce TSE infectivity by 42% (comparing to whole blood) [137]. It is important to note that although transmission through blood products has been reported in vCJD, there are no known cases to date of transmis- sion from sCJD patients through blood transfusion [138].

Codon 129 polymorphism is an important susceptibility factor for the development of vCJD, and almost every case reported so far has been 129MM (except for one symptomatic probable vCJD and the two presymptomatic blood product transfusion cases mentioned above) [139].

The clinical presentation of vCJD is different from sCJD in several ways. Patients with vCJD are usually younger, with a median age of onset around 27 (range 12–74) [140, 141]. The vast majority of cases occurred in persons younger than age 50; and among the patients in the United Kingdom, 12% died at age 20 or younger [142]. The mean disease duration is longer, about 14.5 months (vs. ~7 months for sCJD). Although psychiatric symptoms often occur early in sCJD [51], prominent psychiatric symptoms are often the initial symptoms in vCJD for several months (typically more than six) before obvious neurologic symptoms begin. The EEG only rarely shows the classic PSWCs and, if so, then only at the end stage of disease [143]. Brain MRI usually shows the “pulvinar sign,” in which the pulvinar (posterior thalamus) is brighter than the anterior putamen on T2‐weighted (and probably also on DWI) MRI (and was found in more than 85% of cases in the first exam) (Figure 9.2d) [144]; this finding is very rare in other hPrDs [145, 146]. Posterior thalamic hyper- intensities have been reported in gCJD (in E200K mutations) and in sCJD, but in those cases, the basal ganglia are usually brighter than the posterior thalamus [147]. Diagnostic criteria for probable vCJD are shown in Table 9.3 and have reported sensitivity of 83% and specificity of 100% [140].

Definitive diagnosis of vCJD is based on neuropathologic evidence of the variant form of PrPSc in brain biopsy or autopsy. Because vCJD is acquired peripherally, PrPSc can be found in the lymphoreticular system, including tonsillar tissue [148]. Brain pathology of vCJD shows abundant PrPSc deposition, in particular multiple fibrillary PrP plaques surrounded by a halo of spongi- form vacuoles (“florid” plaques) and other PrP plaques and deposits, especially prominent in the cerebellar molecular layer (Figure 9.3d) [98, 149].

From the blood product vCJD cases, it is now known that transmission from asymptomatic blood donors may occur years before the onset of symptoms, and so there is currently concern over the possibility of a second wave of vCJD in the future [150]. Exposed individuals with MV or VV genotype at codon 129 of the PRNP gene may also have longer incubation times, which could potentially increase the chance of a second wave. In an

Prion diseases and rapidly progressive dementias 113 Table 9.3 Diagnostic criteria for vCJD.

Definite: IA and neuropathological confirmation of vCJD* Probable: I and 4/5 of II and IIIA and IIIB or I and IVA. Possible: I and 4/5 of II and IIIA
I

A) Progressive neuropsychiatric disorder
B) Duration of illness>6 months
C) Routine investigations do not suggest an alternative diagnosis D) No history of potential iatrogenic exposure
E) No evidence of a familial form of TSE

II
A) Early psychiatric features†
B) Persistent painful sensory symptoms‡ C) Ataxia
D) Myoclonus or chorea or dystonia
E) Dementia

III
A) EEG does not show the typical appearance of sporadic CJD§ in the

early stages of illness
B) Bilateral pulvinar high signal on MRI scan

A) Positive tonsil biopsy¶

Source: Modified with permission from Heath et al. [140].

* Spongiform change and extensive prion protein deposition with florid

plaques throughout the cerebrum and cerebellum.

† Depression, anxiety, apathy, withdrawal, and delusions.

‡ Includes frank pain and/or dysesthesias.

The typical appearance of the EEG in sporadic CJD consists of generalized triphasic periodic complexes at approximately 1 per second. These may occasionally be seen in the late stages of vCJD.
¶ Tonsil biopsy is not recommended routinely nor in cases with EEG appearances typical of sporadic CJD but may be useful in suspect cases in which the clinical features are compatible with vCJD and MRI that does not show bilateral pulvinar high signal.

EEG, electroencephalography; MRI, magnetic resonance imaging; TSE, transmissible spongiform encephalopathy; vCJD, variant Jakob–Creutzfeldt disease.

initial study in the United Kingdom, vCJD prions were found by immunostaining in 3 of 11246 (~1 in 4000) appendix samples collected from 1995 to 2000 [151]. A more recent, larger study found that the rate of vCJD‐affected appendices was 16 of 32 441 (~1 in 2000), about double the earlier study, suggesting an overall prevalence of 493 per million population [152]. Because the sam- ples were anonymized, it is only possible to assume that there are asymptomatic persons in the UK population with vCJD prions in their lymphoreticular system (subclinically infected) who are at a minimum carriers of the disease. It is not clear what their risk is of developing symptomatic vCJD and/or transmitting it to others through medical/surgical procedures or blood products.

treatment and management

In spite of all active efforts, there are no currently available drugs to change disease progression in hPrD, and so, sympto- matic treatment is the only available option. Past efforts included quinacrine, an antimalarial drug, the antibiotic doxycycline, and the analgesic flupirtine, none of which recently have been

114 Non-Alzheimer’s and Atypical Dementia

shown to be effective in halting the progression of CJD [153–156]. Intraventricular pentosan polysulfate, an anticoagulant, was used in a few cases in the United Kingdom and in Japan, but its benefit is still uncertain. At best, it might prolong survival, but not affect disease progression and disability [157–160]. Symptomatic treatment may include the empirical use of SSRIs to treat depression and agitation, atypical antipsychotics (partic- ularly quetiapine) to treat agitation and psychoses, and clonaz- epam to treat severe myoclonus or agitation.

Two other management points are fundamental. As men- tioned before, a significant percentage of gPrD have no evident positive family history (and sporadic PrD and gPrD may be clinically indistinguishable), and so genetic testing should be considered for every PrD patient (genetic counseling is indis- pensable prior to testing for PRNP mutations). Also, family and caregiver education is paramount in the disease process. In some countries around the world, there are organizations (such as the CJD Foundation in the United States; http://www.cjdfoundation. org) specialized in providing the necessary information on the care of patients with PrD [161]. More on family and caregiver issues will be discussed in Chapter 15.

Prion decontamination and preventive measures

Decontamination of prions requires methods that will denature proteins, as prions resist normal inactivation methods used to kill viruses and bacteria. Typical methods for reducing the load of or inactivating prions include very high temperatures for prolonged periods, autoclaving at higher than normal temperatures, pres- sure, and time and with or without denaturing agents (many of which are caustic). Those measures often damage medical equip- ment and instrumentation [162]. WHO guidelines state that the preferred method is steam sterilization for at least 30 min at 132°C in a gravity displacement sterilizer. If a prevacuum sterilizer is used, they note 18 min at 134°C also is effective. Another option is 1M sodium hydroxide or 2% sodium hypochlorite for 1 h with 134°C autoclaving for at least 18min. Nonfragile items may be immersed in 1N sodium hydroxide, a caustic solution, for 1h at room temperature and then steam sterilized for 30 min at a tem- perature of 121°C [116, 163]. Due to the risk of transmission to subsequent patients, when feasible, many hospitals dispose of neurosurgical and other surgical equipment potentially exposed to prions by incineration. Our own medical center has developed its own policies and procedures for patients with suspected or confirmed hPrD, which are in some ways stricter than WHO guidelines, in part due to the large number of patients with PrD assessed at UCSF (http://infectioncontrol.ucsfmedicalcenter.org/ sites/infectioncontrol.ucsfmedicalcenter.org/files/Sec% 204.2%20Human%20Prion%20Policy.pdf ).

Aside from prion decontamination, additional preventive measures have been taken (some of which have been commented above) to avoid further iCJD cases. Known pathogenic PRNP

mutation carriers are asked not to donate blood, even though the actual risk of transmissibility in humans is unknown [164]. Patients who received potentially contaminated human pituitary hormones were likewise advised in some countries [123, 165]. Otherissuesinvolvingthoseat‐riskindividualsarestillunknown (such as the necessary precautions needed to avoid transmission after a general surgery), pointing out the need for further research.

Differential diagnosis of rapidly progressive dementias

Case 3

Mrs. W, a 59‐year‐old woman, with a past medical history of depression, began to have subacute onset of gait problems, followed after a month by apathy, myoclonic jerks in her upper limbs, and later dystonic posturing of her hands. Cognitive decline soon followed, and at the time of her evaluation (2 months after onset), she was wheelchair bound, would only speak a few words, and had a flexed posture of her trunk and dystonia in her hands, myoclonus in her face and upper limbs, as well as bilateral pyramidal signs. MRI showed gadolinium‐enhancing bilateral basal ganglia hyperintensities (Figure 9.5), and biopsy of the lesions gave the diagnosis of large cell lymphoma. Her lymphoma was treated, and she had a slow but steady improvement; after a few weeks, she was able to walk again with assistance, and her cognition had improved markedly.

Figure 9.5 (Case 3)—Bilateral basal ganglia hyperintensities in axial FLAIR MRI scan with edema tracking along the limbs of the internal capsule. The lesions were gadolinium enhancing.

Table 9.4 Mnemonic acronym for RPD differential.

V ascular
I nfectious
T oxic‐metabolic
A utoimmune
M etastasis/neoplasm
I atrogenic
N eurodegenerative
S ystemic/seizures/structural

Source: Adapted from Geschwind et al. [1]. Reproduced with permission of Wiley.

Differential diagnosis

The mnemonic acronym VITAMINS may be helpful in the clini- cal reasoning of RPD cases (Table 9.4), as it helps covering the most frequent causes of RPD [1, 2, 166]. The items vascular, infec- tious, toxic‐metabolic, autoimmune (including paraneoplastic), neurodegenerative, and systemic causes are covered in other chapters of this book. Neoplasms will be briefly discussed here.

Neoplasms

CNS neoplasms—primary or secondary—usually present as mass lesions on brain MRI scans and so can be easily identified as the RPD etiology. There are a few rare conditions, however, in which MRI findings are not so obvious, such as primary CNS lymphoma (PCNSL), intravascular lymphomatosis (angiotropic large cell lymphoma), and gliomatosis cerebri [1].

PCNSLs represent 4% of the primary CNS tumors and were diagnosed in 0.7% of the cases referred with suspected CJD for autopsy at the NPDPSC (lymphomas represented more than 70% of their neoplastic cases) [8, 167]. They are predominantly diffuse large B‐cell‐type non‐Hodgkin lymphomas, and the median age of onset is around 60 years [168, 169]. The CNS involvement may occur in the brain, leptomeninges, eyes, and spinal cord [170]. Immunodeficiency is the main risk factor, and focal neurological deficits are seen in 70% of cases (whereas neuropsychiatric symptoms in around 40%) [171]. When PCNSL manifests in the brain, it presents as a focal mass lesion (isohypointense or hyperintense on T2‐weighted imaging, with homogeneous contrast enhancement [or with ring enhance- ment in immunocompromised patients] and little surrounding edema) in more than 50% of cases (and multifocal in other 25% of cases) [172, 173]. Most lesions are located in the cerebral hemispheres, thalamus, basal ganglia, and corpus callosum [174]. In case 3, the evolution of symptoms and basal ganglia hyperintensities were the reason why CJD was considered in the differential diagnosis. Contrast enhancement and edema, however, are not seen in CJD and led to further investigation with the ultimately diagnostic biopsy. DWI hyperintensities (sometimes with concomitant ADC hypointensities) may be seen due to ischemia and/or high cellularity [82]. In the context of RPD, those neuroradiological features must prompt the investigation of the nature of the lesion, usually through biopsy.

There are, however, instances in which neuroradiological findings are far from straightforward, as in the case of lympho- matosis cerebri. It is a rare form of PCNSL that may present as a RPD [175, 176]. Brain MRI typically shows diffuse nonenhancing white matter hyperintensities, resembling leukoencephalopathy [173, 177]. Most of the PCNSL diagnosed at the NPDPSC were of this type [8].

Intravascular lymphomatosis (also called malignant angioen- dotheliomatosis or angiotropic large cell lymphoma) is a rare con- dition in which cutaneous and neurological symptoms (usually subacute dementia) are the most frequently reported (due to occlusion of small vessels). MRI findings include white matter hyperintensities, parenchymal masses, and stroke‐like lesions, with variable contrast enhancement [178, 179]. Despite being rare, difficulty in diagnosis [180] probably led intravascular lymphomatosis to also be diagnosed in 0.7% of the cases autopsied at the NPDPSC [8].

Gliomatosis cerebri is a diffuse infiltrating glial tumor that can also manifest as a RPD [181]. Dementias, headaches, and seizures are the most commonly seen features, and brain MRI shows ill‐defined white and gray matter hyperintensities in T2‐ weighted images. Contrast enhancement may be seen in around 50% of cases [182].

Psychiatric

Psychiatric disorders were diagnosed in 2% of nonprion RPD cases seen at the UCSF [1]. It is important, however, to high- light that many neurodegenerative disorders may be accompa- nied by neuropsychiatric symptoms, and so, even though conversion disorders, malingering, and psychosis may simulate RPD, a very low threshold to investigate the possibility of an underlying neurological cause must be kept. Psychiatric symp- toms are often an early and prominent feature of many forms of PrD [51, 64, 183, 184] At the UCSF, psychiatric conditions causing RPD were more frequently seen in patients who self‐ diagnosed CJD [1].

Diagnostic algorithm

Obtaining a detailed history and physical examination is para- mount in the evaluation of RPDs. From the history, important information, such as work‐related exposure leading to lead intoxication, diarrhea narrowing the diagnosis to disorders such as Whipple’s disease, or a prolonged ICU admission rais- ing suspicion of extrapontine myelinolysis or Wernicke’s encephalopathy, can be obtained. It is important to try to obtain the most accurate information on the specific timing of onset and initial symptoms. Not infrequently, symptoms (often noticed in retrospect) predate what was initially reported to be the first symptom in months (or even years), changing the list of possible differential diagnoses. From the physical examination, signs of hepatic failure can prompt a consideration of hepatic encephalopathy, Wilson’s disease, or acquired hepatocerebral degeneration as possible etiologies; or a facial rash can suggest systemic lupus erythematosus.

Prion diseases and rapidly progressive dementias 115

116 Non-Alzheimer’s and Atypical Dementia

Table 9.5 Clinical diagnosis algorithm.

Initial screening tests

Blood

CBC, chemistry panel, liver function tests, RPR, rheumatological screen (ESR, ANA, CRP, ANCAs), thyroid function, vitamin B12, homocysteine, methylmalonic acid, HIV serology, Lyme disease serology, paraneoplastic/autoimmune antibodies panel
Urine analysis
Cell count and differential, protein, glucose, IgG index, oligoclonal bands, VDRL

Urine
CSF
Brain MRI
EEG
Review for potentially treatable causes Further testing based on initial screen

With and without contrast. Include DWI and ADC sequences (Might be helpful)

Infectious

Refer to Chapter 13

Autoimmune

Refer to Chapter 10

Neoplastic

Serum LDH and tumor markers, CSF cytology and flow cytometry, CT scan with and without contrast, whole‐body PET scan, mammogram

Vascular

Refer to Chapter 4

Toxic‐metabolic or systemic

Refer to Chapters 11, 12 and 14 Low threshold to order serum ceruloplasmin/copper
Screen for heavy metal intoxication (exposure?), other vitamin deficiency (B1, niacin), and porphyria

Parathyroid or adrenal diseases

Degenerative

Refer to Chapters 3, 5–7 CSF Aβ, total and phospho‐tau, 14‐3‐3, NSE

If negative, consider brain biopsy

Source: Adapted from Geschwind et al. [1, 2]. Reproduced with permission of Elsevier.
ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibodies; anti‐TG, antithyroglobulin antibody; anti‐TPO, antithyroperoxidase antibody; CBC, complete blood count; CRP, C‐reactive protein; CSF, cerebrospinal fluid; CT, computed tomography; EEG, electroencephalogram; ESR, erythrocyte sedimenta- tion rate; NSE, neuron‐specific enolase; PET, positron emission tomography; RPR, rapid plasma reagin; VDRL, Venereal Disease Research Laboratory test.

Following the history and exam, initial screening tests should be ordered (Table 9.5), including basic blood and urine tests, CSF analysis, and brain MRI, which help in narrowing possible diagnose (s). The initial screening and every step further in the investigation should focus primarily on finding potentially reversible causes of CJD. After the initial screen, some tests may be virtually diagnostic, such as a positive antibody in the setting of a case suggestive of one of the paraneoplastic or antibody‐ mediated limbic encephalopathy syndromes or typical MRI findings of sCJD in a patient whose other tests were negative for alternative causes. In some cases, however, the initial screen only helps to narrow the differential, and at this point, the VITAMINS mnemonic should be used again to direct further investigation.

If the secondary investigation suggests the possibility of inflammatory, infectious, or neoplastic causes and further investigation is still necessary to provide adequate treatment, a brain biopsy may be considered. Brain biopsies historically have been infrequently performed in the setting of dementia, and recently due to advances in the diagnosis of degenerative dementias (including CJD) and autoimmune disorders, biopsies perhaps are even less frequently required. Around 60–70% of brain biopsies were diagnostic in two dementia series [185–187] but changes in treatment due to the result occurred in only 11% of cases [186]. Biopsy‐related complications (such as infection, seizures, and hemorrhage) were reported in 11–21% of proce- dures in one study [185], and so the risk–benefit ratio of a biopsy must be considered in each case. Due to concerns of

prion infectivity of neurosurgical material and the greater ability to diagnose CJD with MRI, we feel that a brain biopsy should not be performed only to confirm a diagnosis of CJD, but rather to find another etiology for the dementia.

Summary

Assessing a case of RPD is usually a diagnostic challenge. The causes of RPD range from conditions in which the diagnosis is fairly straightforward (such as a neoplastic mass seen in an MRI scan) to fatal disorders such as CJD and also include potentially treatable causes (such as metabolic, infectious, or autoimmune) for which early diagnosis is invaluable. A detailed history and thorough physical exam are of utmost importance in the assess- ment of RPDs. Those evaluations, along with initial screening (including blood and urine tests, CSF analysis, and brain MRI) should either point to a diagnosis or narrow the differential. Further testing may be required to achieve a final diagnosis, but it is important to keep in consideration potentially reversible causes of RPD, which are found in about 10% of cases referred to PrD centers.

One of the most frequent causes of RPDs are PrDs. sCJD is the most frequent form of PrD and is characterized by RPD and pyramidal, extrapyramidal, cerebellar, and visual signs and symptoms. DWI Brain MRI is currently the most accurate test to diagnose CJD, but other tests are usually required in the clini- cal setting to rule out reversible causes. Other forms of PrDs

include genetic (gCJD or fCJD, GSS, and FFI) and acquired/iat- rogenic forms, which comprise 10–15% and 1–3% of PrD, respec- tively. There is no cure currently available for any PrDs, and sCJD is associated with a mortality rate of 90% within the first year.

acronyms

AD Alzheimer’s disease
bvFTD behavioral variant of frontotemporal dementia CJD Jakob–Creutzfeldt disease
CNS central nervous system
CSF cerebrospinal fluid
DWI diffusion‐weighted imaging
EEG electroencephalogram
FFI fatal familial insomnia
FLAIR fluid‐attenuated inversion recovery
gCJD genetic CJD
gPrD genetic prion disease
GSS Gerstmann–Sträussler–Scheinker syndrome iCJD iatrogenic CJD
LBD Lewy body dementia
MRI magnetic resonance imaging
PCNSL primary central nervous system lymphoma PrD prion disease
PrP prion protein
PSWCs periodic sharp wave complexes
RPD rapidly progressive dementia
sFI sporadic fatal insomnia
TSE transmissible spongiform encephalopathies vCJD variant CJD
VD vascular dementia

acknowledgments

Dr. Geschwind’s work regarding this chapter was supported by NIH R01 AG‐AG031189, PO1‐AG021601, and the Michael J. Homer Family Fund.

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ChAptEr 10
Autoimmune dementias

Andrew McKeon and Sean J. Pittock

Mayo Clinic, Rochester, MN, USA

Introduction

In the evaluation of a patient with cognitive decline, clinicians should consider the possibility of an autoimmune etiology on their list of differential diagnoses. The importance of not overlooking this possibility rests in the experience that these patients have a potentially immunotherapy‐responsive, reversible disorder [1].

Traditionally,neurologistshaveusuallyconsideredautoim mune dementias within the framework of subacute‐onset delirium and limbic encephalitis only. The development and widespread availability of neural antibody marker testing has changed this perspective so that other presenting symptoms such as personality change, executive dysfunction, and psychi atric symptoms are increasingly recognized in an autoimmune context. Clues that are helpful in identifying patients with an autoimmune dementia can be summarized within a triad of (i) suspicious clinical features (a subacute onset of symptoms, a rapidly progressive course, and fluctuating symptoms) and radiological findings, (ii) the detection of CSF or serological biomarkers of autoimmunity, and (iii) a response to immuno therapy (see Table 10.1 for Key Points). This rapidly evolving field is still in its infancy, and much of the clinical data, including that related to treatment and outcomes, is documented in single cases or small retrospective cases series only.

Nomenclature

Diagnostic terms often used to describe such patients include “autoimmune encephalopathy” (which implies delirium is present) and autoimmune dementias (where there is no delirium) and immunotherapy‐responsive encephalopathy (as these patients typically have improvements after treatment with corticosteroids). For brevity’s sake, we will refer to autoimmune cognitive impair ment with or without encephalopathy as autoimmune dementia throughout this chapter. The nomenclature pertaining to autoimmune dementias can seem confusing. Disorders have

been classified with respect to clinical phenotype (e.g., progressive encephalomyelitis with rigidity and myoclonus [aka PERM]) [2], eponym (Morvan’s syndrome) [3], pathology (e.g., non vasculitic autoimmune meningoencephalitis (NAIM)) [4], or associated antibody (e.g., the N‐methyl‐d‐aspartate receptor (NMDAR) antibody‐associated encephalitis) [5]. In some instances, there is more than one name in the literature for a particular disorder; both Hashimoto encephalopathy [6] and steroid‐responsive encephalopathy associated with autoim mune thyroiditis (SREAT) [7] refer to the same entity: a triad of cognitive problems, thyroid antibodies detected serologically, and established clinical improvement with immunotherapy. While each description contributes something to our under standing of these disorders, from the standpoint of the practicing neurologist, immunotherapy responsiveness unites these and other autoimmune dementias.

Epidemiology

The incidence and prevalence of autoimmune dementias are unknown. They are thought to be rare but are likely under recognized. An autoimmune or inflammatory cause of cognitive decline accounts for 20% of dementia in patients under 45 years of age [8].

Clinical features

Symptoms

Autoimmune dementias typically have a subacute onset with progression more rapid than would be expected for most neuro degenerative disorders, with the exception of Creutzfeldt–Jakob disease (CJD). While limbic encephalitis (a fluctuating confu sional state accompanied by one or more of seizures, agitation, memory loss, and hallucinations) is the best recognized clinical presentation [9], other symptoms of dementia including apraxia, aphasia, behavioral change, and disturbances in orientation and

123

124 Non-Alzheimer’s and Atypical Dementia Table 10.1 Key points for autoimmune dementias.

Clinical manifestations are diverse and often multifocal
Personal history or family history of autoimmunity or cancer might provide important diagnostic clues
Antibodies targeting nonneural antigens (e.g., thyroid, antinuclear) serve as clues for neurological autoimmunity, but do not provide a definitive diagnosis
Neural‐specific autoantibodies serve as markers of neurologic autoimmunity and cancer
A trial of immunotherapy (steroids, IVIG, and/or plasma exchange) serves as a diagnostic test. Trials of multiple treatment types may be required
Autoimmune dementias are frequently relapsing and immunotherapy over years may be required

reasoning have been reported [10–12]. Delirium (impaired atten tion and consciousness) is a common, but not universal, presen tation. Marked fluctuations in the clinical course and spontaneous remission suggest an autoimmune cause but can also be seen in patients with toxic and metabolic causes of dementia, in patients with psychogenic disorders, and in patients with depression.

A sleep history may also be informative. Patients with Ma2 antibody encephalitis might complain of hypersomnia [13]. Conversely, patients with voltage‐gated potassium channel‐ complex autoimmunity often complain of insomnia [14]. Patients with sleep apnea syndrome (either central or obstructive) typically have fluctuating cognitive complaints related to a lack of restorative sleep rather than an autoimmune dementia [15].

Case 1

A 58‐year‐old man with a remote history of thyroid carcinoma, in remission, presented with acute onset of word‐finding difficulty and memory problems when giving a presentation to colleagues at work. His evaluation included an MRI of head which demonstrated a left temporal T2 signal abnormality (Figure 10.1a) and an EEG which demonstrated left temporal epileptiform discharges. Neuropsychometric evaluation was remarkable for poor performance on mainly verbal memory scores. Serological evaluation revealed voltage‐gated potassium channel (VGKC) complex antibodies, with value of 1.00 nmol/L (normal, ≤ 0.02 nmol/L). PET–CT imaging of body did not demonstrate any new carcinoma. He received intravenous methylprednisolone infusions (1000 mg) daily for 5 days, followed by weekly for 6 weeks. He improved considerably and was “90% better.” At that stage, the methylprednisolone dosing interval was widened to

(a)

one dose every other week. Within 2 weeks, he and his wife noted that he was regressing considerably with respect to memory. He also became emotionally labile and depressed. Repeat MRI imaging demonstrated atrophy of the left hippocampus and new T2 signal abnormality in the right hippocampus (Figure 10.1b). He was treated with seven exchanges of plasmapheresis over 14 days and noted marked improvements. These improvements continued over the next 3 months on prednisone 60 mg by mouth daily. In addition, azathioprine was initiated at 2.5 mg/kg/day as a remission‐maintaining drug (mycophenolate mofetil, methotrexate, and hydroxychloroquine are alternatives in this situation; there is no evidence to support the use of one drug over the other). Surveillance neuropsychological evaluation revealed improvements in memory scores almost to within the normal range, although his MRI had not changed. He remained in remission as prednisone alone was tapered slowly over the following 6 months.

(b)

Figure 10.1 Case 1: FLAIR axial MRIs (radiological orientation). (a) At initial symptom onset, T2 signal abnormality is seen in the left hippocam pus. (b) After relapse, T2 signal is less prominent in the left hippocampus. New, subtle T2 signal abnormality is now seen in the right hippocampus (arrow). Bilateral temporal lobe atrophy is seen. See text.

Autoimmune dementias 125

Case 2

A 47‐year‐old woman presented with subacute onset of psychosis and severe headaches in 2001. Investigation revealed a lymphocytic pleocytosis on CSF (other CSF data was not available) and a normal MRI brain scan. After 3 months of persistent symptoms despite standard psychiatric treatments, she was treated with steroids empirically and improved significantly but had residual cognitive problems (impairments of verbal intellect, problem solving, visuospatial appreciation, memory and cognitive speed) preventing her return to work. She remained stable with moderate cognitive impairment from early 2002 until November 2009 when she had acute onset of confusion, worsening amnesia, agitation, crying, visual and auditory hallucinations, and behavioral disturbance. She also had one generalized seizure. Again, her CSF demonstrated a lymphocytic

pleocytosis with 100 white cells, and oligoclonal bands were present. MRI imaging was unremarkable. CSF paraneoplastic evaluation sent to the Mayo Clinic Neuroimmunology Laboratory identified NMDAR antibodies (Figure 10.2). Evaluations for teratoma including clinical examination, pelvic ultrasound, PET imaging, and finally pathology (after bilateral salpingo‐oophorectomy and hysterectomy) were all negative for cancer. She subsequently received intravenous methylprednisolone for 3 days and then five treatments of plasma exchange over 10 days and had marked improvements. The behavioral outbursts, crying, confusion, and agitation ceased. Her cognition improved back to her premorbid 2009 baseline of moderate generalized dysfunction. Maintenance therapy included a slow taper of oral prednisone over 9 months and ongoing maintenance of azathioprine (2.5mg/kg/day).

Figure 10.2 NMDAR antibody (relevant to Case 2). Indirect immunofluorescence staining pattern of patient’s serum on a composite of mouse neural tissue, provided courtesy of Dr. Vanda A. Lennon, Neuroimmunology Laboratory, Mayo Clinic, Rochester, MN. Hippocampus (Hi) stains brighter than cerebral cortex (Co), basal ganglia (BG), and thalamus (Th). Granular layer (GL) of cerebellum also stains brightly, typical for NMDAR antibody; molecular layer (ML) is negative. (See insert for color representation of the figure.)

A fluctuating mental state accompanied by a sleep disorder and parkinsonism can be seen in diffuse Lewy body disease [16] (see Chapter 6).

In some disorders, characteristic noncognitive features are important also. For example, in a patient with a history of visual loss and hearing loss, in addition to cognitive symptoms, Susac’s syndrome (an immunotherapy‐responsive endotheliopathy) should be considered [17]. Other symptoms and signs common in Susac’s syndrome include memory loss, psychiatric symp toms, and headache. Patients with mitochondrial disorders can also present with fluctuating encephalopathies and visual and hearing impairments.

past and family history

This information is crucial. A history of cancer may be relevant, since an autoimmune, paraneoplastic dementia may be the herald of a recurrence of cancer. Patients with autoimmune dementia frequently have one or more coexisting autoimmune disorders, such as hypothyroidism, SLE, and rheumatoid arthritis. Likewise, a smoking history, review of systemic symptoms, and a family history of autoimmunity and cancer might be informative.

Examination findings

Impairments in one or more categories of attention, memory, reasoning, calculation, and praxis can be documented using brief bedside evaluations such as the MMSE [18], the Montreal Cognitive Assessment (MoCA; http://www.mocatest.org), or the Kokmen Short Test of Mental Status [19]. More extensive neuropsychological testing, however, is often required to fully characterize the degree of cognitive impairment. This serves both to document the abnormalities present and as a pretreat ment baseline. Since autoimmune neurological disorders are often multifocal [20, 21], other neurologic symptoms and signs may accompany the cognitive impairment. These may include seizures, ataxia, brainstem signs, parkinsonism, myoclonus, tremor, myelopathy, or a peripheral nervous system disorder.

Differential diagnoses

Both potentially reversible etiologies (Table 10.2) and neurode generative causes for cognitive symptoms need to be considered. Unlike autoimmune dementias, neurodegenerative disorders, with the exception of prion diseases, are usually character ized by indolent onset and slow progression over years.

126 Non-Alzheimer’s and Atypical Dementia
Table 10.2 Potentially reversible causes of cognitive impairment.

Potentially reversible causes of cognitive impairment

Cancer (neoplasia)
Autoimmune encephalopathies and dementias Psychiatric illness
Toxic
Inflammatory CNS disorders (other than autoimmune) Vasculopathies
Endocrine
Metabolic
Infection of the central nervous system
Nutritional deficiency
Drugs
Seizure disorders

Examples

Primary CNS lymphoma (including intravascular and meningeal presentations) Immunotherapy‐responsive disorders of presumed autoimmune etiology Anxiety, depression, psychosis
Alcohol, opiates, cocaine, amphetamines, organic solvents

Multiple sclerosis, acute disseminated encephalomyelitis, neurosarcoidosis, neuro‐Behçet’s disease CNS vasculitis, posterior reversible leukoencephalopathy (PRES), subdural hematoma, venous thrombosis Disturbances in pituitary, thyroid, parathyroid, endocrine pancreatic, or adrenal function
Respiratory, renal or liver failure. Obstructive sleep apnea syndrome. Mitochondrial disorders* (e.g., MELAS) HSV, HHV‐6, HIV, fungal (e.g., cryptococcus), mycobacterial, Whipple’s disease, neurosyphilis
Vitamin B12, vitamin E, thiamine, folic acid,
Benzodiazepines, antidepressants, antipsychotics, antiepileptics, analgesics
Nonconvulsive status epilepticus

The anagram CAPTIVE MINDS may aid memory.
* Mitochondrial diseases can remit, although they are not currently treatable or reversible.

Neurodegenerative disorders include Alzheimer disease, fron totemporal dementia, diffuse Lewy body disease, Parkinson’s disease with dementia, progressive supranuclear palsy, and corticobasal degeneration (see Chapters 3, 5–7, and 9). Mito chondrial diseases can also lead to dementia but often have other distinguishing features, such as retinopathy, hearing loss, short stature, and/or neuropathy (www.genetest.org). Among the treatable causes to consider (Table 10.2) are some other idiopathic inflammatory disorders that are also immunotherapy responsive. Each has well‐characterized clinical, radiologic, and pathologic diagnostic features and recommended treatments. Examples include multiple sclerosis, CNS vasculitis (also known as primary angiitis of the CNS), sarcoidosis, and neuro‐Behçet’s disease.

During an MS relapse, a patient may develop subacute cogni tive symptoms with delirium and impaired attention, and subsequent improvements may occur during remission [22].

Headache and rapidly progressive dementia are two charac teristic presentations of CNS vasculitis [23]. The diagnosis is aided by cerebral angiography and definitively proven by demonstrating multifocal inflammation and necrosis of small arteries, primarily in the leptomeninges; some have a coexisting amyloid angiopathy. This type of biopsy might be necessary to rule out intravascular lymphoma, which can have similar angio graphic findings to CNS vasculitis [24].

Although noncognitive deficits (such as cranial neuropathies) are most common in CNS sarcoidosis, some patients may present with cognitive deficits [25]. The diagnosis often proves elusive in patients without systemic disease, and brain biopsy may be required to establish the pathological hallmark of an inflamma tory infiltrate with noncaseating granulomas.

Behçet’s disease is characterized by uveitis, oral aphthae, and genital ulcerations. Presentations of neuro‐Behçet’s disease may include a rapidly progressive subcortical dementia character ized by amnesia and a frontal dysexecutive syndrome [26]. In addition, patients can present with pyramidal tract, spinal cord, and sphincter dysfunction. Brain MRI often reveals focal or

diffuse T2‐weighted hyperintensities, particularly in the basal ganglia, thalamus, upper brainstem, and mesial temporal structures [26].

Rarer infiltrative, inflammatory disorders of the central nervous system, which may be steroid responsive, include Langerhans cell histiocytosis [27], crystal‐storing histiocytosis [28], and lymphomatoid granulomatosis [29].

Neurological testing

Defining abnormalities with objective tests: Neuropsychological testing, imaging, and EEG
There are several components to testing when evaluating a patient with autoimmune dementia. Some testing aids with documenting objective abnormalities, which serves as a baseline before a trial of treatment is undertaken. Resolution of neuropsy chological, EEG, MRI (Figure 10.3), or functional imaging abnor malities after immunotherapy serves as an objective marker supporting patient‐reported improvements.

Neuropsychological testing, in particular, provides a detailed assessment of deficits and can be very informative in mild cases where the abnormalities are subtle. In addition, other mitigating factors leading to cognitive complaints (such as depression) can be identified by a neuropsychologist. Unfortunately, there is a dearth of literature on the precise cognitive profile of patients with autoimmune dementia. Comprehensive cognitive testing, however, is probably best, including evaluation of memory, frontal‐executive function, and processing speed [12].

MRI may reveal findings atypical for neurodegenerative disorders. Mesial temporal lobes are a common location for T2 signal abnormalities in autoimmune dementias. Large extra temporal abnormalities and subtle white matter or gyriform enhancement are sometimes observed [11, 30]. Gyriform T2 signal abnormalities are often seen in CJD but have also been observed in patients with autoimmune encephalopathies ini tially misdiagnosed with CJD [30]. Avid enhancement should raise concern for an alternative etiology such as a primary brain

(a) (b)

Figure 10.3 FLAIR axial MRIs in a patient with LGI1 (“VGKC”) antibody and limbic encephalitis with left greater than right medial temporal lobe hyperintensities (a) that had radiologic and clinical improvements (b) after corticosteroid therapy. Source: McKeon et al. [1]. Reproduced with permission of Wolters Kluwer.

tumor or sarcoidosis. Other causes of large hemispheric T2 signal abnormalities include mitochondrial disorders and progressive multifocal leukoencephalopathy. Patients with Susac’s syndrome typically have multifocal leptomeningeal enhance ment and T2 signal abnormalities centered around the corpus callosum [17].

Functional imaging (PET or SPECT) may reveal areas of abnormal cerebral metabolism corresponding to clinical symp toms. These modalities are particularly useful in the absence of MRI or EEG abnormalities.

EEG may also help characterize the disorder and provide a pretreatment baseline. Common abnormalities include focal or bilateral mesial temporal abnormalities, but extratemporal abnormalities may also occur [11]. These can include generalized or focal (frontal, parietal, or occipital) slowing, or spike‐and‐slow‐ wave epileptiform discharges.

routine CSF testing

CSF testing can be very informative for an autoimmune diagnosis. Findings supportive of an autoimmune etiology include an elevated CSF protein (>100mg/dL), mild CSF pleocytosis, abnormal numbers of CSF‐exclusive oligoclonal bands, and elevated IgG index and synthesis rate all support an autoim mune etiology. It should be emphasized that these findings are only supportive and not diagnostic of an autoimmune demen tia, since any one of them can be detected in other disorders: elevated protein (any neurological disorder), pleocytosis (CNS infection), and elevated CSF oligoclonal bands (65% of multiple sclerosis patients [31], 7% of patients with neurodegenerative disorders [32], and 4% of CJD patients [33]).

Autoantibody testing

Nonneural autoantibodies

Seropositivity for nonneural antibodies may warrant further investigation for an autoimmune pathogenesis for dementia. Unfortunately, many of these commonly ordered tests including both organ (such as thyroid autoantibodies) and nonorgan‐ specific autoantibodies (such as antinuclear antibody or antibodies targeting the extractable nuclear antigen) lack specificity and are commonly encountered in the normal population. For example, the detection of thyroid autoantibodies in a patient with cogni tive complaints should only raise suspicion of an autoimmune basis requiring further evaluation. The detection of antinuclear antibodies and double‐stranded DNA antibodies in a patient with subacute‐onset cognitive complaints will raise suspicion for lupus cerebritis (also known as CNS lupus; see Chapter 14). This poorly understood disorder is classified along with other mani festations including stroke and peripheral neuropathy under the umbrella of neuropsychiatric lupus. Common features include memory loss, headache, seizures, and movement disorders [34, 35]. There have been some reports of autoantibody markers of neuropsychiatricdisease,butnonehavebeenconfirmedtobeof sufficient specificity to warrant clinical use [36, 37]. Similarly, no specific biomarker has been identified as a marker of autoimmune dementia occurring in patients with other nonorgan‐specific autoimmune diseases, such as Sjögren’s syndrome [38].

Neural autoantibodies

Detection of neural autoantibodies in serum or CSF serves two purposes: to inform the physician of a likely autoimmune etiology and to raise suspicion for a paraneoplastic cause (Table 10.3).

Autoimmune dementias 127

128 Non-Alzheimer’s and Atypical Dementia
Table 10.3 Antibodies with specificity for neural antigens, accompanying cognitive and other neurological disorders, and oncological accompaniments.

Antibody specificity

VGKC complex

NMDA receptor GAD

AMPA receptor

GABAB receptor
DPPX (subunit of Kv4.1 potassium channel) mGluR5
ANNA‐1 (anti‐Hu)

ANNA‐2 (anti‐Ri) ANNA‐3

AGNA (SOX1 antibodies) PCA‐2

CRMP‐5 IgG (anti‐CV2)

Amphiphysin

Anti‐Ma proteins (usually Ma2, sometimes Ma1) NMO‐IgG

Ganglionic AChR complex

Reported cognitive disorders

Limbic encephalitis, amnestic syndrome, executive dysfunction, personality change, disinhibition Amnestic syndrome

Limbic encephalitis, other encephalitides

Limbic encephalitis

Encephalitis
Delirium, amnestic syndrome

Limbic encephalitis Limbic encephalitis

Dementia, limbic encephalitis

Limbic encephalitis

Limbic encephalitis Limbic encephalitis

Subacute‐onset dementia, personality change, aphasia

Limbic encephalitis, aphasia, other subacute‐onset dementias Limbic encephalitis

Reports of encephalopathies in children
Reports of reversible encephalopathies

Other neurologic findings

Hypothalamic disorder, brainstem encephalitis, ataxia, extrapyramidal disorders, myoclonus, peripheral and autonomic neuropathy Anxiety, psychosis, seizures, extrapyramidal disorders

Stiff person syndrome, stiff person phenomena, ataxia, seizures, brainstem encephalitis, ophthalmoplegia, parkinsonism, myelopathy Nystagmus, seizures

Seizures
Seizures, depression, cerebellar ataxia, myoclonus, stiffness, dysautonomia
—
Brainstem encephalitis, autonomic neuropathies, sensory neuronopathy Brainstem encephalitis, myelopathy, peripheral neuropathy
Brainstem encephalitis, myelopathy, peripheral neuropathy
Neuropathy, Lambert–Eaton syndrome
Ataxia, brainstem encephalitis, Lambert–Eaton syndrome, peripheral and autonomic neuropathies
Depression, chorea, ataxia, myelopathy, radiculopathy, neuropathy, Lambert–Eaton syndrome
Stiff person phenomena, myelopathy, neuropathy
Hypothalamic disorder, brainstem encephalitis

Optic neuritis, transverse myelitis

Somatic and autonomic peripheral neuropathies

Cancer association References

Small cell lung carcinoma; [39–43] thymoma; adenocarcinoma of
breast, prostate
Teratoma, usually ovarian [5]

Thymoma [20]

Thymic tumors, lung [44] carcinomas, breast carcinoma
Small cell lung carcinoma [45]

B cell lymphoma, B‐CLL
Hodgkin lymphoma [48]

Small cell carcinoma

[49, 50]

Small cell carcinoma or breast [51] adenocarcinoma
Small cell carcinoma [52]

Small cell carcinoma
Small cell carcinoma [55]

Small cell carcinoma, [56] thymoma

Breast adenocarcinoma, small [57] cell carcinoma
Testis, small cell carcinoma, [58] other solid organ cancers

Some reports of thymoma
and other solid tumors Adenocarcinomas, thymomas [61]

[46, 47]

[53, 54]

[59, 60]

Source: McKeon et al. [1]. Reproduced with permission of Wolters Kluwer.

The neurological associations of neural autoantibodies tend to be diverse and multifocal, although certain syndromic associa tions may apply. For example, limbic encephalitis is a classical neurological presentation accompanying ANNA‐1 (anti‐Hu) [49] and GABAB receptor antibody [45, 62]. Chorea and cogni tive symptoms are well‐recognized accompaniments of CRMP‐5 IgG (anti‐CV2 antibody) [56]. Dalmau et al. reported patients with NMDAR antibody [5] (Figure 10.2). These patients frequently reported to psychiatrists with psychosis and other psychiatric complaints early on (as in Case 2), only to develop florid encephalopathies and respiratory failure later on. The autoanti body nomenclature also evolves with increasing knowledge of antigen specificity. VGKC complex antibodies have been known as such because the radioligand used in the radioimmunoassay (125I‐α‐dendrotoxin) binds to Kv1.1, Kv1.2, and Kv1.6 subunits of VGKCs [39, 40]. Recent data has identified leucine‐rich glioma‐inactivated 1 (LGI1, which might be coprecipitated with VGKCs) as the antigen targeted by antibodies from patients with limbic encephalitis seropositive by the 125I‐α‐dendrotoxin

immunoassay [41, 42]. There has been some controversy regard ing the incidence of cancer among patients with VGKC anti bodies. One small series of 10 patients reported no cancer among VGKC complex autoantibody seropositive patients [39]. Other authors have reported incidences ranging from 11 to 33% [41, 43, 63]. The identification of a marker of neural autoim munity (regardless of target) should direct the physician toward a trial of immunotherapy.

The positive predictive values for cancer of individual anti bodies vary from less than 30% for alpha 3 ganglionic AChR antibody [61] to over 80% for ANNA‐1 (anti‐Hu, pulmonary or extrapulmonary small cell in almost all cases) [49]. Since neuro logical presentations are often multifocal and diverse, compre hensive antibody testing is usually more informative than testing for one or two selected antibodies [21]. Also, a profile of seropositivity for multiple autoantibodies may be informative for cancer type. For example, in a patient presenting with a rap idly progressive dementia who has muscle acetylcholine recep tor binding and modulating antibodies, striational antibody,

alpha 3 ganglionic AChR, and CRMP‐5 IgG (anti‐CV2), those findings should raise a high suspicion for thymoma. Antibody testing on CSF is additionally helpful particularly when serum testing is negative. However, simultaneous testing on serum and CSF is recommended for some NMDAR antibody testing, since CSF is usually more informative.

testing for cancer

When suspicious for a paraneoplastic cause because of risk factors from the history or because of specific serological or CSF finding, then a search for cancer is appropriate. A thorough physical examination and CT of chest, abdomen, and pelvis are commonly undertaken as primary screening tests in this setting. Other tests are appropriate also and may be required depending on the index of suspicion in an individual patient. Pelvic ultra sound (including transvaginal imaging) and gynecological examination are usually required to evaluate for ovarian carci noma or teratoma. Mammography and breast examination are required to evaluate for breast carcinoma. Testicular ultrasound, prostate‐specific antigen, and prostate examination by digital rectal examination are required to evaluate for testicular and prostate carcinomas, respectively. If neuroblastoma is suspected, and if CT imaging is negative, then imaging using radiolabeled metaiodobenzylguanidine (MIBG) should be considered. Endo scopic examination of the upper and lower gastrointestinal tracts and bronchial tree should also be considered where appropriate. PET–CT imaging increases the diagnostic yield for

cancer by 20% in those patients who have had standard evalua tions that have not revealed cancer [64].

Other tests aid the search for markers of autoimmunity and for cancer. Finally, it is important to exclude other causes of dementia, in particular other potentially reversible causes.

treatment

There is no definitive evidence‐based approach to treating auto immune dementias. Much of the authors’ practice emanates from small case series [12], individual case reports, and expert opinion [1, 65]. However, a rational approach can be applied to treatment. This can be done by using the acute trial of treatment to serve also as a “diagnostic test.” If this is successful, then a maintenance phase of treatment can be embarked upon (Figure 10.4).

Acute therapy

A response to immunotherapy is both diagnostically and thera peutically important. The authors typically initiate a trial of high‐dose IV corticosteroid therapy or high‐dose intravenous immune globulin (IVIG). IVIG and plasma exchange are espe cially useful where corticosteroids are contraindicated, such as patients with type 1 diabetes mellitus or who are at risk for that disorder (Table 10.4). Plasma exchange may also be effective [66] where IVIG or corticosteroids have been poorly tolerated; only partial responsiveness to other immunotherapies has been

Autoimmune dementias 129

Acute treatment

IV methylprednisolone
1g IV daily for 3–5 days, then weekly for 6–8 weeks
or
IVlg
0.4g–1g/kg IV daily for 3–5 days, then weekly for 6–8 weeks or
Plasma exchange (severe attacks, incomplete response to steroids)

No improvement

Substantial objective improvements noted at reevaluation

Chronic (remission maintenance) treatment

Continue acute IV steroid/IVlg therapy, taper over 4 – 6 months or
Oral prednisone taper over 4–6 months
and consider
Oral azathioprine
or
Oral mycophenolate mofetil
or
IV rituximab

Consider IV rituximab or cyclophosphamide for severe cases

Figure 10.4 A nonevidence‐based algorithm for the treatment of patients with suspected autoimmune dementias.

130 Non-Alzheimer’s and Atypical Dementia
Table 10.4 Some commonly used therapies for autoimmune dementias.

Drug

Methylprednisolone

Prednisone

Immunoglobulin Plasma exchange

Azathioprine Mycophenolate mofetil Cyclophosphamide

Dose

500–1000 mg 15–30 mg/kg

60 mg

0.4 g/kg
1 exchange

Route

IV (usually through a central line) PO

PO
IV or PO

Frequency

Daily for 3–5 days, followed by weekly for 4–8 weeks

Daily for 3 months, then taper by 10 mg/d each month until at 10 mg, then taper by 1 mg/d each thereafter

Daily for 3 days, then alternate weeks for 6–8 weeks
5–7 treatments, every other day over 10–14 days

Two daily divided doses Two daily divided doses

Monthly (IV) Daily (PO)

Some common and severe side effects encountered

Insomnia, increased appetite, psychiatric disturbance, Cushing’s syndrome, skin thinning, diabetes, hypertension, cataracts, recurrent infections, osteoporosis, hip avascular necrosis. Addisonian crisis on rapid withdrawal of physiologic doses of corticosteroid
Insomnia, increased appetite, psychiatric disturbance, Cushing’s syndrome, skin thinning, diabetes, hypertension, cataracts, recurrent infections, osteoporosis, hip avascular necrosis. Addisonian crisis on rapid withdrawal of physiologic doses of corticosteroid
Headache, aseptic meningitis, deep venous thrombosis, anaphylaxis, renal failure

Hypotension, electrolyte imbalance, infection, thrombosis, and pneumothorax related to central line

Hypersensitivity reaction, rash, myelotoxicity Diarrhea, hypertension, myelotoxicity, CNS lymphoma, renal failure
Alopecia, mucositis, infertility, myelotoxicity, hemorrhagic cystitis

Therapeutic phase

Acute and chronic

Acute

Chronic Chronic

Chronic

1–2 mg/kg/d 500–2000 mg/d

500–1000 mg/m2/mo (IV) 1–2mg/kg/d (PO)

Source: McKeon et al. [1]. Reproduced with permission of Wolters Kluwer.

established, and further improvements can be expected; or where a rapid response is desired in critically ill patients.

After an initial trial of therapy (usually 6–12 weeks) has been completed, the patient should be reevaluated for subjective and objective evidence of clinical improvement. The reevaluations necessary (clinical, radiological, and electrophysiological) should ideally be completed at the same institution and by the same clinicians to try to avoid interrater variability and differ ences in testing techniques. This is of greatest importance for the neurological and neuropsychological evaluations. Having received corticosteroid therapy, patients frequently report increased energy and generally feel better, but without clear objective improvement. If one modality of treatment has been unsuccessful, then one or both of the other acute therapies can be tried sequentially to see if immunotherapy responsiveness is likely to occur.

In a Mayo Clinic study, predictors of immunotherapy respon siveness included a subacute onset, a fluctuating course, a short interval between symptom onset and treatment, the detection of a cation channel‐specific autoantibody, and an inflammatory spinal fluid [12]. In the authors’ experience, the earlier treat ment with immunotherapy is initiated, the better the outcome. This is illustrated to some extent in the two described cases. In Case 1, the patient was promptly treated since the diagnosis of an autoimmune dementia was made within a week of symptom onset. Prompt resumption of treatment was also undertaken when he relapsed. The patient is now in remission with near normal cognition. The fortunes of Case 1 contrasts with Case 2

in which primary psychiatric diagnoses were considered for many months during the initial event in 2001 (several years before the NMDAR antibody was described by Dalmau and colleagues) [5]. Some improvements occurred with immunotherapy, but there were residual cognitive deficits. The second episode of neuropsychiatricsymptomsin2009wasrecognizedearlyasthe NMDAR antibody‐associated encephalopathy and was treated rapidly, with rapid return to her premorbid 2009 baseline.

Maintenance therapy

Objective improvements occurring during the acute phase of treatment include improved memory and thinking, a return to work, or resumption of living independently. The occurrence of any or all of these should prompt formulation of a long‐term treat ment strategy (Table 10.4), since approximately 80% of patients will have a relapse of cognitive symptoms once acute immuno therapy is discontinued [12]. The aims of maintenance therapy include maintaining remission and reducing dependence on corti costeroids, IVIG, and plasma exchange. These can be achieved by the addition of a steroid‐sparing purine analog, usually adminis tered orally on a daily basis (azathioprine, mycophenolate mofetil, methotrexate, hydroxychloroquine, or cyclophosphamide) or intravenously (cyclophosphamide). The authors use azathioprine or mycophenolate mofetil as first line treatments, since both have been used widely in myasthenia gravis and neuromyelitis optica. Careful monitoring of blood counts, liver, and renal function tests is necessary throughout treatment with these medications, partic ularly in the first 3 months.

Once one of these immunosuppressants has been established for 6–12 weeks, the interval between infusions of corticosteroids and IVIG can be gradually extended from weekly to every other week, to every 3 weeks, then monthly, and then discontinue. The overlap of maintenance immunosuppressant and corticos teroid (or IVIG) treatment required is usually 3 months for azathioprine and 6–8 weeks of mycophenolate mofetil. If at that stage the patient is still in remission, the maintenance immuno suppressive agent alone can be continued. In some patients, faster withdrawal of steroids or IVIG results in relapse, and in others, even slow tapering of these treatments is poorly toler ated. For this latter group, daily oral prednisone at a dose of 1mg/kg/day, maintaining that dose for 3 months, with a slow taper over 6–9 months may be effective in maintaining remission. Withdrawal of chronic oral corticosteroids should be done cautiously (particularly for doses below 10mg of prednisone/ day) with guidance from an endocrinologist or internist, to avoid emergence of adrenocortical failure.

The optimum duration of maintenance immunosuppression for a patient with autoimmune dementia who has achieved remis sion is unknown. The authors generally recommend between 2 and 3 years of immunosuppression in those that have achieved remission before attempting to withdraw all immunotherapy.

Patients need to be thoroughly counseled regarding the side effects of therapies (Table 10.4). Patients commencing long‐ term corticosteroid therapy should have a bone density DXA scan at the baseline and take calcium 1500 mg/day and vitamin D 1000IU/day [67]. These patients should also receive trimetho prim/sulfamethoxazole, one double‐strength tablet three times per week as prophylaxis against Pneumocystis carinii pneumo nia [68]. Prophylaxis against gastroduodenal ulceration and inflammation can also be considered in high‐risk patients but is not mandatory.

prognosis

Outcomes vary among patients with autoimmune dementias. Some patients achieve early (sometimes spontaneous) remissions, while others require lifelong immunosuppressant medication to maintain remission. In one study, 57% of patients who received chronic, maintenance immunosuppressive therapy experienced symptom relapse while reducing the dose of immunotherapy or increasing the interval between infusions of immune globulin and methylprednisolone [12]. Of those followed for 1 year or longer, 62% remained in remission long term.

Conclusion

The rapid identification of subacute cognitive decline as autoim mune dementia facilitates optimum treatment with immuno therapy and an expedited search for a limited stage of cancer in some patients. Clinical, neuropsychological, radiological, and

electrophysiological evaluations, where appropriate, before and after a trial (or trials) of immunotherapy enable confirmation of the diagnosis in suspected cases. Chronicity of symptoms and relapsing courses are common. Long‐term therapy with a combination of slowly tapered infusions of IVIG or corticos teroids and an oral immunosuppressant is done empirically but may permit long‐term remission. Controlled studies are needed to determine the optimum treatments and duration of therapy.

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Autoimmune dementias 133

ChapTer 11
Toxic and metabolic dementias

Michelle Mattingly1, Katie Osborn2 and Leon Prockop1

1 University of South Florida, Tampa, FL, USA
2 Geisel School of Medicine at Dartmouth, Hanover, NH, USA

Introduction

Toxic and metabolic forms of dementia (TMD) are critical to identify as they are often treatable, if not curable, unlike most other dementias discussed in this book. Cognitive impairment might be a direct consequence of medical illness or metabolic perturbations. Although technically not dementia, delirium should always be considered as an etiology of cognitive impair ment. First, we discuss toxic causes of dementia, followed by a review of major metabolic etiologies of cognitive impairment.

Toxic dementias

Exposure to toxic substances, either acutely or chronically, can lead to dementia. Table 11.1 includes a list of several toxic agents that might cause dementia [1]. This section of the chapter will focus on three agents that are among the most common causes of toxic cognitive dysfunction—carbon monoxide, etha nol, and lead.

Carbon monoxide

Carbon monoxide (CO) is a leading cause of death from poison ing in the United States and is responsible for 40 000 emergency department visits and 5000 to 6000 deaths per year [2]. CO is a tasteless, odorless, nonirritating but highly toxic gas, which makes it difficult to detect. Therefore, the true incidence of CO poisoning is unknown.

CO is a by‐product of the incomplete combustion of hydro carbons. Common sources of CO exposure include intentional suicides as well as unintentional exposures from home heating, automobile exhaust, and smoke inhalation [2]. CO poisoning may occur as a result of a building fire or from fuel‐powered generators and heaters, particularly in poorly ventilated spaces. The latter commonly occurs during winter storms, earthquakes, and hurricanes following a power outage.

Case presentation (reprinted with permission from Prockop [3])
Chronic CO exposure
VB, a 39‐year‐old woman, and SB, her 8‐year‐old daughter, had lived in an apartment for several years without incident. In the fall of 1998, both suffered recurrent illnesses characterized by lethargy, headache, and occasional vomiting diagnosed as “flu” when medical assistance was sought. On several occa sions, they stayed with friends while recuperating. Symptoms cleared quickly, only to recur on resuming residence in the apartment. VB, an educator, noted new learning dysfunction. SB’s previously high grades declined. Suspecting an environ mental toxin, VB summoned local health officials who found 106 ppm CO in a random apartment air sample. Although they vacated the apartment, headaches, malaise, and intellectual problems persisted such that VB discontinued efforts toward a PhD degree. SB experienced low school grades and had a B rather than a prior A average. On neurological examination, both were within normal limits except for cerebellar dysfunc tion characterized by loss of check with rebound in both with mild truncal ataxia in VB. Neuropsychological tests in VB demonstrated moderate to severe cognitive deficits, especially those involving executive functions. In SB, neuropsychological tests yielded scores from borderline to severe impairment in nonverbal sequences, complex copying, visuospatial judgment, and organization. Compared to premorbid estimated levels of functioning, both showed deficits involving higher‐order cog nitive functioning, reading comprehension, and qualitative conceptualization. MRI and MRS in both were normal.

Clinical symptoms/features

The brain and the heart are most susceptible to CO toxicity due to their high metabolic rates. Clinical symptoms of CO poison ing tend to be nonspecific and can mimic a variety of common disorders. Symptoms range in severity from mild, flu like (simu lating a viral infection) to more severe leading to coma and

134

Table 11.1 Toxic causes of dementia (differential diagnosis).

Toxic and metabolic dementias 135

Agent

METALS Arsenic

Bismuth Lead

Manganese Mercury

Tin

RECREATIONAL ABUSE Nitrous oxide

ENVIRONMENTAL/FOOD Ciguatera (from fish)

Shellfish
Carbon monoxide

Methyl alcohol

SOLVENTS Carbon disulfide

Trichlorethylene Hexacarbons

INSECTICIDES Organophosphates, carbamates

Occupational or Other exposure

Pesticides, pigments, paint, electroplating, seafood, smelter, semiconductors
Over ingestion of bismuth salicylates (e.g., PeptoBismol®)

Solder, lead shot, illicit whiskey, insecticides, auto body shop, storage battery manufacture, smelter, paint, water pipes, gasoline sniffing

Iron industry, welding, mining, smelter, fireworks, fertilizer, dry
cell batteries
Thermometers, other gauges, dental office (amalgams), felt hat manufacture, electroplating, photography

Canning industry, solder, electronics, plastics, fungicides

Dental offices

Accidental or deliberate exposure in motor vehicles, faulty gasoline‐fueled heaters

Contaminated illicit whiskey

Rayon manufacture, preservatives, textiles, rubber cement, varnish, electroplating
Paints, degreasers, spot removers, decaffeination, dry cleaning, rubber solvents

Paints, paint removers, varnish, degreasers, rapid‐drying ink, glues, cleaning agents, glues for making shoes in poorly vented cottage industry, glue sniffing, MNBK in plastics

Manufacture, application

Syndrome

Acute

Encephalopathy with dementia

Encephalopathy, ataxia, myoclonus Encephalopathy with dementia

Encephalopathy

Headache, tremor with dementia

Delirium

Encephalopathy with dementia

Sensory neuropathy with temperature inversion Acute neuropathy Anoxic encephalopathy with dementia

Retinal blindness

Encephalopathy with dementia

Narcosis Narcosis

Cholinergic syndrome

Chronic

Neuropathy

Possible irreversibility, death Encephalopathy, neuropathy, motor neuron disease‐ like syndrome

Parkinsonism

Neuropathy, encephalopathy with dementia, tremor

Encephalomyelopathy with dementia

B12‐deficient myelopathy

Encephalopathy, delayed neuropsychiatric syndrome, dementia

Neuropathy, Parkinsonism

Encephalopathy, trigeminal neuropathy, dementia Neuropathy, encephalopathy, ataxia, dementia

Ataxia, neuropathy, myelopathy

death. The general symptoms of CO poisoning include head ache, malaise, difficulty concentrating, dizziness, nausea, fatigue, and weakness. When not fatal, a wide spectrum of CO‐ induced encephalopathy ranges from reversible dysfunction to severe irreversible dementia. Table 11.2 lists some of the clinical

signs and symptoms associated with CO poisoning and corre lated carboxyhemoglobin (COHb) levels [2, 4].

Neurologic symptoms include dementia, cerebellar dysfunc tion, and parkinsonism [5]. A delayed neuropsychiatric syn drome may follow acute exposure by 3–240 days, with cognitive

136 Non-Alzheimer’s and Atypical Dementia

Table 11.2 Clinical signs and symptoms associated with CO poisoning and correlated COHb levels.

function are common sequelae. Persistent cognitive dysfunc tion lasting more than one month appears to occur in 25–50% of individuals with associated loss of consciousness or COHb levels greater than 25% [13–16]. Even those individuals with less severe and lower level CO poisoning might develop cogni tive impairments [17].

Neuroimaging

In general, neuroimaging demonstrates evidence of morpho logic damage that correlates to that reported in postmortem pathological studies. A distinct constellation of brain and MRI abnormalities includes globus pallidus lesions, white matter changes, and diffuse low‐density lesions throughout the brain. Abnormalities in the globus pallidus is common on both CT and MRI studies. Cerebral edema might occur early and some times predicts poor outcome (e.g., death or severe permanent damage). Globus pallidus changes do not always predict out come. Diffuse deep white matter MRI abnormalities correlate better with clinical status and prognosis; these changes are prob ably related to hypoxia/ischemia associated with CO toxicity [18–20].

The brain MRI might appear normal in some cases of dementia caused by CO exposure; in such circumstances, brain MRS abnormalities are often present. As MRS examines brain metabolites, the abnormal MRS often reflects decreased n‐acetylaspartase in the basal ganglia bilaterally [3].

Laboratory findings

Ambient air levels of CO should be obtained as soon as possible after CO exposure. The Centers for Disease Control and Prevention (CDC) [21] guidelines indicate the key to confirm ing the diagnosis in measuring the patient’s COHb level, which can be tested either in whole blood or exhaled air. COHb level should be obtained immediately as the half‐life of COHb is 4–5 h. Normal levels are <2% nonsmokers and 5–13% for smok ers. An elevated COHb level of ≥2% for nonsmokers or >12% for smokers strongly supports a diagnosis of CO poisoning. Pulse oximetry is unreliable for the diagnosis of CO intoxication because it is unable to distinguish oxyhemoglobin from COHb. A thorough and accurate assessment of clinical symptoms and CO exposure history is critical to determine the type and inten sity of treatment as COHb levels do not correlate well with severity of illness, outcomes, or response to treatment.

Pathophysiology and pathology

CO toxicity is caused by impaired oxygen delivery and use, lead ing to cellular hypoxia. Inhalation results in CO binding rapidly to Hb, leading to the formation of COHb. The oxygen‐carrying capacity of the blood decreases, causing tissue hypoxia. The affinity of Hb for CO is 210 times its affinity for oxygen, and CO easily displaces oxygen from Hb. COHb also impairs the release of oxygen from Hb by increasing oxygen binding to Hb, result ing in decreased oxygen delivery to cells. CO also might directly cause mitochondrial damage [22].

Severity

Mild Moderate Severe

Fatal

COHb level

<15–20% 21–40* 41–59*

60+%

Signs and symptoms

Headache, nausea, vomiting, dizziness, blurred vision
Confusion, syncope, chest pain, dyspnea, weakness, tachycardia, rhabdomyolysis Palpitations, dysrhythmias, hypotension, myocardial ischemia, cardiac arrest, respiratory arrest, pulmonary edema, seizures, coma Death

* At moderate to severe levels of COHb poisoning the correlation between blood levels and symptomatology is poor.

and personality changes and psychotic behavior [5, 6]. This syn drome is characterized by a relapse of symptoms associated with CO poisoning, occurring after a transient period of improvement. Whereas the physical and cognitive symptoms associated with severe acute exposure are obvious, the cognitive sequelae of low‐ level exposure are more easily misdiagnosed or overlooked [7].

Affective and personality changes following CO exposure are occasionally more prominent and/or life changing than cogni tive impairment. Depression, anxiety, obsessive–compulsive behaviors, delusions and hallucinations, violent outbursts, fear, elated mood, apathy, lack of motivation, and irritability are commonly reported symptoms [8, 9]. Depression and anxiety likely result from a combination of factors that include neural injury and psychological reactions to the physical and cognitive sequelae that occur following CO poisoning.

Neurologic exam

Although not necessarily specific to CO intoxication, common neurological exam findings may include abnormalities on the Romberg test, impaired heel–toe gait, dysdiadochokinesis, and poor performance on finger nose testing and serial sevens. Impaired fine movements, nystagmus, ataxia, compromised mental status examination, impaired reflexes, and intention tremor may also present. In severe cases, a tonic disorder or decerebrate rigidity associated with increased deep tendon reflexes and extensor plantar responses may be observed. Cortical blindness may be transitory and characterized by visual loss but intact pupillary reactions to light. Visual field defects, paracentral scotomas, decreased light sensitivity, and decreased dark adaption have been reported [10]. Flame‐shaped superfi cial retinal hemorrhages have been reported in long‐term, suba cute CO poisoning but are nonspecific [11]. Papilledema can be evident on funduscopic examination. The classic cherry‐red discoloration of the skin and cyanosis are rare.

Neuropsychological findings

Cognitive impairment occurs in 15–49% of individuals exposed to CO [12]. No consistent pattern of cognitive deficits following CO poisoning has been observed, but impaired mem ory, attention, information processing speed, and executive

The neuropathology of CO toxicity has been well described in postmortem studies [23] and in acute cases, includes pete chial hemorrhages of the white matter, in particular involving the corpus callosum. In cases surviving more than 48 h, there is multifocal necrosis involving globus pallidus, hippocam pus, pars reticularis of the substantia nigra, laminar necrosis of the cortex, and loss of Purkinje cells in the cerebellum, along with white matter lesions. The typical pallidum lesions are well defined—bilateral globus pallidus macroscopic infarctions, usually asymmetrical, extending anteriorly, supe riorly, or into the internal capsule. Occasionally, only a small linear focus of necrosis is found at the junction of the internal capsule and the internal nucleus of the globus pallidus. Less commonly, hemorrhages in the hippocampus are seen. CO intoxication usually spares the hypothalamus, walls of the third ventricle, thalamus, striatum, and brainstem. Myelin damage is constant and ranges from discrete, perivascular foci in the corpus callosum, the internal–external capsule and the optic tracts usually seen in comatose patients who died within 1 week, to extensive periventricular demyelination and axonal destruction observed in comatose patients with longer survival, sometimes leading to formation of plaques of demyelination [5].

Treatment

Tissue hypoxia is the major outcome of CO intoxication; there fore, based on chemical and pathophysiological data, oxygen is the “natural antidote” [24].

The CDC [21] recommends the following guidelines for the management of CO poisoning:
• Administer 100% oxygen until the patient is symptom free,

usually about 4–5h. Serial neurologic exams should be per formed to assess progress and to detect the signs of develop ing cerebral edema.

• Consider hyperbaric oxygen therapy (HBO) when the patient has a COHb level of more than 25–30%; there is evidence of cardiac involvement, severe acidosis, transient or prolonged unconsciousness, neurological impairment, abnormal neu ropsychiatric testing; or the patient is ≥36 years in age. HBO is also administered at lower COHb (<25%) levels if suggested by clinical condition and history of exposure.

Although some nonrandomized studies indicate that HBO reverses both the acute and delayed effects of CO poisoning, other data are conflicting. Therefore, it is not clear whether HBO influences the rates of either late sequelae or morbidity. It is generally agreed that HBO hastens resolution of symptoms and is usually indicated [25–29].

ethanol

Ethanol is a specific type of alcohol, and the only type that can be consumed. Within this section ethanol and alcohol will both be used to refer to the effects of Ethanol, given that alcohol is the more frequently used term. Ethanol intoxication is the consequence of an accumulation of it and its metabolites in the

bloodstream that occurs faster than can be metabolized by the liver. In the United States, roughly 10% of adults meet diagnos tic criteria for an alcohol abuse or dependence disorder. Of those, approximately 50% who become dependent exhibit neu rocognitive impairments when assessed 3–4weeks following abstinence [30]. A variety of dementia symptoms and neuro logical dysfunction can occur after ethanol ingestion [31] (Table 11.3).

Clinical and neurologic symptoms/features

Ethanol acts as a central nervous system depressant (Table 11.4). Acute overconsumption can lead to tremors, seizures, hallucina tions, ataxia, neuropathy, stroke, stupor, respiratory depression, coma, and death. Visual findings may include suppression of

Table 11.3 Major dementia issues in alcoholics (sometimes nutritional).

Toxic and metabolic dementias 137

Disorder

Wernicke syndrome

Korsakoff syndrome

Cerebellar degeneration

Polyneuropathy Amblyopia

Clinical features

Dementia with lethargy, inattentiveness, apathy, and amnesia Ophthalmoparesis

Gait ataxia
Dementia, mainly amnesia, with or without confabulation Gait ataxia; limb coordination relatively preserved
Distal limb sensory loss and weakness; less often autonomic dysfunction Optic atrophy, decreased visual acuity, central scotomas; total blindness rare.

Probable deficiency

Thiamine

Probably thiamine plus other vitamins plus ethanol neurotoxicity Probably thiamine plus other vitamins plus ethanol neurotoxicity Probably thiamine plus other vitamins plus ethanol neurotoxicity

Table 11.4 Metabolic causes of dementia (differential diagnosis).

Disorder

Endocrine 1. Thyroid

(a) Hypo

(b) Hyper 2. Pituitary (a) Hypo

(b) Hyper 3. Adrenal (a) Hypo

(b) Hyper Hepatic

Cardiac/pulmonary/hypoxia Vitamin deficiency

Electrolyte disturbances Glucose derangement

Clinical features

Encephalopathy, dementia Dementia

Encephalopathy, dementia
Visual disturbances/increased LCP

Lethargy, fatigue, dementia
Seizures, dementia
Encephalopathy, dementia Encephalopathy, dementia Encephalopathy, dementia, peripheral neuropathy

Encephalopathy, dementia Encephalopathy, seizures, dementia, peripheral neuropathy

138 Non-Alzheimer’s and Atypical Dementia

rapid eye movement during sleep, slow saccadic eye movements, and interrupted jerky pursuit movements. Gait and balance dis turbances are also common and may persist after detoxification [32, 33]. Chronic overconsumption can cause liver damage, as well as severe withdrawal symptoms, including seizures, halluci nations, and autonomic dysfunction (i.e., delirium tremens) [34].

Ethanol affects cognition both directly and indirectly. Ethanol is a direct neurotoxin and when sufficiently abused may lead to dementia. Ethanol, or possibly the components of alcohol, such as certain compounds in red wine including res veratrol, however, appear to have neuroprotective properties and reduce the risk of dementia, including Alzheimer’s type, when ingested in low‐to‐moderate amounts [35]. Further, both abstaining from and chronically abusing alcohol are associated with elevated risks of dementia. The relationship between drinking behavior and risk for dementia is described as a J‐ curve, meaning those who abstain from alcohol completely appear to develop dementia at higher rates than those who regularly drink moderate amounts of alcohol (e.g., up to three glasses of alcohol per day), whereas individuals who chroni cally abuse alcohol are also at high risk of developing dementia [36]. There is evidence of the beneficial effects of light–moderate, nonbinge consumption of alcohol, as well as experimental demonstration that moderate alcohol exposure can initiate cytoprotective mechanisms [37]. Intoxication, withdrawal, brain trauma, central nervous system infection, hypoglycemia, alterations in bodily systems (e.g., immune, hormonal), cere bellar degeneration, polyneuropathy, fetal alcohol syndrome, hepatic failure, and Marchiafava–Bignami disease are indirect effects of alcohol abuse, as are pellagra and Wernicke–Korsakoff disorder, resulting from nutritional deficiencies [31].

Neuropsychological findings

The precise etiology of neuropsychological impairment in alcohol abusers is controversial. Acute impairment tends to correlate reasonably well with BAC. Acute neuropsychological dysfunction is evident when BAC exceeds 50mg/dL (see Table 11.5). The chronic effects of alcohol on the brain have been well studied. Alcohol dementia is characterized by gradu ally progressive, multidomain cognitive dysfunction with prominent neuropsychological deficits on tasks measuring

Table 11.5 Central nervous system (CNS) effects after ethanol ingestion as a function of blood‐alcohol content (BAC).

mg/dL Typical presentation

20–50 Tranquility, mild sedation, mild fine motor coordination deficits 50–100 Judgment impairment, further coordination deficits
100–150 Unsteady gait, nystagmus, slurring of speech, behavioral

inhibition, impaired memory 150–300 Delirium and lethargy

300–400 Unconsciousness in the alcohol‐naïve; chronic consumers may still appear unaffected in context of extreme tolerance

≥400 Potentially fatal

visuospatial skills, abstraction, learning, and memory [30]. Language skills and global intellectual functioning remain rela tively intact with chronic alcohol consumption. In contrast, Wernicke–Korsakoff syndrome, a brain disorder produced by thiamine deficiency, is characterized primarily by acute to sub acute onset of severely impaired short‐term recall, confabula tion (fabrication), oculomotor abnormalities, and gait ataxia, with relatively preserved long‐term memory and global intel lectual functions. There can also be comorbidity of alcohol dementia and Wernicke–Korsakoff resulting in global cogni tive impairment [30].

Cognitive impairment due to alcohol abuse likely reflects the combination of acute and chronic brain damage including alco hol intoxication, vitamin deficiency, metabolic disorders, and cerebrovascular diseases. The increased likelihood of psychopa thology and head trauma/brain injury in individuals who abuse alcohol further complicate the diagnosis and prognosis. Ethanol‐related dementia is believed to represent approximately 10% of all dementia cases [38].

Neuroimaging

Chronic alcohol consumption is associated with cerebral atro phy of both grey and white matter with preferential involvement of the frontal lobes [7]. Reports indicate that alcoholic patients with dementia have reduced numbers of neurons in the superior frontal cortex [39]. Cerebellar atrophy, particularly of the ver mis, is also common. These pathological changes are confirmed by computed tomography (CT) or MRI brain imaging [40]. Research has indicated that drinking cessation might lead to a reduction in cerebral atrophy [41, 42], accompanied closely by improved cognition; amnesia associated with Wernicke– Korsakoff ’s is generally permanent, however [31].

Biomarkers/laboratory findings

Symptoms associated with acute ethanol or alcohol toxicity tend to progress proportionally to the amount ingested, which is measured directly via BAC level. Although there is some inter individual variability, O’Connor [34] provides the guidelines for expected effects by BAC in Table 11.5.

Diagnosis is typically clinical, but in cases of acute intoxica tion, BAC should also be measured, and blood glucose level should be checked to rule out hypoglycemia. In chronic alcohol abuse, complete blood count (CBC), magnesium (Mg), liver function tests, and prothrombin time/partial prothrombin time (PT/PTT) should be ordered. In cases of alcohol withdrawal, the clinician should rule out of other central nervous system inju ries or infections [34].

Several blood markers have been used to assess the effects of chronic alcoholism in clinical practice. These include elevated serum gamma‐glutamyltransferase (GGT) and aminotrans ferase (ALT, AST) levels and mean corpuscular volume (MCV). These have poor specificity and limited sensitivity to determine postmortem evidence of chronic alcohol use, however [43]. New markers include carbohydrate‐deficient transferrin (CDT),

fatty acid ethyl esters (FAEES), fatty acid methyl esters (FAMEs), ethyl glucuronide (EtG), phosphatidylethanol (PEth), 5‐hydroxy tryptophol to 5‐hydroxyindole‐3‐acetic acid (5‐HTOL/5‐HIAA) ratio, sialic acid, beta‐hexosaminidase, blood acetate, acetalde hyde adducts, and dolichol [44].

There are a variety of inpatient and outpatient therapeutic alcohol treatment programs available in most countries, includ ing the United States. Relapse rates are high, however, and psy chotherapeutic treatment should follow medical detox.

Lead

Lead is a natural, abundantly occurring metal used frequently in manufacturing and industry, and it has been extensively researched as a neurotoxicant [54]. Lead neurotoxicity can be due to acute or chronic exposure. Acute lead encephalopathy in children, attributed to pica or ingestion of flaking lead‐containing paint, was first reported in 1904 [1]. Lead poisoning, however, is among the oldest occupational illnesses and remains a common cause of metal poisoning today.

Clinical symptoms/features and neurologic
exam findings
Acute lead exposure may involve the rapid onset of nausea, head aches, cognitive changes, and emotional dysregulation. Medical symptoms can include hypertension, abdominal pain, constipa tion, and joint/muscle pains. Chronic exposure, which is more typical of industrial workplace environments, reflects more prominent neurodegeneration and psychiatric manifestations.

Pathophysiology and pathology

Ethanol neurotoxicity likely has several mechanisms, includ ing glutamate excitotoxicity and oxidative stress, which is sometimes exacerbated by thiamine deficiency [45–48]. The neuropathological correlates of alcoholism have been well documented via autopsy studies [45, 49–53]. In general, find ings support the tendency for individuals with alcohol depend ence to exhibit reductions in brain weights and increased pericerebral spaces consistent with hydrocephalus ex vacuo, as well as pronounced neuronal loss in the mammillary bodies, thalamus, basal forebrain, dorsal and medial raphe, and cere bellar vermis.

Treatment

Interested readers should refer to Table 11.6 for a brief overview of the medical management of ethanol intoxication and with drawal [31].

Table 11.6 Medical management strategies for ethanol intoxication and withdrawal.

Medication

Disulfiram

Naltrexone Acamprosate Nalmefene Topiramate

Magnesium supplementation

Thiamine

Diazepam, lorazepam, chlordiazepoxide, carbamazepine oxazepam, etc.

Phenobarbital

Mechanism of action

Interferes with metabolism of acetaldehyde (intermediary product in the oxidation of alcohol)

Opioid antagonist

Synthetic analog of y‐aminobutyric acid Opioid antagonist

Anticonvulsant/antiepileptic drug (AED)

Metal ion; necessary cofactor in thiamin‐dependent metabolism

Vitamin B1 Benzodiazepines

Barbiturate; sedative hypnotic

Effects

Alcohol consumption within 12h of taking disulfiram leads to facial flushing, suffusion of conjunctivae, throbbing headache, tachycardia, hyperpnea, sweating, vomiting, and potentially fainting and collapse, all of which typically lasts up to 3 h. These intense discomforts discourage alcohol consumption Decreases relapse rate and number of drinking days during relapse

May decrease relapse rate and number of drinking days during relapse
May decrease relapse rate and number of drinking days during relapse

May decrease relapse rate and number of drinking days during relapse

Correction of electrolyte abnormalities and thiamin deficiency

Prevent Wernicke–Korsakoff syndrome and symptoms of severe withdrawals or delirium tremens
Counteracts and/or prevents withdrawal symptoms, especially delirium tremens and seizures with withdrawal from severe dependence

Acts as potential substitute when benzodiazepines are ineffective

Side effects/risks

Adherence rates are poor; contraindicated for patients who are pregnant

Adherence rates are modest; contraindicated in patients with acute hepatitis or liver failure

Still currently under study

Still currently under study; some problems with memory and general neurocognitive functioning have been reported
IV/IM administration should continue for at least 3–5 days; advanced disease necessitates hospitalization

IV delivered; should remain in ICU over course of symptoms

Can cause intoxication and dependence; for short‐term management of withdrawal. For patients with significant liver problems, short acting benzodiazepines (e.g., lorazepam)

or one metabolized by glucuronidation (e.g., oxazepam)
Respiratory depression a risk with concomitant use

Toxic and metabolic dementias 139

140 Non-Alzheimer’s and Atypical Dementia

Lead‐exposed workers frequently complain of fatigue, head aches, restlessness, irritability, and poor emotional control [55–57]. There is some evidence that chronic lead exposure may impair postural balance and speed of peripheral nerve function, as well as contributing to forearm extensor weakness. Psychosis with hallucinations, restlessness, and nightmares are typical psychological symptoms produced by organic lead exposure [55, 58]. Delirium, convulsion, and coma might even occur in high concentration exposure. In sum, the deleterious effects of lead on the brain range from mild cognitive decline to encepha lopathy, parkinsonism, and dementia [59].

Although acute toxicity is rare, chronic toxicity causes both central and peripheral effects, the former more common in chil dren and the latter in adults. Adults with chronic lead exposure and blood lead levels from 25 to 60 μg/dL often experience irri tability, headache, and depressed mood, with signs of impaired visual–motor dexterity and reaction times. Even more overt effects, for example, weakness and atrophy of peripheral mus cles with wrist drop, occur with long‐term blood levels of 60 μg/ dL or more. Peripheral neuropathy is usually accompanied by blood lead levels greater than 70 μg/dL. Chronic exposure over months or years adversely affects calcium‐dependent enzyme systems, ATPases, and mitochondrial oxidative phosphoryla tion and cell growth; interferes with heme synthesis, membrane integrity, and steroid metabolism; and causes motor axon degeneration and demyelination [60]. Additional potential con sequences include anemia, reduced sperm count, renal failure, chronic encephalopathy, delayed motor and sensory nerve con duction, hearing loss, and gout.

Neuropsychological findings

Lead exposure is considered a significant risk factor for acceler ated cognitive decline [61, 62]. A consistent pattern of neuro cognitive deficits associated with lead exposure has not been identified, although visuospatial and visual memory impair ments are frequently reported as the most prominent declines [63, 64]. A cross‐sectional study of workers in a leaded glass plant found deficits in psychomotor speed, motor strength, and verbal memory [56]. Other studies, however, have found no or few abnormal cognitive deficits in exposed persons, which may be due to moderately low exposure or current blood levels. Leaded fuels contain multiple neurotoxic substances; therefore, the neuropsychological deficits likely result from a combination of triethyl lead, solvents, and possible hypoxia [65]. Chronic exposure to lead tends to be more harmful to cognition than acute exposure as bone lead levels predicted poorer cognitive performance, whereas blood lead level did not [66]. Anxiety, depression, phobia, and antisocial behavior are linked to lead exposure [67].

Laboratory findings

Lead introduced into the bloodstream is excreted at a clearance rate of 1–3mL/min in urine and bile with a half‐life of approxi mately 30 days. The remaining lead binds to red blood cells, is

distributed throughout soft tissues of the body, and accumulates in bone [68]. Lead’s half‐life in the bones ranges from 20 to 30 years. Blood lead levels are more reflective of acute exposure, whereas bone lead levels better reflect cumulative exposure over time [69].

Whole‐blood lead concentration is the most reliable diagnos tic test because urinary lead levels increase and decrease more rapidly than blood levels in response to changes in lead expo sure. Mean whole‐blood level in adults without known exposure to occupational hazard is less than 5μg/dL. Standard recom mendations now consider levels safe up to 30 μg/dL; some con sider a higher limit of 50 μg/dL to be safe. Workers are monitored closely if levels exceed 40μg/dL. The upper limit of normal measurement for lead in urine is 150 μg/dL creatinine [1].

Pathophysiology and pathology

Lead interferes with multiple enzyme systems in the body with primary targets to include the heme synthesis enzymes, thiol‐ containing antioxidants, and enzymes (superoxide dismutase, catalase, glutathione peroxidase, glucose 6‐phosphate dehydro genase, and antioxidant molecules like GSH). The induction of oxidative stress, intensification of apoptosis of neurocytes, and interference with Ca(2+)‐dependent enzymes are all mecha nisms of lead neurotoxicity [70]. Edema, capillary disruption, proliferation of glia, and diffuse anoxic injury are all postmor tem pathological findings in lead toxicity [71].

Treatment

Treatment combines decontamination of the exposure source, supportive care, and the use of chelating agents; the primary focus of treatment for lead exposure, however, is to reduce the level of circulating lead in the bloodstream. In affected people, chelation therapy should commence at levels of ≥40μg/dL. Supportive care might include treatment of increased ICP by standard use of IV mannitol and glucocorticoids, the latter because the pathophysiology of lead encephalopathy involves capillary leak. For chelation of patients with lead encephalopa thy, calcium disodium edentate, or calcium ethylenediaminetet raacetic acid (EDTA), should be administered at 30 mg/kg every 24h. Some advocate initiating chelation with a single dose of dimercaprol (British anti‐Lewisite [BAL]), 4–5 mg/kg deep intramuscularly. Alternatively, meso‐2,3‐dimercaptosuccinic acid (DMSA or succimer) is advocated for treatment of moder ately severe chronic lead intoxication [1]. Although cessation of lead exposure and chelation effectively lower blood lead levels, thereby reducing pharmacological effects of lead, they show no therapeutic benefit against potential morphological changes in brain during neurodevelopment [72].

Metabolic dementias

Cognitive impairment might be a direct consequence of medi cal illness or metabolic perturbations. For patients with poten tial endocrine disease, and liver or kidney failure, certain blood

tests are essential to rule out metabolic causes for dementia. For example, it is important to obtain thyroid function studies because hypo‐ and hyperthyroidism are potentially reversible causes of cognitive impairment. Vitamin B12 deficiency is asso ciated with hematologic, neurologic, and psychiatric manifesta tions. It is linked to memory decline, irritability, and dementia in some cases. Elevated levels of methylmalonic acid and/or homocysteine levels might indicate early vitamin B12 deficiency or suggest other metabolic pathway abnormalities [73–75]. Potential intoxication from illicit substance or other iatrogenic medications as a cause for cognitive dysfunction should be con sidered. Getting an accurate medication history and urine and/ or blood tests might confirm such intoxication.

A variety of hormone abnormalities have been linked to cog nitive impairment or dementia. Much attention has been focused on sex hormones, steroid hormones derived primarily from the gonads, including estrogens (e.g., 17β‐estradiol and estrone), progestogens (e.g., progesterone), and androgens (e.g., testosterone and dihydrotestosterone). Thyroid hormone defi ciency is a well‐known cause of dementia. Psychological stress— linked to excess secretion of cortisol, a glucocorticoid produced within the adrenal cortex—has also been considered a theoreti cal contributor to dementia, but clinical implications are unclear. Sex hormones, glucocorticoids, and thyroid hormone are all members of a nuclear receptor superfamily. These hormones function primarily as intracellular ligand‐activated transcrip tion factors, which bind to hormone‐responsive DNA elements to modulate expression of target genes. Receptors for estrogen, progesterone, androgen, cortisol, and thyroid hormone are found in human brain, expressed in subsets of neuronal or glial cells with unique topographically restricted distributions. A review of the full breadth of metabolic disorders with associated neurocognitive sequelae is beyond the scope of this chapter and has been reviewed elsewhere [76]. This section will focus on three common metabolic issues that have been shown to cause dementia: thyroid dysregulation, hepatic dysfunction, and disorders of glucose metabolism.

Thyroid

The thyroid, a small gland of approximately 2in.2 lying just below the Adam’s apple, is integral to proper metabolic func tioning, as it stimulates bodily tissues to produce proteins and manages intracellular oxygen consumption. Accordingly, it is involved in maintenance of heart, respiratory, and metabolic rates, as well as influencing growth, heat production, and repro ductive and digestive functions [77].

Clinical symptoms/features

Hypothyroidism and hyperthyroidism (i.e., thyrotoxicosis) are among the most commonly diagnosed endocrine disorders. Thyroid hormone is essential for fetal brain development and continues to impact brain health throughout adulthood. The most common cause of hypothyroidism in the United States is an autoimmune condition known as Hashimoto’s disease, in

which lymphocytes accumulate in the thyroid and lead to a reduction in thyroid function. Hashimoto’s disease can cause a host of symptoms associated with inadequate thyroid hormone secretion: fatigue, weight gain, depression, memory deficits, cold intolerance, and joint/muscle pains among others. Rates are much higher among women than men, and onset is most common among individuals between 30 and 50 years of age [78]. Conversely, Graves’ disease is a common autoimmune dis order leading to overactivity of the thyroid gland. Graves’ dis ease typically leads to anxiety, concentration difficulties, diplopia, irritability, weight loss, and tremor. It is also most common among women over the age of 20 [79].

Neuropsychological findings

Individuals with both hyperthyroidism and hypothyroidism can exhibit neuropsychological impairment. Decreased concentra tion, slowed reaction time, decreased complex visual processing and spatial organizational abilities, and poor constructional skills are the most common neuropsychological deficits observed in patients with hyperthyroidism or Graves’ disease [80]. A majority of individuals concurrently meet the criteria for major depressive disorder and generalized anxiety disorder rela tive to other hospitalized medical patients. Hyperthyroidism can also cause physiologic tremors similar in appearance to essential tremors or cause preexisting essential tremors to worsen in severity [81].

Neuropsychological deficits, however, have not been found in all studies. Vogel, Elberling, Hording, and colleagues [82] found higher ratings in psychiatric measures prior to treatment but no differences on neuropsychological test performance in patients with Graves’ disease. The authors further reported that after reaching a euthyroid level, previously reported psychiatric and cognitive impairments decreased considerably.

Research on the neurocognitive functioning of individuals with primary hypothyroidism indicates multiple areas of poten tial deficits. The most common neuropsychological deficits observed in hypothyroidism include reduced processing speed, diminished attention and concentration, impairments in learn ing and memory, executive dysfunction, and global cognitive deficits or dementia [83]. Similar to hyperthyroidism, hypothy roidism is associated with frontal systems compromise and high potential for psychiatric comorbidities [83, 84].

Neuroimaging

Stern and colleagues proposed that the cognitive deficits pre sent in hyperthyroidism reflect frontal systems dysfunction (i.e., frontal cortex and associated subcortical structures) [85–87]. Bhatara and colleagues found reduced cerebral metab olism in the right frontal lobes of Graves’ patients compared to healthy controls using MR spectroscopy [88]. Preliminary data obtained by Stern and colleagues suggests that patients with Graves’ disease who have abnormal single‐photon emission computed tomography (SPECT) scans demonstrate impaired performance on tests of verbal list learning, planning and

Toxic and metabolic dementias 141

142 Non-Alzheimer’s and Atypical Dementia

organization, visuospatial skills, perseveration, and mild to moderate depressive symptoms [89]. PET scanning has demon strated generalized decrease in regional cerebral blood flow and in cerebral glucose, suggesting no specific localized deficits in overall reduction brain activity [90]. SPECT studies have also reflected diffuse cerebral hypoperfusion in hypothyroid indi viduals [91]. SPECT findings associated with hyperthyroidism tend to show bilateral temporoparietal defects similar to what is often observed with Alzheimer’s disease. Accordingly, Graves’ disease is an important treatable/reversible differential diagnos tic consideration that can be easily overlooked for patients who present with clinical and radiological findings suggestive of “possible” Alzheimer’s disease [92].

Treatment

Thyroid dysregulation represents a treatable yet sometimes overlooked cause for dementia in adults. Neurocognitive symp toms are improved by maintaining thyroid levels within the nor mal ranges; some research, however, suggests medical treatment of hypothyroidism is associated with partial and inconsistent patterns of neurocognitive recovery [93]. Thyroxine treatment does not appear to improve cognitive function in otherwise healthy patients with subclinical hypothyroidism [84].

Dementia associated with hyperthyroidism responds well to treatment with a beta‐blocker, resulting in improved behavioral and attention‐related cognitive functioning, along with enhanced tracer uptake in the frontal region of the brain. Subsequent methimazole intervention has been shown to further improve memory and visuoconstructional skills [92].

hepatic disorders

Cirrhosis is not an isolated liver disorder but can have conse quences for the whole body as well as on brain functioning. The impact of liver failure on the brain is evident in mental status and/or behavioral changes. These neurological and/or psychiat ric consequences of liver failure are collectively termed hepatic encephalopathy (HE).

HE is a common neuropsychiatric complication in patients with hepatic insufficiency from acute liver failure or cirrhosis or from portosystemic shunting even in the absence of intrinsic liver disease. Symptom presentation is diverse and ranges in severity. HE results in a diminished quality of life, a poorer prognosis in patients with underlying liver cirrhosis [94], and is an independent predictor of mortality in patients with acute‐ on‐chronic liver failure [95, 96]. In its most severe form, it can lead to coma or death. Mortality is extremely high in overt HE with cerebral edema, and temporizing measures are often found to be inadequate [97]. Mortality at 1 year for patients with severe HE in intensive care unit (ICU) is 54% [98].

Clinical symptoms/features

The onset of neurological symptoms in chronic HE is usually insidious. Patients with HE may present with subtle and mild alterations in intellectual abilities, cognitive functions, emotional

and behavioral regulation, and psychomotor/fine motor skills, possible indications of emerging encephalopathy. Confusion, disorientation, and poor coordination are common [99]. Personality changes, decreased energy level, impaired sleep– wake cycle, impaired cognition, diminished consciousness, asterixis, hemiplegia, and loss of motor control may also be pre senting symptoms.

Minimal hepatic encephalopathy (MHE) refers to the sub clinical stage of HE, in which routine clinical neurological and mental status examinations are normal, but subtle deficits can be documented on comprehensive neuropsychological testing. Subclinical manifestations of HE can be found in upward of 50% of cirrhotic patients without overt encepha lopathy [100]. The mildest form of HE, MHE, is associated with a significant compromise of quality of life, which is pre dictive of the onset of overt HE and is associated with a poorer prognosis for outcome [101].

Diagnostic criteria

There is no consensus on the diagnostic criteria for HE; a 1998 consensus group at the 11th World Congress of Gastroenterology in Vienna, however, proposed a standardized nomenclature for HE that characterizes both the type of hepatic abnormality and the duration/characteristics of neurological complications [102]. Diagnosis requires the exclusion of other causes of altered mental status. Overt HE consists of neurological and psychiatric abnormalities that can be detected by bedside clinical tests, whereas minimal HE can only be distinguished by specific psy chometric tests due to lack of findings of clinical exam. Overt HE occurs in at least 30–45% of patients with cirrhosis and in 10–50% of patients with transjugular intrahepatic portosys temic shunts [103, 104].

Neurological exam

Clinical diagnosis of overt HE is based on the combination of impaired mental status and impaired neuromotor function, such as hyperreflexia, hypertonicity, and asterixis [105]. Parkinsonian‐like symptoms, such as rigidity and tremors, as well as the aforementioned symptoms of confusion, disorienta tion, impaired sleep–wake cycle, impaired cognition, dimin ished consciousness, choreoathetoid movements, Babinski sign, transient focal symptoms, hemiplegia, and loss of motor control may also be evident on a neurologic examination. Exam may also show loss of facial expression, speech disturbances, and visual misperceptions (visual agnosia, macropsia, distor tion and prolongation of the images, spatial disorientation, and a predominance of visual hallucinations). Rarely, auditory, tac tile, olfactory, and gustatory hallucinations also have been reported [105].

Neuropsychological findings

Neuropsychological impairment has been well documented in patients with cirrhosis and end‐stage liver disease [102, 106]. Neuropsychological testing in HE reflects deficits in attention,

working memory, processing speed, visuomotor abilities, speeded fine motor movements, and executive function. In con trast, verbal abilities including verbal memory tend to be rela tively preserved in HE and particularly in MHE. Several studies have demonstrated that many patients diagnosed with cirrhosis without clinical signs of encephalopathy perform poorer on neuropsychological tests when compared to healthy controls [107–113]. Schomerus [114] demonstrated that 60% of the cir rhotic patients with no clinical signs of HE were considered unable to drive, and driving capacity was questionable in 25%.

Cognitive impairment in persons with chronic liver disease was assumed to be a consequence of cirrhosis‐associated HE until recently. Conditions such as portal‐systemic shunting, however, also can result in cerebral dysfunction, thought to be an outcome of high ammonia concentration and astrocyte swelling, hallmarked by decreased recent memory, fluctuating consciousness, and disorientation [115, 116]. There is growing evidence of cognitive deficits in many patients with hepatitis C virus (HCV) infection prior to the development of cirrhosis that appear unrelated to markers of liver dysfunction, viral load, or genotype [117–123].

Hilsabeck and colleagues [120] found that a significant per centage of patients with chronic HCV experience cognitive defi cits such as compromised attention, learning, psychomotor speed, and mental flexibility. Impaired cognitive test perfor mance was also evident in up to 50% of individuals who have not yet developed cirrhosis, depending on the neuropsychologi cal test administered. Testing revealed sustained attention and concentration; slowed processing speed were the most challeng ing tasks for these patients whereas visuoconstructional skills were within normal limits. Problems with learning, psychomo tor speed, and mental flexibility are also present [120]. Greater neuropsychological impairment was present in those individu als with greater levels of fibrosis suggesting that the longer one experiences chronic hepatic injury, the more likely they are to develop neurocognitive impairment. In summary, HCV and other chronic liver diseases adversely affects cognition, particu larly attention and concentration, even in the absence of cirrho sis early in the disease process. Depression is a common comorbidity with approximately 25% of HCV‐infected patients meeting diagnostic criteria for concurrent depression [124, 125] and 50–60% reporting clinically significant depressive symp toms on self‐report [126].

Neuroimaging

Classic MR imaging abnormalities in HE include bilateral and symmetric high signal intensity in the globus pallidus on T1‐ weighted images, which is likely a reflection of increased tissue concentrations of circulating manganese, and “an elevated glu tamine/glutamate peak coupled with decreased myo‐inositol and choline signals on proton MR spectroscopy, representing disturbances in cell volume homeostasis secondary to brain hyperammonemia” [127]. White matter abnormalities can be detected with MR imaging techniques such as magnetization

transfer ratio measurements, fluid‐attenuated inversion recov ery sequences, and diffusion‐weighted images [127]. These MR imaging abnormalities are believed to reflect mild diffuse brain edema, which seems to play an essential role in the pathogenesis of HE.

Laboratory findings

Diagnosis of HE requires exclusion of other causes of altered mental status. Laboratory abnormalities typically include evi dence of electrolyte disturbances (such as hyponatremia and hypokalemia) and hepatic biochemical and synthetic dysfunc tion. Arterial and venous ammonia levels correlate with the severity of HE up to a certain point. Gastrointestinal bleeding, renal failure, hypovolemia, extensive muscle use, urea cycle dis order, parenteral nutrition, urosepsis, and the use of certain drugs (e.g., valproic acid) are additional nonhepatic causes of hyperammonemia that need to be excluded. Clinical presenta tion and clinical response to treatment are most important. Other laboratory tests of liver and renal function, electrolytes, glucose, cultures, and drug screening should be considered to assess for precipitating causes of HE.

Pathophysiology and pathology

The pathogenesis of HE is not well defined; it is believed, how ever, to involve alterations in various neurotransmitter systems within the brain. Involvement of the γ‐aminobutyric acid (GABA) receptor complex in HE, in particular the benzodiaze pine receptor site, as well as increased serotonin turnover has been postulated [128]. Patients with liver failure or portal‐ systemic shunt surgery have increased circulation of ammonia entering the brain through the blood–brain barrier. This leads to the accumulation of glutamine in brain astrocytes and brain swelling. Benzodiazepine‐like agonists, inflammatory cytokines, manganese, and neurosteroids may play a role [129–132].

Treatment

Acute management of HE should focus on providing supportive care, identifying and treating any precipitating causes, reducing nitrogenous load in the gut, and assessing the need for long‐ term therapy and liver transplant evaluation. Pharmacological treatment of HE includes the use of nonabsorbable disaccha rides such as lactulose and lactitol and antibiotics such as rifaxi min [133].

Oral dose of lactulose for acute overt HE begins at 10–30g (15–45mL) every 1–2h until a bowel movement occurs. Readjustment to 10–30g (15–45mL) two to four times daily is then recommended as the next step, titrated and continued indefinitely to induce two to three soft bowel movements daily. Nasogastric tube or rectal administration as an enema (300 mL in 1L of water ever 6–8h) can be used for comatose patients until the patient awakes and can start oral therapy. Rifaximin (550 mg twice daily) can be used to treat HE [134].

Correction of precipitating factors is critical. Increased nitro gen load (e.g., gastrointestinal bleed, infection, excess dietary

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144 Non-Alzheimer’s and Atypical Dementia

protein), decreased toxin clearance (e.g., hypovolemia, renal failure, constipation, portosystemic shunt, medication non compliance, acute‐on‐chronic liver failure), and altered neuro transmission (e.g., sedating medication, alcohol, hypoxia, hypoglycemia) are the most common precipitating factors for HE that need to be evaluated and treated if present.

Glucose

One of the most common metabolic diseases resulting in blood glucose imbalance is diabetes mellitus. The overwhelming majority of diabetes diagnoses fall into one of two broad eti opathogenetic categories: (i) Type 1 diabetes is characterized by a halting of insulin secretion secondary to an autoimmune path ogenic process in which pancreatic islet cells are destroyed. (ii) Type 2 diabetes is a much more prevalent condition in which a resistance develops to insulin, and pancreatic islet cells are una ble to produce enough additional insulin to sufficiently com pensate. Although both types of diabetes are present across the lifespan, Type 1 tends to be diagnosed during late adolescents or early adulthood, whereas Type 2 is more prevalent among older adults [135].

Clinical symptoms/features

The varied and complex complications associated with both Type 1 and Type 2 diabetes have been well documented [136]. This list ranges across a host of neurological and nonneurologi cal problems, including but not limited to retinopathy with or without vision loss, nephropathy/renal failure, autonomic and peripheral neuropathy, cardiovascular complications, cerebro vascular disease, sexual dysfunction, affective disorders, and gastrointestinal issues.

The impact of hypoglycemia and hyperglycemia on the nerv ous system has been well studied [137]. Recent studies have focused on the effects of hypoglycemia and older individuals with Type 2 diabetes mellitus (DM2) [138]. The link between diabetes and cognitive decline is obscured by coexisting depres sion, hypertension, and cardio‐ and cerebrovascular diseases.

As the primary source of energy for neurons is glucose, brain hypoglycemia is very harmful to brain function and might cause permanent cognitive dysfunction leading to dementia, depend ing on the severity of hypoglycemia. Depending on the level of hypoglycemia, seizures also occur, which might be additionally detrimental to brain function [139]. Well‐controlled studies, however, of the threshold for the development of seizures secondary to hypoglycemia are lacking.

Neuropathology

Impaired glucose tolerance might increase the occurrence of pathological changes associated with vascular dementia [140]. The pathological vascular damage changes may be the anatomi cal basis for the increased risk of cognitive impairment or dementia in DM2 [141]. Hyperglycemia is common among acute ischemic stroke patients [142]. It is also well known that hyperglycemia adversely affects the outcome of cerebral

infarction [143, 144]; this association has been documented in recent stroke treatment trials [145].

The link between hyperglycemia in diabetes mellitus and dementia is obscured by other comorbidities associated with DM2, including depression, hypertension, and cardio‐ and cere brovascular diseases. Impaired glucose tolerance appears to increase the occurrence of the pathological changes associated with vascular dementia and Alzheimer’s Disease [140]. Pathological vascular damage changes, however, might be the anatomicalbasisfortheincreasedriskofdementiainDM2[141].

Recent studies have focused upon the effects of hypoglycemia on older people DM2 [146]. Infection‐related hypoglycemia, especially in institutionalized demented patients, is a significant health‐care problem that may aggravate dementia [147].

Neuropsychological findings

Diabetes‐associated cognitive deficits have been observed by physicians and researchers since as early as the 1920s [148]. Diabetes is associated with accelerated cognitive decline and structural brain abnormalities, and deficits have been observed across a range of neuropsychological domains [149]. Cukierman et al. [150] reviewed prospective data relating to diabetes and cognitive function over time and found that people with diabe tes have a greater rate of decline in cognitive function. Specifically, they found a 1.5‐fold greater risk of cognitive decline and a 1.6‐fold greater risk of future dementia when com pared to individuals without diabetes. In the Framingham study [151], individuals with diabetes were more likely than were non diabetics to obtain scores below the 25th percentile on more tests. Specific areas of decline have been observed in implicit memory, processing speed, psychomotor speed and efficiency, sustained attention, cognitive flexibility, and visual attention and perception [152]. The frequency of reported differences in neuropsychological performance among diabetic patients does not appear to account, however, for severe hypoglycemic epi sodes [153].

Neuroimaging

A burgeoning body of neuroimaging research is documenting the effects of glucose imbalance and diabetes on structural brain integrity [154–158]. Cortical and subcortical atrophy have been noted along with microvascular disease and other subcortical white matter abnormalities. In general, brain atrophy tends to be modest and other abnormalities usually subtle in nature, although earlier onset of DM has been shown to correlate with more severe findings on MRI.

Treatment

The benefits of maintaining normal blood glucose levels for min imizing neurocognitive and medical symptoms and lessening risks for complications among patients with diabetes have been well verified through randomized controlled trials and large‐ scale cohort studies [159–161]. Experimental animal studies also indicate THAT optimal glycemic control may lower risk for

developing poststroke dementia [162]. Furthermore, decreased mortality is achieved by normalizing blood sugar after a stroke [163]. Therefore, normalization of blood glucose after a stroke is an appropriate clinical goal, and in general, current treatment for Type 1 and Type 2 diabetes emphasizes maintenance of normal blood glucose levels in order to achieve optimal neurological, medical, and neuropsychological functioning.

Summary

The role of toxic and metabolic disorders in dementia is quite complex. Because the effects of these conditions are so diverse and often little specific clinical evidence is available, animal models have helped provide additional evidence for the likely effects in humans. In this chapter, three specific toxic causes of dementia and three specific metabolic causes of cognitive impairment and dementia have been addressed in some detail. It is critical to consider toxic and metabolic causes in every patient with cognitive impairment, especially because early diagnosis and treatment might lead to improvement and per haps even reversal of the dementia or cognitive decline.

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Toxic and metabolic dementias 149

Chapter 12 Leukoencephalopathies/leukodystrophies

Gregory M. Pastores1,2 and Swati A. Sathe3

1 Mater Misericordiae University Hospital, Dublin, Ireland
2 Yale University School of Medicine, New Haven, CT, USA
3 Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, USA

Introduction

The leukoencephalopathies encompass a group of heterogeneous disorders that can lead to cognitive problems as a consequence of brain white matter involvement. Many of the acquired leukoen cephalopathies that cause cognitive decline such as inflammatory, vascular, infectious, neoplastic, and toxic diseases are covered elsewhere in the book. Our focus will be on the hereditary forms of white matter disorders, that is, leukodystrophies, in particular the adult‐onset conditions leading to dementia as a predominant feature (Table 12.1). Strictly, the term leukodystrophy is applied to conditions which have a genetic basis, progressive course, and white matter involvement (Table 12.2) [1]. In several, the biochemical and/or molecular defect is known, enabling diag nostic confirmation, which then allows appropriate genetic counseling and prognostication.

The leukodystrophies are familiar to most in their so‐called classic expression with onset usually in childhood. It must be recognized that there are late‐onset presentations of almost every childhood leukodystrophy. In such cases, disease course is often insidious, and diagnosis can be significantly delayed. It is not uncommon for patients with late‐onset leukodystrophy to be initially suspected and treated as primary or secondary progressive multiple sclerosis (MS) [2]. Given the complex clinical presentations and similarity with more common adult‐ onset white matter diseases, underdiagnosis of leukodystrophy is likely. A negative family history or low disease prevalence often complicates this issue.

Review of systems and laboratory assessments in patients with a leukodystrophy often show no indication of electrolyte imbalance, thyroid or liver disease, vitamin deficiency, brain mass, drug intoxication, or chronic infection. In most cases, cerebrospinal fluid (CSF) studies, including cell counts, glucose, and oligoclonal bands, also are normal. In metachromatic leukodystrophy (MLD) or globoid cell leukodystrophy (GLD), however, there is increased CSF protein levels; the diagnosis of

these two lysosomal disorders can be confirmed by biochemical enzyme testing (discussed in the following) [3].

Although certain MRI features in leukodystrophy are quite characteristic, they might also suggest several alternate diagnoses. Those include white matter diseases such as MS, cerebrovascular diseases (e.g., Binswanger’s disease), or chronic exposure to toxic substances (e.g., chemotherapy). The pattern and distribution of white matter changes on MRI in patients with a leukodystrophy might suggest a particular disorder or narrow the list of differen tial diagnoses [4]. Until proven otherwise, symmetrical changes consistent with white matter disease is indicative of a leukodys trophy. The differential diagnosis of a leukodystrophy can also be aided by incorporating the results of a neurological evaluation and genetic testing (see Table 12.3 for a review of clinical and MRI features associated with the disorders reviewed in this chapter). Figure 12.1 provides a framework for the clinical workup of a patient with suspected leukodystrophy or leukoencephalopathy.

The management of patients with most leukodystrophies currently unfortunately is primarily symptomatic. Hematopoietic stem cell transplantation and pharmacologic treatments are options in selected cases. For disorders that are potentially treat able, early diagnosis is critical for the best possible outcome.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Illustrative case history 1

A 41‐year‐old gentleman was seen because of migraine with aura since age 24 and multiple recurrent episodes of unilateral numbness and tingling, attributed to MS. Regarding the migraines, his visual auras were reported as bright spots and lines. Some episodes of headache were associated with confusion which typically occurred about half an hour after the onset of head ache. During the headache, he is unable to recognize people he

150

Table 12.1 Selected leukodystrophies.
Disorder Cause

• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

• Adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP): hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD)

• Adult‐onset autosomal dominant leukodystrophy (ADLD) with autonomic dysfunction

• Adult polyglucosan body disease (APBD)

• Alexander disease

• Mitochondrial disorders, including mitochondrial encephalomyopathy, lactic acidosis, and
stroke‐like episodes (MELAS) and myoclonic epilepsy and ragged‐red fibers (MERRF)

• Lysosomal storage disorders, including metachromatic leukodystrophy (MLD), globoid cell
leukodystrophy (GLD) and Fabry disease (FD)
Table 12.2 Clinical signs of a leukodystrophy.

• A period of normal development generally precedes the onset of neurological signs and symptoms

• Spasticity develops which is usually bilateral and symmetrical

• Other long‐tract signs include motor weakness and ataxia

• Optic atrophy occurs late

• If peripheral myelin is affected, then neuropathy with loss of ankle
reflexes is seen

• Seizures are uncommon but can be encountered

• Behavioral and cognitive changes can occur at any stage

• Environmental precipitants can quickly exacerbate an underlying
metabolic disorder of myelin
knows and does not fully comprehend what is being said to him, his speech is affected, and he has word‐finding difficulty. His problems usually resolve within hours, and he has partial memory for the episode.
At age 35, he suffered from an acute episode of numbness and clumsiness in the left face and arm with a field cut, with com plete recovery. A brain MRI done at the time showed extensive white matter disease. He was diagnosed with MS after excluding HIV, Lyme disease, and lupus. He was treated with glatiramer acetate for 1 year without benefit, following which he was given interferon beta‐1 for another year, again without clear benefit. Over the past 6 years since the first episode, he has had four additional episodes of left‐sided numbness and clumsiness with left field cut.
Over the past 10–15 years, there has been a gradual decline in his memory and concentration. He keeps a diary to remember appointments and his schedule. Additionally, he has to pay close attention to his daily work routine as a machine operator to ensure that he correctly follows the sequence. There are also subtle changes in his personality such that he is more emotional and cries easily. His past medical history revealed major depres sion with suicidal ideation at age 24, elevated triglycerides (treated successfully with niacin), and no history of hyperten sion/diabetes/asthma or heart disease. His family history was remarkable for one older brother with migraine and episodes of arm and face numbness, attributed to MS. His father died at age

• Notch3 gene mutation (19q12) • CSF1R gene mutation (5q32)

• LMNB1 mutation (5q23)
• Glycogen branching enzyme (GBE1) deficiency (3p16) • Glial fibrillary acidic protein (GFAP) (17q21)
• MELAS (mtDNA A3243G); MERRRF (mtDNA A8344G)

• MLD (arylsulfatase A; 22q13), GLD (β‐galactocerebrosidase; 14q21), FD (α‐galactosidase A; Xq22)

Leukoencephalopathies/leukodystrophies 151

42 from bone cancer, and his mother, age 65, has hypertriglyc eridemia, osteoarthritis, and cervical spondylosis. She has no history of migraine, stroke, or dementia.

On neurological examination, he was alert and oriented with fluent speech. Comprehension, repetition, and naming were intact. Three object recall was 2/3 (3/3 with cues). Neuropsychological testing showed impairment in attention, processing speed, and executive function, including deficits in timed measures and measures of error monitoring, but with spared memory. Cranial nerve, motor, and sensory examinations were normal. There was no pronator drift. Rapid alternating movements were accurate. There was no double simultaneous extinction. Deep tendon reflexes were bilaterally symmetric, 2+. Both plantars were flexor. Gait was normal and there were no cerebellar signs. His clinical course, brain MRI findings (Figure 12.2), and family history were deemed consistent with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The absence of optic nerve and spinal cord involvement on brain MRI, the absence of oligoclonal bands in the CSF, and the absence of hypertension are pertinent negative findings that help to distin guish cases of CADASIL from MS, small vessel disease, or primary angiitis of the nervous system. A significant proportion of patients with CADASIL often are initially diagnosed and treated for MS. Thus, evaluation of patients suspected to have MS should include careful consideration of red flags, which are features in the history, examination, or diagnostic tests that are not typical or suggestive of MS and may point toward the diagnosis of a leukodystrophy [5].

Background

CADASIL is included in this chapter although it is not a leukodys trophy in the conventional sense, but a vascular disease. Van Bogaert’s description in 1955 of “Binswanger’s disease with a rapid course in two sisters” probably depicts the first description of CADASIL. The acronym stands for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoen cephalopathy, which essentially describes the key features of the disorder (i.e., hereditary small vessel disease leading to strokes

Table 12.3 Key features of leukodystrophies and leukoencephalopathies discussed in this chapter.

Disease Age at (adult) onset

Key clinical features

Cognitive profile

Psychiatric findings

Distinguishing MRI features

Genetics

Diagnosis

CADASIL 30–50s; milder cases in 60s

Stroke/TIAs, migraines, confusional episodes, seizures

Slowed processing speed, frontal‐ executive deficits

Apathy, depression, lability

• Patchy, punctate WM lesions, approaching confluency. Anterior temporal lobe and external capsule often affected

Notch3 gene mutation, GOM on skin biopsy with or without Notch3 immunostaining

HDLS 39 (±15 SD) (ALSP)

Dementia, stiffness, clumsiness, weakness, ataxia, extrapyramidal, and/or pyramidal dysfunction
Rapid‐onset cases reported
Normal NCS, VEPs, SSEPs, and ERGs

Frontal syndrome with memory impairment, intellectual deterioration.

Often initial symptoms, depression, apathy, and blunting

• Moderate frontal‐predominant atrophy, enlarged ventricles

AD (reduced penetrance)

Clinical features, MRI/MRS, and brain pathology

POLD 43 (±13 SD) (ALSP)

Dementia, seizures, pyramidal (spastic paresis), ataxia, dysphagia, dysarthria. Normal NCS, VEPs, SSEPs, and ERGs

Frontal‐executive

Mood disorder, apathy, disinhibition, aggressiveness, and euphoria; might present like Pick’s. Psychosis less common

• Frontal‐predominant atrophy and WM disease

AD (reduced penetrance; possibly some sporadic cases)

Clinical features, MRI/MRS, and brain pathology

APBD 40s–60s

Tetrad: Urinary freq/urgency, gait disorder (spasticity), sensory > motor polyneuropathy, cognitive impairment. Less common EP, cerebellar ataxia, ALS, and cardiomyopathy. NCS – sensorimotor polyneuropathy

Dementia in approximately 60%; when present, involves memory loss

Not described. Possible depression

• Multiple, diffuse PVWM changes, including the mesencephalon and cerebellum, cavitations (not always present)

AR, rare sporadic.

Sural n. biopsy PBs in myelinated axons, decreased GBE in WBCs and cultured fibroblasts, mutation(s) in GBE gene

ADLD 30s–40s

Early autonomic dysfunction, pyramidal (spasticity) and pseudobulbar signs, and cerebellar dysfunction such as action tremor

Absence of gross impairment

Absence of profound psychiatric features

• Early on: extensive, symmetrical, CSO WM involvement; sparing U‐fibers and CC

AD (highly penetrant)

Duplication of LMNB1 gene.

NO peripheral neuropathy. Normal NCS, VEPs. SSEPs abnormal. Autonomic skin innervation

• Later: extensive symmetrical CSO, CR, CC, U‐fibers, EC, IC, brainstem WM involvement

• Often mistaken for MS or ischemic vascular disease

• Callosal and deep WM lesions (patchy, confluent, or diffuse depending on stage)

CSF1R gene mutation

• Might show punctate restricted diffusion in rapid‐onset cases

• Occipital involvement rare
• Sparing of U‐fibers and cerebellar WM • Cerebellar atrophy might occur

• PVWM disease
• Pyramidal tract involvement

• Spinal cord atrophy and cerebellar atrophy

• Sparing of optic radiations and cerebellar WM • Extensive cerebral atrophy with sparing

pons and cerebellum • No cystic changes

Adult‐onset Alexander Disease

Teens to 60s

Common: pyramidal tract signs (spasticity and hyperreflexia), cerebellar signs (ataxia, nystagmus, dysmetria), urinary symptoms, bulbar/pseudobulbar signs (palatal myoclonus and dysphagia, dysphonia) Less common: dysautonomia, sleep apnea and RLS; poor fine motor skills.

Frontal‐executive, memory

Not described

• Atrophy and T2 hyperintensity in the medulla and cervical cord

Usually sporadic; rare AD

GFAP gene mutation

MLD (adult onset)

(Adult form) Teens to 40s–50s.

Elevated CSF protein
Peripheral neuropathy (might be subclinical in late‐onset forms)

Progressive mental deterioration

Behavior/mood Behavior/mood

Symmetric, confluent, T2 hyperintense WM, demyelinating appearance, often sparing of U‐fibers

AR AR

Elevated urine sulfatide or ARSA gene mutation

GLD/ Krabbe (adult onset)

Variable; Includes those with subtly earlier symptoms, but diagnosed as adults versus adult onset after age 20, as late as 60s

Elevated CSF protein
Peripheral neuropathy (might be subclinical in late‐onset forms)

Progressive mental deterioration

Symmetric, confluent, T2 hyperintense WM, severe demyelination

Very low GALC enzyme activity in leukocytes isolated from whole heparinized blood and cultured skin fibroblasts. In carriers, GALC assay often WNL; test for GALC gene mutation. Most common mutation in adult‐onset Krabbe is c.857G>A mutation

Fabry

Teens to approximately 40s

Renal insufficiency, cardiomyopathy. Corneal and lenticular opacities Strokes, SIVD

Might occur poststroke

Depression

Consistent with ischemic vascular disease: PVWM disease, WM signal intensity abnormalities and single or multiple lacunar infarcts, large ischemic cerebral infarctions. Posterior thalamus involvement (pulvinar sign—T1 bright) might occur

X linked

Deficiency of the lysosomal hydrolases α‐galactosidase A (AGAL); in females, AGAL might be normal, so need GAL gene mutation

X‐ALD (adult onset)

Variable; AMN in 20s–middle age; female carriers might present >35 years old with mild disease

Spastic gait

Subacute decline. Cognitive deficits correlate with MRI findings. Might present as FTD

More common in childhood forms

Either caudorostral WM progression starting from initial parieto‐occipital
Involvement beginning in the splenium of CC (65% of cases) or a rostrocaudal progression starting frontally beginning in the genu of CC (35% of cases). Tract involvement in the corticospinal, spinothalamic, visual, and auditory pathways

X linked

Elevated VLCFAs (tissues, serum, and other fluids)— might be WNL in females, so check for ALDP gene mutation

SEPs, VEPs, and BAERs often abnormal

• Supratentorial WM hyperintensities present if onset age <40, absent if onset > 40 onset

Acroparesthesias/pain might occur Female carriers often affected; variable presentation

Tortuosity and dilatation of the larger vessels

AD, autosomal dominant; ALS, amyotrophic lateral sclerosis; ALSP, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia; AMN, adrenomyeloneuropathy (form of X‐ALD); AR, autosomal recessive; ARSA, arylsulfatase A; CC, corpus callosum; CSO, centrum semiovale; EC, external capsule; EP, extrapyramidal symptoms; ERG, electroretinogram; GALC, galactocerebrosidase; GBE, glycogen branching enzyme; GFAP, glial fibrillary acidic protein; IC, internal capsule; NCS, nerve conduction studies; PBs, polyglucosan bodies; PVWM, periventricular white matter; RLS, restless legs syndrome; SIVD, small vessel ischemic vascular disease; SSEPs, somatosensory evoked potentials; TIAs, transient ischemic attacks; VEPs, visual evoked potentials; VLCFAs, very‐long‐chain fatty acids; WM, white matter.

• Mild–moderate, symmetric, cerebral WM hyperintensities

• Abnormal contrast enhancement if onset age <40; absent if >40 onset

Peripheral nerve biopsy: non-membrane bound cytoplasmic PAS-positive polyglucosan bodies

Brain MRI: diffuse periventricular leukoencephalopathy involving the mesencephalon and the cerebellum; lesions typically do not enhance

Glycogen branching enzyme (GBE) de ciency in leukocytes, muscle or other tissue

Autosomal recessive

GBE gene mutation (not always identi ed)

Adult polyglucosan body disease (APBD)

Suggestive clues*

Skin biopsy: granular osmiophilic material (GOM)^

Brain MRI: involvement of external capsule
and the anterior temporal lobe;
Absence of optic nerve and spinal cord involvement

Brain MRI: progressive frontal-predominant atrophy;
WM changes in the periventricular areas with later spread into the deep WM; occipital involvement rare

Brain DTI: Punctuate areas of decreased ADC

Brain pathology: widespread loss of myelin sheaths, gliosis and axonal destruction with numerous axonal spheroids

Autosomal dominant (reduced penetrance)

CSFR1 mutation

Adult-onset leukoencephalopathy

with axonal spheroids and pigmented glia (ALSP) (encompassing both hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD))

CSF: elevated protein levels

palatal myoclonus and sleep disorders

Brain MRI: Sparing of U- bers and the corpus callosum

BAER and SSEP show poor waveforms

Autosomal dominant

LMNB1 mutation

Autosomal dominant

Notch3 mutation

CADASIL

Brain MRI: diffuse periventricular WM changes

Lysosomal storage disorders

Autosomal recessive

Brain MRS: elevated lactate peak

Mitochondrial defect

Matrilineal inheritance

MELAS (A3243G) MERRRF (A8344G)

*Not an exhaustive listing

^Sensitivity: 40–50%

PAS-periodic acid-Schiff

White matter signal abnormalities on Brain MRI

Metachromatic leukodystrophy (MLD) Globoid cell leukodystrophy (GLD)

Adult-onset autosomal dominant

leukodystrophy with autonomic dysfunction

Adult-onset Alexander disease GFAP mutation

Sporadic or Autosomal dominant

Brain and spinal MRI: Atrophy and signal changes in the medulla oblongata and upper cervical spinal; Symmetrical cerebral white matter abnormalities with a frontal predominance

Brain pathology: Rosenthal bres in astrocytes

No gross cognitive impairment and psychiatric features

Cognitive impairment

Figure 12.1 Flow chart listing selected leukodystrophies, their characteristic features, and mode of inheritance.

Autonomic abnormalities Pyramidal and pseudobulbar signs Cerebellar dysfunction

Gait disorder (paraparesis or quadraparesis) urinary incontinence sensorimotor polyneuropathy autonomic dysfunction

Migraine
stroke
mood disturbances, apathy

Spastic gait Psychiatric problems

Psychiatric problems Parkinsonism Spastic paresis Ataxia Epilepsy

Neurosensory de cits Cardiomyopathy Endocrine problems (e.g., diabetes)

Figure 12.2 FLAIR brain MRI in a 50‐year‐old with CADASIL. Some classic MRI findings of CADASIL including T2‐weighted medial temporal lobe hyperintensities (solid arrow), cavitations in the white matter (dashed arrows), and confluent white matter disease are shown.

and dementia). The overall prevalence of CADASIL is unknown, but one small study from Scotland provided an estimate of 4.14 cases per 100 000 [6].

Clinical presentation

Several main symptoms are described in CADASIL including migraine with aura, ischemic events (stroke), seizures, episodes of confusion (unexplained neurological episodes), mood distur bances, apathy, and cognitive impairment [7]. These symptoms occur in a successive manner over decades. Extraneurologic symptoms usually do not occur with CADASIL; this contrasts with Fabry disease (another entity associated with brain white matter changes, often erroneously attributed to MS). In Fabry disease, patients often develop renal insufficiency and cardio myopathy prior to onset of the central nervous system (CNS) disease (discussed in the following).

Forty to 50% of patients with CADASIL have migraine with aura, which is usually the first symptom, with onset on average at age 30 years (range 6–48 years) [7]. The most common auras are visual and sensory; however, 50% of patients also have atypical attacks with basilar, hemiplegic, or prolonged aura, and some patients have very severe attacks with confusion, fever, meningitis, or coma.

Sixty to eighty five percent of patients with CADASIL suffer transient ischemic attacks (TIA) and ischemic strokes in the absence of other risk factors, at a mean age of 49 years (range 20–70 years) and at an estimated incidence of 10 episodes per 100 patient‐years [7]. Ischemic events are almost invariably subcortical presenting as lacunar syndromes, for example, pure motor or sensory deficit, ataxic hemiparesis, and clumsy hand–dysarthria syndrome. Recurrent strokes over the years lead to significant morbidity with motor weakness, spasticity,

gait difficulties, urinary urgency with or without incontinence, and pseudobulbar palsy.

Depressive episodes are described in 20% of cases, which may alternate with manic episodes [8]. Independent of depression, apathy is seen in about 40% of cases [9].

Cognitive impairment, the second most frequent clinical mani festation after migraine, follows a distinctive pattern of neuropsy chological abnormalities similar to subcortical ischemic vascular dementia [10]. Executive dysfunction and attentional deficits are frequently impaired early in the course of the disease, often occurring as early as 35–50 years of age [11]. Cognitive dysfunction is accompanied by a narrowing range of interests. Patients with an overt stroke fare worse on tests of executive dysfunction [12].

Prominent areas of deficit are processing speed, for example, in timed measures of the Trail Making Test parts A and B (TMT‐A and TMT‐B) and a symbol digit test [10–12]. In patients with both early and advanced disease, TMT‐B is abnormal, indicative of problems with processing speed and set shifting. Deficits are recorded frequently in verbal fluency, which has a strong executive component, especially in letter fluency more so than category or semantic fluency. Similarly, impairment in error monitoring on neuropsychological testing emphasizes the executive deficit [10–12].

On memory testing, there is often mild or worse impairment on both immediate and delayed free recall, but cued recall and recognition are often intact. This suggests that the encoding component of memory is relatively preserved. Memory prob lems are usually due to retrieval deficits, as is commonly found in small vessel disease‐induced vascular cognitive impairment [12]. Visuospatial functions and abstract reasoning are largely preserved, particularly during early disease stages.

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156 Non-Alzheimer’s and Atypical Dementia

Lacunar infarcts, cerebral microbleeds, hippocampal volume, and brain atrophy are all shown to be independently associated with executive dysfunction when adjusted for age [13]. White matter hyperintensities appear to be less directly related to the cognitive decline. Cognitive decline progresses with age and at late stages involves verbal or visual memory, language, reasoning, and visuospatial abilities [10]. Severe aphasia, apraxia, or agnosia is rare.

Seizures, intracerebral hemorrhages, territorial infarcts (possibly coincidental), and extrapyramidal features are rarely reported [7].

Imaging

Typically, punctiform or nodular T2/FLAIR hyperintensities in periventricular areas and in the centrum semiovale are the first sign on MRI, which progress over decades to diffuse, extensive, and somewhat symmetrical hyperintensities, often with cavita tions [7, 10]. White matter abnormalities probably precede the onset of clinical symptoms by at least 10–15 years; in any case, the brain MRI abnormalities are consistently seen by the age of 35. The frequency and severity of these T2 white matter abnormalities progress with age. MRI involvement of the external capsule and the anterior part of the temporal lobe is characteristic of CADASIL, helping to differentiate it from MS [7, 10].

Lacunar infarcts, which are often punctate or larger in size, appear later in life as T1 hypointense lesions in the same areas as the T2 signal changes [13]. Recent infarcts (within the past~10 days) show hyperintensity (restricted diffusion) on diffusion‐weighted MRI. With advancing age, microbleeds are commonly seen on gradient echo images. On diffusion tensor imaging (DTI), increased water diffusion is seen in the thalamus that may not be observed on standard T2/FLAIR neuroimaging. These DTI abnormalities are more strongly correlated with measures of executive dysfunction and clinical disability in comparison to T2 hyperintensities. Thus, diffusion histograms might be used as a marker of disease progres sion. In addition to white matter findings, global brain atrophy progresses three times more rapidly in patients with CADASIL compared to normal aging, and the extent of brain atrophy corre lates with cognitive impairment and disability scales [14].

pathology

Macroscopic neuropathological examination of the brain shows diffuse myelin pallor and rarefaction of white matter in perive ntricular areas and centrum semiovale, lacunar infarcts in white matter and basal ganglia, and dilated Virchow–Robin spaces [7, 10]. Neuronal apoptosis in the cortex correlates with the extent of subcortical ischemic lesion load.

Microscopically, the arteriopathy, characterized by thicken ing of the arterial wall causing luminal stenosis, deposition of nonamyloid granular osmiophilic material (GOM) in the media extending into the adventitia, and eventual disintegration of smooth muscle cells, is found in the small penetrating cerebral and leptomeningeal arteries. This in part explains the unusual pattern of white matter abnormalities seen in CADASIL. The endothelium is largely normal.

Extracellular GOM, located close to the cell surface of smooth muscle cells, is pathognomonic of CADASIL. Arteriopathy is found in other organs, such as the spleen, liver, kidneys, muscle, aorta, and skin, although clinical manifestations are restricted to the CNS. Therefore, a skin biopsy sample demonstrating this pathologic change is used for diagnosis; the sensitivity of this test is 40–50% [7, 10]. Immunostaining with NOTCH3 monoclonal antibody to detect the accumulation of NOTCH3 protein in the vessel wall is highly sensitive (85–95%) and specific (95–100%) [7, 10].

Molecular genetics

CADASIL, caused by mutations in the Notch3 gene encoded on chromosome 19q12, is inherited in an autosomal dominant manner. The Notch3 gene encodes a single‐pass transmem brane receptor of 2321 amino acids with an extracellular domain containing 34 epidermal growth factor repeats (EGFR). Each EGFR has six cysteine residues. More than 95% of the 150 mutations described thus far are missense mutations found in exons 2–24, and that lead to addition or deletion of a cysteine residue in the EGFR [7, 10]. De novo mutations and homozy gous mutations are rarely reported.

Molecular testing by screening exons 2–24 is the gold stand ard for the diagnosis of CADASIL; the test is 100% specific when a mutation involving cysteine residue is detected, and the sensitivity is close to 100%.

In asymptomatic adult first‐degree family members of patients with CADASIL, genetic testing raises psychological and ethical concerns similar to other adult‐onset autosomal domi nant neurodegenerative disorders such as Huntington’s disease. There is no recommendation to screen children, as currently there is no benefit in terms of treatment.

Mechanisms underlying symptoms

NOTCH3 is predominantly expressed in vascular smooth mus cle cells of small arteries in particular. CADASIL mutations cause gradual accumulation of the extracellular domain of NOTCH3 protein in the form of microscopic aggregates around vascular smooth muscle cells and pericytes of brain arteries and capillaries, in close proximity to deposits of GOM [15]. Total loss of Notch3, however, does not cause CADASIL pathology. Evidence strongly suggests that CADASIL mutations act through gain of novel function mechanisms and that the change in the number of cysteine residues in NOTCH3 is the common denominator which affects the survival and function of vascular smooth muscle cells [15].

Chronic subcortical ischemia and compromised cerebral hemodynamics in addition to altered vasoreactivity resulting from structural and functional changes in brain arteries might lead to recurrent lacunar infarcts and microstructural alterations that ultimately cause cognitive decline, motor disability, cortical atrophy, and neuronal apoptosis [13]. The pathophysiology of mood disorders and migraine with aura is mostly unknown. Cortical morphology (i.e., depth and width of cortical sulci) in

the mediofrontal and orbitofrontal areas, in contrast to cortical thickness, has been strongly and independently associated with apathy in CADASIL [16]. One recent study suggests that increased rapid‐onset cortical plasticity may contribute to largely preserved cognitive and motor function in patients with CADASIL despite extensive ischemic small vessel disease [16].

treatment

At present, there is no treatment for CADASIL. Migraine with aura is treated similarly to migraine in general population, with the exception that ergot derivatives and triptans are not consid ered safe in views of their vasoconstricting property [7, 10]. Usual prophylactic drugs such as antiepileptic drugs, tricyclic antidepressants, or antihypertensives can be used. Anecdotally, acetazolamide has been reported to be effective.

Secondary stroke prevention similar to noncardioembolic ischemic stroke is usually recommended: use of antiplatelet drugs and treatment of vascular risk factors. Use of anticoagu lants is avoided because of the increased risk of intracerebral hemorrhage in the presence of cerebral microbleeds. Donepezil was tested in CADASIL patients with cognitive impairment. Inclusion criteria were a Mini‐Mental State Examination score of 10–27 or a TMT‐B time score that is at least 1.5 SD below the mean, after adjustment for age and education [17]. One hun dred sixty‐eight patients were followed for 18 weeks. No effect on the primary endpoint, using the cognitive subscale of the vascular Alzheimer’s disease cognitive assessment scale (ADAS‐ Cog), was noted; improvements, however, were recorded on measures of executive functions [17]. Supportive measures such as physical therapy and rehabilitation, psychological support, and nursing care play an important role in the long‐term man agement of elderly debilitated and demented individuals. Genetic counseling for asymptomatic members at risk of carry ing the mutation is vital prior to testing.

adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia: hereditary diffuse leukoencephalopathy with spheroids and pigmentary orthochromatic leukodystrophy

Patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodys trophy (POLD) manifest with behavioral changes, depression, dementia, epilepsy, and motor impairment including parkin sonism, spastic hemi‐, para‐, or tetraparesis, and/or ataxia [18, 19]. There has been compelling evidence from clinical presentation, imaging, and pathological studies that HDLS and familial POLD belong to the same disease spectrum. Comparative morphologic study of patients with HDLS and POLD shows no distinctive pathologic features [20]. This data and other literature suggest that HDLS and POLD should collectively be referred to as adult‐onset leukoencephalopathy with axonal spheroids and

pigmented glia (ALSP) [21]. Recent genetic analyses have con firmed that POLD and HDLS are due to mutations in the same gene, CSF1R, a tyrosine kinase receptor expressed on the sur face of microglia, and to a lesser extent in neurons. Therefore, these two conditions likely are a single clinicopathologic entity [97, 98]. For historical reasons, we will discuss these two condi tions separately but emphasizing their similarities.

pOLD

Orthochromatic leukodystrophies (OLD) constitute a group of heterogeneous noninflammatory demyelinating disorders. The use of the term orthochromatic refers to characteristic birefrin gence, to distinguish the findings from metachromatic (leukod ystrophy caused by arylsulfatase A deficiency, discussed in the following) in which granules take on a brown stain in the pres ence of acidic cresyl violet. Peiffer et al. divided OLD into four forms: (i) pure forms, (ii) special forms, (iii) OLD combined with phakomatoses and other disorders, and (iv) symptomatic forms [22]. The family described by Van Bogaert and Nyssen in 1936 with adult‐onset OLD associated with pigmented mac rophages and other glia (POLD) represents the pure forms of OLD [23]. To date, the majority of POLD cases are sporadic. Eight POLD families with recessive as well as, less commonly, dominant inheritance have been reported. The average age at onset (AAO) (±SD) was 43 ± 13 years with a life expectancy of 6 years from diagnosis [24]. Initial reported symptoms in POLD involve a frontotemporal phenotype with mood disorders; exec utive dysfunction; behavioral changes including disinhibition, aggressiveness, euphoria, and apathy; and variable memory impairment [24, 25]. Presentation consistent with a diagnosis of Pick’s disease has been reported. Psychosis sometimes occurs. Cognitive decline, including memory impairment, but with frontal predominance occurs in most patients leading to end‐ stage dementia. Motor impairment follows and is commonly due to prominent pyramidal tract involvement producing spas tic paraparesis, tetraparesis, or hemiparesis. Ataxia, dysphagia, and dysarthria have been reported [24, 25]. Seizures occur in most patients during the course of illness.

A few MRI studies show progressive frontal‐predominant atrophy and white matter changes in the periventricular areas during the earlier periods which later spread into the deep white matter [24, 25] (Figure 12.3). SPECT (99mTc‐ECD) showed frontoparietal hypoperfusion in one patient with POLD [26]. In one case, proton MRS enabled distinction of POLD from other disease processes such as ischemia, gliosis, or tumors, with met abolic derangements (e.g., decreased NAA/Cr ratio and increased Cho/Cr ratio that reflect demyelination accompanied with neuroaxonal loss) seen even in the normal‐appearing white matter [26]. Brain pathology shows noninflammatory demyeli nation and axonal destruction with pigmented macrophages and other glia [24]. Ultrastructurally, the pigmented granules resemble lipopigment ceroid, with fingerprint, multilamellar, and granular morphology, not unlike that seen in ceroid lipo fuscinosis; these findings suggest a disease process that might be

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(a)

(b) (c)

Figure 12.3 Brain MRI in ALSP/POLD. Axial (a), coronal (b), and sagittal (c) T2‐weighted images of a case are presented. There is significant atrophy of the bilateral frontal lobes. There are areas of diffuse hyperintensity in the white matter of the bilateral frontal lobes and the corpus callosum. Note that there is substantial callosal atrophy, which is especially severe at the genu and body (c). A small focus of signal abnormality is identified within the splenium of the corpus callosum. Other parts of the brain appear to be relatively well preserved. Source: Itoh et al. [24]. Reproduced with permission
of Springer.

due, in part, to oxidative damage [25]. The literature describes cases of POLD as sporadic (in the absence of a family history) or inherited in an autosomal recessive or dominant form.

The management of patients with POLD is largely symptomatic.

hDLS

Axelsson and colleagues, in 1984, described a large family with adult‐onset autosomal dominant leukoencephalopathy charac terized pathologically by the presence of numerous axonal dilations (spheroids) [27]. They coined the term hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS). The average AAO in reported cases is 39±15 years with the average life expectancy of 9 years from presentation [27, 28]. The initial symptoms are most commonly psychiatric, with depression presenting several years before other manifestations. Generalized convulsions, behavioral disturbances such as apathy and emotional blunting, mood disturbances, personality changes, and memory impairment, followed by emotional and intellectual deterioration occur. A frontal syndrome, mainly of the apathetic and emotionally blunted type, has been described in several patients [28]. Motor findings include stiffness, clum siness, weakness, and gait difficulties due to parkinsonism, ataxia, pyramidal dysfunction, or a combination of these.

Brain imaging can help with the diagnosis of HDLS. Brain CT scans might be normal in the early stages but eventually shows moderate, frontal‐predominant atrophy with enlarged lateral and third ventricles. MRI shows frontal‐predominant atrophy with periventricular, callosal, and deep white matter lesions, which are patchy, confluent, or diffuse [29] (Figure 12.4). The variable imaging patterns described might reflect differences in disease stage among reported cases. Importantly, occipital involvement rarely occurs. Unlike most other leukodystrophies, diffusion imaging in at least two patients with a rapid form of HDLS showed multiple lesions with restricted diffusion (dark

on ADC and bright on DWI/FLAIR) [30]. Fluorodeoxyglucose (FDG) PET in one patient with HDLS showed generalized hypometabolism, with asymmetric parietal predominance [31]. SPECT (99mTc‐ECD) showed frontotemporal hypoperfusion in another patient with HDLS [32].

Electrophysiological studies have not been very helpful for diagnosis, as EEGs might be normal, but diffuse or paroxys mal slowing has been reported. No clear ictal or interictal epileptiform patterns were described despite epilepsy being a prominent symptom. Nerve conduction studies, visual evoked potentials (VEPs) and somatosensory evoked poten tials (SEPs), and electroretinograms have been normal in HDLS and in POLD [33].

The pathologic hallmark of HDLS is widespread loss of mye lin sheaths, gliosis, and axonal destruction [34]. Numerous axonal spheroids, containing phosphorylated neurofilaments, ubiquitin, amyloid precursor protein, and mitochondria, as well as autofluorescent sudanophilic lipid‐laden macrophages are found predominantly in the frontal lobe, variably in the parietal or temporal lobes, and in the descending pyramidal tracts at the midbrain, brainstem, and spinal cord levels [35] (Figure 12.5). Neuronal loss and ballooned neurons are seen in the frontal cortex. U‐fibers, cortical mantle, and the cerebellum are largely spared, but cerebellar atrophy sometimes occurs.

Several sporadic patients fulfill clinical and pathologic crite ria for HDLS, except there is no family history [27, 28], although these cases were described prior to identifying the CSF1R gene as the cause of POLD and HDLS. It remains unknown whether these sporadic cases reflect reduced disease penetrance [98]. Among cases with a positive family history, the pattern of segregation has been consistent with autosomal dominant transmission.

Apart from symptomatic care, unfortunately, currently there is no treatment for either familial or sporadic HDLS.

(a) (b)

(c) (d)

Figure 12.4 Magnetic resonance images (axial sections, T2‐weighted) from four HDLS patients: (a) Patient 1 (MRI performed 1.2 years after start of symptoms); localized white matter lesions (arrow) in both frontal and parietal hemispheres involving the corpus callosum (arrow dashed). (b) Patient 2 (MRI performed 1.9 years after start of symptoms); confluent white matter lesions in both frontal and parietal hemispheres with cortical atrophy in the affected areas. (c) Patient 3 (MRI performed 3.5 years after start of symptoms); localized periventricular lesions (arrow) with corresponding frontoparietal atrophy and involvement of the corpus callosum (arrow dashed). (d) Patient 4 (MRI performed 2.5 years after start of symptoms); bilateral frontoparietal white matter changes (arrow) extending into the corpus callosum (arrow dashed). Source: Sundal et al. [99] (TBC). Reproduced with permission of Elsevier.

(b) (c)

(a) (d) (e)

Figure 12.5 White matter lesions of the motor cortex from an ALSP/HDLS case. (a) Marked myelin loss of the subcortical white matter with spared U‐fiber, KB staining. (b–d) Numerous axonal spheroids in the white matter lesion: (b) KB staining, (c) Bodian staining, and (d) immunohistochemistry for ubiquitin. (e) Abundant sudanophilic macrophages (arrowhead) in the white matter, Sudan III (KB Klüver–Barrera). Bar (a) 400 μm, (b–e) 90 μm. Source: Itoh et al. [24]. Reproduced with permission of Springer. (See insert for color representation of the figure.)

160 Non-Alzheimer’s and Atypical Dementia

adult‐onset autosomal dominant leukodystrophy with autonomic dysfunction (LMNB1 mutation)

Adult‐onset autosomal dominant leukodystrophy (ADLD) was first described in an Irish‐American family as a slowly progres sive and fatal disorder simulating chronic progressive MS [36]. It is a highly penetrant, autosomal dominant, adult‐onset disor der presenting in the fourth or fifth decade of life. The genetic basis of this disorder has been established as a tandem genomic duplication, which results in an extra copy of the gene encoding the nuclear lamina protein lamin B1 (LMNB1) on chromosome 5q23 [37].

ADLD is clinically characterized by early autonomic abnor malities, pyramidal and pseudobulbar signs, and cerebellar dysfunction such as action tremor, and symmetrical demyelination of the CNS [38]. In general, there is absence of gross cognitive impairment and psychiatric disorders; peripheral neuropathy is also not described [36–39].

In younger patients, brain MRI shows extensive involvement of the white matter of the centrum semiovale with mild enlarge ment of parietal sulci and lateral ventricles; U‐fibers and the corpus callosum are spared. In the advanced stages of the disease, T2 hyperintense signal is symmetric involving the entire white matter of the centrum semiovale and corona radiata, corpus callosum, subcortical U‐fibers, and the external and internal capsules [40]. The medulla oblongata, the pons, and the mesen cephalon also show T2 hyperintense signal. The white matter of the cerebellum as well as the optic radiations (a layer of white matter immediately lateral to the trigone and occipital horns of lateral ventricles) is spared. Although there is marked cerebral atrophy, infratentorial structures, in particular the pons and cerebellum, are spared [40]. There is no evidence of necrosis or cystic changes on T1‐weighted imaging and nor is there calcifi cation on brain imaging, as seen in some other leukodystrophies. Brain MRI showing symmetrical demyelination serves to distin guish this entity from MS.

Nerve conduction studies and autonomic function studies are usually normal. In early stages of the disease, SEPs show poorly waveforms except wave and increased interpeak laten cies [41]. In more advanced stages, there is loss of waveforms subsequent to wave I. VEPs show no significant abnormalities [41]. EEG shows mild nonspecific generalized slowing [42]. A selective sympathetic failure, sparing cardiovagal function has been shown in one patient, in whom microneurography revealed absent sympathetic activity [43]. The evaluation of auto nomic innervation of skin annexes showed severely depleted and morphologically abnormal noradrenergic dopamine‐ β‐hydroxylase (DβH) immunoreactive fibers with preserved cholinergic vasoactive intestinal polypeptide (VIP) immuno reactive fibers [43].

Neuropathology shows preservation of oligodendroglia with extensive demyelination and lack of astrogliosis and inflamma tion [39, 40]. As noted earlier, the molecular basis of ADLD has

been shown to be duplication of LMNB1; this finding adds ADLD to the category of disease resulting from copy number variation, such as Charcot–Marie–Tooth disease type 1 (resulting from PLP duplication). An increase in cognate RNA and protein (lamin B1) levels has been found in the brain tissue of the affected patients bearing the duplication. Lamin B1 is a member of the intermediate filament family of proteins which serves a fundamental role within the nuclear envelope by anchoring the nucleus to the cytoskeleton [44].

There currently is no definitive treatment for ADLD. Symptomatic treatment of spasticity, urinary symptoms, and tremors is recommended.

adult polyglucosan body disease

Illustrative case history 2

A 56‐year‐old gentleman sought neurological evaluation for progressive leg weakness. Review of systems revealed dizziness on sudden head movements for the past year, reduced concen tration and recent memory problems, and urinary and bowel urgency and erectile dysfunction. On exam, he was noted to be alert, and mental function was preserved on orientation, atten tion, judgment, and immediate and recent memory, but was impaired on delayed recall memory and calculations (MMSE score: 22). Cranial nerve examination was normal. He had moderate motor weakness in the lower extremities, both proxi mally and distally. Sensation was intact in all modalities. Deep tendon reflex was decreased; bilateral knee and ankle jerk were nearly absent. Electrodiagnostic studies showed sensorimotor polyneuropathy. Autonomic testing revealed sweating abnormal ities. A brain MRI showed diffuse white matter changes in bilateral deep parietal area (Figure 12.6). Family history revealed an older brother was wheelchair bound. Sural nerve biopsy revealed polyglucosan bodies in myelinated axons (Figure 12.7), enabling the diagnosis of adult polyglucosan body disease (APBD), which was confirmed following demonstration of decreased glycogen branching enzyme (GBE) activity in cultured fibroblasts.

Background

APBD is a late‐onset autosomal recessive disorder caused by defi ciency of the GBE and characterized by a gradual progressive involvement of both the CNS and peripheral nervous systems (PNS), with onset in the fifth to seventh decade [45, 46]. Although there is a great deal of heterogeneity, most patients develop a tetrad of symptoms including urinary incontinence (frequency and urgency), gait disorder (para‐ or quadriparesis), sensory greater than motor polyneuropathy, and cognitive impairment. Other symptoms also have been reported, though less commonly, including extrapyramidal symptoms, cerebellar ataxia, amyo trophic lateral sclerosis, and cardiomyopathy [45, 46]. When cognitive impairment exists, memory is almost always affected.

APBD should be suspected when patients present with late‐ onset progressive disease with PNS and CNS involvement, such

Figure 12.6 FLAIR Brain MRI of a 59‐year‐old man with APBD, showing periventricular, subcortical, and deep white matter signal abnormalities. Note the typical atrophic cervical spinal cord, typical of APBD.

Leukoencephalopathies/leukodystrophies 161

Figure 12.7 Sural nerve biopsy in APBD showing intra‐axonal basophilic inclusions (polyglucosan bodies) in several nerve fascicles (light micros copy, H&E stain). Further investigations showed that the storage material is not membrane bound, is diastase resistant, and is PAS positive (not shown). (See insert for color representation of the figure.)

as progressive sensorimotor or pure motor peripheral neuropa thy and spastic tetraparesis; neurogenic bladder is often a very early feature, followed several years later by the development of gait abnormalities and neuropathy. Dementia is seen rather late in the disease in about 60% of cases [47, 48]. Rarely, cognitive impairment precedes motor signs [49]. Brain MRI often shows diffuse periventricular leukoencephalopathy involving the mesencephalon and the cerebellum [50, 51]. Brain imaging in later stages also often reveal diffuse cerebral, cerebellar, and spinal cord atrophy. Cavitations in the white matter, as also seen in CADASIL, are often seen in APBD as well.

Recent studies suggest there is a secondary impairment of energy metabolism and disruption of methylation in these patients [52]. Pathologically, white matter degeneration in APBD might result from tissue damage involving axons and myelin [49]. Polyglucosan bodies (intracellular inclusions of amylopectin‐like polysaccharide that has fewer branched points) are greatly increased in neurons and glia. It has been hypothesized that the accumulation of polyglucosan bodies, in addition to its deleterious effects on axonal integrity, may also induce direct or indirect myelin damage.

The diagnosis of APBD can be made in many cases by identi fication of a mutation in the glycogen branching enzyme (GBE1) gene, establishing decreased levels of GBE activity in blood leukocytes or cultured skin fibroblasts, and/or demonstration of nonmembrane‐bound cytoplasmic periodic acid–Schiff‐ positive polyglucosan bodies in peripheral nerves, found most abundantly in myelinated nerve fibers [45]. Polyglucosan bodies are demonstrable in the sural nerve; however, some reports show that a skin biopsy also appears to be simple, reliable, and less invasive diagnostic tool [53]. Pathological findings are considered less diagnostic than identifying a mutation or by decreased GBE levels as polyglucosan bodies are also seen in other diseases such as progressive myoclonic epilepsy (Lafora bodies). At least eight different mutations found in GBE gene on 3p16 are associated with APBD. Most are homozygous, though compound heterozygotes have been identified. APBD has been shown to occur most frequently in patients of Ashkenazi Jewish origin, and in most such cases, a common missense (Tyr329Ser) mutation in the GBE1 gene has been identified [54]. Curiously, there is overlap of mutations with glycogen storage disease type IV (GSD‐IV), which presents as a fulminant fatal disease in

162 Non-Alzheimer’s and Atypical Dementia

infants and children [55]. It is not known why the same mutation can present so differently, but presumably due to the influence of epigenetic factors. In many patients, the disease is possibly sporadic, with no GBE1 mutations identified.

Unfortunately, there is no effective therapy, except for symp tomatic care. Clinical studies suggest that an anaplerotic diet therapy with the odd‐carbon triglyceride (triheptanoin‐C7TG) may interrupt the progression of symptoms and provide some functional recovery [52]. The discovery of a possible mouse model for APBD might hold promise for screening potential treatments [56].

adult‐onset alexander disease

Alexander disease is a rare neurodegenerative disorder character ized by white matter degeneration and formation of cytoplasmic inclusions called Rosenthal fibers, which have been observed in astrocytes [57]. Adult‐onset Alexander disease (AOAD) is asso ciated with different clinical symptoms and brain MRI findings from infantile forms of the disorder, which is characterized by progressive psychomotor retardation with loss of developmen tal milestones, megalencephaly, and seizures [57]. Mutations in the gene encoding the glial fibrillary acidic protein (GFAP) have been found in patients with the infantile‐ and adult‐onset variants [57, 58]. Age at onset and GFAP mutation site have been shown to be important clinical predictors [59].

Clinical features noted in adult patients found to have GFAP mutations include one or more of the following signs and symp toms: bulbar/pseudobulbar signs, including palatal myoclonus, dysphagia, and dysphonia; pyramidal tract signs, including spasticity and hyperreflexia; cerebellar signs, such as ataxia, nys tagmus, and dysmetria; and dysautonomia [57–59]. Cognitive deficits in new learning and recent memory, executive functions, andfinemotordexterityandlessapparentdeficitsininformation processing and visual scanning speed were observed in a 21‐year‐ old patient, followed from ages 15 to 21 [60]. A recent report on 12 Japanese patients showed behavioral problems and/or memory disturbance in three individuals, two of whom were said to have had parkinsonism and frontotemporal dementia or pro gressive supranuclear palsy until GFAP mutations were detected [61]. Interestingly, palatal myoclonus and sleep disorders (e.g., sleep apnea and restless legs syndrome), often observed in affected patients, were not observed in the Japanese cohort [61].

Atrophy and changes in signal intensity in the medulla oblon gata and upper cervical spinal cord are considered diagnostic features of AOAD [62]. Symmetrical cerebral white matter abnormalities, of mild to moderate intensity and with a frontal predominance, can be found in the majority of cases. Supratentorial periventricular white matter abnormalities and abnormal contrast enhancement often are seen in adult‐onset cases before age 40, but in cases with onset over 40 [58, 62], postcontrast enhancement is usually absent and mean diffusivity is not altered, except in areas showing abnormal white matter [62].

Prior to identification of GFAP mutations, the diagnosis of Alexander disease was based on the demonstration of

Rosenthal fibers (intracellular inclusion bodies composed of aggregates of GFAP, vimentin, αβ‐crystallin, and heat shock protein 27 found exclusively in astrocytes) on brain biopsy or at autopsy [57, 59]. Currently, the diagnosis is established when a GFAP sequence variant which has been previously reported as disease causing is found. In cases in which the identified sequence variant has not been previously described, the probability of causality is deemed high when there is involvement of a highly conserved site in the GFAP gene across species (orthologs) or in a similar domain motifs across other human intermediate filament proteins (paralogs) or studies in animals or cell culture systems have shown that the altered sequence leads to astrocyte dysfunction. The majority of cases occur sporadically; individuals with the slowly progressive adult form who have an affected parent have been described, indicative of autosomal dominant transmission [63].

Unfortunately, there is currently no specific treatment for any form of Alexander disease. Experimental approaches under con sideration are directed at putative disease mechanisms, which are not fully elucidated; these include (i) reducing the initial insult arising from GFAP mutations (e.g., misfolded protein and the use of chaperones), (ii) enhancing protective stress responses, and (iii) minimizing detrimental downstream effects [64].

Mitochondrial disorders

Abnormalities on brain MRI, including white and/or gray matter involvement, and cognitive impairment often are encountered in adult patients with a mitochondrial disorder, although rarely as isolated features [65, 66]. Some commonly associated nervous system manifestations are migraine‐like headache, sensorineural hearing loss, progressive external ophthalmoplegia, myopathy, and axonal neuropathy [65, 66]. Multisystem involvement might include hypothyroidism, diabetes mellitus, cardiomyopathy, cardiac conduction abnormalities, vomiting, gastrointestinal pseudo‐obstruction, diarrhea, hepatopathy, anemia, leukopenia, thrombocytopenia, or renal insufficiency [65, 66].

Mitochondrial disorders are metabolic diseases, most fre quently caused by a defect in the respiratory chain that leads to a decrease in the ability of the mitochondria to meet cellular energy demands. The mitochondria are involved in other cellu lar roles as well, including mitophagy and programmed cell death. Defects of mitochondrial function can arise as a result of mutations involving proteins encoded by mitochondrial or nuclear DNA (nDNA) [65, 66]. Mitochondrial dysfunction might also be implicated in the etiopathogenesis of Parkinson’s disease, and mutations in several nuclear‐encoded genes linked with inherited Parkinson’s disease have been hypothesized to result in mitochondrial dysfunction [67].

A detailed discussion of mitochondrial disorders is beyond the scope of this review, which will focus on a selected subset of conditions associated with dementia to illustrate mode of disease presentation and its evolution.

Mitochondrial disorders present as either slowly or rapidly progressing single‐organ or multisystem defects with onset at

any time from birth to adulthood. The involvement of the CNS is estimated in 30–60% of patients [68, 69]. Most information about cognitive decline in mitochondrial diseases is derived from case reports or small case series. If systematically tested, however, cognitive impairment is frequent and more clearly evi dent on neuropsychological testing than might be anticipated from clinical examination alone [68, 69]. Cognitive impairment progresses with disease duration and occurs more frequently in patients with abnormal imaging.

Neuropsychiatric abnormalities are a frequent finding in mitochondrial disorders, although CNS problems are often found in the presence of other systemic features [68, 69]. Acute manifestations include impaired consciousness and alertness, acute or chronic confusional state, and hallucinations. Psychosis has been particularly described in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke‐like episodes (MELAS) and rarely in Kearns–Sayre syndrome (KSS) [69, 70]. In a report on three adult patients exhibiting psychiatric symp toms as the core manifestations accompanied by various degrees of myopathic symptoms, skeletal muscle pathologic findings were compatible with mitochondrial myopathy in all cases [70]. In these cases, mutation analyses revealed mitochondrial DNA (mtDNA) deletion in skeletal muscles, but not in blood.

Cognitive dysfunction in the domains of abstract reasoning, verbal memory, visual memory, language, executive functions, calculation, attention, or visuospatial functions, with relative sparing of functional abilities, has been described and might be the initial manifestation of CNS involvement in patients with a mitochondrial disorder [63, 64]. Dementia may be a feature of MELAS; myoclonic epilepsy and ragged‐red fibers (MERRF), Leigh syndrome; KSS; neuropathy, ataxia, and retinitis pigmen tosa (NARP); Leber hereditary optic neuropathy (LHON); or Muir–Torre syndrome (MTS). Comorbidities associated with each of these individual mitochondrial disorders enable their differentiation.

In a small series of 36 patients with mitochondrial myopathies and encephalomyopathies, general cognitive dysfunction or focal deficits were detected in 61% of the patients, whereas moderate to severe deterioration was seen in 36% of the patients [70]. Seventy‐ eight percent of the patients with CNS involvement showed cognitive deficits of language, memory, or perception. These observations are consistent with the findings of a separate study involving 22 patients with chronic progressive external ophthal moplegia (CPEO) or KSS [71]. In this, the latter patient cohort neuropsychological testing did not reveal signs that would suggest general intellectual decline or dementia, but provided evi dence of specific focal neuropsychological deficits, suggesting particular impairment of visuospatial perception associated to parieto‐occipital lobes and executive deficits associated to the prefrontal cortex [71]. It should be noted that secondary effects on cognition in patients with a mitochondrial disorder might also occur, due to the involvement of other organs (e.g., hyperglycemic encephalopathy due to uncontrolled diabetes or hypo‐ or hyper thyroid and hypoparathyroid encephalopathy) [65, 66].

Diagnosis of mitochondrial disorders

A patient already diagnosed with a mitochondrial disorder can develop cognitive dysfunction, in which case the etiology for dementia is evident. In cases wherein cognitive decline is the presenting feature, however, symptomatic involvement of two or more apparently unrelated organs (e.g., neurosensory and endocrine systems) raises the index of suspicion for a mitochon drial defect. Elevated blood and CSF lactate and pyruvate levels might provide a useful clue; attention must be paid, however, to the fact that uncontrolled seizures also cause elevated lactate levels and improper handling of the specimens (such as not keeping samples cold or analyzed expeditiously) artificially lowers lactate and pyruvate levels, possibly resulting in false‐ negative tests. Brain MR spectroscopy (MRS), especially of the stroke‐like lesions in MELAS, often shows markedly reduced N‐acetyl‐aspartate, choline, creatine peaks, or an increased lactate peak [73]. SPECT studies may show hypoperfusion in temporal or occipital lobes [74].

Diagnostic confirmation may be obtained in patients with clin ically defined syndromes by mutation analysis and demonstra tion of known mtDNA disease‐causing defects [65, 66]. A muscle biopsy with estimation of enzymes involved in respiratory chain can sometimes detect mitochondrial dysfunction, but might not be abnormal in patients without significant muscle involvement. In contrast to point mutations in mtDNA, which can be often demonstrated in a peripheral blood sample, analysis for deletion‐ type mutation may require skeletal muscle biopsy [72].

pathophysiology and molecular genetics
of mitochondrial disorders
Mitochondria are intracellular organelles that change in number based on the substrate and oxygen requirements of the cell. Fundamental biological roles include provision of adenosine triphosphate (ATP), mediation of cell death by apoptosis, heat production by decoupling of the oxidative phosphorylation, and translation and transcription of mitochondrial genes [65, 66]. β‐Oxidation, the citrate acid cycle, degradation of amino acids, parts of heme synthesis, steroid metabolism and uric acid cycle, mitochondrial protein synthesis, and reactions catalyzed by the pyruvate dehydrogenase complex (PDC) also occur in the mitochondria. The brain, skeletal muscles, and sensory organs that rely on mitochondrial aerobic metabolism are more fre quently involved.

Human mtDNA is a 16.5‐kb circular minichromosome encod ing 37 genes, 13 of which code for subunits of the respiratory chain complexes I–V (excluding complex II), 22 encode tRNAs, and two encode rRNAs. A single mitochondrion contains 2–10 mtDNA copies [65, 66]. Thus, each cell houses up to several thousand mtDNA copies, as each cell contains hundreds of mito chondria. Fifty‐four of the 67 respiratory chain proteins and 1000 other mitochondrial proteins are encoded by the nDNA.

mtDNA mutations such as large‐scale rearrangements (partial deletions or duplications) can occur spontaneously, whereas point mutations are usually inherited from the mother

Leukoencephalopathies/leukodystrophies 163

164 Non-Alzheimer’s and Atypical Dementia

(i.e., matrilineal inheritance as opposed to sex linked). Mitochondrial disorders caused by nDNA mutations follow a Mendelian pattern of inheritance. Random mutations in the mtDNA lead to coexistence of wild‐type mtDNA and mutant mtDNA in a single cell or organ, a phenomenon known as het eroplasmy [65, 66]. A high proportion of the mutant mtDNA in an organ or a cell predicts a more severe phenotype. Phenotype in a mitochondrial disorder depends on the severity of the mutation, the affected gene, tissue distribution, cellular oxygen requirement, and threshold effect, which implies that if the load of mutant mtDNA copies exceeds a certain amount, the effect of a mutation can be no longer compensated for by wild‐type mtDNA.

Recently, investigations undertaken in a 57‐year‐old woman with progressive neurodegeneration characterized by psychosis, dementia, and akinesia–rigidity revealed a novel mitochondrial transfer RNA (Phe) (MTTF) mutation [75]. Evaluations revealed neuropsychological features indicative of predominant frontal lobe dysfunction suggestive of progressive supranuclear palsy or Huntington’s disease (subcortical dementia). Her brain MRI showed brainstem, cerebellar, and widespread cortical atrophy, but no evidence of white matter disease.

therapy of mitochondrial disorders

Treatment of mitochondrial dementia includes general measures such as regular physiotherapy as tolerated by the individual, avoidance of stress, fasting, extreme temperature, or drugs known to induce secondary respiratory chain insufficiency [65, 66]. Use of ketogenic diet (65% fat) or substitution of fat by carbohy drates and supplementation of respiratory chain components such as coenzyme Q have also been recommended [65, 66]. Administration of metabolites or cofactors such as carnitine in order to restore secondarily lowered levels of free carnitine, cre atine, thiamine, or riboflavin is recommended. Comorbid condi tions such as seizures or endocrine abnormalities need appropriate control. The progressive course of cognitive involvement unfortu nately is typically unaffected by these therapeutic approaches.

Lysosomal storage disorders

White matter signal abnormalities on brain MRI has been described in several lysosomal storage disorders (LSDs); although cognitive impairment can be a feature, it is often not the initial mode of presentation or the only clinical problem [3]. As with mitochondrial defects, LSDs are oligo‐ or multi systemic disorders; the pattern of organ involvement, however, is more a function of tissue substrate storage and not energy deficits, and symptoms bear no relationship to dietary intake or fasting [3]. Pertinent disorders include late‐onset forms of MLD and GLD (Krabbe disease), Fabry disease, and other conditions.

Although not an LSD, X‐linked adrenoleukodystrophy (ALD; a peroxisomal defect) is briefly described in this section.

MLD and GLD(Krabbe disease)

Behavioral abnormalities with modifications of mood, peculiar social reactions, and a progressive mental deterioration have been described in adult‐onset MLD and Krabbe disease [79, 80], demyelinating leukodystrophies, caused by defi ciency of the lysosomal enzymes hydrolase arylsulfatase A (ARSA) and β‐galactocerebrosidase, respectively [81, 82]. Both disorders are inherited in an autosomal recessive man ner. Peripheral neuropathy is common, due to peripheral myelin involvement; although in patients with late‐onset forms of the disease, this finding may not be evident on presentation [83].

Brain MRI characteristics of MLD and GLD include promi nent T2‐weighted hyperintensity with T1‐weighted hypointen sity (relative to gray matter structures), consistent with demyelination [3]. The lesions found are frequently confluent, withapredominantlyfrontaland/orperiventriculardistribu tion (Figure 12.8).

Fabry disease

Fabry disease is an X‐linked disorder caused by deficiency of the lysosomal hydrolases α‐galactosidase A (AGAL). Although the classic features of disease occur in affected males, a significant proportion of carrier females (up to 70%) develop clinical problems; this likely due to X‐inactivation of the normal chromosome and the fact that the signs and symp toms of disease among affected females, however, are highly variable and often milder and tend to occur at a later age [76]. In addition to problems related to cerebrovascular disease, patients usually suffer from progressive renal insufficiency and cardiomyopathy. Ophthalmic examination might show corneal and lenticular opacities in a verticillate (whorled) pattern [76]. An Italian study examining newborn blood spots found that adult‐onset cases likely are highly underesti mated and much more common than the classic younger‐onset forms [90].

Although strictly not a leukodystrophy, brain MRI of adult patients with Fabry disease often show signal abnormalities, most of which are consistent with leukoaraiosis rather than demyelination [76, 77]. Patients with Fabry disease are esti mated to have 20‐fold higher risk of TIA or stroke compared to the general population. Signal abnormalities often are found in watershed regions, corresponding to brain vascular distribution, a finding that further suggests a role for ischemia in the disease process. White matter lesions on MRI, presumably ischemic, can be focal, multifocal, and confluent [76] (Figure 12.9). In spite of these findings, most affected individuals with Fabry disease reportedly do not have overt cognitive problems [76]. Dementia is rarely a presenting feature, although adult‐onset cases pre senting as vascular dementia cases have been reported [91, 92]. Patients with Fabry disease are at risk for cerebrovascular disease and might develop cognitive impairment following a stroke [78] or progressive small vessel ischemic vascular disease [91]. Cerebrovascular changes might be the only manifestation

(a)

Leukoencephalopathies/leukodystrophies 165

(b)
Figure 12.8 Brain MRI in MLD. Axial T2 (a) and FLAIR (b) images show diffuse hyperintensity in the cerebral white matter with sparing of U‐fibers.

Source: Kanekar and Gustas [96]. Reproduced with permission of Elsevier.

Figure 12.9 T2‐weighted magnetic resonance images in a patient with Fabry disease, showing multifocal white matter hyperintensities approaching confluency. Source: Mohanraj et al. [92]. Reproduced with permission of BMJ Publishing Group.

of some patients in their 30s–40s, whereas others might be asymptomatic, but with cerebrovascular disease on MRI [91]. Fabry disease should be considered in patients with unexplained cerebrovascular disease [76, 91, 92]. A relatively specific MRI

finding of Fabry disease appears to be T1 hyperintense lesions in the posterior thalamus and pulvinar, due to mineralization, occurring mostly in older (>30 years old) males with cardio myopathy or renal disease (Figure 12.10) [76, 93–95].

166 Non-Alzheimer’s and Atypical Dementia

(a) (b)

Figure 12.10 Fabry disease. Axial CT (a) scan at the level of deep gray matter nuclei shows calcification in the pulvinar nuclei of thalamus (arrowheads). Corresponding areas show hyperintensity on T1‐weighted image (b). Source: Kanekar and Gustas [96]. Reproduced with permission of Elsevier.

aLD

X‐linked ALD is caused by mutations in ABCD1 gene, which encodes a peroxisomal membrane half‐ATP‐binding cassette transporter. A defect of ABCD1 (also known as ALDP, which stands for adrenoleukodystrophy protein) is associated with impaired peroxisomal beta‐oxidation and accumulation of satu rated very‐long‐chain fatty acids (VLCFA) in tissues and body fluids [84]. Affected individuals typically present with the child hood cerebral form (which manifests most commonly between ages 4 and 8 years), but onset in adulthood is well described [84]. The latter patients often have a spastic gait consistent from involvement of long tracts (adrenomyeloneuropathy), but do not always develop intellectual decline, but adult‐onset forms might present as frontotemporal dementia [84]. Cognitive impairment or behavioral changes are more characteristic of the childhood cerebral form. Brain MRI in adult‐onset cases of X‐ALD have shown tract involvement in the corticospinal, spinothalamic, visual, and auditory pathways. Internal capsule and brainstem pyramidal involvement is common. More com monly, white matter hyperintensities begin in the splenium of the corpus callosum and move caudally–rostrally to the occip itoparietal cortex. T2 hyperintensities might also start in the genu of the corpus callosum and move frontally [84, 85].

Recently, Uchida and colleagues described a 46‐year‐old Japanese patient with adult‐onset X‐linked ALD who presented with topographic disorientation [86]. Intellectual function was relatively preserved and amnestic symptoms were absent. Brain MRI images revealed T2 signal hyperintensity along

the occipitopontine tract and lateral lemnisci, but not in the corticospinal tract in the brainstem [86].

Diagnosis of LSDs

In the relevant clinical context, the diagnosis of MLD or Krabbe or Fabry disease might be established, based on the demonstra tion of deficient enzyme activity with several caveats. As 10–15% of the general population exhibit a pseudo‐deficiency of ARSA activity, the enzymatic diagnosis of MLD requires demonstra tion of excess urine sulfatide excretion and/or presence of known defects in the cognate gene [81]. The diagnosis of Fabry disease in females with normal AGAL activity necessitates dem onstration of a causal AGAL gene defect, as up to one‐third of carrier females have residual enzyme activity which overlaps with that found in otherwise healthy individuals within the general population [76]. X‐linked ALD is associated with elevated levels of VLCFA, although female carriers might have levels that overlap with values for the general population; thus, diagnosis of carrier females necessitates demonstration of an underlying ALDP gene defect [84].

Management

Hematopoietic stem cell transplantation for MLD, Krabbe disease, and X‐linked ALD is available [87]. These therapeutic options might modify disease course, but often only when treatment is initiated in the early stages of the disease process. Dietary therapy with Lorenzo’s oil (a 4:1 mixture of glyceryl trioleate and glyceryl trierucate) has been reported to slow

progression in patients with X‐linked ALD when initiated in the early stages of the disease process in children younger than 6 years of age and adrenomyeloneuropathy in patients without cerebral involvement [88]. Adrenal hormone replacement therapy is indicated in patients with X‐linked ALD and adrenal insufficiency.

Enzyme replacement therapy is available for Fabry disease [89]. Adjunctive therapies for the primary and secondary pre vention of stroke include antiplatelet agents and statins. Angiotensin‐converting enzyme inhibitors or sartans are also prescribed in patients with proteinuria for its renoprotective properties.

Summary

Although infrequent to rare, the diagnosis of a leukodystrophy is important so as to avoid the often common situation wherein an affected individual is mistakenly considered to have and inappropriately treated as a case of primary or secondary chronic progressive MS or another disorder. Certain disorders in this class, whose incidence is likely significantly underestimated, include CADASIL, ALSP, and Fabry disease [90]. Table 12.3 presents a summary of key clinical, including MRI, differentiat ing features of several disorders discussed in this chapter. The diagnosis of a leukodystrophy, when confirmed by biochemical and/or molecular testing, enables appropriate genetic counseling, prognostication, and management.

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Leukoencephalopathies/leukodystrophies 169

CHapter 13
Infectious causes of dementia

Cheryl A. Jay1,2, Emily L. Ho3,4 and John Halperin5,6,7

1 University of California, San Francisco, San Francisco, CA, USA
2 San Francisco General Hospital (SFGH), San Francisco, CA, USA
3 University of Washington, Seattle, WA, USA
4 Swedish Neuroscience Institute, Seattle, WA, USA
5 Atlantic Neuroscience Institute, Summit, NJ, USA
6 Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, USA 7 Overlook Medical Center, Summit, NJ, USA

Introduction

Viruses, bacteria, fungi, and parasites most commonly reach the brain hematogenously during disseminated infection, although a few pathogens target specific neuronal or glial cells. Acute cerebral infections, such as community‐acquired bacterial meningitis and most viral encephalitides, might begin with cognitive and personality dysfunction, but the rapid deteriora- tion of alertness over subsequent hours to days causes little diagnostic confusion with most neurodegenerative disorders. Neuropsychological dysfunction is often a long‐term, disabling complication of many acute brain infections.

Patients with subacute or chronic infections develop cogni- tive and behavioral disturbances in several settings. A few nonprion chronic cerebral infections, such as HIV‐associated dementia (HAD) and general paresis, manifest primarily as either a rapidly progressive or a more indolent dementia. Memory and behavioral complaints, with or without abnor- malities by neuropsychological testing, are common among patients with some chronic cerebral or systemic infections in which other clinical features predominate. Neuropsychological dysfunction often is the predominant feature in the early weeks and months of other nonacute brain infections, includ- ing the long list of pathogens that cause chronic meningitis. The general approach to such patients is beyond the scope of this chapter and has been the subject of reviews [1, 2]. The focus here will be infections whose manifestations overlap with neurodegenerative disorders, along with briefer discus- sions of the neuropsychological sequelae of acute cerebral infections.

Viruses

Human immunodeficiency virus
(HIV)‐associated dementia
Case: A young man with AIDS for 8 years and previously treated neurosyphilis presented to a clinic for evaluation of memory and gait difficulties for several weeks, on a background of a decreasing CD4+ T‐cell count in the past year. He was not on antiretroviral therapy because of poor adherence related to active methamphetamine use. His physician noted him to be less jovial and talkative than usual. On examination, he had impaired reverse digit span and short‐term memory. Reflexes were symmetrically diminished in the legs, with flexor plantar responses bilaterally. There was length‐dependent sensory loss to the knees and wrists. Although Romberg’s test was negative, he walked on a slightly broad base with impaired tandem gait.

Laboratory studies revealed a low CD4+ T‐cell count at 98cells/mm3 (normal=500–1500cells/mm3) with HIV viral load of greater than 200000copies/mL. Serum rapid plasma reagin (RPR) serology was 1:2 (1:1024 2 years previously prior to the treatment for neurosyphilis). CT was normal. MRI showed symmetric periventricular white matter abnormalities, compatible with HIV infection (Figure 13.1). CSF showed mildly elevated protein of 77 mg/dL (normal 15–45 mg/dl), glu- cose of 56mg/dL, 7RBC/mm3, and a slight pleocytosis of 12WBC/mm3 (91% lymphocytes), with negative cryptococcal antigen and Venereal Disease Research Laboratory (VDRL) test. He was presumptively diagnosed with HAD, began combina- tion antiretroviral therapy (cART), and was referred to drug rehabilitation (follow‐up continued below).

170

(a) (b)

(c) (d)

Figure 13.1 Neuroimaging in HIV‐associated dementia studies obtained from a patient with untreated HIV infection, cognitive impairment, and gait disorder (see text). Noncontrast head CT (a) and T1‐weighted brain MRI after gadolinium administration (b) are normal. FLAIR (c) and T2‐weighted (d) images demonstrate ill‐defined, symmetric white matter abnormalities, consistent with HIV‐associated dementia.

Infectious causes of dementia 171

Soon after outbreaks of opportunistic infections (OIs) in Los Angeles among men who have sex with men heralded the HIV/ AIDS pandemic in 1981, the nervous system emerged as a major site of clinical involvement [3]. Manifestations included cerebral OIs and neoplasms from severe immunocompromise, peripheral neuropathy, and a dementing illness initially referred to as suba- cute encephalitis [3–5]. The clinical syndrome, termed AIDS dementia complex (ADC) [4], and its neuropathologic substrate

[5] were defined further in 1986. HIV encephalopathy [6] and AIDS‐related dementia [7] were other terms for the occasionally static but more characteristically progressive cognitive, motor, and behavioral impairments that characterized the syndrome before cART [4, 6, 7]. Typical early symptoms include apathy, slowed thinking, impaired memory, and gait difficulty; neuro- logical examination might be normal or reveal psychomotor slowing, hyperreflexia (sometimes masked by concomitant distal

172 Non-Alzheimer’s and Atypical Dementia

symmetric polyneuropathy), and pathological reflexes [4, 7]. In untreated patients, these early features often progress over months to mutism, quadriparesis, and incontinence [4]. Occasional patients may present with psychosis or mania [4, 7]. The Memorial Sloan Kettering (MSK) scale for ADC (Table 13.1), a staging system devised for patient care and clinical research in the late 1980s [8], remains in use. Host risk factors for dementia in the pre‐cART era included low CD4 count, hemoglobin, or body mass, as well as constitutional symptoms, advancing age, and elevated cerebrospinal fluid (CSF) HIV viral load [9, 10]. Before cART, dementia was common, affecting approximately half of the HIV‐infected patients [11].

In 1991, the AIDS Task Force of the American Academy of Neurology (AAN) defined the criteria for HAD and a milder condition, minor cognitive motor disorder (MCMD) [12]. The advent of cART with at least three antiretroviral drugs, in the mid‐1990s, dramatically improved the outlook for HIV+ patients with access to treatment. Death rates fell, as did the incidence of HAD along with neurologic and systemic OIs [13, 14]. With improved survival, the prevalence of HAD increased, as did the frequency of less severe degrees of cognitive impair- ment [9–11, 13]. Progression over months was less common in treated patients, suggesting that cART had beneficial effects on the natural history of HAD, including slowing down the course. Dementia is now seen at higher CD4 counts than in the pre‐ cART era [13]. Risk factors for cognitive impairment in patients on cART include advancing age, particularly older than 50 years of age, and possibly hepatitis C coinfection [10]. With

Table 13.1 Memorial Sloan Kettering scale for AIDS Dementia Complex (ADC).

increasing numbers of older HIV+ patients, due in part to long‐term survival on cART, distinguishing HAD and related conditions from age‐related neurodegenerative disorders could become a more common clinical problem [15].

In 2007, a working group of the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke revised the AAN research nosology and associated diagnostic criteria, in part reflecting changes in clinical fea- tures and epidemiology in the era of cART [16]. This most recent update defined three conditions as comprising the HIV‐ associated neurocognitive disorders (HANDs): asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV‐1‐associated dementia. The revised criteria emphasize acquired cognitive impairment, assessed by neuropsychologi- cal testing when possible, in at least two cognitive domains, typically impaired attention and learning with slowed infor- mation processing. The updated HAD criteria usually corre- spond to MSK stage score of two or greater. Significant functional impairment and the absence of delirium or other evident causes for dementia (including cerebral infection or neoplasm, stroke, other neurologic diseases, or substance abuse) are other key elements. The prevalence of HAND is approximately 50%, with a shift from HAD to milder forms in the era of cART [10, 16].

The differential diagnosis of cognitive impairment in patients with known HIV infection is broad. Substance abuse, psychiat- ric disorders, toxic‐metabolic encephalopathies, neurosyphilis (discussed later in this chapter), and neurodegenerative disor- ders are considerations throughout the course of HIV disease. At CD4 counts below 200 cells/mm3, cerebral malignancies and OIs are important and life‐threatening diagnostic concerns [8– 10]. Depression is common in HIV+ patients and can be diffi- cult to distinguish from early HAD. Primary central nervous system (CNS) lymphoma in the setting of HIV classically causes altered mental status with focal cerebral dysfunction or head- ache, typically evolving over months. The predilection of this B‐cell lymphoma for periventricular regions and the corpus cal- losum [9] means that patients with bifrontal involvement may present primarily with personality change and cognitive impair- ment with minimal visual or motor dysfunction, at least in the early stages. Progressive multifocal leukoencephalopathy, an infection of oligodendrocytes by JC virus, typically manifests as worsening lateralized visual or motor impairment, evolving over months, consistent with asymmetric hemispheric white matter involvement, or occasionally as progressive brainstem dysfunction, but presentation with dementia has been reported [17]. Cerebral toxoplasmosis is a common cerebral OI in the setting of HIV/AIDS. Most commonly, this protozoal infection presents with headache, fever, focal cerebral dysfunction, impaired alertness, and other features of expanding cerebral mass lesions, although rarer meningoencephalitic forms with unusually bland neuroimaging have resembled HAD [18]. Cryptococcal meningitis, another common cerebral OI in HIV+ patients, is discussed later in this chapter.

Stage 0 Stage 0.5

Stage 1

Stage 2 Stage 3

Stage 4

Normal
Absent, minimal, or equivocal symptoms of cognitive or motor dysfunction characteristic of ADC
Mild signs (snout reflex, slowed ocular or limb movements) without impairment of work or capacity to perform activities of daily living (ADL)
Normal gait and strength
Able to perform all but the more demanding aspects of work or ADL Unequivocal evidence (symptoms, signs, neuropsychological testing) of functional intellectual or motor impairment
Can walk without assistance
Cannot work or maintain more demanding aspects of daily life but able to perform basic self‐care activities
Ambulatory but may require single prop
Major intellectual incapacity (unable to follow news or personal events, sustain complex conversation; considerable slowing of all output) or motor disability (unable to walk unassisted, requiring walker or personal support, usually with slowing and clumsiness in arms)
Nearly vegetative, with rudimentary intellectual and social comprehension and responses; nearly or absolutely mute Paraparetic or paraplegic with double incontinence

Source: Price and Brew [8]. Reproduced with permission of Oxford University Press and Richard W. Price.
Requires documented HIV‐1 infection and exclusion of other causes of acquired cerebral dysfunction, such as opportunistic infections and metabolic encephalopathies.

Cytomegalovirus (CMV) encephalitis sometimes presents as a rapidly progressive dementia, usually in very advanced AIDS, when CD4 count falls below 50 cells/mm3 [9, 19, 20]. Nearly one‐ third of the patients with CMV encephalitis and concurrent HIV infection have evidence of brainstem or cerebellar dysfunction [20]. Concomitant myelitis, radiculitis, retinitis, esophagitis, hepatitis, or colitis can also be useful diagnostic clues, since these are other common sites of CMV infection [9, 20]. CSF findings of polymorphonuclear pleocytosis with hypoglycorrhachia, resembling bacterial meningitis, and neuroimaging revealing ventriculitis are also suggestive, although the absence of either or both does not exclude CMV encephalitis. CSF CMV polymerase chain reaction (PCR) is more specific than sensitive for the diag- nosis. CMV encephalitis is fatal without treatment but, if caught early, might respond to ganciclovir or foscarnet [9, 20].

It should be emphasized that throughout the HIV/AIDS epi- demic, dementia has been reported as the presenting manifesta- tion of previously undiagnosed HIV infection [21, 22]. HIV testing is thus an appropriate part of the evaluation for patients with unexplained cognitive impairment.

HIV entry into the CNS has been demonstrated early in the course of infection, via infected monocytes [9–11, 23]. Occasionally, this is associated with typical aseptic meningitis but more commonly with asymptomatic mild lymphocytic CSF pleocytosis and elevated protein [9–11, 23–25]. Productive infection of neurons has not been demonstrated, suggesting that indirect mechanisms of brain injury, such as chronic inflamma- tion or viral protein neurotoxicity, may underlie the myelin pal- lor and multinucleated giant cells seen in patients dying with HAD in the pre‐cART era [5, 10, 23]. As the epidemiology and natural history of HANDs in the cART era have evolved, so also has the neuropathology, with more prominent inflammation in the brains of treated patients [10].

The diagnostic evaluation for HIV+ patients with cognitive dysfunction should include review of medications and screening for depression and substance use disorders, along with appropri- ate blood tests for thyroid disease, vitamin B12 deficiency, and neurosyphilis. Neuroimaging, with and without contrast when safe and feasible, to exclude multifocal OIs and malignancies typically reveals cerebral atrophy [9, 10]. MRI is superior to CT (Figure 13.1) in demonstrating symmetric, ill‐defined, nonen- hancing white matter hyperintensities on T2‐weighted images [10], but these are neither necessary nor sufficient for a diagnosis of HAD. CSF protein often is mildly elevated; white cell count depends in part on CD4+ count [24, 25]. Pleocytosis is unusual among patients with CD4 counts below 50 cells/mm3, regardless of treatment status [24]. At higher CD4+ counts, patients not on cART, with or without neurologic symptoms, may demonstrate mildly elevated CSF white count (<30cells/ mm3). Pleocytosis normalizes within months of virologic control of HIV on cART, in concert with CSF HIV viral load falling near or below the limit of detection [11, 24, 25].

Small clinical studies in the pre‐cART era demonstrated that zidovudine monotherapy, albeit at doses higher than typically

used currently, slowed the progression of dementia [9, 23]. Zidovudine, unlike most other antiretrovirals in use at the time, achieved good CSF levels, generating debate about the degree to which CSF (and, it is assumed, cerebral) penetration is impor- tant in treating HAD [9, 10, 23, 26]. In addition to zidovudine, nevirapine and ritonavir‐boosted indinavir penetrate well into the CNS, followed by abacavir, emtricitabine, delavirdine, efa- virenz, and indinavir; boosted darunavir, fosamprenavir, or lopinavir; and maraviroc and raltegravir [10, 26]. Other antiret- roviral drugs do not penetrate the CNS as well [9–11]. Patients who develop HANDs while not on cART should be started on therapy [9–11, 23]; whether patients who develop HANDs while on cART benefit from modifying the regimen toward drugs with good CNS penetration remains uncertain. Controlled tri- als of adjunctive antioxidant and neuroprotective agents have been disappointing [9, 10].

Case follow‐up

The patient was begun on abacavir, lamivudine, zidovudine, and nevirapine, which led to an increased CD4+ T‐cell count and a decrease in viral load to undetectable levels. Over the next year, his attention, memory, and gait improved. Subsequently, he suffered a relapse of his methamphetamine use, nonadher- ence with his antiretroviral regimen, and was lost to follow‐up.

Subacute sclerosing panencephalitis

Subacute sclerosing panencephalitis (SSPE) is caused by cere- bral infection with defective measles virus occurring long after acute measles infection [27–32]. Incidence estimates range from four to nearly 30 SSPE cases per 100 000 measles cases [27]. As a consequence of a preventable childhood infection, SSPE has become quite rare in countries with effective measles vaccina- tion programs, and the diagnosis is easily missed [27, 28]. SSPE is typically a disease of childhood and adolescence, although adult‐onset cases have been reported, with symptoms beginning as late as 49 years of age [28, 29].

Acute measles acquired very early in life increases the risk for SSPE, and pregnancy may also be a risk factor [27–29]. Symptoms begin months to decades after acute measles, which might not have been diagnosed, and include cognitive impairment, behav- ioral and personality changes, visual dysfunction, myoclonus, and seizures, usually developing over months [27, 28]. The myo- clonus is typically generalized, without associated loss of con- sciousness and is common, but not always present [27, 28]. When myoclonus is present, the differential diagnosis includes prion disorders, corticobasal syndrome, dementia with Lewy bodies, hypoxia, thyrotoxic encephalopathy, and progressive myoclonic epilepsies such as mitochondrial cytopathies, Lafora’s disease, neuronal ceroid lipofuscinoses, Unverricht–Lundborg syndrome, and the sialidoses [27]. In the absence of myoclonus, the clinical syndrome suggests a neurodegenerative disorder, making the recognition of SSPE especially challenging [30].

The diagnosis should be considered through middle age in patients with cognitive or behavioral decline, particularly

Infectious causes of dementia 173

174 Non-Alzheimer’s and Atypical Dementia

associated with myoclonus. Neuroimaging may be normal in early SSPE. As the disease advances, subcortical and periven- tricular white matter and basal ganglia abnormalities may be seen, progressing to hemispheric, brainstem, and cerebellar atrophy [27]. EEG may be normal or nonspecifically slow in early disease but typically demonstrates synchronous, stereo- typed high‐voltage periodic complexes usually associated with myoclonic jerks in midstage SSPE [27]. Routine CSF studies may be entirely normal or show mild lymphocytic pleocytosis and protein elevation, with elevated CSF gamma globulin concentra- tion [27, 28, 30]. Antimeasles antibodies are elevated in CSF and establish the diagnosis, in the appropriate clinical setting and with characteristic EEG abnormalities [27–31]. Brain biopsy might be necessary in rare cases, such as in very early or advanced disease, when EEG may not show periodic complexes [27].

Neuropathologic findings include parenchymal inflamma- tion in hemispheres spreading to brainstem and spinal cord, with demyelination and neuronal and glial viral inclusions [27, 32]. The occipital lobes are often involved in early disease, per- haps accounting for visual symptoms, although retinitis or optic nerve involvement also occurs [27, 32].

Fulminant cases resembling acute viral encephalitis have been reported [29], but the typical course is progression to death over several years [27, 28]. Oral isoprinosine alone or in combi- nation with alpha interferon (intramuscular, intravenous, or intrathecal) or ribavirin (intraventricular or intravenous) might prolong survival, with varying degrees of symptomatic improve- ment [27]. Myoclonus is managed with benzodiazepines and antiepileptic agents but can be refractory to treatment [27]. Previous concerns that the measles vaccine might cause SSPE have not been realized. Prevention with vaccination remains the best intervention for this devastating infection [27].

Hepatitis C

Seroprevalence rates for antibodies to hepatitis C virus (HCV), indicating exposure to the hepatotropic single‐stranded RNA virus, are below 2% in most industrialized nations and higher in Africa (0.8% in Ethiopia to more than 15% in Rwanda and Egypt), Latin America (0.7% in Mexico to 11.2% in Bolivia), and parts of Asia (5.6% in Thailand, 6.2% in Vietnam, 10.7% in Mongolia) [33]. Most infected individuals develop chronic liver disease, which can progress to cirrhosis and hepatocellular car- cinoma [33–35]. Extrahepatic disease is common, and neuro- logic complications include peripheral neuropathy and stroke, in addition to hepatic encephalopathy from portal hypertension [35]. Coinfection with HIV and HCV is common, as both viruses are transmissible by exposure to blood, including injec- tion drug use [33].

Even in the absence of cirrhosis, fatigue and functionally lim- iting memory impairment are common complaints in early HCV disease [35–37]. Abnormal neuropsychological testing, particularly in attention and executive function, compared to controls has been reported in patients with HCV without cirrhosis in many, but not all, studies [36]. Proton magnetic

resonance spectroscopy demonstrated elevated choline to cre- atine ratio in the basal ganglia of patients with HCV and histo- logically mild liver disease [37]. Selection of proper testing batteries, control for psychiatric comorbidities, and relevance of abnormal functional imaging are among many methodologic concerns in these studies [35, 36]. In the setting of HIV coinfec- tion, HCV infection was associated with adverse effects on cog- nitive function in patients with advanced HIV disease [38], but not in the setting of well‐controlled HIV infection [39] or hemophilia [40]. Interestingly, HCV is not strictly hepatotropic and can replicate in peripheral blood mononuclear cells [33, 41]. The identification in the brain of macrophages and micro- glia harboring HCV is reminiscent of the pathogenesis of HAD and related disorders [10, 41]. Treatment for HCV consists of ribavirin with alpha interferon, the latter of which can cause depression or cognitive impairment [36].

Cognitive sequelae of viral encephalitis

Viruses are common causes of acute infectious encephalitis, although extensive diagnostic evaluation often does not reveal the specific pathogen [42]. Herpesviruses, neurotropic double‐ stranded DNA viruses, are important diagnostic considerations year‐round. Herpes simplex virus 1 (HSV‐1) accounts for 5–10% of encephalitis cases in the United States [42–44]. Reactivation of latent HSV‐1 in trigeminal ganglia most com- monly causes labial vesicular lesions known as cold sores and, rarely, spreads proximally to the brain, resulting in HSV‐1 encephalitis [44, 45]. In addition to fever, headache, and sei- zures, common presenting symptoms include behavioral and personality change and aphasia, consistent with involvement of one or both medial temporal lobes or orbitofrontal cortices [44, 45]. High‐dose intravenous acyclovir lowered mortality to 28%, compared to 70% in historical controls [46]. Even with treat- ment, many survivors have persistent neuropsychological impairment including anterograde and retrograde amnesia, anomia, semantic memory deficit, executive dysfunction, mood disorders, and dementia [43–46].

Arbovirus (arthropod‐borne virus) infections occur classi- cally as summer outbreaks and are important causes of enceph- alitis globally. West Nile virus, first isolated from an African patient in 1937, rapidly became endemic in North America after a 1999 outbreak in New York City [47]. The mosquito‐ borne virus most frequently causes the acute febrile illness known as West Nile fever and, occasionally, West Nile neuroin- vasive disease involving the meninges, brain, or anterior horn cells [47, 48]. Impaired function or quality of life was noted 18 months after the acute illness in half or more patients after West Nile infection, even those without neuroinvasive disease [48]. Neuropsychological testing revealed psychomotor slow- ing [47]. Acute mortality for tick‐borne encephalitis, the pre- dominant European arbovirus, is low, but persistently impaired memory is a common long‐term complication, with normal cognitive testing in only 10% of survivors and dementia evident in one‐third [49].

Data are even more scant for neuropsychological outcomes from other forms of viral encephalitis [45]. Cognitive dysfunc- tion tends to remain stable or improve slowly over time [50].

Bacteria

Neurosyphilis: General paresis

Case

A middle‐aged man was brought to the emergency department for cognitive decline and personality change. His family described him as progressively disoriented, hostile, and moody for over several months. Earlier that week, he had struck his wife. The patient did not have any pain, incontinence, or a gait disorder. He took atenolol for hypertension and had no other medical problems and no previous psychiatric history. The patient worked as a kitchen assistant; did not use tobacco, alco- hol, or illicit drugs; and had no family history of dementia. On examination, he was disheveled, mildly agitated, and afebrile, with normal vital signs and no meningismus. The neurologic exam was limited by the rare dialect that he spoke—he was ori- ented only to name, with normal speech and language, and impaired registration. Other exam findings included normal pupils, slightly brisk right patellar and bilateral ankle reflexes, flexor plantar responses, and normal proprioception and gait.

Electrolytes and liver and renal function tests were normal. Head CT showed marked generalized atrophy for his age, with- out hydrocephalus or mass lesion, with no additional abnor- malities on MRI (Figure 13.2). Lumbar puncture showed normal opening pressure of 80mm H2O. CSF protein was elevated at 110mg/dL and glucose was slightly low at 42mg/dL (serum 82 mg/dL). Tube #1 of CSF showed 2500 RBC/mm3 and 19WBC/mm3 (84% lymphocytes). Tube #4 showed 695RBC/ mm3 and 12 WBC/mm3 (84% lymphocytes). VDRL was 1:128 in serum and VDRL was 1:16 in CSF, confirming a diagnosis of neurosyphilis. Thyroid‐stimulating hormone and vitamin B12 were normal, and HIV serology was negative. An EEG showed diffuse slowing. The patient underwent treatment for neuro- syphilis with penicillin four million units intravenously every 4 h for 2 weeks. Behavioral symptoms were managed with risp- eridone, haloperidol, and lorazepam (case continued below).

The incidence of primary syphilis in the United States has risen in recent years, especially among men who have sex with men[51–54].CausedbyinfectionwiththebacteriumTreponema pallidumspp.pallidum(hereafterreferredtoasT.pallidum),the CNS may be involved at any stage of disease, from primary to tertiary syphilis [55]. Although manifestations of late sympto- matic neurosyphilis include tabes dorsalis, meningovascular syphilis, and optic atrophy, it is general paresis of the insane, also known as dementia paralytica, a condition involving treponemal infection of the brain parenchyma, which is most likely to pre- sent with cognitive decline and neuropsychiatric symptoms [56].

First described by Antoine Laurent Jessé Bayle in 1822 as a syndrome consisting of severe mental dysfunction accompanied

by other neurologic symptoms [57], general paresis occurs years after initial infection (ranging from 3 to 30 years, peak at 10–20 years). Previously, neurosyphilis accounted for large propor- tions of patients admitted to mental asylums (in the 1920s, more than 20% of such patients in the United States [58]). The search for treatment for this debilitating disease led to Julius Wagner‐ Jauregg being awarded the Nobel Prize in Medicine in 1927 for demonstrating that general paresis patients benefited from malaria therapy [59]. Although the prevalence of general paresis was reported to be approximately 5% of all cases of syphilis, since the advent of penicillin, general paresis has become very rare in developed countries [60].

Symptoms of general paresis include subacute, chronic, relapsing‐remitting changes in personality, affect, and cogni- tion. By history and on examination, patients have depression, mania, emotional lability, irritability, apathy, and/or, rarely, hal- lucinations [60]. Patients might also have delusions, disorienta- tion, impaired memory (especially short term), impaired ability to calculate, poor judgment, lack of insight, and poor personal hygiene and grooming [56, 60–63, 63a]. In addition, there may be impaired speech (including aphasia and anomia), pupillary abnormalities (including the Argyll Robertson pupil), apraxia, ataxia, tremors, and abnormal reflexes (usually hyperreflexia) [56, 60–63, 63a]. Accompanying symptoms may include head- aches, incontinence, and seizures [56, 61, 62]. Without treat- ment, patients progress invariably to vegetative degeneration and then death [56].

Given its myriad symptoms, general paresis is difficult to dis- tinguish from many other psychiatric and dementing illnesses. In a case series from 1969 of

deemagclinic

Non‐Alzheimer’s and Atypical Dementia