Demetia

Marcelo Merello
Sergio E. Starkstein Editors
Movement Disorders
in Dementias
123
Movement Disorders in Dementias
Marcelo Merello • Sergio E. Starkstein
Editors
Movement Disorders
in Dementias
Editors
Marcelo Merello, MD, PhD Sergio E. Starkstein, MD, PhD
Neuroscience Department School of Psychiatry
Raul Carrea Institute for and Clinical Neurosciences
Neurological Research (FLENI) University of Western Australia Fremantle
Universidad Catolica Argentina Fremantle, WA
Buenos Aires Australia
Argentina
ISBN 978-1-4471-6364-0 ISBN 978-1-4471-6365-7 (eBook)

DOI 10.1007/978-1-4471-6365-7
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To our fathers, Jorge and Leonardo, and to
our 20 years of uninterrupted friendship.
MM and SS
Foreword
Neurologists today need to deal in their daily practice with cognitive impairment in
patients with movement disorders, particularly but not limited to those with
Parkinson’s disease. This book offers a somewhat opposite view, which is the occur-
rence of movement disorders in patients in whom dementia is the primary clinical
manifestation. Movement disorders, as currently understood, comprise a large vari-
ety of conditions, not all of which are related to basal ganglia dysfunction. However,
the contribution of the ascending dopaminergic projection to cognitive processing is
well known, and, indeed, the now old-fashioned concept of “subcortical” dementia
originated from observations in patients with progressive supranuclear palsy. On the
other hand, it is now recognized that cognitive impairment very often evolves in
parallel with altered gait and equilibrium and that the pathology of many neurode-
generative diseases is sufficiently widespread to impinge upon several circuits and
brain regions, thus producing multiple clinical combinations. No doubt, dementia
and movement disorders are a current hot topic.
Drs. Merello and Starkstein, therefore, deserve the most sincere and warm con-
gratulation for this initiative and the outcome. This book provides a comprehensive
account of a variety of different movement disorders in the setting of the major
diseases and processes associated with cognitive impairment. The list of authors is
impressive, as experts in the field have written each chapter. Nowadays, the world
of publishing is moving quickly toward electronic editions only in what seems an
inevitable trend. However, Merello and Starkstein’s Movement Disorders in
Dementias is exactly the book one wants to have on the desk to read leisurely and
consult very often when thinking about specific patients with cognitive and motor
impairments. I am looking forward to the smell of a new, just-printed, highly intel-
lectual work!
Pamplona, Spain Jose A. Obeso, MD, PhD
vii
Preface
Since the end of the twentieth century, the cognitive and psychiatric comorbidities
of movement disorders have received increasing attention. On the other hand, the
study of movement disorders in dementia has been relatively neglected. To our
knowledge, there are no specific books devoted to clarify the variety, mechanism,
and treatment of motor problems in dementia.
It was 14 years ago that we decided to write a book on the non-motor problems
of Parkinson’s disease (PD). By then, research and clinical evidence were rapidly
accumulating regarding the high frequency of specific cognitive deficits, affective
disorders, and anxiety in PD. Apathy was also emerging as a prominent comorbid
condition of PD, and the mechanism and treatment of psychotic symptoms were an
area of intense investigation. We now present a book that inverts that focus, that is,
it examines the motor problems in dementias due to different mechanisms.
An increasing number of studies have demonstrated a high frequency of parkin-
sonism and other movement disorders such as myoclonus, paratonia, and dyskinesia
in Alzheimer’s disease (AD). In addition, the introduction of medication to treat the
cognitive impairment as well as novel antipsychotic drugs contributed to the variety
and severity of movement disorders in AD. The association between dementia and
movement disorders is also evident in the high proportion of patients with fronto-
temporal dementia and comorbid parkinsonism and the association between cogni-
tive deficits and a variety of movement disorders such as the “alien hand syndrome”
and “psychomotor” symptoms such as apraxia in corticobasal syndrome.
Cognitive dysfunction and parkinsonism are closely related, and regardless of
which of them is the primary problem, the other is invariably present. For many
years, dementias and parkinsonism have been separately addressed, through differ-
ent specialties, by different researchers, and in different books and journals.
However, emerging concepts on topics such as neurodegeneration with synucle-
inopathies, tauopathies, and amyloid deposit mechanisms have generated a trend to
lump these disorders together.
In his masterpiece The History of Mental Symptoms, German Berrios asks what
he considers the crucial question in the history of PD: why did it take so long for
cognitive and psychiatric symptoms to be considered part and parcel of PD? The
ix
x Preface
answer to this question is that patients did not live long enough to show the non-
motor comorbidities or that, following James Parkinson’s description, neurologists
refused to accept their presence. Perhaps a similar process occurs in dementia, with
most of the focus being given to the cognitive aspects of this disorder, while the
motor aspects are not so well attended. It is interesting that in his seminal paper “On
the relationship between senile cerebral atrophy and aphasia,” Arnold Pick already
described motor problems in patients with dementia. The patient Augustus H had
brisk knee reflexes and a fast clonus, a 52-year-old man developed progressive
weakness of the right extremities and speech disturbance, and the third patient com-
plained of pain in the right leg “gradually losing the use of it.”
This book will mainly focus on extrapyramidal signs and symptoms in the most
common or novel types of dementia and will address the issue of the artificial
boundary between dementia and parkinsonism, the two most common degenerative
disorders.
Recognized specialists in the field of movement disorders provided chapters on
topics generally restricted to dementia experts. The first chapters address important
general aspects on the relationship between motor disorders and dementia, such as
the association between medications and motor problems, and motor disorders
common to many types of dementia, such as gait disorders, falls, and motor mani-
festations of psychiatric complications of dementia. The following chapters provide
an in-depth analysis on the relationship between motor and cognitive symptoms,
addressing their common pathogenesis and specific treatments.
The book was timely written in 1 year, which warrants up-to-date information
and views. We hope we have covered the topic widely enough, so that the book will
appeal to a wide readership, including general practitioners, gerontologists, and
neurologists. We expect this book to become the main reference in the field for
years to come.
Buenos Aires, Argentina Marcelo Merello, MD, PhD

Fremantle, WA, Australia Sergio E. Starkstein, MD, PhD
Contents
1 Neurodegenerative Disorders: Dementia and Parkinsonism,

Lumping Together or Splitting Apart? ................................................. 1
Marcelo Merello and Malco Rossi
2 Gait Disorders in Patients with Cognitive
Impairment or Dementia........................................................................ 17
Moran Dorfman, Anat Mirelman,
Jeffrey M. Hausdorff, and Nir Giladi
3 Falls in Patients with Dementia ............................................................. 45
Lynn Rochester, Sue Lord, Alison J. Yarnall, and David J. Burn
4 Treatment of Parkinsonism in Patients with
Non-Parkinson Dementia ....................................................................... 61
Raja Mehanna and Hubert H. Fernandez
5 Psychiatric Complications of Alzheimer’s Disease Overlapping
with Parkinsonism: Depression, Apathy,
Catatonia, and Psychosis ........................................................................ 73
Sergio E. Starkstein and Jaime Pahissa
6 Drug-Induced Movement Disorders in Elderly Patients ..................... 87
Santiago Perez-Lloret, Jean-Louis Montastruc, and Olivier Rascol
7 Scales for Measuring Parkinsonism in Demented Patients ................. 117
Carmen Rodriguez-Blazquez, Anna Sauerbier, K. Ray Chaudhuri,
and Pablo Martinez-Martin
8 Movement Disorders in Alzheimer’s Disease ....................................... 129
Sergio E. Starkstein and Marcelo Merello
9 Movement Disorders in Frontotemporal Dementia ............................. 141
Emma Devenney and John Hodges
xi
xii Contents
10 Dementia with Lewy Bodies ................................................................... 155

Anne-Catherine Vijverman, Carmela Tartaglia, and Susan Fox
11 Dementia in Parkinson’s Disease and Atypical Parkinsonism ........... 179
Maria Stamelou and Kailash Bhatia
12 Vascular Dementia and Parkinsonism .................................................. 199
Laura Silveira-Moriyama, Egberto R. Barbosa,
Paulo Caramelli, Jan Zijlmans, and Andrew J. Lees
13 Progressive Apraxia of Speech and Primary
Progressive Aphasias............................................................................... 213
Keith A. Josephs and Jennifer L. Whitwell
14 Normal Pressure Hydrocephalus ........................................................... 231
Paolo Missori, Antonio Daniele, and Carlo Colosimo
15 Movement Disorders in Infectious Dementias...................................... 253
Francisco Cardoso and Paulo Caramelli
Index ................................................................................................................. 273
Contributors
Egberto R. Barbosa, MD, PhD Department of Neurology, University of Sao

Paulo School of Medicine, Hospital Das Clinicas, Sao Paulo, SP, Brazil
Kailash Bhatia, FRCP Sobell Department for Motor Neuroscience
and Movement Disorders, UCL, Institute of Neurology, London, UK
David J. Burn, FRCP, MD Campus for Ageing and Vitality, Institute for Ageing
and Health, Newcastle University, Newcastle Upon Tyne, UK
Paulo Caramelli, MD, PhD Department of Internal Medicine,
Faculty of Medicine, The Federal University of Minas Gerais,
Belo Horizonte, MG, Brazil
Francisco Cardoso, MD, PhD Department of Internal Medicine, Faculty of
Medicine, The Federal University of Minas Gerais,
Belo Horizonte, MG, Brazil
K. Ray Chaudhuri, MD, FRCP, Dsi National Parkinson Foundation
Centre of Excellence, King’s College London, London, UK
National Institute for Health Research (NIHR) Mental Health Biomedical
Research Centre and Dementia Unit at South London, London, UK
Department of Neurology, Maudsley NHS Foundation, London, UK
Carlo Colosimo, MD Department of Neurology and Psychiatry,
“Sapeinza” University of Rome, Rome, Italy
Antonio Daniele, MD, PhD Institute of Neurology, Policlinico “A. Gemelli”,
Catholic University of the Sacred Heart, Rome, Italy
Emma Devenney, MB, BCH, BAO, MRCP FRONTIER - Frontotemporal
Dementia Research Group at Neuroscience Research, Australia
Moran Dorfman, MSPT Movement Disorders Unit, Department of Neurology,
Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel
xiii
xiv Contributors
Hubert H. Fernandez, MD Department of Neurology, Cleveland Clinic Lerner

College of Medicine, Cleveland, OH, USA
Susan Fox, MRCP, PhD Movement Disorders (Neurology), Toronto Western
Hospital, Toronto, ON, Canada
Nir Giladi, MD Movement Disorders Unit, Department of Neurology,
Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel
Jeffrey M. Hausdorff, BSE, MSME, PhD Movement Disorders Unit,
Department of Neurology, Tel-Aviv Sourasky Medical Center,
Tel Aviv, Israel
Department of Medicine, Harvard Medical School, Boston, MA, USA
Department of Physical Therapy, Sagol School of Neuroscience, Tel-Aviv
University, Tel-Aviv, Israel
John Hodges, MBBS, MD, FRCP, FMedSci, FRACP Neuroscience Research
Australia, FRONTIER, Sydney, NSW, Australia
Keith A. Josephs, MD, MST, MSc Department of Neurology, Mayo Clinic,
Rochester, MN, USA
Andrew J. Lees, MD, FRCP National Hospital for Neurology and Neurosurgery,
Reta Lila Weston Institute, UCL Institute of Neurology, London, UK
Sue Lord, PhD Institute for Ageing and Health, Clinical Ageing Research Unit,
Campus for Ageing and Vitality, Newcastle University,
Newcastle Upon Tyne, UK
Pablo Martinez-Martin, MD, PhD Research Unit, Alzheimer Center Reina
Sofia Foundation for Networked Biomedical Research on Neurodegenerative
Disease (CIBERNED), CIEN-Foundation, Carlos III Institute of Health,
Madrid, Spain
Raja Mehanna, MD Department of Neurology, University of Texas Health
Science Center in Houston, Houston, TX, USA
Marcelo Merello, MD, PhD Neuroscience Department, Raul Carrea Institute for
Neurological Research (FLENI), Universidad Catolica Argentina, Buenos Aires,
Argentina
Anat Mirelman, PhD Movement Disorders Unit, Department of Neurology,
Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
Paolo Missori, MD Department of Neurology and Psychiatry, Policlinico
“Umberto I,”, “Sapienza” University of Rome, Rome, Italy
Jean-Louis Montastruc, MD, PhD Department of Pharmacology, Toulouse
University Hospital, Toulouse, France
Jose A. Obeso, MD, PhD Department of Neurology & Neurosurgery,
Neurosciences—Movement Disorders Laboratory, Clinica Universidad de
Contributors xv
Navarra; Senior Researcher, Center for Applied Medical Research (CIMA),

University of Navarra, Pamplona, Spain
Jaime Pahissa, MD Department of Psychiatry, CEMIC University, Centro de
Educación Médica e Investigationes, Clínicas “Norberto Quirno”, Buenos Aires,
Argentina
Santiago Perez-Lloret, MD, PhD, CPI Clinical Pharmacology and
Epidemiology Laboratory, Medicine School, Catholic University of Argentina,
Buenos Aires, Argentina
Département de Pharmacologie et Service de Pharmacologie Clinique, Faculté de
Médecine, Centre Midi-Pyrénées de PharmacoVigilance, de Pharmaco épidémi-
ologie et d’Informations sur le Médicament, de l’Université de Toulouse, Centre
Hospitalier Universitaire, Toulouse, France
Olivier Rascol, MD, PhD Department of Pharmacology, Toulouse University
Hospital, Toulouse, France
Lynn Rochester, PhD Institute for Ageing and Health, Clinical Ageing Research
Unit, Campus for Ageing and Vitality, Newcastle University,
Carmen Rodriguez-Blazquez, MSc Department of Applied Epidemiology,
National Centre of Epidemiology and Centre for Networked Biomedical Research
on Neurodegenerative Diseases (CIBERNED), Carlos III Institute of Health,
Madrid, Spain
Malco Rossi, MD Movement Disorders Section, Neuroscience Department,
Raul Carrea Institute for Neurological Research (FLENI), Buenos Aires,
Argentina
Anna Sauerbier National Parkinson Foundation International Centre
of Excellence, King’s College London, London, UK
National Institute for Health Research (NIHR) Mental Health Biomedical
Research Centre and Dementia Unit at South London, London, UK
Department of Neurology, Maudsley NHS Foundation Trust, London, UK
Laura Silveira-Moriyama, MD, PhD National Hospital for Neurology
and Neurosurgery, Reta Lila Weston Institute, UCL Institute of Neurology,
London, UK
Neurology Department, FCM, University of Campinas, UNICAMP,
Hospital Das Clinicas, Campinas, SP, Brazil
Maria Stamelou, MD, PhD Second Department of Neurology, Attiko University
Hospital, Athens, Greece
Sobell Department for Motor Neuroscience and Movement Disorders,
UCL, Institute of Neurology, London, UK
Neurology Clinic, Philipps University Marburg, Marburg, Germany
xvi Contributors
Sergio E. Starkstein, MD, PhD School of Psychiatry and Clinical

Neurosciences, University of Western Australia Fremantle, Fremantle, WA,
Australia
Carmela Tartaglia, MD, FRCPC Memory Clinic (Neurology), Toronto Western
Hospital, Toronto, ON, Canada
Anne-Catherine Vijverman, MD Department of Movement Disorders
(Neurology), Toronto Western Hospital, Toronto, ON, Canada
Jennifer L. Whitwell, PhD Department of Radiology, Mayo Clinic,
Rochester, MN, USA
Alison J. Yarnall, MBBS, MRCP Institute for Ageing and Health, Clinical
Ageing Research Unit, Campus for Ageing and Vitality, Newcastle University,
Jan Zijlmans, MD, PhD Department of Neurology, Amphia Hospital, Breda,
NA, The Netherlands
Chapter 1
Neurodegenerative Disorders: Dementia
and Parkinsonism, Lumping Together
or Splitting Apart?
Marcelo Merello and Malco Rossi
Abstract Neurodegenerative diseases encompass several entities characterized by

variable clinical features. Clinical presentation, anatomical regions affected, neuro-
pathology, or molecular aspects of this group of diseases overlap frequently, render-
ing the “perfect” classification an almost impossible mission in many cases despite
presence of the hallmark molecular findings. In this chapter, we will review the
different classifications of neurodegenerative disorders as well as the artificial
boundaries between movement disorders and dementias.
Keywords Dementia • Parkinsonism • Amyloidopathies • Tauopathies •

Synucleinopathies • FUSpathies • Filament inclusion disorders
Introduction
Neurodegenerative diseases are characterized by death and progressive loss of neu-

rons in distinct areas of the central nervous system. Classification is based on clini-
cal presentation, anatomical regions affected, inclusion bearing cell type, and
conformational protein altered. Clinical features resulting from these mechanisms
reflect which anatomical regions or functional systems are affected by neuronal
damage and include cognitive decline, dementia, alteration in high-order brain func-
tions, movement disorders, or, in the majority of cases, a combination of all of these.
M. Merello, MD, PhD (*)

Neuroscience Department, Raul Carrea Institute for Neurological Research (FLENI),
Universidad Catolica Argentina, Buenos Aires, Argentina
e-mail: [email protected]
M. Rossi, MD
Movement Disorders Section, Neuroscience Department, Raul Carrea Institute for
Neurological Research (FLENI), Buenos Aires, Argentina
M. Merello, S.E. Starkstein (eds.), Movement Disorders in Dementias, 1

DOI 10.1007/978-1-4471-6365-7_1, © Springer-Verlag London 2014
2 M. Merello and M. Rossi
Traditionally, neurodegenerative diseases are categorized according to the spe-

cific clinical features observed and/or distinctive underlying neuropathology
(Graeber et al. 1997; Duckett and Stern 1999). However, heterogeneity between
them is common, and several authors have therefore questioned the validity of this
classification (Armstrong 2008; Armstrong et al. 2005; Feany and Dickson 1996;
Förstl 1999; Hainfellner et al. 1998). Although attempts to overcome these draw-
backs have been made by putting together guidelines after agreements among lead-
ing experts on which represent the most useful clinical and pathological features for
diagnosis (Litvan et al. 1996; Tierney et al. 1988), they are still not enough. The
discovery of aggregates of insoluble and/or misfolded proteins has led to further
molecular classifications, establishing a “hallmark molecular finding.” However,
even this degree of characterization has been unable to rule out overlap or coexis-
tence of clinical and/or neuropathological features of more than one disorder in the
same individual (Armstrong et al. 2005).
The Risk of Classification
In 1942, the great Argentine writer Jorge Luis Borges wrote an essay entitled “El
idioma analítico de John Wilkins” (The Analytical Language of John Wilkins) in
which he laid out the challenges of human attempts to classify the world (Borges
2001). To illustrate his argument, Borges reproduced a classification of animals
purportedly found in “a certain Chinese encyclopedia entitled “Celestial
[Emporium]” of Benevolent Knowledge.” Borges observed that “it is clear that there
is no classification of the Universe not being arbitrary and full of conjectures.” It
may appear odd that Borges should see conjectures in classifications, which are by
definition rather explicit. This is because he considered that a full understanding of
things to be classified and of their mutual relationships is necessary for the classifi-
cation to make sense (Borges 2001).
Over 100 neurodegenerative disorders affect humans, among which many over-
lap either clinically or pathologically, rendering their practical classification most
challenging. The issue is further complicated by the fact that different combinations
of lesions can give rise to different clinical conditions (Luheshi and Dobson 2009;
Burn and Jaros 2001). Furthermore, the same neurodegenerative processes, espe-
cially at the beginning, can affect different areas of the brain, thus varying signifi-
cantly at different stages of the neurodegenerative process.
Classic categorization of neurodegenerative disorders is based on predominant
lesion topography. Thus, they may be grouped, for instance, as cortical, of the basal
ganglia, cerebellum, or as motoneuron disorders. Or diseases may be classified
based on main clinical features into dementias, movement disorders, motoneuron
disease, or ataxias. However, topographical classification of the disorders does not
coincide with expected clinical manifestations. So neurodegeneration predomi-
nantly affecting the cerebral cortex may induce dementia or other non-dementing
conditions, whereas diseases that predominantly involve the basal ganglia in
1 Neurodegenerative Disorders 3
addition to movement disorders also produce dementia in most cases. To make

things ever more confusing, accompanying signs arising from autonomic dysfunc-
tion, pyramidalism, and ocular movements are also often present.
Over the past three decades, significant advances in histological techniques such
as immunohistochemistry and the incorporation of gene array, PCR, Western blot,
and laser-guided micro dissection have supplemented classical histological
approaches. These new techniques have improved both sensitivity and specificity of
neuropathological diagnostic criteria and significantly influenced the classification.
Based on the use of these novel technologies, new perspectives pushed the classifi-
cation to be structured on molecular characteristics and to no longer depend on
neuropathological hallmarks or clinical signs and symptoms. However, using this
more modern approach, neuropathological entities that used to belong to very dis-
tinct clinical or neuropathological categories were lumped together because of a
common molecular defect.
For example, disorders characterized by dementia, chorea, ataxia, or myopathy
such as HD, spinal cerebellar atrophy, and myotonic dystrophy now fall into the
category of the trinucleotide repeat diseases (Cummings and Zoghbi 2000);
Creutzfeldt–Jakob disease and fatal familial insomnia fall into the category of the
prion diseases (Prusiner 1998); PD, diffuse Lewy body dementia, and multiple sys-
tem atrophy fall into the category of the synucleinopathies (Galvin et al. 2001),
whereas diverse disorders such as corticobasal degeneration, progressive supranu-
clear palsy, frontotemporal dementia, motoneuron, and Pick disease fall into the
category of the tauopathies (Goedert 2001).
Models of Neurodegenerative Diseases
The complexity linked to classifying the majority of patients seen in clinical prac-
tice testifies the extent to which the boundaries between different disorders may in
reality be less distinct than previously believed and have inspired some researchers
to suggest that neurodegenerative diseases characterized by abnormal protein
deposits should be viewed as existing along a continuum of symptoms and patholo-
gies, rather than as discrete entities. For instance, Armstrong et al, in an elegant
review (Armstrong 2012), have postulated that different models of neurodegenera-
tive disorders could be argued. They hypothesize that although distinct diseases
may exist (“discrete” model), they may also exhibit overlapping features (“overlap”
model), and the most challenging concept they put forward is that distinct diseases
do not really exist, but form part of a “continuum” in which there is constant varia-
tion in clinical/pathological features from one case to another (“continuum” model).
This last one would infer that many different pathways may exist through which
different individuals ultimately present the same process, abnormal protein deposi-
tion. It is worth noting that the “hallmark molecular findings” themselves are not
necessarily the cause of the underlying disease and clinical symptoms. Instead they
may be a response to the disease processes, although at some stage the “hallmark
molecular finding” may actually begin to contribute to disease progression. A more

detailed look at the pathology associated with diseases present along this spectrum
reveals not only abnormal protein deposits but also widespread evidence of an
underlying chronic inflammatory reaction, characterized by activated microglia and
upregulation of various inflammatory markers.
Clinical Classification
Neurodegenerative diseases are usually classified depending upon the predominat-

ing clinical syndrome. Therefore, they are usually divided into those in which the
main symptom is mental decline, the dementias, those where the main effect causes
movement disorders like parkinsonism, or the ataxias or motoneuron diseases.
When the affected anatomical region is the element taken into consideration, then
they are classified according to topography as cortical, of the basal ganglia, cerebel-
lar, and motoneuron disorders. However, while AD is by far the most frequently
cited cause of dementia affecting cerebral cortex anatomy (Ott et al. 1995), it can be
also observed as a prominent feature of many other diseases affecting the caudate,
the putamen, the substantia nigra, the red nucleus, certain thalamic and brainstem
nuclei, the cerebellum, or even the motoneurons. As is the case of Huntington’s
chorea, a widely known basal disorder in which dementia is a very, if not the most,
common feature (Paulsen 2011), the high prevalence of dementia in Parkinson’s
disease (Dubois et al. 2007), ataxic patients (Braga-Neto et al. 2012; Valis et al.
2011), or even in patients with amyotrophic lateral sclerosis (Goldstein and
Abrahams 2013) is no less frequent.
The opposite situation occurs in dementias with clear cortical involvement such
as presenilin mutation in AD (Niwa et al. 2013), FTD (Espay and Litvan 2011), PPA
(Kremen et al. 2011), Creutzfeldt–Jakob disease (Maltête et al. 2006), or even
argyrophilic grain disease (Uchikado et al. 2004) in which parkinsonism is a promi-
nent feature. Some diseases of the cerebellum can readily be grouped into pure
ataxias; mixed forms where lesions affect several cerebellar and brain structures or
even the spinal cord, as is the case in Friedreich ataxia; or lower and upper motor
neurons, substantia nigra, and peripheral nerve in Machado–Joseph disease
(Koeppen and Mazurkiewicz 2013; Rüb et al. 2008).
Movement disorders are neurologic syndromes in which there is either an excess
of movement or a paucity of voluntary and automatic movements unrelated to weak-
ness or spasticity (Fahn et al. 2011). Excessive movements or hyperkinesias, dyski-
nesias, and abnormal involuntary movements are terms used interchangeably. Paucity
of movement is characterized by decreased amplitude of movement also referred to
as hypokinesia. Slow movement or bradykinesia is a term used interchangeably with
loss of movement or akinesia. The long list of causes of parkinsonian syndromes
including Parkinson’s disease and Parkinson´s plus are the most common and repre-
sentative cause of paucity of movement, while Huntington’s chorea and dystonia are
the most emblematic hyperkinetic disorder syndromes (Fahn et al. 2011) (Table 1.1).
Table 1.1 Classification of movement disorders

Hypokinesias: Akinesia/bradykinesia (parkinsonism), freezing phenomenon, gait apraxia,
hesitant gaits blocking (holding) tics, hypothyroid slowness, cataplexy and drop attacks,
rigidity catatonia, psychomotor depression, and obsessional slowness stiff muscles
Hyperkinesias: Dyskinesias, moving toes and fingers, akathitic movements, myoclonus ataxia/
asynergia/dysmetria, myokymia and synkinesis, athetosis
Myorhythmia, ballism, paroxysmal dyskinesias, chorea, periodic movements in sleep, dystonia,
REM sleep behavior disorder, hemifacial spasm, restless legs
Hyperekplexia, stereotypy, hypnogenic dyskinesias, tics, jumping disorders
Tremor
Fahn et al. (2011)
Table 1.2 Classification of parkinsonian disorders

Primary (idiopathic Parkinson’s disease)
Secondary (infectious, toxins, drugs, tumor, trauma, vascular, metabolic)
Parkinson´s plus syndromes (MSA, PSP, corticobasal degeneration, parkinsonism dementia
complex of Guam)
Parkinsonisms of dementias (DLBD, AD, FTDP-17, CJD)
Heredodegenerative disorders (Wilson, NBIA, Huntington’s, and spinocerebellar-nigral
degenerations SCA 1-2-17, neuroacanthocytosis, DRPLA, neuronal inclusion body disease
Niemann–Pick type C, Gaucher, PLA2G6-associated disorders)
Benign parkinsonism (Dopa-responsive dystonia, SWEDD)
Parkinson´s plus disorders is a term proposed by Stanley Fahn and refers to dis-
orders with features of parkinsonism in addition to other neurologic feature, such as
ophthalmoplegia, ataxia, dysautonomia, amyotrophy, cortical signs, cerebellar
signs, or dementia. This group presents multiple system atrophies (parkinsonian,
cerebellar, and mixed forms), including corticobasal degeneration, PSP, parkinson-
ism, and motor neuron disease. Combination of parkinsonism with dementia such as
in Guamanian complex, Creutzfeldt–Jakob, Alzheimer’s, and Pick, as well as vari-
ous hereditary diseases in which parkinsonism and dementia can be present together,
such as Wilson, NBIA, Huntington’s, and spinocerebellar-nigral degenerations, are
also included in the classification. Other non-degenerative disorders such as normal
pressure hydrocephalus also correspond to this category. Parkinsonism occurring in
dopa-responsive dystonia, also known as benign parkinsonism, which can have its
onset in adults but is also seen in children, completes the group (Table 1.2).
Dementia is a clinical syndrome characterized by acquired loss of cognitive and
emotional abilities, severe enough to interfere with daily functioning and quality of
life. Several dementia classifications have been attempted from the clinical point of
view (Table 1.3). Neuropsychological profiles of dementia reflect the impact of dis-
ease on distinctive neuroanatomic networks associated with complex cognitive
domains. For example, prominent amnesia is associated with medial temporal dys-
function, whereas aphasia is a consequence of left perisylvian dysfunction. The rela-
tionship between clinical symptoms and underlying neuropathology, however, is
less straightforward, as indicated by the multiple neuropathological diagnoses asso-
ciated with the various clinical dementia syndromes (Mesulam 2000). It has been
Table 1.3 Classification of dementia

Dementia of Alzheimer’s type (DAT)
Dementia of frontal lobe type and Pick disorders
Behavioral variant of FTD
Primary progressive aphasia
Semantic dementia
Nonfluent variant of PPA
Logopenic variant of PPA
Dementia with parkinsonism
DLBD
LB variant of AD
Progranulin mutation AD
PD-D
Dementias due to prions
Atypical dementia syndrome: CBD, progressive subcortical gliosis, PSP, Huntington’s disease,
cerebellar degeneration (OPCA, SCA), ALS
Non-degenerative Dementias
Vascular
Nonvascular
long said from both the clinical (Pillon et al. 1993) and etiological perspectives
(Darvesh and Freedman 1996) that dementia can be split into cortical and subcorti-
cal types. The typical clinical findings of cortical dementing processes include
prominent memory lost, dyscalculia, dysphasias, dyspraxias, and agnosias. The dif-
ferentiating features of subcortical dementia were said to be a profound slowing of
cognition, milder memory disturbances, frontal executive dysfunction, and changes
in personality and affect in the absence of aphasias, apraxias, and agnosias
(Cummings 1986). While this has been initially generally accepted, other authors
have highlighted the difficulties with the distinction, arguing that the neuropsycho-
logical profiles of cortical and subcortical cases are not sufficiently dissimilar
(Brown and Marsden 1988). Furthermore, cortical symptomatology can often occur
in the so-called subcortical disease and vice versa (Hughes et al. 1993). Perhaps
constant redefinition and reclassification of the frontotemporal syndromes represent
the best example of overlap and lack of boundaries between cortical and subcortical
motor and cognitive disorders. The psychiatric manifestations of subcortical disease
come primarily in the form of personality changes and affective disorders. Apathy
and irritability are particularly common (Aarsland and Karlsen 1999), and depres-
sion is said to be significantly more common in subcortical disorders such as
Parkinson’s disease than in Alzheimer’s (Aarsland and Karlsen 1999). While amnes-
tic symptoms of dementia have the highest likelihood of being associated with
dementia of AD type (DAT) pathology, early aphasia, progressive visuospatial defi-
cits, and changes in personality are usually seen in primary progressive aphasias,
semantic dementia, or behavioral forms of frontotemporal dementia, which can also
be associated with AD neuropathology (Figs. 1.1 and 1.2). As dementia progresses
from early to late stages, symptom domain boundaries become blurred, and distinc-
tive profiles disappear, with dementia becoming a single terminal clinical entity.
FTD-
AD DLBD
Pick complex
PPA
Nonfluent Semantic Logopenic AD
variant variant variant variant
of dlbd
PAOS
Motor neuron FTD CBS/PSP IPD

disease
Fig. 1.1 Clinical and molecular relationship within the main types of dementia (circles) and
between them and the major movement disorders syndromes (squares). FTP frontotemporal
dementia, AD Alzheimer’s disease, DLBD dementia with Lewy bodies disease, PPA primary pro-
gessive aphasia, PAOS progressive apraxia of speech, CBS vorticobasal syndrome, PSP progres-
sive supranuclear palsy, IPD idiopathic Parkinson’s disease
Cognitive decline affecting multiple domains
With Insidious onset and

progressive course
Without altered consciousness
With functional decline
Without significant depression
Dementia
Early cerebellar/
Mainaly cognitive Early behavioural/ pyramidal signs/
Early Parkinsonism language alterations akinetic mutism/
alteration
seizures
DLBD
PSP FTD
AD CBD CJD
PPA
CJD
Fig. 1.2 Clinical algorithm for dementias

Molecular Classification
Recognition of a common mechanistic theme shared by many neurodegenerative

disorders began to emerge in the last two decades. Many of these disorders are char-
acterized neuropathologically by intracellular and/or extracellular aggregates of
proteinaceous fibrils implicated in progressive brain degeneration. Thus, despite
differences in the molecular composition of these filamentous lesions, growing evi-
dence suggests that similar pathological mechanisms may underlie all these
disorders.
Onset and progression of brain degeneration in neurodegenerative disorders may
be linked to abnormal interactions between brain proteins, leading to their assembly
into filaments, and aggregation of these filaments within brain cells or in the extra-
cellular space. Originally, the majority of neurodegenerative disorders were classi-
fied into two major molecular groups: tauopathies (AD, PiD, argyrophilic grain
disease (Saito et al. 2004; Goedert 2001a, b), PSP, corticobasal degeneration, and
FTDP-17) and the synucleinopathies, (PD, DLB, and multiple system atrophy)
(Goedert 2001a, b). However, a substantial number of cases lack both α-synuclein-
immunoreactive inclusions and tau filaments. Furthermore, presence of amyloid
beyond the accepted limits of normal aging strongly supports the hypothesis of its
role in neurodegeneration. Imbalance between production and clearance, as well as
aggregation of peptides, causes Aβ to accumulate, and this excess may be the initi-
ating factor in Alzheimer’s disease. However, Aβ has also been increasingly found
in PD, DLBD, and other neurodegenerative disorders (Kotzbauer et al. 2012;
Jellinger and Attems 2008) (Table 1.4).
β-Amyloid (Aβ): Amyloidopathies
β-Amyloid derives from the amyloid precursor protein (APP). APP undergoes proteo-
lytic cleavages by β- and γ-secretases to generate β-amyloid (Kayed et al. 2003). Since
secretases are linked to presenilin genes, presenilins are implicated in the proteolytic
Table 1.4 Molecular Amyloidopathies

classification of Tauopathies
neurodegenerative disorders
RNA–DNA binding proteins: TDP-43 and FUSpathies
Neuronal intermediate filament inclusion disorders
Synucleinopathies
Non-Lewy body synucleinopathies
Non-synucleinopathies with Lewy bodies
Polyglutamine disorders
Prion diseases
Neurodegeneration with brain iron accumulation and
neuroferritinopathies
Mixed disorders
cleavage of APP. APP fragments may undergo degradation or oligomerization and

extracellular plaque formation, which is a characteristic feature of the neuropathology
of Alzheimer’s disease (AD). In addition, 1–40 and 1–42, carboxy-terminally trun-
cated Aβ peptides (1–37, 1–38, 1–39) may be found. As there is evidence that Aβ42 is
toxic to cells (Selkoe 2001; Tanzi and Bertram 2005), it has been implicated in AD
pathogenesis (Hardy 2006), known as the AD “amyloid hypothesis.”
Amyloid has also been implicated in the genesis of inherited disorders such as in
British and Danish familiar dementia. Elongated proteolytic processes resulting
from mutation in the ITM2B gene lead to release of amyloidogenic peptides ABRI
(Familiar British dementia) and ADAN (Familiar Danish dementia), which cause
cerebral angiopathy and deposition of extracellular protein aggregates in combina-
tion with neurofibrillar degeneration (Holton et al. 2001, 2002).
Tau: Tauopathies
Tau is a microtubule-associated protein (MAP) that stabilized them and promotes

their assembly. Six different isoforms of tau are expressed in the adult human brain.
Neurofibrillary inclusions of tau protein are present not only in AD accompanying
amyloid pathology but also in a wide range of neurodegenerative disorders. Even
initially they were considered a nonspecific response of neurons to diverse noxa,
discovery of mutations in the tau gene (MAPT) in frontotemporal dementia linked
to chromosome 17 (FTDP-17) (Hutton 2001) highlighted its role in neurodegenera-
tion. As a result, a long list of disorders displaying tau filaments have been grouped
together under the name of tauopathies, which includes Pick disease, corticobasal
degeneration, and progressive supranuclear palsy, among others (Ludolph et al.
2009; Galpern and Lang 2006).
RNA–DNA Binding Proteins: TDP-43 and FUSpathies
The major proteins, but not the only ones, that accumulate in the most common
forms of FTD and ALS are RNA–DNA binding proteins and mutations in the TDP-
43 gene, found in both disorders (Neumann et al. 2006). Another member of the
family, the FUS-TLP, has been found mutated and accumulated in neuronal inclu-
sions in rare forms of FTD and ALS (Mackenzie and Rademakers 2007).
Neuronal Intermediate Filament Inclusion Disorders
Neuronal intermediate filament inclusion disorders (NIFID) is a relatively new term

referring to a heterogenic phenotype, in which patients present a range of symptoms
starting with dementia, progressing to movement disorders and ending in motoneu-

ron disease. The disorder is characterized by neuronal and glial inclusions of FUS,
plus spheroid cytoplasmatic and axonal inclusions conformed by intermediate fila-
ment (IF) (Mackenzie et al. 2010).
α-Synuclein: Synucleinopathies
Since α-synuclein was identified as the major structural component of Lewy bod-
ies, Parkinson’s disease was raised to the level of major class disease.α-Synuclein
is a phosphoprotein. The physiological function of α-synuclein is not known; it is
a lipid-binding protein located in neurons at the synapse level, where it is involved
in vesicle traffic and neurotransmission (Goedert 2001a, b; Abeliovich et al.
2000). Other functions such as chaperone protein, inhibitor of phospholipase D2,
and participation in oxidative stress have also been described. Lewy bodies are
intracytoplasmic inclusions containing α-synuclein aggregations and the hall-
mark pathological signature of Parkinson’s disease and diffuse Lewy body dis-
ease. However, they are also present in 7–37 % of normal aging individuals
(Zaccai et al. 2008) and most notably in cases of Alzheimer’s disease (Hansen
et al. 1990).
Non-Lewy Body α-Synucleinopathies
In certain circumstances, α-synuclein pathological aggregates may not form Lewy

bodies but α-synuclein-immunoreactive oligodendroglial inclusions, known as glial
cytoplasmatic inclusions, as in the case of multiple system atrophy (Papp et al.
1989).
Lewy Bodies in Disorders Other than Synucleinopathies
Aside from being present in normal aging, Lewy bodies have been described in
conditions other than α-synuclein disorders such as AD, PSP, Guam disease, FTD,
and Down syndrome (Ozawa et al. 2004; Uchikado et al. 2006; Dickson et al. 2002;
Jellinger 2008; Yamazaki et al. 2000; Gregory et al. 2009). Less commonly, they
have also been found in Niemann–Pick type C, a sphingolipid storage disorder
which results from autosomal recessive inherited deficiencies of lysosomal and
intracellular lipids, trafficking proteins (Carstea et al. 1997). Acid β-glycosidase-
associated neurodegeneration is an inherited disorder in which an enzyme known
as β-glycosidase loses its capacity to catalyze glucosylceramide breakdown to
ceramide causing Gaucher disease types I, II, and III (Clark et al. 2009; Sidransky
et al. 2009) and PLA2G6-associated disorders. PLA2G6 mutations which encode

phospholipase A2 include a series of disorders from infantile neuroaxonal dystro-
phy to juvenile onset dystonia parkinsonism (Morgan et al. 2006; Paisan-Ruiz et al.
2009).
Polyglutamine Disorders
Huntington’s disease is the pathognomonic disorder in which a genetic mutation

encoding abnormal expansions of preexisting tandem repetition of bases (from trip-
lets to quintuplets) present in different genes leads to molecular changes resulting in
polyglutamine aggregation and further neurodegeneration. Besides HD (Ross and
Tabrizi 2011), abnormal tandem of bases expansions are responsible for Friedreich
ataxia (Patel and Isaya 2001), spinal bulbar atrophy (Katsuno et al. 2012), dentato-
rubropallidoluysian atrophy (Koide et al. 1994), and the full range of spinocerebel-
lar ataxias (SCA) (Durr 2010).
Prion Diseases
Abnormal conformers of normal cellular proteins with increased tendency to aggre-

gate and be transmissible from cell to cell carrying infective properties (Lee et al.
2010) have been named prions and are unequivocally implicated in hereditary and
sporadic neurodegenerative disorders, including Creutzfeldt–Jakob. Genetic predis-
position has been found in a polymorphism of the prion protein gene (PRNP) pres-
ent even in sporadic cases (Mead et al. 2009).
Neurodegeneration with Brain Iron Accumulation
NBIA corresponds to a group of disorders characterized by brain iron accumula-

tion, axonal swelling, and presence of spheroids. NBIA type I is a neurodegenera-
tive disorder characterized by dementia, parkinsonism dystonia, and choreoathetosis
caused by a mutation of the pantothenase kinase gene (PANK2) (Zhou et al. 2001).
Although suggested, it remains to be proven whether cases with brain iron accu-
mulation and neurodegeneration due to mutation of the PANK2 gene are associ-
ated with Lewy body pathology (Gregory et al. 2009). NBIA type II represents a
more heterogeneous group of disorders including infantile neuroaxonal dystrophy,
a condition which produces psychomotor retardation, hypotonia leading to tetra-
paresis, areflexia, cerebellar signs, rigidity, deafness, blindness, and mental dete-
rioration, caused in general by a mutation in the PLA2G6 gene (Khateeb et al.
2006).
Neuroferritinopathies
Recent genetic and molecular data have led to considerable changes in the classifi-
cation and nomenclature of tauopathies (Williams 2006; Hasegawa 2006; van
Slegtenhorst et al. 2000). Original simplistic molecular classifications have become
considerably more complex, mainly as a result of studies performed in FTD group
cases. In light of the described complexity, discrimination between different disease
entities is often only possible after describing the location of “hallmark molecular
inclusions.” These may be in the cytoplasm (neuronal cytoplasmatic inclusions
NCI), in the nuclei (neuronal intranuclear inclusions NII), or in glial cells (glial
inclusions GI). The latter may in turn be glial cytoplasmic inclusions (GCI) or astro-
cytic “plaques” (Neumann et al. 2006).
Conclusion
Neurodegenerative diseases encompass several entities characterized by variable

clinical features. Clinical presentation, anatomical regions affected, neuropathol-
ogy, or molecular aspects of this group of diseases overlap frequently, rendering the
“perfect” classification an almost impossible mission in many cases despite pres-
ence of the hallmark molecular findings. The accepted fact that distinct diseases
exist as unique entities is jeopardized in many cases by the fact that distinct diseases
exist but exhibit overlapping features. The concept that distinct diseases do not exist
and neurodegenerative diseases represent a “continuum” in which there is progres-
sive variation in clinical/pathological features from one case to another, allowing
them to be lumped together, is hard to reconcile with current knowledge, unless
neurodegenerative disease were considered as points of a multidimensional contin-
uum. The fact remains that none of the current classification are free from arbitrary
definitions and all are plagued by conjectures.
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345–9.
Chapter 2
Gait Disorders in Patients with Cognitive
Impairment or Dementia
Moran Dorfman, Anat Mirelman, Jeffrey M. Hausdorff, and Nir Giladi
Abstract Cognitive impairment and dementia are common in aging. In recent

years, there is a growing body of evidence that suggests that gait is reliant on cogni-
tive function and that gait impairments and falls are affected by a wide spectrum of
age-associated changes in cognitive function. Several studies have suggested that
gait abnormalities can already be present in the early stages of cognitive decline,
even before dementia has been diagnosed. In this chapter, we describe the relation-
ship between gait and cognition as a function of the severity of cognitive decline.
We begin with a review of the current understanding of age-associated changes in
both cognition and motor function and the interrelation between these domains in
older adults. We then review reports on gait changes in mild cognitive impairment,
dementia, and Alzheimer’s disease dementia, as well as alterations of motor func-
tion throughout the course of cognitive decline. Finally, we summarize information
on therapeutic interventions designed to improve gait and reduce fall risk based on
the interactions between gait and cognitive function.
M. Dorfman, MSPT • N. Giladi, MD (*)

Movement Disorders Unit, Department of Neurology,
Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
A. Mirelman, PhD
J.M. Hausdorff, BSE, MSME, PhD
Department of Medicine, Harvard Medical School, Boston, MA, USA
Department of Physical Therapy, Sagol School of Neuroscience,
Tel-Aviv University, Tel-Aviv, Israel

18 M. Dorfman et al.
Keywords Gait • Motor • Mild cognitive impairment • Dementia • Alzheimer’s

disease • Aging • Falls
Introduction
Understanding the relationship between age-associated decline in cognitive func-

tion and mobility has been evolving. These common geriatric symptoms have long
been viewed as distinct and separate domains. For example, gait impairments and
fall risk in older adults were typically considered to be unrelated to age-associated
changes in cognitive function, despite the higher risk of falls in people with demen-
tia. There is now evidence to support the notion that the relationship between cogni-
tive function and falls is not one of “all or none” (Montero-Odasso et al. 2012c).
Instead, it appears that gait impairments and falls are both affected by a wide spec-
trum of age-associated changes in cognitive function (Chen et al. 2012; Segev-
Jacubovski et al. 2011). Recent findings suggest that safe ambulation among older
adults is more than a motor process and that it involves cognitive function as well.
As such, it is important to consider gait impairments in the context of cognitive
decline, and vice versa. In this chapter, we describe the relationship between gait
and cognition as a function of the severity of cognitive decline. We first review the
current understanding of age-associated changes in the relationship between cogni-
tion and gait in older adults. We then describe gait changes that occur in mild cogni-
tive impairment as an early precursor of dementia and the alterations occurring with
disease progression among patients with dementia. Finally, we briefly review
emerging brain imaging evidence on the understanding of gait disturbances and
falls among patients with dementia and summarize the growing number of thera-
peutic interventions designed to improve gait and reduce fall risk that have been
based on the interactions between gait and cognitive function.
Age-Associated Changes in Gait
There is no clear definition of “normal aging,” making it a challenge to identify

which consequences of aging should be considered as being abnormal (Elble et al.
1994). Indeed, there is a wide spectrum of functional decline among older adults.
Some abnormalities of posture and movement are more common with advanced
age, but clear cutoffs and thresholds have not been defined, and certainly not at the
individual level. Walking disability increases with age: while gait dysfunction is
uncommon in persons under 65 years of age, the prevalence increases to 14 % in the
next decade and affects almost 50 % of persons over the age of 85 years (Odenheimer
et al. 1994). At least 20 % of noninstitutionalized older adults have some difficulties
in walking or require the assistance of another person or assistive equipment
(Montero-Odasso et al. 2012c; Ostchega et al. 2000). The locomotor capacity of
older people also generally decreases. This deterioration results from multiple
2 Gait Disorders in Patients with Cognitive Impairment or Dementia 19
aspects of functional decline of the nervous and the musculoskeletal systems; how-
ever, the extent to which these can be attributed to normal aging is not clear
(Alexander 1996; Hausdorff 2007).
Many studies have quantitatively examined the kinematics of walking in older
people in order to define normal walking. Most of these studies have found that dur-
ing aging, gait velocity decreases, stride length becomes shorter, the base of support
widens to increase stability, and double-limb support and stride-to-stride variability
increase (Giladi et al. 2005; Maki 1997; Verghese and Xue 2011). The magnitude of
these changes depends, to a large degree, on the inclusion and exclusion criteria
applied. Among older adults with very “successful aging,” these changes in gait
may be small and nonsignificant (Odenheimer et al. 1994), whereas gait dysfunc-
tion can become debilitating in others. Imaging studies have been used to better
understand the origin and impact of clinical changes in gait among older adults. For
example, the volume of white matter hyperintensities (WMH) and/or periventricu-
lar high signals and ventricular volumes have been associated with mobility prob-
lems and falls among older adults (Holtzer et al. 2006; Maki 1997; Odenheimer
et al. 1994; Yogev-Seligmann et al. 2008). The source of these subclinical changes
and the impact of microvascular alterations on gait among older adults remain to be
more fully delineated. Nonetheless, despite the heterogeneity in function and the
existence of a subgroup of individuals among whom gait appears to be no different
from that of younger adults, there is some decline in gait that can generally be
observed in older adults that is partially related to aging.
Gait and Cognition
Gait disorders are common among subjects with cognitive impairments (Chen et al.
2012; Holtzer et al. 2006; Yogev-Seligmann et al. 2008). Gait is a complex task that
requires cognitive input from multiple systems to maintain upright posture, in addi-
tion to the reliance on the motor control system (Hausdorff et al. 2005; Montero-
Odasso et al. 2012c; Woollacott and Shumway-Cook 2002; Yogev-Seligmann et al.
2008). Walking in the real world is not an automatic motor task since it integrates
high-level cognitive functions, such as attention, obstacle negotiation, and set shift-
ing, in order to successfully ambulate in complex environments while carrying out
multiple tasks (Yogev-Seligmann et al. 2008). Given these requirements of every-
day walking, it is not surprising that emerging evidence suggests that early distur-
bances in cognitive abilities are associated with slower gait and gait instability
during both single- and dual-task walking (Montero-Odasso et al. 2009a).
Risk of Falls
Falls are a serious health problem in the elderly population (Ganz et al. 2007). Falls
contribute to functional decline and loss of mobility and independence, and
recurrent falls reflect frailty, immobility, and acute and chronic health impairments.
The impact of falls is a major concern since about one-third of older adults living in
the community over the age of 65 years experience falls every year (Hausdorff et al.
2001; Tinetti 1994), with the figure reaching as high as 50 % among adults over the
age of 85 years (Blake et al. 1988). Cognitive impairment and dementia are known
risk factors for falls (Harlein et al. 2009), and the incidence of falls in older people
with cognitive impairment is approximately three times higher than that of cogni-
tively intact adults, ranging from 1.1 to 6.4 (Asada et al. 1996; de Carle and Kohn
2001; Kallin et al. 2004; Shaw 2007; Tinetti et al. 1988; van Doorn et al. 2003). The
higher risk of falls among people with dementia increases the risk for serious inju-
ries, morbidity, and institutionalization (Kallin et al. 2004; Tinetti 1994; van Dijk
et al. 1993). Furthermore, the population of fallers with cognitive decline is approxi-
mately five times more likely to be admitted to institutional care compared to people
with cognitive problems who do not fall (Morris et al. 1987). Cognitive decline
apparently exacerbates both the risk of falls and the impact of falls on function and
health-related quality of life.
Until recently, falls and dementia had been studied and assessed as separate
geriatric disorders. These two events are now considered as being intertwined,
and so studying their interconnection paves the way to better understanding of
motor–cognitive interactions (Montero-Odasso et al. 2012c; Sheridan and
Hausdorff 2007) (see Fig. 2.1). In general, most falls among older adults occur
during weight shifting while walking particularly while attention is directed to
another task (Nevitt and Cummings 1993). There is interplay between gait vari-
ability, cognition, a particular executive function (EF), attention, and the risk of
falls (Sheridan and Hausdorff 2007). Falls can be described as a complex, multi-
factorial phenomenon which is caused by several risk factors (Ganz et al. 2007).
Eight categories of risk factors were identified in a review by Harlein et al.
(Harlein et al. 2009). According to those authors, the type and severity of demen-
tia, motor impairments, vision impairments, behavioral disturbances, functional
impairments, fall history, neuroleptics, and low bone mineral density play an
important role as factors that can lead to falls among people with cognitive decline.
The association between type of dementia and falls was examined by Ballard
et al. (1999) who noted that people with dementia with Lewy bodies were found
to be more likely to fall and that the incidence of multiple falls was extremely high
in this population (five or more falls in 3 months) (Ballard et al. 1999). Nakamura
et al. assessed the influence of the severity of dementia on falls and found that the
number of fallers was higher in the intermediate stage of the disease compared
with the milder stage (Nakamura et al. 1996). Their findings, however, were not
confirmed by other studies (Asada et al. 1996; Buchner and Larson 1987). The
discrepancy in the findings can be explained by the use of different methods
assessing severity.
Motor impairments, particularly gait disturbances, are considered one of the
most consistent predictor of falls among older adults with cognitive decline
(Ganz et al. 2007). Impaired gait, reduced muscular strength, and impaired bal-
ance (Harlein et al. 2009) as well as impairments in activity level and mobility
Slow gait velocity

Instability Falls – fractures
MCI
Cognitive impairment Dementia
b
Slow gait velocity
Cognitive impairment MCI

Executive function-working Dementia
memory
Fig. 2.1 Parallel decline in gait and cognitive function with aging. (a) Traditional view. Gait per-
formance and cognitive function deteriorate with aging, yielding two geriatric entities: falls and
dementia. (b) Alternative view. Cognition predicts mobility decline and falls, and mobility decline
and slow gait predict cognitive deterioration. These phenomena occur concurrently. MCI mild
cognitive impairment (Reprinted with permission from Journal of the American Geriatrics Society
(Montero-Odasso et al. 2012c))
measures (Suttanon et al. 2013) contribute to fall risk in this population. Other
measures of disability, such as peripheral neuropathy, musculoskeletal prob-
lems, and impaired tandem gait as a marker for ataxia, have also been shown to
increase the risk of falls in patients with Alzheimer’s disease (AD) (Buchner and
Larson 1987). In a prospective study on 135 Japanese older adults (Suzuki et al.
2012), Suzuki et al. proposed a model of 11 fall-related behaviors that may be
effective indicators to predict falls. The indicators consisted of intrinsic motor
and behavioral aspects, such as being agitated and wandering, inability to main-
tain seated balance in a wheelchair, and impairments in judgment, such as imme-
diate desire to urinate or defecate. Interestingly, according to this model,
behaviors such as delirium, awareness of self, symptoms of Parkinson’s disease,
and wandering were not related to falls (Suzuki et al. 2012). In addition to intrin-
sic factors, psychotropic medications were found to also increase the risk of falls
by causing sedation and postural hypotension (Ensrud et al. 2002; Husted et al.
2000; Thapa et al. 1995). These reports suggest that falls and risk of falls in older
adults and specifically those with cognitive deficits or dementia are multifacto-
rial in nature.
Gait Variability and Risk of Falls
Gait variability is a measure of gait consistency and reflects the stride-to-stride fluc-
tuations in walking. Gait variability offers a complementary way of quantifying
locomotion and its changes with aging and disease, and it is considered a reliable
measure of fall risk as well (Hausdorff 2005). The variability of several spatiotem-
poral gait parameters has been widely studied, among them stride time, stance time,
stride length, and step width (Brach et al. 2005, 2008; Richardson et al. 2004).
Stride time variability reflects one of the final pathways of the outcomes that the
central nervous system regulates (Hausdorff 2005). The general assumption is that
there is an inverse association between stride time variability and gait stability
(Montero-Odasso et al. 2012c). Gait variability tends to be higher in people with
AD compared to age-matched controls, and it has been associated with a higher risk
of falls among these individuals (Nakamura et al. 1996; Visser 1983). Cognitive
deterioration, especially EF, is associated with increased gait variability and thus
independently associated with future falls (Beauchet et al. 2008; Buracchio et al.
2011; Chen et al. 2012; Herman et al. 2010; Yogev-Seligmann et al. 2008).
Dual Task
Dual-task paradigms are used by clinicians to assess cognitive involvement during

gait in older adults by measuring the interaction between cognition and mobility
(Hausdorff et al. 2008; Yogev-Seligmann et al. 2008). Assessment of dual-task abil-
ities may provide important information on gait, such as its automaticity and the risk
for falls that might not be apparent during a routine examination. The use of a dual-
task paradigm is a sensitive method to identify gait problems when cognitive reserve
is limited (Beauchet et al. 2009). Gait changes while performing a dual task were
found to be significantly associated with an increased fall risk in older adults
(Beauchet et al. 2009; Herman et al. 2010; Montero-Odasso et al. 2012c; Segev-
Jacubovski et al. 2011; Springer et al. 2006). Dual-task-related gait changes partly
depend on the capacity to allocate attention between two tasks performed simulta-
neously and are mainly related to executive dysfunction. EF refers to a variety of
higher cognitive processes that modulate and use information from the posterior
cortical sensory systems to produce behavior (Perry and Hodges 1999). Deficits in
EF probably reduce the ability to recruit compensatory mechanisms to counter age-
associated changes in gait and balance and thus increase the risk of falls (Yogev-
Seligmann et al. 2008). A systematic review and meta-analysis of 27 prospective
cohort studies revealed an association between cognition and serious fall-related
injury. Montero-Odasso et al. reported that dual-task load increased gait variability
in people with mild cognitive impairment (MCI) compared with healthy controls
(Montero-Odasso et al. 2012b). Individuals with AD who have greater deterioration
in EF compared to healthy controls have greater dual-task cost than cognitively
normal adults (Sheridan et al. 2003). The difficulty in the performance of dual task-
ing may represent impaired brain capacity and difficulty in sharing cognitive
resources between walking and cognitive tasks. Several studies showed that sub-
jects with dementia exhibited greater gait changes compared to normal age-matched
controls during the execution of dual tasks (Allali et al. 2008; Camicioli et al. 1997a,
b; Woollacott and Shumway-Cook 2002), particularly in stride time and stride-to-
stride variability. Interestingly, the magnitude of the effect of the secondary task on
gait stability is reportedly in direct relationship with the complexity of the given
dual task (Montero-Odasso et al. 2012b) and to the individual’s cognitive capacity,
with the greatest deterioration of gait performance observed in patients with cogni-
tive impairments (Muir et al. 2012). These findings may help to explain the greater
risk of falls and injuries among older adults with cognitive impairment or
dementia.
Gait Changes in Mild Cognitive Impairment (MCI)
MCI is defined as a transition state between normal cognition and dementia in older
adults (Petersen 2007). It has been recently established that cognitive decline is
accompanied by early motoric decline, manifesting either as two separate biological
processes or as a cascading intertwined process (Aggarwal et al. 2006; Boyle et al.
2005, 2007; Kluger et al. 1999; Louis et al. 2005; Verghese et al. 2002, 2007).
Table 2.1 summarizes some of the key findings on gait changes in MCI.
Older people are often defined as having MCI based on impairments in memory
(amnestic) or non-memory (non-amnestic) domains (Moretti et al. 2013). Both
MCI subtypes have poorer performance on most gait variables, such as gait veloc-
ity, stride length, gait variability, cadence, swing time, and double support time,
than age-matched healthy controls (Verghese et al. 2008). Conversely, the two
MCI subtypes differ in certain gait domains. Subjects with amnestic MCI have
poorer swing time, stride time variability, and stride length variability than those
with non-amnestic MCI, suggesting that individuals with amnestic MCI tend to
have more variability and a decreased rhythmical pattern of gait and control than
individuals with non-amnestic MCI (Verghese et al. 2008). Serious gait alterations,
such as hemiparetic gait and frontal or parkinsonian gait, are also more frequent in
amnestic MCI than non-amnestic MCI (Verghese et al. 2008). MCI patients with
two or more vascular factors were shown to have greater frontal–subcortical dys-
function (Montero-Odasso et al. 2012a). An interaction was found between a high
vascular burden (two or more vascular factors) and the triad of executive dysfunc-
tion, gait disorders, and depressive symptoms among MCI patients (Montero-
Odasso et al. 2012a). A magnetic resonance spectroscopy and volumetric imaging
study exhibited an association between lower metabolite ratios and volume of the
primary motor cortex and poor gait performance in both single- and dual-task con-
ditions in mild cognitive impairment. These findings point to a possible involve-
ment of decreased neuronal function in the primary motor cortex causing gait
disorders (Annweiler et al. 2013), although other pathways are also likely to be
involved.
Table 2.1 Gait and falls in mild cognitive impairment (MCI)
24
Reference Participants Outcome measures Summary of findings

Cross-sectional studies
Louis et al. 2,230 participants (mean age Neurologic assessment, including a Mild parkinsonian signs, especially rigidity, are associated with
(2005) 77.2 ± 6.6 years): 608 participants with modified motor portion of the amnestic MCI
MCI including 255 participants with Unified Parkinson’s Disease Amnestic MCI vs no MCI was 51 % higher in participants with
amnestic MCI (mean age Rating Scale mild Parkinson’s signs compared to those with no mild
78.1 ± 7.0 years) and 353 with Parkinson’s signs
non-amnestic MCI (mean age
77.1 ± 6.6 years) and 1,622 participants
cognitively intact
Boyle et al. 598 participants cognitively intact (mean Clinical evaluations, including Parkinsonism signs, especially gait disturbance, bradykinesia,
(2005) age 79.6 ± 6.8 years) and 237 assessments of parkinsonian signs and rigidity, were more common in MCI subjects compared
participants with MCI (mean age and cognitive function to cognitively intact subjects
82.8 ± 6.9 years) Lower levels of cognitive function, particularly in perceptual
speed, were associated with higher levels of parkinsonism
among individuals with MCI
Participants with non-amnestic MCI showed more gait
disturbances compared to participants with amnestic MCI
Verghese et al. 295 participants cognitively intact (mean Clinical and quantitative gait Neurologically impaired gaits were more common in amnestic
(2008) age 79.3 ± 4.7 years), 54 participants performance MCI than in non-amnestic MCI and controls. Quantitative
with amnestic MCI (mean age gait in multiple parameters was worse in both MCI types
82.6 ± 5.7 years), and 62 participants than in controls. Factor analysis revealed three independent
with non-amnestic MCI (mean age factors representing pace, rhythm, and variability. Subjects
81.8 ± 6.2 years) with amnestic MCI had worse rhythm and variability scores
than those with non-amnestic MCI and controls. Subjects
with non-amnestic MCI had worse performance in the pace
domain than the other two groups. Subjects with MCI and
gait abnormalities had higher disability scores than subjects
with MCI without gait abnormalities
M. Dorfman et al.
2
Muir et al. 22 participants cognitively intact (mean Evaluation of gait performance while Gait velocity and stride time variability were not significantly
(2012) age 71.0 ± 5.0 years), 29 participants performing single and dual tasks under the single-task condition
with MCI (mean age 73.6 ± 6.2 years), In contrast, gait velocity decreased and strides time and stride
and 23 participants with AD (mean age time variability increased under the dual-task condition in
77.5 ± 5.0 years) people with MCI and AD
The greatest deterioration of gait performance occurred under
complex motor task tests
Montero- 35 participants with MCI (mean age Assessment to determine whether Participants with two or more vascular factors had greater
Odasso 75.5 ± 1.1 years) community-dwelling older adults frontal–subcortical dysfunction
et al. with MCI and a high vascular There was an interaction between a high vascular burden, two or
(2012a) burden were more likely to exhibit more vascular factors, and the three components of the triad
the frontal–subcortical triad of The number of vascular factors was directly associated with the
executive dysfunction, gait number of frontal–subcortical dysfunctions
disorders, and depressive
The vascular burden was associated with the number of frontal–
symptoms than those with a low
subcortical dysfunctions
vascular burden
Montero- 25 participants cognitively intact (mean Gait assessment under single (usual There was a significant difference within and between groups of
Odasso age 71.5 ± 4.1 years) and 53 partici- walking) and dual tasking increasing gait variability as dual-task complexity increased
et al. pants with MCI (mean age (naming animals and subtracting
(2012b, c) 75.1 ± 6.3 years) serial 7 s) Gait velocity decreased within groups as dual-task complexity
increased
Annweiler 20 participants with MCI (mean age Gait velocity and stride time The neurochemistry and volume of the primary motor cortex
Gait Disorders in Patients with Cognitive Impairment or Dementia
et al. 76 ± 11 years) variability while performing were associated with gait performance while carrying out
(2013) single and dual tasking single and dual tasking. Cortical volume correlated with
Ratios of N-acetylaspartate to creatine faster gait velocity during single (P = 0.029) and dual tasking
and choline to creatine and cortical (P = 0.037) and with decreased stride time variability during
volume were calculated in the single tasking
primary motor cortex
(continued)
25
Table 2.1 (continued)
26
Reference Participants Outcome measures Summary of findings

Prospective studies
Asada et al. 86 community-dwelling elderly with Fall-related injury by self-report Significant factors associated with fall-related injury were falls in
(1996) dementia (mean age 77.5 ± 8.1 years) the past (OR 3.6; 95 % CI 1.3–9.9), better physical function
and 98 community-dwelling elderly (OR 1.04; 95 % CI 1.00–1.08), and Assessment of Basic
without dementia (mean age Care for the Demented (ABCD) scale (OR 0.7; 95 % CI
73.7 ± 7.3 years) (1-year follow-up) 0.6–0.8)
Nakamura 97 participants with AD (2-year Association of fall-related injuries Gait speed decreased as the illness progressed, stride length
et al. follow-up) and gait function in relation to shortened, grip strength (as an index of muscular strength)
(1996) severity of dementia weakened, and stride length variability increased. Only stride
length variability was a significant predictor of fall-related
injuries
The number of fallers was higher in the medium stage of the
disease compared with the milder stage
Ballard et al. 30 participants with Lewy bodies dementia Falls according to definition of the Significant factors associated with fall-related injury were falls in
(1999) (mean age 76 years) and 35 partici- Kellogg International Work the past (OR 16.0; 95 % CI 4.4–58.0), dementia with Lewy
pants with Alzheimer’s disease (mean Group bodies (OR 3.8; 95 % CI 1.3–10.8), and parkinsonism
age 80 years) (3-month follow-up) (P = 0.003)
Aggarwal et al. 558 participants cognitively intact (mean Motor assessment using perfor- At baseline, participants with MCI had impaired motor function
(2006) age 74.6 ± 6.7 years), 198 participants mance-based measures of upper vs cognitively intact participants and superior motor function
with MCI (mean age 78.7 ± 7.0 years), and lower extremity function and vs those with dementia
and 60 participants with AD (mean age a modified version of the motor
Baseline levels of lower extremity motor performance,
81.9 ± 6.7 years) (longitudinal, yearly section of the Unified
parkinsonian gait, and bradykinesia in MCI participants were
repeat tests up to 10 years) Parkinson’s Disease Rating Scale
inversely related to risk of AD
A MEDLINE literature search was conducted using the terms “gait,” “gait disorder,” “gait disorders,” “falls,” “walking,” “Alzheimer’s disease,” “dementia,” or “mild
cognitive impairment” to identify potential papers. After review of the abstracts and cross-references, the relevant papers were studied and categorized into the entries
shown in the tables. A formal meta-analysis process was not employed
M. Dorfman et al.
AD Alzheimer-type dementia
Gait Changes as an Early Indicator of Dementia
The prevalence of dementia-associated gait disturbances depends on the type of demen-

tia and the severity of cognitive impairment. Gait disturbances in vascular dementia
(VaD) are more common in the early stages of the disease, while AD patients usually
do not begin to demonstrate gait changes until later stages of the disease (Verghese
et al. 2002). Several studies have shown that slow gait speed predicts cognitive decline
(Camicioli et al. 1998; Inzitari et al. 2007; Taniguchi et al. 2012) and dementia
(Verghese et al. 2002, 2013; Waite et al. 2005). A longitudinal cohort study found sig-
nificant differences in gait speed and finger tapping speed between people who devel-
oped MCI and those who remained cognitively intact (Buracchio et al. 2010). In
addition, a change-point analysis for MCI converters was used in an effort to determine
the approximate time at which decline in motor function developed (Buracchio et al.
2010). The findings showed that a decrease in gait speed accelerated by 0.02 m/s per
year in subjects with MCI, that this change began 12.1 years prior to the onset of MCI,
and that it appeared earlier in men than women (Buracchio et al. 2010). Alternatively,
it has also been hypothesized that cognitive changes precede or occur concomitantly
with slowing gait because gait requires intact, complex, and integrated cognitive pro-
cesses (Atkinson et al. 2010; Heuninckx et al. 2005; Njegovan et al. 2001; Soumare
et al. 2009; Tabbarah et al. 2002; Watson and Leverenz 2010). The Sydney Older
Persons Study examined 6-year outcomes of 630 community-dwelling participants
aged 75 years or more at recruitment. The people with cognitive impairment in combi-
nation with gait and motor slowing were the most likely to deteriorate into dementia
over the 6-year study period and most likely to die sooner (Waite et al. 2005).
Baseline gait status was found to influence the cumulative risk to develop any
dementia and the cumulative risk to develop VaD, but not the cumulative risk to
develop Alzheimer’s disease (Aggarwal et al. 2006; Boyle et al. 2005, 2007; Kluger
et al. 1999; Louis et al. 2005; Verghese et al. 2002, 2007). Executive dysfunction
may impair gait, and gait impairments reduce the capacity to walk (Della et al.
2004). In an interesting prospective study of 422 community-residing older adults,
subjects with neurologic gait abnormalities at baseline had a greater risk of develop-
ing dementia. These subjects had an increased risk of non-AD, but not of AD. Of
non-Alzheimer’s dementias, abnormal gait, such as unsteady gait, frontal gait, and
hemiparetic gait, predicted the development of VaD. The predictive capability of
early gait abnormalities in elderly people without dementia (Verghese et al. 2002)
suggests that gait abnormalities may be considered as biomarkers for the future
development of dementia, possibly reflecting an early preclinical underlying cere-
brovascular and/or neurodegenerative disease (see Fig. 2.2).
Gait Changes in Dementia
Table 2.2 summarizes some of the key findings on gait changes in dementia. The
prevalence of vascular dementia and other non-AD is 30–50 % of all dementias in
older adults (Chui et al. 2000; Roman 2004; Verghese et al. 2002). Gait disorders
Fig. 2.2 Kaplan–Meier a

curves for the cumulative risk 1.0
Proportion surviving free

of (a) any dementia, (b)
vascular dementia, and (c) 0.8
Alzheimer’s disease dementia Normal gait (n = 337)
of dementia
according to gait status at 0.6
enrollment. Dotted lines
represent 95 % confidence 0.4
intervals (From New England
Journal of Medicine, 0.2
Abnormal gait (n = 85)
Verghese et al. (2002).
Copyright © 2002 0.0
Massachusetts Medical 0 5 10 15 20
Society, Reprinted with Years of follow-up
permission from
Massachusetts Medical b
Society) 1.0 Normal gait (n = 337)
of vascular dementia
0.8
0.6
0.4 Abnormal gait (n = 85)
0.2
0.0
0 5 10 15 20
Years of follow-up
c
1.0
of alzheimer’s disease
Normal gait (n = 337)

0.8
0.6
0.4 Abnormal gait (n = 85)
0.2
0.0
0 5 10 15 20
Years of follow-up
occur late in the progression of Alzheimer’s disease, while they present earlier or
even precede vascular dementia (McKhann et al. 1984; Roman et al. 1993). Patients
with AD present with a decrease in gait velocity and stride length as well as an
increase in double support and stride length variability than healthy older adults
(Alexander et al. 1995; Nakamura et al. 1996; Tanaka et al. 1995; Visser 1983).
These changes could be considered as reflecting a more exaggerated impact of
“aging.” These gait features decline further as the disease continues to progress (van
Iersel et al. 2004). Furthermore, individuals with VaD exhibit even slower walking
2
Table 2.2 Gait and falls in dementia

Reference Study design Participants Outcome measures Summary of findings
Studies reporting on gait changes as an early indicator of cognitive decline
Verghese et al. Prospective cohort with 422 subjects without dementia at Association between Subjects with neurologic gait abnormalities had a
(2002) 6.6 years of baseline: 337 subjects with neurologic gait status at greater risk of developing dementia. These
follow-up normal gait (mean age baseline and the subjects had an increased risk of non-AD but
78.93 ± 3.03 years) and 85 development of dementia not of AD
subjects with abnormal gait Abnormal gait predicted the development of VaD in
(mean age 79.97 ± 3.11 years) non-AD. Among the types of abnormal gait,
unsteady gait, frontal gait, and hemiparetic gait
predicted VaD
Waite et al. (2005) Prospective 6-year 630 community-dwelling Motor and cognitive Participants with cognitive impairment in
study participants aged ≥75 years at assessment combination with gait and motor slowing were
recruitment the most likely to experience dementia over the
6-year study period and also the most likely to
die
Buracchio et al. Prospective cohort 204 participants cognitively intact Annual medical histories, Gait speed predicts MCI 12.1 years in advance
(2010) study with a at baseline: 109 remained neurologic examinations, An acceleration of gait speed decline occurred
20-year follow-up cognitively intact (mean age and neuropsychological earlier in men than women
79 ± 8.85 years) and 95 testing For finger tapping speed, the change point occurred
converted to MCI (mean age after the onset of MCI
83.5 ± 7.0 years)
Gait changes in dementia

Visser et al. (1983) Cross-sectional 11 AD patients (mean age Gait and balance evaluation AD patients had significantly shorter step length,
78.8 years) and 11 matched lower gait speed, lower stepping frequency,
controls (mean age 78.3 years) greater step-to-step variability, greater double
support ratio, and greater sway path compared
to the control group
(continued)
29
30
Reference Study design Participants Outcome measures Summary of findings

Alexander et al. Cross-sectional 17 patients with probable AD and Participants walked 6 m at a AD patients had decrease in gait speed compared to
(1995) 39 healthy older adults comfortable speed the controls
registration with LEDs While clearing obstacles, the AD patients exhibited
and cameras slow crossing speed and landed closer to the
obstacle. The percent of trials in which a subject
made contact with an obstacle was significantly
higher in AD patients
Tanaka et al. Cross-sectional 15 participants with AD, 15 Participants walked 10 m at AD patients showed significantly slower velocity
(1995) participants with VaD, and 15 preferred speed and shorter step length than healthy controls,
controls and VaD patients exhibited a reduction on these
two variables compared to AD patients
Nakamura et al. Prospective cohort 97 patients with AD Participants walked 10 m The number of fallers was significantly higher in
(1996) study with a 2-year three times at preferred moderate-stage AD patients than in the
follow-up speed mild-stage AD patients
Walking speed and stride length were significantly
lower and the stride length variability was
significantly higher in the moderate-stage AD
patients compared to the mild-stage AD patients
M. Dorfman et al.
2
Nakamura et al. Cross-sectional 45 AD patients and 15 control Gait and posture evaluation Mild-stage AD participants increased postural sway
(1997) subjects and examination of rCBF associated with a reduced mean value of rCBF
in different clinical stages in the cortex
Reduced mean rCBF values in the cortex and in the
frontal lobe of moderate-stage AD participants
were associated with increased postural sway
and stride length variability and with decreased
stride length
Reduced rCBF in the basal ganglia and in the
frontal lobe was also associated with increased
postural sway, double support time, and stride
length variability and with decreased walking
speed and stride length in severe-stage
participants
Van Iersel et al. Cross-sectional 63 participants with dementia Participants walked twice at After adjustment for parkinsonism and walking
(2006) (mean age 79.8 ± 7.4 years) preferred speed and twice aids, participants with dementia walked faster
and 62 participants without while counting than participants without dementia
dementia (mean age backwards (dual task)
74.7 ± 6.5 years)
AD Alzheimer-type dementia, VaD vascular dementia, rCBF regional cerebral blood flow
31
velocities compared to patients with AD (van Iersel et al. 2004). Another common
gait feature in people with dementia is a relatively shorter step length, which cor-
relates to decreased gait velocity and disease progression (Alexander et al. 1995;
Nakamura et al. 1997; Tanaka et al. 1995; Visser 1983). Patients with AD exhibit
significantly slower gait velocity and shorter step length compared to healthy con-
trols, and patients with VaD exhibit an even greater reduction in gait speed and
stride length relative to patients with AD (Tanaka et al. 1995). The short step length
and decreased velocity also contribute to an increase in double support time and
increase in stride length variability which, in turn, can increase unsteadiness and the
risk of falls (Alexander et al. 1995; van Iersel et al. 2004).
The authors of a prospective study of the relationship between falls and stride
length variability in 96 Japanese patients with AD observed a significant increase in
fall incidence among moderate-stage AD patients compared to mild-stage AD
patients, as well as a significant decrease in gait parameters, such as gait speed and
stride length (Nakamura et al. 1996). In addition, stride length variability was sig-
nificantly higher (worse) in patients with more severe AD than in patients with mild
AD. Furthermore, there was a significant difference only in stride length variability
when gait measures of fallers and non-fallers were compared according to the sever-
ity of dementia (Nakamura et al. 1996). The results of that study highlight the
important relationship between specific aspects of gait and falls in patients with
dementia. In contrast to those findings, however, only van Iersel et al.’s study dem-
onstrated that patients with dementia walked faster than patients without dementia,
and those authors considered that frontal lobe disinhibition and lack of insight might
be responsible for this phenomenon (van Iersel et al. 2006).
“Cautious gait” is characterized by a decrease in gait velocity, step length, and
static and dynamic balance, a widened base of support, hesitation and freezing, and
a reduction in postural responses (Scherder et al. 2007). Cautious gait is likely to
appear in the early stages of AD (O’Keeffe and Lavan 1996; Prehogan and Cohen
2004), while a “frontal gait disorder” is more common in more advanced stages of
AD and it is characterized by pseudoparkinsonian symptoms, such as shuffling, and
start and turn hesitation (O’Keeffe and Lavan 1996). The number of patients exhib-
iting parkinsonian symptoms increases during the course of evolving dementia.
These symptoms reflect extrapyramidal signs, such as bradykinesia, cogwheel
rigidity, rest tremor, and parkinsonian gait (Burns et al. 2005). Burns et al. suggest
that extrapyramidal signs are related to basal ganglia pathologies that may account
for the increasing prevalence of extrapyramidal signs as AD progresses (Burns et al.
2005).
Gait disorders in AD could be explained by a high burden of age-related subcor-
tical hyperintensities on the frontal–subcortical circuits together with hippocampal
degeneration (Annweiler et al. 2013). Increasing lines of evidence from clinical
practice, epidemiological studies, and neuroimaging studies show that the vascular
burden plays a key role in the onset and progression of AD (van Norden et al. 2012).
Therefore, it is not surprising that the vascular component of AD appears to be
involved in gait disorders among patients with AD. Gait velocity, stride length, and
step width are the gait parameters most commonly affected in the presence of WMH
(Annweiler et al. 2012). In their review, Annweiler et al. (2012) suggested that
quantitative parameters of gait, such as slower gait velocity and shorter stride length
in AD-related gait disorders, are associated with WMH specifically in the frontal
area and the basal ganglia, which are both part of the frontal–subcortical circuits.
These findings could also account for the correlation between the lower hippocam-
pal volume and function and qualitative gait disorders, such as higher stride length
variability. Interestingly, the nigrostriatal dopamine system was found to remain
unaffected. Zimmerman et al. reported that higher stride length variability in AD
was associated with lower metabolism in the hippocampal cortex (Zimmerman
et al. 2009) which has been suggested as the first cortical region damaged in AD
(van Norden et al. 2012).
Interventions to Improve Gait in Dementia
For many years, dementia was not treated due to the notion that further deterioration
was unavoidable once it had been diagnosed. In contrast to normal aging, only a
limited number of studies have examined therapeutic methods to enhance gait and
motor performance in patients with dementia. These few studies generally target
cognition and behavior. It has been reported that improvement in cognition, particu-
larly EF, may influence gait (Tanaka et al. 1995; Yogev-Seligmann et al. 2008), but
only a few studies have directly assessed the effect of interventions on gait, balance,
or falls in dementia. Table 2.3 summarizes interventions aimed at enhancing motor
performance in dementia. These interventions can be divided into non-pharmacologic
and pharmacologic types. The former includes cognitive training (Schwenk et al.
2010) which is based on the notion that dual-task deficits have been linked to func-
tional decline and falls (Camicioli et al. 1997a; Yogev-Seligmann et al. 2008).
Studies among patients with dementia have shown that music therapy may improve
behavioral and psychological symptoms as well as cognitive functions and that it
may also have a potential positive cardiovascular effect (Raglio et al. 2012).
Unfortunately, only one study focused on the benefit of music therapy on motor
performances (Clair and O’Konski 2006). There is some evidence that physical
activity delays the onset of dementia in healthy older adults and slows down cogni-
tive decline. A physical exercise program appears to be a promising non-
pharmacologic strategy for slowing down cognitive decline (Balsamo et al. 2013).
In addition to having a positive influence on cognition, several studies demonstrated
that intensive dementia-specific motor training also increased the level of physical
activity in this population (Hageman and Thomas 2002; Hauer et al. 2012; Rolland
et al. 2007; Schwenk et al. 2010; Toulotte et al. 2003; Venturelli et al. 2011;
Zieschang et al. 2013), with evidence of retention of gains even at 9 months after the
end of training (Zieschang et al. 2013).
Pharmacologic interventions to improve cognition, particularly EF, have also
been shown to influence motor abilities and gait performance (Auriel et al. 2006;
Ben-Itzhak et al. 2008). Initial findings in older adults suggested that
Table 2.3 Interventions for improving gait in dementia
34
Duration of
Reference Study design Participants Type of intervention intervention Outcome measures Summary of findings
Non-pharmacologic treatment of gait disturbances in patients with dementia or cognitive decline
Hageman and Pre–posttest 26 elderly demented Moderate physical 2–3 times/week Comfortable and Improvement was observed on all
Thomas design patients (mean age activity, progressive for 6 weeks fast gait gait measures, but the only
(2002) 79.9 ± 5.5 years) resistance, and lower velocity over a significant change was in fast
extremity exercise 6-m distance gait time
using Thera-Band and the TUG
Toulotte et al. RCT 20 elderly demented The intervention group Once/week for Get up and go test, Gait speed, flexibility, and static
(2003) patients with a history received physical 45 min, sit on chair and balance improved. The
of falling (mean age activity training: 16 weeks reach test, 10-m intervention group did not fall
81.4 ± 4.7 years) strength exercise, walk test, and while the control subjects fell 6
proprioception, static posturography times during the 16 weeks. The
and dynamic balance, intervention group started to
and flexibility. No fall again after the end of
exercise for controls training
Clair et al. Pre–posttest 28 patients with advanced Comparison of gait 16 weeks Speed, cadence, No significant differences in gait
(2006) design dementia parameters in three and stride were observed, but caregiver
conditions of music length burden apparently benefited
therapy from the use of acoustic
stimuli
Rolland et al. RCT Intervention group of 67 The intervention group 1 h twice weekly Katz ADL score, Improvement in the intervention
(2007) patients with AD had a program of during ADL score group was observed on the
(mean age combined walking, 12 months measures of 6WTt, but there was no effect
82.8 ± 7.8 years) and exercise, muscle physical on cognitive responses
control group of 67 strength, balance, and performance,
patients with AD flexibility tasks. The nutritional
(mean age control group received status,
83.1 ± 7.0 years) routine medical care behavioral
disturbance, and
depression
M. Dorfman et al.
2
Schwenk et al. RCT Intervention group of 20 Intervention subjects 2 h twice weekly, Improvement in Specific training improved
(2010) patients with mild to received cognitive 12 weeks dual-task performance on a challenging
moderate dementia training of progres- performance dual-task condition (e.g.,
(mean age sively dual-task compared to serial three subtractions while
80.4 ± 7.1 years) and training. Controls baseline single walking), but not under less
control group of 29 received low-intensity tasks challenging dual-task
patients with mild to exercise conditions
moderate dementia
(mean age
82.3 ± 7.9 years)
Venturelli et al. RCT Intervention group of 11 The intervention group Minimum 30 A 6WT, the Barthel Improvement in the intervention
(2011) patients (mean age performed simple min of index of ADL, group was observed on the
83 ± 6 years) and aerobic activities. The moderate and MMSE 6WT and ADLs. Both groups
control group of 10 control group carried exercise, 4 had a decline in MMSE, but
patients (mean age out daily organized times a week the intervention group’s was
85 ± 5 years) with activities (e.g., bingo, during slower
advanced AD patchwork sewing, and 24 weeks
music therapy)
Hauer et al. RCT Intervention group of 62 Intervention subjects 3-month Strength, physical Intensive, dementia-adjusted
(2012) patients with mild to received progressive intervention function, and training was feasible and
moderate dementia resistance and and 3-month physical activity substantially improved motor
(mean age functional training. follow-up performance
82.3 ± 6.6 years) and Controls received a
control group of 60 low-intensity motor

patients with mild to placebo activity
moderate dementia
(mean age
82.9 ± 7.0 years)
(continued)
35
36

Study Duration of Outcome
Reference design Participants Type of intervention intervention measures Summary of findings
Zieschang et al. RCT 91 participants with mild The intervention group ===== Strength and Intensive dementia-specific motor
(2013) to moderate dementia received a progressive function were training sustainably improved
resistance and measured functional performance
functional training. before the start 9 months after the end of
The control group of the training training
received a low- (T1), directly
intensity motor after training
placebo activity ceased (T2),
3 months after
training ceased
(T3), and
9 months after
training ceased
(T4)
Pharmacologic treatment of gait disturbances in patients with dementia or cognitive decline
Gurevich et al. Pre–posttest 26 patients with PD and Patients received 12 weeks Tremor and Rivastigmine caused only slight
(2006) design dementia (mean age rivastigmine mean cognition worsening of tremor in
75.2 ± 4.9 years) dose of 8.0 mg/day demented PD patients, while
improving cognition
Litvineko et al. Open control Intervention group of 21 Intervention group 52 weeks Cognitive, The intervention group had better
(2008) trial PD patients with received galantamine neuropsychiat- cognitive score and significant
dementia (mean age 4 mg twice daily for ric, and motor improvements in gait, freezing
68.6 ± 9.3 years) and the first 4 weeks and symptoms of gait, and falls compared to
control group of 20 then 8 mg twice daily the controls
PD patients with to the end of the
dementia (mean age 24-week trial period.
72.6 ± 8.6 years) Controls continued
taking
M. Dorfman et al.
2
Assal et al. Pre–posttest Intervention group of Intervention group 24 weeks Stride time before Stride time was shorter under dual
(2008) design nine subjects with received galantamine and after task after treatment. There
mild to moderate AD treatment at a mean 6 months of was no change in controls
(mean age dose of 17.8 ± 3.5 mg/ galantamine
77.9 ± 2.1 years) and day according to treatment
18 controls without standard criteria during single
dementia (mean age and dual tasking
78.1 ± 1.0 years) while walking
Montero-Odasso Open-label 6 mild AD subjects 6 AD patients received 4 months Gait velocity and Gait speed and gait variability
et al. (2009b) design (mean age donepezil during gait variability improved under both single-
79.9 ± 4.0 years) and 1 month with 5 mg/ and dual-task walking in the
8 no-treatment MCI day of donepezil and intervention group compared
control subjects 3 months with 10 mg/ to control group. The
(mean age day of donepezil. 8 increases in gait speed were
75.6 ± 6.2 years) MCI patients received sustained and continued to
no treatment during improve after 4 months, while
4 months MCI patients had decreased
mean gait velocity and
increased gait variability
Beauchet et al. Pre–posttest Intervention group of Intervention group 211 ± 78.2 days Mean and CV of Stride CV improved in the
(2011) design 17 AD patients (mean received memantine stride time were intervention group. There was
age 83.8 ± 5.8 years) 20 mg once daily in determined no other significant difference
and 32 AD controls the morning (titrated before and after between groups
who did not take any in 5-mg increments 4 weeks of

anti-dementia drug over 4 weeks) memantine
(mean age treatment
80.0 ± 6.6 years)
TUG Timed Up and Go test, RCT randomized controlled trial, PD Parkinson’s disease, MCI mild cognitive impairment, CV coefficient of variation, MMSE Mini-Mental
State Examination, ADL activities of daily living, 6WT 6-min walking test
37
methylphenidate (MPH) can enhance cognitive and motor function and that it may
have a role as a therapeutic option for reducing fall risk (Auriel et al. 2006; Ben-
Itzhak et al. 2008; Shorer et al. 2013). However, there is no study specific to people
with dementia. The use of MPH (i.e., Ritalin) is well known in treating children
with attention deficit hyperactivity disorder, but much less is known about its poten-
tial to improve motor function and gait among elderly people.
Acetylcholinesterase (AChE) inhibitors (e.g., donepezil, galantamine, and riv-
astigmine) are the most useful symptomatic treatment for AD and VaD (Seltzer
et al. 2004). It has been suggested that AChE inhibitors may improve gait perfor-
mance (Assal and van der Meulen 2009) by enhancing attentional resource alloca-
tion. The effects of donepezil and galantamine were evaluated in a few small studies
and noted that patients treated with donepezil and galantamine had better motor
performances (Assal et al. 2008; Drever et al. 2011; Litvinenko et al. 2008; Montero-
Odasso et al. 2009b). However, one should keep in mind that AChE inhibitors may
provoke parkinsonian symptoms in AD (Trabace et al. 2000), although Gurevich
et al. found that rivastigmine caused only slight worsening of tremor without delete-
riously affecting other PD symptoms while improving cognition among demented
PD patients (Gurevich et al. 2006). Memantine is another symptomatic treatment
for AD, and it reportedly has a beneficial effect on global cognitive function
(McShane et al. 2006). Memantine-related decrease in stride time variability among
people with AD has also been reported (Beauchet et al. 2011). It has been suggested
that the combination of memantine plus vitamin D may be more protective than
memantine alone against the neuronal loss and the subsequent declines in cognitive
and gait performance in AD (Annweiler et al. 2012; Annweiler and Beauchet 2011).
Overall, the findings of both the pharmacologic and non-pharmacologic studies for
improving gait and reducing falls in the presence of dementia need to be replicated
and investigated in large-scale, prospective, randomized, and controlled trials.
Summary and Future Directions
Cognitive alterations are the dominant symptom in dementia, but falls and gait distur-
bances are ubiquitous among affected individuals. A growing body of literature dem-
onstrates that gait abnormalities can also be present in the early stage of the disease,
even before dementia has been diagnosed. These gait abnormalities may serve as a
biomarker and assist in the prediction of dementia. The results of the studies men-
tioned in this review emphasize the importance of routinely including gait assess-
ment—specifically, gait speed and gait variability—in the examination of patients
with cognitive decline (Hausdorff and Buchman 2013). Questions about the underly-
ing mechanisms linking motor and cognitive function still remain unanswered. It is
hoped that improvement in our ability to quantify and understand microvascular
changes will lead to better understanding of the interactions between aging, gait alter-
ations, and cognitive impairment and provide better targeted treatment to combat the
functional deterioration in older adults with cognitive impairments and dementia.
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Chapter 3
Falls in Patients with Dementia
Lynn Rochester, Sue Lord, Alison J. Yarnall, and David J. Burn
Abstract Falls are a major problem in dementia with an annual reported incidence
of about 70–80 %, double that of older adults without cognitive impairment.
Remaining mobile and free from falls is a priority, and understanding falls in
dementia is of critical importance to mitigate the burden caused not only to the
patient but also the carer. Despite this, there is currently no convincing evidence to
mitigate falls risk in dementia. Gait and balance impairments are important falls risk
factors as are cognitive impairment, and more recently the interdependency between
these features has been recognized and is influencing assessment and the develop-
ment of novel therapeutic strategies. This chapter covers four relevant and important
key areas: (1) prevalence, incidence, and risk of falls with respect to different types
of dementia including a focus on disorders in gait and balance which are important
contributors and medication; (2) emerging evidence for contributory mechanisms;
(3) evolving concepts relating to the interrelationship between gait, balance, cogni-
tion, and falls; and finally (4) approaches to mitigate falls risk and implications for
clinical practice.
Keywords Dementia • Falls • Gait • Balance • Cognitive impairment • Risk

factors
L. Rochester, PhD (*) • S. Lord, PhD • A.J. Yarnall, MBBS, MRCP

Institute for Ageing and Health, Clinical Ageing Research Unit,
Campus for Ageing and Vitality, Newcastle University, Newcastle Upon Tyne, UK
D.J. Burn, FRCP, MD
Campus for Ageing and Vitality, Institute for Ageing and Health, Newcastle University,

46 L. Rochester et al.
Introduction
The increased worldwide prevalence of neurodegenerative disease means that by

2020 an estimated 42 million people will have a diagnosis of dementia (Ferri et al.
2005). Falls are a major problem in dementia with an annual reported incidence of
about 70–80 % (Allan et al. 2009; Shaw 2002), double that of older adults without
cognitive impairment (Tinetti et al. 1988). The consequence of falls in older adults
with dementia makes sober reading and includes an increased risk of serious injury
(Tinetti et al. 1988; Kallin et al. 2005), institutionalization (Morris et al. 1987), and
mortality (Morrison and Siu 2000). Remaining mobile and free from falls is a thera-
peutic priority in older adults and those with dementia, and understanding falls in
dementia is of critical importance to mitigate the burden caused not only to the
patient but also the carer (Lowery et al. 2000a). The most recent clinical practice
guideline for prevention of falls in older persons (American Geriatric Society/
British Geriatric Society 2011) concluded that “There is insufficient evidence to
recommend for or against multifactorial or single interventions to prevent falls in
older persons with known dementia living in the community or in long-term care
facilities,” due in large part to lack of studies and poor quality of studies.
Gait and balance impairments are risk factors for falls as are cognitive impairment
and dementia. More recently the interdependency between these features has been rec-
ognized and as a consequence is influencing assessment and the development of novel
therapeutic strategies. This chapter addresses falls in patients with dementia and
explores the relationship between disorders that arise in gait and balance in dementia
subtypes and falls. We define a fall as an event whereby a person comes to lie on the
ground or another lower level with or without loss of consciousness (World Health
Organisation2013). The most common forms of dementia (Alzheimer’s disease (AD),
vascular dementia (VAD), dementia with Lewy bodies (DLB), and Parkinson’s disease
with dementia (PDD)) are the main focus, however, where relevant mild cognitive
impairment is discussed as a precursor to dementia. Rather than carrying out an exhaus-
tive review of the body of literature, we instead refer to the key studies to illustrate criti-
cal points. Studies are limited to mild to moderate dementia which mainly involves
individuals dwelling in the community rather than as residents of nursing homes. Four
key areas are covered: (1) prevalence, incidence, and risk of falls with respect to differ-
ent types of dementia including a focus on disorders in gait and balance which are
important contributors; (2) emerging evidence for contributory mechanisms; (3) evolv-
ing concepts relating to the interrelationship between gait, balance, cognition, and falls;
and finally (4) approaches to mitigate falls risk and implications for clinical practice.
Epidemiology, Prevalence, Incidence,

and Risk of Falls in Dementia
Falls are the fifth leading cause of death among older adults (World Health
Organisation 2013) and as such constitute a major health concern. Approximately
one third of people over the age of 65 fall each year, with an increase in prevalence
3 Falls in Patients with Dementia 47
Table 3.1 Annual prevalence and incidence of falls (falls/1,000 persons) and prevalence of gait
and balance disorders in different dementia subtypes
Controls AD VAD DLB PDD PD
Falls prevalence (%) 36 47 47 77 90 61
Falls incidence 1,023 2,486 3,135 9,087 19,000 4,617
(falls/1,000
people)
Gait disorder N (%) 3/42 (7) 10/40 (25) 31/39 (79) 24/32 (75) 43/46 (93) 20/46 (43)
Taken from Allan et al. (2005, 2009)
in dementia. Broadly speaking, people with dementia are two to three times more
likely to fall than age-matched healthy counterparts, with institutionalized adults
also at a higher risk compared with community living (Kröpelin et al. 2013).
Although estimates vary widely according to the method of data collection, type of
dementia, and domestic environment, figures suggest a prevalence of around 40 %
for community-dwelling adults (Allan et al. 2009; Salva et al. 2012) and 60 % for
people living in residential care (Eriksson et al. 2008). Several reports indicate a
higher prevalence in people with dementia associated with Parkinson’s disease (PD)
compared with dementia related to vascular disease – differences that are also
reflected in incidence figures (Table 3.1). Annual incidence figures are consistent for
prospective studies, with estimates as noted above between 70 and 85 %, twice that
of healthy older adults (Shaw 2002). Incidence figures for retrospective studies are
less consistent and produce much lower estimates (Shaw 2002). The prevalence and
incidence of falls is set to increase given the aging population, which is estimated to
triple from 600 million to 2 billion by 2050 (World Health Organisation 2009),
a third of who will end their lives with dementia (Department of Health 2009).
Compared with demented older adults who do not fall, fallers have a higher risk
of functional decline and are five times more likely to be institutionalized (Salva
et al. 2012). Falls in dementia are also a common cause of hospitalization. In a lon-
gitudinal study of 682 people with AD, falls resulted in admission in just over a fifth
of the 26.2 % hospitalized (Voisin et al. 2010). People with dementia constitute a
significant proportion of the total population of elderly hip fracture patients in hos-
pitals (about 30–50 %) (Stenvall et al. 2012). Other specific issues include increase
risk of delirium, poor recovery, increased institutionalization, and increased mortal-
ity (Scandol et al. 2013).
An extensive body of research has identified risk factors for falls in people with
cognitive impairment and dementia. The evidence is difficult to summarize because
of inconsistencies in the classification and severity of cognitive impairment and the
environment in which people are tested. Overall, the key factors include type of
dementia, gait and postural impairment, medication, neurocardiovascular instabil-
ity, and environment (Kröpelin et al. 2013; Shaw 2007; Harlein et al. 2009). Below
we focus on three of the major risk factors for falls in patients with dementia –
dementia subtype, gait and balance impairments, and medication.
(a) Type of Dementia. Dementia itself is a recognized risk factor for falls with
recent studies reporting the annual prevalence of falls in people with dementia
living in the community range from 35 to 90 % (Allan et al. 2009; Shaw 2002;
Salva et al. 2012) and those in residential care between 40 and 62 % (Eriksson
Key
1.0
control
AD
VAD
0.8 DLB
PDD
Cumulative survival
0.6
0.4
0.2
0.0
0 50 100 150 200 250 300 350

Time to first fall (days)
Fig. 3.1 Survival curve showing time to first fall by diagnosis (Reprinted from Allan et al. (2009))
et al. 2008). Cohorts are typically heterogeneous in nature and include demen-
tias of mixed etiology and a broad range of severity. Understanding falls risk
with respect to dementia subtype is highly relevant to a better understanding of
the underlying mechanisms and to identify and target key at-risk groups for
intervention. Allan et al. (2005) reported retrospective falls in dementia sub-
types (AD, VAD, DLB, and PDD) and found that although people with demen-
tia were more likely to report single or multiple falls in the previous year, the
risk of falls was highly dependent upon subtype (see Table 3.1). A follow-on
prospective study confirmed these findings and described the annual incidence
of falls according to dementia and dementia subtype (Allan et al. 2009). Fall
prevalence and rates with respect to dementia subtype are shown in Table 3.1,
while Fig. 3.1 shows the time to first fall. It is clear that Lewy body dementias
(DLB and PDD) have a far higher risk for falls than AD and VAD, a feature that
also informs the diagnostic criteria for DLB (McKeith et al. 2000). It is also
pertinent that fall-related injuries were greater in Lewy body dementias, while
Lewy body disease and parkinsonism were identified as risk factors for falls in
patients with dementia (Allan et al. 2009; Lowery et al. 2000b).
(b) Gait and Balance Impairment. Gait and balance disturbances are more common
in older adults with a 35 % prevalence of gait disorders in older adults over the
age of 70 (Verghese et al. 2006) and are important risk factors for falls (Ambrose
et al. 2013). Classification schemes identify specific syndromes of gait such as
hypokinetic-rigid gait, cautious gait, and higher-level gait disorders (Snijders
et al. 2007) that include gait deficits such as slow, cautious gait; freezing of gait;
start hesitation; balance impairment; and associated cognitive impairments.
These features are also associated with increased falls risk, for example, parkin-
sonism (slow gait with freezing) (Lim et al. 2008; Kerr et al. 2010; Latt et al.
2009) as well as mild cognitive impairment (Taylor et al. 2012; Camicioli and
Majumdar 2010). The prevalence of gait and balance impairments is even
greater in dementia (Ambrose et al. 2013; Taylor et al. 2012; van Iersel et al.
2004) accompanying the increased falls risk. The prevalence and severity of
gait disorders are also dependent upon the dementia subtype (Allan et al. 2005)
(see Table 3.1). The highest level of gait and balance impairments was also
similar in pattern to falls rates with respect to dementia subtype being greatest
in LBD, especially PDD, and the lowest in AD, although all groups had a higher
prevalence of gait and balance impairment than controls. It is also worth noting,
however, that the high incidence of falls in DLB could not be attributed purely
to movement disorders such as parkinsonism as falls risk was found to be
increased even in those without extrapyramidal signs (Imamura et al. 2000).
What is evident is the added burden apparently placed by gait and balance dis-
orders on falls risk in dementia, highlighting the complex relationship between
gait, balance, cognition, and falls and will be discussed in section “The Complex
Relationship Between Gait, Balance, Cognition, and Falls: Emerging Concepts.”
(c) Medication. As discussed earlier, advanced age is the greatest risk factor for
increased dementia risk. As age increases, so too does the number of medica-
tions prescribed, with polypharmacy itself a risk factor for falls in older adults
(Neutel et al. 2002). In addition, patients with cognitive impairment and associ-
ated behavioral symptoms may be treated with psychotropic medications, which
have long been associated with increased falls risk (Ensrud et al. 2002; Fick
et al. 2007; Leipzig et al. 1999; Sheahan et al. 1995). Mechanisms through
which falls occur in association with psychotropic medications may include
fatigue/somnolence, decreased awareness of surroundings, confusion, ortho-
static hypotension, or syncope. Benzodiazepines in particular, used to treat sleep
disturbance in older adults and REM sleep behavior disorder in DLB and PDD,
increase the risk of fall and subsequent hip fracture by at least 50 % (Cumming
and Le Couteur 2003). More recently it has been recognized that antidepres-
sants are associated with falls, with selective serotonin reuptake inhibitors asso-
ciated with the highest adjusted hazard ratios for falls (1.66) (Coupland et al.
2011). Specific medications that may increase falls risk in patients with PDD
include dopaminergic agents, which may precipitate falls through dyskinesias
(Robinson et al. 2005). Therefore, it is prudent to consider rationalization of
medications that may not be required or which may increase falls risk.
Common Mechanisms for Gait, Balance, and Cognitive

Impairment: Contributors to Falls Risk?
A better understanding of the relationship between gait, balance, and cognitive

decline is important to help explain the increased risk of falls in dementia. Potential
candidates include the contribution of cholinergic dysfunction and small vessel
cerebrovascular disease (CVD) to gait, balance, and cognitive impairment.
Cholinergic Dysfunction
In PD and PDD, falls are frequent and are closely related to cognition especially
attention (Latt et al. 2009; Allcock et al. 2009; Burn et al. 2003; Burn et al. 2006),
leading to an assumption that they may have a similar neurochemical mechanism,
and therefore cognitive disturbance and falling may not be independent. Two major
cholinergic projection systems in the brain could contribute and are shown in
Fig. 3.2a. The pedunculopontine nucleus (PPN) in the brainstem contains choliner-
gic neurons that have a powerful influence on gait and postural control (Jenkinson
et al. 2009; Karachi et al. 2010). Thalamic acetylcholinesterase (AChE) activity
reflects cholinergic activity from neurons in the PPN (Bohnen and Albin 2011),
which is reduced in early PD (Bohnen and Albin 2011; Gilman et al. 2010; Shimada
et al. 2009) and more so in PD fallers (Bohnen et al. 2009a), suggesting a relation-
ship with gait and postural dyscontrol. Cholinergic function (estimated using short-
latency afferent inhibition) was also found to be highly associated to gait in PD (see
Fig. 3.2b) even after adjusting for age and motor dysfunction (Rochester et al.
2012). Cholinergic neurons in the nucleus basalis of Meynert (nbM) play a role in
attentional control and executive function (Yarnall et al. 2011) which also contribute
to gait disturbance in PD (Lord et al. 2010, 2011a, b; Rochester et al. 2008; Yogev-
Seligmann et al. 2005).
Small Vessel Cerebrovascular Disease
Leukoaraiosis or lesions of the white matter (WML) are seen as areas of increased
signal intensity on brain scans and are common findings in older adults who are
otherwise fit and well (LADIS study group et al. 2011). WML are associated with
small vessel cerebrovascular disease (CVD) as a result of hypertension (an addi-
tional risk factor for falls in dementia) causing structural lesions in white matter
tracts which can lead to changes in motor and cognitive function (LADIS study
group et al. 2011). Structural changes can also occur in normal-appearing white
matter and lead to motor and cognitive impairments (LADIS study group et al.
2011). In older adults without cognitive impairment, WML are associated with gait
and balance disorders (Zheng et al. 2011; de Laat et al. 2011; Baezner et al. 2008;
Rosano et al. 2006), in particular reduced speed and increased variability (Srikanth
et al. 2009). They are also associated prospectively with increased falls risk (Srikanth
et al. 2009; Blahak et al. 2008). Lesions in frontal-subcortical motor circuits were
significantly associated with balance disturbances and increased falls risk (Blahak
et al. 2008). In adults with high-level gait disorders (HLGD), a gait syndrome
reflecting a more cautious hesitant gait, associated changes in white matter were
found with diffusor tension imaging in pathways related to both motor and cognitive
function (Kafri et al. 2013). The roles of WML and CVD are also increasingly rec-
ognized as contributory features to the pathophysiology of different dementia
a Striatum
Thalamus
nbM
PPN
1.8 1.8
b Control PD
r = –.040, p = .860 r = –.606, p = .003
1.6 1.6
Walking speed
1.4 1.4
(m.s–1)
1.2 1.2
1.0 1.0
.8 .8
20 40 60 80 100 120 140 20 40 60 80 100 120 140

SAI (% of MEP) SAI (% of MEP)
Fig. 3.2 (a) Schematic representation of cholinergic output in the cortex (Reprinted from Yarnall
et al. (2011) with permission from John Wiley and Sons). Cholinergic interneurons in the striatum
are shown in blue. The pedunculopontine nucleus (PPN; shown in red) provides the majority of
cholinergic input to the thalamus, with other projections to the nucleus basalis of Meynert (nbM),
striatum, substantia nigra, subthalamic nucleus, globus pallidus interna, cerebellum, and spinal
cord. The nbM (shown in green) sends cholinergic projections to the cerebral cortex and also to
thalamic nuclei. (b) Correlation of walking speed and short-latency afferent inhibition (SAI) in PD
(n = 22) and control participants (n = 22) showing a significant association for PD only (Reprinted
from Rochester et al. (2012), by permission of Oxford University Press)
subtypes leading to speculation that CVD and WML burden might be contributory
pathological features in gait, balance, and cognitive impairment and therefore a
common mechanism of falls in dementia. For example, AD is linked to CVD with
evidence to suggest that CVD may accelerate the pathology and symptoms
associated with AD (Honjo et al. 2012). Furthermore, AD with cerebrovascular

disease (CVD) has worse gait and balance than AD without cerebrovascular disease
(Inzitari et al. 2013), and a systematic review found that in AD gait impairment was
associated with a higher burden of WML with changes associated with frontal-
subcortical lesions and atrophy and hypometabolism of the hippocampus (Annweiler
et al. 2012). Comorbid WMD has also been reported to be a greater determinant of
axial motor impairment than nigrostriatal dopaminergic denervation potentially
contributing to balance impairment and falls risk in PD and possibly PDD (Bohnen
et al. 2011). WML have also been shown to contribute to cortical cholinergic deaf-
ferentation (Bohnen et al. 2009b) and highlight the potential interactions between
pathology and underlying mechanisms across pathology and dementias. These
mechanisms are helpful to inform potential therapies to reduce falls risk in
dementia.
The Complex Relationship Between Gait, Balance,

Cognition, and Falls: Emerging Concepts
Until relatively recently, falls and dementia were treated as two relatively unrelated
entities (Fig. 3.2a), with distinct pathways and causal features. This view is chang-
ing. A 2010 addition to American and British Geriatric Societies (American
Geriatric Society/British Geriatric Society 2011) clinical practice guidelines for
prevention of falls suggests that further to questioning patients about a fall, clini-
cians should also ask about the presence of any gait problems. This move reflects
the wider, recent recognition of the complex interrelationship between gait, cogni-
tion, and falls, as depicted in Fig. 3.2b.
For the past decade, the link between cognition, gait, and falls has intensified.
The notion that safe and effective gait (and by corollary, absence of falls) is due
solely to an intact motor system has given way to a more complex model that
reflects the cognitive control of balance and gait (Montero-Odasso et al. 2012).
This “top-down” control is evident well before dementia states emerge. The cogni-
tive “cost” of balance and walking is revealed when the motor system is stressed
during assessment. The most common approach to producing “stress” is to use a
dual-task testing paradigm, when the subject performs a simultaneous (usually cog-
nitive) task during a balance task or during gait. For any adult, dual tasking is atten-
tion demanding but the effect is marked in people with cognitive impairment and
dementia. In a seminal study in 1997, Lundin-Olsson (Lundin-Olsson et al. 1997)
reported increased falls in institutionalized adults with dementia who were unable
to continue walking when a conversation was initiated. This gave rise to the “stops
walking when talking” test as a predictive measure of falls. Attention is a powerful
modifier of gait and falls and may “drive” other cognitive features also involved.
Allcock and colleagues (2009) demonstrated that power of attention and reaction
time variability scores were significantly associated with falls, even when adjusted
for motor severity. However, the relationship between dual task and falls is not
clear cut, given the wide range of response to dual task and protocols used in test-
ing. The link between cognition, balance, and gait has focused attention on gait
measurement and what it can reveal about future cognitive (and health) states. In
longitudinal cohorts of community-dwelling older adults, gait impairment has been
shown to predict mild cognitive decline and dementia (Verghese et al. 2007), along
with falls (Ambrose et al. 2013) and adverse health outcomes (Abellan van Kan
2009).
The recent emphasis on cognitive control of gait and falls does not preclude the
important contribution of sensorimotor function to balance, gait, and falls which is
well established in the literature for non-demented fallers. For example, muscle
strength and vision have been shown to be key determinants of balance, gait, and
falls, and a comprehensive falls assessment includes these in a wider battery along
with proprioceptive testing (Lord et al. 2003). The relative contribution of cognitive
function to motor function is likely to be different in dementia, with cognitive func-
tion overriding other systems. This has not been studied in detail. However, knowl-
edge of the role of cognition in pre-dementia states provides a basis for novel
interventions, which are discussed below.
Mitigating Falls Risk in Dementias: Linking Traditional

and Contemporary Approaches
As stated at the beginning of the chapter, the most recent clinical practice guideline
for prevention of falls in older persons (American Geriatric Society/British
Geriatric Society 2011) concluded that “There is insufficient evidence to recom-
mend for or against multifactorial or single interventions to prevent falls in older
persons with known dementia living in the community or in long-term care facili-
ties,” due in large part to lack of studies and poor quality of studies. Widely accepted
falls reduction programs for older adults (e.g., FAME, Otago Falls Programme, Tai
Chi) emerge from research that has excluded people with dementia or cognitive
impairment (Gillespie et al. 2009). Exercise is feasible for people with dementia,
but has focused on cardiovascular fitness rather than exercise to improve balance
(Hill et al. 2009). Multicomponent interventions that target endurance, strength,
and balance have been shown to improve physical functioning (Blankevoort et al.
2010), but the translation to falls is less convincing. Individualized, tailor-made
programs may be more effective than generic interventions. A recent RCT reported
beneficial outcomes for people with dementia who were exposed to an individual-
ized, multidisciplinary medical and rehabilitation regime after hip fracture (Stenvall
et al. 2012), and a recent pilot study reported a 32.6 % reduction in falls and
decreased agitation in people with dementia living in a residential care home
through the use of individualized therapies based on behavioral and cognitive pro-
files (Bharwani et al. 2012). Current evidence points to the need for targeted selec-
tion of participants, with consideration given to severity and type of dementia,
presence of gait abnormalities and functional limitations, previous history of falls,
living environment, and age. The most critical of these is likely to be severity of
dementia: above a certain threshold interventions will be ineffective (Shaw 2002).
Physical activity is overall protective of cognitive decline and protective for first
falls in dementia (Allan et al. 2009), but this may depend on the setting. Sherrington
(Sherrington et al. 2008) reported that exercise alone had no benefit in reducing
falls in people with dementia living in care homes, possibly because the exercises
were mostly in sitting which does not sufficiently challenge postural mechanisms.
Over time, interest in physical activity diminishes and mobility becomes more
fragmented and related to less purposeful actions such as wandering during delir-
ium. This trajectory of change needs to be considered when designing falls inter-
vention program.
These studies do not tackle the complex interaction between cognitive impair-
ment and gait and balance impairment which are common and related risk factors
for falls in dementia as depicted in Fig. 3.3. Taking this contemporary view, new
approaches are emerging that aim to address the role of cognition in control of gait
and postural control using either pharmacological or non-pharmacological thera-
pies (see Table 3.2 for examples) (see Montero-Odasso et al., for review (Montero-
Odasso et al. 2012)) and are briefly considered below. This type of approach is
typically aimed far earlier in the disease process targeting those with mild dementia
or even earlier with mild cognitive impairment.
a
Slow gait velocity
MCI
Cognitive Impairment Dementia
b
Slow gait velocity
Cognitive impairment MCI

Executive function-working Dementia
memory
Fig. 3.3 Traditional and contemporary views of the decline in cognition and mobility and their
relationship with falls. (a) Traditional view. (b) Alternative, emerging view (Reprinted from
Montero-Odasso et al. (2012) with permission from John Wiley and Sons)
Table 3.2 Falls interventions in dementia: tradition and contemporary approaches with selected
examples
Traditional Contemporary
Single domain intervention approach Pharmacological approaches targeting cognitive
(e.g., exercise) (Sherrington et al. impairment – cholinergic dysfunction (Montero-
2008) Odasso et al. 2012; Chung et al. 2010)
Multifactorial intervention based on Exercise to reduce CVD as a potential risk factor
generic risk factors (Stenvall et al.
2012)
Multifactorial intervention based on Tailor-made intervention, based on individual profile of,
risk factors specific to participants e.g., falls history, behavior, and cognitive impair-
(e.g., residential setting, severity of ment (Bharwani et al. 2012)
dementia) (Oliver et al. 2007) Cognitive remediation using complex cognitive and
motor skill training typically involving dual-task
scenarios and decision making (Montero-Odasso
et al. 2012; Schwenk et al. 2010)
Pharmacological Approaches
Some interesting preliminary pharmacological trials have reported the effects of

cognitive enhancers on gait and falls. These approaches target the underlying com-
mon neurotransmitters involved in both cognition and motor control which act as a
common mechanism as well as a potential therapeutic target. The cholinergic system
(discussed earlier) is such an example. Cholinesterase inhibitors (ChEIs) (e.g., done-
pezil, galantamine, and rivastigmine) are used as symptomatic treatments to improve
cognitive function (mainly attention) in AD, VAD, and also in PDD. There is also
interest to see if they have a concurrent effect on gait and falls. The mechanism for
action is unclear and may be mediated through improved attentional cognitive con-
trol of gait or directly through improved motor function. Early evidence in pilot trials
in people with AD show improvements in gait function (Assal et al. 2008; Montero-
Odasso et al. 2009) with some suggestions of reduced fall rates in PD (Chung et al.
2010) which is encouraging and is leading the way to larger clinical trials.
Non-pharmacological Approaches
Cognitive remediation therapies are also receiving interest and have been shown to
improve executive function and attention in older adults with some emerging evi-
dence in people with MCI and dementia (Montero-Odasso et al. 2012). These types
of approaches involve complex cognitive and motor skill training typically involv-
ing dual-task scenarios and decision making. A recent study in people with demen-
tia combining gait and cognitive exercise training (dual-task training) saw improved
gait performance compared to simple exercises (Schwenk et al. 2010). Activity has
been recognized as being protective against falls in dementia (Allan et al. 2009) and
may be effective to target the risk factors for CVD and WML, providing a further
potential therapeutic target for falls interventions (Srikanth et al. 2009).
Additional Considerations
Any fall, especially in older, frailer adults, is associated with risk of fracture.
Fragility fractures are a major cause of morbidity and mortality, with 1-year mortal-
ity following fractured neck of femur up to 30 % (Wiles et al. 2011). Dementia is an
independent risk factor for fracture in PD (Melton et al. 2006), where the risk of
osteoporosis is increased due to reduced bone mineral density, vitamin D insuffi-
ciency, immobility, and reduced body mass index (Dobson et al. 2013; Ishizaki et al.
1993; Sato et al. 1997). In extrapyramidal disorders, hip fractures are more common
than upper limb fractures, probably due to the mechanism of falling, with some
evidence that this may also be true in AD (Williams et al. 2006). Therefore, bone
health should be assessed in these patients, using tools such as the WHO FRAX tool
(Kanis et al. 2008) or QFracture algorithm (Hippisley-Cox and Coupland 2012),
with subsequent referral for dual energy X-ray absorptiometry (DXA) where appro-
priate. Investigation for secondary causes of osteoporosis (such as vitamin D levels
and thyroid function tests) and attention to lifestyle factors (such as diet and smok-
ing) should be initiated where necessary. The treatment of osteoporosis should fol-
low locally agreed guidelines, with consideration to reduced mean life expectancy
in older people with more advanced dementia: here quality of life and reduction in
morbidity are important considerations. Lastly, occupational therapy home assess-
ment and visual assessment and treatment may also reduce the rate of falling in
community-dwelling older adults (Gillespie et al. 2009), although again the evi-
dence in those with additional cognitive impairment is lacking.
Ultimately, earlier intervention may however be more appropriate when potential
for compensation is greater. Targeting falls risk in mild cognitive impairment and
treating this as a prodromal stage for dementia may ultimately yield the greatest
benefits. Taking a combined approach to target multiple underlying mechanisms and
behavioral remediation of gait and cognitive impairment may represent potentially
exciting future developments to ameliorate falls risk in people with dementia.
Clinical Implications
• Gait and balance are useful biomarkers for falls risk in dementia and should be
included in assessment.
• Currently, there is no clear evidence for effective interventions.
• Emerging approaches to mitigate risk should be considered.
• Early intervention may be more beneficial using MCI as a prodromal state for
dementia when there is greater potential for compensation.
• Rationalization of medications, in particular with respect to centrally acting
medications, should be considered at an early stage to limit potential iatrogenic
harm.
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Chapter 4
Treatment of Parkinsonism in Patients
with Non-Parkinson Dementia
Raja Mehanna and Hubert H. Fernandez
Abstract Parkinsonism and dementia can co-occur in patients without Parkinson’s

disease, and most of patients with neurodegenerative parkinsonism develop signifi-
cant cognitive impairment. Parkinsonism–dementia syndromes notably include
dementia with Lewy bodies, progressive supranuclear palsy, corticobasal syndrome,
normal-pressure hydrocephalus, vascular parkinsonism and dementia, drug-induced
parkinsonism and dementia, frontotemporal lobe dementia, and Alzheimer’s dis-
ease. Therapeutic options for parkinsonism in these patients are limited, and data
are scarce. In this chapter, we summarize the available information on this topic.
Keywords Parkinsonism • Dementia • Treatment • Dementia with Lewy bodies •

Progressive supranuclear palsy • Corticobasal syndrome • Normal-pressure hydro-
cephalus • Frontotemporal lobe dementia • Alzheimer’s disease
Introduction
Parkinsonism is a disorder characterized by the clinical tetrad of tremor at rest,

rigidity, akinesia (or bradykinesia), and postural instability (Mehanna and Jankovic
2013a; Fernandez et al. 2007). It can be subcategorized based on etiology into the
following: primary (i.e., idiopathic Parkinson’s disease), secondary (e.g., drug-
induced parkinsonism, vascular parkinsonism, parkinsonism due to normal-pressure
R. Mehanna, MD
Department of Neurology, University of Texas Health Science Center in Houston,
Houston, TX, USA
H.H. Fernandez, MD (*)
Department of Neurology, Cleveland Clinic Lerner College of Medicine,
Cleveland, OH, USA

62 R. Mehanna and H.H. Fernandez
Table 4.1 Dementia Dementia with Lewy bodies

syndromes that can be Progressive supranuclear palsy
associated with parkinsonism,
Corticobasal syndrome
other than PDD (Liepelt-
Normal-pressure hydrocephaly
Scarfone et al. 2012; Possin
and Kaufer 2010) Vascular parkinsonism and dementia
Drug-induced parkinsonism and dementia
Frontotemporal lobe dementia
Alzheimer’s disease
Others:
Prion diseases including Gerstmann-Sträussler-Scheinker
syndrome
Metabolic derangements that have a predilection for basal
ganglia structures such as:
Wilson disease
Neurodegeneration with brain iron accumulation
Idiopathic basal ganglia calcification (Fahr disease)
hydrocephalus, etc.), and atypical parkinsonism (also referred to as Parkinson-plus

syndromes). In contrast to PD patients, those with atypical parkinsonism usually
lack rest tremor, tend to have a more rapid progression and poor response to
levodopa, and have additional (“plus”) features, such as significant dysautonomia
(in multiple system atrophy [MSA]), early gait instability (in progressive supranu-
clear palsy), limb dystonia and myoclonus (in corticobasal syndromes), behavioral
features (in frontotemporal lobe dementia), and early cognitive impairment (in most
atypical parkinsonian syndromes) (Mehanna and Jankovic 2010; Fernandez et al.
2007). At some point, the majority of patients with neurodegenerative parkinsonism
develop significant cognitive impairments that, in many cases, progress to frank
dementia (Wurtman 2013) (Table 4.1). In addition, patients with neurodegenerative
dementia are prone to developing parkinsonism. The description of these parkinson-
ism–dementia syndromes has been covered in other chapters of this book. In this
chapter, we will focus on the treatment of parkinsonism in the most frequent parkin-
sonism–dementia syndromes other than Parkinson’s disease dementia (Table 4.2).
Dementia with Lewy Bodies (DLB)
The treatment of parkinsonian in patients with DLB follows the same treatment
principles of idiopathic PD, where dopamine replacement remains the cornerstone
of treatment. There are, however, some differences (Poewe 2005). The main con-
cern is that pro-dopaminergic agents used to treat parkinsonism more readily exac-
erbate or cause hallucinations in DLB (McKeith et al. 2003; Frank 2003; Zupancic
et al. 2011) as compared to idiopathic PD.
Because of their greater hallucination-inducing potential, dopamine agonists are
generally not considered first-line agents in DLB and in fact should be avoided
(Rascol et al. 2000; Parkinson Study Group 2000; Drach 2011).
4 Treatment of Parkinsonism in Patients with Non-Parkinson Dementia 63
Table 4.2 Treatment of parkinsonism in non-idiopathic PD demented patients

Diagnosis First line (efficacy) Other options Comments
DLB Levodopa (50–55 %) Zonisamide Avoid dopamine agonists,
anticholinergics, and
selegiline
PSP Levodopa (38–54 %) Pramipexole, ropinirole, Might need higher doses of
amantadine, zolpidem levodopa than PD
CBS Levodopa (26 %) Amantadine, anticholinergics
(for tremor), selegiline,
anticonvulsants,
pramipexole, ropinirole
NPH VPS (50–70 %) Levodopa
VPD Levodopa (33 %) Amantadine Control vascular risk factors
DIPD Levodopa (NA) Stop the offending agent
FTLD Levodopa (NA) Dopamine agonists, No empiric data
selegiline
AD Levodopa (NA) Dopamine agonists, No empiric data
selegiline
DLB dementia with Lewy bodies, PSP progressive supranuclear palsy, CBS corticobasal syn-
drome, NPH normal-pressure hydrocephaly, VPD vascular parkinsonism and dementia, DIPD
drug-induced parkinsonism and dementia, FTLD frontotemporal lobe dementia, AD Alzheimer’s
disease
The efficacy and safety of levodopa in DLB has been assessed only in small
series of up to 20 patients (Molloy et al. 2005; Bonelli et al. 2004; Goldman et al.
2008). Clinically significant improvement of parkinsonism after an oral dose of
levodopa has been reported in up to 50 % of patients with DLB (Bonelli et al.
2004), but this series did not report adverse events. However, in a series of 19
patients with DLB, Goldman et al. (2008) reported that only 22 % had improve-
ment in their motor symptoms with levodopa without worsening of their halluci-
nations. In a more recent series comparing the effect of levodopa on 24 DLB and
21 PD patients, Lucetti et al. (2010) reported a positive response to an acute oral
load of 250 mg of levodopa in 55 % of the DLB patients and 90 % of the PD
patients. A positive response was defined as an improvement of at least 15 % in the
tapping test and at least 25 % in the walking test and rigidity score or tremor score.
Patients were then treated with up to 600 mg per day of levodopa and reassessed
at 6 and 12 months. At both follow-up visits, DLB patients who responded to the
initial acute levodopa dose showed a greater motor benefit compared to DLB who
did not satisfactorily respond to the acute levodopa dose challenge. However,
when compared to PD acute levodopa responders, the benefit observed in DLB
acute levodopa responders was comparable at 6 months but was less at 12 months,
implying a more rapid reduction of levodopa efficacy in DLB. In this series, 2
DLB (8.3 %) patients were excluded because of exacerbation of hallucination on
levodopa and not included in the analysis. Moreover, 30 % of the DLB patients
were on clozapine and 50 % were on acetylcholinesterase inhibitors, which could
have prevented or masked potential worsening of hallucination from levodopa.
Overall, parkinsonism tends to respond less well to levodopa in DLB than in PD
or PD with dementia (PDD) (McKeith et al. 1996, 2005; Molloy et al. 2005;
Bonelli et al. 2004; Goldman et al. 2008; Drach 2011). Levodopa-induced dyski-
nesia were reported less frequently in DLB than in PD patients in one retrospec-
tive study of 25 DLB and 64 PD patients (Papapetropoulos et al. 2006), but this
could not be confirmed in prospective series (Lucetti et al. 2010). Should this be
true, it would be another indicator of decreased sensibility of DLB patient to dopa-
mine replacement therapy. In a cross-sectional study comparing the motor pheno-
type in 43 PDD and 26 DLB cases to that of 38 patients with PD and no dementia
(Burn et al. 2003), the postural instability/gait difficulty-phenotype was signifi-
cantly overrepresented in DLB compared to the uncomplicated PD group (69 %
versus 38 % of cases).
In the less frequent cases where tremor is the dominant symptom of parkinson-
ism, anticholinergic drugs should still be avoided as they can worsen the cognitive
deficit and/or induce delirium (Drach 2011). Amantadine 150 mg/day was reported
to partially improve parkinsonism in one patient with DLB (Sato et al. 2010), but it
can also worsen psychosis (Drach 2011) and is usually not recommended (Possin
and Kaufer 2010).
Although not routinely used in clinical practice, a daily dose of 25–100 mg of
zonisamide in addition to levodopa was shown to decrease off time without worsen-
ing dyskinesia in a randomized, double-blinded, controlled trial on 347 PD patients
(Murata et al. 2007). While no such trial exists for DLB patients, some cases have
been reported. Sato et al. (2010) reported motor improvement in one DLB patient
after 4 weeks of a daily dose of 25 mg of zonisamide, and with marked gait improve-
ment. The dose was then increased progressively to 75 mg daily with additional
improvement of aggression, apathy, and irritability. No side effects were reported.
The patient was also on a stable dose of amantadine 150 mg per day and donepezil
5 mg per day. Odawara et al. (2010) reported three additional DLB patients in whom
zonisamide was added to levodopa for motor symptom control. Two patients had
mild to moderate motor improvement at 25 mg/day, with dizziness at 50 mg/day.
The third patient had no motor improvement but experienced drowsiness at 100 mg
per day. All side effects improved after decreasing the dose. Interestingly, the first
two patients had previously responded to levodopa while the third one did not. The
effects of zonisamide on parkinsonism can be mediated by an increase in dopamine
synthesis at doses between 25 and 100 mg per day (Murata et al. 2007) as well as an
increase in extracellular levels of dopamine and serotonin (Farooq et al. 2008;
Murata et al. 2007).
In summary, and in an attempt to optimize motor control without worsening
cognitive or psychotic symptoms, low doses of levodopa should be used, possibly in
combination with zonisamide. Dopamine agonists, anticholinergics, and amanta-
dine should be avoided, as well as selegiline (Possin and Kaufer 2010), and perhaps
other monoamine oxidase B (MAO-B) inhibitors. Data on catechol-O-
methyltransferase (COMT) inhibitors in the DLB population are wanting, although
presumably they are less likely, but far from exempt, in precipitating hallucinations
among demented parkinsonian patients.
Progressive Supranuclear Palsy (PSP)
Although the response to levodopa may be poor or transient (van Balken and Litvan
2006), and parkinsonism in PSP seem to be less responsive to levodopa than other
Parkinson-plus syndromes (Birdi et al. 2002), patients with PSP more often still
receive a trial of levodopa/carbidopa. At least two studies involving up to 170 PSP
patients have demonstrated an improvement of motor symptoms with levodopa in
38–54 % of patients (Nieforth and Golbe 1993; Golbe et al. 1990). The amplitude
and duration of this response were however not specified (Burn and Warren 2005).
Another retrospective study of 12 PSP patients showed a more modest response but
reported significant adverse effects such as worsening of parkinsonism and postural
hypotension in more than half the patients (Kompoliti et al. 1998a). It should be
noted that the minimum clinically beneficial levodopa dose may be higher in PSP
than that in PD (Lubarsky and Juncos 2008) and may require up to 1 g of levodopa
per day. However, the response remains modest and is often short lived (3–5 years).
Over time, dopaminergic therapy can reversibly worsen most motor and behavioral
symptoms of PSP, and the difficult decision to stop these medications may need to
be taken. However, since this drug-induced worsening can be dose dependent, a
gradual de-escalation of dopaminergic drugs will give the opportunity to look for a
lower dose with a more favorable risk–benefit ratio (Lubarsky and Juncos 2008).
Moreover, abrupt discontinuation of dopaminergic drugs should be avoided to pre-
vent a withdrawal-induced neuroleptic malignant-like syndrome (Serrano-Duenas
2003; Yoshikawa et al. 1997). Finally, PSP patients are less likely to develop severe
motor fluctuations, dyskinesias, or dopaminergic-induced visual hallucinations than
PD patients (Aarsland et al. 2001), suggestive of a more dopamine-resistant
pathology.
In patients who do not respond to levodopa, dopamine receptor agonists such
as pramipexole or ropinirole may be considered. Indeed, unlike levodopa, these
medications act directly at the postsynaptic terminal in the striatum, bypassing the
substantia nigra that is commonly affected with severe neuronal loss in PSP
(Rabinovici and Miller 2010). If used as a first-line treatment, the response to
these agents is often comparable or inferior to that of levodopa (Burn and Warren
2005).
Amantadine has been reported to transiently improve parkinsonism in 15 % of
PSP patients (Irene and Yves 1992).
Finally, based on decreased frontal cortical GABA receptors on brain imaging of
PSP patients, a crossover trial of the GABA agonist zolpidem on 10 PSP patients
was conducted (Daniele et al. 1999). A single 5 mg zolpidem dose was found to
improve the motor subscale of the United Parkinson’s Disease Rating Scale by more
than 20 %, while a dose of 10 mg of zolpidem or 250 mg of levodopa failed to exert
such a response. The main side effect of this drug was mild drowsiness in 50 % of
the patients and moderate drowsiness in an additional 10 %. These results have not
been duplicated.
Corticobasal Syndrome (CBS)
CBS is notoriously resistant to levodopa, even more so than PSP. However, although
the response to levodopa may be poor or transient, patients often receive a trial of
levodopa. In a retrospective review of 147 patients with CBS, Kompoliti et al.
(1998b) reported carbidopa/levodopa use in 87 % of the patients with a median
daily dose of 300 mg (range 100–2,000 mg) but with improvement in only 26 % of
the patients exposed to the drug. Twenty-five percent were treated with pergolide or
bromocriptine, of whom only 6 % improved. Selegiline was used in 20 % of the
patients and produced motor benefits in only 10 % of patients. Amantadine was
prescribed in 16 % and improved bradykinesia, rigidity, and gait in 13 % of patients.
Anticholinergic agents were used in 27 % of the patients and improved parkinson-
ism in 10 %. Finally, anticonvulsants were given to 9 % of the patients and improved
parkinsonism, especially tremor, in 23 % of them, a success rate second only to
levodopa. However, the study did not report the magnitude and duration of observed
improvements. Dyskinesias did not occur even at high doses of dopaminergic
therapy.
Overall, the response of parkinsonism to therapy is limited, with levodopa being
the most efficacious agent. In patients who do not respond to levodopa, dopamine
receptor agonists such as pramipexole or ropinirole may be considered. Indeed,
unlike levodopa, these medications act directly at the postsynaptic terminal in the
striatum, bypassing the substantia nigra which, similar to PSP, is also affected with
severe neuronal loss in CBS (Rabinovici and Miller 2010). Finally, anticonvulsants
might be useful in tremulous CBS patients.
Normal-Pressure Hydrocephalus (NPH)
In addition to subcortical dementia and urinary incontinence, NPH is characterized

by a wide-based gait with short steps, stiff legs, start hesitation, and freezing, the
so-called magnetic gait (Possin and Kaufer 2010). Moreover, NPH patients fre-
quently exhibit bradykinesia and flexed posture (Fahn et al. 2011).
Ventriculoperitoneal shunt surgery is the only established treatment of normal-
pressure hydrocephalus (Liepelt-Scarfone et al. 2012) and has the maximal benefits
if performed when cognitive impairment is still mild and of recent origin, with gait
improving the most after surgery. Substantial improvement can be seen in 50–70 %
of patients (Vanneste 2000) with benefits sustained up to a mean of 6 years (Pujari
et al. 2008). When present, bradykinesia also improves markedly after the shunting
procedure (Akiguchi et al. 2008). While NPH is typically poorly responsive to
levodopa (Morishita et al. 2010), parkinsonism in NPH and obstructive hydrocepha-
lus have been reported that could be levodopa responsive (Jankovic et al. 1986;
Clough 1987; Zeidler et al. 1998; Racette et al. 2004).
Vascular Parkinsonism and Dementia
Binswanger disease, or subcortical ischemic vascular dementia, is a heterogeneous

syndrome associated with multiple subcortical infarcts and/or diffuse subcortical leu-
koaraiosis and can be associated with vascular parkinsonism (Possin and Kaufer
2010). Overall, only about a third of patients with vascular parkinsonism improve
with levodopa (Mehanna and Jankovic 2013b) with patients with vascular lesions in
or close to the nigrostriatal pathway and rare cases with abnormal DAT-SPECT
imaging being more likely to respond. While levodopa can improve bradykinesia and
rigidity, amantadine can be beneficial for apathy and bradyphrenia (Liepelt-Scarfone
et al. 2012). The management should include, if not emphasize, physical and occupa-
tional therapy as well as detection and treatment of atherosclerosis, hypertension,
diabetes mellitus, and other stroke risk factors (Mehanna and Jankovic 2013b).
Drug-Induced Parkinsonism and Dementia
Because it is readily treatable by discontinuing the offending agent, an iatrogenic

cause of parkinsonism–dementia should always be considered, and a review of the
patient’s medication list is mandatory. This is even more critical as drug-induced
parkinsonism can be clinically indistinguishable from idiopathic Parkinson’s dis-
ease. The most frequently incriminated drugs are the typical or conventional neuro-
leptics. However, atypical neuroleptics, especially in the Parkinson-vulnerable
elderly and cognitively impaired population, still carry a risk and represented 46 %
of the 6.8 % cases of drug-induced parkinsonism in a retrospective review of 354
parkinsonian patients (Esper and Factor 2008). Other agents include antiemetic
agents such as metoclopramide and promethazine, anticonvulsants such as valproic
acid, and lithium (Esper and Factor 2008). In addition, parkinsonism can be induced
in demented patients by antipsychotic drugs prescribed to control behavioral symp-
toms (Czarnecki et al. 2008). This is often seen in the management of Alzheimer’s
disease, especially in long-term care facilities.
Discontinuing the offending agent often leads to a resolution of the symptoms,
but this might take up to 18 months (Fahn et al. 2011; Lim et al. 2013). Meanwhile,
if symptoms are severe, low doses of levodopa can be used for symptomatic relief.
Frontotemporal Lobe Dementia (FTLD)
No empiric data exists for the treatment of parkinsonism in FTLD, but some expert
opinions have been published on the subject. A trial of levodopa should be attempted in
FTLD patients with parkinsonism, but the response to levodopa may be poor or transient
(Rabinovici and Miller 2010). Dopamine receptor agonists, such as pramipexole or rop-
inirole, should be considered in cases of levodopa failure (Rabinovici and Miller 2010).
Contrary to patients with DLB, FTLD patients are less prone to hallucinations;
thus, dopaminergic medications can be used more liberally. While not specifically
assessed for the treatment of parkinsonism in FTLD, the potential benefit of dopa-
mine agonists on apathy, perseveration, and executive functioning (Imamura et al.
1998; Rahman et al. 2001; Allain et al. 2003) and of selegiline on neuropsychologi-
cal symptoms (Moretti et al. 2002) should prompt the consideration of these anti-
parkinsonian treatments in FTLD patients with parkinsonism.
Parkinsonism associated with FTLD is usually of the non-tremulous type. If
tremor is a major source of complaints, anticholinergic medications can be consid-
ered but should be used very sparingly as they may worsen the cognitive and neuro-
psychiatric symptoms.
Frontotemporal dementia with parkinsonism is an autosomal dominant syn-
drome linked to chromosome 17 than be caused by tenths of different mutations
(Graff-Radford and Woodruff 2007). It can be subdivided in two clinical pheno-
types (Reed et al. 2001), one with a dementia-predominant symptomatology and the
other with a parkinsonism-predominant phenotype. Most patients respond poorly, if
at all, to levodopa (Wszolek et al. 2006). FTLD can also overlap clinically and
pathologically with PSP and/or CBD (Graff-Radford and Woodruff 2007). In these
cases, the symptomatic treatment of parkinsonism would be as detailed in the sec-
tion on PSP and CBD, respectively.
Alzheimer’s Disease (AD)
Although parkinsonism develops in 15–45 % of patients with AD (Fahn et al. 2011)

and its presence correlates with greater cognitive impairment and worse prognosis
compared to AD patients without parkinsonism (Kurlan et al. 2000; Wilson et al.
2003), there are no data available regarding the treatment of parkinsonism in AD
except for an old report of familial AD presenting with levodopa-responsive parkin-
sonism (Giménez-Roldán et al. 1987). Such treatment can be extrapolated from the
medical management of parkinsonism in other types of dementia, with low-dose
levodopa as the cornerstone, while dopamine agonists carry a higher risk of halluci-
nations. However, as reported in the section on FTLD, dopamine agonists and sele-
giline could, in theory, benefit motor and cognitive symptoms, although the data
supporting this practice are wanting. Finally, a significant portion of AD patient can
experience drug-induced parkinsonism when using atypical antipsychotic agents to
control agitation and other behavioral manifestations.
Conclusion
Parkinsonism associated with dementia is overall less responsive to levodopa com-

pared to idiopathic PD or even PDD. Nevertheless, a trial of levodopa should be
considered for lack of a better treatment. However, levodopa can worsen
hallucinations in DLB as well as motor and behavioral symptoms in advanced PSP

and other atypical parkinsonian disorders. Dopamine agonists may also be benefi-
cial in Parkinson-plus syndromes that have a lesser likelihood of developing
levodopa-induced psychosis, such as PSP, CBS, FTLD, and AD. Support for the use
of other antiparkinsonian drugs is even more limited and therefore should be used
more sparingly. Finally, in these Parkinson-vulnerable populations, even atypical
antipsychotic agents should be used very cautiously, and vigilance to the possibility
of drug-induced parkinsonism should always be exercised since parkinsonian symp-
toms are potentially reversible.
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Chapter 5
Psychiatric Complications of Alzheimer’s
Disease Overlapping with Parkinsonism:
Depression, Apathy, Catatonia, and Psychosis
Sergio E. Starkstein and Jaime Pahissa
Abstract Depression is a frequent comorbid condition in Alzheimer’s disease

(AD) and is associated with the presence of parkinsonism. Apathy in AD was
reported to predict more severe parkinsonism, suggesting that apathy may be an
early manifestation of a more aggressive AD phenotype characterized by loss of
motivation, increasing parkinsonism, a faster cognitive and functional decline, and
more severe depression.
Catatonia may be found in a small proportion of patients with AD, but rates are
higher in hospitalized patients. Catatonia is significantly associated with more
severe parkinsonism and depression and older age. Psychotic symptoms are rela-
tively frequent in the late stages of AD. Current treatment with atypical antipsychot-
ics has a concomitant risk of increased parkinsonism.
Keywords Depression • Apathy • Catatonia • Psychosis • Parkinsonism •

Introduction
Psychiatric conditions, such as depression, apathy, and psychosis, are frequent

comorbid conditions in Alzheimer’s disease (AD). One of the major clinical chal-
lenges is to address the overlap between motor and psychiatric comorbidities in AD.
S.E. Starkstein, MD, PhD (*)

School of Psychiatry and Clinical Neurosciences, University of Western Australia Fremantle,
Fremantle, WA, Australia
J. Pahissa, MD
Department of Psychiatry, CEMIC University, Centro de Educación Médica e Investigationes,
Clínicas “Norberto Quirno”, Buenos Aires, Argentina

74 S.E. Starkstein and J. Pahissa
For instance, depression and apathy may mimic the bradykinesia and bradyphrenia
of AD patients with parkinsonism; catatonia may mimic rigidity and blunted expres-
sion, and side effects of psychotropic drugs may produce not only parkinsonism but
also “positive” motor disorders such as akathisia and dyskinesia.
This chapter will review the phenomenology, frequency and treatment of depres-
sion, and apathy and catatonia in AD, with special emphasis on their motor mani-
festations in AD. We will conclude by examining the motor side effects on
antipsychotic medication frequently used in dementia.
Depression in Alzheimer’s Disease and Parkinsonism
AD and Depression: Diagnostic Issues
A major challenge in diagnosing depression in AD is how to identify those symp-

toms that pertain to depression from similar symptoms in AD. For instance, loss of
interest in AD may be due to the patients’ limitations with their daily activities; loss
of pleasure may be related to the patients’ diminished capacity to participate in their
usual hobbies and leisure activities; loss of concentration is a common symptom in
both depression and AD; and sleep problems are a well-known independent comor-
bid condition in dementia (Cohen-Cole and Stoudemire 1987).
The diagnostic dilemma becomes even more problematic when dealing with AD
patients and comorbid parkinsonism, given that these patients show bradyphrenia, bra-
dykinesia, and a high prevalence of REM sleep behavioral disturbance, which may be
confused with the psychomotor retardation and sleep disturbance typical of depression.
Four strategies have been used to diagnose depression among patients with neu-
rologic conditions. “The inclusive approach” diagnoses depression considering all
the symptoms present, regardless of the medical condition (Cohen-Cole and
Stoudemire 1987). The “exclusive approach,” on the other hand, does not include
for diagnosis those symptoms considered to be related to the physical illness (Gallo
et al. 1999). The “substitutive approach” replaces overlapping symptoms of depres-
sion with psychological symptoms (Olin et al. 2002a). Finally, the “specific symp-
tom approach” only considers for diagnosis those symptoms that were identified as
belonging to a specific “depressive cluster” using specific statistical techniques,
such as latent class analysis (Starkstein et al. 2011).
The American Psychiatric Association Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition (DSM-IV) (APA 1994) criteria for major depres-
sion includes nine symptoms, five of which must be present and at least one of the
five must be “depressed mood” or “loss of interest or pleasure.” All must be judged
to be significant in terms of severity, duration, distress, and impairment. The recently
published DSM-V (APA 2013) does not include major changes to these criteria.
Given the symptom overlap, the question arises as to the validity of the DSM-IV/V
criteria for major depression in AD.
5 Psychiatric Complications of Alzheimer’s Disease Overlapping with Parkinsonism 75
Lyketsos et al. suggested that the individual symptom approach in AD may

ignore the high overlap of symptoms and should not be used for diagnostic pur-
poses. Using latent class analysis, they identified a group with affective symptoms
of depression as well as symptoms of anxiety and apathy. They proposed a specific
set of diagnostic criteria for “AD-associated neuropsychiatric disturbance” (Lyketsos
et al. 2001).
The National Institute of Mental Health (NIMH) conveyed a work group that
proposed standardized diagnostic criteria for depression in AD (Olin et al. 2002b).
These criteria are similar to the DSM-IV criteria for major depression but with the
addition of irritability and social isolation and the replacement of loss of interest
with loss of pleasure in response to social contact. Other modifications included the
requirement of three rather than five symptoms for the diagnosis of depression and
that symptoms do not have to be present nearly every day (Olin et al. 2002b).
Starkstein et al. examined the validity of the construct of major depression in a
large series of patients with AD using LCA and found that all nine DSM-IV diag-
nostic criteria for major depression identified a cluster with high statistical signifi-
cance. A second cluster included patients with an intermediate frequency of
depressive symptoms, most of whom met DSM-IV criteria for minor depression,
whereas a third cluster included patients with a very low frequency of depressive
symptoms. Interestingly, anxiety and apathy were found to be significant predictors
of depression in AD, whereas irritability was not. The authors concluded that the
DSM-IV diagnostic criteria for major depression may be used without modifica-
tions in AD (Starkstein et al. 2011).
Frequency of Depression in AD
The frequency of depression in AD has been reported to range from 10 to 80 %

(Migliorelli et al. 1995). This wide variation may be explained by relevant con-
founders, such as differences in psychiatric assessment techniques and diagnostic
criteria, and sources of patients (e.g., patients screened from psychiatric clinics,
neurologic clinics, or patients recruited from more representative community
samples).
Migliorelli et al. examined 103 patients with probable AD with a structured psy-
chiatric interview and standardized diagnostic criteria. They found that 51 % of the
patients had depression (28 % had dysthymia and 23 % major depression). Women
had a significantly higher prevalence of both major depression and dysthymia than
men. Patients with major depression had an earlier onset of depression, and the
prevalence of major depression was similar across the different stages of the illness
(Migliorelli et al. 1995).
Starkstein et al. examined the frequency of major and minor depression in a
series of 670 AD patients attending a memory clinic using the Structured Clinical
Interview for DSM-IV. The main finding was that 26 % of the patients had major
depression and another 26 % had minor depression (Starkstein et al. 2005a).
Richard et al. examined the association of late-life depression with dementia in a

multiethnic community cohort study that included 2,160 community-dwelling
Medicare recipients aged 65 years or older. Depression was assessed using the
10-item version of the Center for Epidemiologic Studies Depression Scale (CES-
D), and depression was defined by a CES-D score of 4 or more. Their results showed
that dementia was diagnosed at baseline in 217 participants and that participants
with dementia were depressed twice as often as were those without dementia (odds
ratio = 2.2; 95 % CI = 1.6–3.1) (Richard et al. 2013).
Management of Depression in AD
Studies of antidepressants for depression in AD produced inconclusive results, but

the consensus based on recent randomized-controlled trials (RCT) is that antide-
pressants may not confer benefit over placebo.
A large RCT using the SSRI sertraline was conducted by Rosenberg et al. who
enrolled 131 AD patients with mild–moderate AD meeting the NIMH criteria for
depression in AD. The main finding was that neither remission rate nor scores on the
Cornell Scale for Depression in Dementia (CSDD) were significantly different between
sertraline and placebo groups after 12 weeks of treatment. Regardless of type of treat-
ment, depression severity improved by an average of 50 %, and 40 % of the partici-
pants were judged to be either “better” or “much better” in their mood at treatment
completion (Rosenberg et al. 2010). A 24-week study extension also failed to show a
significant benefit of sertraline over placebo (Weintraub et al. 2010). Parkinsonism or
other motor problems were not listed as a significant side effect of sertraline.
A recent multicenter RCT recruited 326 AD patients diagnosed with depression
based on CSDD scores of 8 or more. Participants were allocated to receive sertraline
(target dose 150 mg/day), mirtazapine (target dose 45 mg/day), or placebo. After
13 weeks of follow-up, there were no significant differences between the two active
treatment and placebo groups on depression outcome. Parkinsonism was not listed
as a prominent side effect of either sertraline or mirtazapine (Banerjee et al. 2011).
A Cochrane review of antidepressant efficacy for depression in dementia which
examined the efficacy of tricyclic antidepressants (TCAs) and selective serotonin
reuptake inhibitors included four studies with a total of 137 participants. Evidence
offered weak support for the effectiveness of psychoactive drugs for depression in
AD (Bains et al. 2002). Parkinsonism or other motor disorders were not found to be
common side effects of these drugs, although the anticholinergic effect of TCAs
was associated with postural hypotension and increased risk of falls.
A meta-analysis by Thompson et al. included 5 studies, which involved 82 sub-
jects treated with antidepressants and 83 subjects who received placebo treatment.
The authors reported a significantly higher efficacy for antidepressants over placebo
in terms of both treatment response and remission of depression, and parkinsonism
was not reported as a significant side effect (Thompson et al. 2007).
A recent meta-analysis that included 299 patients (Nelson and Devanand 2011)
found that response and remission rates did not significantly differ between placebo
and active treatment. Parkinsonism was not reported a significant side effect of the
active compounds (Nelson and Devanand 2011).
Enache et al. identified 11 RCTs for depression in AD or other types of dementia,
with a total of 1,514 patients included. Of these, five studies reported that the antide-
pressant (sertraline, clomipramine, maprotiline, moclobemide, or citalopram) was more
effective than placebo, whereas six studies using sertraline, mirtazapine, venlafaxine,
imipramine, fluoxetine, or estrogen replacement therapy were negative. No parkinson-
ism was significantly associated with any of these medications (Enache et al. 2011).
The impact of discontinuing antidepressants among individuals with dementia
was examined in a RCT that included 128 patients with dementia who had been
prescribed escitalopram, citalopram, sertraline, or paroxetine for 3 months or more.
The main finding was that patients who discontinued antidepressant treatment had
significantly higher depression scores after 25 weeks as compared to the continua-
tion group. Parkinsonism or other motor problems were not reported as relevant side
effects of any of the psychotropic compounds (Bergh et al. 2012).
In conclusion, the efficacy of antidepressants in AD remains unclear. Two large
RCTs demonstrated lack of efficacy for sertraline as compared to placebo, and one
of them also showed lack of efficacy for mirtazapine. On the other hand, discontinu-
ation of antidepressants was found to lead to a significant relapse of depression.
Parkinsonism or other motor problems were not reported as significant side effects
in any of the major RCTs or meta-analyses. One limitation of these studies is that
the method used to asses for parkinsonism was not clearly specified.
Depression in AD and Parkinsonism
The question arises as to whether AD patients with parkinsonism may have a higher
frequency of depression as compared to AD patients without parkinsonism. Choi
et al. (2013) assessed parkinsonism in a series of 2,614 neuroleptic-free AD patients
using a structured neurologic evaluation. After controlling for demographic, clini-
cal, and cognitive variables, they found that parkinsonism in AD was significantly
associated with higher depression scores, as measured with the Geriatric Depression
Scale-15 (GDS-15) (Choi et al. 2013). Starkstein et al. (1996a) compared 33 patients
with AD and 33 patients with PD matched for age, gender, and MMSE score. Major
depression was significantly more frequent among PD patients (30 %) as compared
to AD patients (6 %) (P < 0.05).
Apathy and Parkinsonism
Diagnostic Issues
Apathy is defined as a psychiatric syndrome characterized by deficits in goal-

directed behavior as manifested by the simultaneous diminution in the cognitive and
Table 5.1 Diagnostic criteria for apathy

(A) Lack of motivation relative to the patient’s previous level of functioning or the standards of
his or her age and culture as indicated by either subjective account or observation by others
(B) Presence for at least 4 weeks during most of the day, of at least one symptom belonging to
each of the following three domains:
Diminished goal-directed behavior
1. Lack of effort or energy to perform everyday activities
2. Dependency on prompts from others to structure everyday activities
Diminished goal-directed cognition
3. Lack of interest in learning new things or in new experiences
4. Lack of concern about one’s personal problems
Diminished concomitants of goal-directed behavior
5. Unchanging or flat affect
6. Lack of emotional responsivity to positive or negative events
(C) The symptoms cause clinically significant distress or impairment in social, occupational, or
other important areas of functioning
(D) The symptoms are not due to diminished level of consciousness or the direct physiological
effects of a substance
emotional concomitants of goal-directed behavior (Marin 1991). Starkstein et al.

(2001) validated a set of standardized criteria for the diagnosis of apathy in AD.
They assessed a series of 319 patients with AD using the apathy scale (a severity
rating scale) and found that 37 % of the sample met ad hoc criteria for apathy. These
criteria include lack of motivation relative to the previous level of functioning and
the presence during most of the day for at least 4 weeks of diminished goal-directed
behavior, diminished goal-directed cognition, and blunted affect and emotion. An
important finding of the study was a significant overlap between depression and
apathy in AD: while 13 % of the AD sample had apathy and no depression, 24 %
had both depression and apathy.
To our knowledge, there is a single structured interview for apathy validated for
use in AD. Starkstein and coworkers developed the Structured Clinical Interview
for Apathy (SCIA) to screen for symptoms and diagnose apathy based on the diag-
nostic criteria described above (Starkstein et al. 2005b). The SCIA includes a series
of questions assessing the domains of motivation, effort, dependency on others,
interest and concern, and affect and emotion. Based on responses to these questions,
a diagnosis of apathy may be made using the Starkstein’s and Leentjens’ diagnostic
criteria (Starkstein and Leentjens 2008) (Table 5.1).
Frequency of Apathy in AD
Starkstein et al. (2001) examined the prevalence of apathy in a study that included a
consecutive series of 319 patients with AD, 117 patients with depression but no
dementia, and 36 age-comparable healthy individuals (Starkstein et al. 2001). Based
on apathy scale scores, apathy was diagnosed in 37 % of the AD patients, as
compared to 32 % among depressed patients without dementia, and in none of the

healthy controls. About two-thirds of the AD patients with apathy were also
depressed. Mulin et al. (2011) examined the frequency of apathy in a series of 306
patients with AD in a cross-sectional, multicenter study. Apathy was assessed with
the Neuropsychiatric Inventory (NPI) and diagnoses carried out using the European
Psychiatric Association Task Force on Apathy European diagnostic criteria for apa-
thy (Mulin et al. 2011). Apathy was diagnosed in 55 % of the sample (Mullin et al.
2011). Finally, a recent study by Vilalta-Franch et al. (2013) assessed the 1-year
prevalence of incidence of apathy in a sample of 491 patients with AD. They reported
a prevalence of apathy of 21 % and an incidence of 11 % (Vilalta-Franch et al. 2013).
Treatment of Apathy in AD
There are no RCTs specifically designed to assess the efficacy of psychotropic com-
pound to treat apathy in AD, and most of the literature is based on small case series
or RCTs with apathy as a secondary outcome measure.
In a study of a series of 40 AD patients treated with the anticholinesterase inhibi-
tor tacrine, Kaufer and colleagues (1998) reported a significant reduction of apathy
in the group with moderate dementia (Kaufer et al. 1998), without significant motor
side effects. Mega and coworkers (2005) examined changes in the severity of apathy
in 19 patients with mild to moderate AD examined before and after treatment with
the cholinesterase inhibitor galantamine. There was no significant change in clinical
outcomes (Mega et al. 2005), but no parkinsonism was reported. A recent 6-week
RCT that included 67 AD patients with apathy treated with methylphenidate
(Rosenberg et al. 2013) failed to show significant benefits of the active compound
as compared to placebo.
Psychostimulants have been used to treat apathy in AD in small series of patients,
but no formal RCTs have been carried out. Galynker et al. (1997) reported a reduc-
tion in negative symptoms, as measured with the Scale for the Assessment of
Negative Symptoms (SANS) in 12 patients with AD treated with methylphenidate.
Parkinsonism was not reported to be a side effect of treatment (Galynker et al. 1997).
Siddique et al. (2009) assessed the efficacy of the SSRI citalopram (mean dose =
30 mg/day) on apathy NPI scores in a sample of 44 patients with AD previously
treated with placebo in the context of a RCT (Siddique et al. 2009). While patients on
citalopram showed a reduction of 60 % on the NPI apathy scale as compared to pla-
cebo treatment, this difference was not statistically significant (Siddique et al. 2009).
Apathy in AD and Parkinsonism
Parkinsonian signs are frequent in AD (see chapter by Starkstein and Merello) and
are associated with a faster cognitive decline, worse quality of life, and early
nursing home admission. Cross-sectional studies in AD reported a significant asso-

ciation between parkinsonism and apathy (Starkstein et al. 2001). In a recent longi-
tudinal study, Starkstein et al. (2006) examined the predictive validity and
longitudinal progression and correlates of apathy in AD. The first study included a
series of 354 patients that were followed for 1–4 years. At baseline, apathy was
significantly associated with older age and depression. The frequency of apathy
increased from 14 % in the stage of very mild AD to 61 % in the stage of severe AD.
At follow-up, patients with apathy at baseline or patients who developed apathy
during follow-up had a significant increase in depression scores and greater func-
tional and cognitive decline.
A second study specifically examined the longitudinal association between apa-
thy and parkinsonism in AD (Starkstein et al. 2010). The study included 169 patients
with AD who were assessed with the Unified Parkinson’s Disease Rating Scale
(UPDRS) both at baseline and 1–4 years later. The main finding was that patients
with apathy at baseline or those who developed apathy during follow-up had a sig-
nificant increase in parkinsonism as compared with patients with no apathy at both
assessments. The association between apathy and increasing parkinsonism was
unrelated to age, gender, the severity of cognitive deficits, the presence of depres-
sion, or use of psychotropic medications. On the other hand, neither the presence of
parkinsonism nor depression at baseline was significantly associated with more
severe apathy at follow-up. The authors concluded that apathy may be an early
manifestation of a more aggressive AD phenotype characterized by loss of motiva-
tion, increasing parkinsonism, a faster cognitive and functional decline, and more
severe depression.
Catatonia
Before Kahlbaum described catatonia in 1874 (Kahlbaum 1874), a syndrome of

catalepsy had been described as muscular rigidity, fixed posturing, and insensitivity
to pain (Fink et al. 2010). Kahlbaum added the symptoms of echophenomena, gri-
macing, mannerisms, mutism, perseveration, posturing, negativism, rigidity, stereo-
typies, and staring. Catatonia is a motor and mood dysregulation syndrome that is
found among men and women of all ages. Some of the catatonic symptoms are simi-
lar to parkinsonism, and it is therefore important to make an early diagnosis given
that prompt treatment of catatonia is usually followed by good therapeutic results.
Diagnosis of Catatonia
The onset of catatonia is often acute, manifested by repetitive behaviors; stupor,

sometimes alternating with agitated behaviors; and delirium. Some rare forms may
be malignant, leading to death (Stauder 1934). While catatonia is often associated
with psychiatric disorders, such as schizophrenia, mood disorders, neuroleptic

malignant syndrome (NMS), and serotonergic malignant syndrome, it can also be
observed in a variety of neurologic and other medical conditions.
The DSM-IV included the category of “catatonia secondary to a medical disor-
der,” while the DSM-5 criteria also include the category of “Unspecified Catatonia”
for presentations with typical catatonic symptoms but without meeting the full cri-
teria. The DSM-5 criteria for “Catatonic Disorder Due to Another Medical
Condition” is met in the presence of three or more of the following symptoms: (1)
stupor, (2) catalepsy, (3) waxy flexibility, (4) mutism, (5) negativism, (6) posturing,
(7) mannerisms, (8) stereotypy, (9) agitation, (10) grimacing, (11) echolalia, and
(12) echopraxia (American Psychiatric Association 2013).
There are currently several scales to measure the severity of catatonia. Northoff
and coworkers (1999) designed the Northoff Catatonia Scale (NCS), based on the
phenomenological description of catatonia by Kahlbaum (Northoff et al. 1999). The
NCS distinguishes the categories of motor, affective, and behavioral catatonia, and
it also includes motor phenomena not included in the DSM-5, such as festination
(uncoordinated, inappropriate, jerky-like, and hasty movements which cannot be
voluntarily controlled by the patient), athetotic movements (choreatic-like move-
ments with a screw-shaped character); dyskinesias (involuntary fast movements,
which cannot be voluntarily controlled by the patient, disturbing the normal patterns
of movements), gegenhalten or paratonia (the resistance to passive movements with
proportional strength to the increase of muscle tone), rigidity (muscular hypertonus
which might be even and steady or cogwheel-like). muscular hypotonus (lose of
active movement with an apparently decreased muscle tone in passive movements),
sudden muscular tone alterations (rapid switches between muscular normotonus,
hypotonus, and hypertonus), and akinesia (absence and paucity of movements for at
least a half hour).
Francis and coworkers developed the Bush-Francis Catatonia Rating Scale
(BFCRS), a 23-item rating scale that operationally defines each catatonic sign, rates
its severity, and provides a standardized schema for clinical examination (Bush
et al. 1996). These authors (Bush et al. 1996) suggested that two or more signs of
catatonia present during 1 h or more or that can be reproduced in two or more occa-
sions are sufficient for diagnosis (Bush et al. 1996). In clinical settings, the presence
of even one catatonic sign should raise the suspicion of catatonia, and a full clinical
examination should be undertaken, including assessment of brain structural abnor-
malities using CT or MRI scans and EEG to rule out nonconvulsive status epilepticus
and encephalopathic states (Fink et al. 2010).
Frequency of Catatonia in AD
A recent study examined for the presence of catatonia all those patients referred to
a consultation liaison service in a general hospital. Using the BFCS, the authors
diagnosed catatonia in 9 % of the consults (Jaimes-Albornoz and Serra Mestres
2013). Rates of catatonia may be higher among hospitalized medical patients given
that withdrawn patients (such those with a hypokinetic delirious) may not be recog-
nized as catatonic (Zarr and Nowak 1990; Carroll et al. 2000; Cottencin et al. 2007).
Treatment of Catatonia
The treatment of catatonia is usually effective, with complete resolution in most

cases (Francis 2010).
Treatment should be started with lorazepam, 2–6 mg/day by any route of admin-
istration, although some patients may require titration to higher doses (12–16 mg/
day) (Jaimes-Albornoz and Serra-Mestres 2012). A recent open-label study in 20
catatonic patients showed that zolpidem (single oral dose of 10 mg) may be a useful
treatment option for catatonia (Francis 2010). Finally, electroconvulsive therapy
(ECT) has demonstrated great efficacy to treat catatonia even after pharmacologic
treatment failed (Francis 2010).
Catatonia in AD and Parkinsonism
Starkstein et al. (1996b) reported that 20 % of 79 older adults with major depression
referred to a psychiatric service met DSM-IV criteria for catatonia. A regression
analysis demonstrated that UPDRS scores, HAM-D scores, and older age contrib-
uted significantly to catatonia scores. When patients with catatonia were matched
with non-catatonic patients with PD based on UPDRS scores, catatonic patients had
significantly higher scores on the DSM-IV clusters of stupor, excessive motor activ-
ity, extreme negativism, and posturing. Furthermore, apomorphine did not improve
catatonic symptoms (Starkstein et al. 1996b).
Movement Disorder Due to Antipsychotic Medication in AD
Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is
often associated with psychotic symptoms. The prevalence of psychosis in AD was
recently estimated to be 7 %, with a 2-year cumulative incidence of 15 % (Vilalta-
Franch et al. 2012). Psychotic symptoms persisted for 1 year or more in 69 % of
patients with psychosis at baseline (Vilalta-Franch et al. 2012).
De Deyn et al. (2013) examined the efficacy of aripiprazole in a RCT that
included 208 AD patients with psychosis. Aripiprazole was started at 2 mg/day and
titrated upward up to 15 mg/day) depending on efficacy (mean dose = 10 mg/day).
Efficacy was similar for both active drug and placebo groups, and there were no
between-group differences on the frequency of parkinsonism (De Deyn et al. 2013).
Schneider et al. (2006) evaluated the effectiveness of atypical antipsychotic
drugs for the treatment of psychosis, aggression, or agitation in AD. This RCT
included 421 outpatients with AD and psychosis, aggression, or agitation who were
randomly assigned to receive olanzapine, quetiapine, risperidone, or placebo for up
to 36 weeks. The main outcomes were the time from initial treatment to the discon-
tinuation of treatment for any reason and the number of patients with at least mini-
mal improvement on the Clinical Global Impression of Change (CGIC) scale at
12 weeks. Overall, 24 % of patients who received olanzapine, 18 % of patients who
received risperidone, 16 % of patients who received quetiapine, and 5 % of patients
who received placebo discontinued their assigned treatment owing to intolerability
(P < 0.01). No significant differences were noted on the CGIC scale by the end of
the follow-up. Behavioral improvement was observed in 32 % of patients assigned
to olanzapine, 29 % of patients assigned to risperidone, 26 % of patients assigned
to quetiapine, and 21 % of patients assigned to placebo (P = 0.22) (Schneider
et al. 2006). Parkinsonism was significantly more frequent in patients on olanzap-
ine (12 %) or risperidone (12 %) as compared to quetiapine (2 %) or the placebo
groups (1 %).
Devanand and coworkers (2012) examined the risk of a recurrence of psychotic
symptoms after discontinuation of risperidone (mean dose = 0.97 mg daily) in
patients with AD for 4–8 months. The severity of psychosis and agitation were
reduced with risperidone, although there was a mild increase in parkinsonism, and
discontinuation of risperidone was associated with an increased risk of relapse.
During the first 16-week period, there were no significant differences in adverse
events as defined by increases above prespecified thresholds on scales measuring
parkinsonism between patients receiving risperidone and those receiving placebo.
Moreover, there were no significant differences between patients who received ris-
peridone continuously for 32 weeks and those who received placebo with respect to
parkinsonism and other movement disorders (Devanand et al. 2012).
Rocca et al. (2007) reported findings on a retrospective, naturalistic study on the
effects of 6 months’ treatment with risperidone, olanzapine, or quetiapine on behav-
ioral disturbances in outpatients with mild to moderate AD. All three drugs produced
significant improvements in behavioral disturbances, and medications were well tol-
erated with no significant differences emerging among treatments (Rocca et al. 2007).
Chiabrando et al. (2010) studied the prescriptive profile of antipsychotic drugs in
392 patients with dementia (49 % with AD) in terms of the choice of active sub-
stance and the clinical characteristics of patients. Hallucinations were present in
50 % of the cases and aggression in 53 %. There was an increased consumption of
quetiapine and a parallel decrease in the use of risperidone and olanzapine during
the study period. Neuroleptic doses were on average much lower than those used for
treating non-AD psychoses. The most frequently observed adverse events were
tremors (Chiabrando et al. 2010).
Conclusion
Parkinsonism is a frequent finding in AD, and several psychiatric disorders may

mimic this movement disorder. Depression is highly prevalent in AD, and these
patients may present with psychomotor retardation akin to bradyphrenia and brady-
kinesia. Apathy is another frequent behavioral comorbid condition in AD, and loss
of motivation may lead to hypokinetic states. Catatonia is a relatively rare finding in
AD, but many symptoms overlap with parkinsonism, making the differential diag-
nosis difficult. Finally, it is important to note that due to the high prevalence of
psychotic symptoms in AD, a large proportion of AD patients are on neuroleptic
medication, with a concomitant risk of increased parkinsonism.
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Chapter 6
Drug-Induced Movement Disorders
in Elderly Patients
Santiago Perez-Lloret, Jean-Louis Montastruc, and Olivier Rascol
Abstract Movement disorders such as dystonia, akathisia, parkinsonism, chorea,

stereotypies, myoclonus, or tics can be observed during exposure to a large number
of drugs commonly used for the treatment of diverse medical conditions. The most
frequent drugs connected to movement disorders are antipsychotics, but they can
also be observed with a variety of drugs, such as metoclopramide, prochlorperazine,
cinnarizine, flunarizine, H1 antihistaminergic drugs, trimetazidine, or serotonin
reuptake inhibitors. Clinical observation is crucial for differential diagnosis of drug-
induced movement disorders. Neuroimaging by positron emission tomography
(PET) or single photon emission computed tomography (SPECT) may be of help
for diagnosing drug-induced parkinsonism or tardive dyskinesia. The first therapeu-
tic measure is to withdraw the offending drug when possible. When needed, musca-
rine receptor blockers can be used to treat acute dystonia, propranolol or alprazolam
for akathisia, and reserpine or methyldopa for life-threatening tardive syndromes.
Keywords Drug-induced movement disorders • Adverse drug reactions •

Pharmacovigilance • Parkinsonism • Akathisia • Dystonia • Tremor • Chorea •
Myoclonus • Tardive syndromes
S. Perez-Lloret, MD, PhD, CPI (*)

Clinical Pharmacology and Epidemiology Laboratory, Medicine School,
Catholic University of Argentina, Buenos Aires, Argentina
Département de Pharmacologie et Service de Pharmacologie Clinique, Faculté de Médecine,
Centre Midi-Pyrénées de PharmacoVigilance, de Pharmaco épidémiologie et d’Informations
sur le Médicament, de l’Université de Toulouse, Centre Hospitalier Universitaire,
Toulouse, France
J.-L. Montastruc, MD, PhD • O. Rascol, MD, PhD
Department of Pharmacology, Toulouse University Hospital, Toulouse, France

88 S. Perez-Lloret et al.
Movement Disorders in the Elderly
Movement disorders can occur in previously unaffected elderly patients or during

the course of neuropsychiatric conditions (Haddad and Dursun 2008; Casey 1985).
Such movement disorders need to be differentiated from those induced by drugs. In
the following paragraphs, we will mention the most frequent movement disorders,
and we will briefly discuss their prevalence in the elderly population.
Idiopathic Parkinson’s disease (PD) is the most frequent movement disorder in
the elderly (Poewe 2006) and affects over one million people in Europe and North
America (Andlin-Sobocki et al. 2005; Lang and Lozano 1998). A systematic review
of 25 incidence studies found incidence rates between 9 and 19 cases per 100,000
habitants per year, being the mean age of symptom onset was 60–65 years (Twelves
et al. 2003). In some studies, incidence was as high as 263 per 1,000,000/year
(Perez et al. 2010). Prevalence in subjects above 50 years old is between 2 and 5 %
(de Rijk et al. 1997; Wenning et al. 2005).
Primary generalized dystonias are progressive, disabling disorders that typically
begin in youth. Dystonia affects about 16 every 100,000 habitants of all ages
(Steeves et al. 2012), but prevalence in subjects above 70 years is 131 per 100,000
(Das et al. 2007). Essential tremor is the most frequent cause of tremor besides
drugs. Its overall prevalence in the elderly is between 2 and 14 % (Barbosa et al.
2013). The most frequent hyperkinetic movement disorder is Huntington’s chorea
with an incidence of 0.38 per 100,000 per year and a prevalence of 5.70 per 100,000
(Pringsheim et al. 2012). Other movement disorders are less frequent.
As mentioned earlier, a variety of movement disorders can occur in other neuro-
psychiatric symptoms. In Huntington’s disease, for example, tardive dyskinesia
(TD) resulting from exposure to antipsychotic drugs often prescribed for psychiatric
symptoms of the disease has to be differentiated from chorea or dystonia. There are
also a variety of complex repetitive hyperkinetic disorders presenting as manner-
isms, stereotypies, and compulsions that may appear identical to certain movement
disorders such as tics or dystonia, further complicating differential diagnosis. Lastly,
hypokinetic conditions including bradyphrenia, catatonia, rigidity, catalepsy, nega-
tivism, and mutism are generally difficult to distinguish from various forms of drug-
induced parkinsonism.
Drug-induced movement disorders (DIMD) were identified soon after antipsy-
chotic marketing began in the 1950s. Initially, use of these drugs was linked to acute
adverse extrapyramidal syndromes including acute dystonia, akathisia, and parkin-
sonism (Tarsy 1983). Later, TD was also recognized as an adverse drug reaction to
antipsychotics. Since those years, many other drugs have been connected with
DIMD including psychiatric or nonpsychiatric drugs such as serotonin-specific
reuptake inhibitors, metoclopramide, or some calcium-channel blockers, among
others (Bakheit 1997; Casey 1990; Mena and de Yebenes 2006; Orti-Pareja et al.
1999; van Harten et al. 1999).
6 Drug-Induced Movement Disorders in Elderly Patients 89
Clinical Characteristics of Drug-Induced Movement

Disorders in the Elderly
Symptoms and time to onset of DIMDs vary significantly and include parkinsonism
as well as motor restlessness (akathisia), dystonia, and the entire spectrum of hyper-
kinesias (namely, chorea, stereotypies, myoclonus, dystonia, and tics) (Caligiuri
et al. 2000). They can be categorized as acute (immediate), continuous (insidious),
or persistent (tardive) (Table 6.1) (Rodnitzky 2002). Dystonia represents the most
frequent acute drug reaction. Its development is fast, and in some cases it may be as
severe as to require hospitalization. Continuous DIMDs persist only while the
offending drug is being administered and remit after its discontinuation, either
immediately or a variable period of time after discontinuation. They include akathi-
sia, tremor, parkinsonism, chorea, and myoclonus. In case of parkinsonism, lack of
remission after discontinuation could indicate that drug exposition unmasked a pre-
existent PD (Lopez-Sendon et al. 2013). Finally, tardive syndromes consist in a
variety of DIMDs appearing long after beginning drug use. Typically, offending
drug discontinuation will not relieve this kind of disorders (Rodnitzky 2002).
Table 6.1 Drug-induced movement disorders

DIMD Main characteristics
Acute (immediate)
Dystonia Sustained involuntary muscular contractions or spasms resulting in
abnormal postures or twisting and repetitive movements.
Symptoms are associated with distress, with or without pain
Continuous (insidious)
Akathisia Subjective feeling of restlessness and need to move. Objective
symptoms: walking in place, foot taping, rocking while seated
Parkinsonism Tremor, rigidity, and slowness of movements affecting bilateral
upper and lower extremities. Gait imbalance, masked facies,
micrographia, and stooped posture may be present
Tremor They can be postural, intentional, or action tremors. Their
frequency can vary between 4 and 12 Hz
Chorea Irregular, sudden-onset, explosive, purposeless movements
Myoclonus Brief, involuntary, muscular jerks
Persistent (tardive)
Dyskinesia Tardive dyskinesia: choreathetoid involuntary movements affecting
Dystonia the orofacial region and tongue. Lip smacking, chewing
Akathisia movements, and tongue protrusion are common. Symptoms are
Myoclonus not painful but highly distressing
Tics
Tremor
Acute Dystonia
Ninety-five percent of acute dystonic movements develop within 96 h of starting

drug exposure. It is characterized by jerks or prolonged muscle spasms often involv-
ing the craniocervical region (eyes, mouth, throat, neck) or even oculogyric crises
(van Harten et al. 1999; Casey 1992).
Involvement of trunk and limbs is less common than in idiopathic dystonia (van
Harten et al. 1999; Casey 1992). Acute dystonic reactions can be dramatic and at
times of enough severity to warrant lifesaving measures, such as involvement of
laryngeal muscles causing acute respiratory distress. Principal risk factors are male
gender, young age, previous episode of acute dystonia, recent cocaine use, hypocal-
cemia or hypoparathyroidism, and dehydration (van Harten et al. 1999; Casey
1992).
Main differential diagnosis are psychogenic dystonia, catatonia, or tardive dysto-
nia. Psychogenic dystonia can be suspected in cases in which dystonia disappears
whenever patients believe they are unobserved or other psychogenic movement dis-
orders or nonorganic neurological features are present, or if symptoms of somatiza-
tion disorder are present, or in the static form of dystonia. Catatonia is often
accompanied by symptoms such as rigidity, akinesis, cerea flexibilitas, and mutism,
which are not seen in acute dystonia nor related to drug treatment. The main differ-
ence between acute and tardive dystonia is that the latter occurs only after months
or years of treatment with antipsychotics and does not improve rapidly after admin-
istration of muscarinic receptor blockers.
Acute Akathisia
Akathisia (Greek “not to sit”) consists in difficulty remaining still and a subjective
sense of restlessness (Bakheit 1997; Akagi and Kumar 2002). It is a well-known
adverse drug reaction of antipsychotics, antiemetics, and antidepressants, among
others (Akagi and Kumar 2002). Difficult to detect reliably, it may present unex-
pectedly in a variety of clinical settings and be accompanied by unpleasant oral or
genital paresthesia, burning, or lancinating pain not responding to conventional
treatments. Principal risk factors are advanced age, presence of an affective disor-
der, cognitive impairment, female gender, and mental retardation.
Principal differential diagnoses are restless legs syndrome (RLS), mania (in
bipolar patients), and dyskinesias (Bakheit 1997). RLS is characterized by muscle
discomfort, pain and restlessness, or crawling sensations relieved by walking.
Unlike akathisia, which ceases during sleep, RLS occurs mostly at night.
Hyperactivity associated with anxiety states is often indistinguishable from akathi-
sia, especially in psychotic patients on neuroleptics. However, sympathetic overac-
tivity, for example, excessive sweating, palpitations, hyperventilation, tremulousness,
and dilated pupils, characteristic of anxiety and panic attacks, is not seen in patients
with akathisia. In bipolar affective disorders, akathisia can be confused with spon-
taneous mania, although usually milder and short-lived. In addition, spontaneous
mania is usually accompanied by delusions, hallucinations, and bizarre behavior.
Dyskinesia, in contrast to akathisia, is often unilateral or if bilateral tends to be
more pronounced in the more severely affected arm and leg. As a rule, it increases
in severity approximately 1–2 h after each levodopa and/or dopamine agonist dose,
although not always.
Parkinsonism
DIP is the second most common cause of parkinsonian syndrome (Mena and de
Yebenes 2006). The diversity of drugs involved in the production of DIP and the
wide range of clinical disorders in which they are used poses a tough diagnostic
challenge (Esper and Factor 2008). Several population-based studies suggest a prev-
alence between 1.7 and 2.7 % (Barbosa et al. 2006; Benito-Leon et al. 2004; Seijo-
Martinez et al. 2011).
DIP is characterized by its symmetrical presentation with bradykinesia dominat-
ing the overall clinical picture (Mena and de Yebenes 2006; Gershanik 1994).
Typical resting tremor is not frequently observed but when present is postural and of
higher frequency than in idiopathic disease. It develops insidiously after the offend-
ing drug is introduced, taking weeks or months to manifest fully. Cognitive impair-
ment is also frequently present (Kim et al. 2011). Main risk factors are older age,
female gender, and cognitive impairment (Barbosa et al. 2006; Kim and Byun 2009).
The main differential diagnoses are idiopathic PD and the parkinsonian form of
multiple system atrophy (Mena and de Yebenes 2006). DIP should be suspected in
older patients, more prone to take different medications for underlying chronic con-
ditions, including whenever symmetrical symptoms are present, disease onset is not
compatible with idiopathic Parkinson’s disease, or akinesia and postural tremor pre-
dominate over rigidity and rest tremor (Esper and Factor 2008; Gershanik 1994).
Other drug-induced symptoms like akathisia or tardive dyskinesia can provide clues
to potential parkinsonian syndrome origin.
Tremors, Chorea, and Myoclonus
Tremor is classified according to the behavior it is associated with (Morgan and

Sethi 2005). Resting tremor is usually 4–6 Hz, occurs with the limb supported
against gravity, and decreases with movement. Action or postural tremor varies
widely in amplitude and frequency and occurs with maintained posture or move-
ment. Finally, intentional tremor is terminal kinetic tremor (typically <5 Hz) with
larger amplitude during final stages of target-directed movements.
Drug-induced tremors are generally dose-responsive and lack progression,

unlike tremors in PD and essential tremor (Morgan and Sethi 2005). Main risk fac-
tors are older age, liver failure, CNS lesions, or anxiety.
Main differential diagnoses are chorea and myoclonus. Choreas are irregular,
sudden-onset, explosive, purposeless movements (Montastruc and Durrieu 2004).
They usually include facial, shoulder, or finger movements. They are facilitated by
emotion and attention and inhibited by rest, calm, and sleep. They are infrequently
caused by drugs, except for the well-known levodopa-induced dyskinesias in par-
kinsonian patients. Notwithstanding, contraceptives can cause choreas especially in
the case of patients with antecedents of rheumatic fever. Antiepileptic can also be
related to choreas.
Myoclonus is brief, involuntary, muscular jerks that can generate movement or
not (Montastruc and Durrieu 2004). Penicillins are frequent causes of myoclonus.
They can also occur with antiepileptic or antidepressant overdose, in the context of
an encephalopathy.
Tardive Dyskinesia and Other Syndromes
Tardive syndromes often run a persistent course despite cessation of triggering drug
therapy. In some instances, they may become permanent and irreversible. They
should be considered in patients presenting abnormal involuntary movements after
at least 3 months of total cumulative neuroleptic exposure, although they are more
common after longer periods of exposure (1–2 years) (Casey 1990; Caligiuri et al.
2000). They can develop even after antipsychotics dose reduction (unmasked TD)
or even after the causative drug has been withdrawn (covert or withdrawal TD).
TD consists of involuntary movements usually involving muscles of the tongue,
lips, mouth, or face (i.e., the so-called buccolinguomasticatory syndrome) (Haddad
and Dursun 2008; Casey 1990; Caligiuri et al. 2000; Paulson 2005). Upper facial
muscles are less frequently affected by involuntary movements; however, it is pos-
sible to see increased blinking, blepharospasm, arching of the eyebrows, ocular tor-
sion, and deviation.
Other parts of the body can be affected, though less frequently, and a wide range
of movements can be observed including myoclonic jerks, tics, chorea, and dystonia.
Gait can be abnormal, with a broad base, leg jerking, and repetitive irregular flexion
and extension of the knees (Haddad and Dursun 2008; Tarsy 1983; Casey 1990).
While standing in place, affected individuals tend to shift their weight from one leg
to the other or exhibit pacing or marching in place. The diaphragm and accessory
respiratory muscles are often involved causing a fast and irregular breathing pattern
(respiratory dyskinesia). The movements are more pronounced when the patient is
alert or excited and disappear during sleep. Patients can sometimes suppress the
movements through intense voluntary effort. Main risk factors are older age and
female gender, presence of affective disorders, alcoholism, diabetes mellitus, electro-
convulsive treatment, iron deficiency, mental retardation, or organic brain disorder.
Most important differential diagnosis is chorea (Haddad and Dursun 2008).

Movements in TD tend to be more patterned, repetitive, and stereotypic than in
chorea.
Dystonic phenomena account in up to 20 % of tardive syndromes found in psy-
chiatric inpatients and are similar to acute dystonia (Orti-Pareja et al. 1999; Burke
et al. 1982). Motor and vocal tics following chronic neuroleptic treatment can occa-
sionally be seen as part of the tardive syndrome. This type of clinical presentation
has been described and referred as tardive tourettism (Jankovic 1995). In a small
number of cases, myoclonus can be the predominant feature of TD. Tardive tremor
has been also added to the clinical spectrum of TD (Jankovic 1995).
Diagnostic Work-Up
During the course of any drug treatment, movement disorders not necessarily related
to intake may occur. Nonetheless, prescription drugs should always be considered a
differential diagnosis for any movement disorder, especially if the patient is on an
agent known to induce them. It should be kept in mind that subjects may not readily
recall all the medications they receive.
Causality assessment is indispensable but many times difficult. The following
aspects of the event should be considered (Rehan et al. 2009; Edwards and Aronson
2000; Montastruc et al. 2006):
• Timing in relation to drug intake. When symptoms begin soon after drug expo-
sure starts, diagnosis may be easy; however, connecting symptoms to long-term
drug use may be difficult.
• Plausibility of the event. If the event result from a known pharmacodynamic
property of the drug (i.e., D2-blockage properties of neuroleptics), it may be
easier to connect to the drug. Nonetheless, in some cases DIMD pathophysiol-
ogy may not be known.
• Exclusion of other causes. DIMD may be diagnosed only after exclusion of
every other possible cause for the event observed.
• Dechallenge may be of aid when feasible. Disappearance of DIMD after drug
discontinuation is indicative of a link to the drug. Nonetheless, some DIMDs
such as TD do not disappear after drug discontinuation.
• Rechallenge, when possible, may lead to the reappearance of the movement dis-
order, thus reassuring its drug-induced nature.
Clinical observation is crucial for DIMD differential diagnosis. In the case of DIP,
while motor symptoms may not allow proper differentiation with PD, the absence of
non-motor symptoms favors the former (Kim et al. 2013a). DIP patients have normal
olfactory function except when dopaminergic loss was present in patients (Bovi et al.
2010). Clinical laboratory is in general not helpful for the diagnosis of DIMDs.
Nonetheless, increased serum hyperprolactinemia can be used as a marker of dopa-
mine receptor blockage when antipsychotics are used (Kinon et al. 2003).
For DIP and TD however, some diagnostic tools are available. Firstly, acute
dopaminergic challenge with either levodopa or apomorphine may represent a use-
ful tool for differentiating PD from DIP (Merello et al. 2002). Schizophrenic patients
with DIP show a noteworthy absence of response to levodopa or apomorphine dur-
ing a levodopa acute challenge (Merello et al. 1996).
Assessment of dopaminergic nigrostriatal pathway integrity can also be useful
distinguishing DIMD, in which they are intact, from Parkinson’s disease, in which
they are not. This can be accomplished by imaging with positron emission tomog-
raphy (PET) or single photon emission computed tomography (SPECT) using
ligands binding to dopaminergic nigrostriatal system markers (Tolosa et al. 2003).
The presence of the dopamine transporter in the presynaptical buttons of the dopa-
minergic neurons located in the striate nuclei can be assessed by [123I]FP-CIT
SPECT (Tolosa et al. 2003). Death of dopaminergic neurons, for example, in PD,
leads to a reduced number of dopamine transporter, which cause a reduction in the
intensity of the signal that the striatal level in the SPECT. In the case of [18F]-dopa-
PET, what is evaluated is the integrity of presynaptical dopaminergic structures in
charge of uptaking and processing DOPA to form dopamine. Results are interpreted
in an analogous way to those of SPECT.
Nonetheless, these techniques may not be enough in schizophrenic patients, in
whom D2-receptor blockade may coexist with a dopamine nigrostriatal terminal
defect (Tinazzi et al. 2012). In doubtful cases, combination of techniques might be
useful for differential diagnosis (Kim et al. 2013b; Lee et al. 2007). Assessment of
cardiac sympathetic denervation by using 123I-metaiodobenzylguanidine (MIBG)
myocardial scintigraphy may also provide further clues about the origin of the par-
kinsonian syndrome (Kim et al. 2013b; Lee et al. 2007).
For TD diagnosis, neuroimaging studies may helpful, as anomalies in basal gan-
glia and other brain regions in schizophrenic patients with TD have been identified
(Khiat et al. 2008). These anomalies include caudate nuclei, left lentiform nuclei,
and temporal sulci volume differences as well as reduction in T2 relaxation time in
the left caudate nuclei.
Offending Drugs
Many psychotropic and nonpsychotropic drugs have been related to DIMD

(Tables 6.2 and 6.3). In this section, we will review the most important ones.
Antipsychotics
Centrally acting dopamine receptor blockers, such as haloperidol and phenothi-

azine, are the agents most commonly associated with DIMD (Haddad and Dursun
2008; Orti-Pareja et al. 1999). The proposed mechanism for these adverse drug
Table 6.2 Movement disorders induced by psychotropic drugs
Drug-induced Tardive
Drug Acute dystonia Akathisia parkinsonism dyskinesias Tremors Myoclonus Other choreas Tic
Anesthetics/SNC depressors
Propofol x (Brooks x (Brooks 2008) x (Jimenez-
2008) Jimenez
et al. 1997)
Procaine x (Montastruc et al.
1994)
Ethanol x (Montastruc et al. xx (Morgan and
1994) Sethi 2005)
Anticonvulsants
Valproic acid x (Jimenez-Jimenez x (Mena and de xx (Morgan and x (Montastruc x (Jimenez-
et al. 1997) Yebenes 2006; Sethi 2005) and Durrieu Jimenez
Nguyen et al. 2004) et al. 1997)
2004; Masmoudi
et al. 2006)
Carbamazepine x (van Harten x (van Harten x (Jimenez-
6 Drug-Induced Movement Disorders in Elderly Patients
et al. 1999) et al. 1999; Jimenez

Blayac et al. et al. 1997)
2004)
Topiramate
Phenytoin x (van Harten x (Jimenez-Jimenez x (Mena and de x (Lang 1992) xx (Montastruc x (Rodnitzky
et al. 1999) et al. 1997) Yebenes 2006; and Durrieu 2002)
Nguyen et al. 2004)
2004)
Phenobarbital x (Lang 1992) x (Montastruc x (Jimenez-
and Durrieu Jimenez
2004) et al. 1997)
Gabapentin x (Reeves et al. x (Morgan and xx (Asconape x (Jimenez-
1996) Sethi 2005) et al. 2000) Jimenez
95
et al. 1997)
(continued)
96
Lamotrigine xx (Rodnitzky 2002) x (Morgan and

Sethi 2005)
Tiagabine x (Morgan and
Sethi 2005)
Oxcarbazepine x (Morgan and
Sethi 2005)
Levetiracetam x (Mena and de
Yebenes 2006)
Ethosuximide x (Montastruc et al. x (Jimenez-
1994) Jimenez
et al. 1997)
Pregabalin x (Perez-Lloret et al. x (Perez-Lloret
2009) et al. 2009)
Antidepressants
Tricyclics x (Montastruc x (Bakheit 1997) x (Nguyen et al. x (Orti-Pareja xx (Morgan and x (Montastruc x (Rodnitzky
and 2004) et al. 1999; Sethi 2005) and Durrieu 2002)
Durrieu Blayac et al. 2004)
2004) 2004)
SSRIs xx (van Harten xx (Bakheit 1997) x (Mena and de xx (Jimenez- xx (Morgan and x (Montastruc x (Rodnitzky x (Jimenez-
et al. 1999) Yebenes 2006; Jimenez and Sethi 2005; and Durrieu 2002) Jimenez
Jimenez-Jimenez Molina 2000; Jimenez- 2004; and Molina
and Molina 2000; Blayac et al. Jimenez and Jimenez- 2000)
Nguyen et al. 2004) Molina Jimenez and
2004; Jimenez- 2000) Molina
Jimenez et al. 2000)
1996)
Trazodone x (Montastruc et al. x (Montastruc
1994) and Durrieu
S. Perez-Lloret et al.
2004)
Bupropion x (Montastruc et al. x (Montastruc
1994) and Durrieu
2004)
Venlafaxine x (Montastruc
and Durrieu
2004)
Nefazodone x (Montastruc
and Durrieu
2004)
Mirtazapine x (Montastruc
and Durrieu
2004)
Antiemetics
Metoclopramide xx (van Harten xx (Jimenez-Jimenez xx (Mena and de xx (Orti-Pareja xx (Morgan and xx (Montastruc
et al. 1999) et al. 1996) Yebenes 2006; et al. 1999; Sethi 2005) and Durrieu
Jimenez-Jimenez Blayac et al. 2004)
et al. 1996) 2004;
Jimenez-
Jimenez
et al. 1996)
Domperidone x (Bonuccelli
et al. 1991)
Clebopride x (Montagna et al.
1992)
(continued)
97
98
Antipsychotics
Typical xx (van Harten xx (Bakheit 1997; xx (Bakheit 1997; xx (Bakheit xx (Blayac et al. xx (Montastruc x (Montastruc
et al. 1999) Jimenez-Jimenez Jimenez-Jimenez 1997; 2004) and Durrieu and
et al. 1996) et al. 1996) Jimenez- 2004) Durrieu
Jimenez 2004;
et al. 1996) Blayac
et al. 2004)
Atypical x (Bakheit x (Bakheit 1997; x (Bakheit 1997; x (Bakheit 1997; x (Bakheit 1997; x (Bakheit
1997; Gareri et al. Gareri et al. 2006) Gareri et al. Gareri et al. 1997;
Gareri 2006) 2006) 2006) Montastruc
et al. 2006) and Durrieu
2004;
Gareri et al.
2006)
Anxiolytics
Buspirone x (LeWitt et al. x (LeWitt et al. 1993) x (LeWitt et al. 1993) x (LeWitt et al. x (Jimenez- x (Montastruc
1993) 1993) Jimenez and Durrieu
et al. 1997) 2004;
LeWitt et al.
1993)
Diazepam x (Lang 1992) x (Jimenez-Jimenez x (Montastruc
et al. 1997) and Durrieu
2004)
Clonazepam x (Montastruc
and Durrieu
2004)
Lorazepam x (Jimenez-Jimenez x (Orti-Pareja
et al. 1996) et al. 1999)
CNS stimulants
Methamphetamine/ x (Morgan and Sethi x (Morgan and x (Rodnitzky x (Montastruc
amphetamines 2005) Sethi 2005) 2002) and
Durrieu
2004;
Blayac
et al. 2004)
Cocaine x (van Harten x (Chung and Chiu x (Morgan and Sethi x (Weiner et al. x (Morgan and xx (Jimenez- x (Montastruc
et al. 1999) 1996) 2005) 2001) Sethi 2005) Jimenez and
et al. 1997) Durrieu
2004;
Blayac
et al. 2004)
Methylphenidate x (Chung and Chiu xx (Rodnitzky x (Montastruc
1996) 2002) and
Durrieu
2004;
Blayac
et al. 2004)
Drugs for cephalea

Sumatriptan x (Oterino and
Pascual
1998)
Methysergide x (Jimenez-Jimenez
et al. 1997)
Drugs for dementia
Donepezil x (Mena and de
Yebenes 2006)
Rivastigmine x (Mena and de
Yebenes 2006)
(continued)
99
100
Pyridostigmine x (Nguyen et al.
2004)
Bethanechol x (Montastruc et al.
1994)
Opiates
Meperidine x (Jimenez-Jimenez x (Nguyen et al. x (van Harten
et al. 1997) 2004) et al. 1999;
Gareri et al.
2006)
Morphine xx (Montastruc
and Durrieu
2004)
Oxycodone x (Lang 1992)
Methadone x (Clark and x (Lang 1992) x (Jimenez-
Elliott 2001) Jimenez
et al. 1997)
Fentanyl x (Blayac et al. x (Petzinger
2004) et al. 1995)
Tramadol x (Montastruc
and Durrieu
2004)
Other drugs
Lithium xx (Bakheit 1997) xx (Mena and de x (Orti-Pareja xx (Morgan and x (Montastruc x (Jimenez-
Yebenes 2006; et al. 1999; Sethi 2005) and Durrieu Jimenez
Nguyen et al. Blayac et al. 2004) et al. 1997)
2004; Jimenez- 2004;
Jimenez et al. Jimenez-
1996) Jimenez
et al. 1996)
Tetrabenazine x (Sachdev 1995) xx (Mena and de x (Jimenez-
Yebenes 2006) Jimenez
et al. 1997;
Blayac et al.
2004)
Trihexyphenidyl x (Blayac et al. x (Rodnitzky
2004) 2002)
x uncommon/single report, xx common (frequency >10 %)
101
Table 6.3 Movement disorders induced by nonpsychotropic drugs
102
Drug Acute dystonia Akathisia parkinsonism dyskinesias Tremors Myoclonus Other choreas
Antibiotics
Amphotericin B (Mott et al. 1995) x (Morgan and
Sethi 2005)
Penicillin xx (Montastruc
and Durrieu
2004)
Cephalosporins xx (Montastruc
and Durrieu
2004)
Chloroquine x (van Harten
et al. 1999)
Acyclovir x (Morgan and x (Jimenez-
Sethi 2005) Jimenez et al.
1997)
Vidarabine xx (Morgan and
Sethi 2005)
Co-trimoxazole x (Morgan and
Sethi 2005)
Foscarnet x (Dubow et al.
2008)
Asthma/allergies
Chlorpheniramine x (Montastruc xx (Nguyen et al. x (Lang 1992) x (Jimenez-
et al. 1994) 2004) Jimenez
et al. 1997)
Theophylline x (Jimenez-
Jimenez
et al. 1997)
B2-adrenergic xx (Rodnitzky xx (Morgan and
agonists 2002) Sethi 2005)
Antineoplastics
Cytosine arabinoside x (Nguyen et al. 2004) x (Morgan and
Sethi 2005)
Vincristine x (Nguyen et al. 2004) x (Morgan and
Sethi 2005)
Methotrexate x (Nguyen et al. 2004)
5-Fluorouracil x (Nguyen et al. 2004)
Doxorubicin x (Bower and
Muenter 1995)
Thalidomide x (Morgan and
Sethi 2005)
Ifosfamide x (Morgan and
Sethi 2005)
Interferon alfa xx (Morgan and x (Jimenez-
Sethi 2005) Jimenez et al.
1997)
Cardiovascular disorders
Amiodarone xx (Mena and de x (Werner and xx (Morgan and x (Werner and
Yebenes 2006; Olanow Sethi 2005; Olanow 1989)
Nguyen et al. 1989) Montastruc
2004) and Durrieu
2004)
Procainamide xx (Morgan and
Sethi 2005)
(continued)
103
104
Pindolol x (Morgan and
Sethi 2005)
Diltiazem/verapamil x (Dick and x (Mena and de
Barold 1989) Yebenes 2006;
Nguyen et al.
2004; Jimenez-
Jimenez et al.
1996; Dick and
Barold 1989)
Drugs for vertigo
Prochlorperazine/ xx (Mena and de
thiethylperazine Yebenes 2006)
Cinnarizine/ x (van Harten x (Orti-Pareja xx (Nguyen et al. x (Orti-Pareja
flunarizine et al. 1999) et al. 1999; 2004) et al.
Jimenez- 1999;
Jimenez et al. Jimenez-
1996) Jimenez
et al.
1996)
Endocrine disorders
Levothyroxine xx (Rodnitzky xx (Morgan and
2002) Sethi 2005;
Jimenez-
Jimenez
et al. 1997)
Calcitonin x (Morgan and
Sethi 2005)
Contraceptives x (Jimenez-Jimenez x (Shale and x (Rodnitzky
et al. 1997) Tanner 2002)
1996)
Corticosteroids xx (Rodnitzky
2002)
Veralipride x (Nguyen x (De Leo et al. 2006) x (De Leo x (De Leo et al. x (De Leo et al.
(menopause) et al. 2004) et al. 2006) 2006)
2006)
Hypoglycemics x (Ross 1990) x (Jimenez-
Jimenez
et al. 1997)
Anabolic steroids x (Shale and x (Jimenez-
Tanner Jimenez et al.
1996) 1997)
Reflux/gastric ulcers
Cimetidine x (Lang 1992) x (Morgan and x (Rodnitzky
Sethi 2005) 2002)
Ranitidine x (Lang 1992) x (Rodnitzky
2002)
Misoprostol x (Morgan and
Sethi 2005)
Lansoprazole x (Angles et al. 2002)
Bismuth xx (Rodnitzky
2002)
(continued)
105
106
Other drugs
Cyclosporine/ x (Nguyen et al. 2004) xx (Morgan and
tacrolimus Sethi 2005;
Montastruc
and Durrieu
2004)
Naproxen sodium x (Montastruc et al.
1994)
x uncommon/single report, xx common (frequency >10 %)
reactions is dopamine receptor blockage at the level of the striatum. DIMDs are less
frequently associated with the atypical antipsychotics, but dose-related movement
disorders occur with olanzapine, risperidone, and quetiapine at higher doses as well
(Gareri et al. 2006). Nonetheless, a recent intention-to-treat, secondary analysis of
data from an earlier randomized controlled trial failed to find the expected reduc-
tions of DIMD frequency for participants randomized to second-generation drugs
(Peluso et al. 2012).
Mechanisms underlying DIMDs are complex and not fully understood. They are
probably related to alterations within subcortical brain regions (e.g., basal ganglia
and thalamus) and do not involve the corticospinal pyramidal motor system.
Incidence of acute dystonia in treated patients varies from 2 to 64 % according
to different series, and pathogenesis remains unclear. All antipsychotics bind to D2
receptors; it has therefore been suggested that blockage of these receptors in the
caudate, putamen, and globus pallidus is partly responsible for causing acute dysto-
nia (Rupniak et al. 1986).
DIP is observed on average in about 4 % of patients taking neuroleptics (Noyes
et al. 2006; Rochon et al. 2005). DIP is caused by several mechanisms interfering
with the normal nigrostriatal dopamine neuron function. Generally, compounds
responsible for DIP block striatal dopamine D2 receptors, requiring blockade to
exceed 75 % in order to trigger DIP (Remington et al. 2006). Several recent reports
suggest certain neuroleptics produce DIP not only related to excessive blockade of
dopamine receptors but also mediated through direct and persistent toxic effects on
nigrostriatal dopamine neurons (Ulrich et al. 2005).
Akathisia affects about 28 % of patients on antipsychotics (Peluso et al. 2012).
The underlying pathophysiologic mechanism of akathisia is thought to be an imbal-
ance between cortical and nigrostriatal dopaminergic innervation, favoring increased
functional activity of the mesolimbic and nigrostriatal systems, in particular the
nucleus accumbens (Bakheit 1997).
The annual incidence of TD is about 5 % overall, including transient (3 %) and
persistent (2 %) TD (Tarsy and Baldessarini 2006). Risk of TD has proven to be
lower with atypical antipsychotics compared to classic ones. A recent review of
clinical trials on several modern antipsychotics vs. haloperidol in schizophrenia
showed that risperidone, olanzapine, quetiapine, amisulpride, or ziprasidone
induced TD in 2.1 % of cases, which is lower than the aforementioned annual TD
rate for classic antipsychotics. Indeed, among patients under 50, risk of new-onset
TD with haloperidol (5.4 %) was 6.8 times greater than atypical antipsychotics
(Correll et al. 2004). Conversely, TD incidence with modern drugs among patients
over 50 was similar to rates in younger individuals exposed to haloperidol, suggest-
ing an important agent-age interaction (Correll et al. 2004). The incidence of TD
varied remarkably little among modern agents except for increased risk with higher
doses of risperidone.
The pathophysiologic basis of TD remains speculative, but various neurochemi-
cal hypotheses have been proposed, including striatal dopaminergic hypersensitiv-
ity, basal ganglia cholinergic deficiency, dysfunctions of striatonigral γ-aminobutyric
acid (GABA)-mediated neurons, glutamate-induced excitotoxicity, and oxidative
stress (Casey 2004; Galili et al. 2000; Silvestri et al. 2000). It has been proposed that
antipsychotics result in increased dopamine turnover, followed by excess free radi-
cal production and subsequent damage to striatal GABAergic fibers, with reduced
inhibitory activity on motor circuits (Casey 2004; Galili et al. 2000; Silvestri et al.
2000). Concurrently, chronic blockade of dopamine receptors results in excessive
glutamate activity and resultant excitotoxicity. Likewise, chronic dopamine recep-
tor blockade results in receptor supersensitivity and persistent changes within basal
ganglia motor circuit.
Antidepressants
Traditional, tricyclic antidepressants, such as amitriptyline and imipramine, rarely

produce movement disorders except for high-frequency, postural tremors that have
been linked to their serotonergic properties (Morgan and Sethi 2005). Conversely,
serotonin reuptake inhibitors produce a variety of hypokinetic and hyperkinetic
movement disorders, including tremor, dystonia, bruxism, myoclonus, and other
hyperkinesias with higher frequency (Jimenez-Jimenez and Molina 2000). Recent
reports showed that akathisia is the most frequent serotonin reuptake inhibitor-
related movement disorder, followed by dystonia, parkinsonism, and dyskinesia
(Jimenez-Jimenez and Molina 2000). Interestingly, some serotonin receptor ago-
nists used in PD, such as sarizotan, can worsen parkinsonism (Olanow et al. 2004).
The most plausible hypotheses for the induction of movement disorders by sero-
tonin reuptake inhibitors are related to the interaction between the serotonergic and
dopaminergic systems (Davies and Tongroach 1978; Dray et al. 1978; Di Mascio
et al. 1998). Serotonin reuptake inhibitors would induce a 5HT2 receptor-mediated
inhibition of nigral dopaminergic release in the striatum, thus causing the move-
ment disorders.
Other Drugs
DIMDs can be associated with many other medications, including antiemetics

which may block central dopamine receptors (droperidol, metoclopramide, or pro-
chlorperazine), lithium, or calcium-channel blockers (cinnarizine, flunarizine),
among others. Many of these drugs are widely prescribed and can be leading causes
of DIMD. Metoclopramide, for example, has emerged as the most common cause
of tardive dyskinesia in some movement disorder clinics (Kenney et al. 2008;
Pasricha et al. 2006). H1 antihistaminergics are a frequent cause of DIP (Bondon-
Guitton et al. 2011). This effect is explained by their chemical formula, as these
drugs are phenothiazine derivatives and are thus D2-receptor blockers.
Tremor commonly occurs with lithium treatment and occasionally chorea
(Montastruc and Durrieu 2004; Jimenez-Jimenez et al. 1997). The antiepileptic
drug valproate is commonly associated with tremor (Nouzeilles et al. 1999).

Pregabalin has been shown to cause parkinsonism (Perez-Lloret et al. 2009).
Interference with substance P neurotransmission in the basal ganglia is the proposed
mechanism. For many years, chorea has been recognized as a complication of estro-
gen- and progesterone-containing products (Vela et al. 2004).
Parkinsonism induced by cinnarizine or flunarizine is still a serious medical prob-
lem in some countries due to the wide use of these products in the elderly, of whom
up to one-third may suffer from an irreversible deficit (Garcia-Ruiz et al. 1992). The
pathophysiologic mechanisms underlying calcium-channel blocker-induced move-
ment disorders remain uncertain but are most likely due to D2-receptor block result-
ing from piperazine core (Chouza et al. 1986). Another drug with the same structure,
trimetazidine, frequently causes parkinsonism (Masmoudi et al. 2012).
Management
The first therapeutic measure is to withdraw the offending drug when possible. This
sole measure will probably suffice for most patients. Nonetheless, in some instances,
extra measures will need to be taken. A summary of such measures is offered in
Table 6.4.
In most instances, acute dystonia presents spontaneous resolution shortly after
drug withdrawal. Nonetheless, if treatment is needed, such as in the case of stridor,
antihistamines and/or benzodiazepines can be of help (van Harten et al. 1999;
Povlsen and Pakkenberg 1990). Intramuscular or intravenous administration of
muscarinic receptor blockers (biperiden 5 mg or procyclidine 5 mg) or antihista-
mines (promethazine 50 mg) is usually effective within 20 min. Occasionally, sec-
ond or third injections are necessary. After resolution, treatment with anticholinergics
should be continued for at least 24–48 h to prevent recurrence.
Anticholinergics have been commonly prescribed as a preventive treatment of
DIP in patients treated with antipsychotics without strong evidence to support this
use. Preliminary unconfirmed evidence supporting the use of vitamin E as a neuro-
protective has been published (Mena and de Yebenes 2006). Once DIP is diagnosed,
the best possible treatment is discontinuation of the causative drug (Mena and de
Yebenes 2006). In the majority of cases, however, it subsides gradually over a period
Table 6.4 Therapeutic intervention for some drug-induced movement disorders

Movement disorder Recommended measure/s
Acute dystonia Biperiden 5 mg, procyclidine 5 mg, or promethazine 50 mg i.v.
Acute akathisia Propranolol, alprazolam, mianserin (akathisia related to lithium)
Parkinsonism Levodopa, dopamine agonists (poor response)
Tardive syndromes Prevention: use the lowest possible dose of antipsychotics. Reserpine,
methyldopa (reserved for debilitating or life-threatening syndrome).
Tetrabenazine
of weeks or months, but in some cases it may persist as long as a year or more
(Mena and de Yebenes 2006). Patients show global improvement soon after drug
withdrawal, and cognitive and mood disturbances subside more slowly, while
tremor may persist 18 months after drug discontinuation in a significant number of
patients. In those patients in whom parkinsonism becomes persistent and irrevers-
ible after drug withdrawal, diagnosis of latent idiopathic parkinsonism should be
considered. Hyposmia and dopaminergic loss as observed by neuroimaging tech-
niques are indicative of such subclinical disease (Kim et al. 2013b).
Propranolol, alprazolam, or antiserotonergic drugs have been reported to be
effective in the treatment of akathisia (Bakheit 1997; Amsterdam et al. 1994).
Lithium-induced akathisia was claimed to be particularly responsive to mianserin, a
noradrenaline and serotonin reuptake inhibitor. Although low serum iron is com-
monly associated with neuroleptic-induced tardive akathisia, the value of iron sup-
plements is doubtful and may even be harmful.
The best treatment for TD is prevention. To accomplish this, the lowest effec-
tive dose of antipsychotics should be identified for each patient and regularly
rechecked. After TD develops, drug withdrawal is followed by improvement from
0 to 92 % of patients, depending on the study (Casey 1990). This wide range is due
to multiple factors including patient variables (e.g., age), treatment variables (drug
dose and cumulative exposure), and temporal aspects (early diagnosis, duration of
treatment, and duration of TD follow-up). Age is consistently correlated with TD
improvement, with younger patients more likely to improve. It may take up to 5
years for complete remission to occur. Shorter neuroleptic exposure and age under
60 after onset of TD are correlated with greater likelihood of remission.
Dyskinesias, however, may reappear when antipsychotics are reinstituted. In a sig-
nificant number of patients, they may become irreversible despite antipsychotics
cessation.
Treating TD is a clinical challenge. Unfortunately, no drugs are uniformly safe
and effective over extended treatment periods. Reducing dopaminergic function is
the most effective way of suppressing (masking) TD (Jeste and Wyatt 1982). This
strategy is justified only in those rare cases when TD is severe, debilitating, or life-
threatening. Functional reduction of dopamine can be achieved with presynaptical
depletion (reserpine) or by false transmission (methyldopa). Tetrabenazine has been
successfully used for tardive dyskinesia, tardive tremor, and tardive tourettism treat-
ment (Jankovic 2009). Botulinum toxin can be used to treat tardive dystonia
(Jankovic 2009). Muscarinic receptor blockers should not be used as they may lower
the threshold for the appearance of tardive syndrome (Klawans and Rubovits 1974).
Conclusion
Movement disorders are common adverse drug reactions. They should be envi-
sioned when treatment with possible offending drugs is initiated. Off-label use of
movement disorder-inducing drugs or use beyond recommended doses should be
discouraged. If a patient must receive a movement disorder-inducing drug, minimal

doses should be prescribed and careful follow-up is recommended.
In this chapter, we provided an extensive albeit not exhausting list of potential
offending agents. Nonetheless, clinicians should remain alert, as DIMD may be
encountered either with innovative, insufficiently studied drugs or with well-known
drugs but used in new or wider populations or under new therapeutic regimens.
Future research should also focus on identifying new treatments for DIMD, which
at present are sorely lacking.
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Chapter 7
Scales for Measuring Parkinsonism
in Demented Patients
Carmen Rodriguez-Blazquez, Anna Sauerbier, K. Ray Chaudhuri,

and Pablo Martinez-Martin
Abstract The term “parkinsonism” refers to a syndrome combining motor symptoms

such as bradykinesia, rigidity, tremor, and other clinical signs characteristic of
Parkinson’s disease. A large range of these disorders can simultaneously express par-
kinsonism and dementia, although with variable occurrence particularly related to the
onset of disease and expression of clinical symptoms. Therefore, motor and cognitive
assessment in these conditions are relevant, for both clinical research and practice.
Most of the rating scales applied in this situation are measures coming from the realm
of the movement disorders, used for evaluation of Parkinson’s disease, multiple system
atrophy, progressive supranuclear palsy, etc. Also, there are generic scales designed for
assessment of motor state that may be useful in the appropriate context. Some of the
most frequently used scales are reviewed in this chapter, with particular attention to
their description and basic clinimetric properties.
Keywords Rating scales • Assessment • Parkinsonism • Parkinson’s disease •

Progressive supranuclear palsy • Multiple system atrophy • Dementia • Dementia with
Lewy bodies • Dementia associated with Parkinson’s disease • Alzheimer’s disease
A. Sauerbier • K.R. Chaudhuri, MD, FRCP, DSc

National Parkinson Foundation International Centre of Excellence, King’s College London,
London, UK
National Institute for Health Research (NIHR) Mental Health Biomedical Research
Centre and Dementia Unit at South London, London, UK
Department of Neurology, Maudsley NHS Foundation Trust, London, UK
C. Rodriguez-Blazquez, MSc
Department of Applied Epidemiology, National Centre of Epidemiology and Centre for
Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED),
Carlos III Institute of Health, Madrid, Spain
P. Martinez-Martin, MD, PhD (*)
Research Unit, Alzheimer Centre Reina Sofia Foundation and Centre for Networked
Biomedical Research on Neurodegenerative Diseases (CIBERNED),
CIEN-Foundation, Carlos III Institute of Health, Madrid, Spain

118 C. Rodriguez-Blazquez et al.
Abbreviations
AD Alzheimer’s disease
DLB Dementia with Lewy bodies
ESRS Extrapyramidal Symptom Rating Scale
FAST Functional Assessment Staging
ICARS International Cerebellar Ataxia Rating Scale
MDS-UPDRS Movement Disorder Society-sponsored version of the UPDRS
MSA Multiple system atrophy
NNIPPS-PPS Natural History and Neuroprotection in Parkinson Plus Syndromes
– Parkinson Plus Scale
PD Parkinson’s disease
PDD Dementia associated with Parkinson’s disease
PEPS Pyramidal and Extrapyramidal Scale
PIGD Postural instability gait difficulty
POS-PP Palliative Care Outcome Scale-Parkinsonism Plus
PSP Progressive supranuclear palsy
PSPRS Progressive Supranuclear Palsy Rating Scale
RSGE-CD Rating Scale for Gait Evaluation in Cognitive Deterioration
SCOPA Scales for Outcomes in Parkinson’s Disease
UMSARS Unified Multiple System Atrophy Rating Scale
UPDRS Unified Parkinson’s Disease Rating Scale
Dementia and Parkinsonism
Parkinsonism is considered to be an umbrella term which includes a combination of

motor signs such as bradykinesia, rigidity, postural instability, and impaired gait,
manifestations characterizing Parkinson’s disease (PD) but shared by several condi-
tions that express other “red flags” signs simultaneously. In terms of neurodegenera-
tive disorders causing dementia and parkinsonism, the most common are Alzheimer’s
disease (AD), dementia with Lewy bodies (DLB), and PD. Dementia and parkin-
sonism may coexist in varying patterns. For instance, appearance of parkinsonian
features in patients with AD is usually a late and not an inevitable occurrence, while
the development of dementia in patients with a clinical diagnosis of DLB is thought
to be an early event. In Parkinson’s disease, dementia associated with Parkinson’s
disease (PDD) reflects another spectrum where signs of executive dysfunction may
be present in a very early state, whereas frank PDD is usually a late feature.
In relation to PD, the prevalence of dementia increases with the age and the pro-
gression of PD (Dubois et al. 1990; Hughes et al. 2000; Aarsland et al. 2007). As a
consequence, dementia will be present in a large number of PD patients usually
beyond 20 years disease duration (Hely et al. 2008). Indeed, the cumulative incidence
of dementia in PD patients may be as high as 80 % (Aarsland et al. 2003, 2005; Buter
et al. 2008). However, cognitive decline is present in approximately one third of the
7 Scales for Measuring Parkinsonism in Demented Patients 119
Table 7.1 Examples of conditions that can associate simultaneously dementia and parkinsonism
Neurodegenerative Other
Parkinson’s disease Cerebrovascular disease
Dementia with Lewy bodies Normal-pressure hydrocephalus
Corticobasal degeneration Creutzfeldt-Jakob disease
Multiple system atrophy HIV-associated dementia
Progressive supranuclear palsy Traumatic brain injury
Huntington’s disease Alcoholic dementia
Frontotemporal dementia
PD patients at an early stage of disease (Reid et al. 1989; Foltynie et al. 2004), and it
has been suggested that the possible onset of PDD might be predictable by measuring
if PD patients suffer from early cognitive impairment (Pedersen et al. 2013). PD
patients with postural instability gait difficulty (PIGD) are at higher risk to get demen-
tia and also have a faster rate of cognitive decline (Burn et al. 2006; Alves et al. 2006).
Furthermore, a study by McKeith et al. (2006) showed that extrapyramidal motor
symptoms are more impaired (McKeith et al. 2006) and are associated to more rapid
noncognitive disease progression (Williams et al. 2006) in DLB than in AD.
In addition, it has been reported that in patients with AD and parkinsonism, psycho-
sis appears more frequently than in patients without AD and parkinsonism (Zubenko
et al. 1991; Mayeux et al. 1985). By analyzing the parkinsonian signs in AD, it may be
possible to predict the risk to develop a psychosis (Caligiuri et al. 2003).
In Table 7.1, we list the common conditions that can be associated with dementia
and parkinsonism. This list is not exhaustive as many rare metabolic and genetic
conditions can cause dementia with a degree of parkinsonism, but in this chapter we
will not be able to cover these conditions.
We have attempted to subdivide these conditions to neurodegenerative and other
disorders (see Table 7.1).
Scales to Measure Parkinsonism in Dementia
Scales and questionnaires are commonly used to determine the type of manifesta-
tions of the underlying condition, to measure their severity and frequency, and to
establish their relationships with demographic, historical, functional, and psycho-
social factors. They are needed, for example, to determine the patients’ current
health state and its course over time, to compare groups of patients, to inform the
outcomes of clinical practices and trials, to file and share information, to assign
resources, and to make decisions in Health Policy. For multicenter and interna-
tional collaborations, it is important to harmonize measurements in order to obtain
homogeneous results. A survey by Ramirez Diaz et al. (2005), for example,
emphasized the need of unified tools and evaluation criteria in order to get robust
data collection.
In general, scales can be divided into generic, which means that they are usable in
any condition, or specific, meaning that they can just be used for one condition in par-
ticular. Furthermore, scales can be classified in several ways: self-completed or rater-
completed; single-item, multi-item, or composite; unidimensional or multidimensional;
and disease-centered and patient-centered measures. Only a few of the above condi-
tions (Table 7.1) have validated scales including specific assessment of parkinsonism.
In order to review scales for selection of the most appropriate, for a research
study or clinical practice, for instance, some aspects have to be considered. The
most relevant are shown in the Table 7.2 that includes the most commonly consid-
ered and relevant points for description and clinimetric information of a scale. For
example, the systematic reviews on scales performed by the Movement Disorder
Society Task Force have been based on a similar scheme (www.movementdisorders.
org/publications/ebm_reviews/).
Concerning patients with dementia, it has to be considered that they are usually
not fully capable to adequately complete self-assessments or respond to interviews.
That is the reason why, in the setting of dementia, this kind of evaluations needing
the patients’ inference cannot be used or have to be completed by a proxy (care-
giver, health professional), a situation challenging the reliability and validity of the
assessment. However, the rating scales used for evaluation of parkinsonism are rater
based and completed by a health professional who performs the motor examination.
Patient’s collaboration for doing some maneuvers (e.g., tapping fingers or hand,
rapid alternative movements, walking a distance, etc.) is necessary, but usually there
is a response option (e.g., unable to do, cannot perform the task, unable to test, etc.)
adequate for the situation lacking of patient’s collaboration. Therefore, data quality
is usually satisfactory for this kind of assessment.
A brief review of the scales useful to evaluate parkinsonism in patients with
dementia ensues.
Unified Parkinson’s Disease Rating Scale (UPDRS)
In 1987 (Fahn and Elton 1987) the Unified Parkinson’s Disease Rating Scale
(UPDRS) was introduced, which has now become one of the most used scales in
Parkinson’s disease (Ramaker et al. 2002). This scale takes about 10–20 min to
complete and is available from the original publications. It is a public domain scale
that evaluates impairment and disability for basic activities of daily life (Movement
Disorder Society Task Force 2003). It contains 42 items, which are separated into
four domains: (1) mentation, behavior, and mood; (2) activities of daily living; (3)
motor items, which are relevant in the context of the present chapter; and (4) com-
plications. In addition, it covers a modified Hoehn and Yahr Staging (1967) and
the Schwab and England Scale. Besides the importance for this chapter, section
of the “UPDRS” is completed by a health professional and focused on the clini-
cal examination of motor impairment characteristic of parkinsonism, needing not
the input of patients themselves. Concerning the psychometric properties in PD,
Table 7.2 Elements for description and evaluation of a scale

1. Description of the scale
Scale name
Descriptive aspects Construct to be measured
Components: number of items and subscales
Answer options and type of scoring
Time frame
Application (interview, observation, by phone, etc.)
Time to complete the scale
Rater (patient, proxy, professional, etc.)
Generic/specific
For generic scales: is the scale validated in the specific condition
in which will be used?
Copyright? Public domain?
How to obtain the scale (and manual for users)
2. Attributes of the scale
Feasibility Appropriateness of questions for the target population?
Acceptability Floor and ceiling effects?
Score distribution
Scaling assumptions Appropriate location of items in the subscales
Dimensionality Factors (concordant with subscales?)
Reliability Internal consistency
Inter-rater reliability
Test-retest reliability
Validity Face validity
Content validity
Criterion-related validity
Hypotheses testing (convergent, known-groups, structural,
internal validity)
Responsiveness and Sensitive to changes in the construct?
interpretability Minimally clinical important difference (or similar) determined?
Cumulative distribution function?
Other: correlation with other measures?
Cross-cultural adaptations and Translations/adaptations
others Alternative modes of administration
Overall impression Advantages and disadvantages
internal consistency, inter-rater and test-retest reliability, and construct validity are
satisfactory as a whole (Martinez-Martin and Forjaz 2006), and the scale is sensitive
to changes. The scale has been translated to several languages and has been widely
used in different studies and settings (Movement Disorder Society Task Force
2003). However, some ambiguities in the written text, as well as lack of adequate
instructions for the raters and the missing of many non-motor aspects, promoted the
revision of the scale to a new version (MDS-UPDRS) free of these shortcomings
(Movement Disorders Society Task Force 2003).
Cubo et al. (2000) and Kroonenberg et al. (2006) have reported that the motor
examination of the UPDRS can also be used for patients with progressive
supranuclear palsy (PSP). Section III, motor examination, has been used to assess
the motor impairment in multiple system atrophy (MSA) (Seppi et al. 2005) show-
ing similar clinimetric properties in MSA than in PD (Tison et al. 2002a) and a high
correlation with the International Cerebellar Ataxia Rating Scale (ICARS) in MSA
patients (Tison et al. 2002b). UPDRS motor scores have been used to assess extra-
pyramidal symptoms in AD (Ellis et al. 1996; Caligiuri et al. 2003) and to distin-
guish between these DLB patients and AD patients (Kaur et al. 2013) and are
sensitive to changes due to treatment with cholinesterase inhibitors in PDD (Rolinski
et al. 2012).
Modified versions of the UPDRS motor section have been used to characterize
AD patients (Wilson et al. 2000; Park et al. 2006) and to predict the risk of develop-
ing dementia in older people (Louis et al. 2010).
Movement Disorder Society-Sponsored Version

of the UPDRS (MDS-UPDRS)
The Movement Disorder Society-sponsored version of the UPDRS (MDS-

UPDRS) is a revised form of the UPDRS specifically addressed to overcome the
problems identified in the latter scale (Movement Disorders Society Task Force
2003) to achieve a scale more comprehensive, including a wide range of non-
motor symptoms, more understandable through the fewer use of medical jargon,
and also more applicable for patients with different levels of disability (Goetz
et al. 2007). It also has standardized translation and teaching programs (Goetz
et al. 2010, 2012). To fulfill the entire scale takes about 30 min; however, to com-
plete the motor section, the patients only need 10 min. Studied psychometric
attributes are adequate (Goetz et al. 2008; Martinez-Martin et al. 2013), although
the inter-rater reliability as well as the content validity have not been tested yet.
The test-retest reliability has only been addressed in the Spanish validation study
(Martinez-Martin et al. 2013). The scale is available in several languages (www.
movementdisorders.org/publications/rating_scales) and more translations and
local validations will follow in the near future. By comparing the MDS-UPDRS
to the UPDRS scale, in particular, the motor domains of these two scales corre-
lated significantly (Goetz et al. 2008; Merello et al. 2011). An association between
the MDS-UPDRS motor scores and cognitive impairment has been described in
LRRK2- associated PD patients (Ben Sassi et al. 2012) and is a promising tool to
assess bradykinesia in parkinsonian syndromes (Pal and Goetz 2013). Müller
et al. (2013) have demonstrated that the PIGD motor phenotype as assessed by
the MDS-UPDRS motor section is a risk factor for the development of dementia
associated to PD. In PSP, MDS-UPDRS scores correlated with degeneration of
white matter tracts detected using diffusion tensor imaging (Whitwell et al. 2011).
To date, the MDS-UPDRS performance has not been tested in other patients with
dementia.
Unified Multiple System Atrophy Rating Scale (UMSARS)
The multidimensional Unified Multiple System Atrophy Rating Scale (UMSARS)

(Wenning et al. 2004) is a disease-specific scale, which is useful in order to detect
the disease severity and progression as well as several important aspects of MSA
(Geser et al. 2006).
The scale, which takes about 30–45 min, has to be completed by a health profes-
sional. The UMSARS is divided into 4 different domains: (1) historical review in
order to detect disease-related impairments (12 items), (2) motor examination (14
items), (3) autonomic examination, and 4) global disability. The items in the four
domains can be rated from 0 (no impairment) to 4 (severe impairment).
The inter-rater reliability for the first and second domain has been shown to be at least
substantial, in some cases even excellent (Wenning et al. 2004). Except for ocular motor
dysfunction, these results have been confirmed by Krismer et al. (2012). Furthermore,
for the first and second domain of the scale, the internal consistency was reported to be
high (Wenning et al. 2004). According to the study by Wenning et al. (2013), even rela-
tively unexperienced health professionals can reliably complete the UMSARS as long as
they underwent clear training instructions. Regarding the second domain, which cap-
tures motor impairment, it is correlated significantly with the motor domain of the
UPDRS, which likely results from the fact that it is based on this. The UMSARS is
sensitive to changes due to disease progression (Wenning et al. 2013) and to treatment
(Novak et al. 2012), and it can be used as an outcome measure in clinical trials.
Progressive Supranuclear Palsy Rating Scale (PSPRS)
The Progressive Supranuclear Palsy Rating Scale (PSPRS) (Golbe and Ohman-
Strickland 2007) is a useful and practical tool that can be used as a routine measure-
ment for assessment of PSP patients’ disability and disease progression and also may
be used as variable for clinical trials and indicator of prognosis. It takes about 10 min
to fulfill the 28 items divided into 6 main groups. These groups contain daily activities
(by history), behavior, bulbar, ocular motor, limb motor, and gait/midline. Whereas 6
of the total of 28 items are rated on a 3-point scale (0–2), the missing 22 items are
rated on a 5-point scale (0–4). A maximum of 100 points can be obtained. The scale
has an excellent overall reliability, moderate convergent validity, and predictive valid-
ity in relation to subsequent survival (Golbe and Ohman-Strickland 2007).
Pyramidal and Extrapyramidal Scale (PEPS)
The Pyramidal and Extrapyramidal Scale (PEPS) especially detects motor symp-
toms in patients with dementia or mild cognitive impairment because of the small
vessel disease and has been developed and validated by Kim et al. (2011a). The
scale can be particularly used to follow the disease process. The scale consists of 34
items, which are subdivided into five domains: (1) corticospinal (6/60), (2) corti-
cobulbar (9/60) tract symptoms and signs, (3) extrapyramidal symptoms/signs
(30/60), (4) gait abnormalities (9/60), and (5) gait severity (6/60). The patient can
reach a maximum of 60 points.
The test-retest and the inter-rater reliability coefficients were satisfactory. In
addition, the motor signs scores as measured by the UPDRS were significantly cor-
related with the total and extrapyramidal signs scores from the PEPS (Kim et al.
2011a). Moreover, the motor deficits as assessed by the PEPS correlated with supra-
and infratentorial lesions identified by magnetic resonance imaging (Kim et al.
2011b). The scale has not been used beyond the original authors.
Extrapyramidal Symptom Rating Scale (ESRS)
The Extrapyramidal Symptom Rating Scale (ESRS) (Chouinard and Margolese

2005) addresses particularly drug-induced movement disorders. It is a clinician-
rated tool composed by 62 items that are scored in a 7-point scale for frequency and
movement amplitude. Six factors have been identified: (1) hypokinetic parkinson-
ism, (2) orofacial dyskinesia, (3) trunk/limb dyskinesia, (4) akathisia, (5) tremor,
and (6) tardive dystonia. Psychometric properties are adequate (Knol et al. 2010) in
terms of inter-rater reliability, convergent validity, and sensitivity to change. It is a
widely used scale for assessing adverse effects of pharmacologic treatment in
behavioral and psychological symptoms in dementia (De Deyn and Wirshing 2001).
Natural History and Neuroprotection in Parkinson Plus

Syndromes: Parkinson Plus Scale (NNIPPS-PPS)
This scale has been especially developed to measure disease severity and progression
in MSA and PSP in order to predict the survival and as a sensitive instrument for clini-
cal trials (Payan et al. 2011). The scale comprises 83 items, summarized into 15
dimensional sub-scores and a total score with a maximum of 309 points. This scale
shows a very appropriate content as well as a good convergent validity. Furthermore,
the internal consistency of the total score and the inter-rater reliability have been found
excellent (Payan et al. 2011). The scale is able to predict survival and is responsive to
changes, although PSP patients show higher progression rates than MSA patients.
Nonetheless, the scale has not been tested beyond the original validation study.
Other Scales
Other PD rating scales that have been used to assess extrapyramidal motor signs in
dementia patients (Ellis et al. 1996) are the Webster scale (Webster 1968) and the
Columbia University Parkinson’s Disease Rating Scale (Yahr et al. 1969). However,
there is a lack of data of these scales’ performance and psychometric attributes in

dementia patients. Similarly, Scales for Outcomes in Parkinson’s Disease (SCOPA)-
Motor includes a 10-item “clinical examination” section useful to assess the motor
impairment in Parkinson’s disease (Marinus et al. 2004; Martinez-Martin et al.
2005).
On the other hand, the Functional Assessment Staging (FAST) scale (Reisberg
1988), a tool specifically designed to assess functional decline in AD, has been also
used to characterize cognitive impairment and dementia in PD patients on the basis
of specific deficits in functional capacity (Sabbagh et al. 2009). In MSA and PSP
patients, the Palliative Care Outcome Scale-Parkinsonism Plus (POS-PP)
(Higginson et al. 2012), a modified version of the POS-Symptoms (POS-S) (Hearn
and Higginson 1999) with items on Parkinson’s related symptoms, has been applied
in a longitudinal study to identify predictors of change. A Rating Scale for Gait
Evaluation in Cognitive Deterioration (RSGE-CD), that contains parkinsonian
components, has been recently validated (Martinez-Martin et al. 2012).
Conclusion
There is a variety of scales assessing the signs that characterize the parkinsonian
syndrome. Most of these scales have been designed to evaluate disorders in which
the motor aspects are relevant and frequently the most typical aspect of the disease
and have not been properly validated in populations experiencing dementia as pre-
dominant feature. However, management and clinical assessment of parkinsonism
is important for a complete evaluation of a patient with dementia and parkinsonism.
As such, development of specific scales which can be reliably and reproducibly
applied to demented parkinsonian patients remains a key unmet need. Further large-
scale studies are required to develop these tools in an international framework.
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Chapter 8
Movement Disorders in Alzheimer’s Disease
Sergio E. Starkstein and Marcelo Merello
Abstract Movement disorders are a frequent finding in AD and an important issue

for differential diagnosis especially with diffuse Lewy body dementia and
Creutzfeldt–Jakob disease. Temporal occurrence through the evolution of the dis-
ease and severity are crucial for differential diagnosis. In addition, psychiatric com-
plications of AD either itself or due to the use of neuroleptics represent another
source of motor symptoms. In this chapter, we will review mainly those movement
disorders resulting from the neurodegenerative process.
Keywords Alzheimer’s disease • Parkinsonism • Dystonia • Corticobasal syn-

drome • Paratonia
Alzheimer’s Disease
Alzheimer’s disease (AD) is the most common type of dementia, affecting more
than five million people in the USA (Bateman et al. 2012). AD accounts for over
70 % of dementia cases among individuals over the age of 70 years (Tarawneh and
Holtzman 2012), and its incidence increases exponentially with age (Kukull et al.
2002). Without successful treatment, AD will affect about 200 million individuals
by the year 2050 (Thies and Bleiler 2011). Neuropathological changes are known to
start several decades before the first clinical symptoms (Jack et al. 2010; Price and
S.E. Starkstein, MD, PhD (*)

School of Psychiatry and Clinical Neurosciences,
University of Western Australia Fremantle, Fremantle, WA, Australia
M. Merello, MD, PhD
Neuroscience Department, Raul Carrea Institute for Neurological Research (FLENI),
Universidad Catolica Argentina, Buenos Aires, Argentina

130 S.E. Starkstein and M. Merello
Morris 1999; Braak and Braak 1997), especially among those with autosomal domi-
nant AD. Brain changes compatible with dementia are present in about 65 % of
80-year-olds (Villegmane et al. 2011; Rowe et al. 2010).
Diagnosis of AD
Since 2007, two sets of diagnostic criteria have been introduced in clinical practice.
Dubois and coworkers proposed the International Work Group (IWG) criteria for
the diagnosis of AD (Cummings et al. 2013). The novelty of these criteria is that
they require a clinical phenotype characterized by anterograde amnesia; supportive
evidence of biomarkers, such as positron emission tomography (PET) brain amy-
loid scans and brain metabolic activity and structural analysis using PET and mag-
netic resonance imaging, respectively; and genetic and cerebrospinal fluid (CSF)
analysis. Thus, the IWG criteria integrate the assessment of biomarkers to clinical
criteria, providing a more biological approach to diagnosis. The IWG criteria for
probable AD include the core diagnostic criteria for a gradual and progressive
impairment of episodic memory over more than 6 months. The recall deficit does
not improve with cueing or recognition, and the memory deficit may be an isolated
finding or be associated with other cognitive deficits. Additionally, one or more of
the following supportive features are referred for a diagnosis of probable AD: (1)
medial temporal lobe atrophy, (2) low 1–42 beta amyloid or increased total tau in
the CSF, (3) hypometabolism in bilateral temporoparietal regions, or (4) a proven
AD autosomal dominant mutation (Dubois et al. 2010). This strategy also allows
classifying groups into those with prodromal AD (memory deficits, one or more
positive biomarkers, and no impairments on activities of daily living (ADLs)) and
AD dementia, when deficits in ADLs are present. Finally, the use of biomarkers
identifies four diagnostic groups: (1) asymptomatic at-risk state with positive bio-
markers, (2) preclinical AD with an autosomal dominant mutation, (3) prodromal
AD with memory deficits and a biomarker for AD, and (4) AD dementia.
The second set of criteria were recently proposed by McKhann and coworkers
(2011). The authors proposed core clinical criteria for AD which include the pres-
ence of cognitive and neuropsychiatric symptoms that produce impairments in
ADLs representing a clear decline from previous levels of functioning. Cognitive
impairment is diagnosed based on a clinical history assessed with the patient and an
informant, as well as an objective cognitive impairment. The diagnosis of probable
AD also requires anterograde amnesia, poor judgment, impaired visuospatial abili-
ties, impaired language, and personality changes such as apathy and disinhibited
behaviors. For a diagnosis of probable AD, patients not only have to meet the above
criteria but also must have an insidious onset, history of worsening, and initial and
prominent cognitive deficits characterized by anterograde memory deficits, word-
finding deficits, or impaired reasoning.
The above set of criteria also include the major biomarkers for AD, such as a
brain beta amyloid deposition (e.g., low CSF A-beta 42, positive PET amyloid imag-
ing), or biomarkers of neural degeneration (increased CSF tau, hypometabolism
8 Movement Disorders in Alzheimer’s Disease 131
in temporoparietal cortices, and atrophy in medial temporoparietal regions).

Nevertheless, the authors suggested that AD biomarkers should not be used in the
routine assessment of patients. The authors finally suggested a category of “pos-
sible” dementia for those individuals who meet clinical criteria for a non-AD
dementia (e.g., frontotemporal dementia, vascular dementia), but also have positive
biomarkers for AD, or positive AD neuropathology.
Future studies will need to validate the above diagnostic criteria. In this context,
it is important to stress that the accuracy for the “old” NINCDS-ADRDA criteria
was reported to range from 68 to 88 % (Risse et al. 1990; Boller et al. 1989; Gilleard
et al. 1992; Burns et al. 1990). A recent study that used different sets of neuropatho-
logical criteria for the diagnosis of AD demonstrated that only 50 % of 411 patients
with a clinical diagnosis of AD had the neuropathology of AD (Shim et al. 2013),
with most of the remaining patients having the neuropathology of AD combined
with the pathology for dementia of Lewy bodies, vascular dementia, or both.
A recent study (Lowe et al. 2013) examined the concordance of the NIAA-AD
criteria and findings in the ADNI study. The main finding was that 95 % of patients
meeting criteria for probable AD had the typical AD pattern of brain hypometabo-
lism and a positive amyloid scan. On the other hand, 30 % of individuals with amy-
loid positive scans had no typical AD hypometabolism. Moreover, conflicting
evidence was also found between hippocampal atrophy as measured with magnetic
resonance imaging (MRI) and PET brain hypometabolism. Therefore, biomarker
findings were substantially inconsistent at the individual level. The problem of con-
flicting biomarker results will have to be examined in future studies. It should also
be examined whether specific biomarkers are significantly related with movement
disorders, as explained below. We will now review the most common movement
disorders among patients with AD as diagnosed with NINCDS-ADRDA criteria.
Whether the new diagnostic criteria identify subgroups with increased risk of move-
ment disorders should be the focus of future studies.
Parkinsonism
Rigidity and postural instability develop in roughly 30 % of patients with Alzheimer’s

disease, whereas a similar percentage of patients with Parkinson’s disease eventu-
ally have dementia due to Alzheimer’s disease or other causes (Richards et al.
1993). Parkinsonism in dementia represents a challenge and can be associated with
greater functional impairment, particularly with walking and continence (Richards
et al. 2002). Many factors contribute to the variability in reported parkinsonism in
AD. Some of the inconsistencies derive from variability in the definitions of parkin-
sonism, the use of unstructured clinical evaluation rather than standardized scales,
inconsistent consideration of treatments with neuroleptics, and moreover inclusion
of subjects at varying noncomparable stages of disease. In addition, small sample
size and variable levels of participation at follow-up result in limited power. Also,
many studies considered motor signs globally, and only a few reports have focused
on individual domains of motor signs. In addition, most previous studies considered
motor signs only at a single point during the course of AD, typically at the baseline
visit or less frequently at any point during the disease course, but patients’ lack of
follow-up and evolution of motor signs during disease progression or even its asso-
ciation with different outcomes are difficult to describe.
In one early attempt to describe parkinsonism in AD, we used the motor section
of the UPDRS to divide patients into two groups: (a) Alzheimer’s disease–parkinson-
ism: patients included in this group had rigidity, bradykinesia, and resting tremor;
rigidity plus bradykinesia only; or resting tremor only. Bradykinesia was defined as
a score >1 on the finger tapping, rapid hand movements, and alternating movements
of the hands sections of the UPDRS. Rigidity was defined as a score >1 in the UPDRS
(only cogwheel rigidity was considered). (b) Alzheimer’s disease–extrapyramidal
signs: patients included in this group had extrapyramidal signs other than bradykine-
sia, rigidity, or resting tremor (flexed posture, gait disorders, masked facies). In our
cross-sectional study of 78 patients, we found that 23 % of the patients showed par-
kinsonism, 56 % showed isolated extrapyramidal signs, and only 21 % had no extra-
pyramidal signs. Whereas the frequency of parkinsonism was significantly higher
than in age-comparable normal controls, the prevalence of isolated extrapyramidal
signs was not significantly different. Secondly, parkinsonism in Alzheimer’s disease
failed to improve after the apomorphine test. Thirdly, patients with Alzheimer’s dis-
ease–parkinsonism had significantly more severe deficits on neuropsychological
tasks assessing abstract reasoning, set-shifting abilities, and executive functions than
patients with Alzheimer’s disease but no extrapyramidal signs, whereas patients with
Alzheimer’s disease and isolated extrapyramidal signs had scores in between both
groups. Lastly, patients with Alzheimer’s disease–parkinsonism showed a signifi-
cantly higher frequency of both major depression and dysthymia than patients with
Alzheimer’s disease and no extrapyramidal signs (Merello et al. 1994). The relation-
ship between parkinsonism and psychiatric symptoms in AD was later confirmed in
a larger study on 169 patients meeting diagnostic criteria for AD followed between 1
and 4 years after the baseline evaluation. Patients with apathy at baseline or those
who developed apathy during follow-up had a significant increase in parkinsonism at
follow-up when compared with patients with no apathy at both assessments. The
association between apathy and increasing parkinsonism was unrelated to age, gen-
der, the severity of cognitive deficits, the presence of depression, or use of psychotro-
pic medications. On the other hand, neither the presence of parkinsonism nor
depression at baseline was significantly associated with more severe apathy at fol-
low-up (Starkstein et al. 2009). In addition Park et al. described that the risk of sleepi-
ness was 2.37 times greater in AD participants with parkinsonian features when
compared to the AD participants without parkinsonism (Park et al. 2011).
There is little published information on patterns of progression of parkinsonism
in AD. Several studies have shown that the probability of meeting criteria for par-
kinsonism increases with time (Morris et al. 1989; Stern et al. 1996; Chen et al.
1991). Wilson et al. (2000) reported an average of 4.5 % of annual increases in
bradykinesia, 6.1 % on rigidity, and 8.9 % on gait and posture. While large cohort
studies reported an average annual increase of 1.5 % on UPDRS scores on people
with PD, Wilson et al. reported that in persons with AD, parkinsonism progressed
more than twice as fast (Wilson et al. 2000). The same authors interestingly reported
that there was an average annual increase of 1.39 units in postural tremor (95 % CI,
0.76–2.02), whereas little change was evident in resting tremor (mean, 0.33 units;
95 % CI, 0.12–0.54).
Motor signs in AD are important because they may predict cognitive and func-
tional decline, institutionalization, and death, and as compared to patients with AD
without motor signs, patients with AD with motor signs have higher annual total
cost of care (Murman et al. 2003; Morris et al. 1989; Soininen et al. 1992; Haan
et al. 2002). Scarmeas et al. even found certain selectivity of each motor sign to
determine specific outcome. In that way, presence of tremor was associated with
increased risk for cognitive decline, presence of bradykinesia with increased risk for
functional decline, and presence of postural–gait impairments with increased risk
for institutionalization and death (Scarmeas et al. 2005).
The modification of parkinsonism in AD after dopaminergic therapy presents an
important clinical as well psychopathological implicancies. We have not found clin-
ical improvements after the apomorphine injection in 11 Alzheimer’s disease
patients with parkinsonism suggesting that parkinsonism in AD is not related to
presynaptic nigrostriatal dysfunction (Merello et al. 1994). This may be in agree-
ment with DaTscan studies which showed indemnity of nigrostriatal pathway in AD
patients with parkinsonism (Vaamonde-Gamo et al. 2005). On the other hand, we
have examined the presence of significant regional cerebral blood flow (rCBF) dif-
ferences between AD patients with and without parkinsonism. Nine patients with
AD and parkinsonism showed significantly lower rCBF in the superior frontal,
superior temporal, and parietal regions of the left hemisphere than AD patients
without parkinsonism. Rigidity and bradykinesia independently accounted for the
decreased rCBF in these areas. These findings suggest that the presence of EPS in
AD may result from dysfunction in specific brain regions other than basal ganglia
(Starkstein et al. 1995).
Parkinsonism in AD Versus Parkinsonism in DLBD

or Creutzfeldt–Jakob Disease
AD subjects had some degree of measurable parkinsonism, which worsened with

the cognitive severity of the disease. Up to 50 % of patients with DLB are reported
to have extrapyramidal motor symptoms at diagnosis and 75 % at some stage during
the illness (McKeith et al. 1992). Besides the well-known “1-year rule” which
clearly discriminates the temporal relationship between parkinsonism and dementia
in AD and DLBD patients (Fig. 8.1), those subjects with a late-stage AD (MMSE
0–10) had a similar degree of parkinsonism to those with early-stage LBV (MMSE
26–30) but had significantly less parkinsonism compared with those subjects with
early-stage DLB (MMSE 26–30) (Kaur et al. 2013). By studying 9 different parkin-
sonian features in AD and DLBD patients (masked facies 4.2 %/48 %, hypophonia
3.4/30.8 %, rigidity 9.8 %/44 %, gait disturbance 14 %/43 %, bradykinesia
Parkinsonism
DLBD
Dementia
Parkinsonism
AD
Dementia
Parkinsonism
PD-D
Dementia
1 Year span
Years
Fig. 8.1 Temporal relationship between parkinsonism and disease evolution in Parkinson’s
disease-related dementia, diffuse Lewy body dementia, and Alzheimer’s disease
19 %/55 %, impaired chair rise 15 %/29 %, rest tremor 3 %/13 %, postural instabil-
ity 12 %/26 %, and postural tremor 6 %/12 %), logistic regression models consis-
tently demonstrate that all 9 EPSs differentiate DLB from AD, regardless of age,
sex, education, or MMSE, and being masked facies the one that best differentiated
AD from Lewy body (odds ratio, 6.5; P < 0.001; 95 % confidence interval, 3.8–
11.1), Kaur et al. (2013) findings were in agreement with those of Ballard et al. and
Galasko et al. (Ballard et al. 1997; Galasko et al. 1996), which demonstrate that rest
tremor, action tremor, bradykinesia, facial expression, and rigidity subscales of the
UPDRS were helpful in differentiating DLB from AD. Patients with DLB experi-
ence a greater level of functional impairment than subjects with AD of similar cog-
nitive ability largely attributable to parkinsonism (Chap. 10). The loss of
dopaminergic neurons in DLB can be confirmed in vivo with a presynaptic dopa-
mine transporter marker DaTscan, whereas there are no changes in DaTscan in AD
compared with controls (Piggott et al. 1999).
In patients with rapidly progressive dementia and motor signs, Creutzfeldt–Jakob
disease (CJD) should be the first suspected diagnosis. However, the presence of
dementia, myoclonus, and rigidity with a longer course of disease may suggest AD or
even DLBD. In an elegant study, Tschampa et al. (2001) described that myoclonus and
extrapyramidal signs were especially common in patients with CJD and patients with
DLB and in more than 50 % of patients with AD. Extrapyramidal signs in patients with
AD and with DLB were restricted to limb rigidity (>50 % respectively) and parkinson-
ism (58 % in patients with DLB, 8 % in CJD, and 11 % in AD). Patients with CJD
additionally showed hyperkinetic signs (40 %). Nearly all patients with CJD and 37 %
of patients with AD had cerebellar signs, not noted in DLB. Regarding hyperkinetic
movement disturbances, dystonia and athetosis were seen exclusively in CJD patients
(Edler et al. 2009). In other comparative studies, dystonia and athetosis were also seen
in CJD patients only, but dystonia has also been reported to be present at a low fre-
quency of 6 % in DLB patients (Louis et al. 1997; Burkhardt et al. 1988) (Fig. 8.2).
AD
Slow progression
Disease duration >2 years
Initial memory impairment
Dementia
Hypertonia
Myoclonus
Sleep disruption
DLBD Cognitive fluctuations Behavioural
Disease duration >2 years disturbances
Parkinsonism
Paratonia
Dystonia
Cerebellar signs
Pyramidal signs
Akinetic mutism
Seizures
Chorea
CJD
Fig. 8.2 Movement disorders occurring in Alzheimer’s disease, diffuse Lewy body disease, and
Creutzfeldt–Jakob disease
Corticobasal Syndrome
Corticobasal syndrome, with asymmetric parkinsonism, dystonia, and apraxia, is

increasingly recognized as a presentation of sporadic cases of AD (Duker et al.
2012; Chand et al. 2006). There are only a few reports of AD clinically presenting
with the corticobasal syndrome. All 7 cases presented with typical clinical features
and fulfilled the proposed research criteria of corticobasal syndrome, but pathologi-
cally, all cases had SP and NFT consistent with AD (Doran et al. 2003; Lleo et al.
2002; Boeve et al. 1999; Chand et al. 2006). On the other hand, alien limb phenom-
enon has been scantly reported in AD (Ball et al. 1993). NFTs found in the striatum,
substantia nigra, dorsal raphe, and even the midbrain tectum are known to occur in
advanced AD and are likely to contribute to the clinical signs of dystonia, parkin-
sonism, and even myoclonus. In addition, descriptions of families with mutations in
the presenilin 1 (PS1) gene (the most common cause of autosomal dominant early-
onset AD) (Sherrington et al. 1995) have revealed a heterogeneous clinical pheno-
type, including pyramidalism, spastic paraparesia, ataxia, myoclonus seizures, or
also corticobasal syndrome with dystonic features (Zekanowski et al. 2003; Anheim
et al. 2007; Kauwe et al. 2008; Wisniewski et al. 1998).
Myoclonus
The prevalence of myoclonus increases during disease progression, and up to 50 %

of AD patients eventually develop myoclonus. Although myoclonus develops in the
latter stages of the illness, an earlier age of AD onset, faster progression (Gauthier
et al. 2006), and familial causes of AD are associated with a higher incidence of
myoclonus appearance at earlier stages of the disease (Caviness 2003). Myoclonus
in AD is considered to be of cortical origin with electrophysiological characteristic
of cortical reflex myoclonus.
Pisa Syndrome
Pisa syndrome was originally coined to describe a rare form of tardive dystonia or
acute dystonia associated with the use of neuroleptics. The typical clinical picture is
the tonic lateral flexion of the trunk associated with a mild backward rotation and
not related to musculoskeletal sustained fixed abnormalities. There is a current
debate whether it corresponds to the same entity of persistent lateral deviation and
whether it is associated with camptocormia. It has been described in a Parkinson’s
disease patient, and the sign has been included as supportive criterion for multiple
system atrophy. EMG showed abnormal tonic hyperactivity on the side of the devia-
tion in the paravertebral thoracic muscles and in the abdominal oblique muscles
(Tassorelli et al. 2012). It has been suggested that Pisa syndrome corresponded to a
dystonia of the trunk probably associated with a dopaminergic–cholinergic imbal-

ance or serotoninergic or noradrenergic dysfunction. This is further supported by its
recently reported improvement after PPN DBS (Shih et al. 2013). Anticholinergic
drugs may be effective in treating Pisa syndrome in about 40 % of patients. On the
other hand, four Pisa syndrome cases have been reported among patients with AD
treated with cholinesterase inhibitors in which problem resolved in 1–4 weeks after
the discontinuation of cholinesterase inhibitors, and after rechallenge of ChEIs,
three patients presented again Pisa syndrome within 1–7 weeks (Miyaoka et al.
2001; Villarejo et al. 2003). Further three cases were reported in pharmacovigilance
ChEIs studies (Vanacore et al. 2005) arguing the relationship between ChEIs use
and Pisa syndrome.
Paratonia
Paratonia is one of the associated movement disorders characteristic of dementia.

Paratonic rigidity consists of a resistance to passive movement of a limb whereby
the degree of resistance varies depending on the speed of movement. Resistance
increases when the limb is moved more rapidly and decreases or even disappears
when it is moved more slowly. Paratonia has been also called “gegenhalten.” It has
been suggested that AD patients who develop paratonia represent a subtype of
patients with a more rapid decline (Gladstone and Black 2002) and that the presence
of paratonia might represent executive and planning impairments (Bennett et al.
2002). In a series of 86 patients with advanced dementia composed of 52.3 %
(n = 45) AD, 25.6 % (n = 22) vascular dementia, 17.4 % (n = 15) AD plus vascular
dementia, and 2.3 % (n = 2) DLBD, Hobbelen et al. found paratonia in 77–82 % of
the patients (Hobbelen et al. 2008). Other study found that paratonia was present in
48, 70, and 83 % of persons in GDS stages 4, 5, and 6, respectively, and there was a
significant correlation between the presence of paratonia and cognition (MMSE),
illness stage (GDS), depression (HAM-D), and the number of frontal lobe release
signs (Vahia et al. 2007). There is a potential utility of paratonia as an independent
marker of disease stage in AD. Besides, failure to precisely characterize paratonia
in dementia has important implicancies as it can lead to improper use of antiparkin-
sonian medication and may be confused with parkinsonian rigidity.
Dystonia
Dystonia in AD patients has been described in the context of a corticobasal syn-

drome as an unusual presentation form either in older patients or in early-onset
cases associated with progranulin mutations (Spina et al. 2007). Dystonia in AD
patients secondary to mirtazapine (van den Bosch et al. 2006), neuroleptics
(Magnuson et al. 2000), and rivastigmine (Pavlis et al. 2007) has been also described.
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Neurol. 2003;184:991–6.
Chapter 9
Movement Disorders in Frontotemporal
Dementia
Emma Devenney and John Hodges
Abstract Our understanding of frontotemporal dementia (FTD) and its related

syndromes has advanced significantly in recent years. One of the most prominent
areas of progress is in the overlap syndromes of FTD and movement disorders, at a
clinicopathological and genetic level. The aim of this chapter is to discuss the clini-
cal, pathological, and genetic complexities of disorders of movement typically seen
in FTD.
Keywords Frontotemporal dementia • Movement disorder • Parkinsonism

• Apraxia • Dystonia • Myoclonus • Amyotrophic lateral sclerosis
Abbreviations
ALS Amyotrophic lateral sclerosis

bvFTD Behavioral variant frontotemporal dementia
CBS Corticobasal syndrome
FTD Frontotemporal dementia
PNFA Progressive nonfluent aphasia
PSP Progressive supranuclear palsy
SD Semantic dementia
VBM Voxel-based morphometry
E. Devenney, MB, BCH, BAO, MRCP

J. Hodges, MBBS, MD, FRCP, FMedSci, FRACP (*)
FRONTIER - Frontotemporal Dementia Research Group at Neuroscience Research,
Sydney, NSW, Australia

142 E. Devenney and J. Hodges
Background
Frontotemporal dementia is an umbrella term which encompasses a heterogeneous

group of syndromes with a variety of overlapping clinical, imaging, and pathological
features. Patients typically present below the age of 65 years, and the prevalence rates
in this age group are only marginally less than in Alzheimer’s disease (AD) (Ratnavalli
et al. 2002). Arnold Pick first described the constellation of symptoms including apha-
sia, apraxia, and behavioral changes, at the turn of the last century, associated with
frontal and temporal atrophy. The pathology associated with this syndrome was
described later with the identification of round, silver staining inclusions, also known as
“Pick’s bodies” (Onari 1926) which led to controversy concerning the term Pick’s dis-
ease which was applied by some to the clinical entity and by others to a distinctive
pathological appearance which is present in a minority of cases with the clinical syn-
drome (Hodges et al. 2004). In 1994, the Lund and Manchester groups coined the
phrase frontotemporal lobar dementia (FTLD) (Clinical and neuropathological criteria
for frontotemporal dementia. The Lund and Manchester Groups 1994) which led to an
upsurge in interest culminating in the development of international consensus criteria in
1998 when the preferred term frontotemporal dementia (FTD) was adopted (Neary
et al. 1998). A number of clinically recognized subtypes of FTD have emerged: a sub-
type defined by behavioral and executive deficits known as behavioral variant FTD
(bvFTD) and two language variants – semantic dementia (SD) and progressive nonflu-
ent aphasia (PNFA). Very recently more detailed and specific diagnostic criteria for
both the behavioral syndrome (Rascovsky et al. 2011) and the aphasic variants (Gorno-
Tempini et al. 2011) have been published by international consensus groups. Of rele-
vance to this chapter, these syndromes are considered to be on a spectrum with
extrapyramidal disorders, notably corticobasal syndrome (CBS) and progressive supra-
nuclear palsy (PSP), as well as amyotrophic lateral sclerosis (ALS) (Boeve 2007).
The pathology in FTD is characterized by severe focal atrophy of frontal and
temporal regions, subcortical gliosis, and neuronal loss. The classification of sub-
types depends upon the presence of intraneuronal protein inclusions which are typi-
cally either phosphorylated tau protein or ubiquitinated TAR-DNA binding protein
(TDP-43). These two account for over 90 % of cases, while fused in sarcoma (FUS)-
positive pathology and ubiquitin proteasome system pathology due to CHMP2B
mutations FTD-3, are present in a small proportion of cases. Up to 40 % of patients
report a family history of dementia although this is often a single relative with late-
onset dementia. In 10–20 % of all cases, there is a history suggestive of an autoso-
mal dominant gene mutation (Goldman et al. 2005). Mutations in
microtubule-associated protein tau (MAPT), progranulin (GRN) or the recently dis-
covered hexanucleotide repeat expansion in the noncoding region of chromosome 9
(C9ORF72) accounts for the majority of familial cases with the latter appearing to
be the most common occurring in up to one-third of cases of familial FTD as well
as familial ALS (DeJesus-Hernandez et al. 2011; Renton et al. 2011).
The behavioral variant of FTD is the most common subtype of FTD and is
characterized by an alteration in personality and social conduct into which patients
9 Movement Disorders in Frontotemporal Dementia 143
have little or no insight but is a cause of considerable distress for carers (Mioshi
et al. 2009). The diagnosis hinges on a detailed carer interview to elicit key behav-
ioral features, notably apathy, alterations in social conduct and inhibitory control,
loss of empathy, mental rigidity, stereotypic speech and motor behaviors, and a
change in eating habits toward sweet cravings and a lack of satiety. In addition,
patients may exhibit prominent executive deficits. It has been suggested that mem-
ory is spared in FTD, however recent studies have demonstrated poor performance
of tests of episodic memory (Hornberger et al. 2010). In contrast to Alzheimer’s
disease, orientation is well preserved. In parallel, patients typically have neuroimag-
ing evidence of atrophy in the orbitofrontal cortex, insula, and medial thalamus on
MRI or hypoperfusion in these areas on functional imaging (Schroeter et al. 2008).
Unlike some of the other FTD syndromes, it is difficult to predict pathology;
approximately 50 % of cases have FTLD-tau pathology, while the other 50 % have
FTLD-TDP deposition. Of all variants, bvFTD appears to be most likely associated
with ALS, particularly in those patients harboring the C9ORF72 genetic mutation.
Semantic dementia is characterized by progressive anomia and impaired word
comprehension secondary to dissolution of semantic networks in the anterior tempo-
ral lobe (Hodges et al. 1992). The loss of vocabulary affects mainly nouns in the early
stages and shows a marked familiarity effect, in that even advanced cases can recog-
nize high-frequency words. In contrast, phonology and syntax are relatively pre-
served, and speech remains fluent although simplified with use of higher-frequency
substitutions and filler words such as “thing” and “that place.” Patients initially func-
tion very well at home; however as the disease progresses, object knowledge and use
becomes impaired, and this parallels the language deficits with lower-frequency
objects initially compromised. The anterior temporal lobe atrophy is usually asym-
metrical and predominantly left sided in most cases (Hodges et al. 1992). Deficit in
person recognition (prosopagnosia) is the key feature of the right predominant syn-
drome, which progresses to a cross-modal loss of face, name, and voice recognition
(Evans et al. 1995). Behavioral features, similar to those found in bvFTD, are com-
mon in patients with SD and particularly in those with the right temporal variant.
Pathologically SD is relatively homogenous with the majority of cases showing TDP-
43 pathology, and of all FTD variants, it is most likely to be sporadic.
In contrast to SD, PNFA patient’s speech is strikingly nonfluent with speech
distortion, pauses, groping, and agrammatism (Gorno-Tempini et al. 2011). The
distortion of speech is due to breakdown in motor planning, referred to as speech
apraxia, causing impairment of rhythm and the normal stress patterns of speech.
These deficits occur in the presence of spared word comprehension. Sentence com-
prehension however can be impaired due to problems understanding the grammati-
cal elements of sentences. Word repetition is often impaired due to articulatory
errors. FTLD-tau is most frequently present in these cases. Patients with PNFA
commonly develop Parkinsonism and apraxia which may lead to a change in syn-
dromic diagnosis to corticobasal syndrome (CBS) or progressive supranuclear palsy
(PSP) (Kertesz et al. 2005). In a large longitudinal clinicopathological study Kertesz
and colleagues (Kertesz et al. 2005) identified evolution to CBS or PSP in almost
half of 22 cases of PNFA.
Frontotemporal Dementia with Parkinsonism
Prevalence and Clinical Features
Of the movement disorders, Parkinsonism is the only one commonly described in

patients with FTD although the exact prevalence is unclear largely due to differ-
ences in what is meant by Parkinsonism. The majority of information comes from
large clinicopathological studies of FTD, as there have been few cohort studies
dedicated solely to the characterization of parkinsonian features in FTD. One such
cohort study objectively evaluated extrapyramidal features according to the Unified
Parkinson’s Disease Rating Scale-III (UPDRS-III) in 75 bvFTD patients. Almost a
quarter of patients satisfied criteria for Parkinsonism, most commonly due to bra-
dykinesia and rigidity, with tremor in only 29 % of cases (Padovani et al. 2007).
A positive correlation was found between parkinsonian features and delusions
and hallucinations implicating dopaminergic dysfunction and striatal pathology,
although the study lacked pathological confirmation of this hypothesis. The recently
described C9ORF72 mutation commonly presents with prominent psychotic fea-
tures (Snowden et al. 2012) and Parkinsonism can also develop suggesting that
cases with the C9ORF72 mutation may have been included in these earlier studies.
In another cohort study, 80 % of bvFTD patients presented with at least a single fea-
ture of Parkinsonism (Diehl-Schmid et al. 2007). In contrast to the previous study,
the UPDRS was modified to a dichotomous variation, and patients were considered
to have Parkinsonism if they showed evidence of any one of (1) resting tremor, (2)
rigidity, (3) akinesia, or (4) parkinsonian gait/posture. Again akinesia was the most
common feature present in 84 %, followed by parkinsonian gait/posture in 71 %
and rigidity in 36 %. Tremor was even less frequent, being present in only 7 %
of patients. The exclusion of patients taking antipsychotic medications is a major
strength of these studies, thus excluding the confounding factor of drug-induced
Parkinsonism.
Several clinicopathological series have also reported the prevalence of
Parkinsonism in FTD patient populations which have the benefit of longitudinal
follow-up as well as pathological confirmation of the clinical diagnosis. A large
clinicopathological study in Cambridge in 2004 studied extrapyramidal features in
FTD patients: 1/8 PNFA patients, 5/26 bvFTD patients, and 3/9 FTD-ALS patients
had evidence of parkinsonian features at presentation with no evidence of parkinso-
nian features in 9 SD patients (Hodges et al. 2004). Parkinsonism tends to evolve
with disease progression as evidenced by reports from a large clinicopathological
study at the University of Pennsylvania (Forman et al. 2006): extrapyramidal signs
at presentation were present in almost half of the cohort, while 82 % of FTD patients
had such signs at last examination.
In contrast to PNFA and bvFTD, semantic dementia rarely, if ever, manifests
with Parkinsonism (Davies et al. 2005). Although Parkinsonism has been consid-
ered to be a particular feature of familial FTD, there is no clear evidence that it is
more or less common than in sporadic disease (Piguet et al. 2004).
Pathology and Neural Correlates
The neural basis of parkinsonian features in FTD remains unclear. A degree of atrophy
of the basal ganglia and histopathological changes in the striatum have been reported
(Mann et al. 1993). Another study found a significant inverse correlation between the
degree of severity of parkinsonian symptoms and the degree of uptake of a dopamine
transporter ligand, suggesting that striatal dysfunction is a factor in these conditions
(Rinne et al. 2002). This idea was corroborated in a case series of six patients who satis-
fied criteria for both dementia with Lewy bodies (DLB) and FTD at presentation: two
cases came to autopsy, pathological study of these cases revealed gliosis and neuronal
loss in the basal ganglia and substantia nigra with pigment loss in the latter (Claassen
et al. 2008). While Parkinsonism in FTD has been linked to underlying tau pathology
(Hodges et al. 2004), TDP-43 pathology was actually present in each of these cases.
Frontotemporal Dementia and Parkinsonism

Linked to Chromosome 17 (FTDP-17)
As CBS and PSP are discussed in detail in another chapter, the remainder of this
chapter will focus on the inherited forms of FTD.
Background
Parkinsonism in FTD has been reported in the literature since the turn of the century
but was initially overlooked in favor of the prominent behavioral and language fea-
tures. In 1998 a dementia and Parkinsonism syndrome was linked to chromosome
17q21-22 in an Irish kindred which sparked considerable interest in this area (Lendon
et al. 1998). The first frontotemporal dementia and Parkinsonism consensus consor-
tium met in Ann Arbor in 1996 to discuss the clinical and neuropathological features
of this and 12 other kindreds with FTDP-17, as it then became known (Foster et al.
1997). Despite clinical heterogeneity within and between families, a severe behav-
ioral disorder characteristic of FTD and Parkinsonism without resting tremor was
common to all. Neuropathologically, there was atrophy of the frontal and temporal
cortices, as well as the basal ganglia and depigmentation of the substantia nigra. A
defect in the microtubule-associated protein tau (MAPT) gene on chromosome 17
was discovered 2 years later in a proportion of FTDP-17 families (Hutton et al. 1998),
but it was almost another decade before a mutation in the progranulin gene (GRN)
was discovered to account for the remaining FTDP-17 families (Gass et al. 2006).
Over 40 mutations in the MAPT gene have now been described, all of which
have underlying tau pathology, and account for approximately 30 % of all famil-
ial FTD (Houlden et al. 1999; Poorkaj et al. 2001; Rosso et al. 2003; Stanford
et al. 2004). Over 50 mutations of the GRN gene have been described; these GRN
Table 9.1 Comparison of features: FTDP-17 MAPT vs. FTDP-17 GRN

Characteristic MAPT GRN
Age at onset 25–65 years, usually in 40s >50 years
Disease duration 3–10 years, mean 5 years 1–15 years, mean 7 years
Penetrance >95 % 90 % by 70 years
Clinical feature
Parkinsonism Infrequent Frequent
Apraxia Very rare Infrequent
ALS features Very rare Never
Psychosis Infrequent Frequent
Imaging
Symmetry Symmetrical Asymmetrical
Distribution of Anteromedial temporal lobe and Inferior fontal, inferior temporal, and
atrophy orbitofrontal cortex inferior parietal lobes
carriers exclusively exhibit TDP-43 pathology and this mutation is reportedly

present in 6–25 % of familial FTD (Baker et al. 2006; Cruts et al. 2006).
Clinical Features
At a clinical level, FTDP-17 associated with MAPT and GRN mutations has com-
mon and contrasting features (Table 9.1). Both show an autosomal dominant pattern
of inheritance (Foster et al. 1997). MAPT mutation carriers can present initially with
either a predominant parkinsonian syndrome or a dementia (Baba et al. 2005;
Tsuboi et al. 2002), with the precise mutation determining the clinical phenotype;
the N279K mutation has a predominant parkinsonian presentation (Wszolek et al.
2000), personality and behavioral changes characterize the P301L and 10 +16 muta-
tion (Kodama et al. 2000; Janssen et al. 2002), and the S305S mutation does not
appear to favor either (Stanford et al. 2000; Reed et al. 2001).
Although the reported age of onset ranges from 25 to 65 years in MAPT carriers,
the majority of patients first exhibit signs in their 40s and live for 3–10 years with the
disease (Boeve and Hutton 2008; Espay and Litvan 2011). An exception to this is the
R406W mutation carriers who have a much longer disease duration with reports of
patient surviving into their 70s (Van Swieten et al. 1999). GRN mutations tend to pres-
ent later than MAPT, with most patients developing symptoms after 50 years of age
with a mean disease duration of 5 years (3–22 years) and a shorter disease duration
in late-onset disease (Van Swieten and Heutink 2008). The MAPT mutation is almost
fully penetrant, although there are reports of asymptomatic individuals living into old
age (Hutton et al. 1998). In contrast, GRN carriers exhibit incomplete penetrance with
10 % of carriers remaining asymptomatic at 70 years (Gass et al. 2006; Boeve and
Hutton 2008). Parkinsonism has been reported in approximately 40 % of GRN cases
(Le Ber et al. 2007). In common with MAPT mutation carriers, the Parkinsonism is
generally symmetrical with bradykinesia, rigidity, and rarely resting tremor and with
modest or little response to levodopa (Tsuboi et al. 2002). Features typically associated
with PSP, including supranuclear gaze palsy, eyelid apraxia, myoclonus, dysphagia,
dysarthria, and pyramidal features, have all been reported in MAPT mutation carriers
(Stanford et al. 2000), while dystonia is infrequent in all mutation carriers.
TDP-43 pathology is common to both patients with FTD in association with GRN
mutations and patients with ALS. Despite this commonality, features of ALS are not
found in GRN carriers which suggests a distinct pathogenetic mechanism in GRN
carriers. ALS features are also rarely found in MAPT carriers. (Seelaar et al. 2007;
Pickering-Brown et al. 2008; Tsuboi 2006). By contrast although apraxia is rare in
MAPT carriers, it can be a feature of GRN carriers. Severe behavioral disorders are
found in the majority of carriers of both mutations, in addition to frontal dysexecutive
cognitive deficits (Boeve and Hutton 2008; Le Ber et al. 2007). In one published GRN
case, the patient developed features of Kluver-Bucy syndrome with prominent hyper-
sexuality, hyperphagia, and psychotic features (Boeve et al. 2006). In general, psy-
chotic features have been reported in up to a quarter of GRN carriers and include
hallucinations and/or delusions which in some cases has led to misdiagnoses of
schizophrenia. Hallucinations include visual (animals and people) reported in 25 % in
one series and tactile (insects crawling over the skin) in another series (Le Ber et al.
2007; Beck et al. 2008). Psychotic features are also reported in MAPT carriers but
appear to be less common (Saito et al. 2002; Spina et al. 2007). Nonfluent aphasia
often accompanies the behavioral and personality deficits in GRN carriers but is rarely
the predominant feature, and semantic dementia is very rare (Pickering-Brown et al.
2008). A dynamic aphasia has also been documented in a number of patients, charac-
terized by a decreased output of speech without evidence of a motor speech disorder
or agrammatism, resulting in mutism in a selection of patients (Beck et al. 2008).
Imaging in FTLD-17
Gray and white matter atrophy patterns can aid in the distinction between the genetic
causes of FTLD-17 and may offer insight into the neural basis of symptomatology
in these diseases. In brief, voxel-based morphometry (VBM) analyses have deter-
mined significant variations in the neuroimaging signatures of GRN and MAPT
mutations. GRN mutation carriers have smaller brain volumes and tend to atrophy
faster than MAPT carriers. The most striking difference is in the hemispheric asym-
metry seen in GRN carriers compared to relatively symmetrical atrophy in MAPT
carriers. As might be expected given the high prevalence of apraxia, GRN carriers
tend to have an atrophy pattern involving the inferior parietal lobe as well as inferior
frontal and temporal lobes. In contrast, MAPT carriers exhibit a symmetrical antero-
medial temporal lobe and orbitofrontal atrophy with involvement of the fornix.
Involvement of the long intrahemispheric association tracts has also been docu-
mented in those with GRN mutations (Rohrer et al. 2010a; Whitwell et al. 2012).
ALS, FTD, and Parkinsonism: C9ORF72
It is now clear that ALS overlaps considerably at a clinical, pathological, and genetic
level with FTD to such an extent that the two disorders are considered to form a
continuum with pure ALS at one end of the spectrum and pure FTD (without ALS) at
the other (Lillo and Hodges 2009), although most cases appear to fall somewhere in the
middle with around 20 % of ALS cases also meeting criteria for FTD and a much
greater proportion having subtle behavioral and/or cognitive changes (Strong 2008).
The recent discovery of the C9ORF72 genetic mutation has consolidated this concept
(DeJesus-Hernandez et al. 2011; Renton et al. 2011) and extended this overlap to
involve Parkinsonism. Parkinsonism has been reported in up to 30 % of patients with
this mutation, although reports have varied between studies (Snowden et al. 2012;
Boeve et al. 2012; Sha et al. 2012). The Parkinsonism mirrors that found in other inher-
ited and sporadic cases of FTD with bilateral rigidity and bradykinesia without tremor.
It has been proposed that intermediate numbers of repeat copies of the mutation confer
a significant risk of developing Parkinson’s disease (Nuytemans et al. 2013). The
imaging finding in C9ORF72 carriers are variable. A proportion present with frontal
and temporal atrophy typically found in patients with FTD, while others have rela-
tively normal MRI imaging. Atrophy of subcortical structures including the thalamus
and cerebellum are emerging as a diagnostic marker of the C9ORF72 mutation
(Whitwell et al. 2012). A higher burden of TDP-43 pathology and neuronal cell death
in the substantia nigra of mutation carriers compared to noncarriers may explain the
increased incidence of parkinsonian features in this cohort (Cooper-Knock et al. 2013).
Perry Syndrome
Perry syndrome is a rare genetic disorder due to a G71R mutation in the DCTN1
gene, characterized by Parkinsonism, hypoventilation, weight loss, depression, or
psychiatric disease. In one published case, the patient exhibited slowing of vertical
saccades and a marked behavioral disorder typical of bvFTD but without focal atro-
phy on MRI or convincing executive cognitive deficits (Newsway et al. 2010). This
rare disorder is also linked to FTD, as TDP-43 pathology is common to both.
Dystonia and Myoclonus
Dystonia has been rarely reported in FTD, aside from a handful of instances where
it has been linked with mutations in the MAPT and GRN gene. It has, however, been
described in FTD patients treated with antipsychotic medications. All three patients
in a case series of FTD patients treated with antipsychotic medications developed a
tardive dystonia which manifested as an antecollis (Czarnecki et al. 2008). In another
case series, up to 30 % of FTD patients developed extrapyramidal features when
treated with antipsychotic medications (Pijnenburg et al. 2003). The dangers of such
medication have been well documented in DLB and linked to dopaminergic dysfunc-
tion (Piggott et al. 1998). It seems logical then that a similar danger exists in FTD
cohorts and accords well with the evidence for striatal dysfunction in FTD patients.
Similar to dystonia, myoclonus has been reported rarely and exclusively in cases
of FTDP-17. In these cases, the myoclonus involved the upper extremities and was
described as small, subtle, and action induced, without detectable activation with
rest stimuli (Caviness and Wszolek 2002).
Apraxia
This section considers the literature on apraxia in FTD particularly in PNFA which,
of the FTD syndromes, shows the greatest overlap with CBS at both a clinical and
pathological level (Kertesz et al. 2005). Apraxia is a core component of CBS which
must be present to make the diagnosis, and is common in PSP (Soliveri et al. 2005;
Mathew et al. 2012). Patients with CBS also exhibit features of PNFA and/or behav-
ioral abnormalities. This can make it very difficult to disentangle the literature on
apraxia in FTD since many mixed cases are labeled as CBS rather than PNFA with
apraxia (Sha et al. 2006).
While apraxia is considered common in PNFA, it has not been well character-
ized. Variations in the definition of apraxia and a lack of consensus regarding the
underlying cortical circuitry involved have probably contributed to the dearth of
studies on this topic. Up until 2003 case reports and case series described the pres-
ence of apraxia in PNFA (Kertesz et al. 1994; Karbe et al. 1993). Others reported an
absence of apraxia in PNFA cases (Béland and Ska 1992; Craenhals et al. 1990).
The first prospective case–control study documented some form of apraxia in 90 %
of all PNFA subjects (Joshi et al. 2003): apraxia was present in 70 % for both pan-
tomime and imitation gestures, while 20 % showed apraxia for imitation only.
Unfortunately, this study had limitations: firstly, it is unclear how patients reaching
criteria for CBS or PSP were excluded. Moreover, evaluation of orofacial apraxia
and apraxia of speech (AOS) was not considered.
A comprehensive review of apraxia in 16 PNFA patients, using a standardized
Apraxia Battery and incorporating VBM analyses, was reported by Rohrer et al.
(2010b): three patients also had CBS and two PSP. Using a surrogate measure for
AOS, they found that all patients had evidence of AOS. More recently it has been
suggested that AOS can be the presenting sign of neurodegenerative disease in the
absence of aphasia referred to as primary progressive AOS (PPAOS) (Josephs et al.
2012). Longitudinal studies are needed to determine if such cases evolve into a
PNFA syndrome. In the Rohrer et al. cohort, orofacial apraxia was often associated
with AOS and the neural basis for both localized to the left inferior frontal gyrus.
Even after excluding patients with CBS and PSP over a quarter of PNFA, patients
exhibited features of limb apraxia.
In GRN mutation carriers, estimates of the rate of apraxia range from 16 to 71 % in
the bvFTD phenotype and 25–60 % in PNFA (Le Ber et al. 2007; Beck et al. 2008).
Approximately 6 % of GRN carriers satisfy criteria for CBS with apraxia, asymmetric
Parkinsonism, and rigidity (Le Ber et al. 2007; Pickering-Brown et al. 2008; Beck et al.
2008), while apraxia alone or in combination with CBS features is present in up to 50 %
of carriers. This likely reflects the parietal involvement seen in these cases. Apraxia is
not a common feature of the MAPT or the C9ORF72 mutation.
Future Directions
In summary, there has been great progress in our understanding of neurodegenera-

tive diseases over recent years on clinical, genetic, and pathological levels.
Overwhelming evidence for the overlap between FTD and movement disorders has
been consistently noted. However, this brings a level of increasing complexity to
diagnoses and raises questions regarding underlying pathological mechanisms in
individual patients. As such, there remains much work to be done to determine bio-
markers which accurately delineate the underlying pathology in individual patients
and which in turn will inform future pharmacological interventions.
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Chapter 10
Dementia with Lewy Bodies
Anne-Catherine Vijverman, Carmela Tartaglia, and Susan Fox
Abstract DLB is a progressive multisystem neurodegenerative disorder with wide-

spread alpha-synuclein (αSyn) deposits in the central and peripheral nervous system
as well as within the autonomic nervous system. In addition to dementia, its distinc-
tive clinical features are visual hallucinations, parkinsonism, cognitive fluctuations,
dysautonomia, sleep disorders, and neuroleptic sensitivity. The disease has an insid-
ious onset and progresses to death with variable disease duration of on average
6.4 years. “Dementia with Lewy bodies” (DLB) is the clinical syndrome and “Lewy
body disease” (LBD) refers to the pathological disease. The neuropathological hall-
mark of LBD is the presence of αSyn-positive neuronal inclusions in the form of
Lewy bodies and Lewy neuritis. Neurochemically, DLB is associated with altera-
tions in several neurotransmitter systems, the main changes occurring in the cholin-
ergic, dopaminergic, and serotoninergic systems.
Currently no disease-modifying therapy is available, and management is therefore
focused on symptomatic relief, but the combination of extrapyramidal symptoms,
neuropsychiatric symptoms, and neuroleptic sensitivity makes the pharmacologi-
cal treatment of DLB challenging. The mainstay of treatment includes levodopa
for the parkinsonism and cholinesterase inhibitors for the cognitive deficits. Non-
pharmacological, behavioral strategies aimed at modifying stressors in the environ-
ment should be employed whenever possible.
A.-C. Vijverman, MD
Department of Movement Disorders (Neurology),
Toronto Western Hospital, Toronto, ON, Canada
C. Tartaglia, MD, FRCPC
Memory Clinic (Neurology), Toronto Western Hospital,
Toronto, ON, Canada
S. Fox, MRCP, PhD (*)
Movement Disorders (Neurology), Toronto Western Hospital,
Toronto, ON, Canada

156 A.-C. Vijverman et al.
Keywords Dementia with Lewy bodies (DLB) • Lewy body disease (LBD) • Lewy
bodies (LB) • Movement disorders • Dementia • Neuroleptic sensitivity •
Alpha-synuclein (αSyn) • Hallucinations • Cognitive fluctuations
Abbreviations
5-HT Serotonin (5-hydroxytryptamine)

AD Alzheimer’s disease
ApoE4 Apolipoprotein E ε 4 allele
Aβ42 Amyloid β
CSF Cerebrospinal fluid
DaTSCAN Dopamine transporter SPECT
EEG Electroencephalography
EPS Extrapyramidal signs
GBA1 Glucocerebrosidase gene
LB Lewy bodies
LBD Lewy body disease
LN Lewy neurites
123
MIBG I-meta-iodobenzylguanidine
MRI Magnetic resonance imaging
MSA Multiple system atrophy
NFT Neurofibrillary tangle
PD Parkinson’s disease
PDD Parkinson’s disease with dementia
PET Positron-emission tomography
11
PIB-PET C-Pittsburgh compound B-PET
PIGD Postural instability and gait difficulties
RBD REM sleep behavior disorder
REM Rapid eye movement
sCJD Sporadic Creutzfeldt-Jakob disease
SP Senile Plaque
SPECT Single photon emission computerized tomography
SSRI’s Selective serotonin reuptake inhibitors
TD Tremor dominant
VH Visual hallucinations
αSyn alpha-synuclein
τ Total tau
Introduction
Dementia with Lewy bodies (DLB) is a clinical syndrome characterized by slowly pro-
gressive cognitive, neuropsychiatric, and motor decline. Frederick Lewy was the first to
report abnormal intracytoplasmic protein deposits in a patient with Parkinson’s disease
10 Dementia with Lewy Bodies 157
(PD) in 1912, later called “Lewy body inclusions.” The relationship between the neuro-
pathological finding of cortical Lewy bodies (LBs) and dementia was described almost
40 years later by Okazaki et al. (1961), while it was not until 1984 that Kosaka et al. first
used the term “diffuse Lewy body disease” to describe a new disease entity consisting
of presenile dementia with presence of cortical LBs (Huang and Halliday 2013). Since
then, confusion has arisen as many different names have been used to describe this dis-
order, including diffuse Lewy body disease, Lewy body dementia, senile dementia of
Lewy body type, dementia with Lewy bodies, Lewy body variant of Alzheimer’s dis-
ease, dementia associated with cortical Lewy bodies, and Lewy body disease. In this
chapter, we will use the term “dementia with Lewy bodies” when describing the clinical
syndrome and “Lewy body disease” (LBD) when referring to the pathological disease.
This is in agreement with the 1996 consortium workshop on DLB that published the first
clinical and pathological diagnostic criteria (McKeith et al. 1996). The criteria were
revised in 1999 and 2005, with further clinicopathological correlation studies demon-
strating a need for refinement due to a low sensitivity – though high specificity – of the
previous diagnostic consensus criteria (McKeith et al. 2005). Following the criteria of
2005, a definite diagnosis is reserved for cases with pathological confirmation, whereas
possible and probable DLB are diagnosed in vivo.
DLB shows significant clinical and pathological overlap with other neurodegenera-
tive diseases, including Alzheimer’s disease (AD) and Parkinson’s disease with demen-
tia (PDD). In particular, DLB and PDD are likely the same disorder but with variable
clinical presentation. Many patients with DLB and PDD will have Alzheimer patho-
logical changes at postmortem, thus adding to the clinicopathological confusion.
Epidemiology
An estimate of 26 % of dementia in the elderly (>75 years) is caused by DLB, thereby

making it the second leading cause of neurodegenerative dementia in the elderly after
AD (77 %) (Costa et al. 2003; Zaccai et al. 2005; Parkkinen et al. 2001; Barker et al.
2002) and more prevalent than vascular dementia (18 %) and frontotemporal demen-
tia (5 %) (Barker et al. 2002). The frequency of postmortem diagnosis of LBD is
28 % in patients <60 years of age and only 18 % in 80+ patients (Barker et al. 2002).
There is a greater frequency of LBD among males <70 years of age (38 % versus
24 %) but not among older subjects (Barker et al. 2002). The disease has an insidious
onset with a more rapid progression than idiopathic PD, the mean disease course
from symptom onset until death is 5–8 years (average 6.4 years) (Williams et al.
2006). Rarely it can present with a more rapid progression, death occurring less than
2 years after the first symptom, thereby mimicking other dementias such as sporadic
Creutzfeldt-Jakob disease (sCJD) (Haik et al. 2000; Tartaglia et al. 2012).
Clinical Features
DLB is a progressive multisystem neurodegenerative disorder with central, periph-

eral, and autonomic nervous system involvement. According to the revised
Table 10.1 Clinical consensus criteria for the diagnosis of dementia with Lewy bodies (McKeith
et al. 2005)
Clinical features
Central feature: dementia
Core features
Spontaneous parkinsonian motor signs
Visual hallucinations
Fluctuations with pronounced variations in attention and alertness
Suggestive features
REM sleep behavior disorder
Severe neuroleptic sensitivity
Low dopamine transporter uptake in basal ganglia on SPECT/PET imaging
Supportive features
Repeated falls and syncope
Transient, unexplained loss of consciousness
Severe autonomic dysfunction (orthostatic hypotension, urinary incontinence)
Hallucinations in other modalities
Systematized delusions
Depression
Relative preservation of medial temporal lobe structures on CT/MRI scan
Generalized low uptake and reduced occipital activity on SPECT/PET
Abnormal (low uptake) MIBG myocardial scintigraphy
Prominent slow wave activity and temporal lobe transient sharp waves on EEG
Clinical Diagnosis
Definite DLB: neuropathological confirmation of LBD
Probable DLB
Dementia + 2/3 core features
or
Dementia + 1 core feature + 1 suggestive feature
Possible DLB
Dementia + 1 core feature
or
Dementia + ≥1 suggestive feature
REM rapid eye movements, SPECT single-photon emission computerized tomography, PET
positron-emission tomography, MRI magnetic resonance imaging, CT computerized tomography,
MIBG 123I-metaiodobenzylguanidine, EEG electroencephalography, DLB dementia with Lewy
bodies, LBD Lewy body disease
diagnostic criteria (McKeith et al. 2005) (Table 10.1), the key feature of DLB is
dementia, defined by a cognitive decline substantial enough to interfere with activi-
ties of daily living. The core features of DLB are cognitive fluctuations, visual hal-
lucinations, and spontaneous parkinsonism. Supportive features are REM sleep
behavior disorders (RBD), severe neuroleptic sensitivity, and low dopamine trans-
porter uptake in basal ganglia on single-photon emission computerized tomography
(SPECT) or on positron-emission tomography (PET). Additional suggestive symp-
toms are frequently associated with DLB, although aspecific, and are therefore not
part of the diagnostic criteria.
Motor Manifestations
Spontaneous parkinsonism that is not drug induced is a core feature in the clinical
diagnosis of DLB. Symptoms occur with ~50 % loss of nigrostriatal dopaminergic
neurons (Fearnley and Lees 1991) and are described in up to 50 % of patients with
DLB at diagnosis (McKeith et al. 2004). The parkinsonian features in DLB (Table 10.2)
are more symmetric at onset when compared to the unilateral onset seen in idiopathic
PD (Gnanalingham et al. 1997; Del Ser et al. 2000). The axial bradykinetic-rigid sub-
type, with postural instability and gait difficulties (PIGD), is encountered more fre-
quently than the tremor-dominant (TD) subtype (McKeith et al. 1996; Galasko et al.
1996; Jankovic et al. 1990). Burn et al. found in a cross-sectional study of 107 patients
that 69 % of DLB patients present the PIGD subtype as opposed to 38 % in PD, where
the tremor-dominant (TD) subtype is much more prevalent (Burn et al. 2003).
Extrapyramidal signs and symptoms (EPS) may also occur in later stages of AD
(Lopez et al. 1997). Although not clinicopathologically correlated, Kaur et al. ana-
lyzed data from the US National Alzheimer’s Coordinating Center (Kaur et al.
2013) of 1,826 patients with AD and 130 patients with DLB, characterizing EPS in
both diseases (Table 10.2). Hypomimia and hypophonia occurred in 4.2 % of the
AD group as opposed to more than 48 % in DLB. Likewise, bradykinesia, rigidity,
impaired posture, and postural instability were significantly more prevalent in DLB
when compared to AD (55 % versus 19.3 %). The prevalence of tremor was also
significantly higher in DLB than in AD, 13.9 % versus 3.2 % respectively for resting
tremor in DLB and AD and 12.3 % versus 6.2 % for action/postural tremor.
Myoclonus is a common sign of many dementias. Up to 35 % of patients with DLB
will develop myoclonus (Tartaglia et al. 2012), predominantly occurring in upper
limbs, induced by action and posture but seldom observed in the resting position
(Weiner and Tolosa 2011). It has clinical and electrophysiological characteristics of
cortical myoclonus (Weiner and Tolosa 2011). When associated with rapid cognitive
decline and hallucinations, the Heidenhain variant of sCJD may need to be considered.
Distinguishing diagnostic features in DLB are absence of cortical ribonning on brain
magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) 14-3-3 negativity, and
less common periodic electroencephalographic (EEG) changes (Tartaglia et al. 2012).
Non-motor Manifestations
Cognitive Manifestations
The key clinical feature of DLB is cognitive impairment sufficient to be defined as

dementia. Dementia in DLB is characterized by more severe visuospatial, atten-
tional, and executive dysfunctions compared to relative preservation of memory
(Mosimann et al. 2004). The visuospatial and visuoconstructive decline in DLB are
Table 10.2 Clinical differential diagnosis of DLB, AD, PD, and PDD
160
DLB AD PD PDD
Extrapyramidal symptoms Often more symmetric Rare, usually mild in late Initially often asymmetric Initially often asymmetric
stages
PIGD subtypea 69 % – 38 % 88 %
TD subtypea 31 % – 62 % 12 %
Hypomimiab 48.5 % 4.2 %
Hypophoniab 30.8 % 3.4 %
Rigidityb 44.6 % 9.8 %
Impaired posture/gaitb 43.1 % 14.2 %
Bradykinesiab 55.4 % 19.3 %
Impaired chair riseb 28.9 % 15.4 %
Postural instabilityb 26.2 % 12.5 %
Resting tremorb 13.9 % 3.2 %
Action/postural tremorb 12.3 % 6.2 %
Cognitive impairment Early disturbances in attention Early impairment of Impaired executive and Impaired executive and
and visuoperceptive declarative memory visuoperceptive visuoperceptive functions
functions and attention functions
Fluctuations in cognition Prominent, early second to Moderate day to day Mild day to day variations Mild day to day variations
hourly variations variations
Neuropsychiatric symptoms
Visual hallucinations Typical, early, and persistent Sometimes, late course Often present with Often present with anticholin-
anticholinergic ergic dopaminergic drugs
dopaminergic drugs
Delusions Typical Usually present Present Present
Depression Usually present Usually present Usually present Usually present
DLB Dementia with Lewy bodies, AD Alzheimer’s Disease, PD Parkinson’s Disease, PDD Parkinson’s Disease with dementia, PIGD Postural instability and
gait difficulties, TD tremor dominant
a
Prevalence in cross-sectional study of Burn et al. (2003)
b
Prevalence in cross-sectional study of Kaur et al. (2013)
A.-C. Vijverman et al.
striking, so that even with mild cognitive impairment patients seem to be unable to
draw a clock, to copy overlocking pentagons, or to navigate (Cormack et al. 2004).
This neuropsychological finding sometimes allows discrimination with AD, cer-
tainly in the early stages (Yoshizawa et al. 2013). Language is relatively preserved,
although dysprosody is often seen. Dementia characteristics of DLB and PDD are
very similar, and the distinction is mainly made based on the arbitrary 1-year rule
(McKeith et al. 1996). By definition, patients developing dementia prior to parkin-
sonism or during the first year of disease are diagnosed with DLB. In PDD, the
onset of motor symptoms precedes dementia by at least 1 year, generally occurring
only later in the disease course, but encountered in up to 80 % of all PD patients
during the course of their disease (Aarsland et al. 2003).
Fluctuations in attention and alertness are considered part of DLB’s core fea-
tures according to the diagnostic consensus criteria (McKeith et al. 2005). As
opposed to AD, the transient fluctuating episodes last seconds to hours and may
consist of staring spells, confusion, episodes of decreased attention, or disorga-
nized speech with sometimes a confabulatory or delusional quality. The level of
cognition returns to near normal after those spontaneous fluctuations in awareness
that are generally not triggered by discernible environmental factors. EEG shows
variability in theta rhythm during the spells (Yamamoto and Imai 1988; Doran and
Larner 2004). There can also be a loss of alpha activity and occurrence of slow
wave transient activity in the temporal lobes (Briel et al. 1999). In AD, fluctua-
tions also are a common feature, although less prevalent, and they consist of more
daily variations.
Neuropsychiatric Manifestations
Visual hallucinations (VH), misperceptions, and mood alterations are some of the
frequently encountered neuropsychiatric manifestations of DLB. Spontaneous VH
are a core feature of DLB, often present early in the disease, recurring daily and
lasting minutes at a time (Mosimann et al. 2006). The phenomenology of the VH is
typically of 3-dimensional, detailed mute animate subjects in the central field of
vision, similar as in PDD, although dopaminergic medications are frequently the
trigger in the latter. Auditory and tactile hallucinations are much less common but
can occur. In both DLB and PDD, medical causes of delirium should always be
excluded as a trigger. The VH in DLB might be related to alterations in cortical
acetylcholine together with abnormalities in brainstem and visual systems
(Collerton et al. 2005). This is corroborated by the reduction of visual hallucina-
tions that occurs in DLB when cholinesterase inhibitors (AChI) are started (Barber
et al. 2000; Burn et al. 2006). It remains unclear if there is a relationship between
the occurrence of visual hallucinations and the occipital hypometabolism found in
DLB (Imamura et al. 1999).
Misperceptions, characterized by seeing existing objects as animate subjects, are
frequently encountered as well. Other psychotic symptoms may occur in DLB,
including paranoid delusions, often of spouse infidelity and fear of strangers in the
home. Common mood alterations in DLB include depression and anxiety, although
not specific for DLB (Borroni et al. 2008).
Hypersensitivity to Neuroleptics
Neuroleptics are often used in behavioral and psychological symptoms of demen-

tia. However, due to their dopamine-blocking character, these agents cause or
worsen motor complications and sedation. Increased rigidity, postural falls,
immobility, confusion, pronounced sedation (with rare coma or death), and a
three-fold increased mortality risk are reported side effects from neuroleptics in
DLB, even when used in very small amounts (McKeith et al. 1992; Byrne et al.
1992). Such side effects occur more commonly with so-called typical neurolep-
tics (McKeith et al. 1992; Byrne et al. 1992) but are also seen with atypical neu-
roleptics. About 50 % of patients treated with neuroleptics will develop severe
side effects. If absolutely required, atypical neuroleptics should be used, although
increased sensitivity to these newer drugs has also been seen (Friedman and
Fernandez 2002). Neuroleptic sensitivity might be due to a failure of upregula-
tion of dopamine D2 receptors in the striatum (Piggott et al. 1998) and to dopa-
minergic hypoactivity in DLB (Nishijima and Ishiguro 1989; Sechi et al. 1996).
Autonomic Manifestations
Autonomic postganglionic neurons are probably one of the earliest regions affected by LB
pathology, but autonomic failure doesn’t occur within the first year of disease (Wenning
et al. 1999). Urinary incontinence and orthostatic hypotension are the most common
symptoms, but adrenergic dysfunction (an impaired pressor response to acute sympathetic
stimulation in physical stress), distal anhidrosis, and urinary urgency or retention are also
frequently seen. Dopaminergic agents can exacerbate signs and symptoms of postural
hypotension and should be stopped unless providing a significant benefit.
Sleep
As in other synucleinopathies, REM sleep behavior disorders (RBD) are a frequent

finding in DLB. In RBD, muscle atonia during the REM phase of sleep is lost,
resulting in complex motor activity that makes patients act out their dreams during
sleep (Schenck et al. 1986). The underling mechanism appears to be early Lewy
body pathology in the pedunculopontine nucleus and locus coeruleus together with
resulting cholinergic (and less important noradrenergic) deficits (Boeve et al. 2004).
Presence of RBD can precede neurodegenerative disease manifestations by up to
20 years (Schenck et al. 1986; Tan et al. 1996; Ferman et al. 1999; Postuma et al.
2013), with up to 50 % of RBD patients developing one of the neurodegenerative
synucleinopathies (Boeve et al. 2007).
Etiology and Genetics
Although DLB is generally considered a sporadic disease, Mendelian inheritance

has been shown in families presenting with variable degrees of dementia and par-
kinsonism (Bogaerts et al. 2007). PD is associated with several genetic mutations
following an either autosomal dominant or autosomal recessive inheritance pattern.
Many such individuals with monogenic parkinsonism may develop dementia, and
some genetic mutations appear to have a higher prevalence of dementia as part of
the phenotype, in particular αSyn. Genetic links to DLB are less well described, but
as with idiopathic PD, both environmental and genetic factors are likely playing a
role in the pathogenesis of this disease, since monozygotic twins do not present the
same incidence of DLB (Wang et al. 2009).
Duplications (Chartier-Harlin et al. 2004) and triplications (Singleton et al.
2003) of the αSyn gene are associated with rare kindreds of DLB families, but there
is clinical heterogeneity within the families, ranging from DLB to PD or PDD
(Bogaerts et al. 2007). A genetic defect at the 2q35-q36 locus on chromosome 2 was
identified in two families with autosomal dominant inheritance, but the gene linked
to this locus is not yet found (Bogaerts et al. 2007), and the mutation is most likely
more complex than in monogenic disorders (Meeus et al. 2012).
Mutations in amyloid precursor proteins, presenilin 1 and presenilin 2, were linked to
monogenic Alzheimer’s dementia with variable degree of concomitant amyloid and LB
pathology, the phenotype varying along the spectrum of AD and DLB (Meeus et al. 2012).
Genetic risk factors have been found to increase DLB susceptibility. Mutations in
the glucocerebrosidase gene (GBA1) appear to be associated with synucleinopathies,
with the highest prevalence of these mutations in DLB, followed by PD and multiple
system atrophy (MSA), but not seen in normal controls (Mata et al. 2008; Nalls et al.
2013). Several hypotheses have been proposed to explain the link between GBA1
and synucleinopathies, but the association still remains incompletely understood.
One of the possible underlying mechanisms is impairment of lysosomal degradation
of αSyn due to deficient or mutant glucocerebrosidase (Sidransky and Lopez 2012).
Earlier disease onset, more associated cognitive changes and a higher disease sever-
ity were noted in both DLB and PD GBA1 mutation carriers compared to noncarriers
with parkinsonism (Nalls et al. 2013; Sidransky and Lopez 2012).
Apolipoprotein E ε4 allele (ApoE4), a well-known risk factor for AD (Schellenberg
et al. 1987), has also been associated with DLB, including in pure DLB, where there
are little or no Alzheimer’s disease-like pathological changes in the brain. This sug-
gests that the neurodegeneration associated with ApoE4 is related to a different pro-
cess than the previously thought beta-amyloid processing (Tsuang et al. 2013).
Pathophysiology
The pathophysiology of DLB involves progressive structural and neurochemical

changes in various parts of the nervous system.
Structural Neuropathological Changes
The neuropathological hallmark of LBD is the presence of αSyn-positive neuronal

inclusions in the form of Lewy bodies and Lewy neuritis (LN). They consist of
pathological presynaptic αSyn aggregates caused by altered αSyn processing, but
they are not specific to synucleinopathies. Up to 10 % of normally aging elderly
present αSyn pathology at autopsy (Bennett et al. 2006). Also, in 20 % of the
dementia population, LBs are found in limbic or cortical regions. Even though there
is a (weak) direct relation between the quantity of LBs and likelihood of developing
DLB, it is the pattern of LB involvement that is most important in the pathological
diagnosis of DLB (McKeith et al. 2005). With brainstem-dominant LBD, there is a
low likelihood of developing the clinical DLB syndrome, whereas the likelihood is
much higher with neocortical and limbic Lewy pathology (McKeith et al. 2005),
since neocortical LBs are not seen in normal aging brains (Perry et al. 1990a).
In early DLB, αSyn-positive inclusions are already found in both brainstem and
cortex, whereas in PD there is an ascending progression, from medullary and olfac-
tory nuclei initially to the cortex in later stages. Braak’s six-stage system for PD
(Braak et al. 2003) divided this caudo-rostral progression into six stages with clini-
cal correlate: stage 1 and 2 correspond to premotor PD, stage 3 and 4 are clinically
linked to motor signs in PD, and the last stages are related to combined motor and
cognitive impairment (Braak et al. 2003).
The microscopic identification of LBs is now easier due to more sensitive neuro-
pathological detection tools, αSyn-staining allowing the most reliable detection
(McKeith et al. 2005). Hematoxylin and eosin staining are only capable of ade-
quately identifying brainstem LBs, often underappreciating cortical LBs and miss-
ing LNs (McKeith et al. 2005). Ubiquitin immunohistochemistry has a higher
sensitivity for LBs and LNs but is not very specific, since neurofibrillary tangles
(NFTs) also contain ubiquitin.
LBs are localized in the neuronal cytoplasm and have a spherical eosinophilic
appearance. Although the primary constituent is αSyn in both brainstem and corti-
cal LBs, brainstem LBs have a different microscopic appearance than cortical LBs,
the former being intensely eosinophilic and surrounded by a clear halo and the latter
being less eosinophilic and lacking the halo (McKeith et al. 2005).
Simultaneous with Lewy body pathology, autopsy of DLB patients reveals a con-
siderable amount of coexisting AD pathology, namely, amyloid-containing senile
plaques (SPs) and NFTs. A lower AD pathology burden is associated with a higher
diagnostic accuracy for DLB: a high neocortical neurofibrillary tangle burden miti-
gates against the diagnosis of DLB, even in the presence of cortical LBs (McKeith
et al. 2005). Again the pattern of amyloid involvement is the most important in
distinguishing DLB from AD, with less hippocampal involvement and more
paralimbic involvement in DLB compared to AD (McKeith et al. 2005).
Coexisting vascular pathology may also contribute to cognitive impairment in
patients with any type of dementia, including DLB. The pathological characteriza-
tion of DLB versus PDD has been confusing due to variability in pathological series
published to date. Such differences arise from variable referral bases, e.g., nursing
homes versus community-based referrals. Thus, there still remains controversy
around the pathological phenotype of dementias in parkinsonian syndromes.
Neurochemical Changes
DLB is associated with alterations in several neurotransmitter systems including

cholinergic, dopaminergic, and serotoninergic, accounting for many of the clinical
features that can occur in the absence of significant brain atrophy.
Striatal dopamine transporter deficiencies contribute to the EPS in DLB (McKeith
et al. 2005), but in contrast with PD, there is simultaneous reduction in striatal D2
receptors (Duda 2004). Also, the PIGD subtype, encountered more frequently in
DLB, is thought to be rather a non-dopaminergic motor manifestation linked to
cholinergic deficits, as opposed to the TD subtype that is mainly of dopaminergic
origin (Jankovic et al. 1990). That is why the overall response to levodopa treatment
is lower in DLB compared to PD (Jankovic et al. 1990).
Acetylcholinergic deficits in DLB (Perry et al. 1990a, b, 1994; Shiozaki et al.
1999), resulting in cognitive and neuropsychiatric symptoms, are due to a reduction
in activity of choline acetyltransferase and to a loss of cholinergic neurons (Perry
et al. 1994; Francis and Perry 2007) with preservation of muscarinic receptor activ-
ity (Shiozaki et al. 1999). This cholinergic deficit is more pronounced in DLB com-
pared to AD (Perry et al. 1990b), explaining greater benefits from cholinergic
pharmacological therapy in DLB (Querfurth et al. 2000; Samuel et al. 2000;
McKeith et al. 2000). An imbalance in cholinergic and dopaminergic activity may
exacerbate or precipitate hallucinations (Duda 2004).
Serotonin (5-HT) has long been recognized to play a central role in neuropsychi-
atric symptoms like depression and psychosis (Puzynski and Jakomow 1975). A
reduction of 5-HT levels in the striatum, neocortex, and frontal cortex (Scatton et al.
1983) was reported together with a loss of 5-HT neurons (Halliday et al. 1990) in
the dorsal raphe nucleus. There is also an increase in inhibitory 5-HT1a receptors on
pyramidal neurons of the cortex (Francis and Perry 2007).
Diagnostic Tests
There are no objective diagnostic tests available to confirm the clinical diagnosis of
DLB. Currently, the diagnosis is based on clinical assessment and examination in
vivo. Some imaging modalities may assist in the differentiation from other dementia
or parkinsonian syndromes.
Brain MRI, for example, does not show any DLB-specific structural findings, but
the degree of medial temporal lobe atrophy and hippocampal atrophy is less pro-
nounced than in AD on volumetric MRI measures (Barber et al. 2000). Also, MRI
is useful in excluding any significant structural changes, such as hydrocephalus or

space-occupying lesions.
Functional imaging of the brain, and the nigrostriatal pathways more specifi-
cally, can be obtained by PET or SPECT. However, in many centers, such studies
are only available as research tools. Brain SPECT and 18F-2-deoxy-2-fluoro-D-
glucose PET show occipital lobe hypoperfusion and hypometabolism, respectively,
in the absence of structural occipital changes on MRI (Lobotesis et al. 2001;
Minoshima et al. 2001). This is seen in DLB and PDD but is not encountered in AD
(Lobotesis et al. 2001; Minoshima et al. 2001; Colloby and O’Brien 2004).
Dopamine transporter SPECT (DaTSCAN) in DLB shows, as in PD, low striatal
dopamine transporter activity, reflecting damage to the integrity of the nigrostriatal
system in vivo (Hu et al. 2000). An abnormal DaTSCAN is a suggestive feature and
can be present years before the full clinical syndrome of DLB develops (McKeith
et al. 2005) and may assist in differentiating AD from DLB, since dopaminergic
reuptake is normal in AD (Walker et al. 2002). However, some patients fulfilling the
clinical criteria of probable DLB have a normal DaTSCAN, and therefore DLB can-
not be excluded on the basis of a normal DaTSCAN. Papathanasiou et al. proposed
neocortical predominant LB pathology as a possible explanation for false negativ-
ity, sparing the brainstem in the early stages (Papathanasiou et al. 2012), but Siepel
et al. reported no such association (Siepel et al. 2013).
In vivo estimation of amyloid deposition by means of the amyloid-binding tracer,
11
C-Pittsburgh compound B (PIB)-PET, was suggested as a promising biomarker in
differentiating DLB from PDD, PD, and other neurodegenerative disorders. PIB-
PET detects amyloid-β deposition without any binding to the αSyn-containing cor-
tical LBs (Ye et al. 2008; Fodero-Tavoletti et al. 2007). However, as amyloid burden
increases with age, one third of the normal aging population also has a positive
PIB-PET (Klunk et al. 2006). In addition, PIB-PET can be negative in DLB and can
be positive in PDD. The latter is generally seen in later stages of PDD, probably
accounting for the delay in onset of cognitive impairment (Gomperts et al. 2012).
Thus, due to the high sensitivity but low specificity, PIB-PET is not yet considered
a valid diagnostic tool in differentiating DLB from other parkinsonian diseases
(Gomperts et al. 2012).
Although in vivo detection of αSyn would be of great value, the intracellular
location of the LBs limits the development of such a tool. However, just as CSF
concentration changes of amyloid β (Aβ42), total tau (τ) and hyperphosphorylized
tau are used to diagnose AD, a reduction of αSyn CSF concentration is found in
synucleinopathies as opposed to AD patients, but the quantification of CSF-αSyn
does not allow differentiation among the different synucleinopathies (Tateno et al.
2012). Concomitant amyloid pathology explains why, similarly to AD, CSF-Aβ42 is
reduced in DLB and a likewise increase of CSF values of τ and hyperphosphoryl-
ized τ is observed (Mollenhauer et al. 2011).
123
I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy is a semiquanti-
tative technique that estimates postganglionic sympathetic cardiac innervation (Taki
et al. 2004), because MIBG is a physiological norepinephrine analogue. There is
evidence suggesting that the autonomic postganglionic neurons are one of the
earliest regions affected by LB pathology. LB degeneration of the autonomic ner-

vous system causes postganglionic sympathetic nerves to degenerate (Orimo et al.
2005), resulting in a reduced uptake of MIBG. Thus, there is increasing interest in
the potential diagnostic value of this finding in early detection of DLB.
123
I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy estimates myocardial
sympathetic nerves, with a reduced uptake in DLB (Suzuki et al. 2006). This allows
discrimination with AD, where this feature is not found (Taki et al. 2004). Similar
MIBG findings are seen in PD (Taki et al. 2004) but not in MSA (Chung et al. 2009),
and this technique can therefore not be used to differentiate DLB from other
synucleinopathies.
Neuropsychological examination aids in the differentiation of AD, PDD, and
DLB by means of the pattern of cognitive deficits, but overlap exists so that it is not
completely reliable for diagnostic accuracy.
Management
Currently, no disease-modifying therapy is available and management is therefore

focused on symptomatic relief by pharmacological and non-pharmacological mea-
sures (Table 10.3). The combination of EPS, neuropsychiatric symptoms, and neu-
roleptic sensitivity makes the pharmacological treatment of DLB challenging. Many
drugs are contraindicated in DLB. Behavioral strategies aimed at modifying stress-
ors in the environment should be employed whenever possible. In general, when-
ever required, medications should be started low, increased slowly, and stopped if
no apparent benefit occurs. Also, when a patient with DLB needs surgery, minimiz-
ing length and strength of general anesthetics may be beneficial in preventing post-
operative delirium.
Pharmacological
Parkinsonism
Rigidity and bradykinesia respond less to levodopa therapy in DLB than in idio-
pathic PD (Molloy et al. 2005; Bonelli et al. 2004), with a benefit in only one third
(Molloy et al. 2005; Bonelli et al. 2004). Moreover, DLB patients are more sensitive
to the side effects of dopaminergic agents, especially dopamine agonists, and can
cause or worsen neuropsychiatric side effects (Molloy et al. 2005). Strategies for
decreasing the incidence of adverse events include starting levodopa at lower doses
and increasing more slowly than in PD. The trial should be longer if well tolerated
as often drugs take several weeks to take effect. Given the predisposition to side
effects and the sensitivity to interactions, the treatment should be stopped if no obvi-
ous clinical response has been observed.
Table 10.3 Therapeutic strategies in dementia with Lewy bodies
168
Treatment options
Symptoms Treatment options Details Comments
Parkinsonism Non-pharmacological Physiotherapy and physical exercise Balance, gait, arm swing
Pharmacological
Levodopa Start very slow (50 mg BID or TID), increase Continue several weeks if well tolerated; stop if no
slowly per ½ tablets apparent benefit (30 % responders).
Side effects: (transient) gastrointestinal upset, visual
hallucinations, delusions, orthostatic hypotension
Dopamine agonists Relatively contraindicated because of risk of worsening
behavioral problems
Anticholinergics Strictly contraindicated because of high risk of increased
cognitive and neuropsychiatric symptoms
Cognitive Non-pharmacological Modifying stressors in the environment. –
impairment Physiotherapy
Active social interactions
Pharmacological
Cholinesterase inhibitors
Rivastigmine Start 1.5 mg BID, increase by 1.5 mg every Side effects: worsening parkinsonism (in 10 %: tremor),
2–4 weeks, maximum 6 mg BID (transient) gastrointestinal upset, cardiac arrhythmia
Donepezil Start 5 mg OD for 4 weeks, then increase to Side effects: gastrointestinal (less with slow increase),
10 mg OD (transient) gastrointestinal upset, cardiac arrhythmia
Galantamine 8 mg OD, increase slowly to max 24 mg OD Effective and well tolerated in a 24-week open-label
study, but no RCTs
Memantine Start at 5 mg OD and increase to 10 mg BID Well tolerated
10
Neuropsychiatric symptoms
Visual Non-pharmacological No treatment if not harmful or disturbing –
hallucinations Pharmacological
Atypical neuroleptics
Quetiapine Start at 12.5 mg OD, increase slowly if necessary Sedation
Clozapine Start at 12.5 mg OD, increase per 12.5 mg Sedation
if necessary, max 50 mg OD
Typical neuroleptics – Strictly contraindicated
Depression Non-pharmacological Modifying stressors in the environment –
Pharmacological
Dementia with Lewy Bodies
SSRIs Drug dependent Drug dependent

TCA – Strictly contraindicated
Autonomic impairment
Orthostatic Non-pharmacological Increased fluid intake –
hypotension 30° inclination of bed’s head end –
Slow rising from lying/seated position –
Wearing compression stockings –
Eating small meals –
Pharmacological
Fludrocortisone Start at 0.1 mg QHS, increase slowly to maximum Fluid retention, edema
0.3 mg QHS if necessary
Midodrine Start at 5 mg TID, increase slowly to max 10 mg TID –
Sleep disturbances
EDS Non-pharmacological Physiotherapy and active social interactions to improve –
nighttime sleep
Rule out/treat disturbed sleeping pattern, mood –
disturbances, and drug side effects
Pharmacological
Melatonin Start 3 mg QHS, slowly increase per 3 mg to –
maximum 12 mg QHS
169
Psychostimulants Safety? No prior RCTs

(continued)
170
Treatment options
Symptoms Treatment options Details Comments
RBD Non-pharmacological No treatment if not harmful or disturbing –
Pharmacological
Clonazepam Start 0.25 mg QHS, increase per 0.25 mg Side effects: sedation
to maximum 1 mg QHS
Melatonin Start 3 mg QHS, slowly increase per 3 mg to –
maximum 12 mg QHS
Treatment strategy
Start pharmacological treatment only if symptoms are harmful or disturbing and if non-pharmacological strategies are insufficient
Start low, go slow
Stop treatment if no apparent benefit
Anticholinergics, TCA, and typical neuroleptics are strictly contraindicated
Avoid general anesthesia (Surgery necessary? Possible locoregional anesthesia?) or reduce length and strength of general anesthesia
SSRI selective serotonin reuptake inhibitors, TCA tricyclic antidepressant, EDS excessive daytime sleepiness, RBD REM sleep behavior disorder, RCT randomized con-
trolled trial
Unlike in idiopathic PD, dopamine agonists are relatively contraindicated and

anticholinergics are strictly contraindicated because they often worsen the clinical
picture by inducing behavioral problems. Overall many individuals with DLB are
not taking any dopaminergic agents as the motor symptoms are often relatively mild
in contrast to the cognitive issues and because reduced tolerability and side effects
limit their use.
Cognitive Impairment and Neuropsychiatric Symptoms
Cholinesterase inhibitors such as rivastigmine and donepezil may improve cogni-

tive function and behavioral symptoms in DLB (McKeith et al. 2000). A placebo-
controlled study of a 20-week treatment with rivastigmine (6–12 mg) showed
significant improvement of cognitive symptoms in DLB by ameliorating concen-
tration and simultaneously reducing fluctuations, apathy, anxiety, visual halluci-
nations, and delusions (McKeith et al. 2000; Emre et al. 2004; Rolinski et al.
2012). Compared to donepezil, adverse events are more common with rivastig-
mine (Rolinski et al. 2012). Worsening of parkinsonism is reported with rivastig-
mine, although occurrence rates differ (McKeith et al. 2000; Emre et al. 2004).
Worsening of tremor was reported in up to 10 % (Emre et al. 2004; Rolinski et al.
2012). Similar to AD, the most common reason for discontinuation is gastrointes-
tinal upset.
Changes in glutamatergic activity have been identified in DLB (Dalfo et al.
2004). The N-methyl-D-aspartate receptor antagonist memantine, used in AD
(Reisberg et al. 2003), has also shown benefit in DLB (Aarsland et al. 2009) with
improvement of the clinical global impression of change scores after 24 weeks,
compared to a placebo group. No effects were seen on motor or psychiatric
symptoms (Aarsland et al. 2009), although previous case reports had shown
worsening of cognition (Menendez-Gonzalez et al. 2005) and psychosis (Ridha
et al. 2005).
Visual hallucinations should not be treated unless they are harmful or disturbing
to the patient, taking into account the profound neuroleptic sensitivity these indi-
viduals experience. Other medical causes (acute infection, general anesthesia, etc.)
can cause delirium and trigger or worsen VH and should be ruled out. Typical neu-
roleptics are strictly contraindicated in DLB, due to risk of worsening parkinsonism
(Piggott et al. 1994) as well as the risk of sudden coma or death. Atypical neurolep-
tics of choice are quetiapine and clozapine, since they seem to have less side effects
when treating psychotic symptoms in DLB (Morgante et al. 2004). Patients typi-
cally need very low doses, such as 25–50 mg/day of quetiapine to effectively
reduce VH.
Lastly, as severe cholinergic deficits form the basis of neuropsychiatric symp-
toms in DLB, any drug with anticholinergic properties should be avoided. Therefore,
tricyclic antidepressant should not be used in the treatment of depression in DLB
(Spina and Scordo 2002) as opposed to selective serotonin reuptake inhibitors
(SSRIs) that are a much better choice (Nyth and Gottfries 1990).
Autonomic Impairment
Orthostatic hypotension should first be addressed by conservative measures includ-

ing increased fluid intake, 30° inclination of the bed’s head end, slow rising, wear-
ing compression stockings, eating small meals, etc. If insufficient, fludrocortisone
or midodrine may improve the orthostatic blood pressure drop.
Urinary incontinence should not be treated with anticholinergic agents, certainly
in the presence of orthostatic hypotension.
Sleep
Different types of sleep disruption occur, requiring recognition and management. If

left untreated, such sleep issues may aggravate excessive daytime sleepiness (EDS)
and fluctuations, which can lead to an increase of psychiatric symptoms and reduced
quality of life of the patient and caregivers.
RBD may respond to low dosages of clonazepam, rarely needing up to 1 mg
QHS, but can cause sedation. Melatonin and quetiapine may also be successful
(Boeve et al. 2003). Psychostimulants have been reported to improve EDS (Boeve
et al. 2004) when arising independently from a disturbed sleeping pattern, mood
disturbances, or drug side effects, but no randomized controlled trials exist to con-
firm their safety and tolerability (Dolder et al. 2010).
Non-pharmacological
Although there are no randomized controlled trials or cohort studies evaluating the
benefit of non-pharmacological measures in DLB, such approaches may benefit cog-
nitive and physical skills. The patient should be encouraged to take part in social
activities to maintain active social interactions, stimulating the patient’s arousal and
improving nighttime sleep. On the other hand, as in PD, physical activity is highly
recommended (Goodwin et al. 2008; Keus et al. 2007). Since DLB generally shows
more axial than appendicular EPS, exercises of balance, walking, and arm swing
helps mobility and prolongs independency. Often physiotherapy is needed to help in
mobilizing the patients and teaching them easy exercises to perform on a daily basis.
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Chapter 11
Dementia in Parkinson’s Disease
and Atypical Parkinsonism
Maria Stamelou and Kailash Bhatia
Abstract Parkinson’s disease (PD) is the second most common neurodegenerative

disorder, after Alzheimer’s disease. The prevalence of Parkinson’s disease dementia
(PDD) is roughly estimated to be around 30 %, while PDD will occur in over 80 %
of patients after 20 years of disease, conferring an important impact on patient man-
agement and prognosis. The main clinical syndrome of PDD is that of a frontal-
subcortical dysexecutive visuospatial impairment, as well as neuropsychiatric
features such as hallucinations and delusions and thus quite similar to that of
dementia with Lewy bodies (DLB). The etiopathogenesis is unknown, but
α-synuclein pathology spreading from the brainstem to the neocortex is involved,
and it seems that concomitant Alzheimer’s disease pathology, in particular Aβ
plaques, is crucially implicated. Moreover, genetic factors have been recently high-
lighted as important pathogenetic factors. The diagnosis is based on clinical diag-
nostic criteria for PDD and mild cognitive impairment. There is no neuroprotective
or disease-modifying treatment for PDD. The best evidence for symptomatic treat-
ment exists for the acetylcholinesterase inhibitor, rivastigmine.
With regard to dementia in atypical parkinsonism, much less is known. The prev-
alence of dementia in progressive supranuclear palsy (PSP) and corticobasal degen-
eration (CBD) is high and impairs quality of life in these patients. The cognitive
profile reflects that of a frontal-subcortical dysfunction in PSP and additionally pari-
etal dysfunction in CBD, while memory is in both conditions relatively preserved.
Apathy, depression, and disinhibition are the most common neuropsychiatric
M. Stamelou, MD, PhD (*)

Second Department of Neurology, Attiko Hospital, University of Athens, Athens, Greece
Neurology Clinic, Philipps University Marburg, Marburg, Germany
K. Bhatia, FRCP

180 M. Stamelou and K. Bhatia
features, while hallucinations and delusions occur extremely rarely. Tau pathology
in the cortex and subcortical structures seems to correlate with these cognitive phe-
notypes; however, the understanding of the pathophysiology as well as treatment
options is limited. In contrast, dementia in multiple system atrophy (MSA) still
counts as one of the exclusion criteria for its diagnosis. Recent studies have high-
lighted that executive dysfunction does occur in MSA, but etiopathogenesis and
treatments are still to be researched.
Keywords Dementia • Parkinson’s disease • Mild cognitive impairment • α-synuclein •

Progressive supranuclear palsy • Subcortical dementia • Corticobasal degeneration
Dementia in Parkinson’s Disease
Introduction
Parkinson’s disease (PD) is the second most common neurodegenerative disorder,

after Alzheimer’s disease. The typical clinical motor syndrome of PD is associated
with neurodegeneration and neuronal loss in the substantia nigra and the presence
of inclusions that contain the protein α-synuclein (α-syn) known as Lewy bodies.
However, although the clinical phenotype is predominated by motor features, it is
now well established that a variety of non-motor features belong to the disease. In
particular with regard to cognition, the prevalence of Parkinson’s disease dementia
(PDD) is roughly estimated to be around 30 %, while PDD will occur in over 80 %
of patients after 20 years of disease (Hely et al. 2008). Moreover, mild cognitive
impairment (MCI) may be present in up to 36 % of newly diagnosed cases of PD
(Foltynie et al. 2004; Bronnick et al. 2006; Buter et al. 2008; Litvan et al. 2012;
Burn and Barker 2013; Duncan et al. 2013; Yarnall et al. 2013).
PDD can exacerbate the disabilities caused by motor symptoms in PD, and the
presence of cognitive impairment or dementia in patients with PD is associated with
a loss of independence, a lower quality of life, and a shorter survival time than PD
patients without dementia (Rosenthal et al. 2010). The course of decline in PDD is
progressive over time with periods of rapid worsening (Emre et al. 2007a). Therefore,
PDD has an important impact on patient management and prognosis, which makes
the understanding of its pathophysiology crucial for future therapeutic research.
Clinical Features of PDD
Clinical Risk Factors to Develop PDD
Age is the most prominent risk factor for PDD (Kempster et al. 2010; Levy et al.
2002; Williams-Gray et al. 2009) independently from the age of PD onset. PDD
also correlates with the severity of motor disability, and the aging factor may be
11 Dementia in Parkinson’s Disease and Atypical Parkinsonism 181
additive to the severity of the motor dysfunction (Levy et al. 2000, 2002). Other
factors such as visual hallucinations, and the PD phenotype (e.g., prominent axial
rigidity and bradykinesia as opposed to tremor), confer risk for the development of
PDD (Emre et al. 2007a; Jankovic and Poewe 2012; Galvin et al. 2006). Mild cogni-
tive impairment (MCI) has also been associated with an increased risk of develop-
ing PDD (Litvan et al. 2012; Levy et al. 2002).
Cognitive Deficits
The most common cognitive deficits in PDD include those in attention, executive
functioning, and visuospatial processing. Attentional performance may fluctuate,
leading to a variable level of function and a major impact upon activities of daily
living (Bronnick et al. 2006). In tests such as the letter cancelation test and others,
PDD patients are slower, tend to fluctuate more, and incur on a higher number of
errors than Alzheimer’s dementia (AD) patients, whereas the profile of PDD seems
to be similar to that seen in dementia with Lewy bodies (DLB). Executive dysfunc-
tion has been widely recognized in PDD and the most used tests have been verbal
fluency, digit span backward, Wisconsin Card Sorting Test, Stroop Test, and Trail
Making Test (Kudlicka et al. 2011). Studies assessing visuospatial function have
shown greater deficits in PDD than AD patients (Jeannerod and Jacob 2005). It has
been shown that visual perception, space-motion perception, and object-form per-
ception are globally more impaired in PDD patients than non-demented PD patients,
and AD patients (Mosimann et al. 2004).
In PDD, short-term memory is impaired, both for initial learning and immediate
recall. Traditionally, amnesic deficits in PD have been considered to be mainly of
retrieval, rather than encoding and storage. However, memory loss in PDD has been
associated more with a frontally mediated retrieval deficit thus again a deficit in
executive functioning, than to an intrinsic defect (Emre et al. 2007a). A large meta-
analysis has shown that verbal fluency impairment is more pronounced than that
seen in PD non-demented patients; also, semantic fluency seems to be more com-
promised than phonemic fluency (Henry and Crawford 2004). Significant language
deficits are not typically seen in PDD and occur much less frequently than in AD
(Pillon et al. 1993). When present, language deficits in PDD are more likely associ-
ated to executive dysfunction-related problems in sentence processing rather than
an intrinsic core language deficit (Grossman et al. 2012).
Neuropsychiatric Features
Neuropsychiatric symptoms, including hallucinations and delusions, depression,

anxiety, and apathy, are well reported in PD. Hallucinations tend to be more com-
mon in DLB than in PDD and in the latter more frequent than in AD (Aarsland et al.
2000). Delusions seem to be less frequent than hallucinations in PDD but more
common than in AD and less than in DLB (Aarsland et al. 2005). Dysphoria and
depression occur with approximately the same frequency in PDD and AD (40–
58 %) patients (Aarsland et al. 2001). Anxiety occurs at a similar frequency (30–
49 %) as depressed mood, and these symptoms may frequently coexist in the same
patient (Bronnick et al. 2007). Irritable mood, anger, and aggression are common in
AD, but uncommon in PDD (Engelborghs et al. 2005). Prominent apathy may occur
in PDD but also in other forms of dementia, including frontotemporal dementia,
progressive supranuclear palsy, AD, and DLB. Furthermore, some individuals may
exhibit an impulse control disorder that is characterized by compulsive gambling,
eating, purchasing, sexual behavior, and/or a dopamine dysregulation syndrome
(Weintraub 2008). The etiology of impulse control disorders in PD is thought to be
due to stimulation of hypersensitive ventral striatal-frontal connections by dopami-
nergic therapy rather than a direct consequence of the neurodegenerative process
that is specific to PD and PDD (Weintraub 2008; Weintraub et al. 2013).
Etiopathogenesis of PDD
Neuropathology
Several lines of evidence from studies using α-syn immunohistochemistry in post-

mortem brains implicate cortical α-syn pathology as the strongest correlate of
dementia in PDD demonstrating higher levels of cortical α-syn pathology than do
cases of PD without dementia (Jellinger 2007; Compta et al. 2011; Irwin et al. 2012,
2013; Duda et al. 2002; Hurtig et al. 2000). The Braak hypothesis states that Lewy
body pathology progresses in a sequence from the pons and brainstem via the fore-
brain and limbic system to the neocortex. These stages might progress in parallel
with cognitive decline (Braak et al. 2005). Indeed, many studies have found that the
level of global cortical and limbic α-syn pathology or the levels of α-syn pathology
in specific brain regions, such as the parahippocampal or anterior cingulate gyrus,
can discriminate between PD without dementia and PDD and are the strongest cor-
relate to PDD when compared with other possible factors such as genetic (Irwin
et al. 2012, 2013; Kovari et al. 2003). Neurochemically, cholinergic deficits occur in
patients with PDD, attributed to neuronal loss in basal forebrain cholinergic nuclei,
and are associated with the transition of α-syn pathology into limbic and neocortical
regions (Ballard et al. 2006; Perry et al. 1985; Whitehouse et al. 1983; Yarnall et al.
2011; Shimada et al. 2009).
However, despite the crucial role of a-syn in PDD, the hallmark pathologies of
AD, that is, mainly the levels of Aβ plaques and less the tau neurofibrillary tangles
(NFTs), have been found to inversely correlate with the cognitive status in a subset
of PDD patients (Jellinger 2007; Compta et al. 2011; Kovari et al. 2003; Jellinger
et al. 2002). Cortical α-syn, tau, and Aβ pathologies together have been shown to
more accurately predict dementia than any single marker alone (Compta et al. 2011;
Irwin et al. 2012, 2013; Tsuboi et al. 2005; Kotzbauer et al. 2012). Thus, AD pathol-
ogy (and in particular Aβ plaque pathology) may have an important role in the
pathogenesis of PDD and a possible synergy with α-syn pathology (Masliah et al.
2001; Clinton et al. 2010). Indeed, clinically, patients with PDD and AD pathology
have shorter disease duration, older age at onset of motor symptoms, and shortened
survival times compared to PDD patients without concomitant AD pathology
(Compta et al. 2009, 2011; Irwin et al. 2012, 2013; Halliday and McCann 2010;
Halliday et al. 2008).
In summary, the progression of Lewy body and neurite pathology from subcorti-
cal areas into limbic and cortical structures seems to be the major determinant of the
development of dementia in most individuals with PDD; however, other pathologies
such as that of AD may be implicated in the underlying neuropathology of PDD.
Genetics
Genetic factors may also play an important role in the development of cognitive
impairment in PDD. Some monogenic forms of PD have been associated with
dementia such as those resulting from pathogenic mutations of the α-synuclein gene
(SNCA), whereas others such as mutations in leucine-rich repeat kinase 2 (LRRK2)
or the parkin gene do not seem to be as strongly linked to PDD and DLB (Poulopoulos
et al. 2012; Sidransky et al. 2009). Heterozygous mutations in the b-glucocerebrosidase
(GBA) gene are associated with an increased risk of PD or DLB, and GBA-linked
PD is associated with a higher risk and an earlier age of onset of dementia, as well
as higher levels of cortical and limbic α-syn pathology than noncarrier patients with
PD (Sidransky et al. 2009; Alcalay et al. 2012; Clark et al. 2009; Nalls et al. 2013;
Neumann et al. 2009; Tsuang et al. 2012). Moreover, polymorphisms of DYRK1A,
which encodes a kinase that phosphorylates proteins such as α-synuclein and amy-
loid precursor protein, have been associated with PDD and DLB (Jones et al. 2012).
The APOE ε4 allele has been established as a risk factor for AD and may also
confer an increased risk of dementia in PD, but further studies are needed (Morley
et al. 2012; Tsuang et al. 2013; Wider et al. 2012). The H1/H1 haplotype of the
MAPT gene, encoding for protein tau, has been associated with an increased risk of
some tauopathies, for example, progressive supranuclear palsy (Hoglinger et al.
2011). Interestingly, this variation in MAPT has been associated with PD as well;
however, the risk for PDD as associated with the H1/H1 haplotype in PD has been
less well studied (Neumann et al. 2009; Tsuang et al. 2013; Wider et al. 2012;
Hoglinger et al. 2011). Other possible associations such as the BDNF (Met/Met)
homozygote genotype need further confirmation (Guerini et al. 2009).
Diagnosis of PDD
At the outset it should be clarified that frank dementia in the initial stages of PD is
not considered a typical feature of the disease (Massano and Bhatia 2012). This is
particularly relevant in the differential diagnosis with DLB, in which the cognitive
features are similar to PDD. According to the research criteria for DLB, patients
should have an onset of dementia within 1 year after the onset of motor symptoms,
while in PDD dementia, this occurs at least 1 year after PD onset (McKeith 2006).
Similarly, cognitive dysfunction at early stages should alert the clinician for other
differential diagnoses in particular when other atypical features are present such as
progressive supranuclear palsy (Litvan et al. 1996). Moreover, clinicians should
always search for possible secondary causes if cognitive impairment in Parkinson’s
disease is noted, such as side effects from dopaminergic treatment.
The identification of patients with PDD but even more so of PD patients with
MCI, and thus patients at high risk to develop dementia, is crucial for manage-
ment and prognostic reasons but also for future therapeutic research. Clinical
criteria for PDD have recently been proposed, which however lack clinicopatho-
logical validation (Tables 11.1 and 11.2) (Emre et al. 2007a). Identification of a
dementia syndrome, defined as impairment in at least two of the four core cogni-
tive domains (e.g., attention, executive functioning, visuospatial functioning, and
free recall memory), is needed for diagnosis. Impairment should be severe enough
to affect daily social, occupational, or personal care independent of the effects of
motor or autonomic symptoms. Behavioral symptoms such as apathy, depressed
or anxious mood, hallucinations, delusions, or excessive daytime sleepiness sup-
port the diagnosis of cognitive impairment. The criteria are highly specific when
all eight items are met, but their sensitivity is low (Martinez-Martin et al. 2011;
Dujardin et al. 2010; Barton et al. 2012). However, the criteria are more sensitive
for PDD diagnosis than is the fourth edition of the diagnostic and statistical man-
ual of mental disorders (DSM-4) (Emre et al. 2007a). Moreover, diagnostic crite-
ria for MCI in PD have been proposed recently (Table 11.3) (Litvan et al. 2012).
Possible biomarkers for MCI are currently under research (Duncan et al. 2013;
Yarnall et al. 2013).
Treatment of PDD
The current pharmacological strategy is symptomatic and there is no neuroprotec-

tive or disease-modifying treatment available. Treatment of PDD includes acetyl-
cholinesterase inhibitors that have been shown to improve cognition and the ability
to perform activities of daily living in PDD, with the largest body of evidence for
rivastigmine (Barone et al. 2008; Burn et al. 2006; Emre et al. 2007b; McKeith
et al. 2000; Oertel et al. 2008; Poewe et al. 2006; Schmitt et al. 2010; Seppi et al.
2011; Wesnes et al. 2005). No established clinical or biological markers can predict
which patients will improve, but it is suggested that those with visual hallucinations
and hyperhomocysteinemia respond particularly well (Barone et al. 2008; Burn
et al. 2006). Evidence is less robust for the other cholinesterase inhibitors such as
donepezil. It is however important to point out that these drugs may worsen motor
symptoms, while dopamine agonists used to treat motor symptoms may worsen
cognition, complicating therapeutic options in PDD. Acetylcholinesterase
Table 11.1 Features of dementia associated with Parkinson’s disease (Emre et al. 2007a)
I. Core features 1. Diagnosis of Parkinson’s disease according to Queen Square Brain Bank
criteria (Gibb and Lees 1988)
2. A dementia syndrome with insidious onset and slow progression,
developing within the context of established Parkinson’s disease and
diagnosed by history, clinical, and mental examination, defined as:
Impairment in more than one cognitive domain
Representing a decline from premorbid level
Deficits severe enough to impair daily life (social, occupational, or
personal care), independent of the impairment ascribable to motor or
autonomic symptoms
II. Associated 1. Cognitive features:
clinical features Attention: Impaired. Impairment in spontaneous and focused attention,
poor performance in attentional tasks; performance may fluctuate
during the day and from day to day
Executive functions: Impaired. Impairment in tasks requiring initiation,
planning, concept formation, rule finding, set shifting, or set mainte-
nance; impaired mental speed (bradyphrenia)
Visuospatial functions: Impaired. Impairment in tasks requiring visuospa-
tial orientation, perception, or construction
Memory: Impaired. Impairment in free recall of recent events or in tasks
requiring learning new material, memory usually improves with cueing,
and recognition is usually better than free recall
Language: Core functions largely preserved. Word finding difficulties and
impaired comprehension of complex sentences may be present
2. Behavioral features:
Apathy: Decreased spontaneity, loss of motivation, interest, and effortful
behavior
Changes in personality and mood including depressive features and anxiety
Hallucinations: Mostly visual, usually complex, formed visions of people,
animals, or objects
Delusions: Usually paranoid, such as infidelity or phantom boarder
(unwelcome guests living in the home) delusions
Excessive daytime sleepiness
III. Features which Coexistence of any other abnormality which may by itself cause cognitive
do not exclude impairment, but judged not to be the cause of dementia, e.g., presence
PDD, but make of relevant vascular disease in imaging
the diagnosis Time interval between the development of motor and cognitive symptoms
uncertain not known
IV. Features Cognitive and behavioral symptoms appearing solely in the context of
suggesting other other conditions such as the following:
conditions or Acute confusion due to either systemic diseases or abnormalities or drug
diseases as intoxication, major depression according to DSM IV
cause of mental Features compatible with “probable vascular dementia” criteria according
impairment, to NINDS-AIREN (dementia in the context of cerebrovascular disease
which, when as indicated by focal signs in neurological exam such as hemiparesis,
present, make it sensory deficits, and evidence of relevant cerebrovascular disease by
impossible to brain imaging and a relationship between the two as indicated by the
reliably presence of one or more of the following: onset of dementia within
diagnose PDD 3 months after a recognized stroke, abrupt deterioration in cognitive
functions, and fluctuating, stepwise progression of cognitive deficits)
Table 11.2 Criteria for the diagnosis of probable and possible PDD (Emre et al. 2007a)
Probable PDD (A) Core features: Both must be present
(B) Associated clinical features:
Typical profile of cognitive deficits including impairment in at least two of
the four core cognitive domains (impaired attention which may fluctuate,
impaired executive functions, impairment in visuospatial functions, and
impaired free recall memory which usually improves with cueing)
The presence of at least one behavioral symptom (apathy, depressed or
anxious mood, hallucinations, delusions, excessive daytime sleepiness)
supports the diagnosis of probable PDD; lack of behavioral symptoms,
however, does not exclude the diagnosis
(C) None of the group III features present
(D) None of the group IV features present
Possible PDD (A) Core features: Both must be present
(B) Associated clinical features:
Atypical profile of cognitive impairment in one or more domains, such as
prominent- or receptive-type (fluent) aphasia or pure storage-failure type
amnesia (memory does not improve with cueing or in recognition tasks)
with preserved attention
Behavioral symptoms may or may not be present
or
(C) One or more of the group III features present
(D) None of the group IV features present
inhibitors might affect concurrent plaque pathological changes in patients with

DLB (Ballard et al. 2007). There is inconsistent evidence for the glutaminergic
agent memantine having a beneficial effect in PDD (Seppi et al. 2011; Aarsland
et al. 2009; Emre et al. 2010; Larsson et al. 2011; Leroi et al. 2009; Ondo et al.
2011; Svenningsson et al. 2012).
In 2011, the Movement Disorder Society taskforce on evidence-based medicine
published a revised review of treatments for non-motor symptoms of PD and con-
cluded that rivastigmine is effective and clinically useful in the treatment of demen-
tia; evidence for donepezil, galantamine, and memantine was insufficient. All
drugs had acceptable risks without the need for specialized monitoring. Evidence
from placebo-controlled studies supported the use of clozapine for psychosis
(Seppi et al. 2011).
Histamine H3 receptor antagonists are being developed mainly for fatigue and
sleep disturbances in PD but are also thought of as procognitive drugs in AD (Chazot
2010). Effects on cognition in PD have not yet been reported. Cognitive interven-
tion programs are useful in AD and MCI (Jean et al. 2010). They might be particu-
larly relevant in PD because increased dopamine release has been noted after
cognitive training (Backman et al. 2011). Preliminary reports were positive, and
results of the first randomized trial showed that intensive cognitive training led to
improvement in various cognitive tasks compared with the control group immedi-
ately after the intervention (Paris et al. 2011). Novel pharmacological treatments,
cell-based therapies, gene transfer, antibodies blocking amyloid or α-synuclein
aggregation, and trophic factor approaches are under development.
Table 11.3 Criteria for the diagnosis of PD-MCI (Litvan et al. 2012)
I. Inclusion criteria
Diagnosis of Parkinson’s disease as based on the UK PD Brain Bank Criteria (Gibb and Lees
1988)
Gradual decline, in the context of established PD, in cognitive ability reported by either the
patient or informant or observed by the clinician
Cognitive deficits on either formal neuropsychological testing or a scale of global cognitive
abilities (detailed in section III)
Cognitive deficits are not sufficient to interfere significantly with functional independence,
although subtle difficulties on complex functional tasks may be present
II. Exclusion criteria
Diagnosis of PD dementia based on MDS Task Force proposed criteria (Emre et al. 2007a)
Other primary explanations for cognitive impairment (e.g., delirium, stroke, major depression,
metabolic abnormalities, adverse effects of medication, or head trauma)
Other PD-associated comorbid conditions (e.g., motor impairment or severe anxiety, depres-
sion, excessive daytime sleepiness, or psychosis) that, in the opinion of the clinician, signifi-
cantly influence cognitive testing
III. Specific guidelines for PD-MCI level I and level II categories
(A) Level I (abbreviated assessment)
Impairment on a scale of global cognitive abilities validated for use in PD or
Impairment on at least two tests, when a limited battery of neuropsychological tests is
performed (i.e., the battery includes less than two tests within each of the five cognitive
domains, or less than five cognitive domains are assessed)
(B) Level II (comprehensive assessment)
Neuropsychological testing that includes two tests within each of the five cognitive domains
(i.e., attention and working memory, executive, language, memory, and visuospatial)
Impairment on at least two neuropsychological tests, represented by either two impaired
tests in one cognitive domain or one impaired test in two different cognitive domains
Impairment on neuropsychological tests may be demonstrated by:
Performance approximately 1–2 SDs below appropriate norms or
Significant decline demonstrated on serial cognitive testing or
Significant decline from estimated premorbid levels
IV. Subtype classification for PD-MCI (optional, requires two tests for each of the five cognitive
domains assessed and is strongly suggested for research purposes)
PD-MCI single-domain—abnormalities on two tests within a single cognitive domain (specify
the domain), with other domains unimpaired or
PD-MCI multiple-domain—abnormalities on at least one test in two or more cognitive
domains (specify the domains)
Dementia in Atypical Parkinsonism
The term “atypical parkinsonism” usually refers to disorders that present with par-
kinsonism and some features which are atypical for PD such as, for example, sym-
metric parkinsonism, symptoms unresponsive to dopaminergic treatment, and
additional signs (e.g., among others alien limb phenomenon, vertical gaze palsy,
early falls). Classically, disorders that belong to the atypical parkinsonian disorders
are progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multi-
ple system atrophy (MSA), and DLB (which has been discussed in PDD), which
are distinct pathological entities. Of those, PSP and CBD belong neuropathologi-
cally to the family of tauopathies, whereas MSA and DLB belong to the
α-synucleinopathies.
Dementia in Progressive Supranuclear Palsy

and Corticobasal Degeneration
Introduction
Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are two
distinct pathological entities (Litvan et al. 1996; Armstrong et al. 2013). The classi-
cal PSP phenotype is characterized by postural instability and early falls, early cog-
nitive dysfunction, and abnormalities of vertical gaze and is referred to as
Richardson’s syndrome (RS) (Williams et al. 2005). The classical CBD phenotype
consists of asymmetric parkinsonism, cortical signs (e.g., apraxia, cortical sensory
loss, alien limb), and possibly other signs such as dystonia and myoclonus and is
referred to as corticobasal syndrome (CBS). However, patients with PSP and CBD
may present with phenotypes other than the classical ones: patients with PSP pathol-
ogy may present as PSP-parkinsonism, CBS, pure akinesia with gait freezing, pro-
gressive nonfluent aphasia, and others; (Lee et al. 2011; Ling et al. 2010; Stamelou
et al. 2012; Williams and Lees 2009a, b) patients with CBD pathology may present
with RS, a frontotemporal dementia (FTD) phenotype, and others (Armstrong et al.
2013; Ling et al. 2010; Stamelou et al. 2012; Kouri et al. 2011). Thus, patients with
PSP and CBD may present with overlapping clinical features including cognitive
ones and also with phenotypes of other dementia syndromes mainly FTD.
In contrast to PD, cognitive and neuropsychiatric features may be the presenting
symptom of PSP and CBD (Donker Kaat et al. 2007). Dementia is evident in both
disorders in clinical practice; however, well-designed, prospective prevalence stud-
ies of dementia in these patients are lacking. From a report of 67 patients, 85 %
showed evidence of cognitive impairment, although dementia criteria were not
applied (Donker Kaat et al. 2007). Similarly, “cognitive problems” were reported as
the initial presenting complaint in 15 % of a prevalent sample of 187 cases (Nath
et al. 2003). Cognitive and neuropsychiatric features have an important impact on
QoL in PSP and CBD (Winter et al. 2011).
Clinical Features of Dementia in PSP and CBD
Clinical Risk Factors for Dementia in PSP and CBD
In contrast to PDD described above, clinical risk factors to develop dementia in these
disorders are not well studied. For PSP, certain phenotypes such as PSP with parkin-
sonism seem to develop dementia later than the classical phenotype RS, (Williams
et al. 2005) but large prospective studies are missing. The time of onset of the symp-
toms and the duration of disease do not seem to influence the course of dementia in
these disorders, which however may correlate with age and clinical motor disability
scores (Brown et al. 2010). The evolution of cognitive impairment in relation to the
motor symptoms varies greatly not only for the different phenotypes of PSP and
CBD but also within the classical phenotypes RS and CBS (Brown et al. 2010).
Cognitive Features of PSP and CBD
Given the rarity of these disorders, most research refers to clinically diagnosed
rather than pathology-confirmed PSP and CBD patients. No prospective longitudi-
nal studies with pathological confirmation are available.
In PSP, prominent deficits are described on tests of attention and executive func-
tion, with verbal fluency being particularly severely affected, as well as deficits in
both verbal and nonverbal memory with a relative preservation of recognition. PSP
patients have impairments in processing speed and cognitive flexibility (Dubois
et al. 1988). In one study, the neurocognitive performance of 200 patients with RS
revealed primary executive dysfunction (e.g., 74 % impaired on the Frontal
Assessment Battery, 55 % impaired on Initiation/Perseveration subscale of the
Dementia Rating Scale), with milder difficulties in memory, construction, and nam-
ing (Gerstenecker et al. 2013; Mimura et al. 1997).
These deficits have been confirmed also in larger clinical studies (Brown et al.
2010).
Patients with CBD typically demonstrate difficulties that reflect impairment of
frontal-subcortical and posterior cortical visuospatial association areas, with execu-
tive problem solving and pre-motor coordination of praxis tasks that are not typically
observed in patients with PSP or AD (Pillon et al. 1995) (Massman et al. 1996).
Executive dysfunction and language difficulties characterize the cognitive profile,
while memory is generally preserved. Difficulty with limb apraxias and relatively
intact memory was found when compared to AD patients (Massman et al. 1996).
Language difficulties including verbal fluency and anomia are common in CBD.
Neuropsychiatric Features of PSP and CBD
The most commonly described neuropsychiatric symptoms observed in PSP patients

include apathy and anhedonia, disinhibition, depression, and bulbar affect, while
hallucinations and delusions are rare (Williams and Lees 2009a). Apathy can be a
consequence of depression; however, in PSP apathy seems to be independent of
depression, the latter being rare (Litvan et al. 1996, 1997; Litvan 1994). From 22
probable PSP and 50 probable AD patients, 91 % PSP patients reported apathy
which was continuously present in the Neuropsychiatric Inventory (NPI), as
opposed to 72 % of AD patients (Litvan et al. 1996; Cummings et al. 1994). The
next most commonly reported symptom is disinhibition (around 36 %), while
hallucinations and delusions are not observed in PSP in contrast to AD patients

(Litvan et al. 1996, 1997; Litvan 1994). Comparing PSP with PD using the NPI and
taking into account confounding factors such as dopaminergic medication showed
that the clinical syndrome in PSP is predominated by apathy and disinhibition,
while PD patients predominantly complained of hallucinations and delusions rather
than apathy or depression (Aarsland et al. 2001).
The most common symptoms in CBD include depression, apathy, agitation, per-
sonality changes, and irritability. In contrast, delusions and hallucinations are, as in
PSP, exceedingly rare. In a clinical series of 15 CBS, 73 % of CBS patients had depres-
sion, 40 % apathy, and 20 % agitation on the NPI and none had delusions or hallucina-
tions (Litvan et al. 1997; Wenning et al. 1998). Twenty-two percent of 36 pathology
confirmed CBD patients reported neuropsychiatric symptoms mainly depression,
compulsive behaviors, and frontal lobe release signs in a retrospective study of pathol-
ogy confirmed CBD, in which none reported hallucinations (Geda et al. 2007).
Etiopathogenesis of Dementia in PSP and CBD
Neuropathology
Microscopically, tau pathology in PSP is specifically concentrated in the globus pal-

lidus, subthalamic nuclei, and substantia nigra, and thus dementia is typically con-
sidered a “subcortical dementia.” There are some lesions in the motor cortex, basal
ganglia, cerebellum, and certain brainstem nuclei. In the brainstem, the periaque-
ductal grey of midbrain as well as the superior colliculus and many nuclei involved
in vertical gaze and alertness show the greatest pathology. The cellular changes in
PSP include argyrophilic neurofibrillary tangles and positive tau immunohisto-
chemistry in the globus pallidus and the characteristic tufted astrocytes (as opposed
to the astrocytic plaques in CBD) primarily identified in the striatum and motor
cortex. Gross evaluation of PSP brain tissue usually reveals mild frontal lobe atro-
phy and marked midbrain atrophy with enlarged cerebral aqueduct. The substantia
nigra is affected and expresses less pigment in the midbrain. There is also pro-
nounced atrophy of the subthalamic nucleus and superior cerebellar peduncles
(Dickson et al. 2007). The distribution of tau pathology in frontal-subcortical struc-
tures seems to reflect the clinical dementia phenotype in these patients, and it has
been shown that phenotypes of PSP with less cognitive impairment like PSP-
parkinsonism have a lower cortical tau burden in pathology, albeit in small numbers
of patients (Williams and Lees 2009a).
The histopathological criteria for CBD require the abnormal deposition of hyper-
phosphorylated tau protein as a distinct type of intracellular inclusions known as
astrocytic plaques. There are ballooned achromatic neurons and inclusions referred
to as “corticobasal bodies” in both grey and white matter in the cerebral cortex and
subcortical areas including the basal ganglia, while hippocampi and temporal corti-
ces are usually unaffected (Dickson et al. 2002). Gross pathology of brains from
CBD patients reveals asymmetric atrophy of the superior parietal and frontal lobes
contralateral to the symptomatic limb apraxia (Dickson et al. 2002).
To which extent concomitant pathologies may be implicated in the natural his-

tory of dementia in these disorders, such as AD pathology, is unknown, as large
studies are missing.
Diagnosis of Dementia in PSP and CBD
In contrast to PDD, there are no formal criteria for the diagnosis of dementia in PSP
and CBD. Clinical diagnosis of PSP relies on widely accepted criteria, which, how-
ever, are based on retrospective studies and lack prospective validation. In the cur-
rent criteria for clinical diagnosis of PSP, cognitive dysfunction is mentioned as a
supportive criterion only (Litvan et al. 1996). In the recently published clinical cri-
teria of CBD, several cognitive and neuropsychiatric domains are taken into account,
to diagnose possible or probable CBD (Armstrong et al. 2013).
In terms of useful cognitive tests, a recent meta-analysis of 141 cognitive tests
used in parkinsonian disorders showed that only 16 were found to be highly useful.
Inferior performance on phonemic and semantic verbal fluency, the Trail Making
Test, and the Wisconsin Card Sorting Test was moderately to very useful in separat-
ing PSP from PD and MSA. Cognitive testing could not differentiate CBS from
other parkinsonian disorders, although sequential orobuccal apraxia was very use-
ful. Obviously, these tests must be interpreted in conjunction with other clinical
characteristics to be helpful diagnostically (Lee et al. 2012).
Treatment of Dementia in PSP and CBD
Therapeutic trials to enhance cognitive function in PSP and CBD are rare and usu-
ally included a few number of patients, in an open-label fashion. A double-blinded
placebo-controlled trial of donepezil (an acetylcholinesterase inhibitor) showed
mild cognitive benefits and deleterious side effects, which exacerbated the parkin-
sonian features of PSP and dramatically worsened the functional status (Litvan et al.
2001). A small study on five PSP patients with rivastigmine showed a possible mild
benefit (Liepelt et al. 2010). Thus, there are currently no evidence-based treatments
for dementia in PSP and CBD, and more research on the pathophysiology underly-
ing PSP and CBD is required to find safe and tolerable pharmacological alterna-
tives. In terms of possible disease-modifying or neuroprotective treatments, two
large double-blind studies using the GSK-3b inhibitor tideglusib, and the microtu-
bule stabilizer davunetide, showed no clinical improvement after 1 year, in none of
the outcome measures including cognitive ones (Höglinger et al. 2013).
Dementia in Multiple System Atrophy
Multiple system atrophy (MSA) is a sporadic, adult-onset, neurodegenerative disease,

clinically characterized by a variable combination of parkinsonism, cerebellar ataxia,
and/or autonomic dysfunction (Gilman et al. 2008). According to the predominant

feature at onset, it is subclassified to MSA with parkinsonism (MSA-P) and MSA
with cerebellar signs (MSA-C). MSA belongs to the α-synucleinopathies and is char-
acterized by the presence of abnormal α-synuclein-positive cytoplasmic inclusions in
oligodendrocytes, termed glial cytoplasmic inclusions (Wenning and Jellinger 2005).
Currently, cognitive dysfunction is an exclusion criterion for the diagnosis of
MSA according to validated, widely accepted clinical criteria (Gilman et al. 2008).
Indeed, as for PD, frank dementia at onset or initial stages in a patient with parkin-
sonism should prompt to investigate for other causes than MSA, such as DLB, PSP,
or CBD. However, sparse evidence exists for some cognitive deficits in MSA. In a
retrospective study on pathologically confirmed cases, dementia has been reported
from 14 % in up to 15.7 %; however, in none was dementia reported within the first
5 years from onset (Gilman et al. 2008). In a large study on over 300 MSA patients,
global cognitive impairment was found in 11–32 % of these patients, which corre-
lated with age, severity of motor symptoms, and lower level of education (Brown
et al. 2010). The etiopathogenesis and possible treatments are currently under
research (Kim et al. 2013).
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Chapter 12
Vascular Dementia and Parkinsonism
Laura Silveira-Moriyama, Egberto R. Barbosa, Paulo Caramelli,

Jan Zijlmans, and Andrew J. Lees
Abstract Cerebrovascular disease is a leading cause of mortality and morbidity

worldwide. Its clinical manifestations vary from acute neurological deficit to
stepwise or slowly progressive chronic deficits. Although originally described
as separate entities, vascular dementia and vascular parkinsonism are overlap-
ping spectrums of cognitive and extrapyramidal manifestations associated with
subcortical vascular damage. In this chapter, we discuss the main concepts
underlying the historical concepts of Binswanger encephalopathy and lower-
body parkinsonism, present the main features of vascular dementia and vascular
parkinsonism, summarize recommendations for clinical management, and close
with suggestions for future research in these prevalent and often neglected
conditions.
L. Silveira-Moriyama, MD, PhD (*)

National Hospital for Neurology and Neurosurgery,
Reta Lila Weston Institute, UCL Institute of Neurology, Queen Square, London, UK
Neurology Department, FCM, University of Campinas,
UNICAMP, Hospital Das Clinicas, Campinas, SP, Brazil
E.R. Barbosa, MD, PhD
Department of Neurology, University of Sao Paulo School
of Medicine, Hospital Das Clinicas, Sao Paulo, SP, Brazil
P. Caramelli, MD, PhD
Department of Internal Medicine, Faculty of Medicine,
Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
J. Zijlmans, MD, PhD
Department of Neurology, Amphia Hospital, Breda, NA, The Netherlands
A.J. Lees, MD, FRCP
National Hospital for Neurology and Neurosurgery,
Reta Lila Weston Institute, UCL Institute of Neurology, Queen Square, London, UK

200 L. Silveira-Moriyama et al.
Keywords Vascular dementia • Vascular parkinsonism • Lower-body parkinsonism •

Binswanger encephalopathy • Cerebrovascular disease
Cerebrovascular Disease
Cerebrovascular disease (CVD) is a leading public health problem and a major

cause of adult and elderly disability. Although acute stroke is associated with a high
mortality, chronic progressive vascular damage accounts for a significant proportion
of the neurological decline associated with ageing and with slowly progressive
forms of neurological disability, including so-called vascular dementia and vascular
parkinsonism.
CVD might be caused by intracerebral micro- or macrobleed or by neuronal
death due to ischemia. The latter one is caused by primary vasculopathies, proco-
agulant hematological conditions, or embolic causes of stroke, mainly heart disease.
The most common cause of chronic ischemic cerebrovascular disease presents in
the elderly and stems from progressive atherosclerotic damage to large, medium,
and small vessels caused by a combination of various risk factors. The main risk
factors are ageing, hypertension, smoking, diabetes mellitus, dyslipidemia, and obe-
sity. In addition, non-atherosclerotic vasculopathies, which are individually rare,
make up a significant proportion of the cerebrovascular disease observed in the
young adult population and include alcohol consumption, drug misuse, vasculitis,
collagen disease, cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL), mitochondrial disease, fibromuscular dys-
plasia, syphilis, HIV, and idiopathic or traumatic arterial dissection, among others.
Hematological causes of stroke include sickle cell disease, polycythemia or throm-
bocythemia of various origins, antiphospholipid antibody syndrome, malignancies
(including myeloma, leukemia, and solid tumors), and the more rare thrombotic
thrombocytopenic purpura, paroxysmal nocturnal hemoglobinuria, and genetic
thrombophilias. Cardiac causes of CVD include atrial fibrillation, vascular heart
disease, bacterial and marantic endocarditis, and less frequently myocardial infarc-
tion and chronic cardiomyopathy.
All of these contributing factors for CVD can happen concomitantly, and there-
fore patients will often present mixed forms of CVD, including large, medium, and
small artery disease, and often watershed syndromes and chronic encephalopathy
(see Table 12.1). Large artery disease usually evolves chronically in the elderly, and
carotid or vertebral artery occlusions are often preceded by the chronic development
of a network of collateral circulation many times limiting the extensive brain dam-
age that could be caused by acute occlusion of an otherwise healthy artery, even
with the physiological anastomosis of the circle of Willis. Classic examples of
medium artery disease include the middle cerebral artery syndrome and the basilar
artery syndromes. The first can cause hemiplegia and hemisensory loss in the milder
cases up to obtundation and life-threatening cerebral edema in the most severe case.
The latter can cause various forms of motor deficits, cranial nerve syndromes, and
the dramatic locked-in syndrome.
12 Vascular Dementia and Parkinsonism 201
Table 12.1 Mechanisms of cerebrovascular disease

Example of clinical
Mechanism Example of causative condition syndrome
Large artery occlusion Atherosclerosis, idiopathic or traumatic Internal carotid artery
arterial dissection syndrome
Medium-sized artery Atherosclerosis, vasculitis Middle cerebral artery
occlusion syndrome
Small artery disease Arteriolosclerosis Lacunar pure complete
hemiparesis
Watershed Hypoxic or hypovolemic state Postanoxic ischemic
encephalopathy after
cardiac arrest
The classic acute manifestation of small artery disease is the lacunar stroke: a
sudden neurological deficit caused by the occlusion of a small artery, generating a
small subcortical or brainstem stroke which is between 1 and 15 mm in size. The
most common lacunar syndromes include pure motor hemiplegia, pure hemisensory
deficit or pure sensorimotor hemisyndrome (all of which can be complete, incom-
plete, or alternate, depending on the location of the stroke), ataxia hemiparesis, and
also dysarthria and clumsy hand syndrome (often associated with thalamic infarc-
tion). The so-called silent small vessel disease will often go unnoticed and asymp-
tomatic even under neurological scrutiny. Nevertheless, small vessel occlusion
might lead to cumulative neuronal loss leading to progressive neurological deficit,
including extrapyramidal features and cognitive decline.
The Evolving Concepts of Vascular Dementia (VaD)

and Vascular Parkinsonism (VP)
Otto Ludwig Binswanger (October, 1852 to July, 1929) had a long-standing career
in clinical neuroscience between receiving his medical degree in 1877 and being
appointed rector of Jena University in 1911. During his career he worked in neurol-
ogy, psychology, and psychiatry and contributed with more than 100 papers encom-
passing subjects from epilepsy to hysteria. It was through his work with
neuropathology that he described eight patients suffering from progressive deterio-
ration of their motor and cognitive capacities, including “aphasic disturbances(…),
hemiamblyopia or hemianopia, hemiparesis with loss of the sense of pressure, posi-
tion or touch(…) combined with the slow and relentless deterioration of intellectual
performances.” He called this syndrome “encephalitis subcorticalis chronica pro-
gressive” because at postmortem examination he found that these patients had “a
pronounced atrophy of the hemispheric white matter, either restricted to one or
more gyri in one brain area or of several hemispheric regions affected with variable
severity; (…) these changes are most clearly found in the area of the occipital and
temporal lobes, so that temporal and occipital horns are widened into bag-like
cavities, while the anterior portion of the lateral ventricle shows relatively little
enlargement and the frontal white matter is almost unaffected by the disease pro-
cess. (…) The cortex does not show any remarkable macroscopic change apart from
a slight narrowing. Invariably, these cases show severe atheroma of the cerebral
arteries it is very likely that the subcortical loss of fibres is caused by a deficiency of
the blood supply resulting from arteriosclerosis.”
The concept that vascular disease could cause progressive neurological disease
was new, and it was Alzheimer who coined the term “Binswanger encephalitis”
when characterizing this process further in patients of his own. Alzheimer described
the microscopic pathology adding that “One can show in the white matter, the pres-
ence of more or less numerous foci which produce wide areas of secondary degen-
eration… Usually the foci are also to be found in the internal capsule, the lenticular
nucleus, the thalamus, and particularly in the pons in the region of the pyramidal
tract… caused by a particularly severe arteriosclerosis of the long vessels deep in
the white matter with intense atrophy of the white matter” (Pearce 1997).
MacDonald Critchley (February, 1900 to October, 1997) was a neurology con-
sultant and later dean at the Institute of Neurology in Queen Square and during his
prolific academic life published extensively in the various fields of neurology. In
1929, he described what he called “arteriosclerotic parkinsonism” which he
described as a “symptomatic variant of paralysis agitans.” Unlike Binswanger’s
clinicopathological work, Critchley’s was a clinical description of a series of
patients which he saw critically in comparison with the sparse literature on vascular
causes of parkinsonism (then including syphilis and larger strokes) and whose clini-
cal features included short-stepping gait, rigidity, and masked faces, often associ-
ated with dementia, pseudobulbar palsy, pyramidal signs, and cerebellar and
sphincter dysfunction (Critchley 1929). Due to the lack of pathological confirma-
tion, and the difficulty in establishing diagnostic criteria, Critchley’s proposal was
heavily criticized although he bravely rejected the idea of a retraction. One of the
main criticisms was that patients did not necessarily presented with classic bradyki-
nesia, to which Critchley responded proposing that the syndrome could be better
referred to as arteriosclerotic pseudoparkinsonism (Critchley 1981).
As with similar neurological conditions which were progressively differentiated
over the twentieth century, the clinical and neuropathological substrates of the con-
ditions described by Binswanger and MacDonald Critchley were further refined by
advances in neuroimaging (especially the advent of CT and MRI imaging, largely
available in the last decades) and neuropathology (including immunohistochemistry
for the various proteins involved in neurodegeneration). Various names have been
used to refer to parkinsonism caused by CVD, and more recently “vascular parkin-
sonism” seems to be the choice among various international centers (see Table 12.2
for historical evolution of the terms).
Although currently it is largely believed that atherosclerosis can cause progres-
sive dementia, vascular parkinsonism remains a somewhat controversial subject; the
differentiation between these two conditions among themselves and their symbiotic
coexistence with other forms of neurodegeneration remains mysterious. Given that
neurodegenerative conditions are most likely the end-spectrum clinical manifesta-
tions of widely prevalent neurodegenerative processes (including cell death associ-
ated with the deposition of characteristic proteins such as alpha-synuclein,
Table 12.2 Names used to describe parkinsonism caused by cerebrovascular disease

Name Example of reference
Arteriosclerotic parkinsonism Critchley (1929)
Arteriosclerotic Critchley (1981)
pseudoparkinsonism
Lower-body or lower-half Fitzgerald and Jankovic (1989)
parkinsonism
Vascular pseudoparkinsonism Chang CM, Yu YL, Ng HK, Leung SY, Fong KY, et al. Vascular
pseudoparkinsonism. Acta Neurol Scand. 1992;86:588–92.
Vascular parkinsonism Jankovic J. Lower body (vascular) parkinsonism. Arch Neurol.
1990;47:728.
Zijlmans JC, Thijssen HO, Vogels OJ, Kremer HP, Poels PJ,
Schoonderwaldt HC, Merx JL, Van ’T Hof MA, Thien T,
Horstink MW, et al. MRI in patients with suspected vascular
parkinsonism. Neurology. 1995;45:2183–8.
Yamanouchi H, Nagura H. Neurological signs and frontal white
matter lesions in vascular parkinsonism. A clinicopathologic
study. Stroke. 1997;28:965–9.
Demirkiran et al. (2001)
Zijlmans et al. (2004a)
Rampello et al. (2005)
Adapted from from Glass (2012)
beta-amyloid, and tau) and that small vessel disease is almost ubiquitous in the
elderly, the differentiation between vascular and primary neurodegeneration is very
challenging both on the research and clinical settings (Gorelick and Pantoni 2013),
and overall all processes contribute to neurological disability (Fig. 12.1). Overall, in
individual cases one process might be grossly more abundant then the other. For
example, in cases of clear-cut idiopathic Parkinson’s disease (PD) fulfilling Queen
Square Brain Bank criteria (Gibb and Lees 1988) and possibly with antemortem
confirmation of nigrostriatal deficit (i.e., SPECT or PET scan), often there is some
degree of small artery disease in the brain imaging by MRI or CT. Although CVD
does not fully justify the entirety of symptoms, which are traditionally attributed to
the neurodegenerative process, there is recent evidence that the neuronal damage
caused by the vascular disease plays an important role contributing to disability, in
particular when it comes to axial symptoms of PD (Bohnen et al. 2011).
Diagnosis of Vascular Dementia and Parkinsonism
The worldwide epidemiology of vascular dementia and vascular parkinsonism

remains scatty at best (Vale et al. 2012). This is due to the difficult differentiation
between vascular and neurodegenerative chronic conditions, the different diagnos-
tic criteria used historically, and also the frequency of CVD being affected by age,
ethnicity, and socioeconomic factors. As a rule of thumb, vascular dementia might
account for up to 15–20 % of dementia cases (Bradley et al. 2008) and be classified
into various types (see Table 12.3). Vascular parkinsonism may only account for
less than 10 % of parkinsonism cases (Glass 2012).
Primary neuronal
degeneration
High likelihood of
Ageing chronic progressive
neurological deficit
Cerebrovascular
disease
Fig. 12.1 Contributing factors for chronic neurological deficit. The interplay of natural mecha-
nisms of ageing (cell apoptosis, decreased neuronal plasticity, etc.) and cumulative neurodegenera-
tive processes (such as the intracellular deposition of abnormal proteins, cell death, glial
dysfunction, etc.) and cerebrovascular disease of the various types contributes to the development
of chronic neurological deficit
Table 12.3 Main types of cognitive impairment associated with cerebrovascular disease
Name Main features
Subcortical ischemic Chronically progressive cognitive loss associated with a cumulative effect
vascular of various small ischemic foci caused by small vessel disease. Also
dementia known as small vessel dementia, lacunar state, Binswanger disease,
Binswanger encephalopathy
Multi-infarct Cognitive decline associated with various successive cortical strokes
dementia
Strategic infarct Cognitive decline arising from stroke affecting cognitive area (e.g.,
dementia angular gyrus, thalamus, basal forebrain, etc.)
Mixed dementia Combination of significant cerebrovascular disease associated with
underlying neurodegeneration, often Alzheimer’s disease or TPD43
proteinopathy
Vascular mild Cognitive decline not fulfilling clinical criteria for dementia which is
cognitive associated with significant cerebrovascular disease on brain imaging
impairment
Others Includes specific vascular diseases with associated cognitive decline
including CADASIL (cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy)
Infarcts can be ischemic or hemorrhagic strokes
Table 12.4 Features supporting vascular dementia by NINDS-AIREN criteria

Criteria Details
Dementia Cognitive decline from a previous higher level
Impairment of memory and of two or more domains (orientation,
attention, language, visuospatial functions, executive
functions, motor control, and praxis)
Documentation by neurological examination or neuropsychologi-
cal evaluation
Enough to interfere with activities of daily living and not due to
physical effects of stroke alone
Cerebrovascular disease Focal signs on neurologic examination consistent with stroke
(CVD) (with or without history of stroke)
And evidence of relevant CVD by brain imaging (CT or MRI)
A relationship between the One or more of the following:
above two disorders (a) Onset of dementia within 3 months following a recognized
stroke
(b) Abrupt deterioration in cognitive functions; or fluctuating,
stepwise progression of cognitive deficits
Summarized from Román et al. (1993)
The presence of ALL these features makes vascular dementia “probable”
Despite various limitations (Tang et al. 2004; Román 2004; Ballard et al. 2004), the
NINDS-AIREN (Román et al. 1993) remains largely used to diagnose vascular
dementia. The NINDS-AIREN criteria classify subjects into definite, probable, and
possible vascular dementia based on main features demonstrating (a) dementia, (b)
cerebrovascular disease, and (c) a link between these two, which are summarized in
Table 12.4. In addition, exclusion criteria and features which make VaD more or less
likely are also provided (Table 12.5). The presence of all features supporting VaD and
no exclusion makes vascular dementia “probable.” Less concrete evidence might still
justify a diagnosis of “possible” vascular dementia, while postmortem confirmation of
significant cerebrovascular disease without evidence of significant neurodegeneration
(i.e., tau and beta-amyloid pathology) closes a diagnosis of “definite” VaD.
In addition to the NINDS-AIREN criteria, the Hachinski ischemic score
(Hachinski and Lassen 1974) seen in Table 12.6 might be useful in clinical practice
as a rough guide to estimate the likelihood of VaD in a patient with cognitive deficit
(Brewster et al. 2012). A meta-analysis of pathologically confirmed cases showed
that using a cutoff of ≤4 for AD and ≥7 for VaD, as originally proposed, yielded a
sensitivity of 89.0 % a and a specificity of 89.3 % to differentiate VaD from AD
(Moroney et al. 1997).
The clinical diagnosis of vascular parkinsonism remains controversial, although
progressive evidence shows that it is a separate clinical entity from neurodegenerative
parkinsonism and that it has its own natural history (see Fig. 12.2). It affects older
subjects than neurodegenerative parkinsonism in general, with a tendency to start on
the eighth decade of life, and, in comparison with Parkinson’s disease, patients pres-
ent with gait difficulties and cognitive decline quicker after disease onset. In addition,
gait problems in PD are usually indicative of advanced disease, coinciding with
Table 12.5 Additional criteria for vascular dementia (VaD) by NINDS-AIREN criteria
Criteria Details
Exclusion criteria (a) Factors precluding neuropsychological testing: disturbance of
consciousness, delirium, psychosis, severe aphasia, or major senso-
rimotor impairment
(b) Systemic disorders or other brain diseases that could account for
deficits
Features which (a) Early onset of memory deficit and progressive worsening of memory
make VaD and other cognitive functions such as language (transcortical sensory
uncertain or aphasia), motor skills (apraxia), and perception (agnosia), in the
unlikely absence of corresponding focal lesions on brain imaging
(b) Absence of focal neurologic signs, other than cognitive disturbance
(c) Absence of cerebrovascular lesions on brain CT or MRI
Features consistent (a) Early presence of a gait disturbance (small-step gait or marche à petits
with probable pas, or magnetic, apraxic-ataxic, or parkinsonian gait)
VaD (b) History of unsteadiness and frequent, unprovoked falls
(c) Early urinary frequency, urgency, and other urinary symptoms not
explained by urologic disease
(d) Pseudobulbar palsy
(e) Personality and mood changes, abulia, depression, emotional inconti-
nence, or other subcortical deficits including psychomotor retardation
and abnormal executive function
Summarized from Román et al. (1993)
Table 12.6 Hachinski Criteria Score

ischemic score
Abrupt onset 2
Stepwise deterioration 1
Fluctuating course 2
Nocturnal confusion 1
Relative preservation of personality 1
Depression 1
Somatic complaints 1
Emotional incontinence 1
History of hypertension 1
History of strokes 2
Evidence of associated atherosclerosis 1
Focal neurological symptoms 2
Focal neurological signs 2
Summarized from Hachinski et al. (1975)
admittance to nursing home, which is one of the most important prognostic markers
in parkinsonism. In VP, gait disturbance and cognitive decline tend to present earlier
in the disease (on average, halfway through the disease course), and patients are only
admitted to nursing home much later and closer to the end of the disease course.
Multiple system atrophy and progressive supranuclear palsy, which are important dif-
ferential diagnoses, present much earlier in life and progress faster than VP.
In a clinicopathological study, the clinical features at presentation varied accord-
ing to the speed of onset and the underlying vascular pathological state, i.e., the
presence of strategic (lacunar) infarction and diffuse subcortical ischemic vascular
Multiple falls)
Multiple system atrophy
Progressive supranuclear palsy Cognitive decline
Parkinson’s disease
Nursing home
Vascular parkinsonism
60 70 80
Age (years)
Fig. 12.2 Natural history of vascular parkinsonism. Milestones of disease progression in patho-
logically proven parkinsonian syndromes. Bars represent the time between average disease onset
and average age at death (average disease duration). The vertical lines indicate the average time to
reach each milestone (Adapted from Glass et al. (2012))
disease (Zijlmans et al. 2004a). Certain clinical features are common in VP, includ-
ing bilateral or acute onset and the presence of an early shuffling gait, falls, cogni-
tive impairment, urinary incontinence, and corticospinal or pseudobulbar signs or
symptoms. Zijlmans et al. (2004a) proposed the first criteria for the clinical diagno-
sis of VP based on a systematic clinicopathological investigation and emphasized
that these criteria would need to be evaluated both prospectively and retrospectively
against patients with pathologically established other forms of parkinsonism to ana-
lyze sensitivity, specificity, and positive and negative predictor values (see
Table 12.7). Testing olfactory function may be helpful in differentiating vascular
parkinsonism from Parkinson’s disease, since in contrast to Parkinson’s disease,
olfactory function may be preserved (Katzenschlager et al. 2004). Likewise, the
presence of a rather symmetrical FP-CIT uptake reduction in the basal ganglia may
help to distinguish VP from PD (Zijlmans et al. 2007).
Clinical Management of Vascular Dementia

and Vascular Parkinsonism
The main approach to the management of VaD or VP regards the risk factors for
progression of vascular disease. These follow the guidelines for cerebrovascular
disease in general and should target the main form of CVD present in each specific
patient. Pharmacotherapy allied with lifestyles changes can be successful in reduc-
ing the rate of progression of the underlying CVD, and might be neuroprotective.
Although isolated studies have shown that individual antihypertensive drugs might
Table 12.7 Proposed clinical criteria for the diagnosis of vascular parkinsonism
Criteria Details
Parkinsonism Bradykinesia (slowness of initiation of voluntary movement with
progressive reduction in speed and amplitude of repetitive actions in
either upper limb or lower limb, including the presence of reduced
step length)
and at least 1 of the following:
Rest tremor
Muscular rigidity
Postural instability not caused by primary visual, vestibular,
cerebellar, or proprioceptive dysfunction
Cerebrovascular Evidence of relevant cerebrovascular disease by brain imaging (CT or MRI)
disease The presence of focal signs or symptoms that are consistent with stroke
A relationship between An acute or delayed progressive onset with infarcts in or near areas that
these 2 disorders can increase the basal ganglia motor output (GPe [globus pallidus
In practice: pars externa] or SNc [substantia nigra pars compacta]) or decrease
the thalamocortical drive directly (VL [ventral lateral] nuclei of the
thalamus, large frontal lobe infarct). At onset, parkinsonism
consists of a contralateral bradykinetic rigid syndrome or shuffling
gait within 1 year after a stroke (VPa)
An insidious onset of parkinsonism with extensive subcortical white
matter lesions, bilateral symptoms at onset, and the presence of
early shuffling gait or early cognitive dysfunction (VPi); the
“classical clinical type”
Exclusion criteria History of repeated head injury
Encephalitis
Neuroleptic treatment at onset of symptoms
The presence of cerebral tumor or communicating hydrocephalus
Other alternative explanations for Parkinson syndrome
Summarized from Zijlmans et al. (2004a)
decrease cognitive decline associated with CVD (Peters et al. 2008), it is likely this
is a class effect rather than specific. Although dyslipidemia has been strongly asso-
ciated with cognitive decline, there is not yet enough evidence that statins can
reduce cognitive decline per se (McGuiness et al. 2010). While experimental evi-
dence suggests it might decrease amyloidogenesis, clinical trials to date failed to
show a neuroprotective effect (Sabbagh and Sparks 2012). There is some evidence
that the use of nonsteroidal anti-inflammatory drugs might decrease the risk of both
dementia and parkinsonism (Noyce et al. 2012), but not nearly enough to recom-
mend its use. There is not enough evidence for the use of either antiplatelets, anti-
coagulants, or surgical vascular treatment (Witt et al. 2007) to prevent incidence or
progression of VaD or VP, but the normal recommendations for these treatments in
the context of CVD do apply.
There is only sparse evidence to support the use of symptomatic treatment in
VP and VaD, and a case-by-case consideration is the usual route. The response
of the parkinsonian symptoms to levodopa is controversial. Most works on VP
show a limited and only occasional good response to levodopa, sometimes in

very high doses (FitzGerald and Jankovic 1989; Winikates and Jankovic 1999;
Demirkiran et al. 2001; Rampello et al. 2005; Santangelo et al. 2010; Jellinger
2002). However, a good response has been seen in the majority of the cases with
postmortem-confirmed diagnosis of VP collected at the Queen Square Brain
Bank (Zijlmans et al. 2004b; Glass et al. 2012), but the fact that this institution
targets specifically cases that had an in vivo diagnosis of PD might be respon-
sible for this bias. Taking the literature on VP into consideration and the fact
that in clinical practice the differentiation between VP and PD might be quite
difficult, a trial of l-dopa is recommended in all cases.
Likewise, other medications for PD might be tried. The controversy regarding
the clinical criteria for VaD, the wide array of assorted cognitive testing, and the
frequent association of VaD with neurodegeneration make the results of clinical tri-
als on symptomatic drugs for VaD heterogeneous and difficult to interpret. There is
no class I evidence for the symptomatic treatment of VaD. Various drugs have been
used empirically in clinical practice with inconclusive results in clinical trials,
including Ginkgo biloba, piracetam, nicergoline, vinpocetine, pentoxifylline, citi-
coline, and cerebrolysin. Selective serotonin reuptake inhibitors and environmental
modifications might be helpful in behavioral disturbances, agitation, depression,
and psychosis (Seitz et al. 2011).
Cholinesterase inhibitors have been shown to be useful for mild to moderate
VaD in placebo-controlled clinical trials (Erkinjuntti et al. 2004), including
donepezil (Black et al. 2003), galantamine (Erkinjuntti et al. 2002), and riv-
astigmine (Ballard et al. 2008), particularly in cases of subcortical ischemic
VaD, probably due to a greater cholinergic deficit seen in such patients, and in
more elderly patients, probably due to concomitant Alzheimer’s pathology.
Memantine might be useful for moderate to severe VaD as well (Wilcock et al.
2002; Kavirajan and Schneider 2007; McShane et al. 2011). However, although
controlled trials did confirm statistically significant improvements in cognitive
function by standardized measurements, the clinical significance of the findings
and the cost-benefit of such treatments are still uncertain, and for this reason
these drugs have not been approved for this therapeutic clinical indication by
the drug agencies.
Conclusion
VaD and VP are part of a spectrum of clinical manifestations of rather common

neuropathological mechanisms which cause cell death through ischemia/hemor-
rhage and neurodegeneration. The synergistic combination of underlying pathology,
the decrease of cognitive reserve, and other predisposing factors unified culminates
with the clinical manifestations observed in these two conditions which often over-
lap in clinical practice.
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Chapter 13
Progressive Apraxia of Speech and Primary
Progressive Aphasias
Keith A. Josephs and Jennifer L. Whitwell
Abstract Apraxia of speech (AOS) is a motor disorder that occurs as a result of

impairment in the planning or programming of movements for speech production.
It is typically associated with cerebrovascular events, although it can also occur in
the context of neurodegeneration where its importance has typically been deempha-
sized to “just a component of a presenting syndrome.” Primary progressive aphasia
(PPA) is such a syndrome in which AOS coexists with other linguistic deficits, typi-
cally agrammatic aphasia. Recently, however, AOS has been demonstrated to occur
in a pure or isolated form, known as primary progressive apraxia of speech (PPAOS),
reaffirming the importance of neurodegenerative AOS. Furthermore, anatomic and
pathologic associations differ between AOS-dominant syndromes and PPA variants.
Understanding the relationship between AOS-dominant variants, including PPAOS
and PPA, and their relationship to movement disorders including corticobasal
degeneration and progressive supranuclear palsy, is important and will be the focus
of this chapter.
Keywords Apraxia of speech • Primary progressive aphasia • Tau • Progressive

supranuclear palsy • Corticobasal degeneration • Agrammatic aphasia
K.A. Josephs, MD, MST, MSc (*)

Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
J.L. Whitwell, PhD
Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA

214 K.A. Josephs and J.L. Whitwell
Part I Clinical
Apraxia of Speech
Apraxia of speech (AOS) is a type of motor speech disorder that occurs as a result
of a defect in the planning and programming of speech production (Darley et al.
1975). Apraxia of speech has characteristics that are distinct from dysarthria,
another type of motor speech disorder. Dysarthria, unlike AOS, reflects a defect of
neuromuscular function (Darley et al. 1969). The salient features of AOS are sound
production errors that may include any combination of distorted sound substitu-
tions, additions, prolongations, and truncations. Articulation is effortful and is asso-
ciated with groping and uncoordinated movements of buccolingual structures.
Apraxia of speech has been most commonly associated with cerebrovascular
events in which the onset is acute and severity maximum. More recently, however,
there has been increased interest in AOS that is progressive in nature (Duffy 2006,
2013). Progressive AOS (PAOS), unlike AOS due to cerebrovascular events, is char-
acterized by a general worsening of AOS features; errors in speech production
become more frequent and more severe over time (Table 13.1). As a result, verbal
communication becomes more problematic. Ultimately, patients with PAOS become
anarthric and are no longer able to verbally communicate.
Progressive Apraxia of Speech
Progressive AOS is one of the cardinal features of a neurodegenerative disorder and

should be viewed in the same light as progressive memory loss or progressive gait
impairment. Progressive AOS can co-occur with other cognitive and motor features
and hence be a component of a neurodegenerative syndrome. In fact, it may be the
most prominent component of the syndrome. Recently, it has been demonstrated that
PAOS can be an isolated feature at presentation and hence can exist in a pure form
in the absence of other cognitive and motor features (Josephs et al. 2012). When
PAOS occurs in isolation, we used the term primary progressive apraxia of speech
(PPAOS) (Duffy 2006; Josephs et al. 2012) (Table 13.1). Patients with PPAOS or
PAOS, in which AOS is the most salient feature, will decline over time, and some-
times other cognitive and motor deficits will develop, resulting in the emergence of
a variety of progressive clinical syndromes (Fig. 13.1). Most commonly, it appears
that patients with PAOS or PPAOS later develop difficulty with balance and gait,
aphasia, limb praxis, Parkinsonism, and eye movement abnormalities (Broussolle
et al. 1992; Josephs et al. 2006a). In fact, it has been observed that some patients
that initially presented with PAOS later develop features of progressive supranu-
clear palsy syndrome (PSPS) or corticobasal syndrome (CBS) (Josephs et al. 2006a;
Josephs and Duffy 2008). Such patients tend to have limb coordination problems,
may begin to fall, and may ultimately become wheel chair bound. Another subset
13 Progressive Apraxia of Speech and Primary Progressive Aphasias 215
Table 13.1 Clinical definitions and demographics based on a cohort of 100 subjects
Mean age Gender
Clinical syndrome Definition at onset dominance
Primary progressive Apraxia of speech is the only feature 69 Female
apraxia of speech present and is characterized by
(PPAOS) distorted sound production
Progressive apraxia ofApraxia of speech is the most prominent 67 Male
speech (PAOS) feature. Additional motor, cognitive, or
language features are present but are
less prominent
Agrammatic variant of Agrammatic aphasia is the only feature 66 Equal
primary progres- present or the most prominent feature.
sive aphasia Apraxia of speech may be present but is
(agPPA) less prominent
Semantic variant of Syndrome characterized by poor naming 64 Equal
primary progres- and loss of word meaning.
sive aphasia
(svPPA)
Logopenic variant of Syndrome characterized by poor naming 63 Equal
primary progres- without loss of word meaning, poor
sive aphasia sentence repetition, and phonological
(lvPPA) errors
Corticobasal syndrome Syndrome characterized by asymmetric N/A N/A
(CBS) ideomotor apraxia, dystonia, parkinson-
ism, and cortical sensory loss. Apraxia
of speech and agrammatic aphasia may
be present.
Syndrome + motor Features of apraxia of speech or agram- N/A N/A
neuron disease matic aphasia are accompanied by
features of motor neuron disease, such
as spastic and flaccid dysarthria, tongue
and limb fasciculation, weakness,
hyperreflexia, and Babinski sign
Presenting symptoms Progressive syndrome Presenting symptoms
PPAOS
PAOS
AOS+
AOS PSPS Agrammatic aphasia
CBS
agPPA
Fig. 13.1 demonstrates how patients presenting with apraxia of speech variants progress over time.
AOS apraxia of speech, agPPA agrammatic variant of primary progressive aphasia, PAOS progressive
apraxia of speech (i.e., AOS > > other cognitive and motor features), PPAOS primary progressive apraxia
of speech (AOS only), CBS corticobasal syndrome, PSPS progressive supranuclear palsy syndrome
of patients with dominant AOS or PPAOS develops agrammatic aphasia in written

and spoken form (Josephs et al. 2006a). In such instances, the AOS remains more
prominent than the aphasia.
Syndromes Associated with Progressive Apraxia of Speech
Progressive apraxia of speech may coexist with other cognitive and motor deficits.
In some instances, the PAOS is the most prominent feature of the presenting syn-
drome. In such instances, the chief complaint is usually that of speech problems;
other presenting features are more subtle and at times may only have been identified
during the neurological and/or speech and language evaluation. In other instances,
when AOS coexists with other cognitive and/or motor deficits, the other features of
the syndrome overshadow the AOS. Typically, when this occurs, the chief complaint
is related to one of the other symptoms and the AOS tends to be mild. Two syn-
dromes that are worth discussing in detail in which PAOS commonly occurs early in
the disease course are primary progressive aphasia (PPA) and CBS.
Primary Progressive Aphasia
The term primary progressive aphasia (PPA) is used in situations in which there is a
progressive disorder characterized by impairment of specific aspects of language
function (Mesulam 1982, 2001). These include grammar, naming, single word com-
prehension, sentence comprehension, and repetition. Three subtypes of PPA are
now recognized (Table 13.1).
Agrammatic Variant of PPA
The first subtype of PPA is the agrammatic variant (agPPA) (Gorno-Tempini et al.
2011). Agrammatic PPA is a syndrome in which the most salient feature is that of
agrammatism in language production. This may be observed in spoken or written
form. In agrammatic PPA, function words and articles may be conspicuously absent,
e.g., “Man fishing with wife on dock. Boat goes by she waves to them.” Importantly,
patients with agPPA commonly also exhibit PAOS (Ogar et al. 2005). Hence, agPPA
is typically characterized by the presence of agrammatic aphasia of greater severity
than the accompanying PAOS (Josephs et al. 2013a). Examination shows little defi-
cits in naming and in sentence repetition for content words, as well as difficulty
understanding complex sentence structures, e.g., “put the brown newspaper under
the blue book in the middle drawer.” Importantly, given that PPA is a disorder of
language, a diagnosis of PPA should only be made when language impairment, not
AOS, is the most prominent feature of the syndrome (Mesulam 2003).
Semantic Variant of PPA
The second subtype of PPA is the semantic variant (svPPA) (Gorno-Tempini et al.
2011; Warrington 1975). In svPPA, the speech output is fluent and may even be
excessively verbose. However, with more careful attention to what is actually being
said, it becomes apparent that the patient is being circumloquacious in order to
avoid certain words that no longer has specific meaning to the patient. Therefore,
specific words may be absent in general conversation and replaced with more gen-
eral words for the item or object being described, e.g., the patient may say animal
instead of hyena or flower instead of hibiscus. There may also be reference to the
fact that the patient no longer understands the meaning of certain words; the patient
may no longer know what the word lapel means and hence will not be able to tell
how a lapel is different from a collar. Examination shows poor naming and loss of
single word meaning and comprehension (Hodges and Patterson 2007). Unlike in
agPPA, AOS rarely, if ever, coexists with svPPA.
Logopenic Variant of PPA
The third subtype of PPA is the logopenic variant (lvPPA) (Gorno-Tempini et al.
2004, 2011). In lvPPA, the speech output may be fluent, but it may also be character-
ized by hesitancy as the patient pauses and searches for words. However, unlike in
svPPA, patients with lvPPA can easily recognize the item when the name is provided
by the examiner, and hence the patient has not lost word meaning. Memory loss is
also often a common complaint in patients with lvPPA. Like in svPPA, patients with
lvPPA perform poorly on naming tasks but there is no loss of word meaning.
Examination also reveals poor repetition of sentences with loss of words or replace-
ment of exact content words. One additional feature of lvPPA is the production of
sound errors known as phonological or phonemic errors. With phonological errors,
one sound is produced for another, e.g., sesipic instead of specific. Importantly,
unlike in AOS, the sounds are not distorted. It can be difficult at times to distinguish
AOS errors from phonological errors, resulting in patients with lvPPA being misdi-
agnosed as having PAOS and vice versa. Apraxia of speech rarely occurs in lvPPA.
Corticobasal Syndrome
Apraxia of speech and agrammatic aphasia, occurring together or separately, can be

early features of corticobasal syndrome (CBS) (Josephs et al. 2006a; Josephs and
Duffy 2008; Assal et al. 2012; Kertesz et al. 2005). As described in the CBS chapter,
CBS is diagnosed in a patient presenting with asymmetric signs and symptoms indica-
tive of cortical and basal ganglia dysfunction. Patients with CBS may present with
asymmetric ideomotor apraxia, cogwheel or gegenhalten rigidity, bradykinesia, action
myoclonus, dystonia, astereognosis, and agraphesthesia (Armstrong et al. 2013).
Patients with CBS, who also have AOS, are more likely to show right limb asymmetry,
i.e., the right side is the more affected side, and often also have agrammatic aphasia.
In CBS in which AOS or agrammatic aphasia are present, the presenting complaint is
usually that of limb dysfunction, as opposed to speech difficulties, although both may
be mentioned as being experienced by the patient.
Overlap with Motor Neuron Disease
Although we have described these syndromes as being relatively pure, it needs to be

recognized that these clinical syndromes can also be associated with motor neuron
disease (MND) (Caselli et al. 1993; Coon et al. 2011; Czell et al. 2013; da Rocha
et al. 2007) (Table 13.1). However, in such instances, the syndrome is also charac-
terized by the presence of flaccid and spastic dysarthria. In fact, it is the dysarthrias
that are most likely to be the dominant feature on examination, not the AOS nor the
aphasia. Therefore, in the absence of flaccid and spastic, or just flaccid dysarthria,
MND is unlikely to be identified. One large series identified patients with AOS that
had MND (Duffy et al. 2007). However, all of the patients had coexisting spastic
and flaccid dysarthria (Duffy et al. 2007). Motor neuron disease almost never coex-
ists with lvPPA and only very rarely coexists with svPPA. In the latter case, a rare
association of svPPA and pure upper MND, i.e., no anterior horn cell disease, has
been described (Josephs et al. 2013b).
Movement Disorders Associated with Apraxia of Speech

and Primary Progressive Aphasia
Apraxia of speech can be associated with movement disorders, although the move-
ment disorder identified tends to be a syndrome as opposed to being an isolated fea-
ture. We previously discussed the association of AOS and CBS at presentation;
patients with AOS may also show features of CBS and PSPS with disease progres-
sion. When this occurs, the patient is usually 5 years out from onset. It is rare, how-
ever, for the classic syndrome of PSPS to co-occur with AOS at presentation
(Whitwell et al. 2013a). When PSPS features develop in patients that originally pres-
ent with PPAOS or PAOS, they tend to be milder than what is typically observed in
PSPS that starts off with balance problems and eye movement abnormalities.
However, slowing of vertical eye movements, balance problems, and falls become
more prevalent and severe over time in patients presenting with PPAOS or PAOS.
Similarly, patients with PPAOS or PAOS may show the emergence of ideomotor
apraxia after many years (Josephs et al. 2006a, 2012). Of the three PPA syndromes,
agPPA is the one most likely to also develop features of CBS and PSPS over time
(Kertesz et al. 2005). In fact, ideomotor apraxia has been shown to be more common
in agPPA than lvPPA (Adeli et al. 2013). Parkinsonian features such as rigidity and
bradykinesia are relatively common later on in the disease course in PPAOS and
PAOS. In PPA, almost 30 % of patients present with at least one parkinsonian sign,
such as bradykinesia, rigidity, tremor, postural instability, or gait disturbance (Kremen
et al. 2011). Parkinsonian features are more common in agPPA than lvPPA and are
almost absent in svPPA (Graff-Radford et al. 2012; Kremen et al. 2011). Dystonia is
much less common but may also be observed later on in the disease course.
Hyperkinetic movements can also occur, although resting tremor is rare. Asymmetric
limb myoclonus can occur later on in the disease course in patients who later develop
the CBS. Stereotypies and ticks have not been emphasized in PPA, PPAOS, or PAOS.
Part II Anatomy
Anatomy of Progressive Apraxia of Speech
Routine clinical studies in patients with PAOS have not been very helpful in identi-
fying the anatomic correlate of PAOS. However, studies using research-based imag-
ing techniques performed using groups of patients have demonstrated that PAOS is
associated with the premotor cortex. Structural magnetic resonance imaging (MRI)
studies using voxel-level techniques, such as voxel-based morphometry, in patients
with PPAOS have shown focal patterns of grey matter atrophy involving the supe-
rior premotor and supplemental motor cortices (Josephs et al. 2012; Whitwell et al.
2013a). White matter atrophy is also observed in the premotor cortex, underlying
regions of grey matter loss, but tends to also involve inferior premotor regions.
Detailed analysis of white matter tracts using diffusion tensor imaging (DTI) has
shown that PPAOS is associated with degeneration of premotor aspects of the supe-
rior longitudinal fasciculus and the body of the corpus callosum (Josephs et al.
2012). Hypometabolism on 18-F fluorodeoxyglucose positron emission tomogra-
phy (FDG-PET) scans is also observed in the superior premotor cortices in patients
with PPAOS (Fig. 13.2a), although hypometabolism on FDG-PET can be very mild,
or even absent, in some patients (Josephs et al. 2012).
Imaging findings in patients with PPAOS overlap to some degree with those asso-
ciated with PSPS, with both syndromes showing atrophy and hypometabolism in the
premotor cortex and degeneration of the superior longitudinal fasciculus and body of
the corpus callosum (Whitwell et al. 2011, 2013a; Knake et al. 2010; Josephs et al.
2008). However, in contrast to PPAOS, patients with PSPS typically show greater
involvement of the prefrontal cortex and striking atrophy in the midbrain (Whitwell
et al. 2013a). Mild midbrain atrophy has however been observed in patients with
PPAOS, likely reflecting the fact that these patients often develop clinical features of
PSPS (Whitwell et al. 2013a). In patients with both PAOS and agrammatic aphasia,
where the AOS is the more dominant feature, VBM and FDG-PET studies show
involvement of the superior premotor cortex extending into the middle and inferior
premotor regions (Fig. 13.2b) (Josephs et al. 2013a). This finding suggests that the
Fig. 13.2 demonstrates focal hypometabolism of the left superior premotor cortex in a patient
with PPAOS (a) with extension of the hypometabolism into middle and inferior premotor cortices
in a patient with PAOS (AOS > agrammatic aphasia) (b)
agrammatic aphasia component is associated with involvement of the inferior pre-

motor cortex. Indeed, correlations have been observed between volume and metabo-
lism in the inferior premotor cortex, particularly the pars triangularis which forms
part of Broca’s area, and the severity of agrammatic aphasia (Whitwell et al. 2013b).
In contrast, the severity of AOS has been shown to correlate to volume of the supe-
rior premotor cortex (Whitwell et al. 2013b). These findings show that AOS and
agrammatic aphasia have distinct neuroanatomical underpinnings.
Anatomy of Primary Progressive Aphasia
Each of the three variants of PPA shows distinct regional abnormalities within the
frontotemporal and parietal cortices. In agPPA, routine brain MRI scans reveal atro-
phy of the left inferior frontal lobe with widening of the left perisylvian fissure
(Fig. 13.3a). Research studies demonstrate atrophy and hypometabolism on FDG-
PET throughout the left premotor cortex (Fig. 13.3b) but also with involvement of
the left insula, striatum, lateral temporal lobes, and often other regions in the left
frontal and parietal lobes (Josephs et al. 2006a, 2010; Gorno-Tempini et al. 2004;
Grossman et al. 2004; Rohrer et al. 2009). Patterns observed in patients with agPPA
are typically more widespread than those observed in patients with PAOS. Relatively
widespread patterns of white matter tract degeneration have also been observed in
agPPA, involving the superior longitudinal fasciculus, corpus callosum, anterior
cingulate, inferior frontal-occipital fasciculus, and temporal lobe tracts such as the
a b
c d
Fig. 13.3 demonstrates the abnormalities that can be identified on MRI and FDG-PET in patients
with the different variants of PPA. In (a), a patient with agPPA shows widening of the left perisyl-
vian area, while in (b), FDG-PET shows premotor cortical hypometabolism, as well as hypome-
tabolism in left temporal and even parietal cortices. On MRI (c) there is left > right anterior medial
temporal lobe atrophy which is also seen on the FDG-PET scan (d) in a patient with svPPA. A
patient with the lvPPA variant shows left parietal atrophy on MRI (e), while FDG-PET shows left
temporal and parietal hypometabolism (f)
e f
Fig. 13.3 (continued)
uncinate fasciculus and inferior longitudinal fasciculus (Galantucci et al. 2011;

Schwindt et al. 2013; Whitwell et al. 2010a; Grossman et al. 2013). White matter
tract degeneration is typically asymmetric, with greater involvement of the left
hemisphere. Patients with agPPA and parkinsonism can also show glucose hypome-
tabolism in the bilateral dorsal and left ventral midbrain (Roh et al. 2010).
In svPPA, there is a distinct pattern of anterior medial temporal lobe atrophy that
is easily detected with routine MRI scans (Fig. 13.3c). Atrophy typically targets the
fusiform and inferior temporal gyri, although atrophy is also observed in the hippo-
campus, amygdala, entorhinal cortex, and middle temporal gyrus (Chan et al. 2001;
Galton et al. 2001; Mummery et al. 2000). This pattern of abnormality is also
observed on FDG-PET scans (Fig. 13.3d). White matter tract degeneration on DTI
predominantly involves temporal lobe tracts, particularly the uncinate fasciculus and
anterior regions of the inferior longitudinal fasciculus (Schwindt et al. 2013;
Whitwell et al. 2010a; Acosta-Cabronero et al. 2012; Agosta et al. 2010; Zhang et al.
2009; Mahoney et al. 2013). The inferior longitudinal fasciculus has been shown to
be involved to a greater degree in svPPA than both agPPA and lvPPA (Hodges and
Patterson 2007; Assal et al. 2012). The left temporal lobe is usually affected more
than the right (Chan et al. 2001; Galton et al. 2001; Mummery et al. 2000), although
equal involvement of left and right temporal lobes can be observed, particularly later
in the disease course when the right side has “caught up with” the left side. Patients
with right greater than left sided atrophy and hypometabolism typically present with
behavioral dyscontrol and loss of facial recognition (Chan et al. 2009; Edwards-Lee
et al. 1997; Thompson et al. 2003; Josephs et al. 2009a), instead of PPA. Patients
often also show atrophy and hypometabolism in the orbitofrontal cortices.
Patients with lvPPA also have distinct and characteristic patterns of atrophy,
with routine head MRI showing atrophy of the left lateral temporal and parietal
lobes (Fig. 13.3e). Group MRI studies and FDG-PET (Fig. 13.3f) show striking
involvement of the left lateral temporal and parietal lobes but can also show involve-
ment of the precuneus, frontal lobes, and even the occipital lobes (Gorno-Tempini
et al. 2004; Josephs et al. 2010; Madhavan et al. 2013; Ridgway et al. 2012). The
medial temporal lobe is usually relatively spared. The right temporal and parietal
lobes may be abnormal but are nearly always less affected than the left. White mat-
ter tract degeneration can be observed on DTI affecting temporal and parietal tracts,
including the left inferior longitudinal fasciculus, uncinate fasciculus, and superior
longitudinal fasciculus (Armstrong et al. 2013; Graff-Radford et al. 2012).
Anatomy of Corticobasal Syndrome with Apraxia of Speech
The pattern of atrophy or hypometabolism observed in patients presenting with

CBS and AOS is similar to the pattern observed in patients presenting with CBS
without AOS. The same is true regardless of whether agrammatic aphasia is present.
In both instances, i.e., AOS is absent or present, patients show involvement of the
premotor cortex, often with extension into the prefrontal cortex and sometimes into
the superior parietal lobe (Josephs et al. 2008; Grossman et al. 2004; Boxer et al.
2006; Huey et al. 2009; Whitwell et al. 2010b; Groschel et al. 2004). The striatum
can also be heavily affected. Atrophy and hypometabolism are often asymmetric,
involving the hemisphere contralateral to the side of the greatest affected limb
(Whitwell et al. 2010b; Koyama et al. 2007; Soliveri et al. 1999). White matter tract
degeneration is also asymmetric and involves frontoparietal association fibers as
well as the body and splenium of the corpus callosum (Borroni et al. 2008).
Therefore, patients presenting with CBS with AOS will show greater abnormalities,
especially in prefrontal regions, compared to patients with PPAOS or PAOS that
later develop features of CBS, at least earlier in the disease course.
Part III Pathology
Pathological Overview
Over the last decade, many investigators interested in AOS and PPA have assessed
the pathological processes associated with these different syndromes (Josephs et al.
2005, 2006a, b; Mesulam 2001; Kertesz et al. 1994, 2005; Davies et al. 2005; Galton
et al. 2000; Graff-Radford et al. 1990; Greene et al. 1996; Hodges et al. 2004; Knibb
et al. 2006; Knopman et al. 1990; Lang 1992; Lippa et al. 1991; Wechsler et al.
1982). Unfortunately, it is very difficult to interpret some of these older studies
since subjects were not separated by phenotype or syndrome and instead were all
lumped as PPA, including those with PAOS and PPAOS. Regardless, these older
studies demonstrated that the pathological processes associated with PPA were
not homogeneous. Taken together, these studies demonstrated that many different
pathologies, including Alzheimer’s disease (Kertesz et al. 2005; Galton et al. 2000;
Greene et al. 1996; Knibb et al. 2006), accounted for PPA. Another problem with
older studies was the fact that modern immunohistochemistry techniques were not
performed, and even if they were performed, they were incomplete, at least com-
pared to more recent studies.
With the advent of immunohistochemistry, and recent discoveries of different
proteins that are associated with dementia in general, pathologists have a better grasp
on the biochemistry and the pathological processes that are associated with these
syndromes. Therefore, current classification first separates Alzheimer’s disease from
non-Alzheimer’s disease pathologies. Non-Alzheimer’s disease pathologies are then
further separated under the broad categories of synucleinopathies, tauopathies, and
TDP-43 proteinopathies (Dickson 2003). Synucleinopathies are not discussed in this
chapter but include multiple system atrophy and Lewy body diseases (Dickson
2003); Lewy bodies are rarely found in PPA patients (Caselli et al. 2002). Further
subclassification of the tauopathies exists and includes diseases in which tau is the
predominant abnormal protein identified histologically (Josephs et al. 2011).
Therefore, tauopathies include progressive supranuclear palsy (PSP) (Hauw et al.
1994), corticobasal degeneration (CBD) (Dickson et al. 2002), Pick’s disease with
Pick’s bodies (PiD) (Dickson 2001), and frontotemporal dementia with Parkinsonism
linked to chromosome 17 (FTDP-17) (Ghetti et al. 2003). Similarly the TDP-43
proteinopathies are subclassified in types A–D (Mackenzie et al. 2011). For both
tauopathies and TDP-43 proteinopathies, subclassification is based on the distribu-
tion of the inclusions, as well as the morphological appearances of the inclusions.
Clinicopathological Associations
There is no one-to-one relationship between the clinical syndromes described in this

chapter and the pathologies discussed here. However, there are strong associations
(Josephs et al. 2011) (Table 13.2). The clinical syndrome of PPAOS, for example, is
strongly associated with tauopathies (Josephs et al. 2006a, 2011; Deramecourt et al.
2010). Although published studies are lacking, clinical evidence suggests that of
the tauopathies that can be associated with PAOS and PPA, PPAOS is most strongly
associated with PSP pathology, less so CBD and PiD (Josephs et al. 2006a). Similar
to PPAOS, PAOS is also associated with tauopathies. However, PAOS may be
more strongly associated with CBD pathology than PSP pathology (Josephs et al.
2006a). The three variants of PPA appear to also have a strong association with
certain pathologies. The svPPA is strongly associated with TDP-43 proteinopa-
thies and is almost always associated with type C pathology (Josephs et al. 2009b;
Mackenzie et al. 2006; Snowden et al. 2007). The lvPPA is strongly associated with
Alzheimer’s disease pathology (Mesulam et al. 2008). In fact, some investigators
have argued not to include lvPPA in the discussion of AOS and PPA since the other
Table 13.2 Clinicopathological associations

Clinical syndrome Most likely pathology Other pathologies
Primary progressive apraxia Progressive supra- Corticobasal degeneration and
of speech (PPAOS) nuclear palsy Pick’s disease
Progressive apraxia of speech Corticobasal Progressive supranuclear palsy
(PAOS) degeneration and Pick’s disease
Agrammatic variant of primary TDP type A Progressive supranuclear palsy
progressive aphasia (agPPA) and corticobasal degeneration
Semantic variant of primary TDP type C TDP type A, Alzheimer’s disease
progressive aphasia (svPPA)
Logopenic variant of primary Alzheimer’s disease TDP type A
progressive aphasia (lvPPA)
Syndrome + motor neuron disease TDP type B TDP type A
variants are associated with non-Alzheimer’s disease pathologies, while lvPPA is

associated with Alzheimer’s disease. Unfortunately, not all lvPPA patients have
Alzheimer’s disease pathology (Mesulam et al. 2008) which is the counterargument
to include lvPPA in such discussions. There is a small subset of lvPPA patients that
shows TDP-43 proteinopathy, similar to svPPA (Mesulam et al. 2008). However,
unlike svPPA that is associated with TDP-43 type C pathology, lvPPA when associ-
ated with TDP-43 pathology is associated with TDP-43 type A pathology (Josephs
et al. 2009b). The most complicated syndromic pathologic association to explain is
that of agPPA. Currently, it is unclear whether agPPA, as defined in this chapter, is
strongly associated with any one pathology. In most cases, agPPA includes patients
with and without AOS, and in such instances both tau and TDP-43 pathologies
have been identified (Snowden et al. 2007; Mesulam et al. 2008). Weak evidence
suggests that agPPA in which AOS is present may be more strongly associated
with tauopathies, particularly CBD, while agPPA in which AOS is absent is more
strongly associated with TDP-43 proteinopathy, especially TDP-43 type A. It is also
worth mentioning that if any of the syndromes described in this chapter are associ-
ated with features of MND, then the underlying pathology is most likely to be that
of TDP-43 type B (Josephs et al. 2009b, 2011; Mackenzie et al. 2006; Snowden
et al. 2007). Therefore, in the presence of flaccid and spastic dysarthria, TDP type
B pathology must be strongly suspected. Future studies are also necessary to assess
clinicopathological associations in those PPA patients with parkinsonism.
Part IV Genetics
There are no genetic abnormalities that completely account for any one of the syn-
dromes discussed in this chapter. However, there have been reports of patients with
a genetic abnormality, namely, a mutation in the progranulin gene on chromosome
17, that have presented with PPA (Mesulam et al. 2007; Mukherjee et al. 2006;
Rohrer et al. 2010; Kelley et al. 2009). Most of these reports did not further classify
the PPA into one of the three variants. However, patients with progranulin gene
mutations are almost always fluent and hence have features that overlap with svPPA
and lvPPA. To our knowledge, there are no definitive, well-characterized patients
with PPAOS or PAOS that have had a mutation in the progranulin gene. Recently,
there have also been a handful of patients with PPA that have been found to have a
repeat expansion in the C9ORF72 gene (Simon-Sanchez et al. 2012; Snowden et al.
2006, 2012; Mahoney et al. 2012). Other investigators with large cohorts of patients
with C9ORF72 repeat expansions, however, have not identified patients with PPA
(Boeve et al. 2012). There are no reports of the repeat expansion accounting for the
PPAOS or PAOS phenotypes. Most patients with FTDP-17, i.e., with a mutation in
the microtubule associated protein tau gene, have not commonly presented with any
of the clinical syndromes discussed in this chapter. There are a few reports of
patients presenting as svPPA, although it is unclear whether these patients were
truly svPPA or whether they had a behavioral presentation in which naming was
also affected as part of the behavioral syndrome (Pickering-Brown et al. 2008).
Summary
There are many different clinical syndromes in which a motor speech disorder or apha-
sia is the defining feature. In some instances, the motor speech disorders and aphasia
co-occur. However, it is important not to lump all these features under the heading of
PPA. In fact, the presence of AOS is strongly predictive of tau pathologies, the pres-
ence of flaccid and spastic dysarthrias of MND and TDP type B pathology, svPPA of
TDP type C pathology, and lvPPA of Alzheimer’s disease. Understanding how to sepa-
rate these clinical features and syndromes will have important prognostic value and
future therapeutic benefit. Parkinsonism is frequent in agPPA and lvPPA, and further
imaging and pathological studies are necessary to better characterize this feature.
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Chapter 14
Normal Pressure Hydrocephalus
Paolo Missori, Antonio Daniele, and Carlo Colosimo
Abstract Although it has been nearly 50 years since its first description of clinical
and radiological, there is considerable uncertainty about the diagnosis of normal
pressure hydrocephalus because it shares the semiotics with the group of dementias.
Hakim’s triad (impaired gait, initially type clumsiness of the lower limbs followed
over time by inability to ambulate or maintain an erect posture; cognitive impair-
ment, initially limited to worsening deficits in memory fixation and execution of
complex actions; the urinary disorder, initially type “urgent urination” and then
complete urinary incontinence) characterizes the progressive course of the adult
chronic hydrocephalus. The clinical onset is typically nonspecific, subtle, and most
often monosymptomatic. The first diagnostic procedure is a head CT scan and/or
brain MRI, which shows an abnormal dilatation of the lateral ventricles and the
third ventricle, associated to variable brain atrophy. Not all subjects will develop a
set of symptoms, since the altered cerebrospinal fluid dynamics can remain stable
for many years or get progressively worse until the appearance of the clinical triad
of normal pressure hydrocephalus. The test of intrathecal infusion (Katzman test)
carried out at constant speed with the introduction of saline solution into the lumbar
subarachnoid space and the concomitant detection of cerebrospinal fluid pressure
establishes that patients with outflow resistance ranging from 12 to 19 mmHg/ml/
min can improve clinically after surgery. This method requires extensive and pro-
longed experience of the center of application and the use of computer systems. The
withdrawal of lumbar cerebrospinal fluid provides for the evacuation of 30–50 cc of
P. Missori, MD (*)
Department of Neurology and Psychiatry, Policlinico “Umberto I”,
“Sapienza” University of Rome, Rome, Italy
A. Daniele, MD, PhD
Institute of Neurology, Policlinico “A. Gemelli”, Catholic University of the Sacred Heart,
Rome, Italy
C. Colosimo, MD
Department of Neurology and Psychiatry, “Sapienza” University of Rome, Rome, Italy

232 P. Missori et al.
cerebrospinal fluid by lumbar puncture under local anesthesia, preceded and fol-
lowed by gait assessment and neuropsychological tests. It also uses the continuous
withdrawal of CSF with an intrathecal catheter placed for 3 days, in order to drain
approximately 135 ml/24 h and the aim of reducing false negatives. After surgery,
the patient is usually able to regain a good quality of life, with independence in daily
living activities. The duration of such postsurgical improvement is variable, but
patients may improve again readjusting the opening pressure of the programmable
valve, although a high comorbidity index is strictly related to a poor outcome.
Keywords Cerebrospinal fluid • Dementia • Gait abnormalities • Hydrocephalus •

Idiopathic • Normal pressure • Programmable valve • Shunt • Urinary incontinence •
Ventricle
Historical Remarks
In ancient times, hydrocephalus was associated to children with progressive enlarge-

ment of the head. Tapping the subcutaneous tissue of the frontal skin was the thera-
peutic procedure adopted for more than 2,000 years (Missori et al. 2010). Fabrizio
d’Acquapendente was the first physician to perform a ventricular drainage in a child
through insertion of a cannula in the frontal ventricle (Missori et al. 2011). The
occurrence of hydrocephalus in adults, without increase of the head size, was a late
clinical discovery. Pathological descriptions in the eighteenth and nineteenth centu-
ries reported increase of “humor” in the ventricular system (Missori et al. 2010), but
diagnosis in adults during life was impossible. The introduction of the withdrawal of
cerebrospinal fluid (CSF) from the lumbar space in meningitic disease allowed the
first therapeutic approach in adults affected by hydrocephalus (Wynter 1891). Hugo
Wilhelm von Ziemssen considered the “spinal paracentesis” “an effective mean of
reducing intracranial pressure in … hydrocephalus, … sometimes improvement in
the subjective troubles and in the condition of the sensorium was striking and of
long duration” (von Ziemssen 1893). Since then, withdrawal of CSF in patients with
chronic hydrocephalus or increased intracranial pressure was extensively performed
(Albert 1918; Browning 1897; Greenfield 1935; MacCordick 1922; Rhodes 1903).
The introduction of the ventriculography by Dandy (Dandy 1918) allowed the radio-
logical diagnosis of pediatric hydrocephalus (Dandy 1918), and later Evans intro-
duced a ratio to differentiate normal from hydrocephalic children (Evans 1942). In
1949, the first cerebrospinal pediatric shunt was applied by Matson, Nulsen, and
Spitz (Matson 1949; Nulsen and Spitz 1951). In that time, the diagnosis of secondary
hydrocephalus in adults was limited to patients with brain tumors and post-traumatic
or post-meningitic hydrocephalus. In the mid-1960s, Adams and Hakim demon-
strated in three adults with hydrocephalus (primary in one and post-traumatic in
two) associated to typical neurological features that withdrawal of 15–20 ml of CSF
determined a marked clinical improvement (Adams et al. 1965). The subsequent
surgical ventriculoatrial shunt allowed a definite clinical improvement. Since then
14 Normal Pressure Hydrocephalus 233
the pressure of the CSF was in the normal range, the disease was named “normal
pressure” hydrocephalus (NPH). For some years, the term was unchanged, but due
to the unknown origin of the disease, the term “idiopathic” NPH was added (Black
1980; Greenberg et al. 1977; Shenkin et al. 1975). During the second half of the
twentieth century, the diagnostic and therapeutic procedures of withdrawal of CSF
became more common after the introduction of spinal catheters and continuous CSF
drainage (Aitken and Drake 1964; Matera and Althabe 1962; Vourc’h 1963; Vourc’h
and Rougerie 1960). The advent of computed tomography represented a milestone
of the radiological diagnosis (Gunasekera and Richardson 1977; Jacobs and Kinkel
1976), with a transposition of the Evans’ index values for hydrocephalus’ diagnosis
from the pneumoencephalography (Gawler et al. 1976; Synek et al. 1976). A further
progress came with the “Charles Miller Fisher test,” in which clinical improvement
persisted many months after a single 20–30 ml CSF tap in patients with NPH (Fisher
1978). This procedure was considered more effective if extended to more days (Di
Lauro et al. 1986). Katzman was the first to suggest an infusion of physiologic solu-
tion into the lumbar subarachnoid space, with monitoring of CSF pressure (Katzman
and Hussey 1970). After infusion of physiologic solution into the lumbar subarach-
noid space and monitoring CSF pressure, the capacity to absorb additional physi-
ologic solution was reduced in patients with NPH and the CSF pressure quickly
increased. The last remark in this history is the guidelines for the diagnosis and
management of idiopathic normal pressure hydrocephalus which came to light from
an international group of researchers in 2005 (Marmarou et al. 2005b). In a five-step
document, all the solved and unsolved questions were addressed, to offer an essen-
tial reference from which prospective randomized studies could originate.
Introduction
The CSF is produced by the choroid plexuses of the lateral and fourth ventricles
and from the capillary ultrafiltrate of the Virchow-Robin spaces, at a rate varying
between 0.2 and 0.6 ml per minute or 600 and 700 ml per day (Wright 1978). This
amount of fluid is reabsorbed through three main systems: the arachnoid villi into
the cerebral venous sinuses, the subarachnoid space along thoracic and lumbosacral
spinal rootlets, and the olfactory pathway (Edsbagge et al. 2004; Johnston 2003;
Luedemann et al. 2002; Mollanji et al. 2002). The equilibrium between produc-
tion and reabsorption allows normal ventricle size during life, and every patho-
logical condition which alters this CSF balance can produce progressive ventricular
enlargement, up to hydrocephalus. This simple concept is challenged by some
brain degenerative disorders (i.e., Alzheimer’s disease, progressive supranuclear
palsy, frontotemporal dementia, vascular dementia, dementia with Lewy bodies,
Parkinson’s disease), in which a progressive tissue loss is replaced by CSF. In these
patients, the atrophy of the brain is the primary event and the increase of the amount
of CSF results from neuronal loss. The characteristic secondary ventricular enlarge-
ment resembles moderate hydrocephalus, but the clinical picture must be carefully
Table 14.1a Prevalence of adult chronic idiopathic hydrocephalus in the literature

Prevalence Criteria for the diagnosis
(%) Sample of NPH
Fisher (1982) 4 Dementia Clinical
Casmiro et al. (1989) 0.5 2 out of 396 subjects over Clinical
65 years
Trenkwalder et al. 0.5 4 out of 982 patients Clinical
(1995) with Parkinson’s disease
Bech-Azeddine et al. 3.5 14 out of 400 patients Clinical
(2001) of a memory clinic
Clarfield (2003) 1 50 out of 5,000 patients with Clinical
dementia
Marmarou et al. (2007) 11.56 17 out of 147 dementia Clinical-radiological
Brean and Eide (2008) 0.022 21.9 per 100,000 adults Clinical-radiological
Hiraoka et al. (2008) 7.6 13 out of 170 adults over Radiological
65 years
Tanaka et al. (2009) 1.4 7 out of 7,497 adults over Clinical-radiological
65 years
evaluated together with neurological examination and brain imaging, since the cor-
rect diagnosis of NPH is promoted by additional tests. Other conditions which may
resemble the clinical picture of NPH (either in early stages or later in the course of
the primary disease) include secondary post-traumatic or posthemorragic hydro-
cephalus, systemic lupus erythematosus, and rarely neurosarcoidosis (Honda et al.
2004; Westhout and Linskey 2008; Wikkelsø et al. 1982). In these conditions, the
clinical course is characterized by faster progression, unlike in NPH patients. Other
rare conditions in which an NPH can occur are myotonic dystrophy and Paget’s
disease (Christensen 1988; Delavallée and Raftopoulos 2006; Martin et al. 1985;
Moiyadi et al. 2006; Riggs et al. 1985; Roohi et al. 2005).
Epidemiology
Currently, the prevalence and incidence of NPH cannot be determined precisely,

although probably it is a common disease and its prevalence increases with age
(Conn 2011; Marmarou et al. 2005b). It is assumed that NPH roams to about 4 % of
all dementias (Fisher 1982). The results of various studies providing data about
prevalence and incidence of NPH are reported in Tables 14.1a and 14.1b. The diag-
nosis is also strongly influenced by the criteria used to establish the diagnosis
of NPH.
A study carried out in San Marino in a population of 396 people over 65 identified
two patients with NPH, with a prevalence of 0.5 % (Casmiro et al. 1989). Similarly,
a German door-to-door investigation on motor disorders in parkinsonism detected
four patients with NPH out of 982 subjects (Trenkwalder et al. 1995). According
to a census of 2000 in the USA reporting about 35 million people over 65, a 0.5 %
Table 14.1b Incidence of adult chronic idiopathic hydrocephalus in the literature

Incidence Criteria for the diagnosis of NPH
Vanneste et al. (1993) 0.13–0.22 100,000/year Clinical
Krauss and Halve (2004) 1.8 100,000/year Clinical-radiological
Tisell et al. (2005) 1–3 100,000/year Clinical-radiological
Brean and Eide (2008) 5.5 100,000/year Clinical-radiological
prevalence of NPH would result in a number of approximately 175,000 patients

affected by NPH (Suzuchi et al. 2000), while a 12 % prevalence of Alzheimer’s
disease would result in 4.5 million of patients. A study conducted in a sample of
400 patients of a memory clinic (Gunasekera and Richardson 1977) detected 14
patients (3.5 %) suffering from IICA (Bech-Azeddine et al. 2001). In a meta-anal-
ysis of 37 studies on dementia, the prevalence of adult chronic idiopathic NPH in
5,000 patients is about 1 % (Clarfield 2003). Accordingly, among patients with
dementia in the USA (between four and six million), the number of patients with
NPH may range between 40,000 and 60,000 (Hebert et al. 2003). These estimates
may increase by four times (160,000–240,000 patients) if we refer to a prevalence
of 4 % of NPH reported by other studies (Relkin et al. 2005). A recent investiga-
tion, performed in the USA on a population of 147 patients, reported a prevalence
of 11.56 % of patients suffering from NPH (Marmarou et al. 2007). Recent studies
performed on healthy population showed a sharp increase in the prevalence of the
NPH. In Norway, a study of 100,000 people identified 21.9 cases (Brean and Eide
2008), while a Japanese work detected an incidence ranging from 2.9 (clinical and
radiological diagnosis) to 7.6 % (radiological diagnosis only) in the healthy popula-
tion of over 65 years (Hiraoka et al. 2008). In Italy, according to a survey carried out
in November 2006, people over 65 years accounts for about 20 % of the population
(about 11 million out of a total of 56 million) (Colitti et al. 2006). Accordingly,
the estimated number of NPH patients may be about 55,000. A retrospective study
performed in the USA showed that in 2000 the number of NPH patients treated by
drainage was only 5,547 per year, suggesting that a limited number of patients are
diagnosed and then treated, as compared to the potential number of subjects to be
treated (Patwardhan and Nanda 2005). Vanneste has estimated that the incidence
of patients with NPH in the Netherlands might be between 1.3 and 2.2 per million
per year (Vanneste et al. 1993). Krauss in Germany calculated an incidence of 1.8
per 100,000 per year (Krauss and Halve 2004). Finally, a Swedish study reported
that the use of derivative systems for patients with NPH is around 30 % of all shunt
surgery, which is between only 3 and 6 per 100,000 people (Tisell et al. 2005). In
Norway, however, a recent study in 2008 reported an incidence of 5.5 patients with
NPH per 100,000 per year (Brean and Eide 2008). Since histological studies show
lesions consistent with Alzheimer’s disease in brain biopsies of patients with NPH,
the coexistence of two diseases leads to underestimate the right number of patients
with NPH (Chakravarty 2004; Silverberg et al. 2003). Thus, it might be speculated
that NPH may occur in 15–20 % of demented patients (Relkin et al. 2005). In Italy,
the prevalence of patients with NPH might be around 836,000 (7 % of the Italian
population over 65 years). As in the next decades an overall aging of population is

expected (in 2050, 33 % of the Italian population will be over 65 years), this will
result in a progressive increase in the number of patients with NPH.
Familial Normal Pressure Hydrocephalus
Few studies reported a possible familial association in NPH (Portenoy et al. 1984). The
description of a large family with four members showing a late-onset primary NPH
across three generations suggests the opportunity to search for underdiagnosed and
asymptomatic NPH in adult family members of patients with NPH (Takahashi et al.
2011). An autosomal dominant transmission has been hypothesized. Another study
reported two sisters with clinical and radiological features of NPH, who underwent
shunt placement with clinical improvement (Cusimano et al. 2011). In both sisters, an
epsilon3-epsilon3 genotype of the apolipoprotein E (ApoE) on chromosome 19 was
detected. Familial aggregation of NPH among first-degree relatives is suggested by an
incidence of 7.1 and 0.7 % among control relatives (McGirr and Cusimano 2012).
Clinical Picture
The most characteristic picture in patients with NPH is the Hakim’s triad: gait dis-
turbance, urinary incontinence, and cognitive decline (Adams et al. 1965). Gait dis-
turbances may occur as the first symptom and vary in the course. In early phases, the
patient may complain of a slow, wide-based walking with small steps and sudden
drops, charged to the shoes or uneven floor (McHugh 1964; Missori et al. 2010;
Roger et al. 1950). In later stages, a cane or wheeled walker may be needed. In late
stages, due to tendency to fall, the patient is completely unable to walk. Differentiating
between Parkinson’s disease and NPH can be challenging for the practicing clini-
cian; in NPH usually the motor impairment is mainly confined in the lower limbs
(lower-body parkinsonism) and the response to levodopa is poor or absent, but in
some cases, the differential diagnosis may not be so straightforward (Table 14.2).
Dopamine transporter brain imaging (DaTSCAN) using single-photon emission
tomography (SPECT) may be useful, since it shows an abnormal picture in all cases
of PD, while the uptake is usually normal in NPH. Disturbances of micturition usu-
ally appear in association with other symptoms of NPH. In early stages NPH patients
often complain daily need to urinate more often than usual, sometimes with urgency.
When the disease worsens, occasional incontinence happens. This symptom is very
harmful to patients and relatives, and in males the attention is often focused on pros-
tatic function and sometimes surgery is even carried out to treat urinary symptoms.
In patients with NPH SPECT, studies showed that urinary dysfunction may be
closely related with right frontal cerebral hypoperfusion, the most common
urodynamic abnormality being detrusor overactivity (Sakakibara et al. 2008, 2012).
Table 14.2 Differences between normal pressure hydrocephalus and Parkinson’s disease gait
Features Normal pressure hydrocephalus Parkinson’s disease
Early stages May occur as the first symptom Usually not the first symptom
Clumsiness of the lower limbs Subtle, if present
Loss of unilateral arm swing
Middle stages Wide-based walking Normal or narrow-based
walking
Small steps Small steps
Stooped stance Stooped stance
Sudden drops Sometimes, festination
Charged to the shoes or uneven floor and freezing
Outward rotated feet and a diminished
height of the steps
Frequent freezing
Late stages Tendency to fall Tendency to fall
Inability to ambulate or maintain Inability to ambulate
an erect posture or maintain an erect posture
Frequent freezing Frequent festination and
freezing
Speed Slow Slow
Stride length Reduced Reduced
Rhythmicity Reduced Reduced
Symmetry Reduced Reduced
Improvement with Mild Moderate
external clues
Response to levodopa None or mild Moderate
Cognitive and behavioral symptoms are key clinical features of NPH and may
appear in early disease stages (Hashimoto et al. 2010). In individual patients with
NPH, however, the cognitive impairment may vary largely, ranging from a mild
cognitive decline to a moderate or severe dementia in other patients.
Various neuropsychological studies have supported the view suggesting that
patients with NPH may frequently show a “subcortical” pattern of cognitive impair-
ment (Cummings and Benson 1984; Devito et al. 2005), which is often seen in
pathologies affecting various subcortical structures and is mainly characterized
by the occurrence of mental slowness, deficits of attention and frontal executive
functions (planning, problem-solving, set-shifting), relatively mild deficits of long-
term memory, and behavioral changes (apathy most frequently, depressive symp-
toms in some patients). Since deficits of executive functions frequently arise from
a dysfunction of the frontal lobes, which are abundantly connected to various sub-
cortical structures (Alexander et al. 1986), the term “frontal-subcortical” cogni-
tive impairment/dementia has also been proposed. Such most frequently reported
“frontal-subcortical” pattern of cognitive impairment observed in patients with
NPH does usually not include aphasic, apraxic, or agnostic deficits, which are by
contrast common in patients with “cortical” dementias (in primis, Alzheimer’s dis-
ease). As to long-term memory deficits, it has been shown that patients with NPH
in early disease stages have usually a relatively preserved ability to store informa-
tion in long-term memory systems (at variance with patients with Alzheimer’s dis-
ease since early disease stages), but are usually impaired mostly in the retrieval of
stored information from long-term memory systems and therefore may benefit from
external cues aimed at facilitating such retrieval (Iddon et al. 1999). This pattern
of memory impairment of NPH patients may be shared by other conditions with a
“frontal-subcortical” pattern of cognitive impairment, such as Parkinson’s disease
(Taylor et al. 1986). In addition, deficits of spatial long-term memory (Iddon et al.
1999), constructional praxic abilities (Goodman and Meyer 2001), and psychomo-
tor speed (Kaye et al. 1990) have been detected in patients affected by NPH.
In a recent study (Saito et al. 2011) aimed at further investigating cognitive
functioning in patients affected by idiopathic NPH, 32 patients with NPH who sig-
nificantly improved after surgery were recruited and underwent a quite extensive
neuropsychological assessment before (n = 32) and 1 year (n = 26) after CSF shunt
surgery. Moreover, a group of patients with Alzheimer’s disease (n = 32) matched to
the NPH group as for several clinical and demographic variables (including overall
cognitive functioning as measured by performance on the mini-mental state exami-
nation, MMSE) and a group of healthy controls (HCs) (n = 30) were recruited. The
results of such study show that patients with NPH showed a significantly worse
performance as compared to healthy controls on most cognitive tasks (MMSE,
tasks of verbal and spatial short-term memory, phonological and semantic verbal
fluency, episodic verbal memory, several tasks assessing visual discrimination, and
the Frontal Assessment Battery (FAB) assessing executive functions), while no sig-
nificant difference was found between the NPH and HCs on a task of object nam-
ing. Moreover, the NPH group performed significantly worse than the AD group
on some cognitive tasks (spatial short-term memory, phonological verbal fluency,
FAB, some tasks assessing visual discrimination), while the AD group was more
impaired than the NPH group on specific cognitive variables assessing episodic
verbal memory. Although deficits of frontal cognitive functions (including execu-
tive functions) were the most prominent in the NPH group, this study pointed out
that memory deficits and visuoperceptual and visuospatial deficits may also occur
in patients with NPH. This recent study (Saito et al. 2011) suggests that, although
deficits of frontal cognitive functions (including executive functions) due to a dis-
ruption of frontal-subcortical circuits are the most prominent in patients with NPH,
memory deficits and visuoperceptual and visuospatial deficits (due to a disruption
of neural circuits involving more “posterior” cortical and subcortical structures)
may also occur in patients with NPH.
As to other behavioral symptoms (Bloom and Kraft 1998; Kito et al. 2009; Koch
et al. 2009), besides apathy and depression, it has been less commonly reported that
patients with NPH may show manic and psychotic symptoms (Kwentus and Hart
1987; Rice and Gendelman 1973), including aggressivity, hypersexuality, and delu-
sional jealousy (Yusim et al. 2008).
A distinguishing feature of NPH is the relatively slow but progressive clinical
evolution (12–24 months), as the patient becomes unable to carry out everyday
activities and to look after himself. However, some patients may show a slower
a b
Fig. 14.1 (a) A 72-year-old female with gait instability. CT scan shows Evans’ index of
39.62 mm/131.88 mm = 0.30. (b) The same patient after 55 months complaining short memory
impairment, recurrent falls, and urgent urination. On control CT scan the frontal horns appear more
enlarged with Evans’ index increase: 43.02 mm/132.84 mm = 0.32
clinical progression both for very mild symptoms and for misdiagnosis. In these
patients, neuroimaging commonly shows a ventriculomegaly. When acute or sub-
acute symptoms of intracranial pressure (headache, alteration of consciousness, cra-
nial nerve deficits, vomiting, dizziness) occur in a short period of time (1–2 weeks)
associated to brain scan of ventricular enlargement, a secondary hydrocephalus
other than NPH or a cerebrovascular disease should be considered as the causative
condition. In the cases in which a previous neuroradiological imaging is available,
a comparison of the Evans’ index between the old and new examination allows a
more secure and reliable assessment of the ventricular progression and of clinical
diagnosis (Figs. 14.1 and 14.2).
Scales for Grading of Severity
Various grading scales have been reported for assessment of patients with NPH.
The use of functional scales based on the degree of disability or stroke rehabilita-
tion scales have been proposed, but these scales were not devised to assess changes
in the severity of main symptoms of NPH (Klinge et al. 2005). The need to develop
assessment scales to be largely shared in the clinical evaluation of patients with NPH
prompted the proposal of two new grading scales (Hellström et al. 2012; Kubo et al.
2008). A major advantage of both scales is the possibility to compare the neurologi-
cal conditions before and after each diagnostic or therapeutic procedure. Cognitive,
gait, and urinary symptoms are assessed in both scales (Hellström et al. 2012; Kubo
et al. 2008), while the examination of balance only in one (Hellström et al. 2012).
In the Swedish scale (Hellström et al. 2012), three different professionals evaluate
a b
Fig. 14.2 (a) A 61-year-old female with short-term memory deficit. MRI shows Evans’ index
of 41.1 mm/142 mm = 0.28. (b) The same patient after 16 years with mild cognitive impair-
ment, progressive gait disturbance, and occasional urinary incontinence: Evans’ index of
51.2 mm/140.1 mm = 0.36. Note the secondary brain atrophy with widening of the Sylvian cisterns
separately the three main groups (cognitive, gait, urinary) of symptoms, and scores
may range from 0 to 100, where 100 is the performance of an age-matched healthy
population. Such scale discriminates well between levels of severity. Following sur-
gery, a patient is considered improved if a >5-point increment can be detected on the
scale. In the Japanese scale (Kubo et al. 2008), the clinical assessment is performed
by two independent physicians. Patients with NPH were assessed with this scale
after a CSF tap test and after shunt surgery. For the triad of symptoms, scores may
range from 0 to 4, with higher scores indicating more severe symptoms. Patients
who obtain an improvement in at least 1 of the 3 domains are judged to have a clini-
cally significant improvement. Reliability and validity in predicting shunt respon-
siveness were assessed for this scale.
Neuroradiological Evaluation
On computed tomography (CT) or magnetic resonance imaging (MRI), the radio-

logical finding of ventricular enlargement is a necessary landmark of NPH, but it is
not sufficient to determine if patients are suffering from NPH. In neurodegenerative
diseases, cerebral atrophy causes secondary ventricular enlargement and a radio-
logical differential diagnosis with NPH can be problematic. The first step in the
evaluation of an image must be the computation of the Evans’ index, by dividing
the maximum width of the frontal horns by the maximum width of the inner table of
a b
Fig. 14.3 (a) A 67-year-old male with slight cognitive impairment, progressive gait disturbance,
and occasional urinary incontinence. Neuroradiological examinations from July 1993 show pro-
gressive ventricular enlargement. In the last MRI (June 2012), the Evans’ index is
59.4 mm/137.60 mm = 0.43, and on T2 coronal image at the level of the posterior commissure, the
callosal angle is more than 90°. After a positive tap test, a programmable shunt was inserted. Ten
months after surgery the patient has a lasting clinical benefit on gait disturbance and urinary incon-
tinence. (b) A 64-year-old female with gait instability and urinary incontinence. On MRI the
Evans’ index shows 47.4 mm/127.1 mm = 0.37. On coronal T1 image at the level of the posterior
commissure, the callosal angle is more than 90°. Two years after surgery the patient is asymptom-
atic. The callosal angle must be interpreted in association to the clinical symptoms and all the
neuroradiological findings
the cranium at the level of the Monro’s foramens in the frontal horns (Evans 1942).
A value equal or more than 0.3 support the diagnosis of probable NPH (Ishikawa
et al. 2008; Marmarou et al. 2005b), but a lower value cannot exclude this diagnosis
(Naruse and Matsuoka 2013). After shunt for NPH, the majority of the patients
assessed by the Evans’ index showed no ventricular changes, despite a satisfactory
clinical improvement (Meier et al. 2003). Since remarkable differences were found
in the Evans’ index calculated at different planes on CT scans, its value has been
questioned and not considered an ideal tool for diagnosis of NPH (Ambarki et al.
2010; Toma et al. 2011a). Other simple criteria which support a radiological diagno-
sis of NPH include a tight high-convexity and medial subarachnoid spaces, enlarged
Sylvian fissures, a small callosal angle (under 90°) on the coronal section of MRI,
and periventricular signal changes (Fig. 14.3) (Hashimoto et al. 2010; Ishii et al.
2008; Kitagaki et al. 1998; Sasaki et al. 2008). The aqueductal CSF stroke volume,
which is the mean volume of CSF passing through the Sylvian aqueduct during
cardiac systole and diastole, is a valuable tool in the preoperative evaluation of NPH
patients. Higher aqueductal stroke volume in patients with short clinical history
may be associated to a post-shunt improvement of clinical symptoms (Bradley et al.
1996; El Sankari et al. 2012; Scollato et al. 2009). The assessment of the ventricular
size and volume may show very variable changes and may not easily correlate with
clinical improvement after CSF withdrawal (Anderson et al. 2002; Lenfeldt et al.
2012; McConnell et al. 2004; Palm et al. 2006). However, if the ventricular and
brain volumes are assessed with a specific software, after prolonged external lumbar
drainage, the brain volume may increase and the ventricular volume may decrease,
more markedly than after a single tap withdrawal (Singer et al. 2012). A study with
functional MRI in NPH patients showed a bilateral increased activation in the sup-
plementary motor area after CSF removal (Lenfeldt et al. 2008b). Moreover, proton
magnetic resonance spectroscopy revealed normalization of N-acetyl-aspartate in
the frontal white matter after a 3-day lumbar drainage (Lenfeldt et al. 2008a).
The Supplemental Tests
The lack of a confident radiological diagnosis of NPH prompted the investigation of

other diagnostic tools. Three diagnostic procedures are widely carried out: the with-
drawal of lumbar CSF (30–50 ml), the external lumbar drainage (a 3-day drainage of
approximately 135 ml/24 h), and the infusion test (lumbar infusion bolus technique:
4 ml, 1 ml/s). The choice among such options seems to be fundamentally related
to the experience of each single center or clinician, more than to evidence-based
studies, since these tools can be used for selecting patients for shunt surgery, but not
for excluding patients from treatment (Wikkelsø et al. 2013). Comparisons among
these procedures have been carefully investigated in various studies, highlighting
advantages and disadvantages (Marmarou et al. 2005a). It should be pointed out
that when the clinical and radiological diagnosis of NPH is highly probable, shunt
surgery may be recommended also in the absence of supplemental tests, with a
degree of certainty ranging from 50 to 61 % (Klinge et al. 2012; Marmarou et al.
2005a). However, it is recommended that all patients with probable or possible NPH
should perform one of these tests, in order to obtain a probability measure of a
successful response to shunt surgery, beyond such 50–61 % degree of certainty.
The tap test has a higher positive predictive value (100 %) for a good response to
surgical shunt, but a low sensitivity (from 21 to 61 %). A negative tap test cannot
exclude patients from surgical treatment. The removal of CSF may improve gait
or cognitive performance neuropsychological tests. The external lumbar drainage
shows high sensitivity (50–100 %) and high positive predictive value (80–100 %).
This procedure requires a hospitalization for some days, but in some patients may
be complicated by replacement of escaped lumbar drain and, rarely, by secondary
meningitis. Changes in walking pattern or neuropsychological tests are important
variables to be assessed before and after CSF removal. In particular, an improve-
ment of gait (speed, number of steps, stride length) is considered that may predict
a good postsurgical outcome, suggesting the opportunity of a surgical treatment
(Matousek et al. 1995; Damasceno et al. 1997; Stolze et al. 2000; Virhammar et al.
2012; Wikkelsø et al. 1982). As compared with the tap test, the CSF resistance
outflow test has a similar positive predictive value (75–92 %), but a higher sensitiv-
ity (57–100 %). To perform this test, the baseline cerebrospinal pressure must be
recorded before and immediately after injection. Patients with a threshold of CSF
outflow resistance ranging from 12 to 19 mmHg/ml/min seem to improve clinically

after surgery, but there is still disagreement about the exact value to be considered
pathological (Czosnyka et al. 2003). This procedure can be performed to assess the
failure of a third ventriculostomy or of a surgical shunt (Aquilina et al. 2012; Malm
et al. 2004).
The Surgical Treatment
Clinical evidence supports the value of surgery in NPH patients, despite the lack
of randomized controlled trials comprising surgical treatment versus no surgery
(Esmonde and Cooke 2002; Toma et al. 2011b, 2012). The best surgical technique to
treat NPH should be aimed at obtaining a diversion of flow of CSF and at favoring
the impaired processes involved in CSF reabsorption. There are two surgical options
to enable such events: the endoscopic third ventriculostomy and the placement of
a CSF shunt from a cerebral ventricle into an absorbing cavity or the vascular sys-
tem. The endoscopic third ventriculostomy is performed through a frontal burr hole.
The endoscope is inserted in the brain to gain the Monro’s foramen and the floor of
the third ventricle. After the identification of landmarks (the mammillary bodies and
tuber cinereum), a catheter pierces a chosen place to put CSF flow between the inter-
peduncular cistern and the third ventricle. A low complication rate, a low mortality
rate, and good neurological improvement are reported (Bouras and Sgouros 2012;
Fountas et al. 2012; Gangemi et al. 2004, 2008). Since in the long-term follow-up
closure of the fenestration and recurrent symptoms after initial successful treatment
occur, these patients should be monitored for some years (Amini and Schmidt 2005;
Cage et al. 2011; Fabiano et al. 2010; Longatti et al. 2004). A randomized clinical
trial comparing the endoscopic third ventriculostomy with the ventriculoperitoneal
shunt (shunt into the abdominal cavity) shows that the shunt has a better neurologi-
cal outcome 12 months after surgery (Pinto et al. 2013). Indeed the surgical shunt is
the most widely performed procedure to treat the NPH. Over the past few decades,
the rate of complications after surgical treatment has decreased considerably, due
to the improvement of the techniques and valve systems (Black 1980; Farahmand
et al. 2009; Greenberg et al. 1977; Larsson et al. 1991; Poca et al. 2004; Savitz and
Bobroff 1999; Zemack and Romner 2008). The ventriculoperitoneal shunt is more
widely performed as compared with the ventriculoatrial shunt, probably due to early
reports indicating a less risk of serious complications and neurosurgeon’s confidence
for the abdominal insertion in pediatric patients (Keucher and Mealey 1979; Mazza
et al. 1980; Olsen and Frykberg 1983; Vernet et al. 1993). This conclusion has been
initially transferred to adult patients (Lam and Villemure 1997). More recent surgi-
cal series show no difference between ventriculoperitoneal and ventriculoatrial shunt
in adult hydrocephalus, and in some cases ventriculoatrial shunt is carried out after
a failure of the ventriculoperitoneal shunt (Farahmand et al. 2009; Murakami et al.
2010; Stranjalis et al. 2012; Zhang et al. 2009). An alternative surgical option in
patients with NPH is the lumboperitoneal shunt (Bloch and McDermott 2012; Chang
et al. 1999; Yadav et al. 2010). Since NPH is a communicating hydrocephalus, it is
possible to drain the lumbar CSF into the abdominal cavity, through an intrathecal
spinal catheter, with a programmable valve. The technique is apparently simple, but
the rate of complication is not low (Karabatsou et al. 2004; Wang et al. 2007). The
ventriculopleural shunt (into the space between the visceral and parietal pleura of
the lungs) is very rarely performed in patients with NPH and is indicated when other
routes are not available (Megison and Benzel 1988). The introduction of programma-
ble (flow-regulated) versus nonadjustable (differential-pressure) valves has changed
the surgical view: the amount of CSF withdrawal can be varied according to the clini-
cal changes which can occur in the early or late postoperative follow-up (Zemack and
Romner 2000). Readjusting the opening pressure may decrease the incidence of clini-
cal complications of underdrainage or overdrainage (Freimann and Sprung 2012).
A low CSF pressure has been proven to have a better outcome, but it is plagued
by overdrainage complications (Boon et al. 1998). Accordingly, the combination of
programmable valve with a gravitational valve (which eliminates overdrainage by
increasing resistance as patient moves upright) may improve the outcome (Lemcke
and Meier 2010; Meier and Lemcke 2006). A recent trial showed that a gravitational
valve (which switches between a low pressure mode in the supine position and a high
pressure mode in the upright position) reduces the risk of overdrainage complica-
tions, as compared with a standard programmable valve (Lemcke et al. 2013).
Outcome
The most relevant feature of patients who undergo surgical treatment for NPH is the
rapid neurological improvement in the early postoperative period. In the majority of
cases, patients regain the ability to walk and control micturition but also, albeit less
frequently, of cognitive and behavioral symptoms. Accordingly, NPH is included
among the infrequent conditions of reversible dementia. In particular, it has been
observed that deficits of episodic verbal memory (Gallassi et al. 1991), construc-
tional praxic abilities (Goodman and Meyer 2001), and psychomotor speed (Kaye
et al. 1990) may improve after shunt surgery, at least in subgroups of NPH patients.
On the other hand, it has been reported that deficits of executive functions may not
improve after surgery (Iddon et al. 1999). By contrast, in a more recent study (Saito
et al. 2011), 1 year after CSF surgery, the NPH group showed a significant improve-
ment on tasks assessing frontal functions (FAB), including executive functions.
In a recent neuropathological study (Cabral et al. 2011), a group of nine patients
with a clinical diagnosis of NPH was examined, and it was observed that in eight out
of such nine patients, there were neuropathological changes consistent with AD.
This study on a small sample of patients with a clinical diagnosis of NPH suggests
that AD may be a frequent pathological comorbidity in patients with NPH and such
comorbidity may at least partially preclude cognitive improvement after surgery.
A study carried out in 36 patients with NPH (Chang et al. 2006) who underwent
neuropsychological testing before and after ventriculoperitoneal shunt insertion
reported that one third of patients showed good cognitive improvement (defined as
improvement by at least 25 % on at least half of the cognitive tests administered).
The degree of cognitive improvement was found to be greater in women than in

men, and there was a significant negative linear relationship between age and prob-
ability of good cognitive improvement. Younger age was found to be a better predic-
tor of improvement on memory tests, while female sex was a better predictor of
improvement on non-memory tests after shunt insertion (Chang et al. 2006).
In conclusion, an extensive neuropsychological assessment in patients with sus-
pected NPH may show the pattern of cognitive impairment in each individual patient
and could be a helpful tool in the differential diagnosis of NPH, in monitoring dis-
ease progression, and in assessing clinical response to surgery (Devito et al. 2005).
After surgery, the patient is usually able to regain a good quality of life, with
independence in daily living activities. The duration of such postsurgical improve-
ment is still difficult to be predicted. At least a 1-year post-shunt monitoring period
may be necessary to evaluate the clinical effects of the surgical procedure (Klinge
et al. 2005, 2012). However, some shunted NPH patients experience years after
surgery a variable decline and recurrence of symptoms, but after readjusting the
opening pressure of the programmable valve (increasing the outflow of CSF),
patients may improve again (Aygok et al. 2005; Koivisto et al. 2013). Accordingly,
a periodic clinical follow-up is mandatory to avoid delays in the valve adjustment.
Several studies showed that comorbidities (mainly cardiovascular and cerebrovas-
cular disorders) may affect significantly long-term outcome in shunted patients with
NPH (Kiefer et al. 2006; Lemcke and Meier 2012; Malm et al. 2013; Meier and
Lemcke 2008, 2010; Mirzayan et al. 2010), suggesting that a high comorbidity
index is strictly related to a poor outcome (Lemcke and Meier 2012; Mirzayan et al.
2010).
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Chapter 15
Movement Disorders in Infectious Dementias
Francisco Cardoso and Paulo Caramelli
Abstract A myriad of infectious diseases may course with a combination of move-

ment disorders and cognitive decline. The spectrum of movement disorder in these
conditions is varied, ranging from parkinsonism to a multitude of hyperkinesias,
including tremor, dystonia, chorea, and myoclonus. As to the profile of cognitive
changes, the most commonly found abnormalities belong to the so-called subcortical
dementia. Among viral infections, postencephalitic parkinsonism and HIV infection
are examples of conditions combining cognitive and movement disorders. The former
is just of historical importance since it vanished as mysteriously as it started. The
majority of HIV + patients develop neurologic complications despite the advent of
highly active antiretroviral therapy. A substantial proportion of these patients display
the combination of movement disorder, particularly parkinsonism, and cognitive
impairment. Neurosyphilis, a spirochetal infection, is also historically relevant, but it
remains as an important cause of dementia although movement disorders are rare.
Prion diseases are uncommon and their infectious forms are even rarer. Nevertheless,
they should always be ruled out in patients with rapidly progressive dementia and
myoclonus. Neurocysticercosis, the most common parasitic disease worldwide, is
increasingly recognized as a cause of cognitive disorder although movement disorders
are exceedingly rare in these subjects. Finally, although the incidence of Sydenham’s
chorea is in decline, it remains as the most common cause of acute chorea in children
and not infrequently it is associated with a dysexecutive syndrome.
Keywords Infections • Prions • Postencephalitic parkinsonism • HIV • AIDS

• Syphilis • Neurocysticercosis • Sydenham’s chorea
F. Cardoso, MD, PhD (*) • P. Caramelli, MD, PhD

Department of Internal Medicine, Faculty of Medicine,
The Federal University of Minas Gerais, Av Pasteur 89/1107,
Belo Horizonte, MG 30150-290, Brazil

254 F. Cardoso and P. Caramelli
Introduction
The aim of this chapter is to describe the clinical features of movement disorders in
conditions where dementia is caused by infectious agents. From a historical point of
view, neurosyphilis is the prototypical infection that combines cognitive and move-
ment disorders. Also with a historical interest is postencephalitic parkinsonism, a con-
sequence of the encephalitis lethargica that plagued Europe in the first decades of the
twentieth century. In the late twentieth century, many patients of the epidemics of HIV
infection also displayed movement disorders in combination with dementia. The aim
of this chapter is to provide a description of the clinical features, epidemiology, and
guidelines of management of movement disorders present in the context of infectious
dementing illnesses. Of note, although outside of the scope of this chapter, there is
evidence suggesting that Parkinson’s disease (PD) may be caused by an infectious
proteinaceous particle that has a prion-like behavior (Olanow and Brundin 2013).
Neurosyphilis
Cognition
Different clinical syndromes emerge in neurosyphilis, such as meningitis, meningo-

myelitis, meningovascular syphilis, general paresis, tabes dorsalis, and optic atro-
phy. Cognitive impairment and behavioral disturbances are common manifestations,
especially in late forms of the disease, such as meningovascular syphilis and general
paresis. Memory decline, dysexecutive syndrome, and topographical disorientation,
together with hallucinations, delusions, apathy, irritability, and aggression, are usual
symptoms and signs found in these patients frequently leading to dementia (Carr
2003; Nitrini et al. 2010).
Although much less frequent than in the past century, neurosyphilis is still identi-
fied as the cause of dementia in some patients (Takada et al. 2003; Nitrini et al.
2010). For this reason, several guidelines for dementia diagnosis recommend sero-
logical tests for syphilis, as a routine procedure, especially in developing countries
(Caramelli et al. 2011), or in cases at high risk or presenting suggestive clinical
features, in developed nations (Sorbi et al. 2012).
Phenomenology of Movement Disorders
Pseudoathetosis as a result of sensory ataxia is the movement disorder classically

described in association with tabes dorsalis, a clinical form of tertiary syphilis.
There are, however, reports of rare individuals with neurosyphilis who presented
with parkinsonism, corticobasal syndrome, chorea, and dystonia (Nitrini 2000;
Benito-León et al. 2004; Spitz et al. 2008; Ozben et al. 2009; Chauhan and Pickens
2011; Tong et al. 2013)
15 Movement Disorders in Infectious Dementias 255
Epidemiology
In the past century, there has been a significant decline of the prevalence of neuro-
syphilis. However, in the last years there is a resurgence of this condition, with clini-
cians seeing more patients (Kent and Romanelli 2008). Although coinfection with
HIV is well recognized, this is not the main factor responsible for increase of the
incidence of neurosyphilis (Zetola and Klausner 2007). Movement disorders are
rarely seen in patients with the latter: in a recent series from China, they were seen
in no more than seven of 169 subjects (Tong et al. 2013).
Treatment
Although treatment with penicillin is invariably effective in eliminating the Treponema,

unfortunately most patients remain with their clinical features unchanged or only par-
tially recovered, especially in the late forms of neurosyphilis (Nitrini 2008). Despite
the lack of controlled trials, clinicians resort to symptomatic measures to ameliorate
specific problems such as L-dopa for parkinsonism and neuroleptics for chorea.
Postencephalitic Parkinsonism
Cognition
Encephalitis may occasionally lead to parkinsonism, being usually caused by virus.

Clinical presentation is characterized by reduced level of consciousness and delir-
ium, with parkinsonian features developing few weeks after the beginning of the
illness. Although mental changes are common, with impaired attention and slow-
ness of thinking, there is no specific cognitive marker. Behavioral changes are also
frequent in postencephalitic parkinsonism, such as psychosis, impulsivity, and
obsessive-compulsive symptoms (Rail et al. 1981).
Despite intensive effort, the etiology of the pandemic encephalitis lethargica that
swept Europe in the beginning of the twentieth century was never determined. The
possibility of influenza virus was ruled out, and there is a recent suggestion that it
was caused by an enterovirus (Dourmashkin et al. 2012). There are occasional reports
of patients who develop parkinsonism following other encephalitic illnesses: western
equine encephalitis, Coxsackie B, measles, Epstein-Barr virus (Hsieh et al. 2002;
Dimova et al. 2006; Roselli et al. 2006), chicken pox encephalitis, and Japanese
encephalitis. The importance of the latter as cause of parkinsonism is shown by a
study of 52 patients, of whom 5 developed pure parkinsonian syndrome poorly

responsive to levodopa, ophthalmoparesis, opsoclonus, as well as isolated lesions of
the substantia nigra on MRI (Pradhan et al. 1999). A review of a large database of
patients who developed PD or parkinsonism in the United Kingdom between 1994
and 2007 showed that there was an association between seasonal influenza and
development of parkinsonism (OR = 3.03) but not PD (Toovey et al. 2011).
Constantin von Economo delineated three main clinical presentations of encephali-
tis lethargica, a condition that bears his name (von Economo 1931). The most common
variety started with an influenza-like illness, followed by increasing drowsiness and
confusion, with progression to continuous sleep, stupor, and finally coma. External
ophthalmoplegia, often with pupillary involvement and oculogyric crises, were early
features of the disease, and some patients developed basal ganglia, cerebellar, or upper
motor neuron signs. A second group of patients presented with severe acute parkinson-
ism, often combined with catalepsy and mutism, whereas a third hyperkinetic group
mimicked acute catatonic schizophrenia with extreme motor restlessness, impulsions,
visual hallucinations, and dyskinesias. Some survivors of the pandemic were left with
postencephalitic parkinsonism. Several features distinguished this parkinsonian disor-
der from PD: lack of or minimal deterioration over decades, presence of oculogyric
crises in many patients, and extreme sensitivity to small doses of L-dopa, improving
within a few days but developing severe complications including dyskinesias, behav-
ioral disturbances, and motor fluctuations. A study of patients with pathologically
proven postencephalitic parkinsonism has confirmed that vertical supranuclear gaze
palsy and eyelid apraxia were common findings in this condition (Wenning et al. 1997).
The following clinical features should be considered major criteria supporting the diag-
nosis of encephalitis lethargica; an acute or subacute encephalitic illness that as part of
its clinical picture displays at least three of the following criteria: (1) signs of basal
ganglia involvement, (2) oculogyric crises, (3) ophthalmoplegia, (4) severe obsessive-
compulsive behavior, (5) akinetic mutism, (6) central respiratory irregularities, and (7)
somnolence or sleep inversion. In fact, a clinicopathologic study confirmed that onset
before middle age, symptom duration lasting more than 10 years, and the presence of
oculogyric crisis, as well as history of encephalitis lethargica, were good predictors of
the diagnosis of postencephalitic parkinsonism (Litvan et al. 1998).
Epidemiology
Postencephalitic parkinsonism, once epidemic, is currently rare, although no

population-based data are available. Encephalitis lethargica has disappeared, but, as
already mentioned, occasionally there are reports on conditions mimicking its clini-
cal features. It remains unclear, however, whether these patients have the same con-
dition as the one described by von Economo. Japanese encephalitis, on the other
hand, is a major public health problem in Asia, where there are 300,000 new cases
each year. Many of these patients eventually develop movement disorders (Pradhan
et al. 1999; Kalita and Misra 2000).
Treatment
The treatment of postencephalitic parkinsonism, regardless of the underlying etiol-

ogy, relies on the use of L-dopa replacement therapy. Most patients do respond to
this medication, but the majority rapidly develops motor and non-motor complica-
tions such as fluctuations, dyskinesias, psychosis, and other behavioral disorders.
HIV Infection
Cognition
Cognitive impairment associated with HIV infection can be classified in three dif-
ferent categories, namely, asymptomatic neurocognitive impairment, mild neuro-
cognitive disorder, and HIV-associated dementia (Antinori et al. 2007). With the
advent of highly active antiretroviral therapy almost two decades ago, a dramatic
decline in the number of cases of moderate to severe dementia occurred. However,
mild forms of cognitive impairment are still very frequent and cause significant
morbidity for the patients (Kranick and Nath 2012).
Asymptomatic neurocognitive impairment is characterized by deficits on objec-
tive neuropsychological testing in two or more cognitive domains in patients with
no cognitive complaints. Subsequent symptomatic decline is observed in many
cases, although it is not predictable. Mild neurocognitive disorder is diagnosed in
patients presenting mild functional decline, which is not explained by another con-
dition, and performing at least one standard deviation below normative values on
neuropsychological testing in two or more cognitive domains. HIV-associated
dementia features cognitive deficits in at least two cognitive domains, falling below
two standard deviations on neuropsychological tests and also by significant func-
tional impairment (Kranick and Nath 2012).
The cognitive profile found in HIV infection includes deficits in information
processing, working memory, prospective memory, decision making, and verbal
fluency. This clinical picture resembles to the one found in subcortical dementias,
such as Parkinson disease and Huntington disease, and reflects damage to frontos-
triatal structures (Ances and Ellis 2007).
Movement disorders are not uncommon in patients with acquired immunodefi-

ciency syndrome (AIDS) and have received much attention in the past (Brew 2001;
Cardoso 2002b). They usually occur in subjects already known to be HIV+ as a
result of opportunistic infections, HIV encephalopathy, or side effects of drugs. In
clinical practice, tremor is the most common movement disorder identified in HIV+
patients (Cardoso 2002b). However, hemichorea-hemiballismus is the most fre-
quently reported dyskinesia in HIV+ subjects (Piccolo et al. 1999; Cardoso 2002a).
Characteristically, this hyperkinesia is an acute complication of patients with estab-
lished AIDS, but in a few instances, hemichorea-hemiballismus may be the present-
ing symptom of HIV infection (Pardo et al. 1998; Cardoso 2002b). Chorea as direct
manifestation of HIV encephalopathy has been reported by some (Passarin et al.
2005; Sevigny et al. 2005). A French group described remission of chorea related to
HIV encephalopathy after introduction of highly active antiretroviral therapy
(Trocello et al. 2006).
Tremor is the second most commonly reported movement disorder in AIDS
patients. As it is often caused by Toxoplasma abscesses located in the mesencepha-
lon or thalamus, patients present with tremor of subacute onset with rest, postural,
and kinetic components, known as Holmes tremor (Koppel and Daras 1990; Micheli
et al. 1997). “Wing beating” tremor, related to middle cerebellar peduncle lesions,
mild postural tremor associated with HIV encephalopathy, and isolated rest tremor
induced by dopamine receptor blockers or trimethoprim-sulfamethoxazole have
also been reported (Swenson et al. 1989; Singer et al. 1990; Manji et al. 1995;
Cardoso 2002a). There are reports on the association of tremor with progressive
multifocal leukoencephalopathy, a common opportunistic infection in HIV+
patients (Rieder and Ziomkowski 2005; Sporer et al. 2005).
Less often, HIV+ patients may develop other hyperkinesias, such as generalized
or focal dystonia, Meige syndrome, myoclonus, painful legs and moving toes syn-
drome, akathisia, tics, stiff person syndrome, oculomasticatory myorhythmia asso-
ciated with Whipple disease, and opsoclonus-myoclonus (Jankovic 1986; Nath
et al. 1987; Tolge and Factor 1991; McDaniel and Summerville 1994; Lannuzel
et al. 2002; Canafoglia et al. 2003; Factor et al. 2003; Shah and Chudgar 2005;
Wicki et al. 2008; Wiersinga et al. 2012). Recently, there is a report of one patient
with acute onset of myoclonus and other neurologic clinical features who was found
to have West Nile virus infection in association with HIV (Josekutty et al. 2013).
There is also one study describing the occurrence of paroxysmal hyperkinesia in six
patients with advanced AIDS without underlying opportunistic infections (Mirsattari
et al. 1999).
Parkinsonism as part of HIV encephalopathy and, less frequently, resulting from
toxoplasmosis abscesses, parenchymatous tuberculosis granuloma, cryptococcal
abscesses, and other opportunistic infections has also been reported in patients with
AIDS (Carrazana et al. 1989; de la Fuente Aguado et al. 1996; Mirsattari et al. 1998;
Bouffard et al. 2003). In one of these studies, the authors describe six patients with
parkinsonism and ten others with “parkinsonian features.” In one half of the sub-
jects, the akinetic rigid syndrome was related to exposure to neuroleptics, whereas
no cause was identified in the remaining ones. These patients, who accounted for
5.2 % of all subjects seen in a Neuro-AIDS clinic, did not present with rest tremor,
and the majority of them also had additional clinical features such as dementia,
seizures, vacuolar myelopathy, and peripheral neuropathy. The CD4 values were
consistently low (mean of 14 cells/mm3). There is also a description of
parkinsonism in an HIV+ patient secondary to interaction between ritonavir, an

antiretroviral agent, and buspirone (Clay and Adams 2003). A Spanish group
described an HIV+ woman with probable progressive multifocal leukoencephalopa-
thy involving one putamen who presented with contralateral eating-induced myoc-
lonus and dystonia of the face (Gaig et al. 2007). A recent report described the
occurrence of PSP-like picture as an initial sign of HIV infection (Jang et al. 2012).
There is also a study describing that the coexistence of HIV and Lyme neurobor-
reliosis may present with tremor (Bremell et al. 2011).
Epidemiology
There are no community-based studies of the prevalence of movement disorders in

HIV infection. However, in a series of patients seen at tertiary referral centers,
approximately 2–3 % of subjects with AIDS develop these complications. In one
study, parkinsonian signs were identified in about 5 % of patients (Mirsattari et al.
1998; Cardoso 2002a).
The introduction of highly active antiretroviral therapy has led to a decrease
in the frequency of HIV encephalopathy as well as of opportunistic neurologic
complications in AIDS patients (Maschke et al. 2000). Although movement dis-
orders have not been specifically studied in these investigations, based on the
decline of reports on this issue as well as the reduced number of HIV+ patients
seen in movement disorders clinic, one may speculate that their incidence has
also decreased.
Treatment
The symptomatic management of chorea-hemiballismus in AIDS patients can be

done with the use of dopamine receptor blockers. As these patients have a dopami-
nergic deficit induced by the HIV, they are susceptible to development of tremor and
parkinsonism when exposed to dopamine receptor blockers. Fortunately,
hemichorea-hemiballismus has a tendency for spontaneous improvement after a
few weeks when it becomes possible to discontinue the neuroleptics.
Parkinsonism associated with HIV encephalopathy is rarely a clinical problem
important enough to deserve symptomatic treatment. Unfortunately, in the rare
instances when it is clinically problematic, patients do not respond to levodopa,
although a few reports suggest that children do improve on this medication
(Mirsattari et al. 1998; Cardoso 2002a). Because of the potential of medications to
induce motor side effects in HIV+ patients, it is extremely important to attempt to
discontinue offending drugs, such as neuroleptics. In case there is a recognized
associated opportunistic infection, patients must also receive specific therapy.
Finally, although its role in the treatment and prevention of motor complications is
not clearly established, initial evidence suggests that highly active antiretroviral
therapy has a positive impact on these problems (Maschke et al. 2000; Sacktor et al.
2000; Brew 2001; Hersh et al. 2001; Cardoso 2002b).
Prions
Cognition
From a population point of view, Creutzfeldt-Jakob disease (CJD) is an uncommon

condition. However, it is the most common form of prion disease, presenting with
dementia in all cases. More often the disease is sporadic (85 % of cases), but it can
be familial in about 10–15 % of patients, iatrogenic in 1 %, and there is also the
variant CJD, limited to the United Kingdom and France (Johnson 2005).
Sporadic CJD manifests initially with cognitive (39 % of cases) or behavioral
(20 % of cases) abnormalities according to one large study (Geschwind et al. 2007).
It is a form of rapidly progressive dementia, with 90 % of patients dying less than
1 year after the onset of symptoms (Johnson 2005).
Familial CJD usually has a longer clinical course than the sporadic form. The
clinical phenotype, including the profile of cognitive and behavioral changes, may
be similar to the one found in sporadic cases, but different presentations may occur,
including features resembling frontotemporal dementia (Nitrini et al. 2001).
Typically, the onset of sporadic CJD is in the sixth and seventh decades of life with
a clinical picture characterized by a rapidly progressive dementia and other behav-
ioral disorders. In most cases, death ensues in less than a year (Brown et al. 1994;
Paterson et al. 2012; Puoti et al. 2012). The age at onset of iatrogenic forms is more
variable, with the latency ranging from a few months to 10–15 years. Shorter laten-
cies are usually observed in surgical cases, whereas patients exposed to contami-
nated hormones developed CJD after a much longer period (Cardoso 2002a).
Movement disorders were identified in 91 % of patients, of whom 81 % had
multifocal cortical myoclonus, of a series of 300 subjects with pathologically veri-
fied sporadic CJD (Brown et al. 1994). Although not always clearly described in the
literature, other movement disorders found in these patients are tremor, rigidity,
parkinsonism, dystonia, and chorea (Brown et al. 1994; Cardoso 2002a, b). Ataxia
is the clinical hallmark of kuru and Gerstmann-Sträussler-Scheinker disease
(Cardoso 2002a; Liberski et al. 2012). Variant Creutzfeldt-Jakob disease (vCJD) is
a novel human prion disease caused by the bovine spongiform encephalopathy
agent (Ironside 2012). In addition to myoclonus, these patients often have ataxia
and chorea (Will et al. 1996; Bowen et al. 2000; Ironside 2012).
Epidemiology
Sporadic prion diseases are rare with the incidence of CJD estimated to be one case
per million population per year (Brown et al. 1987; Puoti et al. 2012). Infectious
prion diseases are even rarer. In the past kuru was common among subjects of the
Fore tribe of the highlands of New Guinea, but it has been eliminated with the disap-
pearance of individuals at genetic risk (those homozygous for the 129 Met allele of
the PRNP gene encoding for prion protein) and cannibalism (Gajdusek 1977;
Liberski et al. 2012).
There are less than 100 published cases of iatrogenic CJD related to corneal and
dura mater transplants, inadequately sterilized neurosurgical instruments, and con-
taminated growth hormone or gonadotrophins prepared from cadaveric pituitary
tissue (Brown et al. 1992).
Most cases of vCJD have occurred in the United Kingdom, with smaller numbers
in 11 other countries (Ironside 2012). There are also recent reports describing indi-
viduals who acquired vCJD by transfusion of blood-derived products of asymptom-
atic patients (Gregori et al. 2011; Ironside 2012; Millar and Makris 2012).
Treatment
Movement disorders are a relatively minor finding in the clinical picture of patients
with prion diseases. Nevertheless, if they cause disability, symptomatic treatment
for movement disorders can be used following guidelines similar to those used for
patients without prion diseases. Unfortunately, the prognosis of these conditions is
ominous not existing any measure effective in halting their relentless and fatal
progression.
Neurocysticercosis
Cognition
Cognitive impairment is a common clinical manifestation of neurocysticercosis

(NC), and its frequency and severity varies according to the disease phase (active
and calcified forms).
In a recent cross-sectional study, 80 treatment-naive patients with NC (40 with
active and 40 with calcified disease) were submitted to a comprehensive neuropsy-
chological and functional evaluation and were compared to a group of matched
healthy controls. Cognitive impairment was identified in 25 % of patients with cal-
cified NC, none of them fulfilling diagnostic criteria for dementia. On the other
hand, 40 % of patients with active disease were cognitively impaired, with dementia
being identified in 12.5 % of all cases (Rodrigues et al. 2012). Importantly, cogni-
tive impairment or dementia could not be explained by the use of antiepileptic drugs
use, seizures, or depression (Ciampi de Andrade et al. 2010).
Hence, NC leads to a spectrum of cognitive changes from mild impairment in a
single domain to multiple cognitive deficits without functional decline and, some-
times, to dementia. These features are more prominent during the active phase of the
disease, with attenuation in the calcified stage.
NC, infestation of the central nervous system by encapsulated larvae of Taenia

solium, is the most common neurologic parasitic disease worldwide (Davis and
Kornfeld 1991; Del Brutto et al. 1996; Cardoso 2002a; Del Brutto 2013). Epilepsy
and intracranial hypertension due to hydrocephalus are present in up to 92 % of NC
patients (Bianchin et al. 2012; Del Brutto 2013; Singh et al. 2013). The clinical mani-
festations are, however, protean, including focal deficits, cognitive and behavioral
changes, meningitis, optic neuropathy, stroke, and others (Davis and Kornfeld 1991;
Croker et al. 2012; Del Brutto et al. 1996; Del Brutto 2013). Interestingly, despite the
high frequency of basal ganglia cysts, movement disorders are rarely reported in NC
(Cosentino et al. 2002). One possible explanation for such an observation is the slow
growth of the cysts that gradually displace the basal ganglia structures without lesion-
ing them. The rare reports of movement disorders in NC encompass the occurrence
of parkinsonism, either related to intraparenchymal lesions or hydrocephalus
(Cardoso 2002a; Sá et al. 2005; Prashantha et al. 2008), or hemichorea-hemiballis-
mus (Cardoso 2002a; Cosentino et al. 2006; Karnik et al. 2011).
Epidemiology
NC remains as a major public health problem in Latin American and India (Del
Brutto 2013). It is, however, becoming increasingly common in regions with high
rates of immigration from endemic areas, such as the South as well as the East Coast
of the United States (Scharf 1988; Croker et al. 2012).
Treatment
Patients with NC and parkinsonism may improve with L-dopa therapy, but the
majority of reported cases just respond to treatment of the intraparenchymal lesions
or the causative underlying hydrocephalus (Cardoso 2002a; Sá et al. 2005;
Prashantha et al. 2008). Subjects who present with hemichorea-hemiballismus are
usually responsive to neuroleptics or tetrabenazine.
The specific treatment of NC remains a highly controversial subject with

unsolved issues, including when to use anticysticercal therapy, the role of steroids,
and indications of surgical therapy (Takayanagui et al. 2011; Baird et al. 2013; Del
Brutto 2013). Nevertheless, most authorities believe that the use of cysticidal drugs
improve clinical findings and is associated with a more favorable long-term progno-
sis. A recent evidence-based guideline of the treatment of parenchymal NC issued
by the American Academy of Neurology concluded that albendazole plus either
dexamethasone or prednisolone should be considered for adults and children with
NC, both to decrease the number of active lesions on brain imaging studies (Level B)
and to reduce long-term seizure frequency (Level B) (Baird et al. 2013).
Sydenham’s Chorea
Cognition
Cognitive functioning has been object of only few studies in Sydenham’s chorea (SC).
Executive dysfunction has been reported in adult patients even when chorea was in
remission (Beato et al. 2010). Simple and brief cognitive tests, sensitive to evaluation
of prefrontal functions, such as phonemic verbal fluency, are able to detect significant
changes; thus, they may be used in clinical practice (Cunningham et al. 2006).
SC is the most common movement disorder associated with bacterial infection.

Typically, patients develop this disease 4–8 weeks after an episode of streptococcal
pharyngitis. In most series, there is a female preponderance. The usual age at onset
of SC is 8–9 years of age, although there are reports of patients developing chorea
in the third decade of life (Cardoso et al. 1997). Chorea rapidly spreads, becoming
generalized, but 20 % of patients remain with hemichorea (Nausieda et al. 1980;
Cardoso et al. 1997). The random and continuous flow of contractions typical of
chorea produces motor impersistence, particularly noticeable during tongue protru-
sion and ocular fixation. The muscle tone is usually decreased, and in severe and
rare cases (8 % of all patients) is so pronounced that the patient may become bedrid-
den (chorea paralytica).
Patients often display other neurologic and nonneurologic symptoms and signs.
Although the distinction between chorea and motor tics may be difficult, the latter,
as well as simple vocal tics, are frequently reported to occur in SC. In a cohort of
108 SC patients carefully followed up at our unit, we have identified vocalizations
in just 8 % of subjects. We have avoided the term “tic” because there was no pre-
monitory sign or complex sound, and, conversely, the vocalizations were associated
with severe cranial chorea. These findings suggest that involuntary sounds present
in a few patients with SC result from choreic contractions of the upper respiratory
tract muscles rather than true tics (Teixeira et al. 2009).
Dysarthria is common, and patients with more severe forms of this condition
may present a remarkably decreased verbal output. There is evidence that many
patients with active chorea have hypometric saccades, and a few also show oculo-
gyric crisis. In the older literature, there are also references to papilledema, central
retinal artery occlusion, and seizures in some patients with SC. Migraine is more
common in children with SC than in controls. In a cohort of 55 patients with this
movement disorder, 21.8 % were found to have migraine, whereas this type of head-
ache was seen in no more than 8 % of 110 matched controls (Teixeira et al. 2005a).
Attention has been drawn to behavioral abnormalities associated with this con-
dition. We investigated the behavior of 56 patients with SC, 50 subjects with
rheumatic fever without chorea, and 50 healthy matched controls. Obsessive-
compulsive disorder was diagnosed in 23 % of the patients with chorea, whereas
just 6 and 4 % of the rheumatic fever group and healthy controls met criteria for
this condition (Maia et al. 2005). Other studies have confirmed that obsessions
and compulsions are commonly seen in patients with SC (Asbahr et al. 1998;
Mercadante et al. 2000; Hounie et al. 2004). We saw one patient with paranoid
psychosis with onset in parallel with SC and also found that another patient with
SC developed trichotillomania (Kummer et al. 2007; Teixeira et al. 2007). These
findings and the observation that hyperactivity, learning disorders, and other
behavioral problems are common in patients with rheumatic fever and chorea
contributed to establish the notion that SC is a model for childhood autoimmune
neuropsychiatric disorders (Swedo 1994).
It must be kept in mind that SC is a major manifestation of rheumatic fever,
although in approximately 20 % of patients, chorea is the sole finding.
Nevertheless, up to 80 % of patients display cardiac involvement in SC, whereas
the association with arthritis is less common, seen in 30 % of subjects (Cardoso
et al. 1997). The current diagnostic criteria of SC are a modification of the Jones
criteria: chorea with acute or subacute onset and lack of clinical and laboratory
evidence of alternative cause are mandatory findings, and the diagnosis is further
supported by the presence of additional major or minor manifestations of rheu-
matic fever (Special Writing Group of the Committee of Rheumatic Fever 1992;
Cardoso et al. 1997, 1999).
Epidemiology
SC is the most common cause of acute chorea in children; however, its prevalence
has decreased in conjunction with the reduction of rheumatic fever in North
America and Western Europe. For instance, in Fairfax County, Virginia, the
annual age-adjusted incidence rate of initial attacks of rheumatic fever per 100,000
children declined from 3.0 in 1970 to 0.5 in 1980 (Schwartz et al. 1983).
Furthermore, Nausieda and colleagues demonstrated that SC accounted for 0.9 %
of children admitted to hospitals in Chicago before 1940, whereas this number

dropped to 0.2 % between 1950 and 1980 (Nausieda et al. 1980). However, at
least eight outbreaks of rheumatic fever with occurrence of chorea have been
identified in the United States (Ayoub 1992). Even in areas where there has been
a decline in the incidence of rheumatic fever, such as Pennsylvania in the United
States, this illness account for almost all cases of acute chorea among children
(Zomorrodi and Wald 2006).
Rheumatic fever has remained a significant public health problem in developing
areas, particularly within the low income population. In the top end of the Northern
Territory in Australia, an area predominantly inhabited by Aborigine people, the
prevalence of rheumatic fever was 9.6 per 1,000 people aged 5–14 years in 1995
(Carapetis et al. 1996). SC occurs in about 26 % of patients with rheumatic fever
(Cardoso et al. 1997). Clinical observation in our unit suggests that there is a decline
of the frequency of SC in Brazil, an area where rheumatic fever used to be endemic.
Treatment
There are few controlled studies of symptomatic treatment of SC (Cardoso 2008).

The first choice of the authors is valproic acid and just if the patient fails to respond
to this medication, the next option is to prescribe neuroleptics. The latter can also be
prescribed as a first-line treatment in patients who present with chorea paralytica.
Risperidone, a relatively potent dopamine D2 receptor blocker, is usually effective
in controlling the chorea. Dopamine D2 receptor blockers must be used with great
caution in patients with SC. We performed a case–control study comparing the
response to these drugs in patients with SC and Tourette syndrome. We demon-
strated that 5 % of 100 patients with chorea developed extrapyramidal complica-
tions, whereas these findings were not observed among patients with tics matched
for age and neuroleptics dosage (Teixeira et al. 2003).
Finally, the most important measure in the treatment of patients with SC is sec-
ondary prophylaxis with penicillin or, if there is allergy, with sulfa drugs up to
21 years of age. In case the onset occurs after this age, the recommendation is to
maintain prophylaxis indefinitely (Cardoso 2002a).
Some controversy exists as to the role of immunosuppression in the management
of SC. Despite mentions of the effectiveness of prednisone in suppressing chorea,
this drug is only used when there is associated severe carditis. A placebo-controlled
study showed that oral prednisone only accelerates the control of chorea; rates of
remission and recurrence were not changed by the active treatment (Paz et al. 2006).
Intravenous methylprednisolone is reserved for patients with persistent disabling
chorea refractory to antichoreic agents (Cardoso et al. 2003; Barash et al. 2005;
Teixeira et al. 2005b). Few reports describe the usefulness of plasma exchange or
intravenous immunoglobulin in SC. Because of the efficacy of other therapeutic
agents, potential complications, and the high cost of the latter treatment modalities,
these options are not usually recommended.
Conclusions
In this chapter we reviewed a number of infectious diseases that course with a com-
bination of movement disorders and cognitive decline. Historically, postencephalitic
parkinsonism and neurosyphilis were the first infectious conditions combining these
features to be studied. The former has vanished, but syphilis remains an important
cause of dementia although movement disorders are rare. Prion diseases are uncom-
mon and their infectious forms are even rarer. Nevertheless, they should always be
ruled out in patients with rapidly progressive dementia and myoclonus. The majority
of HIV + patients develop neurologic complications despite the advent of highly
active antiretroviral therapy. A substantial proportion of these patients display the
combination of movement disorder, particularly parkinsonism, and cognitive impair-
ment. Neurocysticercosis, the most common parasitic disease worldwide, is increas-
ingly recognized as a cause of cognitive disorder although movement disorders are
exceedingly rare in these subjects. Finally, although the incidence of Sydenham’s
chorea is in decline, it remains as the most common cause of acute chorea in children
and not infrequently it is associated with a dysexecutive syndrome.
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Index
A Apathy, 6, 64, 67, 68, 73–84, 130, 132, 143,

Acetylcholinesterase (AChE) inhibitors, 38, 171, 181, 182, 184, 189, 190, 237,
50, 63, 184, 186, 191 238, 254
Acquired immunodeficiency syndrome ApoE4. See Apolipoprotein E ε4 allele
(AIDS), 257–259 (ApoE4)
Acute akathisia, 90–91 Apolipoprotein E ε4 allele (ApoE4), 163
Acute dystonia, 88, 90, 107, 109, 136 APP. See Amyloid precursor protein (APP)
AD. See Alzheimer’s disease (AD) Apraxia, 6, 136, 142, 143, 146, 147, 149–150,
Adverse drug reactions, 88, 90, 94, 107, 110 188–191, 217, 256
Aging, 8, 10, 18, 19, 21, 22, 28, 33, 38, 47, Apraxia of speech (AOS), 149, 214–220,
164, 166, 180, 236 223–226
agPPA. See Agrammatic variant Arteriosclerotic parkinsonism, 202
of PPA (agPPA) Assessment, 22, 38, 46, 52, 53, 56, 79–81, 93,
Agrammatic aphasia, 216–220, 223 94, 120, 123, 125, 130–132, 165, 189,
Agrammatic variant of PPA (agPPA), 238–241, 245
215–222, 225, 226 Atypical parkinsonism, 62, 187–192
AIDS. See Acquired immunodeficiency
syndrome (AIDS)
Akathisia, 74, 88–91, 107, 108, 110, 124, 258 B
Alpha-synuclein (α-syn), 8, 10, 180, 182, 183, Balance, 20–22, 32, 33, 46–54, 56, 172,
186, 202 214, 218
ALS. See Amyotrophic lateral sclerosis (ALS) Behavioral variant frontotemporal dementia
Alzheimer’s disease (AD), 5–10, 21, 22, 27, (bvFTD), 142–144, 148, 149
28, 32, 33, 38, 46, 48, 63, 67, 68, 73–84, BFCRS. See Bush-Francis Catatonia Rating
118, 129–137, 142, 143, 157, 159–161, Scale (BFCRS)
163–167, 171, 180–183, 186, 189–191, Binswanger encephalopathy, 202
202, 205, 224–226, 233, 235, 237, Buccolinguomasticatory syndrome, 92
238, 244 Bush-Francis Catatonia Rating Scale
β-Amyloid (Aβ), 8–9, 163, 166, 182, 203, 205 (BFCRS), 81
Amyloidopathies, 8–9 bvFTD. See Behavioral variant frontotemporal
Amyloid precursor protein (APP), 8, 163, 183 dementia (bvFTD)
Amyotrophic lateral sclerosis (ALS), 4, 142,
147–148
Antidepressants, 49, 76, 77, 90, 92, 108, 171 C
Antipsychotics, 67–69, 74, 83, 88, 90, 92–94, Catatonia, 73–84, 88, 90
107–110 Catechol-O-methyltransferase (COMT)
AOS. See Apraxia of speech (AOS) inhibitors, 64

DOI 10.1007/978-1-4471-6365-7, © Springer-Verlag London 2014
274 Index
CBD. See Corticobasal degeneration (CBD) Dementia associated with Parkinson’s disease,
CBS. See Corticobasal syndrome (CBS) 4, 46–50, 52, 55, 62–64, 68, 118, 119, 122,
Center for Epidemiologic Studies Depression 157, 160, 161, 163, 164, 166, 167,
Scale (CES-D), 76 180–188, 191
Cerebrospinal fluid (CSF), 130, 159, 166, 232, Dementia with Lewy bodies (DLB), 7, 8, 20,
233, 238, 240–245 26, 46–49, 62–64, 68, 69, 118, 119, 122,
Cerebrovascular disease (CVD), 27, 49–52, 133–135, 145, 148, 155–172, 181–184,
55, 200–205, 207, 208, 239 186–188, 192, 233
CES-D. See Center for Epidemiologic Studies Depression, 6, 23, 73–84, 132, 137, 148, 162,
Depression Scale (CES-D) 165, 171, 181–182, 184, 189, 190, 209,
ChEIs. See Cholinesterase 237, 238, 262
inhibitors (ChEIs) Diagnostic and Statistical Manual of Mental
Cholinergic dysfunction, 49, 50 Disorders, Fourth Edition (DSM-IV), 74,
Cholinesterase inhibitors (ChEIs), 55, 79, 122, 75, 81, 82
137, 171, 184, 209 DIMDs. See Drug-induced movement
Chorea, 3, 4, 88, 89, 91–93, 109, 254, 255, disorders (DIMDs)
258–260, 263–266 DIP. See Drug-induced parkinsonism (DIP)
Chromosome 17, 68, 145–147, 225 DIPD. See Drug-induced parkinsonism and
CJD. See Creutzfeldt–Jakob disease (CJD) dementia (DIPD)
Clinical Global Impression of Change (CGIC) DLBD, 8, 133–135, 137
scale, 83 Drug-induced movement disorders (DIMDs),
Cognitive fluctuations, 158 87–111, 124
Cognitive impairment, 17–38, 46–56, 62, 66, Drug-induced parkinsonism (DIP), 61, 67–69,
68, 90, 91, 123, 130, 159–161, 164, 166, 88, 91, 93, 94, 107, 109, 144
168, 171, 180, 183, 184, 188–190, 192, Drug-induced parkinsonism and dementia
204, 207, 237, 238, 241, 245, 254, 257, (DIPD), 63, 67
261, 262, 266 Dual energy x-ray absorptiometry (DXA), 56
Cognitive manifestations, 159, 161 DXA. See Dual energy x-ray absorptiometry
Columbia University Parkinson’s Disease (DXA)
Rating Scale, 124 Dystonia, 4, 5, 11, 62, 88–90, 92, 93,
C9ORF72, 142–144, 147–148, 150, 226 107–110, 124, 135–137, 146–149, 188,
Cornell Scale for Depression in Dementia 217, 219, 254, 258–260
(CSDD), 76
Corticobasal degeneration (CBD), 3, 5, 8, 9,
68, 187–192, 224, 225 E
Corticobasal syndrome (CBS), 7, 62, 63, 66, ECT. See Electroconvulsive therapy (ECT)
69, 136, 137, 142, 143, 145, 149, 188–191, EDS. See Excessive daytime sleepiness (EDS)
214–223, 254 Electroconvulsive therapy (ECT), 82, 92
Creutzfeldt–Jakob disease (CJD), 3–5, 11, Encephalitis subcorticalis chronica
133–135, 260 progressive, 201
CSDD. See Cornell Scale for Depression in ESRS. See Extrapyramidal Symptom Rating
Dementia (CSDD) Scale (ESRS)
CSF. See Cerebrospinal fluid (CSF) Excessive daytime sleepiness (EDS), 170, 172,
CVD. See Cerebrovascular disease (CVD) 184
Extrapyramidal Symptom Rating Scale
(ESRS), 124
D
Dementia, 1–12, 17–38, 45–56, 61–69, 74,
76–79, 82, 83, 99, 118–120, 122–125, F
129–131, 133, 134, 137, 141–150, Falls, 3, 18–26, 29–33, 38, 45–56, 76,
157–159, 161, 163–165, 179–192, 147–148, 162, 187, 188, 207, 214, 218,
199–209, 224, 233–235, 237, 244, 236, 239
253–266 Filament inclusion disorders, 9–10
Index 275
Frontotemporal dementia (FTD), 3, 4, 6, 7, 9, Lewy body disease (LBD), 48, 49, 135, 157,
10, 12, 68, 131, 141–150, 157, 182, 188, 158, 164, 224
224, 233, 260 Lewy body inclusions, 157
Frontotemporal lobe dementia (FTLD), 62, 63, Logopenic variant of PPA (lvPPA), 217–219,
67–69, 142, 143, 147 221, 222, 224–226
FTD. See Frontotemporal dementia (FTD) Lower-body parkinsonism, 236
FTDP-17, 8, 9, 145–147, 149, 224, 226 lvPPA. See Logopenic variant
FTLD. See Frontotemporal lobe dementia of PPA (lvPPA)
(FTLD)
Functional Assessment Staging (FAST)
scale, 125 M
FUSpathies, 9 Magnetic gait, 66
MAP. See Microtubule-associated
protein (MAP)
G MCI. See Mild cognitive impairment (MCI)
Gait, 17–38, 46–56, 62, 64, 66, 92, 118, 119, MDS-UPDRS. See Movement Disorder
123–125, 132, 133, 144, 188, 202, Society-sponsored version of the UPDRS
205–207, 214, 219, 236, 237, 239–242 (MDS-UPDRS)
Gait abnormalities, 27, 38, 53–54, 124 Methylphenidate (MPH), 38, 79
Gait disorders, 17–38, 48, 132 Microtubule-associated protein (MAP), 9
Gegenhalten, 81, 137, 217 Microtubule-associated protein tau
Genetics, 130, 147, 148, 150, 163, 183, (MAPT) gene, 9, 142, 145–148,
225–226 150, 183, 226
Mild cognitive impairment (MCI), 18, 21–27,
37, 46, 49, 54–56, 123, 159, 161, 180, 181,
H 184, 186, 187, 240
Hallucinations, 62–65, 68–69, 83, 91, 144, MND. See Motor neuron disease (MND)
147, 159, 161, 165, 171, 181, 184, Monoamine oxidase B (MAO-B)
189–190, 254, 256 inhibitors, 64
High-level gait disorders (HLGD), 50 Motor, 4–6, 18–21, 23, 27, 33, 38, 50, 52, 53,
HIV infection, 254, 257–260 55, 63–68, 73–74, 76, 77, 79–82, 89, 93,
HLGD. See High-level gait disorders (HLGD) 107, 108, 118–125, 131–134, 143, 147,
Huntington’s disease, 11, 88, 257 156, 159, 161, 162, 164, 165, 171, 180,
Hydrocephalus, 5, 61–63, 165–166, 232–235, 181, 183, 184, 189–192, 200, 201,
239, 243–244, 262 214–216, 218–220, 226, 234, 236,
242, 256, 257, 259–260, 263
Motor manifestations, 74, 159
I Motor neuron disease (MND), 5, 218, 225
ICARS. See International Cerebellar Ataxia Movement disorders, 2–5, 7, 9–10, 49, 82–84,
Rating Scale (ICARS) 87–111, 124, 129–137, 141–150, 158,
Idiopathic, 7, 61, 62, 67, 68, 88, 90, 91, 218–219, 253–266
110, 157, 159, 163, 171, 200, 203, Movement Disorder Society-sponsored
233–235, 238 version of the UPDRS (MDS-UPDRS),
Infectious dementias, 253–266 121, 122
International Cerebellar Ataxia Rating Scale MPH. See Methylphenidate (MPH)
(ICARS), 122 MSA. See Multiple system
atrophy (MSA)
Multiple system atrophy (MSA), 3, 5, 8, 10,
L 62, 91, 122–125, 136, 163, 167, 187–188,
LBs. See Lewy bodies (LBs) 191–192, 206, 224
Lewy bodies (LBs), 3, 10–11, 20, 46, 48, 134, Myoclonus, 62, 89, 91–93, 108, 134, 136,
145, 157, 162–164, 166–167, 180, 182, 146–149, 159, 188, 217, 219, 258,
183, 224 260, 266
276 Index
N Parkinsonism, 1–12, 48, 49, 61–69, 73–84, 88,

The National Institute of Mental Health 89, 91, 108–110, 117–125, 131–136,
(NIMH), 75, 76 143–150, 158, 159, 163, 167–171,
NBIA. See Neurodegeneration with brain iron 179–192, 199–209, 214, 222, 224–226,
accumulation (NBIA) 234, 236, 254–260, 262, 266
NC. See Neurocysticercosis (NC) Parkinson’s disease (PD), 4, 6–8, 10, 21, 37,
NCI. See Neuronal cytoplasmatic 38, 46, 50, 51, 61, 62, 65, 67, 77, 80, 82,
inclusions (NCI) 88, 89, 91–94, 118, 120–122, 125, 131,
NCS. See Northoff Catatonia Scale (NCS) 134, 136, 144, 148, 156–157, 159–161,
Neurocysticercosis (NC), 261–263, 266 163–167, 171, 172, 179–192, 203,
Neurodegeneration with brain iron 205–207, 209, 233, 236–238, 254,
accumulation (NBIA), 5, 11 256, 257
Neurodegenerative disorders, 1–12, 118, 119, Parkinson’s disease with dementia (PDD), 46,
157, 166, 180, 214 50, 64, 118, 157, 160, 161, 163, 164, 166,
Neuroferritinopathies, 12 167, 180–188, 191
Neuroleptic malignant syndrome PD. See Parkinson’s disease (PD)
(NMS), 65, 81 PDD. See Parkinson’s disease with
Neuroleptics, 20, 67, 83, 90, 93, 107, 110, dementia (PDD)
131, 136, 137, 162, 171, 258, 259, Pedunculopontine nucleus (PPN), 50, 51,
262, 265 137, 162
Neuroleptic sensitivity, 158, 162, 171 PEPS. See Pyramidal and extrapyramidal
Neuronal cytoplasmatic inclusions (NCI), 12 scale (PEPS)
Neuronal intermediate filament inclusion Perry syndrome, 148
disorders (NIFID), 9–10 PET. See Positron emission
Neuropathology, 2, 5, 6, 9, 12, 131, 182–183, tomography (PET)
190–191, 201, 202 Pharmacovigilance, 137
Neuropsychiatric Inventory (NPI), PIGD. See Postural instability gait
79, 189, 190 difficulty (PIGD)
Neuropsychiatric manifestations, 161–162 Pisa syndrome, 136–137
Neuropsychiatric symptoms, 68, 88, 130, 165, PNFA. See Progressive nonfluent aphasia
167, 171, 181, 189, 190 (PNFA)
Neurosyphilis, 254–255, 266 Polyglutamine disorders, 11
NIFID. See Neuronal intermediate filament Positron emission tomography (PET), 94, 130,
inclusion disorders (NIFID) 158, 166, 203
NIMH. See The National Institute of Mental POS-PP. See Palliative Care Outcome
Health (NIMH) Scale-Parkinsonism Plus (POS-PP)
NMS. See Neuroleptic malignant POS-S. See POS-symptoms (POS-S)
syndrome (NMS) POS-symptoms (POS-S), 125
NNIPPS-PPS, 124 Postencephalitic parkinsonism, 254–257, 266
Non-Lewy body α-synucleinopathies, 10 Postural instability gait difficulty (PIGD), 64,
Non-motor manifestations, 159–162 119, 159, 160, 165
Normal pressure, 232–233 PPA. See Primary progressive aphasia (PPA)
Normal-pressure hydrocephalus (NPH), 5, PPAOS. See Primary progressive AOS
61–63, 66, 231–245 (PPAOS)
Northoff Catatonia Scale (NCS), 81 PPN. See Pedunculopontine nucleus (PPN)
NPH. See Normal-pressure hydrocephalus Primary progressive AOS (PPAOS), 149,
(NPH) 213–216, 218–220, 223, 224, 226
NPI. See Neuropsychiatric Inventory (NPI) Primary progressive aphasia (PPA), 6, 7,
213–226
Prion diseases, 11, 261, 266
P Prions, 11, 260–261
Palliative Care Outcome Scale-Parkinsonism Programmable valve, 243–245
Plus (POS-PP), 125 Progressive nonfluent aphasia (PNFA),
Paratonia, 81, 137 142–144, 149, 188
Index 277
Progressive supranuclear palsy (PSP), 3, 5, Selective serotonin reuptake inhibitors

7–10, 62, 63, 65, 66, 68, 69, 121–125, 142, (SSRIs), 49, 76, 79, 171, 209
143, 145–147, 149, 182–184, 187–192, Semantic dementia (SD), 6, 142, 143
206, 224, 233, 259 Semantic variant of PPA (svPPA), 217–219,
Progressive supranuclear palsy rating scale 221, 222, 224–226
(PSPRS), 123 Shunt, 66, 232, 235, 236, 238, 240–245
PSP. See Progressive supranuclear Silent small vessel disease, 201
palsy (PSP) Single photon emission computed tomography
PSPRS. See Progressive supranuclear palsy (SPECT), 94, 158, 166, 203, 236
rating scale (PSPRS) SPECT. See Single photon emission computed
Psychosis, 64, 69, 73–84, 119, 165, 171, 186, tomography (SPECT)
209, 255, 257, 264 Spinocerebellar ataxias (SCA), 11
Pyramidal and extrapyramidal scale (PEPS), Sporadic Creutzfeldt–Jakob disease (sCJD),
123–124 157, 159, 260
SSRIs. See Selective serotonin reuptake
inhibitors (SSRIs)
R Structured clinical interview for apathy
Randomized-controlled trials (RCTs), 38, 53, (SCIA), 78
64, 76, 77, 79, 82, 83, 107, 170, 172, 243 Subcortical dementia, 6, 66, 190
Rapid eye movement (REM), 74, 158, 162 svPPA. See Semantic variant of PPA (svPPA)
Rating Scale for Gait Evaluation in Cognitive Sydenham’s chorea (SC), 263–266
Deterioration (RSGE-CD), 125 Synucleinopathies, 3, 8, 10–11, 162–164, 166,
Rating scales, 65, 78, 80, 81, 120–125, 144 167, 188, 192, 224
RCTs. See Randomized-controlled trials
(RCTs)
REM. See Rapid eye movement (REM) T
REM sleep behavior disorders (RBD), 158, Tardive dyskinesia (TD), 88, 92–94, 107, 110
162, 170, 172 Tardive syndromes, 89, 92–93, 110
Restless legs syndrome (RLS), 90 Tau, 9, 130–131, 142, 145, 166, 182, 183, 190,
Risk factors, 20, 46–50, 54–56, 67, 90–92, 202, 203, 205, 224, 226
122, 163, 183, 188–189, 200, 207 Tauopathies, 3, 8, 9, 12, 183, 188, 224, 225
RLS. See Restless legs syndrome (RLS) TCAs. See Tricyclic antidepressants (TCAs)
RNA–DNA binding proteins, 9 TD. See Tardive dyskinesia (TD)
RSGE-CD. See Rating Scale for Gait TDP-43, 9, 142, 143, 145–148, 224, 225
Evaluation in Cognitive Deterioration Treatment, 38, 55, 56, 61–69, 74, 76–77, 79,
(RSGE-CD) 80, 82, 83, 90, 92, 93, 108–111, 122–124,
129, 131, 165, 167, 171, 184, 186, 187,
191, 192, 208, 209, 242–244, 255, 257,
S 259–263, 265
SANS. See Scale for the Assessment of Tremor, 32, 38, 61–64, 66, 68, 83, 88, 89,
Negative Symptoms (SANS) 91–93, 108–110, 124, 132–134, 144–146,
SC. See Sydenham’s chorea (SC) 148, 159, 160, 171, 181, 219, 257–260
SCA. See Spinocerebellar ataxias (SCA) Tricyclic antidepressants (TCAs), 76, 108,
Scale for the Assessment of Negative 170, 171
Symptoms (SANS), 79
Scales for Outcomes in Parkinson’s Disease
(SCOPA), 125 U
SCIA. See Structured clinical interview for UMSARS. See Unified Multiple System
apathy (SCIA) Atrophy Rating Scale (UMSARS)
sCJD. See Sporadic Creutzfeldt–Jakob Unified Multiple System Atrophy Rating Scale
disease (sCJD) (UMSARS), 123
SCOPA. See Scales for Outcomes in Unified Parkinson’s disease rating scale
Parkinson’s Disease (SCOPA) (UPDRS), 80, 82, 120–124, 132,
SD. See Semantic dementia (SD) 134, 144
278 Index
UPDRS. See Unified Parkinson’s disease vCJD. See Variant Creutzfeldt–Jakob disease
rating scale (UPDRS) (vCJD)
Urinary incontinence, 66, 162, 172, 207, 236, Ventricle, 201–202, 232, 233, 243
240, 241 VH. See Visual hallucinations (VH)
Visual hallucinations (VH), 158, 161, 171,
181, 184, 256
V Voxel-based morphometry (VBM), 147, 219
VAD. See Vascular dementia (VAD) VP. See Vascular parkinsonism (VP)
Variant Creutzfeldt–Jakob disease (vCJD),
260, 261
Vascular dementia (VAD), 27, 28, 31, 32, 38, W
46, 67, 131, 137, 157, 199–209, 233 Webster scale, 124
Vascular parkinsonism (VP), 61, 63, 67, White matter hyperintensities (WMH),
199–209 19, 32, 33
VBM. See Voxel-based morphometry WMH. See White matter hyperintensities
(VBM) (WMH)

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What is the main topic covered in the document?

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What are some of the conditions discussed in relation to movement disorders?

What are some of the conditions discussed in relation to movement disorders?

Marcelo Merello

Sergio E. Starkstein Editors

ISBN 978-1-4471-6364-0 ISBN 978-1-4471-6365-7 (eBook)

Library of Congress Control Number: 2014935244

© Springer-Verlag London 2014

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)

Pamplona, Spain Jose A. Obeso, MD, PhD

Buenos Aires, Argentina Marcelo Merello, MD, PhD

1 Neurodegenerative Disorders: Dementia and Parkinsonism,

10 Dementia with Lewy Bodies ................................................................... 155

Egberto R. Barbosa, MD, PhD Department of Neurology, University of Sao

Hubert H. Fernandez, MD Department of Neurology, Cleveland Clinic Lerner

Navarra; Senior Researcher, Center for Applied Medical Research (CIMA),

Sergio E. Starkstein, MD, PhD School of Psychiatry and Clinical

Marcelo Merello and Malco Rossi

Abstract Neurodegenerative diseases encompass several entities characterized by

Keywords Dementia • Parkinsonism • Amyloidopathies • Tauopathies •

Neurodegenerative diseases are characterized by death and progressive loss of neu-

M. Merello, MD, PhD (*)

M. Merello, S.E. Starkstein (eds.), Movement Disorders in Dementias, 1

Traditionally, neurodegenerative diseases are categorized according to the spe-

The Risk of Classification

addition to movement disorders also produce dementia in most cases. To make

Models of Neurodegenerative Diseases

molecular finding” may actually begin to contribute to disease progression. A more

Neurodegenerative diseases are usually classified depending upon the predominat-

Table 1.1 Classification of movement disorders

Table 1.2 Classification of parkinsonian disorders

Table 1.3 Classification of dementia

Motor neuron FTD CBS/PSP IPD

Cognitive decline affecting multiple domains

With Insidious onset and

Without altered consciousness

With functional decline

Without significant depression

Fig. 1.2 Clinical algorithm for dementias

Recognition of a common mechanistic theme shared by many neurodegenerative

β-Amyloid (Aβ): Amyloidopathies

Table 1.4 Molecular Amyloidopathies

cleavage of APP. APP fragments may undergo degradation or oligomerization and

Tau is a microtubule-associated protein (MAP) that stabilized them and promotes

RNA–DNA Binding Proteins: TDP-43 and FUSpathies

Neuronal Intermediate Filament Inclusion Disorders

Neuronal intermediate filament inclusion disorders (NIFID) is a relatively new term

starting with dementia, progressing to movement disorders and ending in motoneu-

Non-Lewy Body α-Synucleinopathies

In certain circumstances, α-synuclein pathological aggregates may not form Lewy

Lewy Bodies in Disorders Other than Synucleinopathies

et al. 2009) and PLA2G6-associated disorders. PLA2G6 mutations which encode

Huntington’s disease is the pathognomonic disorder in which a genetic mutation

Abnormal conformers of normal cellular proteins with increased tendency to aggre-

Neurodegeneration with Brain Iron Accumulation

NBIA corresponds to a group of disorders characterized by brain iron accumula-

Neurodegenerative diseases encompass several entities characterized by variable

Aarsland D, Karlsen K. Neuropsychiatric aspects of Parkinson’s disease. Curr Psychiatry Rep.