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Neurology Asia 2005; 10 : 79 98

Parkinsons disease with dementia and dementia

with Lewy bodies

Department of Medicine, Division of Neurology, University of Alberta; *Neuropsychology Program,

Department of Neurosciences, University of Alberta Hospital, Edmonton, Alberta, Canada

Dementia occurs in up to 30% of people with Parkinsons disease and is a major cause of disability.
Pathologically, Parkinsons dementia, where dementia follows the onset of parkinsonism by at least
one year, overlaps with dementia with Lewy bodies. We review the functional impact, definitions,
neuropsychology, epidemiology and pathophysiology of Parkinsons dementia, dementia with Lewy
bodies and their overlap. Associated psychiatric and imaging findings are also considered. Lastly,
current and emerging approaches to assessment and treatment in patients with these Lewy body
associated dementias are presented.

INTRODUCTION diagnosed and specific diagnoses may be

Parkinsons disease (PD) is the most common
neurodegenerative movement disorder, affecting
about 0.5-5% of the population older than age 65,
both in European and non-European populations.1,2 Both PD and other disorders causing parkinsonism
The prevalence of PD increases with age in most can be associated with dementia and cognitive
studies from less than 1% in people aged 65-69 impairment (Table 1). Dementia can be defined
years to 2-3% or more in people older than age by the presence of an acquired cognitive disorder,
90. The prevalence might decrease in the very affecting two cognitive domains (i.e., among
elderly, possibly reflecting diagnostic uncertainty, memory, language, praxis, visuospatial function
overlap with other diseases, a disproportionate and executive function), leading to a decline in
effect on survival in the oldest old with PD or activities of daily living. 12,13 Nevertheless,
inadequate sample sizes in studies of the oldest definitions differ between studies (see Definition
old (greater than age 85 years).3,4 At a societal of Dementia, below). The population prevalence
level, PD increases health care utilization and of PD, parkinsonism and the degree of
costs.5,6 accompanying cognitive impairment vary
Parkinsons disease is a progressive disorder depending on study methods (methods for case-
associated with acquired parkinsonism and the ascertainment and diagnostic definitions) and the
loss of substantia nigra neurons in the presence of age of the population under study. In most studies
Lewy bodies ( the prevalence of dementia associated with PD is
Parkinsonism is defined by the presence of two 20-40% with an incidence of 2.6-9.5 cases per
cardinal signs among resting tremor, rigidity, 100 patient-years of observation.4,11,14-27 The recent
bradykinesia and postural or gait impairment, recognition of Dementia with Lewy bodies (DLB),
and can be caused by disorders other than wherein dementia and parkinsonism may occur
idiopathic PD. Lewy bodies are eosinophilic within one year of each other and are accompanied
inclusions that stain with antibodies directed by cognitive fluctuations and hallucinations, has
against alpha-synuclein, a ubiquitous synaptic both complicated and illuminated our
protein evident in a number of neurodegenerative understanding of the role of Lewy body pathology
disorders.7 Clinical features that make a diagnosis
of idiopathic PD more likely include asymmetrical This review article appeared orginally in Can
onset, resting tremor, and a favorable response to J Neurol Sc 2004; 31:7-21. The article is
levodopa.8 Good accuracy (approximately 90% reproduced with kind permission from the
positive predictive value) and sensitivity (90%) Journal under the special arrangement of
can now be achieved.9,10 Nevertheless in the Journal Article Exchange between Canadian
general medical setting parkinsonism is often not Journal of Neurosciences and Neurology Asia.
Address correspondence to: Dr Richard Camicioli, Department of Medicine (Neurology), University of Alberta, Glenrose Rehabilitation Hospital, E233,
10230-111 th Avenue, Edmonton, Alberta, Canada T5G 087

Neurology Asia December 2005

Table 1: Causes of parkinsonism associated with DEFINITIONS OF DEMENTIA (TABLE 2)

dementia in older adults. Several different classification systems are used
to diagnose dementia in PD (see Table 2). Among
Lewy Bodies Disorders these are the criteria of Cummings and Benson,42
Parkinsons disease International Classification for Disease (ICD)-
Dementia with Lewy bodies 9,43 ICD-10,44 the Diagnostic and Statistical
Manual (DSM)-III,45 DSM-III-R,46 and the DSM-
Other Movement Disorders IV.47 It is clear from examination of Table 2 that
Progressive supranuclear palsy a patient could fulfill the criteria for one diagnostic
Corticobasal degeneration system yet not another. For example, many
Multiple system atrophy patients without functional decline and/or memory
Huntington disease impairment might meet Cummings and Benson
criteria, but would not meet the DSM criteria.
Primary Dementias
The ICD-9 criteria imply that executive
Frontotemporal dementia
dysfunction and memory impairment are both
Alzheimers disease
mandatory for the diagnosis. The ICD-10 criteria
Other Disorders are vague with respect to whether memory
Cerebrovascular disease impairment and functional decline are required.
Normal pressure hydrocephalus Psychiatric etiologies of cognitive disturbance
ALS-PD-Dementia Complex of Guam are not specifically excluded in the Cummings
HIV Dementia and Benson criteria, but are exclusionary in the
Creutzfeld-Jakob Disease DSM systems. The variability in definitions used
in research contributes to the wide range of PDD
in causing dementia with parkinsonism. Although prevalence rates, and the inconsistencies reported
a number of studies have addressed the between studies examining cognition in PD versus
epidemiology of Parkinsons dementia (PDD), PDD.
the epidemiology of DLB is not as clear.28,29 It could be argued that none of the above
diagnostic systems is adequate with respect to
PDD. Functional decline related to cognitive
decline, as required by the DSM criteria, is often
difficult to discern in the PD population due to
The effect of PD on quality of life correlates with motor difficulties. None of the above systems
progression of symptoms and is most closely classify subtypes of the disorder. Furthermore,
related to depression, disability, postural no operational criteria specific to PDD are
impairment and cognitive impairment.30,31 The available. A consensus conference should be held
degree of cognitive impairment affecting to produce operational guidelines outlining
executive function in patients with PD is specific systematic research criteria for diagnosing
associated with impaired decision making dementia in PD (i.e., akin to the NINCDS-
capacity.32 Moreover, PD is associated with long ADRDA Work Group for Alzheimers disease
term care placement in Canada.33 Independent (AD),48 and the Consensus guidelines for diagnosis
risk factors for nursing home placement among of DLB49).
patients with PD include older age, functional
impairment, cognitive impairment and NEUROPSYCHOLOGICAL DISTINCTION
In addition to affecting independence, and DEMENTIA
despite the availability of effective treatments for
PD, PD and parkinsonism are associated with Dementia in PD is commonly labeled
increased mortality.36-39 Parkinsons dementia subcortical, entailing slowing of cognitive and
confers an increased risk of mortality regardless motor skills, poor free recall of information in the
of whether the patient is living in the community40 context of relatively preserved recognition
or in a nursing home.41 Given the potential impact memory (i.e., suggesting a memory retrieval
of cognitive deficits on meaningful clinical deficit), executive dysfunction (e.g., loss of
outcomes, its early identification in PD and of cognitive flexibility) and mood disturbance (e.g.,
PDD and related conditions is important for future depression).50,51 Aphasia, apraxia, agnosia and
planning. severe amnesia are uncommon.42 This is in contrast

Table 2: Definitions of Dementia

Diagnostic MI Required Other Cognitive Functional Decline Other

Impairment Required (ADL/IADL)
DSM-III Y at least one of: impaired interferes with social Evidence of organic factor judged
abstract thinking; impaired or occupational to be etiologically related or an
judgment; aphasia, apraxia, functioning organic etiologic factor can be
or agnosia; constructional presumed if conditions other than
difficulty; personality change organic mental disorders have
been ruled out and if behavioural
change represents cognitive
impairment in a variety of areas

DSM-III-R Y (STM at least one of: impaired interferes with work or Evidence of organic factor judged
and LTM) abstract thinking; impaired usual social activities to be etiologically related or an
judgment; aphasia, apraxia, or relationships with organic etiologic factor can be
or agnosia; constructional others presumed if there is no
difficulty; personality change psychiatric disorder that could
account for the cognitive

DSM-IV Y (impaired at least one of: aphasia; cognitive deficits cause PD dementia characterized by
ability to learn agnosia; apraxia; disturbance significant impairment cognitive and motor slowing,
new info. or to of executive functioning in social or occupational executive dysfunction and
recall previously functioning and re- memory retrieval problems; not
learned info.) present a decline from better accounted for by
previous level of psychiatric disorder

ICD-9 Y impairment of memory and interferes with Cognitive impairment often

abstract thinking, the ability occupational accompanied by personality
to learn new skills, problem- and/or social change or impaired impulse
solving, and judgment performance control

ICD-10 ? disturbance of multiple N Cognitive impairment often

higher cortical functions accompanied by or preceded by
including memory, thinking, decreased emotional control,
orientation, comprehension, social behaviour or motivation;
calculations, learning no particular distinguishing
capacity, language and clinical features of PD dementia
judgment have yet been demonstrated

Cummings and N acquired deficits in at least 3 N Includes psychiatric, structural,

Benson (1992) of the following: language; metabolic and toxic etiologies
memory; visuospatial skills;
emotional; personality;
calculation; abstraction;
judgment; executive function

ADL = Activities of Daily Living

IADL = Instrumental Activities of Daily Living
LTM = Long-term Memory
MI = Memory Impairment
STM = Short Term Memory
Y = Yes; N = No

Neurology Asia December 2005

to a cortical dementia picture (e.g., AD) which Specific and unique cognitive patterns have
involves deficits in language and visuospatial been identified for PD, PDD, and DLB by
functioning and a memory pattern categorized by investigators employing comprehensive
impaired learning, and rapid forgetting (i.e., no standardized neuropsychological batteries.
benefit from recognition trials). Identification of distinct cognitive profiles
Many neuropsychological studies support this contrasting PD and PDD supports a subtype model
distinction.52,53 For example, although both AD rather than a simple progression model.65,66 There
and PD patients have impaired learning and recall, has also been a suggestion of distinct
PD patients show evidence of a primacy effect neuropsychological profiles based on etiology of
with relative sparing of recognition memory on PD (e.g., sporadic versus familial).67 In this small
word list tasks, compared to AD patients who study, patients in both groups (who did not differ
show a reduced primacy effect and poor with regard to several indicators of disease
recognition memory.54 This suggests a retrieval severity) demonstrated impaired executive
deficit in PD as opposed to a storage deficit in functioning, but only those with sporadic PD
AD, and corresponds to a subcortical (i.e., frontal- showed explicit memory recall impairment.
subcortical) pattern of memory disruption in PD
as opposed to a cortical deficit in AD (i.e., PARKINSONS DISEASE
Parkinsons disease patients without dementia
The utility of the cortical-subcortical dementia
often have impairments on standardized cognitive
distinction has been questioned as simplistic and
tests.68 Many studies are limited by low statistical
inaccurate. In PD, frontal-subcortical circuitry is
power, however, and this has led to inconsistencies
affected, implicating disruption of both systems.55
in the literature.69 Other factors contributing to
Furthermore, cortical changes occur in PD56,57
these inconsistencies include differing criteria
and in DLB58 and there is evidence of subcortical
for ruling out dementia, heterogeneous PD
in addition to cortical degeneration in AD.59,60
samples, variations in methodologies and
Moreover, damage to subcortical structures (e.g.,
thalamus and basal ganglia) can cause cortical measures utilized, differences in duration of
symptoms such as aphasia, and visuospatial illness, and varying degrees of control regarding
medication regimens. Generalities from better
difficulties have been reported in subcortical
designed studies are reviewed here.
dementias.55 If these limitations are recognized,
In PD without dementia, simple verbal
as a general scheme for differentiating clinical
attentional skills (e.g., Digit Span) are typically
cognitive deficit patterns or behavioral syndromes,
preserved.70-75 Mild impairment on visual attention
the cortical-subcortical distinction can be
span tasks has been reported by some authors76
helpful.50,61 The term frontal-subcortical has
but not others.73 Working memory is reduced,
been used increasingly to describe PD and other
notably on more complex measures with dual-
subcortical dementias while the relative
task properties.71,75,77 Learning efficiency and free
contributions of cortical and subcortical
recall is generally mildly reduced compared to
changes remain to be fully elucidated.
normal controls73,77-79 although a few studies do
not report declines.80 Recognition memory is
typically intact72,78-80 although this may be impaired
in patients who are taking anti-Parkinsonian
Some researchers classify patients as demented medication.69 Long-term (i.e., semantic) memory65
or non-demented on the basis of scores on and remote memory72 are spared. Psychomotor
psychometric rating scales or mental status slowing and increased response latencies are
examinations. Cut-off scores of less than 123 on commonly observed76,78,81 and may account for
the Mattis Dementia Rating Scale62 or less than deficits observed on tasks of higher order cognitive
24 on the Mini Mental State Examination63 have processing, which require a certain minimal speed
been used in this manner, and represent of processing.82 Some investigators have reported
performance two standard deviations below the impairments on language measures while others
normative mean. These measures do not account have not.70,83,84 A meta-analysis suggested relative
for age and education and have several sparing of verbal skills.72 Some investigators
psychometric weaknesses.64 They are more useful report specific visuospatial declines among PD
for staging progress/severity rather than for patients without dementia,70,73,85 but others do
diagnostic classification. not.78,85 These differences may, in part, relate to

primary decreases in psychomotor speed or motor choice reaction time tasks is substantially worse
control, abilities often required on visual (e.g., compared to nondemented PD patients.81
timed) tasks. Zakzanis and Freedman72 in their
meta-analysis, found visuospatial tasks to be DEMENTIA WITH LEWY BODIES
minimally affected. Impairment of executive
Lewy body disease may present as a combined
function is most consistently reported in the
cortical-subcortical picture 61,91 that includes
literature and is often the earliest detectable area
deficits in memory, visuospatial function,
of cognitive decline. This includes performance
language, executive function, attention and
on problem-solving tasks, such as the Wisconsin
psychomotor speed. The neuropsychological DLB
Card Sorting Test and the Odd-Man-Out task,
literature is marked by small sample sizes and
that require concept formation, spontaneous
variability in terms of how DLB is defined (e.g.,
generation of efficient strategies, set-shifting and
neuropathological evidence of DLB+AD (i.e.,
the use of feedback to modify response
Lewy body variant of AD), neuropathologically
pure DLB (i.e., without AD), use of DLB clinical
criteria only). Visuospatial/visuoconstructional
performance (e.g., Block Design, copy tasks,
The dementia of PD may exhibit a frontal- shape detection, fragmented letter tasks, etc.) is
subcortical pattern with deficits in problem- disproportionally and more severely impaired
solving, speed of processing, learning efficiency, than typically observed among AD patients.91-100
and recall (with relative sparing of recognition On the clock drawing/ copying task, patients with
memory). 51 Compared to nondemented PD DLB do not improve on the copy portion of the
patients, some studies report that PDD patients task, as do patients with PD and AD. 94,101
perform worse on measures of learning efficiency Psychomotor speed is reduced compared with
and long delay free word-list recall but not on AD patients.94,95,98
recognition trials.83 Others report that PDD Impairment on verbal fluency (FAS, Category)
patients perform worse on recognition trials tasks has also been consistently reported.91-94,101
compared to both PD patients and normals.87 A As well, there is consistent evidence of
recent meta-analysis suggested that PDD patients equivalently impaired semantic memory/
exhibit impairment on recognition measures knowledge accessibility in AD and LBD.91,92,95
relative to controls, and that they perform worse Hansen et al91 and Galasko et al95 reported
than non-demented PD patients.69 Many studies equivalent impairment of AD and DLB patients
of PDD patients report relative sparing of on the Boston Naming Test and Category fluency
recognition memory compared to other types of tasks, yet disproportionate impairment by the
demented patients (e.g., Alzheimers patients), DLB group on letter fluency. This is in contrast
yet significantly lower performances compared to the commonly observed AD verbal fluency
to normals.54 pattern of letter fluency > category fluency.102
Long-term semantic recall is typically spared Lambon et al93 report similar findings, noting
in PDD65,88,89 as is simple attention span.90 naming and verbal fluency impairments in DLB.
Parkinsons dementia patients show mild deficits Also, whereas the DLB group was equally
on verbal measures.72 For example, PDD patients impaired on the two tasks, this groups letter
are impaired compared to normals and PD patients fluency was significantly inferior to that of the
on letter, category and verb production (i.e., action AD group. Calderon et al92 reported equally
word fluency) tasks.83,87 In one study, PDD patients impaired naming, category fluency and letter
performed significantly worse than PD patients fluency between groups of DLB and AD patients,
on the Boston Naming Test.83 Zakzanis and and a trend toward inferior performance on letter
Freedman72 reported that category (i.e., semantic) fluency by DLB patients.
fluency, WAIS-R Performance IQ, and Purdue Patients with DLB are significantly impaired
Pegboard scores were capable of discriminating on attentional tasks including Digit Span,
PDD patients from normal controls (i.e., less than vigilance, sustained attention, divided attention,
5% overlap in test score distributions). Patients selective attention, and reaction time
with PDD are impaired on problem-solving tasks tasks. 91,92,103,104 There is a suggestion that
involving concept formation, hypothesis testing attentional deficits are more widespread and
and set-shifting.89 Psychomotor slowing is also severe than seen in AD (e.g., see Calderon et
evident in PDD and decision-making time on al92). Comparison with AD samples with regard

Neurology Asia December 2005

to Digit Span has produced inconsistent reports participate and more likely to withdraw from
(see Lambon et al93 for review). Fluctuating studies.112 Patients referred to clinics may differ
attention/cognition is characteristic of the LBD from those in population-based studies. For
syndrome.103,105,106 This can be assessed using example, movement disorder clinics might be
observational methods amenable to clinical referred younger or more complicated patients.
practice.107,108 Recent data suggest that cognitive In contrast to PDD there are no current incidence
fluctuation may also occur in PDD, blurring the studies of DLB, reflecting the difficulty in
distinction from DLB.109 separating the onsets of cognitive and motor
Patients with DLB may be better oriented than impairment, and its more recent definition.
AD patients.98,110 More severe memory loss than
normally seen in PD is common, including RISK FACTORS FOR PDD (TABLE 3)
impairments on recognition memory tasks.92,93,98
A case control study of risk factors for PDD
Episodic memory impairment is generally less
identified education (less than high school), motor
severe than in AD92,94,98,100,110 although a few
authors report memory impairment equal to that severity and an older age of onset as predictors.113
seen in AD.91,95 The finding of equally severe Incidence studies have identified similar factors.
Older age, worse motor function, and axial motor
memory impairment in LBD and AD groups by
impairment are associated with dementia.24-26
Hansen et al91 and Galasko et al95 may be related
While global cognitive impairment is associated
to the fact that their Lewy body groups showed
with dementia risk, specific aspects of cognitive
mixed neuropathology (AD+LBD). In
function that have been identified include
neuropathologically pure DLB patients, Salmon
measures of verbal fluency,114 verbal memory
et al94 found significant impairments on all aspects
and executive function.115 One study showed
of a verbal learning and recall task (i.e., California
impairment on the Picture Completion subtest of
Verbal Learning Test), without the typical pattern
the WAIS-R, raising the possibility that aspects
or severity of losses observed in AD. For example,
of visuospatial function may be predictive.23 A
recognition memory was not exceptionally
impaired, and their group did not show an study that examined shared risk factors between
increased propensity for intrusion errors when AD and PDD found that smoking history predicted
dementia in PD while head injury, hypertension
and diabetes were not associated with PDD.116
Dementia with Lewy bodies patients generally
Estrogen use was a protective factor in some
have difficulty in executive function compared to
matched controls (e.g., Trails B, Similarities,
card sorting tests).91,94,99,101 Because the initial
clinical presentation of DLB can be very similar Table 3: Risk factors for dementia in Parkinsons
to AD (with memory complaints and only minimal disease
extrapyramidal signs), referral to a
neuropsychologist for detailed assessment may Demographic
be useful diagnostically. Older age21,24-26
Older age at onset22,23,113
INCIDENCE STUDIES OF PDD Longer disease duration26
Male gender25
Incidence studies offer many advantages over Education25,113
cross-sectional prevalence studies including the Motor impairment
prospective identification of risk factors for Worse motor impairment21,22,24,26
disease and outcomes such as mortality (Table Axial motor impairment and bradykinesia25
3). Because of differential mortality, 39,40 Cognitive
prevalence studies do not reflect the true impact Worse global cognitive function21,26
of dementia in PD.111 Incidence rates in recent Auditory verbal learning and nonverbal reasoning22
Picture completion, Stroop interference, verbal fluency23
studies range from as low as approximately 2.1
Verbal fluency114
per 100 patient years of observation in an earlier
Executive function and verbal learning115
clinic based sample21 with a mean age of 56 years Psychiatric
to as high as 9.5 per 100 patient years in a recent Psychosis26
population-based study that had a mean age of 70 Environmental
years.26 In general, participants who are older and Smoking16,116
more cognitively impaired are less likely to Estrogen use as protective117

GENETIC RISKS AND PDD Dementia has been observed in autosomal
dominant familial PD.154,155 In a study that
The role of genetic factors in PDD is supported examined cognitive function in patients with
by the increased risk of dementia (including AD) familial PD, deficits were observed among family
in family members of patients with PDD.119,120
members,156 consistent with a study where family
The effect of polymorphisms associated with an
members of PD patients showed motor deficits.157
increased risk of AD on the risk of dementia in
PD is not clear. One recent study,121 but not the
majority,122,123 showed an association between the
Apolipoprotein E epsilon 4 (Apo E 4) allele and
increased dementia risk in PD. In another, the Hallucinations are common in PD and are included
Apo E 2 allele increased the risk of PDD.124 in the core criteria for DLB. There is debate as to
Differences between studies might reflect whether or not these constitute two separable
pathological heterogeneity in PDD; for example, disorders.158 Dementia with Lewy bodies is
PD patients with coexistent AD pathology might defined as a dementia occurring in association
have an overrepresentation of the Apo E 4 with two signs or symptoms among parkinsonism,
allele,125,126 but this has not been confirmed.127 visual hallucinations and cognitive fluctuations29
The Apo E 4 may be a shared risk factor for (see Table 4 contrasting PDD and DLB). Patients
these disorders.128,129 Dipeptidyl-carboxypeptidase may have additional manifestations including
1 was found to be associated with PD with frequent falls, syncope and additional psychiatric
coexistent AD pathology while butyrylcho- symptoms.29,159-161 Hallucinations and delusions
linesterase and estrogen receptor polymorphisms occur in PD, PDD and DLB with increasing
were not.130,131 One study found an association frequency, while depression may be equally
with PDD and estrogen receptor gene frequent in each of these disorders.162,163 By the
polymorphisms in a Japanese population. 132 original convention, dementia and parkinsonism
Mitochondrial genes have been implicated in occur within one year of each other in DLB;
both AD and PD.133 however, DLB overlaps pathologically with PD.
Cases of familial DLB have been described.134- Recent studies have specified that clinical
Studies of DLB generally show an association parkinsonism should have been present for at
with Apo E 4.137-139 Other genes associated with least two years to assure that PD patients have
AD that have been examined in relation to DLB clear onset of motor signs prior to dementia.164
include polymorphisms in the amyloid precursor Cognitive fluctuations, thought to be suggestive
protein,140 alpha2-macroglobulin,141 presenilin 1,142 of DLB, also occur in PD.109 Pathologic changes
and alpha-1 anti-chymotrypsin143 with no clear of AD, specifically amyloid plaques, may or may
association. A gene associated with peripheral not coexist with Lewy bodies that are diffusely
dopamine metabolism, CYP2D6, has been distributed throughout the neocortex.158,165 Patients
associated with DLB in some144 but not all with PD who develop early hallucinations (within
studies.145 Age-dependent changes in prevalence one year of treatment) are likely to have a
of alleles, as exemplified by the CYP2D6 allele, premorbid psychotic illness or DLB.166 One key
might affect results.146 Mitochondrial genes,147
and monoamine oxidase polymorphisms,148 have Table 4: Contrasting the classic features of
been examined with conflicting results. Parkinsons disease with dementia (PDD) with
An association between PD and the tau gene, Dementia with Lewy Bodies (DLB).
including polymorphisms associated with
progressive supranuclear palsy and corticobasal PDD DLB
degeneration, has been described in some Parkinsonism More than 1 year Less than 1 year
studies 149,150 but was not confirmed in a Motor Signs Fluctuating Milder
pathologically proven sample 151 and the
relationship between tau polymorphism and Cognition Stable Fluctuating
dementia risk has not been examined.152 Other Hallucinations Drug Related Independent of
loci may be involved in PD.153 The association drugs
between tau mutations and frontotemporal LB Pathology LB/DLB DLB
dementia, often with parkinsonism (but without
Lewy bodies) makes this an important candidate AD Pathology Yes Yes
gene for PDD. Apo E 4 risk ?Onset Association

Neurology Asia December 2005

clinical feature in DLB is the presence of dramatic atrophy.7,161 The relationship with AD may be
neuroleptic sensitivity to conventional and even related to interactions between amyloid and alpha-
some atypical neuroleptics in many patients.167 synuclein toxicity that have been observed in
The recognition of DLB has allowed more prudent model studies.180
treatment of these patients with specific atypical
neuroleptics such as clozapine or quetiapine,
agents that are also effective for psychosis in PD.
The basis of hallucinations in DLB and PD is not The dopaminergic deficit in PD has been known
known, but neurochemical heterogeneity168 or since the 1960s.181 However, additional changes
specific pathological involvement; for example, have been noted in cholinergic,182 noradrenergic183
involvement of the temporal lobe, may be and serotonergic systems.184 Cholinergic deficits,
implicated.169 It has been suggested that REM reflected in decreased frontal choline-acetyl
sleep behavior disorder may be characteristic of transferase (ChAT) have been associated with
Lewy body disorders and other synucleino- cognitive impairment and dementia in PD.185
pathies170 and that such problems may contribute Similar changes have been found in DLB patients
to hallucinations. 171 A comparison of who died with mild impairment.186 Nicotinic
extrapyramidal signs in DLB and PD, revealed changes may occur in PDD and DLB.187 Measures
more severe action tremor, axial symptoms and of serotonin turnover (5-HIAA/5-HT) relative to
rigidity in DLB.172 cholinergic function (5-HIAA/ChAT) may be
associated with hallucinations in DLB, in contrast
PATHOPHYSIOLOGIC RELATIONSHIP to decreased serotonin turnover in PD.188
BETWEEN PDD, DLB AND ALZHEIMERS Cognitive dysfunction has been related to
DISEASE diminished dopamine D1 and D3 receptor binding
in PD and PDD.185,189 An impaired ability to
Pathology compensate for loss of dopaminergic transmission
may be suggested in DLB.190 The loss of D3
Although the pathologic basis for PDD remains binding, reflecting mesolimbic dopaminergic
to be fully delineated, increasing evidence neurons, might be associated with dopamine non-
supports the notion that it is heterogeneous and responsive symptoms.191
that there may be progressive cortical
involvement.173 Coexistent cortical Alzheimer Neuroimaging
pathology may contribute to decline in PD.174
However, such changes are not present to a Deficiencies in [ 18F] fluoro-dihydroxy-
sufficient degree to warrant a diagnosis of phenylalanine by positron emssion tomography
coexistent AD in most cases.165 Cortical Lewy have been noted in PDD patients in the caudate,
bodies have been better recognized since the ventral striatum and anterior cingulate. 192
introduction of ubiquitin and alpha-synuclein Dementia with Lewy bodies can be differentiated
staining. Lewy body densities are significantly from AD and PD on the basis of decreased
associated with cognitive impairment, dopamine transporter binding using [123I]-beta-
independent of Alzheimer-type pathology.175,176 carbomethoxy-3-beta-(4-iodophenyl)-nortropane,
On the other hand many patients with PD without a pre-synaptic dopamine transporter marker: both
dementia have diffuse Lewy bodies177 and the PD and DLB show decreased transporter binding,
presence of cortical Lewy bodies does not which may be more severe in DLB, in keeping
distinguish between DLB and PDD. While with the autopsy-based neurochemical
parahippocampal Lewy bodies were readily studies.193,194
identified in one study, regardless of the Changes in blood flow may correlate with
designation DLB or PDD, DLB patients had frontal and global cognitive dysfunction in PD
more coexistent plaque pathology.58 Others have patients.195-197 Others have not been able to
found weak correlations between cortical Lewy distinguish PDD from AD using
bodies and dementia.178,179 In addition to Lewy fluorodeoxyglucose positron emission
bodies, Lewy neurites are associated with tomography.198-203 Decreases in perfusion or
dementia in both DLB and PDD, but can be glucose metabolism in PDD compared to PD
found in cases of PD without dementia. Moreover, have been shown.204,205 Compared with matched
it is evident that alpha-synuclein staining can also AD patients, PDD patients show a greater decrease
be observed in AD and multiple system in occipital glucose metabolism, with sparing of

medial temporal metabolism, 206 findings considered a standard part of the presurgical
reminiscent of DLB.207 Cholinergic binding is work-up.232 This process allows for determination
reduced in PDD as in AD.208 One study showed of whether the candidate has dementia or cognitive
that DLB, PD and AD could be distinguished by impairment, which increases risk for postoperative
the pattern blood flow measured by 99mTc cognitive decline. Specific aspects of cognition
hexamethylpropylenamineoxime SPECT: DLB may be affected by surgery.233 It is important to
showed greater hypoperfusion compared to PD, establish the persons cognitive capability to
except in the frontal and occipital regions, and understand the decision to have surgery including
frontal perfusion was lower in DLB compared to the risks involved, to provide informed consent
AD.209 In DLB more occipital hypoperfusion may and to assess their ability to remain cooperative
be evident, 210-212 and temporoparietal and alert during the procedure. Evaluation of
hypoperfusion may correlate with cognitive depression, anxiety and psychiatric disturbance
function.213 In another study, decreased blood that could interfere with surgery, or be exacerbated
flow using 99mTc hexamethylpropylena- by the surgical process, is also important.
mineoxime SPECT in LBD did not correlate with
cognitive function, but was similar to that seen in EVALUATION AND TREATMENT OF PDD
AD patients.214
Structural imaging (e.g., CT, MRI) has been Evaluation
applied to the evaluation of dementia in PD.
Guidelines for the evaluation of people with
Atrophy on MRI is associated with cognitive
dementia in the general population have been
decline in PD.215,216 Hippocampal atrophy can be
published, however it is unclear if these apply to
seen in PD with and without dementia,217 a finding
PD patients who develop dementia.13,234-236 Since
that was not replicated in another study,218 but
dementia is part of the natural history of PD, one
shown in a study of older PD patients.219 Patients
might argue that blood work and neuroimaging
with DLB similarly show medial temporal
might not be routinely necessary.237 In the
atrophy,220 but to a lesser degree than in AD. This
pattern in DLB, with sparing of medial temporal community, even though it is unusual to identify
structures compared to AD, has been confirmed completely reversible causes of dementia, it is
more common to identify factors that might
by other investigators.221-223 Atrophy in the
contribute to cognitive impairment.238 The greatest
substantia inominata has likewise been observed
benefit is expected when reversible factors are
in AD and other dementias, including PDD.224
treated and when patients have mild cognitive
Patients with DLB have a rate of brain atrophy
impairment. It would, therefore, seem prudent to
similar to that observed in AD.225 Volumetric
identify dementia and cognitive impairment as it
change of the basal ganglia or occipital lobe has
appears in PD patients and to tailor investigations
not been seen in DLB, but white matter changes
based on clinical assessment, but not to deny
may be observed.226-228
patients an evaluation that might reveal occult
Changes on MR spectroscopy in cortical N-
contributors to cognitive decline.
acetyl aspartate/creatine229 are correlated with
cognitive change, and are associated with Assessment of dementia in the patient with
dementia in PD87 - findings that offer the potential parkinsonism includes a careful history (e.g.,
focusing on the nature of the deficit, onset i.e.,
of a widely available dynamic biomarker for
gradual vs. sudden and course, etc.) and
dementia in parkinsonian syndromes. Similarly,
examination. A review of systems and medications
MR spectroscopy findings have been reported in
is important. Mental status evaluation using
DLB.230 In the future, developments in imaging
standardized instruments such as the Mini-Mental
promise to further advance the development of
State Examination may be helpful, especially if a
MRI as a biomarker in neurodegenerative disease
clear decline is documented.239 On the other hand
as well as a differential diagnostic tool.231
the Mini-Mental State Examination is not sensitive
to deficits in executive dysfunction, common in
PD.240 The development of brief instruments
sensitive to frontal dysfunction, such as the Frontal
Although a complete review of cognitive Assessment Battery and other, related
consequences of stereotactic surgery for instruments241,242 may partially fill this void.
movement disorders is beyond the scope of this Nevertheless, it remains important to assess
article, neuropsychological evaluation is various aspects of individual cognitive domains,

Neurology Asia December 2005

including memory, visuospatial function, possibility of drug withdrawal delirium, as has

language and praxis in patients with movement been observed with amantadine254,255 and the risk
disorders in whom cognitive impairment is of of inducing neuroleptic malignant syndrome.256-259
concern. Referral to a neuropsychologist may be Currently there are no approved cognition-
helpful in patients in whom cognitive dysfunction enhancing drugs for patients with PD. Depression
is of concern. can be treated with counseling and medications.
A psychiatric history addressing psychotic and Psychosis that does not reverse with medication
depressive symptoms is important, given the changes, or elimination of identifiable triggers
prevalence of psychosis and depression in PD.243 can be treated with atypical antipsychotic
Depression can be associated with impaired medications. 260 These include clozapine,
cognition.244 Assessment instruments that can be quetiapine and olanzapine. Typical neuroleptics
helpful for grading the degree of depressive predictably worsen parkinsonism.261 Clozapine is
symptoms are available. These include the Beck,245 the only agent that has been subject to a double
Hamilton,246 Geriatric247 and Cornell248 Depression blind placebo-controlled study for psychosis in
Scales. The physical examination of patients with PD,262 but must be monitored with weekly or two-
PDD should focus on the identification of potential weekly blood tests to monitor for agranulocytosis.
medical conditions that might exacerbate A placebo-controlled trial that was designed to
cognitive dysfunction, including postural compare clozapine to olanzapine263 revealed
hypotension and illnesses unrelated to PD (e.g., worsened motor function with olanzapine.
pneumonia, congestive heart failure, malignancy, Another study found that olanzapine did not
diabetes). New focal neurological signs may improve psychosis.264,265 Similar concerns apply
suggest cerebrovascular disease. One should also in DLB.266 Quetiapine is an atypical antipsychotic
reevaluate the diagnosis, looking specifically for that appears effective in open label experience,
autonomic dysfunction, gaze abnormalities, possibly with less (but not without) potential to
dysmetria, pyramidal signs, neuropathy, and gait exacerbate parkinsonism.267,268 The propensity for
ataxia. improving psychosis without extrapyramidal
Laboratory testing for occult illness includes effects may relate to the kinetics of drug binding
complete blood count, glucose, electrolytes, urea, to D2 dopamine receptors, whose blockade leads
creatinine, liver function tests, thyroid stimulating to parkinsonism.269 Blockade of serotonergic
hormone, and a vitamin B12 level. If there is an recepters (5-HT2A) or subtypes of dopaminergic
acute change, suggesting a delirium, a work-up recepters may also be relevant.
for infection should be included, along with Given the profound cholinergic deficits in PD
metabolic studies and other assessments targeted and PDD, cholinergic enhancing medications are
by the history and physical examination. A rapid under evaluation in PDD. Nevertheless there
progression, focal signs, and prominent gait remain concerns regarding the possibility of
impairment raise the concern of additional exacerbating motor symptoms.270,271 A placebo-
intracranial pathology, motivating imaging. controlled trial of rivastigmine, a cholinesterase
inhibitor, has demonstrated cognitive and
Treatment behavioral improvement in DLB.272 Open label
experience with rivastigmine has been published
Reversible causes should be treated. In particular,
for patients with PDD and has shown improvement
medications that might be contributing to
of psychotic symptoms, sleep disturbance and
cognitive dysfunction should be discontinued.
caregiver distress.273,274 Improved psychosis has
Anticholinergic medications are important to
been similarly shown with donepezil.275,276
eliminate because they are associated with
Recently, a placebo-controlled crossover study
cognitive impairment.249-253 Psychosis can improve
demonstrated significant improvement in PDD
with reduction and elimination of some
patients treated with donepezil.277 Open label
medications, particularly selegeline, amantadine
benefits in cognitive function has also been
and dopamine agonists. In some patients levodopa
reported for PDD with donepezil278 and tacrine.279
might have to be decreased. It is not as clear
Medications that directly affect the nicotinergic
whether reducing antiparkinsonian medications
system may have promise in PDD. 280-282
improve cognition, but simplification of
Modulation of other neurotransmitter systems in
medication regimens is reasonable if cognitive
treating cognitive decline has not been as
impairment is identified. Changes in medication
extensively examined.
should be undertaken with caution due to the

Competency and advance directives provide insight into the pathophysiology of
dementia in addition to predictive potential. Such
Because of the cognitive declines often noted
studies will then need to be coupled with
among PD patients, decision-making competence
pathological investigations of well-defined,
is sometimes called into question. For example,
longitudinally assessed, cohorts of patients, as
capacity to consent to medical treatment may be
has been done in AD. This approach will allow
reduced by impaired executive function. Recent
the border-zone between Lewy body disorders
research on cognitively impaired PD patients
and other age related disorders to be clarified.
reported impaired consent capacity under four
Clearly the future hope is to develop treatments
different legal standards, particularly with regard
that can accompany supportive management with
to comprehension of treatment information
the goal of preventing dementia.
(including risks and benefits) and the provision
of rational/logical reasons for a treatment choice.32
Furthermore, performance on cognitive tests
predicted performance on measures of three of We thank Sheri Foster for assistance with
the four legal competence standards. 32 preparation of the manuscript and Dr. Wendy
Neuropsychological assessment is often Johnston for helpful comments. We also thank
conducted to assist with competency assessment. the staff of the Glenrose Rehabilitation Hospital
Even if the patient is cognitively competent, and Sandra Sebzda from the University of Alberta
planning for the future is at issue in any Hospital for assistance in retrieving references.
progressive neurological condition. That is, it is Dr. Camicioli has received consulting fees or
important to plan for future health care and honoraria from Pfizer, Janssen Ortho, Glaxo-
personal affairs. It is recommended that Smith-Kline and Novartis.
individuals prepare personal directive and
enduring power of attorney documents at a time
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