You are on page 1of 20

Neurology Asia 2005; 10 : 79 98

Parkinsons disease with dementia and dementia


with Lewy bodies
Richard CAMICIOLI, *Nancy FISHER

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


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

Abstract
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


inaccurate.11
Parkinsons disease (PD) is the most common
neurodegenerative movement disorder, affecting
PARKINSONISM AND DEMENTIA
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 (http://www.ICDNS.org). 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

79
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
IMPACT ON QUALITY OF LIFE,
decline, as required by the DSM criteria, is often
AUTONOMY AND MORTALITY
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
hallucinations.34,35 OF CORTICAL VERSUS SUBCORTICAL
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

80
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
impairment

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
functioning

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

81
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
temporal-hippocampal).
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
PSYCHOMETRIC MEASURES IN PD, PDD
typically intact72,78-80 although this may be impaired
AND DLB
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

82
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
patterns.73,77,78,86
pure DLB (i.e., without AD), use of DLB clinical
criteria only). Visuospatial/visuoconstructional
PARKINSONS DISEASE WITH DEMENTIA
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

83
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
cued.
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
studies.117,118
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

84
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
PSYCHOSIS AND PARKINSONISM: PD,
majority,122,123 showed an association between the
PDD, DLB AND THEIR OVERLAP
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
136
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

85
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,
Neurochemistry
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
[18F]
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

86
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
IMPACT OF FUNCTIONAL NEURO-
PD.240 The development of brief instruments
SURGERY ON COGNITION
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,

87
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

88
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
ACKNOWLEDGEMENTS
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
when they are cognitively competent, as a REFERENCES
safeguard, in case cognitive difficulties progress. 1. Kis B, Schrag A, Ben-Shlomo Y, et al. Novel three-
These documents vary in nature by jurisdiction. stage ascertainment method: prevalence of PD and
Typically, however, the personal/advanced parkinsonism in South Tyrol, Italy. Neurology 2002;
directive allows for designation of an agent to 58:1820-5.
2. Chen RC, Chang SF, Su CL, et al. Prevalence,
make decisions on ones behalf should one become incidence, and mortality of PD: a door-to-door survey
mentally/cognitively incompetent. Information in Ilan county, Taiwan. Neurology 2001; 57:1679-
covered includes not only the name of the 86.
individual to whom this decision-making power 3. de Rijk MC, Launer LJ, Berger K, et al. Prevalence
is designated, but also an outline of the individuals of Parkinsons disease in Europe: a collaborative
health care wishes. The Enduring Power of study of population-based cohorts. Neurologic
Diseases in the Elderly Research Group. Neurology
Attorney also names an agent, but this document
2000; 54:S21-3.
is typically concerned only with management of 4. Mayeux R, Denaro J, Hemenegildo N, et al. A
the individuals financial affairs should they population-based investigation of Parkinsons disease
become cognitively incompetent. Declaration of with and without dementia. Relationship to age and
incompetence by two health care professionals is gender. Arch Neurol 1992; 49:492-7.
typically required for activation of these 5. Murman DL, Chen Q, Colucci PM, et al. Comparison
documents. In most states/provinces, if an of healthcare utilization and direct costs in three
degenerative dementias. Am J Geriatr Psychiatry
individual does not have a personal directive and
2002; 10:328-36.
Enduring Power of Attorney and has lost capacity, 6. Parashos SA, Maraganore DM, OBrien PC, Rocca
guardianship/trusteeship are sought (i.e., person WA. Medical services utilization and prognosis in
is no longer capable of assigning an agent for a Parkinson disease: a population-based study. Mayo
personal directive or power of attorney). Clin Proc 2002; 77:918-25.
7. Goedert M. Parkinsons disease and other alpha-
synucleinopathies. Clin Chem Lab Med 2001; 39:308-
SUMMARY
12.
Cognitive impairment is common in PD and is a 8. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for
major cause of disability. While clinical and Parkinson disease. Arch Neurol 1999; 56:33-9.
9. Hughes AJ, Daniel SE, Lees AJ. Improved accuracy
psychological risk factors are continuing to be
of clinical diagnosis of Lewy body Parkinsons
defined, it is likely that imaging and genetic disease. Neurology 2001; 57:1497-9.
predictors will soon be identified. This will 10. Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ. The

89
Neurology Asia December 2005

accuracy of diagnosis of parkinsonian syndromes in 28. Stevens T, Livingston G, Kitchen G, et al. Islington
a specialist movement disorder service. Brain 2002; study of dementia subtypes in the community. Br J
125:861-70. Psychiatry 2002; 180:270.
11. Meara J, Bhowmick BK, Hobson P. Accuracy of 29. McKeith IG, Ballard CG, Perry RH, et al. Prospective
diagnosis in patients with presumed Parkinsons validation of consensus criteria for the diagnosis of
disease. Age Ageing 1999; 28:99-102. dementia with Lewy bodies. Neurology 2000;
12. American Psychiatric Association. Diagnostic criteria 54:1050-8.
from DSM-IV-TR. Washington, DC: American 30. Marinus J, Ramaker C, van Hilten JJ, Stiggelbout
Psychiatric Association, 2000. AM. Health related quality of life in Parkinsons
13. Knopman DS, DeKosky ST, Cummings JL, et al. disease: a systematic review of disease specific
Practice parameter: diagnosis of dementia (an instruments. J Neurol Neurosurg Psychiatry 2002;
evidence-based review). Report of the Quality 72:241-8.
Standards Subcommittee of the American Academy 31. Schrag A, Jahanshahi M, Quinn N. What contributes
of Neurology. Neurology 2001; 56:1143-53. to quality of life in patients with Parkinsons disease?
14. Snow B, Wiens M, Hertzman C, Calne D. A J Neurol Neurosurg Psychiatry 2000; 69:308-12.
community survey of Parkinsons disease. CMAJ 32. Dymek MP, Atchison P, Harrell L, Marson DC.
1989; 141:418-22. Competency to consent to medical treatment in
15. Ebmeier KP, Calder SA, Crawford JR, et al. Dementia cognitively impaired patients with Parkinsons
in idiopathic Parkinsons disease: prevalence and disease. Neurology 2001; 56:17-24.
relationship with symptoms and signs of 33. Rockwood K, Stolee P, McDowell I. Factors
parkinsonism. Psychol Med 1991; 21:69-76. associated with institutionalization of older people
16. Ebmeier KP, Calder SA, Crawford JR, et al. Clinical in Canada: testing a multifactorial definition of frailty.
features predicting dementia in idiopathic Parkinsons J Am Geriatr Soc 1996; 44:578-82.
disease: a follow-up study. Neurology 1990; 40:1222- 34. Aarsland D, Larsen JP, Tandberg E, Laake K.
4. Predictors of nursing home placement in Parkinsons
17. Tison F, Dartigues JF, Auriacombe S, et al. Dementia disease: a population-based, prospective study. J Am
in Parkinsons disease: a population-based study in Geriatr Soc 2000; 48:938-42.
ambulatory and institutionalized individuals. 35. Goetz CG, Stebbins GT. Risk factors for nursing
Neurology 1995; 45:705-8. home placement in advanced Parkinsons disease.
18. Wang SJ, Fuh JL, Teng EL, et al. A door-to-door Neurology 1993; 43:2227-9.
survey of Parkinsons disease in a Chinese population 36. Morgante L, Salemi G, Meneghini F, et al. Parkinson
in Kinmen. Arch Neurol 1996; 53:66-71. disease survival: a population-based study. Arch
19. Aarsland D, Tandberg E, Larsen JP, Cummings JL. Neurol 2000; 57:507-12.
Frequency of dementia in Parkinson disease. Arch 37. Bennett DA, Beckett LA, Murray AM, et al.
Neurol 1996; 53:538-42. Prevalence of parkinsonian signs and associated
20. Bower JH, Maraganore DM, McDonnell SK, Rocca mortality in a community population of older people.
WA. Incidence and distribution of parkinsonism in N Engl J Med 1996; 334:71-6.
Olmsted County, Minnesota, 1976-1990. Neurology 38. Berger K, Breteler MM, Helmer C, et al. Prognosis
1999; 52:1214-20. with Parkinsons disease in Europe: a collaborative
21. Palazzini E, Soliveri P, Filippini G, et al. Progression study of population-based cohorts. Neurologic
of motor and cognitive impairment in Parkinsons Diseases in the Elderly Research Group. Neurology
disease. J Neurol 1995; 242:535-40. 2000; 54:S24-7.
22. Reid WGJ, Hely MA, Morris JGL, et al. A 39. Mitchell SL, Rockwood K. The association between
longitudinal study of Parkinsons disease: clinical parkinsonism, Alzheimers disease, and mortality: a
and neuropsychological correlates of dementia. J comprehensive approach. J Am Geriatr Soc 2000;
Clin Neuroscience 1996; 3:327-33. 48:422-5.
23. Mahieux F, Fenelon G, Flahault A, et al. 40. Louis ED, Marder K, Cote L, Tang M, Mayeux R.
Neuropsychological prediction of dementia in Mortality from Parkinson disease. Arch Neurol 1997;
Parkinsons disease. J Neurol Neurosurg Psychiatry 54:260-4.
1998; 64:178-83. 41. Fernandez HH, Lapane KL. Predictors of mortality
24. Hughes TA, Ross HF, Musa S, et al. A 10-year study among nursing home residents with a diagnosis of
of the incidence of and factors predicting dementia Parkinsons disease. Med Sci Monit 2002; 8:CR241-
in Parkinsons disease. Neurology 2000; 54:1596- 6.
602. 42. Cummings JL, Benson DF. Dementia: A Clinical
25. Levy G, Tang MX, Cote LJ, et al. Motor impairment Approach. Boston: Butterworth-Heinemann, 1992.
in PD: relationship to incident dementia and age. 43. U.S. Department of Health and Human Services.
Neurology 2000; 55:539-44. The international classification of diseases 9th
26. Aarsland D, Andersen K, Larsen JP, et al. Risk of Revision - Clinical Modification (ICD-9-CM). Vol.
dementia in Parkinsons disease: a community-based, 1, 1980.
prospective study. Neurology 2001; 56:730-6. 44. World Health Organization. The ICD-10
27. Rajput AH. Prevalence of dementia in Parkinsons classification of mental and behavioural disorders:
disease. In: Huber SJ, Cummings JL, (Eds). clinical descriptions and diagnostic guidelines.
Parkinsons Disease: Neurobehavioral Aspects. New Geneva: World Health Organization, 1992.
York: Oxford University Press, 1992:119-31.

90
45. American Psychiatric Association. Diagnostic and 63. Folstein MF, Folstein SE, McHugh PR. Mini-mental
statistical manual of mental disorders: DSM-III. state. A practical method for grading the cognitive
Washington, D.C.: American Psychiatric Association, state of patients for the clinician. J Psychiatr Res
1982. 1975; 12:189-98.
46. American Psychiatric Association. Diagnostic and 64. Spreen O, Strauss E. A Compendium of
statistical manual of mental disorders: DSM-III-R. Neuropsychological Tests: Administration, Norms,
Washington, DC: American Psychiatric Association, and Commentary. New York: Oxford University
1987. Press, 1998.
47. American Psychiatric Association. Diagnostic and 65. McFadden L, Mohr E, Sampson M, Mendis T, Grimes
statistical manual of mental disorders: DSM-IV. JD. A profile analysis of demented and nondemented
Washington, DC: American Psychiatric Association, Parkinsons disease patients. Adv Neurol 1996;
1994. 69:339-41.
48. McKhann G, Drachman D, Folstein M, et al. Clinical 66. Graham JM, Sagar HJ. A data-driven approach to the
diagnosis of Alzheimers disease: report of the study of heterogeneity in idiopathic Parkinsons
NINCDS-ADRDA Work Group under the auspices disease: identification of three distinct subtypes.
of Department of Health and Human Services Task Mov Disord 1999; 14:10-20.
Force on Alzheimers Disease. Neurology 1984; 67. Dujardin K, Defebvre L, Grunberg C, Becquet E,
34:939-4. Destee A. Memory and executive function in sporadic
49. McKeith IG, Galasko D, Kosaka K, et al. Consensus and familial Parkinsons disease. Brain 2001;
guidelines for the clinical and pathologic diagnosis 124:389-98.
of dementia with Lewy bodies (DLB): report of the 68. Green J, McDonald WM, Vitek JL, et al. Cognitive
consortium on DLB international workshop. impairments in advanced PD without dementia.
Neurology 1996; 47:1113-24. Neurology 2002; 59:1320-4.
50. Cummings JL, Benson DF. Subcortical dementia. 69. Whittington CJ, Podd J, Kan MM. Recognition
Review of an emerging concept. Arch Neurol 1984; memory impairment in Parkinsons disease: power
41:874-9. and meta-analyses. Neuropsychology 2000; 14:233-
51. Cummings JL. Introduction. In: Cummings JL, (Ed). 46.
Subcortical dementia. New York: Oxford, 1990:3- 70. Goldman WP, Baty JD, Buckles VD, Sahrmann S,
16. Morris JC. Cognitive and motor functioning in
52. La Rue A. Aging and neuropsychological assessment. Parkinson disease: subjects with and without
Critical issues in neuropsychology. New York: questionable dementia. Arch Neurol 1998; 55:674-
Plenum Press, 1992. 80.
53. Huber SJ, Shuttleworth EC, Paulson GW, 71. Hoppe CD, Muller UD, Werheid KD, Thone AD,
Bellchambers MJ, Clapp LE. Cortical vs subcortical von Cramon YD. Digit Ordering Test: clinical,
dementia. Neuropsychological differences. Arch psychometric, and experimental evaluation of a verbal
Neurol 1986; 43:392-4. working memory test. Clin Neuropsychol 2000;
54. Tierney MC, Nores A, Snow WG, et al. Use of the 14:38-55.
rey auditory verbal learning test in differentiating 72. Zakzanis KK, Freedman M. A neuropsychological
normal aging from Alzheimers and Parkinsons comparison of demented and nondemented patients
Dementia. Psychol Assess 1994; 6:129-34. with Parkinsons disease. Appl Neuropsychol 1999;
55. Whitehouse PJ. The concept of subcortical and 6:129-46.
cortical dementia: another look. Ann Neurol 1986; 73. Levin BE, Llabre MM, Weiner WJ. Cognitive
19:1-6. impairments associated with early Parkinsons
56. Hakim AM, Mathieson G. Dementia in Parkinson disease. Neurology 1989; 39:557-61.
disease: a neuropathologic study. Neurology 1979; 74. Huber SJ, Freidenberg DL, Shuttleworth EC, Paulson
29:1209-14. GW, Christy JA. Neuropsychological impairments
57. Alvord EC. The pathology of Parkinsonism. In: associated with severity of Parkinsons disease. J
Minckler J, (Ed). Pathology of the Nervous System. Neuropsychiatry Clin Neurosci 1989; 1:154-8.
New York: McGraw-Hill, 1968:1152-61. 75. Bublak P, Muller U, Gron G, Reuter M, von Cramon
58. Harding AJ, Halliday GM. Cortical Lewy body DY. Manipulation of working memory information
pathology in the diagnosis of dementia. Acta is impaired in Parkinsons disease and related to
Neuropathol (Berl) 2001; 102:355-63. working memory capacity. Neuropsychology 2002;
59. Mann DM, Esiri MM. The site of the earliest lesions 16:577-90.
of Alzheimers disease. N Engl J Med 1988; 318:789- 76. Peavy GM, Salmon D, Bear PI, et al. Detection of
90. mild cognitive deficits in Parkinsons disease patients
60. Bondareff W, Mountjoy CQ, Roth M, et al. Age and with the WAIS-R NI. J Int Neuropsychol Soc 2001;
histopathologic heterogeneity in Alzheimers disease. 7:535-43.
Evidence for subtypes. Arch Gen Psychiatry 1987; 77. Cooper JA, Sagar HJ, Jordan N, Harvey NS, Sullivan
44:412-7. EV. Cognitive impairment in early, untreated
61. Benke T. The neuropsychological assessment of Parkinsons disease and its relationship to motor
dementia. CNS Spectrum 2002; 7:371-5. disability. Brain 1991; 114 (Pt 5):2095-122.
62. Mattis S. Dementia Rating Scale: Professional 78. Taylor AE, Saint-Cyr JA, Lang AE. Frontal lobe
manual. Odessa, Florida: Psychological Assessment dysfunction in Parkinsons disease. The cortical focus
Resources, 1998.

91
Neurology Asia December 2005

of neostriatal outflow. Brain 1986; 109 (Pt 5):845- 95. Galasko D, Katzman R, Salmon DP, Hansen L.
83. Clinical and neuropathological findings in Lewy
79. Breen EK. Recall and recognition memory in body dementias. Brain Cogn 1996; 31:166-75.
Parkinsons disease. Cortex 1993; 29:91-102. 96. Mori E, Shimomura T, Fujimori M, et al.
80. Ivory SJ, Knight RG, Longmore BE, Caradoc-Davies Visuoperceptual impairment in dementia with Lewy
T. Verbal memory in nondemented patients with bodies. Arch Neurol 2000; 57:489-93.
idiopathic Parkinsons disease. Neuropsychologia 97. Salmon D, Galasko D. Neuropsychological aspects
1999; 37:817-28. of Lewy body dementia. In: Perry R, McKeith I,
81. Pate DS, Margolin DI. Cognitive slowing in Perry E, (Eds). Dementia with Lewy Bodies. New
Parkinsons and Alzheimers patients: distinguishing York: Cambridge, 1996:99-114.
bradyphrenia from dementia. Neurology 1994; 98. Shimomura T, Mori E, Yamashita H, et al. Cognitive
44:669-74. loss in dementia with Lewy bodies and Alzheimer
82. Grossman M, Zurif E, Lee C, et al. Information disease. Arch Neurol 1998; 55:1547-52.
processing speed and sentence comprehension in 99. Simard M, van Reekum R, Cohen T. A review of the
Parkinsons disease. Neuropsychology 2002; 16:174- cognitive and behavioral symptoms in dementia with
81. Lewy bodies. J Neuropsychiatry Clin Neurosci 2000;
83. Piatt AL, Fields JA, Paolo AM, Koller WC, Troster 12:425-50.
AI. Lexical, semantic, and action verbal fluency in 100. Walker Z, Allan RL, Shergill S, Katona CL.
Parkinsons disease with and without dementia. J Neuropsychological performance in Lewy body
Clin Exp Neuropsychol 1999; 21:435-43. dementia and Alzheimers disease. Br J Psychiatry
84. McPherson S, Cummings J. Neuropsychological 1997; 170:156-8.
aspects of Parkinsons disease and Parkinsonism. In: 101. Gnanalingham KK, Byrne EJ, Thornton A, Sambrook
Grant I, Adams K, (Eds). Neuropsychological MA, Bannister P. Motor and cognitive function in
Assessment of Neuropsychiatric Disorders, 1996:288- Lewy body dementia: comparison with Alzheimers
311. and Parkinsons diseases. J Neurol Neurosurg
85. Katsarou Z, Bostantiopoulou S, Alevriadou A, et al. Psychiatry 1997; 62:243-52.
A longitudinal study of visuospatial discrimination 102. Monsch AU, Bondi MW, Butters N, et al. A
in parkinsonian patients. Percept Mot Skills 1998; comparison of category and letter fluency in
86:171-80. Alzheimers disease and Huntingtons disease.
86. Richards M, Cote LJ, Stern Y. Executive function in Neuropsychology 1994; 8:25-30.
Parkinsons disease: set-shifting or set-maintenance? 103. Walker MP, Ayre GA, Cummings JL, et al.
J Clin Exp Neuropsychol 1993; 15:266-79. Quantifying fluctuation in dementia with Lewy
87. Summerfield C, Gomez-Anson B, Tolosa E, et al. bodies, Alzheimers disease, and vascular dementia.
Dementia in Parkinson disease: a proton magnetic Neurology 2000; 54:1616-25.
resonance spectroscopy study. Arch Neurol 2002; 104. Sahgal A, Galloway PH, McKeith IG. A comparative
59:1415-20. study of attentional deficits in senile dementias of
88. Mortimer JA, Pirozzolo FJ, Hansch EJ, Webster DD. Alzheimer and Lewy body types. Dementia 1992;
Relationship of motor symptoms to intellectual 3:350-4.
deficits in Parkinson disease. Neurology 1982; 105. Ballard C, OBrien J, Gray A, et al. Attention and
32:133-7. fluctuating attention in patients with dementia with
89. Pillon B, Dubois B, Lhermitte F, Agid Y. Lewy bodies and Alzheimer disease. Arch Neurol
Heterogeneity of cognitive impairment in progressive 2001; 58:977-82.
supranuclear palsy, Parkinsons disease, and 106. McKeith IG. Dementia with Lewy bodies: clinical
Alzheimers disease. Neurology 1986; 36:1179-85. and pathological diagnosis. Alzheimer Reports 1998;
90. Ross HF, Hughes TA, Boyd JL, et al. The evolution 1:83-7.
and profile of dementia in Parkinsons disease. Adv 107. Doubleday EK, Snowden JS, Varma AR, Neary D.
Neurol 1996; 69:343-7. Qualitative performance characteristics differentiate
91. Hansen L, Salmon D, Galasko D, et al. The Lewy dementia with Lewy bodies and Alzheimers disease.
body variant of Alzheimers disease: a clinical and J Neurol Neurosurg Psychiatry 2002; 72:602-7.
pathologic entity. Neurology 1990; 40:1-8. 108. Walker MP, Ayre GA, Cummings JL, et al. The
92. Calderon J, Perry RJ, Erzinclioglu SW, et al. Clinician Assessment of Fluctuation and the One
Perception, attention, and working memory are Day Fluctuation Assessment Scale. Two methods to
disproportionately impaired in dementia with Lewy assess fluctuating confusion in dementia. Br J
bodies compared with Alzheimers disease. J Neurol Psychiatry 2000; 177:252-6.
Neurosurg Psychiatry 2001; 70:157-64. 109. Ballard CG, Aarsland D, McKeith I, et al. Fluctuations
93. Lambon RMA, Powell J, Howard D, et al. Semantic in attention: PD dementia vs DLB with parkinsonism.
memory is impaired in both dementia with Lewy Neurology 2002; 59:1714-20.
bodies and dementia of Alzheimers type: a 110. Connor DJ, Salmon DP, Sandy TJ, et al. Cognitive
comparative neuropsychological study and literature profiles of autopsy-confirmed Lewy body variant vs
review. J Neurol Neurosurg Psychiatry 2001; 70:149- pure Alzheimer disease. Arch Neurol 1998; 55:994-
56. 1000.
94. Salmon DP, Galasko D, Hansen LA, et al. 111. Marder K, Leung D, Tang M, et al. Are demented
Neuropsychological deficits associated with diffuse patients with Parkinsons disease accurately reflected
Lewy body disease. Brain Cogn 1996; 31:148-65. in prevalence surveys? A survival analysis. Neurology

92
1991; 41:1240-3. 129. Zareparsi S, Camicioli R, Sexton G, et al. Age at
112. Levin BE, Katzen HL, Klein B, Llabre ML. Cognitive onset of Parkinson disease and apolipoprotein E
decline affects subject attrition in longitudinal genotypes. Am J Med Genet 2002; 107:156-61.
research. J Clin Exp Neuropsychol 2000; 22:580-6. 130. Mattila KM, Rinne JO, Roytta M, et al. Dipeptidyl
113. Glatt SL, Hubble JP, Lyons K, et al. Risk factors for carboxypeptidase 1 (DCP1) and butyrylcholinesterase
dementia in Parkinsons disease: effect of education. (BCHE) gene interactions with the apolipoprotein E
Neuroepidemiology 1996; 15:20-5. epsilon4 allele as risk factors in Alzheimers disease
114. Jacobs DM, Marder K, Cote LJ, et al. and in Parkinsons disease with coexisting Alzheimer
Neuropsychological characteristics of preclinical pathology. J Med Genet 2000; 37:766-70.
dementia in Parkinsons disease. Neurology 1995; 131. Mattila KM, Rinne JO, Roytta M, Laippala P,
45:1691-6. Lehtimaki T. Lack of association between an estrogen
115. Levy G, Jacobs DM, Tang MX, et al. Memory and receptor 1 gene polymorphism and Parkinsons
executive function impairment predict dementia in disease with dementia. Acta Neurol Scand 2002;
Parkinsons disease. Mov Disord 2002; 17:1221-6. 106:128-30.
116. Levy G, Tang MX, Cote LJ, et al. Do risk factors for 132. Isoe-Wada K, Maeda M, Yong J, et al. Positive
Alzheimers disease predict dementia in Parkinsons association between an estrogen receptor gene
disease? An exploratory study. Mov Disord 2002; polymorphism and Parkinsons disease with
17:250-7. dementia. Eur J Neurol 1999; 6:431-5.
117. Fernandez HH, Lapane KL. Estrogen use among 133. Egensperger R, Kosel S, Schnopp NM, Mehraein P,
nursing home residents with a diagnosis of Graeber MB. Association of the mitochondrial
Parkinsons disease. Mov Disord 2000; 15:1119-24. tRNA(A4336G) mutation with Alzheimers and
118. Marder K, Tang MX, Alfaro B, et al. Postmenopausal Parkinsons diseases. Neuropathol Appl Neurobiol
estrogen use and Parkinsons disease with and without 1997; 23:315-21.
dementia. Neurology 1998; 50:1141-3. 134. Tsuang DW, Dalan AM, Eugenio CJ, et al. Familial
119. Marder K, Tang MX, Alfaro B, et al. Risk of dementia with Lewy bodies: a clinical and
Alzheimers disease in relatives of Parkinsons neuropathological study of 2 families. Arch Neurol
disease patients with and without dementia. 2002; 59:1622-30.
Neurology 1999; 52:719-24. 135. Galvin JE, Lee SL, Perry A, et al. Familial dementia
120. Hofman A, Schulte W, Tanja TA, et al. History of with Lewy bodies: clinicopathologic analysis of two
dementia and Parkinsons disease in 1st-degree kindreds. Neurology 2002; 59:1079-82.
relatives of patients with Alzheimers disease. 136. Brett FM, Henson C, Staunton H. Familial diffuse
Neurology 1989; 39:1589-92. Lewy body disease, eye movement abnormalities,
121. Parsian A, Racette B, Goldsmith LJ, Perlmutter JS. and distribution of pathology. Arch Neurol 2002;
Parkinsons disease and apolipoprotein E: possible 59:464-7.
association with dementia but not age at onset. 137. St Clair D, Norrman J, Perry R, et al. Apolipoprotein
Genomics 2002; 79:458-61. E epsilon 4 allele frequency in patients with Lewy
122. Koller WC, Glatt SL, Hubble JP, et al. Apolipoprotein body dementia, Alzheimers disease and age-matched
E genotypes in Parkinsons disease with and without controls. Neurosci Lett 1994; 176:45-6.
dementia. Ann Neurol 1995; 37:242-5. 138. Benjamin R, Leake A, Ince PG, et al. Effects of
123. Inzelberg R, Chapman J, Treves TA, et al. apolipoprotein E genotype on cortical neuropathology
Apolipoprotein e4 in Parkinson disease and dementia: in senile dementia of the Lewy body and Alzheimers
new data and meta-analysis of published studies. disease. Neurodegeneration 1995; 4:443-8.
Alzheimer Dis Assoc Disord 1998; 12:45-8. 139. Martinoli MG, Trojanowski JQ, Schmidt ML, et al.
124. Harhangi BS, de Rijk MC, van Duijn CM, et al. Association of apolipoprotein epsilon 4 allele and
APOE and the risk of PD with or without dementia neuropathologic findings in patients with dementia.
in a population-based study. Neurology 2000; Acta Neuropathol (Berl) 1995; 90:239-43.
54:1272-6. 140. Hardy J. Lewy bodies in Alzheimers disease in
125. Wakabayashi K, Kakita A, Hayashi S, et al. which the primary lesion is a mutation in the amyloid
Apolipoprotein E epsilon 4 allele and progression of precursor protein. Neurosci Lett 1994; 180:290-1.
cortical Lewy body pathology in Parkinsons disease. 141. Singleton AB, Gibson AM, McKeith IG, et al.
Acta Neuropathol (Berl) 1998; 95:450-4. Alpha2-macroglobulin polymorphisms in
126. Mattila PM, Koskela T, Roytta M, et al. Alzheimers disease and dementia with Lewy bodies.
Apolipoprotein E epsilon4 allele frequency is Neuroreport 1999; 10:1507-10.
increased in Parkinsons disease only with co-existing 142. Singleton AB, Lamb H, Leake A, et al. No association
Alzheimer pathology. Acta Neuropathol (Berl) 1998; between a polymorphism in the presenilin 1 gene
96:417-20. and dementia with Lewy bodies. Neuroreport 1997;
127. Egensperger R, Bancher C, Kosel S, et al. The 8:3637-9.
apolipoprotein E epsilon 4 allele in Parkinsons 143. Lamb H, Christie J, Singleton AB, et al.
disease with Alzheimer lesions. Biochem Biophys Apolipoprotein E and alpha-1 antichymotrypsin
Res Commun 1996; 224:484-6. polymorphism genotyping in Alzheimers disease
128. Li YJ, Scott WK, Hedges DJ, et al. Age at onset in and in dementia with Lewy bodies. Distinctions
two common neurodegenerative diseases is between diseases. Neurology 1998; 50:388-91.
genetically controlled. Am J Hum Genet 2002; 144. Tanaka S, Chen X, Xia Y, et al. Association of
70:985-93. CYP2D microsatellite polymorphism with Lewy

93
Neurology Asia December 2005

body variant of Alzheimers disease. Neurology 1998; disease with dementia and Alzheimers disease. Int
50:1556-62. J Geriatr Psychiatry 2001; 16:184-91.
145. Atkinson A, Singleton AB, Steward A, et al. CYP2D6 163. Aarsland D, Ballard C, Larsen JP, McKeith I. A
is associated with Parkinsons disease but not with comparative study of psychiatric symptoms in
dementia with Lewy bodies or Alzheimers disease. dementia with Lewy bodies and Parkinsons disease
Pharmacogenetics 1999; 9:31-5. with and without dementia. Int J Geriatr Psychiatry
146. Payami H, Lee N, Zareparsi S, et al. Parkinsons 2001; 16:528-36.
disease, CYP2D6 polymorphism, and age. Neurology 164. Apaydin H, Ahlskog JE, Parisi JE, Boeve BF, Dickson
2001; 56:1363-70. DW. Parkinson disease neuropathology: later-
147. Chinnery PF, Taylor GA, Howell N, et al. developing dementia and loss of the levodopa
Mitochondrial DNA haplogroups and susceptibility response. Arch Neurol 2002; 59:102-12.
to AD and dementia with Lewy bodies. Neurology 165. Hurtig HI, Trojanowski JQ, Galvin J, et al. Alpha-
2000; 55:302-4. synuclein cortical Lewy bodies correlate with
148. Takehashi M, Tanaka S, Masliah E, Ueda K. dementia in Parkinsons disease. Neurology 2000;
Association of monoamine oxidase A gene 54:1916-21.
polymorphism with Alzheimers disease and Lewy 166. Goetz CG, Vogel C, Tanner CM, Stebbins GT. Early
body variant. Neurosci Lett 2002; 327:79-82. dopaminergic drug-induced hallucinations in
149. Farrer M, Skipper L, Berg M, et al. The tau H1 parkinsonian patients. Neurology 1998; 51:811-4.
haplotype is associated with Parkinsons disease in 167. McKeith IG. Dementia with Lewy bodies. Br J
the Norwegian population. Neurosci Lett 2002; Psychiatry 2002; 180:144-7.
322:83-6. 168. Perry E, Court J, Goodchild R, et al. Clinical
150. Martin ER, Scott WK, Nance MA, et al. Association neurochemistry: developments in dementia research
of single-nucleotide polymorphisms of the tau gene based on brain bank material. J Neural Transm
with late-onset Parkinson disease. JAMA 2001; 1998; 105:915-33.
286:2245-50. 169. Harding AJ, Stimson E, Henderson JM, Halliday
151. de Silva R, Hardy J, Crook J, et al. The tau locus is GM. Clinical correlates of selective pathology in the
not significantly associated with pathologically amygdala of patients with Parkinsons disease. Brain
confirmed sporadic Parkinsons disease. Neurosci 2002; 125:2431-45.
Lett 2002; 330:201-3. 170. Boeve BF, Silber MH, Ferman TJ, Lucas JA, Parisi
152. Spillantini MG, Goedert M. Tau and Parkinson JE. Association of REM sleep behavior disorder and
disease. JAMA 2001; 286:2324-6. neurodegenerative disease may reflect an underlying
153. Scott WK, Nance MA, Watts RL, et al. Complete synucleinopathy. Mov Disord 2001; 16:622-30.
genomic screen in Parkinson disease: evidence for 171. Arnulf I, Bonnet AM, Damier P, et al. Hallucinations,
multiple genes. JAMA 2001; 286:2239-44. REM sleep, and Parkinsons disease: a medical
154. Gwinn-Hardy K, Mehta ND, Farrer M, et al. hypothesis. Neurology 2000; 55:281-8.
Distinctive neuropathology revealed by alpha- 172. Aarsland D, Ballard C, McKeith I, Perry RH, Larsen
synuclein antibodies in hereditary parkinsonism and JP. Comparison of extrapyramidal signs in dementia
dementia linked to chromosome 4p. Acta Neuropathol with Lewy bodies and Parkinsons disease. J
(Berl) 2000; 99:663-72. Neuropsychiatry Clin Neurosci 2001; 13:374-9.
155. Gwinn-Hardy K. Genetics of parkinsonism. Mov 173. Braak H, Tredici KD, Rub U, et al. Staging of brain
Disord 2002; 17:645-56. pathology related to sporadic Parkinsons disease.
156. Dujardin K, Duhamel A, Becquet E, et al. Neurobiol Aging 2003; 24:197-211.
Neuropsychological abnormalities in first degree 174. Jellinger KA, Seppi K, Wenning GK, Poewe W.
relatives of patients with familial Parkinsons disease. Impact of coexistent Alzheimer pathology on the
J Neurol Neurosurg Psychiatry 1999; 67:323-8. natural history of Parkinsons disease. J Neural
157. Montgomery EB Jr, Baker KB, Lyons K, Koller Transm 2002; 109:329-39.
WC. Abnormal performance on the PD test battery 175. Mattila PM, Rinne JO, Helenius H, Dickson DW,
by asymptomatic first-degree relatives. Neurology Roytta M. Alpha-synuclein-immunoreactive cortical
1999; 52:757-62. Lewy bodies are associated with cognitive impairment
158. Richard IH, Papka M, Rubio A, Kurlan R. Parkinsons in Parkinsons disease. Acta Neuropathol (Berl) 2000;
disease and dementia with Lewy bodies: one disease 100:285-90.
or two? Mov Disord 2002; 17:1161-5. 176. Mattila PM, Roytta M, Torikka H, Dickson DW,
159. Verghese J, Crystal HA, Dickson DW, Lipton RB. Rinne JO. Cortical Lewy bodies and Alzheimer-type
Validity of clinical criteria for the diagnosis of changes in patients with Parkinsons disease. Acta
dementia with Lewy bodies. Neurology 1999; Neuropathol (Berl) 1998; 95:576-82.
53:1974-82. 177. de Vos RA, Jansen EN, Stam FC, Ravid R, Swaab
160. Hohl U, Tiraboschi P, Hansen LA, Thal LJ, Corey- DF. Lewy body disease: clinico-pathological
Bloom J. Diagnostic accuracy of dementia with correlations in 18 consecutive cases of Parkinsons
Lewy bodies. Arch Neurol 2000; 57:347-51. disease with and without dementia. Clin Neurol
161. Lopez OL, Becker JT, Kaufer DI, et al. Research Neurosurg 1995; 97:13-22.
evaluation and prospective diagnosis of dementia 178. Churchyard A, Lees AJ. The relationship between
with Lewy bodies. Arch Neurol 2002; 59:43-6. dementia and direct involvement of the hippocampus
162. Aarsland D, Cummings JL, Larsen JP. and amygdala in Parkinsons disease. Neurology
Neuropsychiatric differences between Parkinsons 1997; 49:1570-6.

94
179. Gomez-Tortosa E, Newell K, Irizarry MC, et al. 194. Ransmayrl G, Seppi K, Donnemiller E, et al. Striatal
Clinical and quantitative pathologic correlates of dopamine transporter function in dementia with Lewy
dementia with Lewy bodies. Neurology 1999; bodies and Parkinsons disease. Eur J Nucl Med
53:1284-91. 2001; 28:1523-8.
180. Masliah E, Rockenstein E, Veinbergs I, et al. Beta- 195. Jagust WJ, Reed BR, Martin EM, Eberling JL,
amyloid peptides enhance alpha-synuclein Nelson-Abbott RA. Cognitive function and regional
accumulation and neuronal deficits in a transgenic cerebral blood flow in Parkinsons disease. Brain
mouse model linking Alzheimers disease and 1992; 115 (Pt 2):521-37.
Parkinsons disease. Proc Natl Acad Sci U S A 2001; 196. Wu JC, Iacono R, Ayman M, et al. Correlation of
98:12245-50. intellectual impairment in Parkinsons disease with
181. Hornykiewicz O. Dopamine miracle: from brain FDG PET scan. Neuroreport 2000; 11:2139-44.
homogenate to dopamine replacement. Mov Disord 197. Wang SJ, Liu RS, Liu HC, et al. Technetium-99m
2002; 17:501-8. hexamethylpropylene amine oxime single photon
182. Hornykiewicz O, Kish SJ. Neurochemical basis of emission tomography of the brain in early Parkinsons
dementia in Parkinsons disease. Can J Neurol Sci disease: correlation with dementia and lateralization.
1984; 11:185-90. Eur J Nucl Med 1993; 20:339-44.
183. Chan-Palay V, Asan E. Alterations in catecholamine 198. Peppard RF, Martin WR, Carr GD, et al. Cerebral
neurons of the locus coeruleus in senile dementia of glucose metabolism in Parkinsons disease with and
the Alzheimer type and in Parkinsons disease with without dementia. Arch Neurol 1992; 49:1262-8.
and without dementia and depression. J Comp Neurol 199. Liu RS, Lin KN, Wang SJ, et al. Cognition and
1989; 287:373-92. 99Tcm-HMPAO SPECT in Parkinsons disease. Nucl
184. DAmato RJ, Zweig RM, Whitehouse PJ, et al. Med Commun 1992; 13:744-8.
Aminergic systems in Alzheimers disease and 200. Sawada H, Udaka F, Kameyama M, et al. SPECT
Parkinsons disease. Ann Neurol 1987; 22:229-36. findings in Parkinsons disease associated with
185. Mattila PM, Roytta M, Lonnberg P, et al. Choline dementia. J Neurol Neurosurg Psychiatry 1992;
acetytransferase activity and striatal dopamine 55:960-3.
receptors in Parkinsons disease in relation to 201. Spampinato U, Habert MO, Mas JL, et al. (99mTc)-
cognitive impairment. Acta Neuropathol (Berl) 2001; HM-PAO SPECT and cognitive impairment in
102:160-6. Parkinsons disease: a comparison with dementia of
186. Tiraboschi P, Hansen LA, Alford M, et al. Early and the Alzheimer type. J Neurol Neurosurg Psychiatry
widespread cholinergic losses differentiate dementia 1991; 54:787-92.
with Lewy bodies from Alzheimer disease. Arch 202. Turjanski N, Brooks DJ. PET and the investigation
Gen Psychiatry 2002; 59:946-51. of dementia in the parkinsonian patient. J Neural
187. Court JA, Piggott MA, Lloyd S, et al. Nicotine Transm Suppl 1997; 51:37-48.
binding in human striatum: elevation in schizophrenia 203. Tachibana H, Kawabata K, Tomino Y, Sugita M,
and reductions in dementia with Lewy bodies, Fukuchi M. Brain perfusion imaging in Parkinsons
Parkinsons disease and Alzheimers disease and in disease and Alzheimers disease demonstrated by
relation to neuroleptic medication. Neuroscience three-dimensional surface display with 123I-
2000; 98:79-87. iodoamphetamine. Dementia 1993; 4:334-41.
188. Perry EK, Marshall E, Thompson P, et al. 204. Antonini A, De Notaris R, Benti R, De Gaspari D,
Monoaminergic activities in Lewy body dementia: Pezzoli G. Perfusion ECD/SPECT in the
relation to hallucinosis and extrapyramidal features. characterization of cognitive deficits in Parkinsons
J Neural Transm Park Dis Dement Sect 1993; 6:167- disease. Neurol Sci 2001; 22:45-6.
77. 205. Goto I, Taniwaki T, Hosokawa S, et al. Positron
189. Joyce JN, Ryoo H, Gurevich EV, Adler C, Beach T. emission tomographic (PET) studies in dementia. J
Ventral striatal D(3) receptors and Parkinsons Neurol Sci 1993; 114:1-6.
disease. Parkinsonism Relat Disord 2001; 7:225-30. 206. Vander Borght T, Minoshima S, Giordani B, et al.
190. Piggott MA, Marshall EF, Thomas N, et al. Striatal Cerebral metabolic differences in Parkinsons and
dopaminergic markers in dementia with Lewy bodies, Alzheimers diseases matched for dementia severity.
Alzheimers and Parkinsons diseases: rostrocaudal J Nucl Med 1997; 38:797-802.
distribution. Brain 1999; 122 (Pt 8):1449-68. 207. Imamura T, Ishii K, Hirono N, et al. Occipital
191. Joyce JN, Ryoo HL, Beach TB, et al. Loss of response glucose metabolism in dementia with lewy bodies
to levodopa in Parkinsons disease and co-occurrence with and without parkinsonism: a study using positron
with dementia: role of D(3) and not D(2) receptors. emission tomography. Dement Geriatr Cogn Disord
Brain Res 2002; 955:138-52. 2001; 12:194-7.
192. Ito K, Nagano-Saito A, Kato T, et al. Striatal and 208. Kuhl DE, Minoshima S, Fessler JA, et al. In vivo
extrastriatal dysfunction in Parkinsons disease with mapping of cholinergic terminals in normal aging,
dementia: a 6-[18F]fluoro-L-dopa PET study. Brain Alzheimers disease, and Parkinsons disease. Ann
2002; 125:1358-65. Neurol 1996; 40:399-410.
193. Walker Z, Costa DC, Walker RW, et al. 209. Defebvre LJ, Leduc V, Duhamel A, et al. Technetium
Differentiation of dementia with Lewy bodies from HMPAO SPECT study in dementia with Lewy
Alzheimers disease using a dopaminergic bodies, Alzheimers disease and idiopathic
presynaptic ligand. J Neurol Neurosurg Psychiatry Parkinsons disease. J Nucl Med 1999; 40:956-62.
2002; 73:134-40. 210. Donnemiller E, Heilmann J, Wenning GK, et al.

95
Neurology Asia December 2005

Brain perfusion scintigraphy with 99mTc-HMPAO bodies, AD, and vascular dementia. Neurology 2001;
or 99mTc-ECD and 123I-beta-CIT single-photon 56:1386-8.
emission tomography in dementia of the Alzheimer- 226. Barber R, McKeith I, Ballard C, OBrien J.
type and diffuse Lewy body disease. Eur J Nucl Med Volumetric MRI study of the caudate nucleus in
1997; 24:320-5. patients with dementia with Lewy bodies,
211. Lobotesis K, Fenwick JD, Phipps A, et al. Occipital Alzheimers disease, and vascular dementia. J Neurol
hypoperfusion on SPECT in dementia with Lewy Neurosurg Psychiatry 2002; 72:406-7.
bodies but not AD. Neurology 2001; 56:643-9. 227. Middelkoop HA, van der Flier WM, Burton EJ, et al.
212. Ishii K, Yamaji S, Kitagaki H, et al. Regional cerebral Dementia with Lewy bodies and AD are not
blood flow difference between dementia with Lewy associated with occipital lobe atrophy on MRI.
bodies and AD. Neurology 1999; 53:413-6. Neurology 2001; 57:2117-20.
213. Colloby SJ, Fenwick JD, Williams ED, et al. A 228. Barber R, Scheltens P, Gholkar A, et al. White
comparison of (99m)Tc-HMPAO SPECT changes matter lesions on magnetic resonance imaging in
in dementia with Lewy bodies and Alzheimers dementia with Lewy bodies, Alzheimers disease,
disease using statistical parametric mapping. Eur J vascular dementia, and normal aging. J Neurol
Nucl Med Mol Imaging 2002; 29:615-22. Neurosurg Psychiatry 1999; 67:66-72.
214. Varma AR, Talbot PR, Snowden JS, et al. A 99mTc- 229. Hu MT, Taylor-Robinson SD, Chaudhuri KR, et al.
HMPAO single-photon emission computed Evidence for cortical dysfunction in clinically non-
tomography study of Lewy body disease. J Neurol demented patients with Parkinsons disease: a proton
1997; 244:349-59. MR spectroscopy study. J Neurol Neurosurg
215. Alegret M, Junque C, Pueyo R, et al. MRI atrophy Psychiatry 1999; 67:20-6.
parameters related to cognitive and motor impairment 230. Molina JA, Garcia-Segura JM, Benito-Leon J, et al.
in Parkinsons disease. Neurologia 2001; 16:63-9. Proton magnetic resonance spectroscopy in dementia
216. Hu MT, White SJ, Chaudhuri KR, et al. Correlating with Lewy bodies. Eur Neurol 2002; 48:158-63.
rates of cerebral atrophy in Parkinsons disease with 231. Bhattacharya K, Saadia D, Eisenkraft B, et al. Brain
measures of cognitive decline. J Neural Transm magnetic resonance imaging in multiple-system
2001; 108:571-80. atrophy and Parkinson disease: a diagnostic algorithm.
217. Laakso MP, Partanen K, Riekkinen P, et al. Arch Neurol 2002; 59:835-42.
Hippocampal volumes in Alzheimers disease, 232. Saint-Cyr JA, Trepanier LL. Neuropsychologic
Parkinsons disease with and without dementia, and assessment of patients for movement disorder surgery.
in vascular dementia: an MRI study. Neurology Mov Disord 2000; 15:771-83.
1996; 46:678-81. 233. Jahanshahi M, Ardouin CM, Brown RG, et al. The
218. Cordato NJ, Pantelis C, Halliday GM, et al. Frontal impact of deep brain stimulation on executive function
atrophy correlates with behavioural changes in in Parkinsons disease. Brain 2000; 123 (Pt 6):1142-
progressive supranuclear palsy. Brain 2002; 125:789- 54.
800. 234. Patterson C, Gauthier S, Bergman H, et al. The
219. Camicioli R, Moore M, Kinney A, et al. Parkinsons recognition, assessment and management of
disease is associated with hippocampal atrophy. Mov dementing disorders: conclusions from the Canadian
Disord 2003;18:784-90. Consensus Conference on Dementia. Can J Neurol
220. Hashimoto M, Kitagaki H, Imamura T, et al. Medial Sci 2001; 28 (Suppl 1):S3-16.
temporal and whole-brain atrophy in dementia with 235. Chertkow H, Bergman H, Schipper HM, et al.
Lewy bodies: a volumetric MRI study. Neurology Assessment of suspected dementia. Can J Neurol Sci
1998; 51:357-62. 2001; 28 (Suppl 1):S28-41.
221. Harvey GT, Hughes J, McKeith IG, et al. Magnetic 236. Hogan DB, Jennett P, Freter S, et al.
resonance imaging differences between dementia Recommendations of the Canadian Consensus
with Lewy bodies and Alzheimers disease: a pilot Conference on Dementiadissemination,
study. Psychol Med 1999; 29:181-7. implementation, and evaluation of impact. Can J
222. Barber R, Ballard C, McKeith IG, Gholkar A, OBrien Neurol Sci 2001; 28 (Suppl 1):S115-21.
JT. MRI volumetric study of dementia with Lewy 237. Shulman LM, Singer C, Levin B, Weiner WJ.
bodies: a comparison with AD and vascular dementia. Diagnostic testing for dementia in patients with
Neurology 2000; 54:1304-9. Parkinsons disease. J Am Geriatr Soc 1996; 44:214-
223. Barber R, McKeith IG, Ballard C, Gholkar A, OBrien 5.
JT. A comparison of medial and lateral temporal 238. Hejl A, Hogh P, Waldemar G. Potentially reversible
lobe atrophy in dementia with Lewy bodies and conditions in 1000 consecutive memory clinic
Alzheimers disease: magnetic resonance imaging patients. J Neurol Neurosurg Psychiatry 2002;
volumetric study. Dement Geriatr Cogn Disord 2001; 73:390-4.
12:198-205. 239. Bayles KA, Tomoeda CK, Wood JA, et al. Change
224. Hanyu H, Asano T, Sakurai H, et al. MR analysis of in cognitive function in idiopathic Parkinson disease.
the substantia innominata in normal aging, Alzheimer Arch Neurol 1996; 53:1140-6.
disease, and other types of dementia. AJNR Am J 240. Jefferson AL, Cosentino SA, Ball SK, et al. Errors
Neuroradiol 2002; 23:27-32. produced on the mini-mental state examination and
225. OBrien JT, Paling S, Barber R, et al. Progressive neuropsychological test performance in Alzheimers
brain atrophy on serial MRI in dementia with Lewy disease, ischemic vascular dementia, and Parkinsons

96
disease. J Neuropsychiatry Clin Neurosci 2002; 259. Weller M, Kornhuber J. Amantadine withdrawal and
14:311-20. neuroleptic malignant syndrome. Neurology 1993;
241. Rothlind JC, Brandt J. A brief assessment of frontal 43:2155.
and subcortical functions in dementia. J 260. Friedman JH, Fernandez HH. Atypical antipsychotics
Neuropsychiatry Clin Neurosci 1993; 5:73-7. in Parkinson-sensitive populations. J Geriatr
242. Huber SJ, Shuttleworth EC, Christy JA, Rice RR. A Psychiatry Neurol 2002; 15:156-170.
brief scale for the dementia of Parkinsons disease. J 261. Tarsy D, Baldessarini RJ, Tarazi FI. Effects of newer
Neuropsychiatry Clin Neurosci 1990; 2:183-8. antipsychotics on extrapyramidal function. CNS
243. Cubo E, Bernard B, Leurgans S, Raman R. Cognitive Drugs 2002; 16:23-45.
and motor function in patients with Parkinsons 262. The Parkinson Study Group. Low-dose clozapine for
disease with and without depression. Clin the treatment of drug-induced psychosis in
Neuropharmacol 2000; 23:331-4. Parkinsons disease. The Parkinson Study Group. N
244. Norman S, Troster AI, Fields JA, Brooks R. Effects Engl J Med 1999; 340:757-63.
of depression and Parkinsons disease on cognitive 263. Goetz CG, Blasucci LM, Leurgans S, Pappert EJ.
functioning. J Neuropsychiatry Clin Neurosci 2002; Olanzapine and clozapine: comparative effects on
14:31-6. motor function in hallucinating PD patients.
245. Beck AT, Steer RA, Brown GK. BDI-II, Beck Neurology 2000; 55:789-94.
Depression Inventory: Manual. San Antonio, Texas: 264. Ondo WG, Levy JK, Vuong KD, Hunter C, Jankovic
Psychological Corp. Harcourt Brace, 1996. J. Olanzapine treatment for dopaminergic-induced
246. Hamilton M. Development of a rating scale for hallucinations. Mov Disord 2002; 17:1031-5.
primary depressive illness. Br J Soc Clin Psychol 265. Gimenez-Roldan S, Mateo D, Navarro E, Gines
1967; 6:278-96. MM. Efficacy and safety of clozapine and olanzapine:
247. Yesavage JA. Geriatric Depression Scale. an open-label study comparing two groups of
Psychopharmacol Bull 1988; 24:709-11. Parkinsons disease patients with dopaminergic-
248. Alexopoulos GS, Abrams RC, Young RC, Shamoian induced psychosis. Parkinsonism Relat Disord 2001;
CA. Cornell Scale for Depression in Dementia. Biol 7:121-7.
Psychiatry 1988; 23:271-84. 266. Walker Z, Costa DC, Ince P, McKeith IG, Katona
249. de Smet Y, Ruberg M, Serdaru M, et al. Confusion, CL. In-vivo demonstration of dopaminergic
dementia and anticholinergics in Parkinsons disease. degeneration in dementia with Lewy bodies. Lancet
J Neurol Neurosurg Psychiatry 1982; 45:1161-4. 1999; 354:646-7.
250. Cooper JA, Sagar HJ, Doherty SM, et al. Different 267. Reddy S, Factor SA, Molho ES, Feustel PJ. The
effects of dopaminergic and anticholinergic therapies effect of quetiapine on psychosis and motor function
on cognitive and motor function in Parkinsons in parkinsonian patients with and without dementia.
disease. A follow-up study of untreated patients. Mov Disord 2002; 17:676-81.
Brain 1992; 115 (Pt 6):1701-25. 268. Fernandez HH, Trieschmann ME, Burke MA,
251. Dubois B, Pilon B, Lhermitte F, Agid Y. Cholinergic Friedman JH. Quetiapine for psychosis in Parkinsons
deficiency and frontal dysfunction in Parkinsons disease versus dementia with Lewy bodies. J Clin
disease. Ann Neurol 1990; 28:117-21. Psychiatry 2002; 63:513-5.
252. Pondal M, Del Ser T, Bermejo F. Anticholinergic 269. Seeman P. Atypical antipsychotics: mechanism of
therapy and dementia in patients with Parkinsons action. Can J Psychiatry 2002; 47:27-38.
disease. J Neurol 1996; 243:543-6. 270. Duvoisin RC. Cholinergic-anticholinergic
253. Bedard MA, Pillon B, Dubois B, et al. Acute and antagonism in parkinsonism. Arch Neurol 1967;
long-term administration of anticholinergics in 17:124-36.
Parkinsons disease: specific effects on the 271. Richard IH, Justus AW, Greig NH, Marshall F,
subcortico-frontal syndrome. Brain Cogn 1999; Kurlan R. Worsening of motor function and mood in
40:289-313. a patient with Parkinsons disease after pharmacologic
254. Miyasaki JM, Grimes D, Lang AE. Acute delirium challenge with oral rivastigmine. Clin
after withdrawal of amantadine in Parkinsons Neuropharmacol 2002; 25:296-9.
disease. Neurology 1999; 52:1720-1. 272. McKeith I, Del Ser T, Spano P, et al. Efficacy of
255. Factor SA, Molho ES, Brown DL. Acute delirium rivastigmine in dementia with Lewy bodies: a
after withdrawal of amantadine in Parkinsons randomised, double-blind, placebo-controlled
disease. Neurology 1998; 50:1456-8. international study. Lancet 2000; 356:2031-6.
256. Reimer J, Kuhlmann A, Muller T. Neuroleptic 273. Reading PJ, Luce AK, McKeith IG. Rivastigmine in
malignant-like syndrome after rapid switch from the treatment of parkinsonian psychosis and cognitive
bromocriptine to pergolide. Parkinsonism Relat impairment: preliminary findings from an open trial.
Disord 2002; 9:115-6. Mov Disord 2001; 16:1171-4.
257. Ueda M, Hamamoto M, Nagayama H, et al. 274. Bullock R, Cameron A. Rivastigmine for the
Biochemical alterations during medication treatment of dementia and visual hallucinations
withdrawal in Parkinsons disease with and without associated with Parkinsons disease: a case series.
neuroleptic malignant-like syndrome. J Neurol Curr Med Res Opin 2002; 18:258-64.
Neurosurg Psychiatry 2001; 71:111-3. 275. Fabbrini G, Barbanti P, Aurilia C, et al. Donepezil in
258. Reutens DC, Harrison WB, Goldswain PR. the treatment of hallucinations and delusions in
Neuroleptic malignant syndrome complicating Parkinsons disease. Neurol Sci 2002; 23:41-3.
levodopa withdrawal. Med J Aust 1991; 155:53-4. 276. Bergman J, Lerner V. Successful use of donepezil

97
Neurology Asia December 2005

for the treatment of psychotic symptoms in patients


with Parkinsons disease. Clin Neuropharmacol 2002;
25:107-10.
277. Aarsland D, Laake K, Larsen JP, Janvin C. Donepezil
for cognitive impairment in Parkinsons disease: a
randomised controlled study. J Neurol Neurosurg
Psychiatry 2002; 72:708-12.
278. Werber EA, Rabey JM. The beneficial effect of
cholinesterase inhibitors on patients suffering from
Parkinsons disease and dementia. J Neural Transm
2001; 108:1319-25.
279. Hutchinson M, Fazzini E. Cholinesterase inhibition
in Parkinsons disease. J Neurol Neurosurg
Psychiatry 1996; 61:324-5.
280. Kelton MC, Kahn HJ, Conrath CL, Newhouse PA.
The effects of nicotine on Parkinsons disease. Brain
Cogn 2000; 43:274-82.
281. Jann MW, Shirley KL, Small GW. Clinical
pharmacokinetics and pharmacodynamics of
cholinesterase inhibitors. Clin Pharmacokinet 2002;
41:719-39.
282. Santos MD, Alkondon M, Pereira EF, et al. The
nicotinic allosteric potentiating ligand galantamine
facilitates synaptic transmission in the mammalian
central nervous system. Mol Pharmacol 2002;
61:1222-34.

98