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Clinical diagnostic criteria for dementia

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Article in Movement Disorders · September 2007

DOI: 10.1002/mds.21507

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Movement Disorders
Vol. 22, No. 12, 2007, pp. 1689-1707
© 2007 Movement Disorder Society

Clinical Diagnostic Criteria for Dementia Associated with

Parkinson’s Disease

Murat Emre, MD,1* Dag Aarsland, MD,2,3 Richard Brown, PhD,4 David J. Burn, MD,5
Charles Duyckaerts, MD,6 Yoshikino Mizuno, MD,7,8 Gerald Anthony Broe, MD,9,10
Jeffrey Cummings, MD,11 Dennis W. Dickson, MD,12 Serge Gauthier, MD,13 Jennifer Goldman, MD,14
Christopher Goetz, MD,14 Amos Korczyn, MD,15 Andrew Lees, MD,16 Richard Levy, MD, PhD,17
Irene Litvan, MD,18 Ian McKeith, MD,19 Warren Olanow, MD,20 Werner Poewe, MD,21
Niall Quinn, MD,22 Christina Sampaio, MD, PhD,23 Eduardo Tolosa, MD,24 and Bruno Dubois, MD25

1
Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Ístanbul Faculty of Medicine, Ístanbul
University, Ístanbul, Turkey
2
Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway
3
School of Medicine, University of Bergen, Norway
4
King’s College, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, London, United Kingdom
5
Institute for Ageing and Health, Newcastle University, Wolfson Research Centre, Newcastle upon Tyne, United Kingdom
6
Neuropathology Laboratory, La Salpetriere Hospital, Paris VI Pierre et Marie Curie University, Inserm U679, Paris, France
7
Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
8
Research Institute for Diseases of Old Ages, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
9
Ageing Research Centre, Prince of Wales Hospital, Randwick, New South Wales, Australia
10
Faculty of Medicine, Prince of Wales Medical Research Institute, University of New South Wales, Randwick,
New South Wales, Australia
11
Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
12
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA
13
Alzheimer Disease and Related Disorders Unit, McGill Center for Studies in Aging, Montreal, Quebec, Canada
14
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA
15
Department of Neurology, Tel-Aviv University, Ramat -Aviv, Israel
16
Department of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom
17
Federation de Neurologie, INSERM U.610, AP-HP, Groupe Hospitalier Pitié-Salpetriere, Paris, France
18
Movement Disorder Program, Department of Neurology, University of Louisville School of Medicine, Louisville, Kentucky, USA
19
Wolfson Research Centre, Newcastle General Hospital, Newcastle upon Tyne, United Kingdom
20
Department of Neurology and Department of Neuroscience, Mount Sinai School of Medicine, New York, USA
21
Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
22
Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Queen Square, London, United Kingdom
23
Laboratorio de Farmacologia Clinica e Terapeutica, Faculdade de Medicina de Lisboa e Instituto de Medicina Molecular,
Lisboa, Portugal
24
Parkinson’s Disease and Movement Disorders Unit, Neurology Service, Institut Clinic de Neurociences, Hospital Clinic de
Barcelona, IDIBAPS, Universitat de Barcelona, Spain
25
INSERM U610, Pavillon Claude Bernard, Hôpital de la Salpêtrière, Paris, France

This article is part of the journal’s CME program. The CME form Neurology, İstanbul Faculty of Medicine, İstanbul University, 34390
can be found on page 1837 and is available online at http://www.move- Çapa İstanbul, Turkey. E-mail: [email protected]
mentdisorders.org/education/activities.html Received 19 February 2007; Accepted 10 March 2007
*Correspondence to: Dr. Murat Emre, Professor of Neurology, Be- Published online 31 May 2007 in Wiley InterScience (www.
havioral Neurology and Movement Disorders Unit, Department of interscience.wiley.com). DOI: 10.1002/mds.21507

1689
1690 M. EMRE ET AL.

Abstract: Dementia has been increasingly more recognized to point-prevelance is close to 30%, older age and akinetic-rigid
be a common feature in patients with Parkinson’s disease (PD), form are associated with higher risk. PD-D is characterized by
especially in old age. Specific criteria for the clinical diagnosis impairment in attention, memory, executive and visuo-spatial
of dementia associated with PD (PD-D), however, have been functions, behavioral symptoms such as affective changes, hal-
lacking. A Task Force, organized by the Movement Disorder lucinations, and apathy are frequent. There are no specific
Study, was charged with the development of clinical diagnostic ancillary investigations for the diagnosis; the main pathological
criteria for PD-D. The Task Force members were assigned to correlate is Lewy body-type degeneration in cerebral cortex
sub-committees and performed a systematic review of the and limbic structures. Based on the characteristic features as-
literature, based on pre-defined selection criteria, in order to sociated with this condition, clinical diagnostic criteria for
identify the epidemiological, clinical, auxillary, and patholog- probable and possible PD-D are proposed. © 2007 Movement
ical features of PD-D. Clinical diagnostic criteria were then Disorder Society
developed based on these findings and group consensus. The Key words: Parkinson’s disease; dementia; Parkinson’s dis-
incidence of dementia in PD is increased up to six times, ease dementia; diagnosis; diagnostic criteria.

Historically, Parkinson’s disease (PD) has been con- tive and neuropsychiatric features, motor and other clin-
sidered largely as a motor disorder. It has been increas- ical features, ancillary examinations, and clinico-patho-
ingly recognized, however, that PD is frequently associ- logical correlations, based on pre-defined criteria for
ated with cognitive deficits, and that dementia eventually selection of publications to be included (Appendix). To
develops in a substantial number of patients. Currently exclude cases with Dementia with Lewy Bodies (DLB),
there are no specific and operationalized criteria to diag- those papers which used the 1-year rule with regard to
nose dementia associated with PD (PD-D). The existing the onset of dementia were grouped together and consti-
criteria in DSM IV subsume PD-D under “dementia due tuted the primary source, whereas those which did not
to other medical conditions”, and the section specifically use the 1-year rule or did not indicate if this rule was
devoted to PD-D is rather descriptive. As potential ther- applied were considered as secondary. Findings and typ-
apeutic approaches for PD-D become available and clin- ical features emerging from these reviews, described in
ical trials are underway, it is important to establish spe- detail later, were tabulated (Table 1) and used to describe
cific and operationalized diagnostic criteria for PD-D in consensus-based definitions of probable and possible
order to include homogenous groups of patients in these PD-D (Table 2).
trials. This would also help to prospectively determine
the natural history and other characteristics of this con- Relation of PD-D to DLB
dition in a more systematic way and would allow more DLB and PD-D share many pathological and clinical
accurate clinico-pathological correlation studies. features, and probably represent two clinical entities on a
The Movement Disorder Society (MDS) recruited a spectrum of Lewy body disease.1 While the time-course
Task Force to define the clinical diagnostic criteria for
of the symptoms and presenting features primarily dif-
PD-D. This article summarizes the process and conclu-
ferentiate these disorders, there are also pathological
sions of this effort.
differences such as different patterns of Lewy body dis-
METHODS tribution. Indeed, there is no rational clinical or patho-
logical basis to dictate a definite time interval between
The Task Force Composition and Procedure development of motor symptoms versus onset of demen-
The MDS Task Force comprised 23 members with tia in differentiating PD-D from DLB. Nevertheless,
different areas of expertise in the field. They were invited based on an empirical approach and to avoid diagnostic
to join the Task Force because of their interest and track confusion in clinical practice, we recommend that a
records in diverse aspects of the disease including epi- diagnosis of PD-D should be made when dementia de-
demiology, clinical aspects, ancillary methods, and pa- velops within the context of established PD, whereas a
thology, and representing various disciplines to include diagnosis of DLB is appropriate when the diagnosis of
neurology, geriatric psychiatry, neuropscyhology, and dementia precedes or coincides within 1 year of the
pathology as well as different geographical regions with development of motor symptoms. This recommendation
differing medical traditions. The group was divided into is operationally consistent with that described in the
five sub-committees, each in charge of systematically Third Report of the DLB Consortium2: “DLB should be
reviewing the literature related to epidemiology, cogni- diagnosed when dementia occurs before or concurrently

Movement Disorders, Vol. 22, No. 12, 2007

 CLINICAL DIAGNOSTIC CRITERIA FOR PD-D 1691

with parkinsonism, and PD-D should be used to describe and found that 3 to 4% of dementia cases in the general
dementia that occurs in the context of well-established population were due to PD-D. The estimated prevalence
PD. The appropriate term will depend upon the clinical of PD-D in the general population aged 65 and over was
situation and generic terms such as Lewy Body disease found to be 0.2 to 0.5%.5 In more recent studies, preva-
are often helpful. In research studies in which distinction lence rates of dementia in PD patients of 48%,6 23%,7
is made between DLB and PD-D, the 1-year rule be- and 22%8 were reported. The Rotterdam study, based on
tween the onset of dementia and parkinsonism for DLB a door-to-door survey, found a lower prevalence rate,
should be used.” though this pattern is typical of such methodology which
usually includes a larger proportion of mildly affected
EPIDEMIOLOGY cases, when compared with clinic-based studies.8
The epidemiology of PD-D has usually been studied A few studies have focused on the prevalence of
among hospital-based populations. Few door-to-door dementia in newly diagnosed PD patients. In the Sydney
studies have reported the prevalence or, in particular, study, prevalence of dementia was 16%.9 Recent popu-
incidence, of PD-D in the general population, and the lation-based studies have reported rates of 8%10 and
methodology for identifying PD-D patients has varied. 17%11 of “marked cognitive impairment” defined as a
Most studies are cross-sectional, providing an estimate of Mini-Mental State Examination score below 24.
the proportion of PD patients who are demented (point
prevalence). For several reasons, including the higher Incidence
mortality rate in PD-D versus non-demented PD sub-
In community based studies, incidence rates of 95.3,12
jects,3 more accurate information can be drawn from the
107.1,13 and 112.5,14 in 1,000 patient-years were re-
few longitudinal studies. These provide information on
ported, indicating that ⬃10% of a PD population will
the incidence of PD-D, while studies including a control
develop dementia per year. The reported relative risk for
group can also deduce the relative risk of developing
developing dementia in PD compared to non-PD subjects
dementia in PD versus non-PD subjects. In addition,
ranges from 1.7,14 to 4.7,8 5.1,6 and 5.9.12 There are
period prevalence, i.e. the proportion of demented pa-
several reasons for this variation, such as case selection
tients in a PD cohort during a specified time, by com-
procedures and the use of different estimates of risk. In
bining prevalence, incidence and mortality rates, pro-
one of the very few incidence studies of dementia in
vides important information concerning the total
general including subjects with PD (diagnosis based on
proportion of PD patients who will eventually develop
self-report), the odds ratio for dementia in PD was 3.5.15
dementia.

Point Prevalence Period (Cumulative) Prevalence

Wide variations of the proportion of PD patients with Since the mortality is higher among demented than
dementia have been reported, which is most likely due to non-demented subjects, point-prevalence is an underes-
variations in methods including the population studied, timate, and period prevalence provides more reliable
age structure, diagnostic criteria for PD, assessment of figures. Compared to an incidence cohort, a prevalence
cognition, and definition of dementia. cohort is usually older and has a higher proportion with
In a review of 27 studies representing 4,336 patients dementia.
with PD, Cummings4 found a mean prevalence of 40%. Only one study to date has prospectively followed
Although the studies were critically considered, most newly diagnosed PD patients to assess the frequency of
studies were based on patients referred to neurology dementia. After 3 and 5 years, 26 and 28% were de-
clinics and may not be representative of unselected PD mented.9 After 15 years, 48% of the evaluated patients
populations. In addition, at that time, studies did not had dementia, a further 36% evidence of mild cognitive
include the identification and exclusion of patients with impairment, and only 15% remained without evidence of
DLB. cognitive impairment.16 In an earlier study with fol-
In the first systematic review of the prevalence of low-up over 8 to 10 years, 70% of the patients showed a
dementia in PD employing strict methodological inclu- “significant deterioration of cognitive functions” and
sion and exclusion criteria, 13 studies with a total of “approximately half of these were evaluated as clinically
1,832 patients were included. Of these 575 were diag- demented.”17 In the only study providing period-preva-
nosed with dementia, yielding a prevalence of 31.5% lence rates based on a strictly epidemiological cohort,
(95% confidence interval 29.3–33.5). This review also 8-year cumulative prevalence of dementia was reported
included 24 studies focusing on dementia populations, to be 78%.18

Movement Disorders, Vol. 22, No. 12, 2007

1692 M. EMRE ET AL.

The mean duration from onset of PD to development onset of motor symptoms. This could be a methodolog-
of dementia was reported to be ⬃10 years,18,19 there are, ical bias however, since patients with early dementia
however, wide variations. Some patients develop cogni- may be excluded due to subjects not fulfilling PD
tive impairment and subsequent dementia within few criteria.
years after onset of PD, whereas others may develop The onset is insidious. In one prospective study, the
dementia 20 or more years after disease onset.20 The type mean annual decline on the MMSE during 4 years was 1
and extent of pathology may vary in patients with early point in non-demented and 2.3 points in the PD-D group,
versus late onset dementia.21 Age is a crucial factor, and the latter figure being similar to the decline observed in
dementia is infrequent in patients with young onset and patients with AD.26 A similar rate of decline was re-
who are chronologically still young at the time of assess- ported in another longitudinal study, mean decline in
ment, despite very long disease duration.22 MMSE over 2 years was 4.5, and comparable to that seen
in patients with DLB, with a mean decline of 3.9
Risk Factors points.27
Many demographic and clinical features have been
assessed as potential risk factors, with inconsistent find- Cognitive Features
ings. The most consistent risk factors in longitudinal
The majority of studies on cognitive function in pa-
studies were higher age, more severe parkinsonism, in
tients with PD have reported on non-demented patients
particular rigidity, postural instability and gait distur-
or on non-selected groups including those with dementia.
bance, and mild cognitive impairment at baseline. Age
A wide variety of cognitive impairments have been re-
and severity of motor symptoms seem to have a com-
ported, even early in the course of the disease, including
bined rather than additive effect on the risk of demen-
memory, visuospatial function, and executive func-
tia.23 Inconsistent findings have been reported for old age
tion.28 –33 Although the latter deficits are often described
at onset, male gender, education, depression, visual hal-
as dominating the cognitive profile, there is some evi-
lucinations, and other clinical features. A recent study
dence of heterogeneity, with some patients expressing an
found that age at onset does not influence the risk for
dementia after adjusting for age.20 A significant relation- amnestic profile, while others present with a predomi-
ship between drug use and risk for dementia has not been nantly dysexecutive or mixed profile.32 There is some
convincingly demonstrated. The effect of genetic dispo- indication from prospective studies that executive defi-
sition as a risk factor is discussed in “Genetic Aspects of cits may be the more important predictors of subsequent
PD-D.” decline.34,35 However, the relationship between initial
deficits and subsequent profile of dementia has not been
Conclusions From Epidemiological Studies clearly established. Therefore, this review was restricted
to studies that report explicitly on cognitive function in
The point prevelance of dementia in PD is close to
groups of PD patients with dementia. Most studies in-
30% and the incidence rate is increased 4 to 6 times as
compared to controls. The cumulative prevalence has cluded patients with mild or moderate dementia, with
been reported to range between 48 and 78% after 15 and little published evidence on the cognitive manifestations
8 years of follow-up, respectively. The main risk vari- of more severe PD-D. Unless clearly stated, the evidence
ables are higher age, more severe parkinsonism, in par- reviewed relates only to the profile of cognitive impair-
ticular rigidity, postural instability and gait disturbance, ment in mild-moderate PD-D. Comparative studies con-
and mild cognitive impairment at baseline. sidered in this review successfully matched dementia
groups on the basis of an extended mental status exam-
THE COGNITIVE AND NEUROPSYCHIATRIC ination (e.g. Dementia Rating Scale [DRS]), or clinical
PROFILE OF PATIENTS WITH PD-D rating of dementia severity.
Most of this review focuses on cognition defined in
Onset and Time Course terms of primary domains. However, some caution must
Mild cognitive impairment was found already at the be exercised, as terms such as “attention” and “executive
time of diagnosis in some patients in an incident cohort function” has been used interchangeably in different
of PD.10 There is some evidence that dementia is merely studies. Many neuropsychological tests tap a number of
a progression of this early cognitive impairment,24 while different domains, and patients may perform poorly on a
other evidence suggests a different profile in PD-D and given test for different reasons. Unfortunately, most pub-
non-demented PD patients.25 Epidemiological studies lished studies have not employed tests that permit the
suggest that dementia usually develops years after the underlying cognitive processes to be defined in detail.

Movement Disorders, Vol. 22, No. 12, 2007

 CLINICAL DIAGNOSTIC CRITERIA FOR PD-D 1693

Attention. appear to be impaired on cued recall.44,48 There is also

Assessment of attention has typically employed com- growing evidence for recognition memory deficits in
posite tasks that confound attention and vigilance with PD-D for both verbal40,46,48 and non-verbal40 material
motor speed and working memory, such as the DRS (see49 for a review). In some studies the recognition
Attention subscale. Deficits on this scale are reliably deficit in PD-D is less severe than that in AD,40,44,46
shown in PD-D, although these tend not to be distin- although comparable deficits have been reported on tests
guishable in severity from those in patients with DLB or of visual recognition memory.40 However, all of these
AD.36 –39 Differential impairments have been found in studies involved patients with predominantly mild-mod-
some studies using other measures. In one, a test involv- erate PD-D. Implicit memory has been studied in one
ing letter cancellation revealed that PD-D and DLB study considered for this review, which found no deficit
groups were not only slower than a group with AD, but in either PD-D or AD.45 On the basis of these studies it
also showed more errors.40 Another study employing a can be concluded that both verbal and visual memory are
composite index of attention also showed a greater def- impaired in PD-D, that the degree of this impairment is
icit in PD-D than AD.41 Finally, in one of the most probably less than that seen in AD, and that recognition
detailed investigations, attention was measured in terms may be less affected than recall in mild to moderate
of variability in performance over time in a series of PD-D.
reaction time tasks.42 This showed increased variability
in both PD-D and DLB groups relative to controls and Executive Function.
patients with AD. Clinically, 29% of the PD-D patients Verbal fluency has been extensively studied in PD-D.
showed evidence of attentional fluctuation compared to It accounts for the major part of the Initiation and Per-
42% of those with DLB. On the basis of these studies, it severation Scale of the DRS, where impaired perfor-
can be concluded that attention is impaired in PD-D and mance is typical in patients with PD-D.36 –39 Relative to
may fluctuate, more so than in AD.
AD, patients with PD-D may be more impaired on this
Memory. scale,36 although other studies have found no significant
Memory complaint was reported to be the presenting difference.37,38,44 In more severe dementia, patients with
problem in 67% of patients with PD-D, compared to 94% PD-D, AD, and DLB appear equally impaired.44 Several
with DLB and 100% with AD.40 On the Memory sub- other studies have used specific tests of verbal fluency,
scale of the DRS significant deficits in mild PD-D have both phonemic and semantic, with similar results. The
been reported, equivalent to DLB, but less severe than severity of the fluency deficit does not appear to differ in
matched groups of patients with AD.36 –39 However, in AD and PD-D.37,43,44
more severe dementia the severity appears to match that Concept formation has been tested using the “Concep-
seen in AD.36 tualization subscale” of the DRS, “Similarities subtest”
Studies using more detailed and comprehensive as- of the Wechsler Adult Intelligence Scale (WAIS),
sessments of memory function have produced variable Raven’s Progressive Matrices (RPM) and Wisconsin
results. Short-term memory has received little attention, Card Sorting Test (WCST). Performance on such mea-
although digit span performance, more an attentional sures is impaired in PD-D relative to controls and/or
test, does not appear to distinguish PD-D and AD.43 non-demented patients with PD.36 – 40,43,50 Compared to
Verbal tests of list learning, paired-associate learning, patients with AD, similar performance is observed on the
and story recall all show deficits in PD-D on initial DRS subscale in most,36,39,40,42 but not in all studies.38
learning and immediate recall that do not differ from On the WCST patients with PD-D were more impaired in
those seen in AD40,43– 46 except for selected measures in terms of total errors, but not on any other index of
one study.38,47 Although delayed free recall has been performance including number of categories sorted,50
reported to be more impaired in AD than PD-D,40,44 other while greater impairment of PD-D patients on the RPM
similarly powered studies have failed to confirm this has been noted.43 There is no evidence that patients with
result.43,45,46 PD-D are generally more perseverative than patients
A common claim is that the memory deficit in PD is with AD, at least as measured by WCST.50 The results of
one of retrieval, rather than encoding and storage. Evi- these studies reveal that executive functions are impaired
dence for this comes primarily from studies in non- in patients with PD-D, probably more so than in patients
demented patients with PD who tend to show intact with AD. There is also some suggestion that the memory
recognition memory and enhanced performance when deficits in PD-D may be more closely associated with
given retrieval cues. However, patients with PD-D also executive dysfunction than those in AD.44

Movement Disorders, Vol. 22, No. 12, 2007

1694 M. EMRE ET AL.

Construction and Praxis. Language.

Typically, drawing tests are used to assess construc- Language function has received little attention in
tional ability and praxis, either copying designs or draw- PD-D, perhaps because clinically evident aphasia is rare.
ing common objects. The Clock-Drawing Test (CDT) is In one study, performance on verbal comprehension,
markedly impaired in PD-D as evidenced by the baseline naming, and repetition did not show any significant dif-
data in the large cohort recruited for a clinical trial.51 A ference between AD and PD-D patients,40 although a
deficit on the same task was identified in a smaller study more severe picture naming deficit in AD has been
that failed to distinguish the performance of patients with reported.44 In another study, patients with AD were also
PD-D, DLB, and AD,52 although there was evidence that found to have significantly more impoverished informa-
the former two groups showed more “planning” errors in tion content of spontaneous speech, more impaired word
their performance. Other studies using design copying list generation, and more severe anomia as compared to
tests all showed impairment in PD-D. These studies have
those with PD-D, and a stepwise discriminant analysis
shown either no difference in performance between
revealed that 96% of patients were correctly classified on
groups with PD-D and AD,36 –38,40,41,43 or more severe
the basis of information content of spontaneous speech
deficits in PD-D,39,53 particularly with more severe de-
(worse in AD) and speech melody (worse in PD-D).55
mentia.36 Comparisons of PD-D and DLB have revealed
either no difference42 or greater deficit in DLB.40 Verbal fluency is sometimes included in the language
Construction/drawing tasks involve significant motor domain, and in this review it is considered as a test of
control and a range of cognitive functions. The contri- executive function. Based on the little available data, it is
bution of motor dysfunction to such deficits has rarely suggested that patients with PD-D have less impairment
been examined in PD-D. This may account for at least in core language functions as compared to AD.
part of the reported performance deficit. In terms of
cognitive function, the tasks tap both visuo-perceptual The Pattern of Cognitive Impairment Across
and visuo-spatial processes, and executive processes in Domains.
terms of planning or response alternation. Little is known
about the primary source of the deficits in PD-D in Rather than considering individual domains, addi-
performing such tasks, although one study employing a tional evidence can be obtained by considering relative
qualitative assessment of the CDT suggested that PD-D performance across domains. In a study by Janvin et
and DLB patients showed more evidence of a planning al.,56 the DRS was used to define a “cortical profile”
deficit than a group with AD.52 Based on these studies, it (performance on the Memory subscale relatively worse
can be concluded that visuo-spatial construction is im- than that on the Initiation and Perseveration subscale)
paired in PD-D, probably to a greater extent than that and a “subcortical profile” with the opposite pattern of
seen in AD. relative performance. Both profiles were present in pa-
tients with mild-moderate PD-D, as well as in DLB and
Visuo-spatial Function.
AD. This may reflect the similar clinical heterogeneity
The assessment of visuo-spatial function without the reported in non-demented PD patients.57 The “cortical”
demands of fine motor control has received little atten- profile predominated in the AD group by a ratio of 2:1
tion in PD-D. One study used the Raven’s Progressive
while the opposite was seen in the groups with PD-D and
Matrices test, which involves complex visuo-perceptual/
DLB. Only PD-D and DLB patients showed a pattern of
spatial function,43 and reported the PD-D group to be
severe global impairment in memory and executive func-
more impaired than a group with AD. However, the test
tion. Another study used pairs of performance indices
also requires significant conceptual processing so that at
least part of the deficit may have been due to executive from a standardized neuropsychological battery.41 In this
problems. In another study, visual perception (as mea- case, a “subcortical” score was derived from tests of
sured by tests of visual discrimination, space-motion, visuo-spatial function, construction, and attention, and a
and object-form perception without needing manual re- “cortical” score from language and delayed memory. In
sponses) was globally more impaired in PD-D than in the PD-D group, the mean subcortical score was greater
non-demented controls, but was not different from DLB. than the cortical score, with the opposite pattern for the
Compared to AD, PD-D patients tended to perform AD group. Although relatively accurate at distinguishing
worse in all perceptual scores.54 It is concluded that the groups, the indices also showed significant overlap
PD-D is associated with substantial visuo-perceptual im- between the groups and cannot be considered of primary
pairments similar to DLB, but different from AD. diagnostic significance.

Movement Disorders, Vol. 22, No. 12, 2007

 CLINICAL DIAGNOSTIC CRITERIA FOR PD-D 1695

Conclusions on the Profile of Cognitive Impairment PD-D and DLB contrasts with relatively low rates re-
Impaired cognitive domains in PD-D include atten- ported in mild-moderate AD (4 – 8% on NPI).67,69,70 The
tion, memory, visuo-spatial, constructional, and execu- significance of hallucinations as marker of Lewy-body
tive functions. There are some phenomenological differ- pathology has been confirmed by both retrospective and
ences between PD-D and AD, particularly in executive prospective post-mortem studies.68,71,72
functions, so that a “subcortical” or “dysexecutive” pat- The phenomonology of hallucinations in PD-D and
tern predominates in PD-D, although there are overlaps. DLB is very similar. Visual hallucinations occur twice as
These differences are most apparent in the early and frequently as auditory ones, the majority being complex,
middle stages of dementia and difficult to identify in the formed hallucinations.62,63,73 Most common are anony-
later stages. Many studies involving a wide range of tests mous people, but they may also be family members,
have failed to distinguish between patients with PD-D body parts, animals, or machines. They tend to be in
and AD with certainty. The differentiation between color, static and centrally located, and occur with similar
PD-D and DLB in terms of cognitive profile is even less frequency and severity in PD-D and DLB.62,73
evident. Many of the tests used may be insufficiently Delusions are less common than hallucinations in
sensitive to disentangle alternative mechanisms under- PD-D, although the two symptoms often coexist. While
pinning impaired performance, such as role of impaired occurring in ⬃17% of patients with PD overall,60,61 their
attention in poor memory function as opposed to primary prevalence in PD-D is 25 to 30%,63– 65 somewhat lower
deficits in memory. than rates seen in AD,64,67,70,74 and particularly in DLB
Neuropsychological assessment serves an important where rates of 57 to 78% have been reported.63,67,74
role in providing objective evidence of cognitive impair- Another study suggested that when delusions occur they
ment to support the clinical diagnosis of dementia in PD. do so with similar frequency over time and severity in
However, its role in differential diagnosis is not conclu- DLB and PD-D,73 and with similar phenomenology.
sive, at least with the standard tests typically employed in Paranoid delusions and “phantom boarder” are among
published studies. While indicative profiles can be de- the most common content in both disorders.63 Mis-iden-
scribed on the basis of sets of tests, the evidence is not tification syndromes appear to be particularly prevalent
yet sufficiently robust to use these as the sole basis of in DLB occurring in up to 40% of patients, compared to
diagnosis. 10% in AD.68 Whether mis-identification delusions are
also characteristic of PD-D is currently unclear. The
Behavioral and Neuropsychiatric Symptoms prevalence of Capgras delusions is reported to be 10% in
DLB, when compared with no cases in patients with
While formal diagnostic criteria can be applied to PD-D.63
elicit symptoms such as depression or anxiety, the ma-
jority of clinical features are identified by informant Mood Disturbance.
ratings, the most popular one in the assessment of PD-D In a community-based sample applying formal diag-
being the Neuropsychiatric Inventory (NPI).58 While nostic criteria, the rate of major depression in PD-D has
there is evidence that symptoms often occur in clusters,59 been reported as 13%, compared to 9% for non-de-
the organization of this review is based on individual mented patients, and 19% for patients with DLB.63 Both
symptoms. The review focused on those symptoms that severity of depressed mood and prevalence of major
occur in a significant proportion of PD-D patients, depression may be higher in PD-D than in AD.43 How-
namely, hallucinations, delusions, mood disturbance, and ever, dysphoric mood as assessed by the NPI occurs with
apathy. the same frequency in PD-D and AD (40 –58%),64 pos-
sibly higher than seen in patients with DLB.65,74
Hallucinations and Delusions. Anxious mood occurs at a similar frequency (30 –
Hallucinations have been reported as common in both 49%) to depressed mood; the two disturbances are fre-
population-based studies of PD (25%)60,61 and in clinic quently co-morbid,75 or occur in the same symptom
samples (40%)62 assessed by NPI, with a substantially cluster.59,65 The prevalence of anxious mood in PD-D,
higher prevalence in PD-D (45– 65%).62– 65 When found DLB, and AD appears similar to that of depressed
in non-demented patients, hallucinations are a major mood.64,68,70,74,76 Irritable mood and problems with anger
predictor of subsequent dementia,18 and nursing home and aggression, common in AD, are not prominent clin-
placement.66 In DLB, hallucinations are even more com- ical features of PD-D, while the frequency in DLB is
mon than in PD-D, with figures in the range of 60 to similar to that seen in AD.76 Irritability has a prevalence
80%.63,67,68 The high prevalence of hallucinations in of less than 10% in non-demented patients with PD,61

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1696 M. EMRE ET AL.

with only a slightly higher rate in PD-D (14%).64 and study patients with older age/high severity had a relative
tends to be infrequent even in patients who show signif- risk of incident dementia of 9.7 when compared with the
icant problems in other domains.59 younger age/low severity group.3 Tremor dominance at
Elevated mood is rare in PD-D, being reported as presentation has been associated with relative preserva-
either absent,43 or occurring in only 2% of the popula- tion of mental status in some, but not all studies.78,79
tion.64 A similar picture is reported in DLB,74 with a Other neurological features at baseline associated with
somewhat higher rate in AD, although it remains rela- increased risk of dementia include symmetric EPS, sub-
tively rare.70,74 optimal response to levodopa (L-dopa) and dystonic
dyskinesias.
Apathy. A number of studies considered putative dopaminer-
Apathy is often regarded as a hallmark feature of gic-responsive and non-responsive features and their re-
frontotemporal dementia67 and progressive supranuclear lationship with PD-D. Non-L-dopa responsive features
palsy,61 where frequencies of 80% or more have been are classically considered to be axial disturbance, includ-
reported. Similar rates are also reported in DLB,67 with ing gait, posture and balance, as well as facial masking
increasing severity with worsening dementia.77 How- and speech disturbance. These features are predictive of
ever, apathy is also a significant problem in AD, with incident dementia,18,80,81 while the “postural instability
frequencies of 50% or more,64,70,74 increasing with cog- gait disorder”(PIGD) phenotype is also over-represented
nitive deterioration.70 In PD-D, lower figures had been in prevalent PD-D.82 In a recent study, patients with
reported with a frequency of 23 to 24%,64 although a tremor-dominant subtype at baseline did not become
recent study analyzing a large sample of mild-moderate demented until they had a transition to PIGD subtype,
PD-D patients reported a higher figure (54%),65 com- and dementia did not occur among patients with persis-
pared to 17% in non-demented patients.61 tent tremor-dominant subtype.83

Conclusions on Behavioral and Neuropsychiatric Rate of Progression

Features Development of dementia may be associated with a
Neuropsychiatric symptoms are common in all types more aggressive motor disease course.78,84 Dementia at
of dementia and are of little specific differential diagnos- baseline was associated with more rapid motor decline in
tic value. Hallucinations stand out as one of the few two studies,85,86 but this remained significant in only one
features that usefully distinguish between DLB/PD-D after adjusting for other baseline factors,86 where PD-D
and AD. In general, patients with PD-D appear to have patients had 7.9 points higher annual decline in UPDRS
less frequent or less severe psychiatric symptoms than motor scores compared to those without dementia at
patients with DLB. Such differences, however, may sim- baseline.86 In the only longitudinal study, a more rapid
ply reflect disparity in the overall dementia severity. decline in UPDRS III scores was reported in PD-D than
Similar issues apply when trying to distinguish demented in PD patients over 2 years (9.7 vs. 5.1 points, respec-
and non-demented patients with PD, as all of the symp- tively).27 Although not statistically significant, the abso-
toms may occur in non-demented patients. Thus, al- lute deterioration at 2 years was greater in the PIGD than
though psychiatric symptoms may be risk factors for the tremor-dominant PD subgroup. Rate of motor decline
developing dementia, and may support the diagnosis of in the PD-D patients was independent of baseline disease
dementia, they do not appear to be useful in differenti- duration.
ating PD-D from DLB and AD in individual cases.
Falls
MOTOR, AUTONOMIC AND OTHER In an early questionnaire-based study dementia (not
FEATURES operationally defined) was not related to falling.87 A
prospective study, however, found dementia to be a risk
Motor Phenotype factor for falls in patients with PD.88 Another question-
The majority of studies identified examined motor naire study in 1,092 patients with a parkinsonian disor-
features/phenotype as risk factors for incident dementia der, examining occurrence of any fall during the previous
in a longitudinal design rather than comparing demented 2 years, found that dementia (definition unspecified) was
versus non-demented PD patients cross-sectionally. In present in 5.1% of non-fallers versus 18.8% of fallers,
general increasing age and severity of extrapyramidal giving an odds ratio of 3.24.89 In a cross-sectional clin-
signs (EPS) are important determinants of dementia, and ical study, gait and balance disorders were more common
their effects are not independent, but synergistic: in one in PD-D (93%), than non-demented PD cases (43%).90 In

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 CLINICAL DIAGNOSTIC CRITERIA FOR PD-D 1697

a retrospective clinicopathological study (73.3% of pa- there were no significant differences between DLB and
tients with documented falls), “cognitive dysfunction” as PD-D subjects.99
a late clinical feature was significantly more common in
fallers (71.7%) versus non-fallers (49.5%).91 L-dopa Responsiveness

Axial symptoms are commonly viewed as less L-dopa

Eye Movements responsive and are assumed to be caused by “non dopa-
Although quantitative electro-oculography (EOG) can minergic” lesions.100 The L-dopa responsiveness could
reveal abnormalities of ocular movements in non-de- therefore be expected to be less pronounced in PD-D
mented PD patients,92 with the exception of convergence where these symptoms predominate. However, available
deficits and age-related limitation of upgaze, the bedside cross-sectional and longitudinal studies have failed to
examination of eye movements in PD is normal. Using directly assess L-dopa response in demented versus non-
EOG to compare saccadic eye movements in patients demented patients.3,14,18,80 – 82,101–103 Those studies re-
with PD, PD-D, DLB, and AD as compared to controls, porting doses of L-dopa have produced inconsistent find-
PD patients had only minimal impairment on reflexive ings indicating either no difference102 between groups or
tasks.93 PD-D and DLB patients were similarly impaired higher doses in patients with cognitive impairment.104
on both reflexive and complex saccades, but AD patients Decreased responsiveness of PIGD symptoms to ade-
only on complex saccades. Nevertheless, there is no quate doses of L-dopa has not been established in a
evidence that bedside clinical examination of eye move- formal study, particularly after controlling for confound-
ments can distinguish between these disorders. ers like subcortical small vessel disease.105 A recent
study using 200 mg single-dose L-dopa challenges failed
Sleep Disorders to detect significant differences in mean improvement on
Circumstantial evidence suggests that REM sleep be- UPDRS motor score; although more non-demented pa-
havior disorder (RBD) may be a risk factor for dementia, tients experienced greater than 20% improvement com-
as PD patients with RBD show impairments of some pared to those with PD-D (90% vs. 65%).106 There was
logical abilities as compared to subjects without RBD,94 also no significant differences in numbers of patients
and the presence of RBD is associated with an increased judged clinically as showing a moderate to marked re-
risk of hallucinations and delusions.95 RBD is also asso- sponse to chronic L-dopa. A similar study included pa-
ciated with DLB, and is considered to be a feature tients with DLB, PD, and PD-D and failed to detect
“suggestive” of the diagnosis.2 In a consecutive series of differences in L-dopa responsiveness between PD and
93 cases with RBD, 10 of 25 patients with PD had PD-D.107 A longitudinal study found greater cognitive
dementia.96 There are, however, no longitudinal studies decline over a 3-year period in those patients with less
to confirm RBD as a risk factor for PD-D. On the other than 50% improvement of UPDRS scores after a L-dopa
hand, excessive daytime sleepiness (EDS) has been re- test performed at baseline.108 A post-mortem study sug-
ported to be a risk factor for PD-D.97 Using the Epworth gested that loss of L-dopa response is correlated with
Sleepiness Scale, 57% of PD-D, 50% of DLB, and 41% dementia via greater loss of striatal D3 receptors.109
of PD subjects were classified as having EDS, when Overall, there is insufficient evidence to allow for firm
compared with 18% of AD and 10% of controls (Boddy, conclusions on differences in the degree of L-dopa re-
personal communication). In the same study, EDS was sponsiveness between PD with and without dementia.
more frequent at baseline in PD-D patients with PIGD
phenotype than PD-D patients without. Furthermore, L-dopa-Induced Motor Complications

sleep quality was poorer in PD-D, PD, and DLB patients, While fewer dyskinesias were reported in the de-
when compared with AD and normal controls. mented PD patients in a cross-sectional study,78 a longi-
tudinal study found greater mental deterioration in those
Autonomic Features patients exhibiting dystonic L-dopa-induced dyskinesias
A higher frequency of symptomatic orthostasis was at baseline.108 These data are insufficient to infer differ-
reported in association with cognitive impairment in PD ences in the occurrence of L-dopa induced motor com-
in one study that used cluster analysis.84 A high fre- plications in PD-D versus PD.
quency of carotid sinus syndrome and orthostatic hypo-
tension has been reported in DLB as compared to pa- Neuroleptic Sensitivity
tients with AD.98 There was a reduction in heart rate While placebo-controlled studies have excluded pa-
variability in all frequency bands in PD patients both tients with PD-D, open label studies with clozapine in
with and without dementia in one study, and notably PD psychosis have included PD-D subjects and found

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1698 M. EMRE ET AL.

that the drug was similarly well tolerated in demented Brain Perfusion and Cerebral Blood Flow Assessed
and non-demented patients, sedation and hypotension by SPECT and PET
being the main side-effects.110 One study reported As compared to healthy controls, PD-D patients ex-
greater risk for low-dose quetiapine (mean dose 50 mg/ hibit brain hypoperfusion or decreased CBF in several
day) to induce motor worsening in PD-D compared to areas of association cortex, in particular in the temporal,
PD without dementia.111Severe neuroleptic sensitivity lateral parietal, precuneus, posterior cingulate, and oc-
has been reported in up to 40% of PD-D patients exposed cipital regions,121–130 whereas in non-demented patients
to neuroleptic drugs.112 there are either no changes128,129 or decreased CBF is
limited to the frontal lobes.121,123 However, extensive
cortical hypoperfusion in non-demented PD patients was
Conclusions on Motor, Autonomic, and Other
reported in two studies, including the parietal and tem-
Features poral cortices,125,127 suggesting that, although temporal-
A PIGD phenotype is more frequent in PD-D, and also parietal-occipital hypoperfusion is usually associated
constitutes a risk factor for incident dementia. Patients with PD-D, it should be used cautiously to distinguish
with PD-D have a more rapid motor decline, and falls are PD-D from non-demented patients.
more frequent. RBD and EDS occur both in demented No difference in the topographical pattern of changes
and non-demented PD patients, but may be more fre- was observed in PD-D as compared to patients with
quent in association with dementia, the presence of RBD DLB.122,123 Over a period of 1-year, reduction in brain
may be useful in differentiating PD-D from AD. The perfusion in PD-D and DLB were comparable. An in-
relative frequency of autonomic symptoms between de- crease in striatal perfusion was interpreted as a compen-
mented and non-demented patients is not known. satory mechanism in response to decreasing dopaminer-
L-dopa responsiveness and L-dopa related dyskinesias gic striatal input.131 The topographical pattern of
may differ between demented and non-demented pa- hypoperfusion in PD-D was similar to that of AD, except
tients, but cannot be relied upon for predictive or diag- that it was more pronounced in AD.129
nostic purposes. Glucose Metabolism
A greater decrease of glucose metabolism was found
ANCILLARY INVESTIGATIONS in the inferior parietal132,133 and occipital133 cortices in
PD-D as compared to PD. A globally similar pattern of
Structural Neuro-Imaging decreased cerebral glucose metabolism, affecting the
Neuroimaging studies examining structural changes in frontal, parietal and parietal association cortices, and
PD-D patients have focused on MRI-based evaluations posterior cingulate area, was observed in PD-D com-
of whole brain113–115; regions of interest were selected in pared to AD,132,134 in PD-D, a greater decrease of glu-
the gray matter113,116 –119 and white matter.120 The re- cose metabolism was observed in the occipital visual
viewed studies indicate that whole brain and regional cortex.134
structural changes are present in PD as compared to AD Studies of Neurotransmitter Abnormalities
and normal controls. Studies suggest greater whole brain
Studies of brain cholinergic transmission, using PET-
atrophy rates in PD-D and a pattern of regional temporal
scan and MP4A binding135 or measuring acetylcholines-
lobe atrophy greatest in AD, followed by PD, then nor-
terase activity,136 demonstrated a more profound cortical
mal controls. Significant differences between non-de-
cholinergic deficit in PD-D as compared to PD, although
mented PD patients and PD-D were reported bilaterally in one study, the difference was not significant.136 Con-
in the occipital lobes. There appears, however, to be an flicting results were obtained regarding the relationship
overlap of the pattern of regional atrophy in PD-D, PD, between dopaminergic loss and PD-D. Whereas Ito et
and DLB, compared to AD and normals. As a result, no al.137 demonsrated that 18F-dopa uptake in PD-D was
consistent pattern of structural changes clearly separates significantly more decreased in the ventral striatum, right
PD-D from non-demented PD or from other comparison caudate nucleus and in the anterior cingulate area as
groups. Sample sizes have not been large enough in the compared to PD, no differences in terms of dopaminergic
cited studies to allow for statistical modeling to control loss and rate of decline between PD and PD-D were
for the increased motor impairment and longer disease found in other studies.138 –139
duration often seen in PD-D compared to non-demented Loss of nigro-striatal dopaminergic terminals can be
PD subjects. visualized using markers of dopamine transporter, such

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 CLINICAL DIAGNOSTIC CRITERIA FOR PD-D 1699

as FP-CIT SPECT. Significant reductions were found in non-demented patients, so that P300 latencies cannot
FP-CIT binding in the caudate, anterior and posterior differentiate PD-D from PD. Prepulse inhibition of the
putamens in subjects with DLB compared to those with N1/P2 component of auditory evoked potentials was
AD and controls. Transporter loss in DLB was of similar significantly reduced in DLB compared to controls and
magnitude to that seen in PD, the greatest loss in all three AD; the impairment was of intermediate intensity in
areas was seen in patients with PD-D.140 Thus, this PD-D.165
method can be used to differentiate patients with DLB or
PD-D from AD patients with extrapyramidal symptoms, Conclusions on Ancillary Investigations
e.g. because of post-synaptic dysfunction such as neuro- Although there are differences between PD-D and
leptic use, but cannot differentiate from other conditions non-demented PD patients in structural and functional
associated with degeneration of nigro-striatal pathways. imaging as well as electrophysiological studies, none of
these techniques can be recommended for routine diag-
In vivo Biochemical Studies Using Proton MR nostic purposes because of lack of specificity. Similarly
Spectroscopy they do not have sufficient discriminative power to dif-
Lactate/N-acetyl aspartate ratio was found to be in- ferentiate PD-D from DLB and AD.
creased in the occipital lobes in PD, and in particular in
PD-D patients as compared to healthy controls, suggest- GENETIC ASPECTS OF PD-D
ing that the impairment of oxidative energy metabolism The effect of genetic disposition as a risk factor has
is greater in PD-D.141 Similarly, Summerfield et al.142 only been studied systematically for APOE genotypes,
found a decreased ratio of N-acetylaspartate in the oc- and the results have been conflicting. A positive corre-
cipital lobes in PD-D as compared to PD. lation of E2 or E4 alleles with PD-D was reported in
some studies,8,166,167 whereas a negative association with
Cardiac Metaiodobenzylguanidine Scintigraphy E4 was found in a number of others.168 –171 Dementia has
Metaiodobenzylguanidine (MIBG) is a specific been reported in familial forms of PD such as PARK1172–174
marker for noradrenergic transporters. Cardiac MIBG and PARK8.175 Dementia is rare in PARK2, PARK6,
uptake is significantly reduced in PD143–147 as well as in and PARK7. There is some evidence for familial aggre-
DLB,148 because of neurodegeneration of post-gangli- gation of dementia in PD176 and increased frequency of
onic sympathetic nerve fibers.149 Cardiac MIBG is useful dementia in the relatives of PD patients with dementia
for the differentiation of PD from MSA143,147,150 –152 and has been found in some,177 but not all178,179 studies.
from PSP,143 as cardiac MIBG uptake usually remains
CLINICO-PATHOLOGICAL CORRELATIONS
normal in these non-Lewy body parkinsonian disorders.
Thus, although specific studies in PD-D are lacking, Studies describing clinico-pathological correlations in
cardiac MIBG may differentiate LB-related dementias patients with PD-D can be broadly classified into three
from non-LB related types, but cannot differentiate groups: those studies suggesting a correlation of demen-
PD-D and DLB. tia with nigral and brainstem pathology, those suggesting
that limbic and cortical LB-type degeneration is the main
EEG correlate, and those suggesting co-incident Alzheimer
PD-D patients were reported to have distinctly slower type pathology as the main correlate of dementia. These
baseline EEG activity than patients without dementia.153 studies and their main findings are tabulated in Table 3.
Significant decrease in relative alpha power was also On the basis of the recent studies using ␣-synuclein
reported in PD-D compared to PD.154 A positive corre- immunohistochemistry, and assessing several potential
lation between EEG frequency and MMS scores was pathological correlates simultaneously, the main patholog-
reported.155 ical correlate of dementia in PD seems to be the LB-type
degeneration in cerebral cortex and limbic structures. AD-
Event-Related Potentials type pathology frequently co-exists, but it often does not
Prolongation of P300 latency in PD-D was reported in reach a severity to justify pathological diagnosis of AD.
several studies, with no difference between PD-D and
DLB.156 –158 Controversial results have been reported in CONCLUSIONS
P300 latency in non-demented PD patients, prolonged The prevelance of dementia in PD is close to 30%, and
latencies being found in some,159,160,161,162 but not in its incidence is increased by 4 to 6 times over the general
other studies,156,157,163,164 Thus, P300 latency is usually age-appropriate population. Main risk factors are old
prolonged in PD-D, but this may be the case also in age, severity of motor impairment, and already compro-

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1700 M. EMRE ET AL.

TABLE 1. Features of dementia associated with Parkinson’s disease

I. Core features
1. Diagnosis of Parkinson’s disease according to Queen Square Brain Bank criteria
2. A dementia syndrome with insidious onset and slow progression, developing within the context of established Parkinson’s
disease and diagnosed by history, clinical, and mental examination, defined as:
• Impairment in more than one cognitive domain
• Representing a decline from premorbid level
• Deficits severe enough to impair daily life (social, occupational, or personal care), independent of the impairment ascribable
to motor or autonomic symptoms
II. Associated clinical features
1. Cognitive features:
• Attention: Impaired. Impairment in spontaneous and focused attention, poor performance in attentional tasks; performance
may fluctuate during the day and from day to day
• Executive functions: Impaired. Impairment in tasks requiring initiation, planning, concept formation, rule finding, set shifting
or set maintenance; impaired mental speed (bradyphrenia)
• Visuo-spatial functions: Impaired. Impairment in tasks requiring visual-spatial orientation, perception, or construction
• Memory: Impaired. Impairment in free recall of recent events or in tasks requiring learning new material, memory usually
improves with cueing, recognition is usually better than free recall
• Language: Core functions largely preserved. Word finding difficulties and impaired comprehension of complex sentences
may be present
2. Behavioral features:
• Apathy: decreased spontaneity; loss of motivation, interest, and effortful behavior
• Changes in personality and mood including depressive features and anxiety
• Hallucinations: mostly visual, usually complex, formed visions of people, animals or objects
• Delusions: usually paranoid, such as infidelity, or phantom boarder (unwelcome guests living in the home) delusions
• Excessive daytime sleepiness
III. Features which do not exclude PD-D, but make the diagnosis uncertain
• Co-existence of any other abnormality which may by itself cause cognitive impairment, but judged not to be the cause of
dementia, e.g. presence of relevant vascular disease in imaging
• Time interval between the development of motor and cognitive symptoms not known
IV. Features suggesting other conditions or diseases as cause of mental impairment, which, when present make it impossible
to reliably diagnose PD-D
• Cognitive and behavioral symptoms appearing solely in the context of other conditions such as:
Acute confusion due to
a. Systemic diseases or abnormalities
b. Drug intoxication
Major Depression according to DSM IV
• Features compatible with “Probable Vascular dementia” criteria according to NINDS-AIREN (dementia in the context of
cerebrovascular disease as indicated by focal signs in neurological exam such as hemiparesis, sensory deficits, and evidence
of relevant cerebrovascular disease by brain imaging AND a relationship between the two as indicated by the presence of
one or more of the following: onset of dementia within 3 months after a recognized stroke, abrupt deterioration in cognitive
functions, and fluctuating, stepwise progression of cognitive deficits)

TABLE 2. Criteria for the diagnosis of probable and possible PD-D

Probable PD-D
A. Core features: Both must be present
B. Associated clinical features:
• Typical profile of cognitive deficits including impairment in at least two of the four core cognitive domains (impaired
attention which may fluctuate, impaired executive functions, impairment in visuo-spatial functions, and impaired free
recall memory which usually improves with cueing)
• The presence of at least one behavioral symptom (apathy, depressed or anxious mood, hallucinations, delusions,
excessive daytime sleepiness) supports the diagnosis of Probable PD-D, lack of behavioral symptoms, however, does not
exclude the diagnosis
C. None of the group III features present
D. None of the group IV features present
Possible PD-D
A. Core features: Both must be present
B. Associated clinical features:
• Atypical profile of cognitive impairment in one or more domains, such as prominent or receptive-type (fluent) aphasia,
or pure storage-failure type amnesia (memory does not improve with cueing or in recognition tasks) with preserved
attention
• Behavioral symptoms may or may not be present
OR
C. One or more of the group III features present
D. None of the group IV features present

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 CLINICAL DIAGNOSTIC CRITERIA FOR PD-D 1701

TABLE 3. Clinico-pathological correlation studies

Routine histology for Lewy bodies

1979 Hakim and Mathieson (1979) 19/34 PD cases with dementia; ATP in 33/34 cases Dementia in PD due to ATP.
1980 Boller et al. (1980) 29 PD; 9 severe and 7 mild dementia; ATP in 9/9 Dementia in PD due to ATP.
with severe and 3/7 with mild dementia
1982 Jellinger and Grisold (1982) 100 PD; 3 types––a) PD ⫹ATP or AD; b) AD Dementia in PD due to ATP.
with normal SN; c) LB with ATP; dementia
severity correlates with ATP
1984 Gaspar and Gray (1984) 18/32 PD with dementia; SN, LC and nbM Dementia in PD is
pathology; loss and decreased ChAT correlate heterogenous, and includes
with dementia; increased ATP more in demented subcortical pathology and
ATP.
1988 Yoshimura (1988) 37/56 PD with dementia; 3 types––a) pure PD; b) Dementia in PD is
PD with ATP; c) PD with VaD heterogenous. In some cases
dementia in PD due to
subcortical pathology.
1988 Kosaka et al. (1988) 35 LBD cases; 23 with dementia Dementia in PD is
heterogenous. In some cases
dementia in PD due to ATP
and in some subcortical
pathology.
1989 Sudarsky et al. (1989) 4 PD with dementia; with SN and nbM pathology Dementia in PD due to
subcortical pathology.
1989 Rinne et al. (1989) 12 PD; dementia in PD correlated with medial SN Dementia in PD due to
neuronal loss subcortical pathology.
Ubiquitin immunohistochemistry for Lewy bodies (Kuzuhara et al., 1988)

1993 Hughes et al. (1993) 44/100 PD with dementia; 29 AD; 4 diffuse cLBs; Dementia in PD is
6 limbic LB; 6 VaD heterogenous, including
cLBs, ATP, subcortical
pathology, or VaD.
1993 Zweig et al. (1993) 13 PD with dementia without ATP; LC neuronal Dementia in PD due to
loss correlates with dementia subcortical pathology.
1993 Vermersch et al. (1993) 24 PD some with dementia; biochemical evidence Dementia in PD due to ATP.
of tau pathology in frontal cortex (relatively
more than temporal cortex)
1997 Churchyard and Lees (1997) 27 PD with dementia; MMSE correlates with Dementia due to LB (amygdala
density of Lewy neurites in hippocampus and and hippocampus).
amygdala
Alpha-synuclein immunohistochemistry for Lewy bodies (Spillantini et al., 1997)

1998 Wakabayashi et al. (1998) 12/22 PD with dementia; more APOE e4; higher Dementia due to LB (limbic
LB densities and amyloid plaques without NFT and diffuse types).
1998 Mattila et al. (1998) 44 PD; cognitive impairment correlates with cLB Dementia due to LB (especially
and NFT if concurrent AD excluded).
1998 Brown et al. (1998) 12 PD with dementia; 6/12 minimal ATP; 6/12 LB Dementia due to either ATP or
LB or both.
2000 Hurtig et al. (2000) 22 PD with dementia; LB better correlate with Dementia due to LB.
dementia than ATP
2000 Mattila et al. (2000). 45 PD some with dementia; LB in 43/45; ATP in Dementia due to LB.
18/45; APOE e4 cases had more LB; LB
correlates best with dementia
2003 Apaydin et al. (2002) 12 PD with dementia; LB (limbic and diffuse) in Dementia due to LB.
dementia; mild ATP; 2 VaD
2003 Kovari et al. (2003) 22 PD with dementia; CDR scores correlate with Dementia due to LB (limbic
LB and SP, not NFT type).
2003 Colosimo et al. (2003) 276 PD; 67/276 diffuse LB and 50 limbic LB; 11 Dementia due to LB, but some
PD with dementia; 9 PD without dementia had cases with LB are not
diffuse or limbic LB demented.
2004 Bertrand et al., (2004) 10/41 PD with dementia; dementia associated with Dementia due to LB.
hippocampal LB and cLB
2005 Braak et al. (2005) 88 PD some with dementia; MMSE correlates with Dementia due to LB, but some
ATP (NFT stage and SP); PD stage correlates cases with advanced stage are
with PD severity and dementia not demented.
2005 Parkkinen et al. (2005) 32/106 LBD had dementia or parkinsonism; LB Dementia due to factors other
also in normals than LB.

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1702 M. EMRE ET AL.

TABLE 3. (Continued)
2005 Pletnikova et al. (2005) 21 PD some with dementia; LB Dementia due to factors other
density correlates with SP; not all than LB.
PD with dementia have LB
2005 Aarsland et al. (2005) 18/22 PD with dementia; LB and Dementia due to LB.
Braak NFT stage correlate with
dementia

PD, Parkinson disease; ATP, Alzheimer type pathology; SN, substantia nigra; LB, Lewy bodies; cLB, cortical Lewy bodies; LC, locus ceruleus;
nbM, basal nucleus of Meynert; VaD, cerebrovascular disease; LBD, Lewy Body Disease; APOE, apolipoprotein E; NFT, neurofibrillary tangles; SP,
senile plaques.

mised cognitive functions at baseline assessment. The posed (Table 2). As there is no gold standard for diag-
clinical features of PD-D include insidious onset and nosis, the sensitivity and specificity of these criteria
slowly progressive course of cognitive impairments in cannot be ascertained. Because the criteria are based on
attention, executive and visuospatial functions as well as a comprehensive review of the existing literature, we
memory, with relatively preserved core language func- propose that they be adopted and tested prospectively to
tions. A dysexecutive profile predominates. Hallucina- assess their clinical utility, sensitivity, and specificity.
tions, delusions, apathy, and mood changes are fre- Such prospective studies may provide the basis for future
quently associated behavioral features (Table 1). revisions.
Dementia in PD is more commonly associated with the
PIGD motor phenotype. Imaging studies demonstrate APPENDIX: INCLUSION CRITERIA FOR
atrophy and hypometabolism, more prominent in the
PUBLICATIONS
temporal and posterior areas. However, there is no single
ancillary investigation which would help to diagnose Search Strategy: Medline search, no time limit, in addition use of
individual patients. Retrospective as well as prospective personal archives and reference list from relevant papers
Evidence Sources: As primary source: Full empirical papers pub-
clinical-pathological studies reveal that dementia in PD lished in English language journals.
best correlates with LB pathology, so that PD-D can be As secondary source: Published abstracts of scientific meetings, or
designated as a LB-associated dementia. English abstracts of non-English journal publications that (1) meet
other criteria below and (2) provide useful new information
The defining feature of PD-D is that dementia devel-
Diagnosis of PD: Study used formal established clinical diagnostic
ops in the context of established PD. Hence, diagnosis of criteria for idiopathic PD or
idiopathic PD before the development of dementia symp- Study did not use formal established criteria, but provided suffi-
toms is the essential first step in the diagnosis. Diagnosis cient details of inclusion/exclusion criteria to suggest patients had
idiopathic PD
of dementia must be based on the presence of deficits in Diagnosis of Dementia: Diagnosis made at the time of the study by
at least two of the four core cognitive domains (attention, a Neurologist, Psychiatrist, or other specialist in dementia and
memory, executive and visuo-spatial functions) as shown Study used formal criteria (DSM/ICD) for dementia following clin-
in clinical and cognitive examination, and be severe ical examination (not retrospective case note examination) or
Study used operational definition based on appropriate age norm-
enough to affect normal functioning. Although there are referenced cognitive impairment measured using an extended mental
some differences in the extent and profile of deficits in status examination such as Mattis Dementia Rating Scale (NB: not
individiual cognitive domains compared to patients with MMSE alone). or
Operational definition based on the presence of significant impair-
AD (more prominent memory impairment in AD, more ment (appropriately defined relative to age-related normative data) in
prominent executive dysfunction in PD-D), these may two or more separate domains of cognitive function.
vary from patient to patient and cannot be used as the Presence of a Control Group: A non-disease control group was not
sole basis of diagnosis. Neuropsychiatric and behavioral required for studies using standard neuropsychological measures with
published age-related normative data, and those used norms to establish
symptoms are frequent, but are not invariable. The pro- the presence/absence of cognitive impairment and its severity.
file of cognitive and behavioral symptoms in PD-D and An age- and education-matched, non-disease control group was
DLB are very similar. There are several suggestive fea- required for studies that used non-standard measures, or where the
measures did not have adequate age-related normative data.
tures which are found more frequently in PD patients A disease control group was not necessary. However, the presence of
with dementia, such as PIGD phenotype and RBD, but a non-neurological patient group was considered to add weight to the
they lack specificity and are hence not included in the interpretation of clinical evidence when factors such as motor impair-
diagnostic criteria. ment or mood may influence neuropsychological test performance.
Minimum Number of Subjects per Group: At least 10 subjects per
Based on the features described above, clinical diag- group.
nostic criteria for probable and possible PD-D are pro- Greater evidential weight was given to studies using larger samples.

Movement Disorders, Vol. 22, No. 12, 2007

 CLINICAL DIAGNOSTIC CRITERIA FOR PD-D 1703

Use of Accepted Scales/Test (for Neuropsychological Assess- 15. Yip AG, Brayne C, Matthews FE. MRC Cognitive Function and
ment): Studies using standard version of published neuropsychological Ageing Study. Risk factors for incident dementia in England and
tests or established behavioral scales or Wales: the Medical Research Council Cognitive Function and
Studies which used non-standard versions of published tests/scales, Ageing Study. A population-based nested case-control study. Age
or novel non-published tests, provided sufficient detail was given to Ageing 2006;35:154-160.
allow an evaluation of the nature of the tests and any deficit identified 16. Hely MA, Morris JG, Reid WG, Trafficante R. Sydney Multi-
and center Study of Parkinson’s disease: non-L-dopa-responsive prob-
Tests were appropriate for the population and tests were interpreted lems dominate at 15 years. Mov Disord 2005;20:190-199.
appropriately (e.g., inferences about cognitive impairment were not 17. Portin R, Rinne UK. Predictive factors for cognitive deterioration
made on the basis of completion-time alone without appropriate and dementia in Parkinson’s disease. Adv Neurol 1986;45:413-
controls). 416.
Statistics: Details of test performance provided in the forms of 18. Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sorensen P.
tables or figures that showed both mean (or median) value, and a Prevalence and characteristics of dementia in Parkinson disease:
measure of variability (SD, SEM, IQR, 95%CI) an 8-year prospective study. Arch Neurol 2003;60:387-392.
Studies which provided details of the statistical procedures employed 19. Hughes TA, Ross HF, Musa S, et al. A 10-year study of the
to analyze the data and criteria for statistical significance (␣ ⬍ 0.05). incidence of and factors predicting dementia in Parkinson’s dis-
The nature of the analysis considered to be appropriate for the data ease. Neurology 2000;54:1596-1602.
(e.g., non-parametric tests for small samples, highly skewed distribu- 20. Aarsland D, Kvaløy JT, Andersen K, et al. The effect of age of
tions, ordinal data) onset of PD on risk of dementia. J Neurol (in press).
21. Ballard C, Ziabreva I, Perry R, et al. Differences in neuropatho-
Acknowledgments: We thank Dr. Hasmet Hanagası for his logic characteristics across the Lewy body dementia spectrum.
help with the organization of references. Neurology 2006;67:1910 –1911.
22. Schrag A, Ben-Schlomo Y, Brown R, Marsden CD, Quinn N.
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