Expert Review of Neurotherapeutics

ISSN: 1473-7175 (Print) 1744-8360 (Online) Journal homepage: https://www.tandfonline.com/loi/iern20

Cognitive and behavioral assessment in

Parkinson’s disease

Saul Martinez-Horta, Andrea Horta-Barba & Jaime Kulisevsky

To cite this article: Saul Martinez-Horta, Andrea Horta-Barba & Jaime Kulisevsky (2019) Cognitive
and behavioral assessment in Parkinson’s disease, Expert Review of Neurotherapeutics, 19:7,
613-622, DOI: 10.1080/14737175.2019.1629290

To link to this article: https://doi.org/10.1080/14737175.2019.1629290

Accepted author version posted online: 10

Jun 2019.
Published online: 17 Jun 2019.

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EXPERT REVIEW OF NEUROTHERAPEUTICS
2019, VOL. 19, NO. 7, 613–622
https://doi.org/10.1080/14737175.2019.1629290

REVIEW

Cognitive and behavioral assessment in Parkinson’s disease

Saul Martinez-Hortaa,b,c,d, Andrea Horta-Barbaa,b,c and Jaime Kulisevskya,b,c,d
a
Movement Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; bBiomedical Research Institute (IIB-Sant
Pau), Barcelona, Spain; cCentro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; dAutonomous University of
Barcelona, Barcelona, Spain

ABSTRACT ARTICLE HISTORY

Introduction: Cognitive impairment and behavioral disturbances are common findings in Parkinson’s Received 14 March 2019
disease (PD). Despite initially being considered late complications of the disease, it is currently accepted Accepted 5 June 2019
that almost all PD patients will exhibit cognitive and behavioral abnormalities from the early and even KEYWORDS
the premotor stages of the disease. Parkinson’s disease; PD-MCI;
Areas covered: The present review focuses on the cognitive profile of PD, the clinical picture of PD-MCI neuropsychiatric symptoms;
and dementia in PD (PDD) and the recommended methods for cognitive assessment in this population. cognition; assessment
The authors also describe the more representative neuropsychiatric alterations and provide an overview
of the recommended methods of assessment.
Expert opinion: Cognitive and behavioral symptoms are inherent to PD, appear in a vast majority of
patients at some point during disease progression and have an enormous impact on health-related
quality of life of patients and caregivers. Validated methods of cognitive and behavioral assessment are
currently developed and must be used in research and clinical settings.

1. Introduction on the assessment procedures to properly capture cognitive

deterioration in PD [7,10]. Moreover, the MDS Rating Scales
Parkinson’s disease (PD) has been historically characterized as
Review Committee reviewed the existing tools to assess cog-
a motor disease. However, it is presently undeniable that the
nition and behavior in this disease, providing consensual-
high frequency of non-motor complications positions the clin-
based recommendations on which instruments appear to be
ical spectrum of PD far beyond just a movement disorder [1,2].
more appropriate [6,11].
The development of cognitive impairment and behavioral
In the present review, we will focus on the cognitive profile
abnormalities has been increasingly recognized as inherent
of PD and the clinical picture of PD-MCI and dementia in PD
features of PD with a devastating impact on the quality of
(PDD). We will also describe the more representative neurop-
life of patients and caregivers [3]. However, the neuropatho-
sychiatric alterations and provide an overview of the recom-
logical substrates of cognitive deterioration and the mechan-
mended methods of assessment.
isms leading to behavioral abnormalities are complex and
heterogeneous in PD. It includes Lewy bodies, neurofibrillary
tangles, senile plaques, vascular pathology, and argyrophilic 2. Cognition in Parkinson’s disease
inclusions as well as genetic risk factors like glucocerebrosi-
Cognitive impairment associated with PD was formally con-
dase (GBA) mutations, APOE4, or the MAPT H1 haplotype [4].
sidered a late complication of the disease occurring in up to
How these mechanisms contribute to different patterns of
80% of long-term survival patients [12,13]. However, compel-
cognitive and behavioral deterioration is unclear, but evidence
ling data demonstrate that more or less severe cognitive
that multiple contributors participates in the heterogeneous
impairment may be recognized even in the initial stages of
picture of cognitive impairment seen in PD.
the disease [2,14]. At these early stages, traditional instru-
Given the complexity and the heterogeneity observed in the
ments of global cognitive assessment (i.e.: MMSE or MDRS)
clinical course of cognitive impairment and on the form of pre-
may not capture significant cognitive changes [6]. This high-
sentation of neuropsychiatric disturbances in PD, multiple efforts
lights that the early manifestations of cognitive impairment in
have been made to properly characterize (i) the different cognitive
PD are often not clinically apparent. However, the formal
profiles occurring along the course of PD; (ii) the whole spectrum
neuropsychological assessment may disclose, significant diffi-
of neuropsychiatric disturbances; and (iii) the instruments to prop-
culties mostly in frontal-dependent tasks such as set-shifting
erly capture these complex clinical complications [5–9].
and working memory [14,15]. In fact, changes in global cog-
The Movement Disorders Society (MDS) Task Force on mild
nitive abilities and especially in executive functions can be
cognitive impairment in PD (PD-MCI) recently provided speci-
seen even in individuals at risk for PD [16].
fic recommendations on the diagnostic criteria for PD-MCI and

CONTACT Jaime Kulisevsky jkulisevsky@santpau.cat Movement Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Mas
Casanovas 90, Barcelona 08041, Spain
© 2019 Informa UK Limited, trading as Taylor & Francis Group
614 S. MARTINEZ-HORTA ET AL.

Article highlights
● In PD, cognitive impairment may be recognized even in the initial
stages of the disease, but traditional instruments of global cognitive
assessment may not capture it.
● Early cognitive impairment in PD is prototypically characterized as
executive dysfunction. However, some individuals also present pos-
terior-cortical alterations.
● Posterior-cortical changes predicts the progression of cognitive
impairment to dementia in PD.
● At the beginning of PD, PD-MCI may affect up to 30% of patients.
Dementia will affect up to 80% long-term survivals but will also affect
up to 35% of patients during the 5 years of disease duration.
● The MDS provided operative criteria for the diagnosis of PD-MCI and
PDD and recommendations on the methods of neuropsychological
assessment.
● The PD-CRS is the more reliable instrument for global cognitive
assessment in PD.
● Neuropsychiatric symptoms of variable severity will affect a large
proportion of PD.
● Disorders of mood and effect, motivation, impulse control and psy-
chotic symptoms are common findings in PD.
● Asking for the presence of neuropsychiatric symptoms and using
adequate instruments to rate its severity is essential to avoid the
common under-recognition of these symptoms.
The characteristic frontal-executive difficulties seen in the
early stage of PD are mostly attributed to dorsal-lateral prefrontal
cortex (DLPFC) malfunctioning and the abnormal dopaminergic
tone within the basal ganglia [17]. However, even during the
early stage of PD, some individuals also present difficulties in
cognitive domains that extends beyond the frontal functions and
that are more associated with posterior-cortical alterations (i.e.:
confrontation naming and/or constructional difficulties) [14,18].
The addition of these posterior-cortical changes is associated
with progressive cholinergic denervation which assumed as
a core feature in the progression of cognitive impairment to
dementia in PD [12,15,18,19].
Focusing on neuroimaging studies, cholinergic cortical pre-
synaptic deficit are known to increase over the course of PD
contributing to the progression of global cognitive deteriora-
tion [20]. More recent data also suggest that progressive
posterior-cortical thinning is also influenced by dopaminergic
denervation [21]. The topography of this progressive cortical
dysfunction is mostly circumscribed to multiple posterior-
cortical territories involving primary and associative occipital,
parietal and temporal areas [22]. Linking these brain changes
with the cognitive features occurring along PD, the degenera-
tion of these posterior-cortical areas appears associated with
the addition of visuoperceptive/visuoconstructive, language
and amnestic difficulties that strongly contribute to the pro-
gression of mild cognitive difficulties to dementia in this
population. Accordingly, cognitive assessment procedures in
PD must cover all the cognitive domains that could be
affected along the course of PD. Then, it must include tasks
associated with frontal-executive functions but also tasks asso-
ciated with posterior-cortical integrity.
Taking into account that mostly all PD patients will receive
pharmacological agents aimed to ameliorate motor symptoms it
is also important to note that some cognitive and behavioral
changes can be influenced by dopaminergic replacement ther-
apy. This is the case of cognitive processes that do not depend on
the proper function of the DLPFC (i.e.: working memory) but have
a dependence on more ventromedial PFC regions (i.e.: reversal
learning) [23,24]. Accordingly, whereas DLPFC-related function
may show some degree of improvement after initiation of dopa-
minergic replacement therapy, other processes associated with
the ventromedial PFC may worsen after initiating treatment [25].
This paradoxical effect is assumed to be a consequence of the
imbalance existing between the prominent dopaminergic dener-
vation of the nigrostriatal pathway and its connections between
the dorsal caudate nucleus and the DLPFC and the relative pre-
servation the mesocorticolimbic pathway and its connections
between the ventral striatum and the ventromedial PFC [26]. As
a consequence, while dopaminergic treatments partially restore
the normal functioning of a circuit that is lacking dopamine, it
disrupts, due to overdosing, the proper functioning of a circuit
that is more preserved [27] (Figure 1).
This negative effect, in coincidence with the high plasmatic
levels of levodopa after intake of a dose, is mainly seen in
patients exhibiting motor fluctuations [24].
It is presently assumed that early cognitive deterioration in
PD can be conceptualized as a form of mild cognitive impair-
ment defining the transitional stage between normal cogni-
tion to dementia [28]. However, the clinical course of cognitive
impairment in PD is not uniform between individuals [29] and
not all individuals suffering from significant cognitive changes
will develop dementia or will develop it after the same period
of time. It stressed the need to define specific diagnostic
criteria for PD-MCI and dementia in PD (PDD) but also to
determine consensual-based assessment approaches to prop-
erly address cognitive changes in PD.
3. Mild cognitive impairment (PD-MCI) and
dementia (PDD) in Parkinson’s disease
To formally provide the scientific and clinicians community
with a homogeneous and operative definition of PD-MCI, the
MDS leaded a Task Force aimed to define the diagnostic
criteria for this entity and the recommended procedures for
its assessment [7,10]. Two assessment procedures were
defined: a) A Level I approach consisting on brief screening
assessments of the global cognitive status of the patient and
b) a Level II approach consisting on a comprehensive neurop-
sychological assessment including two tests for each five
Figure 1. U-shape relationship between DA levels in the PFC and cognitive
performance.
 EXPERT REVIEW OF NEUROTHERAPEUTICS 615

cognitive domains allowing the diagnosis and subtyping of 3.1. Cognitive assessment of PD-MCI
PD-MCI in different profiles. Moreover, specific diagnostic cri-
Abbreviated approaches of cognitive assessment using instru-
teria for PD-MCI were stablished. More recently, the initial-
ments addressing global cognition (i.e.: MoCA, PD-CRS) or brief
accepted criteria was subjected to additional reviews and
neuropsychological assessment batteries (i.e.: batteries focusing
critiques, however, from a practical perspective, the MDS-
in one or two cognitive domains) defines Level I testing.
Task force criteria can be assumed as a valid approach [30,31].
Many general instruments that have been used in neuropsy-
Diagnosis of PD-MCI is currently done based on the accom-
chological testing in PD were not specifically developed to assess
plishment of four key features in the absence of exclusion criteria
cognitive aspects of PD (i.e.: MMSE or MoCA). Others were PD-
as determined by the MDS-Task Force (see Table 1). The diag-
specific instruments (i.e.: Parkinson’s Disease – Cognitive Rating
nosis of PD-MCI is considered in front of gradual cognitive
Scale or SCOPA-COG). The Review Committee of the MDS on
decline reported by the patient, relative or clinician that is objec-
rating scales to assess cognition in PD recently evaluated the
tivized through Level I or Level II testing, and that is not enough
suitability of 12 instruments that are commonly used in Level
sever as have a significant impact on independent activities of
I approach [11]. As expected, most of the general instruments do
daily living. According to Level I, impaired performance on
not fulfill the minimum-recommended standards. From all the
a global cognitive scale validated for use in PD or impairment
evaluated tools, only three were classified as recommended: The
in at least two tests when a limited neuropsychological assess-
PD-CRS, the Montreal Cognitive Assessment (MoCA), and the
ment battery is administered is mandatory to suggest PD-MCI.
Mattis Dementia Rating Scale Second Edition (MDRS-2) [11].
Despite Level I testing is a practical approach, it has limitations in
Both the MoCA and the MDRS-2 showed acceptable prop-
the form of not allowing subtyping patients in different PD-MCI
erties for screening purposes. In the case of the MDRS-2, the
profiles. When using Level II testing, impairment suggestive of
optimal cutoff score for PD-MCI was ≤140/144 (sensitivity
PD-MCI must be measured in at least two tests represented by
86%/specificity 54%) and ≤132/144 for PDD with maximum
either two tests in the same cognitive domain or one test in two
sensitivity and specificity. Regarding the MoCA, cutoffs of 25/
different cognitive domains. Most authors accepted that
26 points for PD-MCI (sensitivity 90%/specificity 75%) and 20/
impaired performance should be at least 1.5 SD bellow norma-
21 points for PDD (sensitivity 81%/specificity, 95%) have been
tive data. However, the appropriateness of using 1.5 or 2 SD
proposed. These findings suggest that both the MDRS-2 and
below expected range is currently under debate and has been
the MoCA are useful tools to identify dementia in PD but have
recently proposed that using a 2 SD cutoff score below appro-
lower specificity in front of PD-MCI [32,33]. However, since no
priate norms may be more adequate in the context of applying
one of these instruments were specifically developed based
the diagnostic criteria for PD-MCI [30].
on the characteristics of mild cognitive deficits in PD, they
A significant cognitive decline on serial cognitive testing or
appeared to be poorly sensitive capturing the transition from
a significant decline from the estimated premorbid level cap-
mild to more severe forms of cognitive deterioration in PD
tured through formal neuropsychological assessment can be
patients.
also considered as PD-MCI [10].

Table 1. Diagnostic criteria for PD-MCI.

I. Inclusion criteria
● Diagnosis of Parkinson’s disease as based on the UK PD Brain Bank Criteria20
● Gradual decline, in the context of established PD, in cognitive ability reported by either the patient or informant or observed by the clinician
● Cognitive deficits on either formal neuropsychological testing or a scale of global cognitive abilities (detailed in section III)
● Cognitive deficits are not sufficient to interfere significantly with functional independence, although subtle difficulties on complex functional tasks may be
present
II. Exclusion criteria
● Diagnosis of PD dementia based on MDS-Task Force proposed criteria
● Other primary explanations for cognitive impairment (e.g. delirium, stroke, major depression, metabolic abnormalities, adverse effects of medication, or head
trauma)
● Other PD-associated comorbid conditions (e.g. motor impairment or severe anxiety, depression, excessive daytime sleepiness, or psychosis) that, in the opinion
of the clinician, significantly influence cognitive testing
III. Specific guidelines for PD-MCI level I and level II categories
(a) Level I (abbreviated assessment)
● Impairment on a scale of global cognitive abilities validated for use in PDa or
● Impairment on at least two tests, when a limited battery of neuropsychological tests is performed (i.e. the battery includes less than two tests within each
of the five cognitive domains or less than five cognitive domains are assessed)
(b) Level II (comprehensive assessment)
● Neuropsychological testing that includes two tests within each of the five cognitive domains (i.e. attention and working memory, executive, language,
memory, and visuospatial)
● Impairment on at least two neuropsychological tests, represented by either two impaired tests in one cognitive domain or one impaired test in two
different cognitive domains
● Impairment on neuropsychological tests may be demonstrated by:
● Performance approximately 1 to 2 SDs below appropriate norms or
● Significant decline demonstrated on serial cognitive testing or
● Significant decline from estimated premorbid levels
IV. Subtype classification for PD-MCI (optional, requires two tests for each of the five cognitive domains assessed and is strongly suggested for
research purposes)
● PD-MCI single-domain – abnormalities on two tests within a single cognitive domain (specify the domain), with other domains unimpaired or
● PD-MCI multiple-domain – abnormalities on at least one test in two or more cognitive domains (specify the domains)
616 S. MARTINEZ-HORTA ET AL.

The PD-CRS was specifically designed to capture the differ-
ential contribution of frontal-subcortical and posterior-cortical
changes to PD-MCI and its transition to dementia [19].
Accordingly, the PD-CRS is composed of a set of tasks that
separately measures processes with a major frontal-subcortical
component or with a major posterior-cortical component.
Previous psychometric studies of the PD-CRS demonstrated
that using a cutoff score of PD-CRS total score <82, this
instrument had a high sensitivity (79%) and specificity (80%)
for discriminating the cognitive status between patients with
normal cognition and PD-MCI [34]. Moreover, clinimetric test-
ing such as intra-rater reliability, test–retest reliability and
responsiveness appeared significantly better in the PD-CRS
than in other instruments (Table 2).
Regarding the impact of mild cognitive deficits in func-
tional independence, it is well accepted that some cognitive
changes occurring early in the course of PD are in many cases,
inseparable from mild functional compromise [35]. This can be
understood as a reasonable consequence of even slight execu-
tive dysfunction over proper organization and adjustment to
complex functional activities of daily living. To address the
impact of cognitive aspects on functional independence, the
only validated instruments to capture cognitive-related func-
tional impairment in PD are the Penn Parkinson’s Daily
Activities Questionnaire (PDAQ) -and its 15-item short form
(PDAQ-15)- and the Parkinson’s Disease – Cognitive Functional
Rating Scale (PD-CFRS) [36–38]. Both the PDAQ and the PDAQ-
15 were developed on the basis of item response theory to be
completed by a knowledgeable informant and to assess cog-
nitive IADLs in PD patients across the cognitive spectrum. In
the PDAQ, cutoff were determined to differentiate non-
demented from PDD (–0.16; sensitivity 78%/specificity 80%)
and to differentiate cognitively intact from PD-MCI/PDD (–
0.83; sensitivity 81%/specificity, 91%). No specific cutoff scores
were determined to specifically differentiate normal cognition
from PD-MCI or normal cognition from PDD. With the PDAQ-
15, the cutoff for the distinction between non-demented (nor-
mal cognition/MCI) and PDD was a score of 43 (sensitivity
82%/specificity 84%) and the optimal cutoff between MCI
and dementia was a score of 37 (sensitivity 83%/specificity
71%). Again, no specific cutoff was provided to differentiate
normal cognition from PD-MCI.
The PD-CFRS consists of 12 items covering the spectrum of
instrumental cognitive changes seen in PD. The different ques-
tions explore the frequency on whether or not the patient has
had trouble in performing an activity (0 = none; 1 = some of
the time; 2 = most of the time; 8 = the subject has never done
the activity in the past) such as handling money, domestic
economy, arranging holidays or meetings, handling personal
mail, controlling drug treatment schedule, organizing daily
activities, handling home electrical appliances, understanding
how to use public transport, solving unforeseen events,
explaining things he/she want to say, understanding the
things he/she read and handling the cell phone. The max-
imum score, obtained by the sum of the ratings, is 24.
The PD-CFRS showed intermediate concurrent validity (ICC
= 0.50), high test-retest (ICC = 0.82), inter-rater reliability (ICC =
0.80) and internal consistency (Cronbach’s α = 0.79), and
higher coefficient of variation to detect cognitive-functional
impairment in non-demented PD patients. Moreover, the PD-
CFRS shows a strong correlation with the total score of the PD-
CRS (r = −0.72, p < 0.0001). According to discriminant analysis,
a PD-CFRS cut-off score of ≥3 was found to be optimal for
detecting functional impairment in PD-MCI patients.
The only other PD-specific questionnaire of daily activities,
the Penn Parkinson’s Daily Activities Questionnaire, although
showed good clinimetric properties to discriminate between
PD patients with and without dementia failed to demonstrate
discrimination between patients with and without PD-MCI
[37].
3.2. Level II cognitive assessment
While Level I testing provide a practical approach for the
screening of global cognitive status of PD patients, the com-
prehensive neuropsychological assessment allows determin-
ing the severity and profile of PD-MCI. Level II testing is
based on a comprehensive battery of neuropsychological
tests covering five cognitive domains of interest (attention
and working memory, executive function, language, memory
and visuospatial function) through two tests for each cognitive
domain. In PD-MCI, an impairment must be present on at least
two tests, either in the same cognitive domain or in different

Table 2. Psychometric properties of level I instruments to assess PD-MCI.

Internal Test-retest Inter-rater Content Construct
Cognitive domains consistency reliability reliability validity validity Acceptability
Generic scales MMSE Memory, orientation, language ND ND ND ND ND ND
MDRS Fronto-subcortical
CAMCOG Orientation, language, memory, attention, calculation, ND ND ND ND ND ND
praxis, perception
FAB Frontal functions ++ ++ ++ +++ +++
PD-specific scales MMP Orientation, visual scanning, attention, verbal fluency, ND ND ND ++ +++ -
visual memory, verbal processing
SCOPA- Memory, attention, executive functions, visuospatial +++ +++ ND + +++ +
COG functions
PANDA Immediate and delayed memory, verbal fluency, ND ND ND ++ +++ -
visuospatial function, attention, working memory
PD-CRS Frontal functions/posterior-cortical functions +++ ++++ ++++ +++ +++ +
MMSE: Mini-mental state examination; MDRS: Mattis Dementia Rating Scale; CAMCOG: Cambridge Cognitive Examination; FAB: Frontal Assessment Battery; MMP:
Mini-Mental Parkinson’s; SCOPA-COG: Scales for Outcomes in Parkinson’s Disease-Cognition; PANDA: Parkinson neuropsychometric dementia assessment; PD-CRS:
Parkinson’s Disease – Cognitive Rating Scale; ND: Not-determined.

cognitive domains. Impairment must be determined by the
performance of 1 to 2 SD below the expected range [31].
The use of two tests for each cognitive domain and the
assessment of five cognitive domains allows subtyping
patients in different profiles of PD-MCI. The existence of two
tests impaired in a single domain with no evidence of impair-
ment in other domains defines a single-domain pattern of PD-
MCI. In the case of impairment in at least one test in two or
more cognitive domains it represents a multiple-domain pat-
tern of PD-MCI.
The list of tests that can be used to compose a reliable
comprehensive neuropsychological assessment battery in PD
is based on current recommendations for which appropriate
sensitivity and specificity of about 81.3% and 85.7% are found:
(1) Attention and working memory: Symbol digit modal-
ities test (SDMT) and Trail Making Test part A.
(2) Executive functions: Clock drawing test and Trail
Making Test part B.
(3) Language: Boston Naming Test and Semantic verbal
fluency test.
(4) Memory: Free and Cued Selective Reminding Test
(FCSRT) and Figural memory.
(5) Visuospatial function: Judgment of Line Orientation and
Copy of pentagons.
Despite these tests showed good psychometric properties in
the studied sample of reference, there are many other options
that can be considered. Accordingly, the MDS-task force
selected a set of tests (Table 3) to be used [30,31].
3.3. Dementia associated with Parkinson’s disease
(PDD)
In PD, dementia is assumed to occur in up to 80% of long-
term survival individuals [39]. However, it is currently accepted
that PDD do not only appear in late-stage patients but can be
also present in up to 36% of patients during the first 5 years of
disease duration [13,39,40]. PDD has a unique
Table 3. Proposed neuropsychological tests for level II assessment*.
Cognitive Domain Neuropsychological Tests
Attention and working memory Digit span forward
Letter number sequencing
Symbol digit modalities test
Trail making test–A
Executive function Clock drawing
Controlled oral word association
Digit span backwards
Progressive matrices
Trail making test–B
Language Boston naming test
Category fluency: animal naming
Similarities
Memory CERAD trials, delayed recall, recognition
Free and cued selective reminding test
Figural memory learning and delayed recall
Logical memory I and II
Visuospatial function Clock copying
Judgment of line orientation
Intersecting pentagons
*Adapted from Goldman JG et al. (2015) [31]
EXPERT REVIEW OF NEUROTHERAPEUTICS 617
neuropsychological profile and neuropathology different
than the observed in Alzheimer’s disease. In PD, attention,
frontal-executive and visuospatial abnormalities are the more
prominent characteristic features of dementia. Conversely,
amnestic deficits at the level of encoding and language diffi-
culties are more prominently observed in Alzheimer’s disease.
Both groups of patients, however, exhibit prominent amnestic
difficulties, although AD patients perform significantly worse
in recognition and cue-facilitated recall and in orientation [41].
The addition of neuropsychiatric symptoms represents
a common comorbid condition of PDD and Alzheimer’s dis-
ease, being the development of complex visual hallucinations
more typically associated with PDD [13]. In both cases, how-
ever, dementia is determined given the significant impact of
cognitive impairment on the level of functional independence.
From a neuropathological point of view, gradual loss of
dopaminergic neurons projecting from the substantia nigra
to the striatum and widespread deposition of Lewy bodies
constituted of α-synuclein protein defines the neuropatholo-
gical hallmark of PD. However, other structural lesions such
amyloid plaques deposition and TAU pathology also contri-
bute to cognitive decline in PD [42]. Marked cholinergic defi-
cits are known to also play a major contribution to PDD [20].
Older age, more severe parkinsonism, male gender, depres-
sion, apathy, psychosis and PD-MCI represent key risk factors
associated with the development of dementia in PD [7,41].
Genetic factors such as GBA mutations [43] and MAPT H1
haplotype are known to accelerate progression to PDD
[44,45]. From a cognitive perspective, not all forms of PD-
MCI appear to associate the same imminent risk for dementia
in PD. As said, frontal-executive deficits appear to characterize
early and progressive cognitive changes in PD but not neces-
sarily dementia. Conversely, the addition of cognitive deficits
extending beyond executive functions suppose and additional
risk for the conversion to dementia [15]. This idea emphasize
on the importance of addressing cognitive assessment
through methods allowing to capture functioning of cognitive
domains other than executive functions. Accordingly, despite
some cognitive domains like language or visuospatial func-
tions may appear mostly spared in many patients, progressive
deterioration in these domains may result in a robust marker
of increased risk for conversion to PDD [15,46].
Regarding diagnostic criteria, PDD must be differentiated
from other parkinsonian syndromes associating significant
cognitive deterioration like Lewy body dementia, progressive
supranuclear palsy or corticobasal degeneration among
others. Despite notable similarities between these entities,
the presence of a set of core features will help on the diag-
nosis. These features include the diagnosis of PD prior to the
instauration of dementia and that the dementia syndrome has
an insidious onset and slow progression associating: a)
Impairment in more than one cognitive domain; b) a decline
from premorbid level; and c) severe impairment on functional
independence on daily activities not attributed to motor or
autonomic symptoms [41,47].
Typical clinical features of PDD include cognitive alterations
that could affect multiple domains such as attention, execu-
tive functions, language, visuospatial functions and memory.
Additionally, behavioral disturbances are a common finding
618 S. MARTINEZ-HORTA ET AL.
associated with PDD being apathy, changes in personality,
delusion and hallucinations and excessive daytime sleepiness
some of the more frequent [47].
As done with PD-MCI, the MDS-task force also determined
the recommendations for the diagnosis of probable and pos-
sible PDD based on Level I and Level II assessment. Regarding
instruments and tests to be used both in Level I and Level II
assessment, recommendations may be the same as those
described for the assessment of PD-MCI since these methods
apply to the assessment of cognitive function in PD in general.
In the case of PD-specific global cognitive assessment instru-
ments and general instruments validated in PDD, the use of
the proposed cut-off scores represent a first step for the
screening of PDD according to Level I procedure. However,
a simple algorithm was proposed as Level I approach to
determine probable PDD. This algorithm requires to confirm
the diagnosis of PD prior the development of dementia and
a current MMSE score <26 (although other scales with vali-
dated cutoff scores may be used), with cognitive deficits
severe enough as to interfere with independence on activities
of daily living and impairment on at least two of the following
tests: Months reversed or Seven backward; verbal fluency or
clock drawing; MMSE pentagons and 3-word recall.
Additionally, the absence of major depression, delirium and
other abnormalities that may obscure the diagnosis [48].
Despite Level I testing is an accepted approach to determine
the presence of PDD, more accurate assessment may be impor-
tant to determine the profile and severity of dementia as well as
to make a definitive diagnosis in cases that remain under
uncertainty. In this case, Level II testing provides a more com-
prehensive examination through the assessment (in the case of
focusing on PDD) of four cognitive domains: Global cognitive
functioning, frontal-subcortical functions, posterior-cortical
instrumental functions and neuropsychiatric symptoms. For
the construction of a comprehensive assessment battery to
assess PDD according to Level II, cognitive tests may be
selected according to the standards explained in the previous
section regarding PD-MCI. For the assessment of neuropsychia-
tric features, it will be important to focus on those entities
frequently over-represented in PDD population like depression,
visual hallucinations and psychosis. Specific recommendations
for the assessment of these behavioral features (and others) will
be described in the following section of this review.
4. Behavioral disturbances in Parkinson’s disease
Depression, anxiety, apathy, psychosis and impulse control
disorders (ICDs) are neuropsychiatric features commonly
occurring in Parkinson’s disease and affecting an important
proportion of patients at some point during the disease [5].
Studies addressing health-related quality of life in patients at
the early stages of PD emphasize the enormous impact that
neuropsychiatric features have on the quality of life of patients
and its association with reduced well-being [3]. Similarly, care-
giver distress during the early stages of PD is strongly asso-
ciated with depression, anxiety, apathy, disinhibition and
personality change [49]. In non-demented PD, large cohort
studies showed that at least one neuropsychiatric symptom
is present in up to the 70% of a sample of 1.351 patients,
being apathy, irritability, agitation, depression, hallucinations,
euphoria and disinhibition the more frequent symptoms [5].
Moreover, some of these symptoms appear to be associated
with and increased risk for the development of dementia [50].
This is the case of apathy, depression and psychotic features
[50–52]. Taking together, there is no debate on the major
importance that behavioral abnormalities have on the overall
course of PD. However, the assessment of neuropsychiatric
symptoms in PD may be difficult given that some symptoms
(i.e.: visual hallucinations or ICDs) are under-reported by
patients but also due to the complexity of addressing the
subjective component of behavioral abnormalities.
Despite multiple instruments and scales are currently avail-
able to assess neuropsychiatric symptoms, similarly as with
cognitive impairment, there is a need to use instruments
showing accurate psychometric properties in a specific popu-
lation like PD.
4.1. Affective disorders: anxiety and depression in
Parkinson’s disease
Approximately 30–50% of PD patients have depressive symp-
toms. From these patients, about 17% accomplish criteria for
major depression, 13% for dysthymia and 22% for minor
depressive episode [53]. Depression can be seen in all stages
of PD and is also a frequent finding about 2 to 5 years before
the diagnosis of PD [54]. The nature of depressive symptoms
in PD seems to be a consequence of a complex interaction
between neuropathological changes and psychological/reac-
tive events to the diagnosis of PD [53]. Moreover, features
resembling depression could overlap with other symptoms
associated with PD such as reduced interest, altered sleep
and appetite, loss of libido, psychomotor retardation or mem-
ory complains among others, making difficult the diagnosis of
depression in PD.
Anxiety disorders also constitute a frequent finding in PD,
affecting a proportion near 30% of patients [53]. Among them,
14% fulfilled criteria for generalized anxiety disorder, 13.8% for
social phobia, 13.3 unspecified anxiety disorder, 13% specific
phobia and 6.8% panic disorder with or without phobia [55].
Regarding associated mechanisms leading to anxiety in PD,
this symptom can be an off-period-related phenomenon
occurring or not in parallel with motor fluctuations [56].
Anxiety can also be totally unrelated to motor fluctuations as
a comorbid symptom or as a presenting symptom of PD [46].
In some cases, as seen with depressive symptoms, anxiety can
precede motor symptoms by years constituting a non-motor
feature that may herald PD. Finally, it can be part of person-
ality traits related to less novelty seeking, more rigid, conven-
tional and cautious personality [57].
Among the multiple instruments and scales to assess
depression and anxiety, few of them were validated in PD or
developed as a PD-specific instrument. A critical review focus-
ing on scales to assess depression in PD, recommended the
Geriatric Depression Scale – 15-item version (GDS-15) for the
screening of depressive symptoms and the diagnosis of
depression in PD [58]. A cut-off score of 9/10 was shown to
distinguish patients with and without major depression.
Moreover, it showed equivalent psychometric properties

than those found in its longer 30-item version. The Hamilton
Depression Rating Scale (HAMD) is a widely used semi-
structured interview developed for the clinical assessment of
depression in adults. In previous studies, the 17-item version
(HAMD-17) displayed good validity and reliability and is
recommended for screening and measuring the severity of
depression in PD. A cut-off score of 13/14 is recommended
for screening purposes, being suggested to use a cut-off score
of 12/13 for the assessment of major depression. Other instru-
ments, including the Beck Depression Inventory (BDI), the
Montgomery–Asberg Depression Scale (MADRS) or the
Hospital Anxiety Depression Scale (HADS) also appears valid
and reliable.
Regarding the assessment of anxiety, a critical review on
multiple existing instruments determined that the Geriatric
Anxiety Inventory (GAI) is a 20-item self-report instrument
valid and reliable to be used in non-demented PD patients
allowing distinguishing patients with and without anxiety dis-
orders using a cut-off score of 6/7 [59]. The Parkinson’s Anxiety
Scale (PAS) was specifically developed to assess anxiety symp-
toms in PD. Validation studies showed good psychometric
properties of the scale. An optimal cut-off of 13/14 was deter-
mined for both the observer-rated and self-rated versions to
discriminate between patients with and without DSM-IV cri-
teria for anxiety disorders. Other widely used instruments like
the Beck Anxiety Inventory, Hospital Anxiety and Depression
Scale and the Hamilton Anxiety Rating Scale did not demon-
strate satisfactory psychometric properties when used in PD
populations.
4.2. Motivation disorders: apathy and ICDs in
Parkinson’s disease
In PD, disorders of motivation can be separated into two main
extremes of the same behavioral dimension. In one extreme,
diminished motivation constitute the main feature of apathy
[60]. This syndrome affects up to 70% of PD patients and is
characterized as a state of diminished goal-directed behavior,
reduced interest in pleasurable activities and flattened affect
that is not attributed to a decreased level of consciousness,
cognitive impairment or depression [61]. This feature is more
prevalent in depressed, advanced and demented patients, but
can also be found as an isolated symptom in early and mid-
stage individuals [60,62]. In fact, apathy is very common in
recently diagnosed PD and is a major clinical determinant of
health-related quality of life [63]. Previous studies of apathy in
PD have found associations between apathy and executive
dysfunction, more severe posterior-cortical neuropsychologi-
cal deficits, difficulties in facial emotion recognition, dimin-
ished sensitivity to incentives and grey matter changes
within key reward and executive-related brain regions
[62,64,65]. Moreover, apathy has been pointed as a heralding
sign of future dementia [50].
Impulse Control Disorders (ICDs) can be identified on the
other extreme of this behavioral continuum. Contrasting with
the lack of motivation and self-initiated purposeful behavior
seen in apathetic patients, ICDs behaviors are characterized by
failures to resist an impulse to perform an action that is
associated with obtaining some pleasure independently on
EXPERT REVIEW OF NEUROTHERAPEUTICS 619
the consequences or harm that it will suppose [66]. Most
common ICDs seen in PD are hypersexuality, compulsive shop-
ping, pathological gambling or binge eating [67]. The devel-
opment of these symptoms has been largely attributed to
a secondary effect of dopaminergic replacement therapy.
Despite the high frequency of apathy in PD, few studies
addressed the validity of the limited existing instruments
aimed to capture this entity. In the unique critical review on
rating scales for apathy in PD, only the Apathy Scale (AS)
appeared as a recommended instrument [68]. The AS is a 14-
item semi-structured interview based on the original Apathy
Evaluation Scale developed by Marin. With a relatively short
time of administration of about 10 min, this instrument
showed acceptable psychometric properties to discriminate
patients with and without clinically relevant symptoms of
apathy when a cut-off score of 13/14 was applied. The item
4 of the UPDRS assessing motivation/initiative also meets
criteria as to be recommended. However, based on the
obvious limitations of a single item assessment, it is consid-
ered to be recommended just for screening purposes [68].
Regarding the assessment on ICDs, there are currently just
two instruments that shown to be valid screening instruments
for these symptoms in the setting of PD. The Questionnaire for
Impulsive-Compulsive Disorders in Parkinson’s Disease–Rating
Scale (QUIP-RS) is composed by four main questions about
thoughts, urges/desires, and behaviors related to compulsive
gambling, buying, eating, and sexual behavior [69,70]. Three
additional questions are focused on medication use, hobbyism
and punding. For each disorder the total score runs from 0 to
16; the total for the four ICDs, from 0 to 64 and the total QUIP-
RS ranges from 0 to 112. The QUIP-RS appears to be an
interesting instrument for screening purposes. However, up
to 40% of PD patients without an ICD diagnosis screen posi-
tive for an ICD in the QUIP-RS. The nature and clinical rele-
vance of this apparent ‘false positives’ must be considered
with caution since some of these positives may be subsyndro-
mical ICDs. Specifically focusing on sexual behavior, there is
a short version of the Sexual Addiction Test for PD (PD-SAST)
[71]. This instrument is a 5-item adaptation of the 25-item
Addiction Screening Test. Scoring is based on yes/no answers
to five questions regarding compulsive sexual thoughts,
desires or behavior. The cut-off score was determined at 2/3
and showed very good psychometric properties against DSM-
IV criteria.
4.3. Psychotic disorders: delusion and hallucinations in
Parkinson’s disease
The psychotic profile of PD patients is variable but trends to
mainly involve visual hallucinations and paranoid delusions
[52,72]. Hallucinations may be conceptualized as perception-
like experiences in the absence of an external stimulus that
may involve any sensory modality in subjects that may or may
not have insight about the unreal nature of these perceptions.
In contrast, illusions are misperception of a real stimulus that
mostly occurs in the visual modality. Delusions refer to false-
fixed beliefs maintained despite evidence to the contrary that
are not amenable to change or reconsideration. Psychotic
symptoms, in general, have been associated with more
620 S. MARTINEZ-HORTA ET AL.
advanced disease stage and worst cognitive prognosis. In fact,
visual hallucinations represent the strongest single predictor
of developing dementia in PD since those patients presenting
visual hallucinations have an increased risk of developing
dementia 20-fold over PD without hallucinations [73]. The
phenomenology of hallucinations in PD is variable but shares
some common patterns between individuals. First manifesta-
tions are usually characterized by feelings of presence or
minor and unstructured hallucinatory phenomena with pre-
served insight [52]. These early symptoms have a tendency to
progress to major or more complex and structured hallucina-
tions with preserved insight which trends to progress to loss
of insight mostly in parallel of cognitive deterioration.
Interestingly, despite the development of hallucinations in
PD is assumed to be partially influenced by the use of
L-Dopa, minor hallucinations are known to be present up to
42% of drug-naïve patients and even from the premotor stage
[74]. The cumulative prevalence of structured major hallucina-
tions is of about 60% in long-term survival patients [52,74].
This prevalence is known to linearly increase from the 20%
during the first 5 to 10 years, the 36% at 12 years, the 50% and
15 years and the 60% at 20 years of follow-up [52,75,76].
Despite the important prevalence of psychotic-like features
in PD and its association with dementia, a gold standard for
the diagnosis of psychosis in PD is not currently available.
Moreover, these features are commonly underreported thus
the assessment of psychosis in PD is complex and needs
considerable clinical expertise. From the review of critical
recommendations on existing tools for the assessment of
psychosis in PD, no one of the explored instruments accom-
plished the criteria to be considered as recommended.
However, tools like the Parkinson Psychosis Questionnaire
(PPQ), the Neuropsychiatric Inventory or the Rush
Hallucination Inventory (RHI) can be relatively useful in the
process of guiding the interview on the detection of psycho-
tic-like features in PD [77–79].
5. Expert opinion
Cognitive and behavioral symptoms are inherent to PD,
appear in a vast majority of patients at some point during
disease progression and have an enormous impact on health-
related quality of life of patients and caregivers.
Substantial efforts have been done during the last years to
better understand the neurobiological mechanisms leading to
cognitive and behavioral changes in PD. Cognitive deficits
were initially mostly attributed to the disruption of executive
functions given the functional changes on the basal ganglia –
thalamo – cortical communication. Despite compelling evi-
dence proved that executive dysfunction is a characteristic
cognitive change seen in mostly all individuals affected by
PD, a more complex cognitive phenotype is now recognized
to also occur in an important proportion of patients. The
addition of posterior-cortical like deficits in association to
widespread cortico-subcortical synuclein pathology and choli-
nergic changes seems to better characterize the progression
of cognitive impairment to dementia in PD. Importantly, spe-
cific diagnostic criteria was defined both for the diagnosis of
PD-MCI and PDD. It stressed the need to validate and to
develop PD-specific cognitive assessment instruments and
methods for accurate neuropsychological examination in this
population. Of the three Level I recommended instruments to
assess PD-MCI, the PD-CRS offers the advantage of relatively
short administration time. In the design of cognitive trials, the
MoCA or Level II cognitive assessment seems more suitable for
screening and the PD-CRS, that incorporate a validated and
reliable alterative version, can be used for repeated
measurement.
Behavioral disturbances also gained increasing attention
during the last years which resulted in an improvement in
the procedures to measure the presence and severity of
these complex features. For the assessment of depression
and anxiety, the GDS-15 and the PAS are, respectively, recom-
mended as valid tools. The AS is an appropriate instrument to
determine the presence of apathy in PD; despite for screening
purposes the item four of the UPDRS can be used. The QUIP-
RS provides a structured guide on the measurement of multi-
ple elements comprising the more common entities that can
appear as ICD in this population. Finally, in absence of specific
gold-standards, clinical expertise is assumed as mandatory to
capture the presence of psychotic-like features, despite scales
like the NPI, the PPQ or the RHI may be helpful to determine
the accomplishment of the revised NINDS criteria for psychosis
in PD.
5.1. Five-year view
As part of the clinical care of patients, the assessment of
cognitive deterioration and behavioral problems in PD is rou-
tinely performed in most movement disorders units. The field
of studying cognitive impairment and neuropsychiatric symp-
toms of PD significantly evolved during the last years.
However, many of these symptoms still being under-
recognized and not all practitioners emphasize on these
symptoms as much as with others associated with PD.
Taking into account how this field is evolving, future perspec-
tives points on a normalization of the implementation of
cognitive and behavioral assessment in routine clinical prac-
tice. Moreover, future clinical trials will focus on cognitive and
behavioral aspects of PD, with special emphasis on dementia
associated with PD.
Funding
This paper was not funded.
Declaration of interest
J Kulisevsky has received honoraria for lecturing or consultation from the
Michael J. Fox Foundation, Merck Serono, AbbVie, Boheringer Ingelheim,
UCB, Zambon, Italfarmaco, General Electric, Teva, Lundbeck, Bial, Prexton,
and Accorda. They have also received public grants from la Marato de Tv3
and Fondo de Investigaciones Sanitarias ISCIII. The authors have no other
relevant affiliations or financial involvement with any organization or
entity with a financial interest in or conflict with the subject matter or
materials discussed in this manuscript apart from those disclosed.
 EXPERT REVIEW OF NEUROTHERAPEUTICS 621

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