Parkinsonism and Related Disorders 18 (2012) 1067e1072

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Parkinsonism and Related Disorders

journal homepage: www.elsevier.com/locate/parkreldis

Neuropsychological profile in patients with early stage of Parkinson’s disease

in Taiwan
Rwei-Ling Yu a, Ruey-Meei Wu a, b, **, Chun-Hwei Tai b, Chin-Hsien Lin b, Ting-Wen Cheng b,
Mau-Sun Hua a, b, *
a
Department of Psychology, National Taiwan University, Taipei 10617, Taiwan
b
Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 10002, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Given the importance of early detection and intervention for disease management, determining the
Received 22 January 2012 vulnerable neuropsychological function in patients with early-stage Parkinson’s disease (PD) is a priority.
Received in revised form Here, we describe the neuropsychological pattern in early-stage PD patients with mild cognitive
30 April 2012
impairment (PD-MCI) and dementia (PDD) in Taiwanese population. The neuropsychological perfor-
Accepted 7 June 2012
mance of 94 patients with PD was compared with that of 84 healthy controls (HCs) and available
normative data, using a comprehensive neuropsychological assessment including tests of executive,
Keywords:
memory, psychomotor speed, attention, visuospatial, and language functions. Our results showed that PD
Parkinson’s disease
Mild cognitive impairment
patients performed significantly worse on executive function (i.e., category of card sorting) and
Neuropsychological function psychomotor speed (i.e., processing speed index). Up to 46.8% were classified as PD-MCI and the majority
of those having single-domain impairment (68.2%); 9.6% met the consensus diagnostic criteria for PDD.
Accordingly, we suggest that early-stage PD patients have cognitive dysfunction predominately in the
anterior brain. Further follow-up study to determine how many percent of PD-MCI develop PDD is
important. The effect of neurocognitive rehabilitation on executive function is also valuable in the
subsequence study.
Ó 2012 Elsevier Ltd. All rights reserved.

1. Introduction Although few studies have focused on PD patients with mild

Patients with PD, a neurodegenerative disease involving frontal
lobe system [1], are twice as likely as healthy aging adults to
develop cognitive impairment [2e4]. A recent study reported that
a mean of 26.7% (range, 18.9%e32.8%) of non-demented patients
with PD have mild cognitive impairment (MCI) [5], including drug-
náive patients [2] and those with newly diagnosed PD [3,6]. One
multicenter study that pooled data from Western cohorts revealed
that the common cognitive dysfunctions in PD are attention/exec-
utive, memory, and visuospatial function [7]. The increased risk of
a more rapid cognitive decline and dementia in PD-MCI cases
underlines the importance of careful monitoring of cognitive
dysfunctions in PD patients without dementia.
* Corresponding author. Department of Psychology, National Taiwan University,
Taipei 10617, Taiwan. Tel.: þ886 2 3366 3101; fax: þ886 2 2362 9909.
** Corresponding author. Department of Neurology, National Taiwan University
Hospital, Taipei 10002, Taiwan. Tel.: þ886 2 2312 3456/5337; fax: þ886 2 2341
8395.
E-mail addresses: robinwu@ntu.edu.tw (R.-M. Wu), huams@ntu.edu.tw
(M.-S. Hua).
disease severity, some researchers have suggested that cognitive
deficits can be present at an early stage of the disease and are more
heterogeneous than previously described [3,6,8]. Several studies
have shown that cognitive dysfunction is most prominent in the
memory [2,3,6] and executive function domains [3,6], while others
have shown that visuospatial deficits can sometimes be the most
severe cognitive impairment [9]. Previous findings have also sug-
gested that MCI in PD patients with predominant posterior cortical
dysfunction might have a more rapid progression to dementia
associated with PD (PDD) [10,11]. However, methodological prob-
lems like variability in the neuropsychological function domains
investigated, the tests used to measure each of the domains, and
the determination of cutoff points for function impairment may be
at least partly responsible for the observed inconsistencies.
Another problem in accurately diagnosing PD with dementia
may be a predominant reliance on Diagnostic and Statistical
Manual of Mental Disorders, fourth edition (DSM-IV), one of the
most widely used diagnosis criteria for dementia. The DSM-IV
states that memory impairment is a necessary neurocognitive
criterion for dementia; however, non-memory cognitive impair-
ments, such as executive dysfunction, predominate in PD patients.

1353-8020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.parkreldis.2012.06.002
1068 R.-L. Yu et al. / Parkinsonism and Related Disorders 18 (2012) 1067e1072

On the basis of this, the Movement Disorders Society (MDS) [12] Table 1
proposed replacing the mandatory role of memory impairment Cognitive domains and neuropsychological tests.

with alternative, such as deficits of executive function, attention, Domain Neuropsychological tests
language, and visuospatial function in patients with PD. That is, Executive function MCST (number of categories achieved,
each of these cognitive deficits plays an equally weighted role in the perseverative and non-perseverative
dementia diagnosis. These two viewpoints are markedly different errors) [17]
Category fluency (fruit, fish, and
in terms of which is the essential neurocognitive deficit in the
vegetable)
dementia diagnosis in PD and require further exploration. Working memory indexa
Though neuropsychological testing heterogeneity can be of Similaritiesa
enormous value, little research has been done using a comprehen- Matrix reasoninga
sive neuropsychological test battery covering most cognitive Color trails test B [18]
Memory function Verbal: logical memoryb
function domains [3,6]. This is particularly a problem in Asian Nonverbal: visual reproductionb
countries. To our knowledge, only one study has investigated the 3-object recallc
neuropsychological function in a Han Chinese population [13]. Psychomotor speed Digit symbol substitutiona
However, the lack of norms and domain-specific cognitive Symbol searchinga
Processing speed indexa
batteries, and the small number of cognitive functions covered
Color trails test A [18]
limited researches studying the manifestations of early PD in Visuospatial function Block designa
cognitive profiles. In fact, most studies pooled PD patients with Pentagon copyc
different disease severities together, but this approach overlooks Attention Digit spana
the importance of disease heterogeneity and early detection of the Color trails-interference [18]
Serial 7sc
vulnerable cognitive function prior to development of full-brown Language Namingc
dementia. To address these issues, we focused on PD patients in Repetitionc
the initial disease stage. We hypothesize that PD patients develop Verbal comprehensionc
cognitive dysfunction in early stage and executive function is the Abbreviations: MCST, Modified Wisconsin Card Sorting Test; WAIS-III [19],
most vulnerable cognitive function, especially in concept formation Wechsler Adult Intelligence Scale-Third Edition; WMS-III [20], Wechsler Memory
ability and cognitive flexibility. Besides, the dementia criteria Scale-Third Edition; MMSE, Mini-Mental State Examination.
a
proposed by the MDS is more applicable for the PD population than Subtest of WAIS-III.
b
Subtest of WMS-III.
DSM-IV. Here, we explore the pattern of cognitive dysfunction in c
Subtest of MMSE.
early-stage patients by using comprehensive neuropsychological
measures encompassing most cognitive domains. In addition, the 2.3. Statistical analysis
proportion of patients with PD-MCI subtypes and PDD, and the
issue of the clinical utility of the two major diagnosis criteria of PDD Demographic and disease-related characteristics were summarized with
descriptive statistics. Chi-square, t, or ManneWhitney U tests were used for
were investigated.
comparison between groups, when appropriate.
To assess the pattern of cognitive dysfunction in PD patients, between-group
2. Methods comparisons were made using a t test for parametric variables or a ManneWhitney
U test for nonparametric variables. Subsequently, a logistic regression analysis was
2.1. Participants conducted to determine which neuropsychological measures differentiated patients
from HCs most effectively. Due to the nature of PD, it is possible that the motor deficits
Participants included 94 individuals with PD and 84 healthy controls (HCs) (e.g., bradykinesia and rigidity) will negatively influence the patient’s performance
(consisting of spouses, relatives of the patients, and community participants), who in processing speed tests. To minimize the effect of motor symptoms, stage 1 patients,
were gender-, age- and education-matched. The patients were recruited from the who have motor symptoms on only one side of their bodies, were investigated.
neurology outpatient clinics at National Taiwan University Hospital, and the clinical Of all the stage 1 patients, only three patients were documented as having an impaired
diagnosis of PD was made according to the UK PD Society Brain Bank criteria [14]. processing speed, and these patients had motor symptoms on their non-dominant
The inclusion criteria for patients were idiopathic PD with a mild level of disease side, which would not limit their processing speed test performance.
severity (Hoehn and Yahr stages, H&Y stage 1e2). Exclusion criteria were age of Additionally, the patients’ cognitive performances were compared with the
onset before 45 years, and history of brain surgery, other neurologic disorders, and available normative data, and an individual was identified as abnormal if the neu-
impairments of visual acuity or hearing ability. Taking into account the impact of ropsychological test result was 1.5 SD below the normative mean (or below the fifth
psychiatric symptoms on cognitive function [15], we also excluded the patients with percentile of normative samples). Meanwhile, a cognitive domain was defined as
psychiatric disorders, such as major depression and psychosis. In addition, patients “impaired” if any one of the test scores in that domain was abnormal. Patients with
with visual hallucination or fluctuating attention that had been diagnosed with PD were classified as having PD-MCI if they had impairment in at least one cognitive
dementia with Lewy body disease [16] were also excluded. Each patient underwent domain with normal social and occupation function. Furthermore, the DSM-IV
a neurological and a neuropsychological examination, during which no remarkable criteria and consensus criteria proposed by the MDS were used to classify patients
neuropsychiatric symptoms were observed. None of the HCs had global cognitive with or without dementia, respectively. Statistical significance was determined
deterioration (Mini-Mental State Examination, MMSE < 24), impairments of hearing when the probability value was less than 0.05. Commercially available software
and visual acuity, or any history of other neurologic or psychiatric disorders. All the (SPSS version 17.0; SPSS Inc., Chicago, IL, USA) was used for the statistical analyses.
participants provided written informed consent prior to enrollment, in accordance
with the ethical standards laid down in the 1964 Declaration of Helsinki. The study
was approved by the Ethical Research Committee of National Taiwan University 3. Results
Hospital.
The demographic and clinical data of the study groups were
2.2. Neurological and neuropsychological assessment summarized in Table 2. There were no significant differences
between HCs and PD groups with respect to gender distribution,
A neurologic examination was performed on all patients to confirm the diag- handedness, age, and years of formal education, as well as pre-
nosis of PD. Information regarding the onset of disease, medical history, and levo-
dopa usage was obtained from a semistructured interview. The duration of disease
morbid verbal intellectual quotient (VIQ).
was defined as the time between the appearance of the first motor symptom as
reported by the patient, and the disease severity was determined using the H&Y 3.1. Profile of cognitive dysfunction in early-stage PD
staging rating scale. Each participant was interviewed by a licensed neuropsychol-
ogist and neuropsychological tests were administered to evaluate five cognitive
domains: executive function, memory, psychomotor speed, attention, and visuo- Patients with early-stage PD performed significantly worse
spatial and language abilities (Table 1). than controls on 19 of 30 neuropsychological measures (Table 3).
 R.-L. Yu et al. / Parkinsonism and Related Disorders 18 (2012) 1067e1072 1069

Table 2
Demographic and clinical characteristics of cognitively intact, MCI, and dementia PD.a

HCs (n ¼ 84) All PD (n ¼ 94) Cognitively intact PD-MCI PDD (n ¼ 9)

PD (n ¼ 41) (n ¼ 44)
Gender, %Male 56 62.8 68.3 56.8 66.7
Handedness, %R/L/A 98.8/0/1.2 98.9/0/1.1 97.6/0/2.4 100/0/0 100/0/0
Age, y 61.00(7.71) 61.64 (6.54) 59.73(6.59) 62.18(5.44) 67.67(7.76)
Education, y 12.31(3.57) 11.90(4.25) 12.93(3.59) 10.95(4.78) 11.89(3.44)
premorbid VIQb 107.9(10.42) 105.05(13.08) 109.33(13.31) 102.56(11.99) 97.73(11.88)
Age of onset, y e 57.61(6.94) 56.15(6.43) 57.77(6.52) 63.44(8.69)
Disease duration, y e 4.03(2.18) 3.59(2.03) 4.41(2.26) 4.22(2.39)
Stages e 1.53(0.50) 1.34(0.48) 1.61(0.49) 2.00(0.00)
LED e 622.0(334.5) 545.7(243.8) 644.38(362.9) 575.2(194.8)
a
Mean and standard deviation.
b
Estimated by demographic variables and the vocabulary subtests.

The effect size, Cohen’s d (d ¼ 0.2e0.49 indicates small, 0.5e0.79
medium, and S0.8 large), of each test was also shown in Table 3.
To determine which tests had greatest ability to differentiate PD
patients from controls, we conducted a logistic regression analysis.
Variables that were associated with cognitive decline in the
univariate analyses were entered into a logistic regression as
independent variables, whereas the diagnosis (PD vs. control
group) was the dependent variable. The results of the logistic
regression indicated that the MCST-C was measure that most
effectively differentiated patients from controls. The set of variables
correctly classified 70.4% of the cases (75.9% of PD patients and
62.7% of controls).
3.2. Proportion in patients with PD-MCI and PDD
Proportions of cognitively intact PD, PD-MCI, and PDD were
depicted in Fig. 1(A). By using DSM-IV criteria, eight (8.5%) patients
were classified as having dementia. One (1.1%) patient has two

Table 3
Neuropsychological performances in the study groups.a

HCs (n ¼ 84) All PD (n ¼ 94) PD-MCI (n ¼ 44) pb pc Cohen’s d

Executive function
MCST-C 5.96(1.22) 4.72(1.98) 4.20(1.95) 0.00 0.00 0.75
MCST-P 2.33(2.75) 5.07(8.05) 4.66(5.22) 0.01 0.00 0.46
MCST-NP 5.35(2.76) 7.70(4.71) 9.77(4.96) 0.00 0.00 0.61
Category fluency 39.25(8.16) 35.38(8.43) 35.52(8.33) 0.00 0.02 0.47
WMI 111.13(12.88) 105.32(13.35) 102.56(13.7) 0.01 0.00 0.44
Similarities 11.79(2.34) 11.05(2.96) 10.55(2.71) 0.05 0.00 0.28
Matrix reasoning 11.86(2.46) 10.53(2.81) 9.65(2.52) 0.00 0.00 0.50
Color trails part B 95.75(24.43) 117.47(53.09) 121.43(39.53) 0.04 0.00 0.53
Memory function
LM-I(r.s.) 38.93(10.92) 32.91(14.22) 28.89(12.09) 0.00 0.00 0.47
LM-II(r.s.) 24.04(9.16) 19.51(11.26) 16.32(9.99) 0.02 0.00 0.44
LM-recognition(r.s.) 25.73(6.57) 23.20(4.85) 22.48(4.34) 0.02 0.00 0.44
VR-I(r.s.) 76.56(13.71) 68.68(20.89) 64.14(18.31) 0.03 0.00 0.45
VR-II(r.s.) 55.6(20.39) 51.36(24.79) 47.02(21.75) 0.44 0.03 0.19
VR-recognition(r.s.) 43.30(2.95) 41.54(4.49) 40.14(4.03) 0.02 0.00 0.46
MMSE-3 objects 2.57(0.64) 2.14(1.00) 2.07(1.02) 0.01 0.01 0.51
Psychomotor speed
DSS 11.85(2.28) 10.29(2.33) 9.70(2.19) 0.00 0.00 0.68
Symbol searching 11.98(2.11) 10.21(2.82) 9.86(2.53) 0.00 0.00 0.71
Processing speed index 110.47(10.89) 101.22(13.01) 98.79(11.73) 0.00 0.00 0.77
Color trails part A 47.88(15.68) 63.62(34.12) 70.71(35.09) 0.00 0.01 0.59
Visuospatial function
Block design 11.48(2.29) 9.87(2.45) 9.30(2.31) 0.00 0.00 0.68
Pentagon copy, %Error 0% 12.2% 22.7% 0.00 0.00 0.51
Attention
Digit span 12.26(3.03) 11.12(2.60) 10.64(2.77) 0.04 0.01 0.40
Digit span-forward 7.78(1.46) 7.76(1.27) 7.65(1.33) 0.66 0.38 0.01
Digit span-backward 5.49(1.61) 4.82(1.48) 4.70(1.58) 0.01 0.01 0.43
Digit span-difference 2.29(1.45) 2.95(1.43) 2.95(1.54) 0.00 0.02 0.46
Color trails-interference 1.10(0.52) 1.20(2.16) 0.98(0.83) 0.09 0.13 0.06
Serial 7s 4.62(0.75) 4.42(1.14) 4.57(1.04) 0.53 0.74 0.21
Language
Naming 2.00(0.00) 2.00(0.00) 2.00(0.00) 1.00 1.00 e
Repetition 1.00(0.00) 1.00(0.00) 1.00(0.00) 1.00 1.00 e
Verbal comprehension 2.97(0.16) 2.90(0.40) 2.89(0.443) 0.22 0.26 0.23

Abbreviations: see Table 1 and 2 and WMI, working memory index; r.s., raw score; LM-I, immediate memory of the logical memory; LM-II, delayed memory of the logical
memory; VR-I, immediate memory of the visual reproduction; VR-II, delayed memory of the logical memory; DSS, digit symbol substitution; MCST-C, MCST-P, and MCST-NP
indicate the achieved categories, perseverative, and non-perseverative errors in the modified card sorting test, respectively.
a
Mean and standard deviation.
b
Comparisons between healthy controls and all PD.
c
Comparisons between healthy controls and PD-MCI.
1070 R.-L. Yu et al. / Parkinsonism and Related Disorders 18 (2012) 1067e1072
Fig. 1. The proportion of (A) cognitively intact PD, PD-MCI, PDD and (B) PD-MCI subtype. Abbreviations: aMCI, amnestic mild cognitive impairment; non-aMCI, non-amnestic mild
cognitive impairment; s, single domain; m, multiple domains.
impaired non-memory cognitive domains (executive and
psychomotor speed) plus social function impairment, but he was
excluded from the dementia list based on the DSM-IV criteria.
3.3. Pattern of cognitive impairment in patients with PD-MCI
The proportions of subtype among PD-MCI were shown in
Fig. 1(B). The percentage of impairment in PD-MCI and PDD were
shown in Fig. 2(A), and across different subtype of PD-MCI, the
profile of impairment was depicted in Fig. 2(B).
4. Discussion
Compared with either controls’ or normative data, our early-
stage PD patients showed impaired performance, particularly in
executive and psychomotor cognitive functions, on a wide range of
standardized neuropsychological tests. Executive function is
a complex construct, and the exact pattern of executive impairment
in PD is still being debated [21]. Our findings are consistent with
other studies indicating that executive function deficits predomi-
nate in patients with PD [6,8] and are compatible with patho-
physiological evidence suggesting that the frontostriatal loop
dysfunction develops at an early stage in the disease course [22,23].
Results from the executive function measurements suggest that the
MCST, conventionally thought to reflect dorsolateral prefrontal
functioning [24], can differentiate patients with PD from control
participants more effectively than other neuropsychological tests.
Patients do appear to benefit from executive function training
(i.e., mental shifting ability) tailored to their needs [25]. Our study
has revealed that a number of specific executive abilities, specifi-
cally concept formation and cognitive flexibility, should be
emphasized in rehabilitation programs designed for PD patients.
Relatively few previous studies have focused on processing speed
function even though it is crucial for everyday functions. Our
findings of processing speed impairment are in agreement with
Muslimovic et al. [6] However, further study using motor-free
measures is needed to determine whether this impairment is one
of the core cognitive dysfunctions in early-stage PD patients.
The PD-MCI cases found in this study are heterogeneous in
nature with a prevailing impairment in executive function, which
markedly differs from a primary deficit of memory most
commonly seen in the MCI of Alzheimer’s Disease (AD). In this
hospital-based population of early-stage PD patients, 9.6% met the
consensus diagnostic criteria [12] for PDD and 46.8% had defects
in at least one cognitive domain. Our findings are compatible with
the literature [5,7,13] and suggest that single-domain MCI is more
common than multiple-domain MCI and that non-aMCI is more
common than aMCI in the PD population. Across the different
types of PD-MCI, executive function was the most commonly
impaired domain. Moreover, the distribution of different domains
of cognitive impairment further revealed the heterogeneity of
PD-MCI.
Similar to the findings described here, Caviness et al. [26] and
Janvin et al. [27] also found that large proportions of PD-MCI
patients exhibited single-domain frontal/executive dysfunction.
However, some of our patients manifested single-domain MCI
characterized by visuospatial impairment. In fact, some studies
have reported that single-domain non-aMCI is associated with later
development of dementia [27]. Others have suggested that visuo-
spatial deficits rather than frontostriatal executive dysfunction play
an important role in dementia development in early PD patients
[28]. If this is the case, visuospatial ability impairment could be
a pivotal predictor of PDD.
Based on the present study and most other available cross-
sectional and limited longitudinal study results, the issue of
whether such a cognitive impairment is persistent in nature along
the disease course remains undetermined. In this study, it seems
that the PD-MCI is a transitional stage of PDD; however, our small
PDD sample size and cross-sectional study design limit this inter-
pretation. More extensive research is needed to determine whether
PD-MCI is a precursor of PDD. Furthermore, the sense of function
heterogeneity in patients does not only implicate the aspect of
dysfunction, but also espouse normal function. Indeed, there were
43.6% of our patients with sound cognitive function. It will be
important and intriguing to further explore potential factors that
may protect cognitive function resilience in early-stage PD patients
without MCI.
 R.-L. Yu et al. / Parkinsonism and Related Disorders 18 (2012) 1067e1072
Fig. 2. The percentage of impairment in (A) PD-MCI and PDD, and (B) different subtype of PD-MCI.
The current study revealed that PDD patients’ cognitive func-
tions are closely associated with the frontostriatal circuitry rather
than the posterior cortical circuitry. Our finding is conflict with the
results from other studies showing that posterior cortical
dysfunction is closely related to dementia in PD [10,11]. The
discrepancy suggests that using DSM-IV criteria, which rely heavily
on memory function to classify PDD patients, will result in false-
negative errors thereby underestimating the disease prevalence.
In view of the different patterns of cognitive impairment between
AD and PD and the heterogeneity of cognitive dysfunction within
the PD population itself, our study favors application of the
dementia criteria proposed by the MDS. The MDS criteria include
most cognitive function domains and weigh each domain equally
rather than predominantly focusing on memory function.
Although this study has provided novel insights into the
cognitive domain dysfunction profile of early-stage PD patients, it
does have some limitations. First, the MCI definition used here was
based entirely on cognitive tests. The original MCI clinical diagnosis
requires the presence of a patient’s subjective cognitive complaints
[29]; however, some evidence suggests that not all early-stage PD
patients have preserved meta-memory/awareness of memory
ability [30], which may lead to over or underreporting [2,26].
Hence, the presence or absence of subjective memory complaints
was not included as part of the MCI definition in this analysis.
Second, a detailed motor rating scale (i.e., part III of the Unified
Parkinson Disease Rating Scale) was not used in this study, and
thus, cognitive performance could not be corrected for motor
impact. Since different pathophysiological mechanisms among the
PD patients with various motor symptoms could contribute to
different cognitive dysfunction [8,11], various motor disturbances
should be taken into account in future studies. Last, participants
recruited in this study did not receive a detailed neuropsychiatric
1071
assessment (i.e., Neuropsychiatric Inventory). Although the role of
neuropsychiatric symptoms in cognitive function remains a very
promising area of research, this line of research was beyond the
scope of the current study.
In summary, cognitive dysfunction is common in early-stage PD
patients, and specific neuropsychological testing of executive
function can effectively differentiate patients from normal controls.
The current study suggests that early-stage PD patients have
cognitive dysfunction predominantly in the anterior brain, and
comprehensive neuropsychological assessments should be
administered to patients in the initial disease stage. Furthermore,
our findings favor the clinical applicability of the dementia criteria
proposed by the MDS over that of the DSM-IV.
Acknowledgments
We are grateful to the participants involved in this study for
their support and the grant from the National Science Council,
Taipei, Taiwan (NSC 98-2410-H-002-026-MY3 and NSC 100-2420-
H-002-019-DR) and National Taiwan University Hospital (NTUH
101-S1889).
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