MDS Task Force on Mild Cognitive Impairment in Parkinson’s disease: Critical Review of PD-MCI

doi:10.1002/mds.23823

Mov Disord. Author manuscript; available in PMC 2012 August 15.

Published in final edited form as:

Mov Disord. 2011 August 15; 26(10): 1814–1824.

Published online 2011 June 9. doi: 10.1002/mds.23823

PMCID: PMC3181006

NIHMSID: NIHMS296543

MDS Task Force on Mild Cognitive Impairment in Parkinson’s disease: Critical Review of PD-MCI

I Litvan,¹ D Aarsland,² CH Adler,³ JG Goldman,⁴ J Kulisevsky,⁵ B Mollenhauer,⁶ MC Rodriguez-Oroz,⁷^* AI Tröster,⁸ and D Weintraub⁹

¹ Division of Movement Disorders, Department of Neurology, University of Louisville, Louisville, KY, USA and Movement Disorders Program, Frazier Rehab Neuroscience Institute, Louisville, KY

² Centre for Age-Related Medicine, Stavanger University Hospital and Akershus University Hospital/University of Oslo

³ Parkinson’s Disease and Movement Disorders Center, Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA

⁴ Section of Parkinson Disease and Movement Disorders, Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA

⁵ Movement Disorders Unit, Neurology Department, Sant Pau Hospital and Institute of Biomedical Research (IIB Sant Pau), Universitat Autònoma de Barcelona and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain

⁶ Paracelsus-Elena-Klinik, Kassel and Georg-August University Goettingen, Germany

⁷ Department of Neurology, Clinic Universidad de Navarra, Medical School, Neuroscience Center, CIMA, Pamplona, Centros de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain

⁸ Department of Neurology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

⁹ Departments of Psychiatry and Neurology, University of Pennsylvania School of Medicine; Parkinson’s Disease and Mental Illness Research, Education and Clinical Centers (PADRECC and MIRECC), Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, USA

^*Current address: Department of Neurology, Hospital Donostia and BioDonostia, San Sebastian, Spain.

The publisher's final edited version of this article is available at Mov Disord

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Abstract

Background

There is controversy regarding the definition and characteristics of mild cognitive impairment in Parkinson’s disease.

Objective

The Movement Disorders Society commissioned a Task Force to critically evaluate the literature and determine the frequency and characteristics of Parkinson’s disease-mild cognitive impairment and its association with dementia.

Methods

Comprehensive PubMed literature review using systematic inclusion and exclusion criteria.

Results

A mean of 26.7% (range, 18.9–38.2%) of non-demented Parkinson’s disease patients have mild cognitive impairment. The frequency of Parkinson’s disease mild cognitive impairment increases with age, disease duration, and disease severity. Impairments occur in a range of cognitive domains, but single domain impairment is more common than multiple domain impairment, and within single domain impairment, non-amnestic is more common than amnestic impairment. A high proportion of patients with Parkinson’s disease-mild cognitive impairment progress to dementia in a relatively short period of time.

Conclusions

The primary conclusions of the Task Force are that: (1) Parkinson’s disease-mild cognitive impairment is common; (2) there is significant heterogeneity within Parkinson’s disease-mild cognitive impairment in the number and types of cognitive domain impairments; (3) Parkinson’s disease-mild cognitive impairment appears to place patients at risk of progressing to dementia; and (4) formal diagnostic criteria for Parkinson’s disease-mild cognitive impairment are needed.

Keywords: mild cognitive impairment, Parkinson’s disease, systematic review

INTRODUCTION

Cognitive impairment is common in Parkinson’s disease (PD), with long-term longitudinal studies reporting that most PD patients develop dementia (PDD).^1–3 The impact of PDD is substantial, with major consequences for functioning,^{4, 5, 6} nursing home admission,⁷ psychiatric morbidity,⁸ caregiver burden ^{9, 10} and mortality.^{11, 12}

Mild cognitive impairment in PD (PD-MCI), defined as a cognitive decline that is not normal for age but with essentially normal functional activities, also appears to be common, even at the time of PD diagnosis and prior to initiation of dopaminergic therapy.¹³ Although the term MCI applied to PD is not without controversy,^{14, 15} it is more frequently used and more widely accepted than alternative terms. Identifying PD-MCI is important clinically, as these patients appear to be at increased risk for developing PDD.¹⁶ The biological validity of PD-MCI is supported by preliminary structural¹⁷ and functional^{18, 19} neuroimaging, electroencephalography,^{20, 21} genetic,^{22, 23} cerebrospinal fluid,^24–26 and autopsy studies²⁷ showing an association between a range neuropathophysiological variables and either cognitive impairment or cognitive decline in non-demented PD patients. From a scientific standpoint, studying PD-MCI offers insight into the neural substrate of the earliest stage of cognitive decline in PD that may lead to early intervention and may guide drug development focused on preventing or delaying the onset of PDD.

In spite of what is known about PD-MCI, the heterogeneity of cognitive deficits from the initial stages of the disease and the relative scarcity of longitudinal studies have made it difficult to definitively determine the following: (1) whether there are different and reproducible subtypes of PD-MCI; (b) what proportion of PD-MCI patients progress to PDD; (3) whether the term MCI can be defined and operationalized in PD to determine those patients at imminent risk of PDD; and (4) whether this risk differs on the basis of MCI subtype.

Given the critical importance of having uniform criteria for PD-MCI both for the identification and management of PD patients and for future therapeutic trials, the Movement Disorders Society (MDS) commissioned a Task Force to: (1) critically evaluate the literature; (2) more accurately determine the frequency and characteristics of PD-MCI and its conversion rate to PDD; and (3) propose formal diagnostic criteria for PD-MCI. The present paper deals with the first two of these issues since they are necessary to address prior to proposing new criteria. Criteria and guidelines for the definition and ascertainment of MCI in PD based on the present “state of the art” will be addressed in a future manuscript.

MATERIALS AND METHODS

Literature Search and Selection of Articles

A comprehensive review of the literature through September 1, 2010 was conducted through Medline (PubMed) using combined free search terms that included “Parkinson,” “cognitive impairment,” and “mild cognitive impairment.” The search was limited to empirical English-language articles. The search retrieved 984 articles using the key terms “Parkinson and cognitive impairment” and 172 articles using “Parkinson and mild cognitive impairment,” with most of the latter articles already retrieved in the first search.

Abstracts (or papers when abstracts lacked information on inclusion and exclusion criteria) were further scrutinized to include only those reports that fit study inclusion criteria: (1) a minimum of 100 non-demented PD patients in cross-sectional studies, or 50 patients in prospective studies; (2) presence of quantitative neuropsychological information covering at least three of five cognitive domains: memory, executive, attention/working memory, visuospatial, and language; and (3) comparison of PD to a local control group or use of normative values. Exclusion criteria were: (1) lack of definition of impaired cognition or dementia, review articles, guidelines, meta-analyses, clinical therapeutic trials (unless the trial was negative), and (2) cognitive studies in demented or surgically-treated PD patients and in other neurological diseases, and articles focused on depression, REM sleep behavior disorder, olfactory dysfunction, impulse control disorders or psychosis without relevant cognitive data. Articles with abstracts that did not disclose all inclusion/exclusion criteria explicitly were included for further review.

Forty-eight articles met study inclusion criteria based on the review. The 48 articles were reviewed by five pairs of Task Force members (approximately 10 articles per pair) who independently extracted key data from the identified articles.^{1, 3, 12, 13, 16, 28–70} The most common reasons for exclusion were lack of definition of impaired cognition or failure to explicitly exclude patients with dementia, ^{1, 3, 29, 30, 33, 36, 42, 44–46, 48, 49, 51, 55–57, 59, 62, 64, 66, 67} sample size not meeting inclusion criteria ^{31, 32, 35, 37, 52, 58, 60, 71, 72}, or evaluation of less than 3 domains of cognition. ^{3, 12, 61, 63, 65, 69}

Data Extraction and Quality Assessment

The Task Force members rated the manuscripts using a structured form that included: (1) type of study (random, door-to-door; multiple sources; hospital based); (2) number of PD patients and percentage of patients with MCI, (3) demographics; (4) diagnostic criteria for PD, MCI, and PDD; (5) neuropsychological tests utilized; (6) number of cognitive domains tested; and (7) the presence of a normal control group or use of tests with normative values. For our final analysis we selected articles that had clearly defined cognitive and PD diagnostic criteria, studied at least three cognitive domains with standard versions of published neuropsychological tests, either included a control group matched by age and education evaluated with the same protocol or utilized test normative values to define MCI, and did not include the same study population as another study (except for prospective studies).

RESULTS

A total of 8 papers met all the inclusion/exclusion criteria. The studies included a total of 776 PD patients from 6 cross-sectional studies and 198 from 2 prospective studies (Table 1) and varied widely regarding design, population, and criteria and methods for defining MCI and dementia.

Table 1

Demographics of studies that met systematic review study inclusion criteria.

Cross-sectional Studies

Table 2 shows the neuropsychological tests and domains explored, MCI criteria used, and MCI subtypes found in each study. Overall, the studies demonstrate that PD-MCI is common in PD patients without dementia (mean cross-sectional prevalence =26.7%, range =18.9–38.2%), its frequency increases with age and duration of PD, single domain impairment is more common than multiple domain impairment, and in the case of single domain impairment, non-amnestic MCI is more common than amnestic MCI.

Table 2

Assessments, PD-MCI criteria and cognitive profiles.

Aarsland et al.²⁸ evaluated a community-based incident cohort of 196 non-demented, drug-naïve PD patients⁷³ and 201 healthy controls (HC). The neuropsychological battery measured global cognition with the Mini-Mental State Examination (MMSE) and evaluated three cognitive domains with additional neuropsychological testing. The authors calculated z-scores for the PD patients based on control data. They categorized MCI cases into one of four subtypes (Table 2). Compared with HC, PD patients were impaired on all neuropsychological tests, and 18.9% met criteria for MCI (Table 1), with a risk ratio (RR) of 2.1 compared with controls. Older PD patients (≥65 years) had a higher RR (2.6) of having MCI than younger cases (<65 years; RR=1.5).

Foltynie et al.³⁴ assessed cognitive function in an incident cohort of 159 PD patients.⁷⁴ Thirteen (8%) of the patients⁷⁴ scored <24 on MMSE and were considered to have dementia, even though dementia at diagnosis was an exclusion criterion. Of the remaining 146 cases, 142 were included in the study, and more than one-third were considered cognitively impaired, defined as scoring ≥1 SD below the normative mean in a pattern recognition task (temporal lobe impairment), the Tower of London task (fronto-striatal impairment), or on both tests (global impairment). The term “MCI” was not used in this study.

Hoops et al.⁴⁰ compared the discriminant validity of the Montreal Cognitive Assessment (MoCA) and MMSE at diagnosing MCI in PD, using a neuropsychological test battery as a gold standard. Among a convenience sample of 132 PD cases at a movement disorders clinic,⁷³ 12.9% had PDD and 20% had MCI based on a test battery that evaluated four cognitive domains.

Mamikonyan et al.,⁴⁷ explored the cognitive performance of 106 PD patients (a convenience sample at a movement disorders clinic), who had intact global cognition based on ther age- and education-adjusted MMSE score. Thirty-one patients (29.2%) were classified as having MCI, defined as scoring ≥1.5 SD below the normative data in at least one of the three domains assessed. The authors concluded that cognitive impairment is frequent in PD patients with normal cognition based on MMSE score, and that memory deficits are common at the stage of PD-MCI.

Muslimovic et al.,¹³ studied 115 PD patients without “global cognitive deterioration” defined as MMSE score <24 and 70 elderly HC in one of the most detailed investigations of cognition in non-demented PD patients. A comprehensive battery of 28 neuropsychological tests was administered, and PD patients were significantly impaired on 20 of these. Twenty-seven patients (23.5%) were cognitively impaired, defined as scoring ≥2 SD below the normative mean on ≥3 cognitive tests, compared with 4% of HC. The domains most commonly impaired were attention/executive function, psychomotor speed and memory.

Pai et al.,⁵³ studied cognitive abilities in 102 non-demented PD patients recruited from a behavioral clinic. They used the Chinese version of the Cognitive Ability Screening Instrument (CASI), a comprehensive screening instrument with normative data that includes subscores for five cognitive domains. They found that 38.2% fulfilled MCI criteria, defined as ≥1.5 SD below the mean in at least one subtest.

Longitudinal Studies

One of the studies reviewed⁶⁸ included the longitudinal assessment of patients on whom baseline data was reported in the cross-sectional studies selected above. ³⁴ Janvin et al.¹⁶ conducted a longitudinal study of cognitive function in a community-based sample of 145 PD cases. Cases and controls were assessed at baseline and at 4 years. Patients with MMSE score <25 at baseline were considered demented and excluded. Of the 145 original cases, 72 PD non-demented cases were studied and compared to 38 HC. After four years, for those who completed follow-up, dementia developed in 18/29 (62.0%) of patients with PD-MCI at baseline, compared with 6/30 (20.0%) of PD patients with normal cognition at baseline. This sample consisted of established PD patients, explaining the higher overall conversion rate to PDD over the same time period used in the CamPaign study (see below). The proportion converting to PDD was numerically higher among those with single domain non-amnestic MCI (69%) compared to amnestic MCI (40%), and in a logistic regression analysis this MCI subtype at baseline predicted PDD development. The authors concluded that PD-MCI is a risk factor for developing PDD.

Williams-Gray et al.,⁶⁸ reassessed 126 non-demented PD patients between 3–5 years after their baseline evaluation, and found that 10% developed PDD over this time period. In this first wave of follow-up, older age, non-tremor dominant phenotype, higher Unified Parkinson’s Disease Rating Scale motor scores, and below average performance on tests of semantic fluency, pentagon copying, spatial recognition memory, and Tower of London were associated with a more rapid rate of decline on the MMSE and progression to PDD. The authors concluded that posterior cortical cognitive deficits increased the risk for the development of PDD, whereas fronto-striatal cognitive deficits did not.

DISCUSSION

The results of our systematic literature search and review are that: (1) an average of 26.7% (range 18.9–38.2%) of non-demented PD patients have PD-MCI; (2) cognitive deficits can be detected in some patients even at the time of PD diagnosis; (3) the frequency of MCI increases with age, and duration and severity of PD; (4) impairments can occur in a range of cognitive domains; (5) non-amnestic single domain MCI is more common than amnestic single domain MCI; and (6) PD-MCI appears to be a risk factor for the development of PDD.

Prevalence and Correlates

The majority of PD patients will develop dementia.^{3, 22} The point prevalence of PDD is approximately 30%, ⁷⁵ and the cumulative prevalence is at least 75% for PD patients surviving more than 10 years.^{2, 3} As MCI precedes PDD, the cumulative prevalence of PD-MCI must be at least as high as that of PDD. Consequently, our finding that approximately 27% of PD patients meet criteria for PD-MCI at any given time is not surprising. Our results are similar to those recently reported by Aarsland et al.,⁷⁶ who used a common methodology for the definition of MCI on pooled data of over 1,000 non-demented PD patients from multiple centers, and found that 25.8% (23.5–28.2%) had MCI.

The lowest proportion of patients with MCI was found in a study of patients at early PD stages,¹³ and the highest proportion in studies including cases with more advanced disease severity and duration.^{16, 68, 76} The variation in MCI frequency present in the articles reviewed also reflects differences in methodology (e.g., study settings and populations, recruitment methods, MCI diagnostic criteria, number of cognitive domains assessed, number of tests used for each domain, and how impairment on a test was defined). The fact that cognitive deficits in PD are detectible in some patients even at the time of clinical diagnosis highlights complexities in differentiating PD from dementia with Lewy bodies (DLB).

The correlates of PD-MCI have not been studied extensively. Of the studies included in this review, there was evidence that increasing age, ^{34, 47} more severe PD, ^{34, 47} late onset of disease, ¹³ and lower educational levels ⁵³ were associated with PD-MCI.

Profile of Cognitive Impairment

Although the cognitive deficits in PD have traditionally been classified as being “subcortical” in nature⁷⁷ (i.e., relatively greater impairments in executive abilities, information processing speed, and working memory compared with episodic memory storage and language), our review showed that a range of cognitive domains are impaired in PD patients without dementia. Other research in PD has demonstrated deficits in executive (i.e., impaired planning and working memory),⁷⁸ visuospatial,⁷⁹ attentional,⁸⁰ memory,⁸¹ and even language abilities.^82–85

In all of the studies reviewed herein, single domain MCI was more common than multiple domain MCI, and non-amnestic MCI was more common than amnestic MCI in patients with impairment in a single domain. Debate exists about the extent to which the mild memory and language deficits in PD are secondary to executive and working memory problems. Additionally, as prospective studies using formal definitions for MCI subtypes are almost non-existent, the usefulness and predictive value of this PD-MCI classification structure is currently hypothetical.

Epidemiology of Progression from PD-MCI to Dementia

The few longitudinal studies of non-demented PD patients find that 20–60% develop PDD over a period of 2–5 years,^{22, 46, 76, 86–89} and even newly diagnosed PD patients on average experience significant decline in a range of cognitive domains over a several-year period.^49,90 The finding that PD-MCI patients are at higher risk for developing dementia is consistent with a clinico-pathologic study reporting cognitive impairment in the earliest stages of clinically manifested PD, possibly related to changes in brainstem monoaminergic nuclei or early involvement of forebrain cholinergic nuclei.⁹¹

Preliminary research suggests that the majority of PD-MCI cases convert to PDD over a several-year period.^{16, 22, 68} The two longitudinal studies included in this review differed in terms of design and methodology. Williams-Gray et al.⁶⁸ followed an incident cohort of non-demented PD patients in two waves, but did not specifically examine progression from a state of “mild impairment” to PDD. The focus of this research to date has been to determine which demographic (increasing age), neuropsychological (semantic verbal fluency and visuospatial deficits), and genetic factors (MAPT H1/H1 tau genotype) predicted conversion to PDD at the second wave of follow-up²². The other study used a cross-sectional sample of survivors from a prevalence sample.¹⁶ In this study, Janvin et al. found that 62% of PD-MCI patients converted to PDD over a 4-year period, compared with 20% of PD patients with normal cognition. The frequency of conversion to PDD over a 4-year period was: multiple domain MCI (63%), single, non-memory domain MCI (69%), single domain, amnestic MCI (40%), and normal cognition (20%).

Regarding other risk factors, in one of the longitudinal studies reviewed increasing severity of depression was associated with an increased risk of conversion from PD-MCI to PDD.¹⁶ In other research not covered in this manuscript, demographic and clinical correlates or risk factors for PDD development have included older age, male sex, lower educational level, longer duration of PD, and greater motor impairment.^{22, 64, 83, 86, 90, 92, 93}

Clinical Impact

PD-MCI appears to be a clinically significant syndrome, as even mild cognitive deficits or self-rated cognitive deficits in early PD are associated with functional impairment^{5, 94} and worse quality of life (QoL).^{95, 96} Thus, identification and intervention at the earliest stage of PD-MCI is a crucial unmet need for the overall care of PD patients. The high frequency of MCI in PD highlights the need for clinicians to routinely screen for cognitive impairment in PD, as the results, including their prognostic implications, may influence clinical decision-making. However, research in this area is preliminary, and additional studies are needed to validate measures that are sensitive to initial changes in independent activities of daily living (IADLs), QoL and interpersonal relationships that can occur at the stage of PD-MCI.

Complexities in the Assessment of Cognition in PD

Assessment of cognition in PD can be complicated by disease or medication-related effects, such as bradykinesia, fatigue, sleepiness, and mood disorders, which can adversely impact test results regardless of cognitive abilities. Specifically, motor slowing (i.e., bradykinesia) and resting or intentional tremor may lead to impaired performance on any timed test, while tremor can interfere with performance on any test requiring motor abilities (e.g., use of a pencil to complete a task). However, there has been very little research examining the impact of these factors on cognitive performance specifically.

Another issue is that the definition of MCI forces a dichotomization (present-absent) of a continuous variable (cognitive test performance), and debate continues regarding the appropriate cut-off score and number of tests used to define PD-MCI. Caviness et al.³² reported that 21% of subjects had PD-MCI if an abnormality on multiple tests within a domain was required, but this rose to 42% if an abnormality on only one test was required. There is concern that the commonly-used definitions of MCI may lack sensitivity to detect early cognitive decline (rather than impairment) in high functioning persons.⁹⁷ Persons functioning at a high level (i.e., above average) premorbidly have to experience sizeable declines before scoring at least 1.5 SD below normative means. Consequently, a considerable proportion of such patients with cognitive decline would be classified as having “normal cognition.” While it can be argued that high premorbid functioning protects against MCI in much the same manner as it does against dementia, this argument ignores the fact that high functioning persons may be in more demanding work or social settings in which even small cognitive declines translate into subtle functional impairments. On the other hand, a key feature in diagnosing MCI pertains to a change in cognition. Thus, MCI is not just a value on a cognitive test relative to the mean; rather, it is critical that the person has experienced a change in cognition compared with baseline.

Additional unresolved issues are whether cognitive decline in PD is linear and whether different profiles of cognitive deficits may have a different evolution and prognosis. Previous studies have noted that time to PDD diagnosis is highly variable⁹⁸ and that cognitive changes after relatively long-term follow-up are not too consistent.⁹⁷ Although a distinct evolution of different cognitive domains cannot be inferred from a study using only the MMSE, the re-analysis of data from a long-term prevalence study identified a variation in the slope of decline, specifically a rapid cognitive deterioration after a relatively stable period.⁹⁹ These data should be examined in light of neuroimaging^{18, 19} and clinical^{52, 68} data showing that the transition from MCI to dementia in PD is characterized by the addition of posterior cortical deficits upon frontal-subcortical ones.

Biomarkers

None of the reviewed papers examined biomarkers specifically as they pertain to PD-MCI. One of the incident cohorts included in this review underwent a second wave follow-up, ²² and in that research the tau MAPT H1/H1 genotype (but not COMT genotype) was found to be a risk factor for PDD, a finding recently confirmed.²² Other genetic polymorphisms (e.g., COMT polymorphisms and BDNF Val66Met genotype ^{100, 101}) have been shown to be associated with impairments in specific cognitive domains or abilities in PD. Several CSF biomarkers for cognitive decline in PD have been proposed.¹⁰² Recent research suggests decreased CSF β-amyloid (Aβ) 1–42 is associated with the early stages of cognitive decline in PD.^{24, 26} This decrease might be due to specific Aβ plaque pathology, but it may be nonspecific, as Aβ 1–42 has been shown to be decreased in neurodegenerative disorders lacking distinct plaque pathology^103–105 and in vivo plaque imaging (PET imaging with the Aβ-binding Pittsburgh Compound B) shows no correlation between the plaque load and cognition in PD. ¹⁰⁶ Instead, the findings suggest a different mechanism of Aβ processing, perhaps due to synaptic α-synuclein pathology. ^{107, 108} Structural neuroimaging, including diffusion tensor imaging, have reported white matter abnormalities in non-demented PD patients.¹⁰⁸ In another study¹⁷ that classified patients as PD normal cognition (PD-NC), PD-MCI, or PDD and used two different imaging analyses, PD-MCI patients compared with PD-NC either had reduced gray matter in the prefrontal cortex and temporal lobes,¹⁷ or were found to have similar regional brain volumes. Using FDG-PET, a PD-related cognitive pattern in non-demented PD patients has been reported, characterized by metabolic reductions in frontal and parietal association areas, and relative increases in the cerebellar vermis and dentate nuclei.¹⁰⁹ The pattern predicted memory and visuospatial performance, and in a subsequent study single domain MCI patients had a PD-related cognitive pattern expression intermediate (but not statistically significantly different) between normal and multiple domain MCI patients.¹⁸ Clearly there is a need for the prospective and longitudinal assessment of accessible biomarkers (including CSF, blood, and neuroimaging) and neuropathological examination to further address this issue.

Conclusions and Future Directions

There has been limited research on the epidemiology and prognostic utility of PD-MCI as a clinical syndrome. Nonetheless, the studies selected for review here, and other studies of PD-MCI not meeting inclusion criteria, yield relatively consistent prevalence estimates of MCI and its subtypes. They also show that single domain MCI is more common than multiple domain MCI, and that non-amnestic, single domain MCI is more common than amnestic, single domain MCI.

The Task Force has used this critical review of the literature and consensus of experts to formulate PD-MCI diagnostic criteria that will be published separately. Once diagnostic criteria for PD-MCI are proposed, prospective studies enrolling subjects with a wide range of pre-morbid ability will be needed to examine the predictive value of both MCI overall and MCI subtypes. Intervention trials can target MCI as a clinical syndrome, perhaps stratifying MCI by subtype to determine if particular interventions (pharmacological vs. behavioral) have differential acute or long-term effects. Although it is not known if or how a diagnosis of PD-MCI should impact clinical management, at a minimum these patients should be carefully monitored for ongoing cognitive decline.

Figure

Search Results

Acknowledgments

Irene Litvan is funded by 5R01AG024040-04.

Author Roles

1. Research project: A. Conception, B. Organization, C. Execution

2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique

3. Manuscript: A. Writing of the first draft, B. Review and Critique

Authors	Research Project	Statistical Analysis	Manuscript
Litvan I	A, B, C	B, C	A, B
Aarsland D	A, C	C	A, B
Adler C	A, C	C	A, B
Goldman J	A, C	C	A, B
Kulisevsky J	A, C	C	A, B
Mollenhauer B	A, C	C	A, B
Rodriguez-Oroz MC	A, C	C	A, B
Tröster AI	A, C	C	A, B
Weintraub D	A, C	C	A, B

Financial disclosure related to research covered in this article: A statement that documents all funding sources and potential conflicts of interest from each author that relate to the research covered in the article submitted must be included on the title page, regardless of date. This material will be available online and may be printed at the discretion of the editors.

Irene Litvan
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Dag Aarsland
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Charles Adler
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Jennifer G. Goldman
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Jaime Kulisevsky
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Brit Mollenhauer
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Maria C. Rodriguez-Oroz
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Alexander I. Tröster
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Daniel Weintraub
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Full financial disclosure for the previous 12 months: A statement that documents all funding sources, regardless of relationship to the current research in the article, from each author must be attached to the article at the end of the manuscript on the last page. This material will be printed or posted on the journal website at the Editors’ discretion.

Irene Litvan
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Grants: 5R01AG024040-04, Parkinson Study Group, Allon Therapeutics, Noscira, National Parkinson Foundation, CurePSP, Signature Partnership (University of Louisville), Litvan Neurological Research Foundation	Other: Endowment/Donations Parkinson Support Center of Kentuckiana

Dag Aarsland
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Charles Adler
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Grants Arizona Biomedical Research Commission, Michael J. Fox Foundation	Other

Jennifer G. Goldman
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Grants: NIH/NINDS, Parkinson’s Disease	Other Merz, Boehringer-
Foundation	Ingelheim

Jaime Kulisevsky
Stock Ownership in medically-related fields: None	Intellectual Property Rights: None
Consultancies: None	Expert Testimony: None
Advisory Boards: Merck-Serono	Employment: None
Partnerships: None	Contracts: None
Honoraria: Lundbeck, Boheringer	Royalties: None
Grants: Boheringer, Merck-Serono, CIBERNED	Other

Brit Mollenhauer
Stock Ownership in medically-related fields:None	Intellectual Property Rights: None
Consultancies: None	Expert Testimony: None
Advisory Boards: Novartis	Employment: None
Partnerships: None	Contracts: None
Honoraria: GlaxoSmithKline, Orion Pharma	Royalties: None
Grants: Michael J. Fox Foundation for Parkinson’s Research	Other Research support TEVA Pharma, Desitin, GE Healthcare, Boehringer-Ingelheim

Maria C Rodriguez-Oroz
Stock Ownership in medically-related fields None	Intellectual Property Rights: None
Consultancies None	Expert Testimony: None
Advisory Boards UCB	Employment: None
Partnerships None	Contracts: None
Honoraria GlasoSmithKline, UCB, Lundbeck, Medtronic	Royalties: None
Grants. FIS, Spanish Government; Health Navarrian Government,	Other None

Alexander Tröster
Stock Ownership in medically-related fields	Intellectual Property Rights: None
Consultancies Medtronic, St Jude	Expert Testimony: None
Advisory BoardsMedtronic, St Jude	Employment: None
Partnerships	Contracts: None
Honoraria Medtronic	Royalties: None
Grants	Intellectual Property Rights: None

Daniel Weintraub
Stock Ownership in medically-related fields: None	Intellectual Property Rights: Assigned copyright of QUIP to University of Pennsylvania
Consultancies: None	Expert Testimony: None
Advisory Boards: GE,	Employment: None
Partnerships: None	Contracts: None
Honoraria: Boehringer Ingelheim, Sanofi Aventis, Johnson and Johnson, Solvay	Royalties: None
Grants: NIH, Fox Foundation	Other: None

References

1. Buter TC, van den Hout A, Matthews FE, Larsen JP, Brayne C, Aarsland D. Dementia and survival in Parkinson disease: a 12-year population study. Neurology. 2008;70:1017–1022. [PubMed]

2. Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG. The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord. 2008;23:837–844. [PubMed]

3. Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sorensen P. Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch Neurol. 2003;60:387–392. [PubMed]

4. Bronnick K, Ehrt U, Emre M, et al. Attentional deficits affect activities of daily living in dementia-associated with Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2006;77:1136–1142. [PMC free article] [PubMed]

5. Rosenthal E, Brennan L, Xie S, et al. Association between cognition and function in patients with Parkinson disease with and without dementia. Mov Disord. 2010;25:1170–1176. [PMC free article] [PubMed]

6. Uc EY, Rizzo M, Anderson SW, Sparks JD, Rodnitzky RL, Dawson JD. Driving with distraction in Parkinson disease. Neurology. 2006;67:1774–1780. [PubMed]

7. Aarsland D, Larsen JP, Tandberg E, Laake K. Predictors of nursing home placement in Parkinson’s disease: a population-based, prospective study. J Am Geriatr Soc. 2000;48:938–942. [PubMed]

8. Aarsland D, Bronnick K, Ehrt U, et al. Neuropsychiatric symptoms in patients with Parkinson’s disease and dementia: frequency, profile and associated care giver stress. J Neurol Neurosurg Psychiatry. 2007;78:36–42. [PMC free article] [PubMed]

9. Aarsland D, Larsen JP, Karlsen K, Lim NG, Tandberg E. Mental symptoms in Parkinson’s disease are important contributors to caregiver distress. Int J Geriatr Psychiatry. 1999;14:866–874. [PubMed]

10. Schrag A, Hovris A, Morley D, Quinn N, Jahanshahi M. Caregiver-burden in parkinson’s disease is closely associated with psychiatric symptoms, falls, and disability. Parkinsonism Relat Disord. 2006;12:35–41. [PubMed]

11. Levy G, Tang MX, Louis ED, et al. The association of incident dementia with mortality in PD. Neurology. 2002;59:1708–1713. [PubMed]

12. Lo RY, Tanner CM, Albers KB, et al. Clinical features in early Parkinson disease and survival. Arch Neurol. 2009;66:1353–1358. [PubMed]

13. Muslimovic D, Post B, Speelman JD, Schmand B. Cognitive profile of patients with newly diagnosed Parkinson disease. Neurology. 2005;65:1239–1245. [PubMed]

14. Troster AI. Neuropsychological characteristics of dementia with Lewy bodies and Parkinson’s disease with dementia: differentiation, early detection, and implications for “mild cognitive impairment” and biomarkers. Neuropsychol Rev. 2008;18:103–119. [PubMed]

15. Dubois B, Burn D, Goetz C, et al. Diagnostic procedures for Parkinson’s disease dementia: recommendations from the movement disorder society task force. Mov Disord. 2007;22:2314–2324. [PubMed]

16. Janvin CC, Larsen JP, Aarsland D, Hugdahl K. Subtypes of mild cognitive impairment in Parkinson’s disease: progression to dementia. Mov Disord. 2006;21:1343–1349. [PubMed]

17. Beyer MK, Janvin CC, Larsen JP, Aarsland D. A magnetic resonance imaging study of patients with Parkinson’s disease with mild cognitive impairment and dementia using voxel-based morphometry. J Neurol Neurosurg Psychiatry. 2007;78:254–259. [PMC free article] [PubMed]

18. Huang C, Mattis P, Perrine K, Brown N, Dhawan V, Eidelberg D. Metabolic abnormalities associated with mild cognitive impairment in Parkinson disease. Neurology. 2008;70:1470–1477. [PubMed]

19. Hosokai Y, Nishio Y, Hirayama K, et al. Distinct patterns of regional cerebral glucose metabolism in Parkinson’s disease with and without mild cognitive impairment. Mov Disord. 2009;24:854–862. [PubMed]

20. Onofrij M, Gambi D, Malatesta G, Ferracci F, Fulgente T. Electrophysiological techniques in the assessment of aging brain: lacunar state and differential diagnosis. Eur Neurol. 1989;29 (Suppl 2):44–47. [PubMed]

21. Caviness JN, Hentz JG, Evidente VG, et al. Both early and late cognitive dysfunction affects the electroencephalogram in Parkinson’s disease. Parkinsonism Relat Disord. 2007;13:348–354. [PubMed]

22. Williams-Gray CH, Evans JR, Goris A, et al. The distinct cognitive syndromes of Parkinson’s disease: 5 year follow-up of the CamPaIGN cohort. Brain. 2009;132:2958–2969. [PubMed]

23. Seto-Salvia N, Clarimon J, Pagonabarraga J, et al. Dementia Risk in Parkinson Disease: Disentangling the Role of MAPT Haplotypes. Arch Neurol. 2011;68:359–364. [PubMed]

24. Alves G, Bronnick K, Aarsland D, et al. CSF amyloid-{beta} and tau proteins, and cognitive performance, in early and untreated Parkinson’s Disease: the Norwegian ParkWest study. J Neurol Neurosurg Psychiatry. 2010;81:1080–1086. [PubMed]

25. Ballard C, Jones EL, Londos E, Minthon L, Francis P, Aarsland D. alpha-Synuclein antibodies recognize a protein present at lower levels in the CSF of patients with dementia with Lewy bodies. Int Psychogeriatr. 2010;22:321–327. [PubMed]

26. Siderowf A, Xie SX, Hurtig H, et al. CSF amyloid {beta} 1–42 predicts cognitive decline in Parkinson disease. Neurology. 2010;75(12):1055–1061. [PMC free article] [PubMed]

27. Adler CH, Caviness JN, Sabbagh MN, et al. Heterogeneous neuropathological findingsin Parkinson’s disease with mild cognitive impairment. Acta Neuropathol. 2010;120:827–828. [PMC free article] [PubMed]

28. Aarsland D, Bronnick K, Larsen JP, Tysnes OB, Alves G. Cognitive impairment in incident, untreated Parkinson disease: the Norwegian ParkWest study. Neurology. 2009;72:1121–1126. [PubMed]

29. Athey RJ, Porter RW, Walker RW. Cognitive assessment of a representative community population with Parkinson’s disease (PD) using the Cambridge Cognitive Assessment-Revised (CAMCOG-R) Age Ageing. 2005;34:268–273. [PubMed]

30. Athey RJ, Walker RW. Demonstration of cognitive decline in Parkinson’s disease using the Cambridge Cognitive Assessment (Revised) (CAMCOG-R) Int J Geriatr Psychiatry. 2006;21:977–982. [PubMed]

31. Caparros-Lefebvre D, Pecheux N, Petit V, Duhamel A, Petit H. Which factors predict cognitive decline in Parkinson’s disease? J Neurol Neurosurg Psychiatry. 1995;58:51–55. [PMC free article] [PubMed]

32. Caviness JN, Driver-Dunckley E, Connor DJ, et al. Defining mild cognitive impairment in Parkinson’s disease. Mov Disord. 2007;22:1272–1277. [PubMed]

33. Cooper CA, Mikos AE, Wood MF, et al. Does laterality of motor impairment tell us something about cognition in Parkinson disease? Parkinsonism Relat Disord. 2009;15:315–317. [PubMed]

34. Foltynie T, Brayne CE, Robbins TW, Barker RA. The cognitive ability of an incident cohort of Parkinson’s patients in the UK. The CamPaIGN study. Brain. 2004;127:550–560. [PubMed]

35. Gill DJ, Freshman A, Blender JA, Ravina B. The Montreal cognitive assessment as a screening tool for cognitive impairment in Parkinson’s disease. Mov Disord. 2008;23:1043–1046. [PubMed]

36. Girotti F, Soliveri P, Carella F, et al. Dementia and cognitive impairment in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1988;51:1498–1502. [PMC free article] [PubMed]

37. Goldman WP, Baty JD, Buckles VD, Sahrmann S, Morris JC. Cognitive and motor functioning in Parkinson disease: subjects with and without questionable dementia. Arch Neurol. 1998;55:674–680. [PubMed]

38. Hayashi R, Hanyu N, Tamaru F. Cognitive impairment in Parkinson’s disease: a 6year follow-up study. Parkinsonism Relat Disord. 1998;4:81–85. [PubMed]

39. Hobson P, Meara J. The detection of dementia and cognitive impairment in a community population of elderly people with Parkinson’s disease by use of the CAMCOG neuropsychological test. Age Ageing. 1999;28:39–43. [PubMed]

40. Hoops S, Nazem S, Siderowf AD, et al. Validity of the MoCA and MMSE in the detection of MCI and dementia in Parkinson disease. Neurology. 2009;73:1738–1745. [PMC free article] [PubMed]

41. Janvin C, Aarsland D, Larsen JP, Hugdahl K. Neuropsychological profile of patients with Parkinson’s disease without dementia. Dement Geriatr Cogn Disord. 2003;15:126–131. [PubMed]

42. Janvin CC, Aarsland D, Larsen JP. Cognitive predictors of dementia in Parkinson’s disease: a community-based, 4-year longitudinal study. J Geriatr Psychiatry Neurol. 2005;18:149–154. [PubMed]

43. Kalbe E, Calabrese P, Kohn N, et al. Screening for cognitive deficits in Parkinson’s disease with the Parkinson neuropsychometric dementia assessment (PANDA) instrument. Parkinsonism Relat Disord. 2008;14:93–101. [PubMed]

44. Klepac N, Hajnsek S, Trkulja V. Cognitive performance in nondemented nonpsychotic Parkinson disease patients with or without a history of depression prior to the onset of motor symptoms. J Geriatr Psychiatry Neurol. 2010;23:15–26. [PubMed]

45. Locascio JJ, Corkin S, Growdon JH. Relation between clinical characteristics of Parkinson’s disease and cognitive decline. J Clin Exp Neuropsychol. 2003;25:94–109. [PubMed]

46. Mahieux F, Fenelon G, Flahault A, Manifacier MJ, Michelet D, Boller F. Neuropsychological prediction of dementia in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1998;64:178–183. [PMC free article] [PubMed]

47. Mamikonyan E, Moberg PJ, Siderowf A, et al. Mild cognitive impairment is common in Parkinson’s disease patients with normal Mini-Mental State Examination (MMSE) scores. Parkinsonism Relat Disord. 2009;15:226–231. [PMC free article] [PubMed]

48. Mavandadi S, Nazem S, Ten Have TR, et al. Use of latent variable modeling to delineate psychiatric and cognitive profiles in Parkinson disease. Am J Geriatr Psychiatry. 2009;17:986–995. [PMC free article] [PubMed]

49. Muslimovic D, Post B, Speelman JD, De Haan RJ, Schmand B. Cognitive decline in Parkinson’s disease: a prospective longitudinal study. J Int Neuropsychol Soc. 2009;15:426–437. [PubMed]

50. Nazem S, Siderowf AD, Duda JE, et al. Montreal cognitive assessment performance in patients with Parkinson’s disease with “normal” global cognition according to mini-mental state examination score. J Am Geriatr Soc. 2009;57:304–308. [PMC free article] [PubMed]

51. Oh JY, Kim YS, Choi BH, Sohn EH, Lee AY. Relationship between clinical phenotypes and cognitive impairment in Parkinson’s disease (PD) Arch Gerontol Geriatr. 2009;49:351–354. [PubMed]

52. Pagonabarraga J, Kulisevsky J, Llebaria G, Garcia-Sanchez C, Pascual-Sedano B, Gironell A. Parkinson’s disease-cognitive rating scale: a new cognitive scale specific for Parkinson’s disease. Mov Disord. 2008;23:998–1005. [PubMed]

53. Pai MC, Chan SH. Education and cognitive decline in Parkinson’s disease: a study of 102patients. Acta Neurol Scand. 2001;103:243–247. [PubMed]

54. Palazzini E, Soliveri P, Filippini G, et al. Progression of motor and cognitive impairment in Parkinson’s disease. J Neurol. 1995;242:535–540. [PubMed]

55. Pedersen KF, Larsen JP, Alves G, Aarsland D. Prevalence and clinical correlates of apathy in Parkinson’s disease: a community-based study. Parkinsonism Relat Disord. 2009;15:295–299. [PubMed]

56. Riedel O, Klotsche J, Spottke A, et al. Cognitive impairment in 873 patients with idiopathic Parkinson’s disease. Results from the German Study on Epidemiology of Parkinson’s Disease with Dementia (GEPAD) J Neurol. 2008;255:255–264. [PubMed]

57. Riepe MW, Kassubek J, Tracik F, Ebersbach G. Screening for cognitive impairment in Parkinson’s disease--which marker relates to disease severity? J Neural Transm. 2006;113:1463–1468. [PubMed]

58. Santangelo G, Trojano L, Vitale C, et al. A neuropsychological longitudinal study in Parkinson’s patients with and without hallucinations. Mov Disord. 2007;22:2418–2425. [PubMed]

59. Santangelo G, Vitale C, Trojano L, Verde F, Grossi D, Barone P. Cognitive dysfunctions and pathological gambling in patients with Parkinson’s disease. Mov Disord. 2009;24:899–905. [PubMed]

60. Starkstein SE, Bolduc PL, Mayberg HS, Preziosi TJ, Robinson RG. Cognitive impairments and depression in Parkinson’s disease: a follow up study. J Neurol Neurosurg Psychiatry. 1990;53:597–602. [PMC free article] [PubMed]

61. Taylor JP, Rowan EN, Lett D, O’Brien JT, McKeith IG, Burn DJ. Poor attentional function predicts cognitive decline in patients with non-demented Parkinson’s disease independent of motor phenotype. J Neurol Neurosurg Psychiatry. 2008;79:1318–1323. [PubMed]

62. Uc EY, McDermott MP, Marder KS, et al. Incidence of and risk factors for cognitive impairment in an early Parkinson disease clinical trial cohort. Neurology. 2009;73:1469–1477. [PMC free article] [PubMed]

63. van Rooden SM, Visser M, Verbaan D, Marinus J, van Hilten JJ. Patterns of motor and non-motor features in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2009;80:846–850. [PubMed]

64. Verbaan D, Marinus J, Visser M, et al. Cognitive impairment in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2007;78:1182–1187. [PMC free article] [PubMed]

65. Verbaan D, van Rooden SM, Visser M, Marinus J, Emre M, van Hilten JJ. Psychotic and compulsive symptoms in Parkinson’s disease. Mov Disord. 2009;24:738–744. [PubMed]

66. Verleden S, Vingerhoets G, Santens P. Heterogeneity of cognitive dysfunction in Parkinson’s disease: a cohort study. Eur Neurol. 2007;58:34–40. [PubMed]

67. Vingerhoets G, Verleden S, Santens P, Miatton M, De Reuck J. Predictors of cognitive impairment in advanced Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2003;74:793–796. [PMC free article] [PubMed]

68. Williams-Gray CH, Foltynie T, Brayne CE, Robbins TW, Barker RA. Evolution of cognitive dysfunction in an incident Parkinson’s disease cohort. Brain. 2007;130:1787–1798. [PubMed]

69. Zadikoff C, Fox SH, Tang-Wai DF, et al. A comparison of the mini mental state exam to the Montreal cognitive assessment in identifying cognitive deficits in Parkinson’s disease. Mov Disord. 2008;23:297–299. [PubMed]

70. Zakzanis KK, Freedman M. A neuropsychological comparison of demented and nondemented patients with Parkinson’s disease. Appl Neuropsychol. 1999;6:129–146. [PubMed]

71. Hayashi A, Nagaoka M, Yamada K, Ichitani Y, Miake Y, Okado N. Maternal stress induces synaptic loss and developmental disabilities of offspring. Int J Dev Neurosci. 1998;16:209–216. [PubMed]

72. Elgh E, Domellof M, Linder J, Edstrom M, Stenlund H, Forsgren L. Cognitive function in early Parkinson’s disease: a population-based study. Eur J Neurol. 2009;16:1278–1284. [PubMed]

73. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol. 1999;56:33–39. [PubMed]

74. Gibb WR, Lees AJ. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1988;51:745–752. [PMC free article] [PubMed]

75. Aarsland D, Zaccai J, Brayne C. A systematic review of prevalence studies of dementia in Parkinson’s disease. Mov Disord. 2005;20:1255–1263. [PubMed]

76. Aarsland D, Bronnick K, Williams-Gray C, et al. Mild cognitive impairment in Parkinson disease: a multicenter pooled analysis. Neurology. 2010;75:1062–1069. [PMC free article] [PubMed]

77. Pillon B, Deweer B, Agid Y, Dubois B. Explicit memory in Alzheimer’s, Huntington’s, and Parkinson’s diseases. Arch Neurol. 1993;50:374–379. [PubMed]

78. Siegert RJ, Weatherall M, Taylor KD, Abernethy DA. A meta-analysis of performance on simple span and more complex working memory tasks in Parkinson’s disease. Neuropsychology. 2008;22:450–461. [PubMed]

79. Cronin-Golomb A, Braun AE. Visuospatial dysfunction and problem solving in Parkinson’s disease. Neuropsychology. 1997;11:44–52. [PubMed]

80. Dujardin K, Degreef JF, Rogelet P, Defebvre L, Destee A. Impairment of the supervisory attentional system in early untreated patients with Parkinson’s disease. J Neurol. 1999;246:783–788. [PubMed]

81. Weintraub D, Moberg PJ, Culbertson WC, Duda JE, Stern MB. Evidence for impaired encoding and retrieval memory profiles in Parkinson disease. Cogn Behav Neurol. 2004;17:195–200. [PubMed]

82. Dubois B, Pillon B. Cognitive deficits in Parkinson’s disease. J Neurol. 1997;244:2–8. [PubMed]

83. Green J, McDonald WM, Vitek JL, et al. Cognitive impairments in advanced PD without dementia. Neurology. 2002;59:1320–1324. [PubMed]

84. Levin BE, Katzen HL. Early cognitive changes and nondementing behavioral abnormalities in Parkinson’s disease. Adv Neurol. 1995;65:85–95. [PubMed]

85. Lewis SJ, Cools R, Robbins TW, Dove A, Barker RA, Owen AM. Using executive heterogeneity to explore the nature of working memory deficits in Parkinson’s disease. Neuropsychologia. 2003;41:645–654. [PubMed]

86. Aarsland D, Andersen K, Larsen JP, Lolk A, Nielsen H, Kragh-Sorensen P. Risk of dementia in Parkinson’s disease: a community-based, prospective study. Neurology. 2001;56:730–736. [PubMed]

87. Levy G, Schupf N, Tang MX, et al. Combined effect of age and severity on the risk of dementia in Parkinson’s disease. Ann Neurol. 2002;51:722–729. [PubMed]

88. Marder K, Tang MX, Cote L, Stern Y, Mayeux R. The frequency and associated risk factors for dementia in patients with Parkinson’s disease. Arch Neurol. 1995;52:695–701. [PubMed]

89. Stern Y, Marder K, Tang MX, Mayeux R. Antecedent clinical features associated with dementia in Parkinson’s disease. Neurology. 1993;43:1690–1692. [PubMed]

90. Kandiah N, Narasimhalu K, Lau PN, Seah SH, Au WL, Tan LC. Cognitive decline in early Parkinson’s disease. Mov Disord. 2009;24:605–608. [PubMed]

91. Braak H, Rub U, Del Tredici K. Cognitive decline correlates with neuropathological stage in Parkinson’s disease. J Neurol Sci. 2006;248:255–258. [PubMed]

92. Aarsland D, Tandberg E, Larsen JP, Cummings JL. Frequency of dementia in Parkinson disease. Arch Neurol. 1996;53:538–542. [PubMed]

93. Tomer R, Levin BE, Weiner WJ. Side of onset of motor symptoms influences cognition in Parkinson’s disease. Ann Neurol. 1993;34:579–584. [PubMed]

94. Martin RC, Okonkwo OC, Hill J, et al. Medical decision-making capacity in cognitively impaired Parkinson’s disease patients without dementia. Mov Disord. 2008;23:1867–1874. [PMC free article] [PubMed]

95. Klepac N, Trkulja V, Relja M, Babic T. Is quality of life in non-demented Parkinson’s disease patients related to cognitive performance? A clinic-based cross-sectional study. Eur J Neurol. 2008;15:128–133. [PubMed]

96. Marras C, McDermott MP, Rochon PA, Tanner CM, Naglie G, Lang AE. Predictors of deterioration in health-related quality of life in Parkinson’s disease: results from the DATATOP trial. Mov Disord. 2008;23:653–659. quiz 776. [PubMed]

97. Troster AI, Woods SP, Morgan EE. Assessing cognitive change in Parkinson’s disease: development of practice effect-corrected reliable change indices. Arch Clin Neuropsychol. 2007;22:711–718. [PubMed]

98. Aarsland D, Kvaloy JT, Andersen K, et al. The effect of age of onset of PD on risk of dementia. J Neurol. 2007;254:38–45. [PubMed]

99. Aarsland D, Muniz G, Matthews F. Nonlinear decline of mini-mental state examination in Parkinson’s disease. Mov Disord. 2010 [PubMed]

100. Foltynie T, Lewis SG, Goldberg TE, et al. The BDNF Val66Met polymorphism has a gender specific influence on planning ability in Parkinson’s disease. J Neurol. 2005;252:833–838. [PubMed]

101. Guerini FR, Beghi E, Riboldazzi G, et al. BDNF Val66Met polymorphism is associated with cognitive impairment in Italian patients with Parkinson’s disease. Eur J Neurol. 2009;16:1240–1245. [PubMed]

102. Mollenhauer B, Trenkwalder C. Neurochemical biomarkers in the differential diagnosis of movement disorders. Mov Disord. 2009;24:1411–1426. [PubMed]

103. Otto M, Esselmann H, Schulz-Shaeffer W, et al. Decreased beta-amyloid1-42 in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Neurology. 2000;54:1099–1102. [PubMed]

104. Holmberg B, Johnels B, Blennow K, Rosengren L. Cerebrospinal fluid Abeta42 is reduced in multiple system atrophy but normal in Parkinson’s disease and progressive supranuclear palsy. Mov Disord. 2003;18:186–190. [PubMed]

105. Noguchi M, Yoshita M, Matsumoto Y, Ono K, Iwasa K, Yamada M. Decreased beta-amyloid peptide42 in cerebrospinal fluid of patients with progressive supranuclear palsy and corticobasal degeneration. J Neurol Sci. 2005;237:61–65. [PubMed]

106. Gomperts SN, Rentz DM, Moran E, et al. Imaging amyloid deposition in Lewy body diseases. Neurology. 2008;71:903–910. [PMC free article] [PubMed]

107. Kramer ML, Schulz-Schaeffer WJ. Presynaptic alpha-synuclein aggregates, not Lewy bodies, cause neurodegeneration in dementia with Lewy bodies. J Neurosci. 2007;27:1405–1410. [PubMed]

108. Schulz-Schaeffer WJ. The synaptic pathology of alpha-synuclein aggregation in dementia with Lewy bodies, Parkinson’s disease and Parkinson’s disease dementia. Acta Neuropathol. 2010;120:131–143. [PMC free article] [PubMed]

109. Huang C, Mattis P, Tang C, Perrine K, Carbon M, Eidelberg D. Metabolic brain networks associated with cognitive function in Parkinson’s disease. Neuroimage. 2007;34:714–723. [PubMed]