eTable 1. Comparison of population characteristics by genotype
eTable 2. Comparison of genotypes across sites
eTable 3. ß Coefficients from linear regression analyses of APOE for selected covariates
eFigure. Box plots of psychometric test scores by APOE genotype
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Mata IF, Leverenz JB, Weintraub D, et al. APOE, MAPT, and SNCA Genes and Cognitive Performance in Parkinson Disease. JAMA Neurol. 2014;71(11):1405–1412. doi:10.1001/jamaneurol.2014.1455
Cognitive impairment is a common and disabling problem in Parkinson disease (PD) that is not well understood and is difficult to treat. Identification of genetic variants that influence the rate of cognitive decline or pattern of early cognitive deficits in PD might provide a clearer understanding of the etiopathogenesis of this important nonmotor feature.
To determine whether common variation in the APOE, MAPT, and SNCA genes is associated with cognitive performance in patients with PD.
Design, Setting, and Participants
We studied 1079 PD patients from 6 academic centers in the United States who underwent assessments of memory (Hopkins Verbal Learning Test–Revised [HVLT-R]), attention and executive function (Letter-Number Sequencing Test and Trail Making Test), language processing (semantic and phonemic verbal fluency tests), visuospatial skills (Benton Judgment of Line Orientation test), and global cognitive function (Montreal Cognitive Assessment). Participants underwent genotyping for the APOE ε2/ε3/ε4 alleles, MAPT H1/H2 haplotypes, and SNCA rs356219. We used linear regression to test for association between genotype and baseline cognitive performance with adjustment for age, sex, years of education, disease duration, and site. We used a Bonferroni correction to adjust for the 9 comparisons that were performed for each gene.
Main Outcomes and Measures
Nine variables derived from 7 psychometric tests.
The APOE ε4 allele was associated with lower performance on the HVLT-R Total Recall (P = 6.7 × 10−6; corrected P [Pc] = 6.0 × 10−5), Delayed Recall (P = .001; Pc = .009), and Recognition Discrimination Index (P = .004; Pc = .04); a semantic verbal fluency test (P = .002; Pc = .02); the Letter-Number Sequencing Test (P = 1 × 10−5; Pc = 9 × 10−5); and Trail Making Test B minus Trail Making Test A (P = .002; Pc = .02). In a subset of 645 patients without dementia, the APOE ε4 allele was associated with lower scores on the HVLT-R Total Recall (P = .005; Pc = .045) and the semantic verbal fluency (P = .005; Pc = .045) measures. Variants of MAPT and SNCA were not associated with scores on any tests.
Conclusions and Relevance
Our data indicate that the APOE ε4 allele is an important predictor of cognitive function in PD across multiple domains. Among PD patients without dementia, the APOE ε4 allele was only associated with lower performance on word list learning and semantic verbal fluency, a pattern more typical of the cognitive deficits seen in early Alzheimer disease than PD.
Cognitive impairment commonly occurs in Parkinson disease (PD) and has a major effect on quality of life, caregiver distress, the need for nursing home placement, and mortality.1-4 At the time of diagnosis, 19% to 24% of PD patients have mild cognitive impairment 5,6 and as many as 80% develop dementia during the course of the disease.7,8 The rate of cognitive decline and pattern of early cognitive deficits in PD are highly variable for reasons that are not well understood.9,10 Identification of biological markers, including common genetic variants, that account for this heterogeneity could provide important insights into the pathological processes that underlie cognitive impairment in PD.
Few genetic studies have been conducted in this area, and most have focused on the end point of dementia. Available evidence suggests that at least 3 genes, apolipoprotein E (APOE [OMIM 107741]), microtubule-associated protein tau(MAPT [OMIM 157140]), and α-synuclein (SNCA [OMIM 163890]), might play a role in determining susceptibility to cognitive impairment in PD. The APOE ɛ4 allele is a well-established risk factor for Alzheimer disease (AD)11 and is also associated with slightly reduced cognition in healthy older adults.12,13 The APOE ɛ4 allele was found to predict earlier onset of dementia or more rapid cognitive decline in patients with PD in some studies14,15 but not others.16,17 The MAPT H1 haplotype is a well-known risk factor for several neurodegenerative disorders, including PD, progressive supranuclear palsy, and corticobasal degeneration.18,19 Two studies found that the MAPT H1 haplotype is a risk factor for dementia in PD,20,21 but these findings require further replication. Finally, rare multiplications of the SNCA gene result in PD, often accompanied by early-onset dementia.22 Common SNCA polymorphisms also convey a risk for PD,23 but whether these same variants predispose patients with PD to develop cognitive impairment early in their clinical course is not known. In this study we examined the association between common variants in APOE, MAPT, and SNCA and cognitive performance in a large, multicenter sample of patients with PD.
The initial study population consisted of 1191 patients with PD enrolled in studies at Emory University, the University of Cincinnati, and the Pacific Northwest, University of Pennsylvania, and University of California, Los Angeles (UCLA), Morris K. Udall Centers of Excellence for Parkinson’s Disease Research. The Pacific Northwest Udall Center (PANUC) consists of 2 sites, one in Seattle (University of Washington/Veterans Affairs Puget Sound Health Care System) and the other in Portland (Oregon Health and Science University/Portland Veterans Affairs Medical Center). All participants met UK PD Society Brain Bank clinical diagnostic criteria for PD,24 except those from UCLA who satisfied clinical diagnostic criteria for PD as described elsewhere.25 Requirements to meet the latter criteria include (1) presence of at least 2 of the following signs: bradykinesia, rigidity, or resting tremor; (2) no suggestion of a cause for another parkinsonian syndrome; and (3) no atypical features. Each participant underwent a detailed neuropsychological assessment (performed in the “on” state if receiving medication), and 7 tests that overlapped between sites were chosen as the core battery (defined in the following section). Thirty-seven participants completed fewer than half of the tests in the core battery and were excluded from the sample. To reduce genetic heterogeneity, all participants underwent genotyping for a panel of ancestry-informative markers designed to estimate admixture proportions from the following 4 ancestral populations: European, East Asian, African, and Amerindian (I.F.M., unpublished data, January 2013). Seventy-five individuals estimated to have less than 90% European ancestry were excluded. The final study population consisted of 1079 participants.
Standard protocol approvals, registrations, and written informed patient consent were obtained. All study procedures were approved by the institutional review boards at each participating site.
All study participants underwent psychometric testing under the supervision of a neurologist or a psychiatrist (University of Pennsylvania) or a neuropsychologist (all other sites) experienced in the assessment of patients with PD. The following 7 tests that were administered by at least 5 of the 6 sites were defined as the core battery: the Montreal Cognitive Assessment (MoCA),26 Hopkins Verbal Learning Test–Revised (HVLT-R),27 Letter-Number Sequencing Test,28 Trail Making Test (TMT),29 a semantic (number of animals generated) and a phonemic verbal fluency test,30 and Benton Judgment of Line Orientation test (JoLO)31 (Table 1). Data from participants enrolled at PANUC-Seattle, PANUC-Portland, the University of Cincinnati, and the University of Pennsylvania Udall Center were reviewed at a diagnostic consensus conference, and participants were classified as having or not having dementia as previously described.32,33 The group without dementia included participants with mild or no cognitive impairment. Scores on tests with less overlap between sites that were not included in the core battery, such as the Logical Memory Test,34 Boston Naming Test,35 and Digit Span and Digit Symbol tests,36 were used in determining cognitive diagnosis when available.
Genomic DNA was extracted from peripheral blood samples using standard methods. All participants underwent genotyping for 29 ancestry-informative markers and 4 single-nucleotide polymorphisms in the 3 genes of interest, including APOE rs429358 and rs7412 (which define the ε2, ε3, and ε4 alleles), MAPT rs1800547 (which differentiates the H1 and H2 haplotypes), and SNCA rs356219. Genotyping was performed using commercially available assays (TaqMan assays [Life Technologies] on the BioMark HD System [Fluidigm Corporation]). The genotyping success rate was 100% for MAPT and SNCA and greater than 99% for APOE.
We assessed each single-nucleotide polymorphism for Hardy-Weinberg equilibrium using an exact test. We selected (a priori) the following 9 variables for analysis from the core battery that represent the primary measures most commonly used in a clinical setting for each test: total scores for the MoCA, Letter-Number Sequencing Test, TMT B minus TMT A, semantic and phonemic verbal fluency, JoLO, and HVLT-R Total Recall, Delayed Recall, and Recognition Discrimination Index (calculated as the true-positive score minus the false-positive score). We tested the association between genotype and cognitive performance using linear regression under an additive genetic model adjusted for sex, years of education, disease duration, age at testing, and site. Disease duration was calculated as the difference between age at testing and age at diagnosis. For association tests involving APOE, MAPT, and SNCA, we used separate Bonferroni corrections to adjust for the 9 comparisons. We used a Pearson χ2 test to compare categorical participant characteristics across sites and genotypes and to compare genotypes across sites. We used analysis of variance to compare continuous participant characteristics across sites and genotypes. All analyses were performed using commercially available software (Stata, version 10.0; StataCorp).
We found small but significant differences in all of the clinical and demographic characteristics of the study participants across sites (Table 2). For example, at UCLA, the mean age at testing and mean age at diagnosis were higher and the mean years of education were lower than for all of the other sites. We found a predominance of male participants at each site, which was particularly marked at the PANUC Portland site (92.2%).
None of the single-nucleotide polymorphisms deviated significantly from Hardy-Weinberg equilibrium. We found no significant differences in population characteristics across genotypes (eTable 1 in the Supplement) or in genotype frequencies across sites (eTable 2 in the Supplement).
The APOE ε4 allele was associated with lower performance on the following 6 of the 9 psychometric variables after correction for multiple testing: HVLT-R Total Recall (corrected P [Pc] = 6.0 × 10−5), Delayed Recall (Pc = .009), and Recognition Discrimination Index (Pc = .04); semantic verbal fluency (Pc = .02); Letter-Number Sequencing (Pc = 9 × 10−5); and TMT B minus TMT A (Pc = .02) (Table 3). Box plots of the data by APOE genotype for the 6 significant variables are presented in the eFigure in the Supplement. However, we found no significant association between the MAPT H1 haplotype or SNCA rs356219 and any of the psychometric test results (P > .05) (Table 3). For psychometric variables that deviated from normality when examining histograms and quantile-quantile plots (MoCA, TMT B − TMT A, JoLO, and HVLT-R Recognition Discrimination Index), results of the aforementioned association analysis were similar when applying data transformations to better achieve a normal distribution (data not shown).
To allow comparison between the effects of APOE and the clinical and demographic covariates included in the regression models, β coefficients for each of these variables are presented in eTable 3 in the Supplement. For example, we found an expected decrease of 1.55 words in mean HVLT-R Total Recall score for each additional copy of the APOE ε4 allele. The effect of 1 APOE ε4 allele on the HVLT-R Total Recall score was equivalent to the effect of 3.5 (ie, βAPOE/βEDUCATION = −1.55/0.44) fewer years of education or an increase in age at testing of 6.0 (ie, βAPOE/βAGE AT TESTING = −1.55/−0.26) years given the same values for all other covariates.
To assess the effects of APOE on cognition in PD before the onset of dementia, we then analyzed the ε4 allele in the subset of patients who had received a cognitive diagnosis via consensus diagnosis conference (n = 775). As in the full sample, the APOE ε4 allele predicted lower performance in nearly all tests before adjustment for multiple comparisons (Table 4). After Bonferroni correction, HVLT-R Total Recall (P = 2 × 10−4; Pc = .002) and semantic verbal fluency (P = .001; Pc = .009) scores remained significant, and Letter-Number Sequencing (P = .009; Pc = .08) and MoCA (P = .01; Pc = .09) scores approached significance. When patients with a diagnosis of dementia (n = 130) were removed and the data were reanalyzed, the only associations that remained significant were HVLT-R Total Recall (P = .005; Pc = .045) and semantic verbal fluency (P = .005; Pc = .045) scores.
In a multicenter cohort of patients with PD, the APOE ε4 allele predicted lower performance across multiple cognitive domains, including memory, attention and executive function, and language processing. In patients without dementia, the effect of the ε4 allele was restricted to HVLT-R Total Recall and semantic verbal fluency scores. In contrast, the MAPT H1 haplotype and SNCA rs356219 were not correlated with scores on any of the psychometric tests.
The APOE ε4 allele is a well-known risk factor for AD. In preclinical and early AD, deficits in episodic memory predominate. However, impairment in semantic verbal fluency, with relative sparing of phonemic fluency, also occurs.37,38 This observation is attributed to the fact that the temporal cortex, one of the first brain regions affected in AD,39,40 plays a larger role in mediating semantic than phonemic verbal fluency.41 In contrast, early cognitive deficits in PD usually involve attention and frontal-executive function mediated in part by cortical-striatal dopamine deficiency, although some patients initially exhibit isolated deficits in other domains.6,42 We observed that in PD patients without dementia, the APOE ε4 allele was only associated with poorer performance on word list learning and semantic verbal fluency (Table 4), a pattern more typical of the cognitive deficits seen in early AD than PD. Thus, individuals with PD who carry the ε4 allele might be particularly vulnerable to early semantic memory impairment, which might in part explain the heterogeneity in cognitive profiles reported in PD patients with mild cognitive impairment.10,43 In AD, the APOE ε4 allele is thought to influence disease risk by accelerating the accumulation of neurotoxic β-amyloid, which ultimately leads to neurodegeneration with accompanying AD neuropathological changes (ie, neuritic plaques and neurofibrillary tangles). Whether the neuropathological substrate of cognitive impairment in PD patients who carry the APOE ε4 allele consistently involves an increased burden of AD neuropathological changes is not clear. However, the APOE genotype was not correlated with measures of AD neuropathological changes in a recent PD autopsy series44 or with brain amyloid burden in PD patients who underwent imaging with Pittsburgh compound B.45 Thus, APOE might affect cognition in PD through mechanisms unrelated to β-amyloid processing.
Previous studies of the effect of APOE on cognitive impairment in PD have yielded mixed results, and the interpretation of these data is complicated by the wide variety of study designs and cognitive measures used. In an incident cohort of 107 PD patients from the United Kingdom undergoing longitudinal assessment for 5 years, the APOE ε4 allele was not associated with the risk for dementia or the rate of cognitive decline.16 Similarly, a population-based study of 64 Norwegian PD patients followed up for 12 years17 found no association between the ε4 allele and development of dementia or time to dementia. However, a subsequent longitudinal study of 212 PD patients from the United States15 reported that ε4 carriers displayed a more rapid decline in total score on the Mattis Dementia Rating Scale than noncarriers. A meta-analysis of 17 cross-sectional studies published in 200916 reported a significantly higher frequency of the APOE ε4 allele in PD patients with dementia (n = 501) compared with those without (n = 1145; odds ratio [OR], 1.74 [95% CI, 1.36-2.23]), although the authors cautioned that small sample sizes, heterogeneity of ORs, and publication bias might have confounded their results. In more recent cross-sectional studies of 879 PD cases from the National Institute of Neurological Disorders and Stroke Neurogenetics repository46 and 234 PD patients from South Korea,47 ε4 carrier status was not associated with Mini-Mental State Examination scores. Finally, in an autopsy-based study in which participants with substantial concomitant AD neuropathological changes were excluded,48 the APOE ε4 allele was overrepresented in PD patients with dementia (n = 81) compared with cognitively intact control subjects (n = 269; OR, 3.1 [95% CI, 1.7-5.6]). One explanation for these seemingly discordant results is that many prior studies had small sample sizes or used insensitive measures of cognition in PD (eg, the Mini-Mental State Examination49) and thus might have lacked adequate power. In contrast, our study included a large sample and used a more extensive psychometric battery to assess cognition. Furthermore, we analyzed cognitive performance using quantitative data, which is a more powerful approach than using categorical variables (eg, with vs without dementia).
In evaluating the role of the APOE ε4 allele in cognition in diseases other than AD, one must consider whether the effects observed differ from the background effect of APOE in the general population. For example, a meta-analysis of 77 studies consisting of 40 942 cognitively intact individuals (11 108 ε4 carriers and 29 834 ε4 noncarriers)13 found that the APOE ε4 allele had a small but significant negative effect on measures of global cognitive functioning (P < .05), episodic memory (P < .01), executive function (P < .05), and perceptual speed (P < .05) but not verbal ability (including verbal fluency), primary memory, visuospatial skill, or attention. In comparison, we observed more robust associations for the APOE ε4 allele in a much smaller sample, and the effects were present across all cognitive domains tested except visuospatial function (Table 3). These data suggest that the deleterious effect of the ε4 allele seen in our PD cohort is in excess of the background APOE effect on cognition.
Relatively few studies have examined the MAPT H1 haplotype as a risk factor for cognitive impairment in PD. The most frequently cited study21 was conducted in an incident cohort of 122 PD patients followed up longitudinally for 5 years. The MAPT H1 haplotype was associated with a more rapid decline in Mini-Mental State Examination score (P = .02) and was a significant risk factor for conversion to dementia (OR, 12.14 [95% CI, 1.26-117.36]). Although patients in the study underwent detailed neuropsychological assessments, association tests between the H1 haplotype and change over time in the other cognitive measures were not performed. A cross-sectional PD case-control study from Spain20 found that the MAPT H1 haplotype was associated with PD in the overall sample, and the effect size was larger in patients with dementia (n = 48; OR, 3.73 [95% CI, 1.64-8.46]) than in those without (n = 154; OR, 1.89 [95% CI, 1.03-3.47]) compared with cognitively intact controls. However, the authors did not test for differences in H1 frequency directly between the demented and nondemented PD groups. A second cross-sectional study50 in Spain found no difference in H1 frequency between PD patients with (n = 86) and without (n = 138) dementia. In our much larger cohort we did not observe an association between the MAPT H1 haplotype and baseline performance on any cognitive tests, and none of the variables examined even approached significance (Table 3). Because of the substantial differences in methods used, one must exercise caution when comparing our findings with those of previous studies. However, our results suggest that the MAPT H1 haplotype is not associated with cognition in PD.
Our study had several limitations. We were not able to examine longitudinal measures of cognition because these data were not yet available for most of the cohort. Thus, we were only able to account for predictors of cognitive function by including demographic characteristics (eg, years of education and age) in the regression models. Some of the cognitive measures used rely in part on motor function, and thus motor symptoms might have interfered with test performance. To lessen these effects our patients underwent testing while in the “on” state. Furthermore, for TMT B we attempted to correct for motor impairment by subtracting the TMT A score. Our participants had a higher than average mean level of education, a known contributor to performance across most cognitive measures. Thus, our sample might not be fully representative of all PD patients. Although our sample size was large compared with those of previous studies, we still might have lacked adequate power to detect small effects of MAPT and SNCA variants on cognition.
We have shown that APOE is an important predictor of cognitive function in PD across multiple domains. Among PD patients without dementia, the APOE ε4 allele was only associated with lower performance on word list learning and semantic verbal fluency, a pattern more characteristic of the cognitive deficits seen in early AD than PD. In contrast, the MAPT H1 haplotype and SNCA rs356219 were not associated with scores on any psychometric tests. Whether other genes exist that modify cognitive performance in PD remains to be determined. We have begun work to address this issue using genome-wide techniques that will incorporate longitudinal data as they become available in our PD cohort. The identification of additional genetic determinants for cognitive impairment in PD will shed new light on the pathophysiology of this disabling nonmotor problem and could provide new targets for therapeutic intervention.
Accepted for Publication: May 2, 2014.
Corresponding Author: Cyrus P. Zabetian, MD, MS, Veterans Affairs Puget Sound Health Care System, GRECC S-182, 1660 S Columbian Way, Seattle, WA 98108 (email@example.com).
Published Online: September 1, 2014. doi:10.1001/jamaneurol.2014.1455.
Author Contributions: Dr Zabetian had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Mata, Zabetian.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Mata, Montine, Edwards, Zabetian.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Mata, Wan, Edwards.
Obtained funding: Leverenz, Trojanowski, Ritz, Factor, Quinn, Montine, Edwards, Zabetian.
Administrative, technical, or material support: Mata, Leverenz, Weintraub, Trojanowski, Hurtig, Van Deerlin, Ritz, Rausch, Rhodes, Factor, Wood-Siverio, Quinn, Peterson, Espay, Revilla, Devoto, Hu, Cholerton, Wan, Montine, Edwards, Zabetian.
Study supervision: Mata, Leverenz, Weintraub, Trojanowski, Hurtig, Van Deerlin, Ritz, Rausch, Factor, Quinn, Espay, Revilla, Cholerton, Montine, Edwards, Zabetian.
Conflict of Interest Disclosures: Dr Mata has received grants from the Department of Veterans Affairs, National Institutes of Health (NIH), and Parkinson’s Disease Foundation. Dr Leverenz has served as a consultant for Boehringer-Ingelheim, Citigroup, Navidea Biopharmaceuticals, Piramal Healthcare, Bayer, and Teva Pharmaceuticals and received grants from the American Parkinson Disease Association, Michael J. Fox Foundation, NIH, Northwest Collaborative Care, and the Jane and Lee Seidman Fund. Dr Weintraub has received funding from the NIH (from the National Institute of Neurological and Communicative Diseases and Stroke [NINDS]), Department of Veterans Affairs, Novartis Pharmaceuticals, and Michael J. Fox Foundation; has received honoraria from Teva Pharmaceuticals, Lundbeck Inc, Pfizer, Avanir Pharmaceuticals, Merck & Co, UCB, Bristol-Myers Squibb Company, Novartis Pharmaceuticals, Eli Lilly and Company, Clintrex LLC, Theravance, CHDI Foundation, and the Alzheimer’s Disease Cooperative Study; and has received licensing fees from the University of Pennsylvania for the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP) and the QUIP Rating Scale and legal proceedings from testifying in a single court case related to impulse control disorders in Parkinson disease. Dr Trojanowski has received funding for travel and honoraria from Takeda Pharmaceutical Company Ltd; has received speaker honoraria from Pfizer Inc; serves as an associate editor of Alzheimer's & Dementia; may accrue revenue on patents for the modified avidin-biotin technique, a method of stabilizing microtubules to treat Alzheimer disease (AD), a method of detecting abnormally phosphorylated tau, a method of screening for AD or disease associated with the accumulation of paired helical filaments, compositions and methods for producing and using homogeneous neuronal cell transplants, rat with straight filaments in its brain, compositions and methods for producing and using homogeneous neuronal cell transplants to treat neurodegenerative disorders and brain and spinal cord injuries, diagnostic methods for AD by detection of multiple messenger RNAs, methods and compositions for determining lipid peroxidation levels in oxidant stress syndromes and diseases, compositions and methods for producing and using homogenous neuronal cell transplants, a method of identifying, diagnosing, and treating α-synuclein–positive neurodegenerative disorders, mutation-specific functional impairments in distinct tau isoforms of hereditary frontotemporal dementia and parkinsonism linked to chromosome-17 genotype predicting phenotype, microtubule-stabilizing therapies for neurodegenerative disorders, and treatment of AD and related diseases with an antibody; and receives research support from the NIH (from the National Institute on Aging and from the NINDS) and from the Marian S. Ware Alzheimer Program. Dr Hurtig has received grants from the Department of Defense; is the movement disorders section editor for UpToDate, an online evidence-based resource for clinical decision making; and receives royalties for his work. Dr Van Deerlin receives research support from the NIH (from the NIA and from the NINDS). Dr Ritz received funding from the NIH, the Department of Defense, and initial funding by a pilot grant from the American Parkinson Disease Association. Dr Rausch received support from the NIH. Dr Rhodes was supported by grants from the NIH. Dr Factor has received honoraria from Scientiae for the CME program, University of Florida speaker program, Merz, Chelsea Therapeutics, and ADAMAS and grants from Ceregene, TEVA, Ipsen, Allergan, Medtronics, Michael J. Fox Foundation, and the NIH; is a section editor for Current Neurology and Neuroscience; and has received royalties from Demos and Blackwell Futura for textbooks. Dr Quinn is supported by grants from the Department of Veterans Affairs and from the NIH. Dr Chung has received a grant from the Department of Veterans Affairs. Dr Peterson is supported by a grant from the Department of Veterans Affairs. Dr Espay has received K23 career development award from the National Institute of Mental Health; has received grant support from CleveMed/Great Lakes Neurotechnologies and Michael J. Fox Foundation; has received personal compensation as a consultant/scientific advisory board member for Solvay (now Abbvie), Chelsea Therapeutics, TEVA, Impax, Merz, Pfizer, Solstice Neurosciences, Eli Lilly, and USWorldMeds; has received royalties from Lippincott Williams & Wilkins and Cambridge; has received honoraria from Novartis, UCB, TEVA, the American Academy of Neurology, and the Movement Disorders Society; and serves as associate editor of Movement Disorders and Frontiers in Movement Disorders and on the editorial board of The European Neurological Journal. Dr Revilla has received funding for travel and honoraria from the Lundbeck speaker’s bureau. Dr Devoto has received support from the Michael J. Fox Foundation. Dr Hu has received grants from the NIH. Ms Wan is supported by grants from the NIH. Dr Montine is supported by grants from the NIH and receives personal compensation in the form of honoraria from invited scientific presentations to universities and professional societies. Dr Edwards is supported by grants from the NIH. Dr Zabetian is supported by grants from the American Parkinson Disease Association, Department of Veterans Affairs, NIH, Northwest Collaborative Care, and Parkinson’s Disease Foundation. No other disclosures were reported.
Funding/Support: This study was supported by grant 1I01BX000531 from the Department of Veterans Affairs, grants P50 NS062684, P50 NS053488, P50 NS038367, and R01 NS065070 from the NIH, by the Consolidated Anti-Aging Foundation, and by the Jane and Lee Seidman Fund.
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: Jacqueline Rick, PhD, Department of Neurology, University of Pennsylvania, Philadelphia, and Dora Yearout, BS, Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, and Department of Neurology, University of Washington School of Medicine, Seattle, provided technical assistance. We thank all participants in this study.
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