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IntroductionThe National Institute on Aging - Alzheimer's Association (NIA-AA) ATN research framework proposes to use biomarkers for amyloid (A), tau (T), and neurodegeneration (N) to stage individuals with AD pathological features and track changes longitudinally. The overall aim was to utilize this framework to characterize pre-mortem ATN status longitudinally in a clinically diagnosed cohort of dementia with Lewy bodies (DLB) and to correlate it with the post mortem diagnosis.MethodsThe cohort was subtyped by cerebrospinal fluid (CSF) ATN category. A subcohort had longitudinal data, and a subgroup was neuropathologically evaluated.ResultsWe observed a significant difference in Aβ42/40 after 12 months in the A+T- group. Post mortem neuropathologic analyses indicated that most of the p-Tau 181 positive (T+) cases also had a high Braak stage.DiscussionThis suggests that DLB patients who are A+ but T- may need to be monitored to determine whether they remain A+ or ever progress to T positivity.HighlightsSome A+T- DLB subjects transition from A+ to negative after 12-months. Clinically diagnosed DLB with LBP-AD (A+T+) maintain their positivity. Clinically diagnosed DLB with LBP-AD (A+T+) maintain their positivity. Monitoring of the A+T- sub-type of DLB may be necessary.

BackgroundGait and balance impairments are among the most troublesome and heterogeneous in Parkinson's disease (PD). This heterogeneity may, in part, reflect genetic variation. The apolipoprotein E (APOE) gene has three major allelic variants (ε2, ε3 and ε4). Previous work has demonstrated that older adult (OA) APOE ε4 carriers demonstrate gait deficits. This study compared gait and balance measures between APOE ε4 carriers and non-carriers in both OA and PD.Methods334 people with PD (81 APOE ε4 carriers and 253 non-carriers) and 144 OA (41 carriers and 103 non-carriers) were recruited. Gait and balance were assessed using body-worn inertial sensors. Two-way analyses of covariance (ANCOVA) compared gait and balance characteristics between APOE ε4 carriers and non-carriers in people with PD and OA, controlling for age, gender, and testing site.ResultsGait and balance were worse in people with PD compared to OA. However, there were no differences between APOE ε4 carriers and non-carriers in either the OA or PD group. In addition, there were no significant group (OA/PD) by APOE ε4 status (carrier/non-carrier) interaction effects for any measures of gait or balance.ConclusionsAlthough we found expected impairments in gait and balance in PD compared to OA, gait and balance characteristics did not differ between APOE ε4 carriers and non-carriers in either group. While APOE status did not impact gait and balance in this cross-sectional study, future work is needed to determine whether progression of gait and balance deficits is faster in PD APOE Ɛ4 carriers.

BackgroundThe criteria for PD-MCI allow the use of global cognitive tests. Their predictive value for conversion from PD-MCI to PDD, especially compared to comprehensive neuropsychological assessment, is unknown.MethodsThe MDS PD-MCI Study Group combined four datasets containing global cognitive tests as well as a comprehensive neuropsychological assessment to define PD-MCI (n = 467). Risk for developing PDD was examined using a Cox model. Global cognitive tests were compared to neuropsychological test batteries (Level I&II) in determining risk for PDD.ResultsPD-MCI based on a global cognitive test (MMSE or MoCA) increases the hazard for developing PDD (respectively HR = 2.57, P = 0.001; HR = 4.14, P =

Quantifying the physiology of aging is essential for improving our understanding of age-related disease and the heterogeneity of healthy aging. Recent studies have shown that, in regression models using "-omic" platforms to predict chronological age, residual variation in predicted age is correlated with health outcomes, and suggest that these "omic clocks" provide measures of biological age. This paper presents predictive models for age using metabolomic profiles of cerebrospinal fluid (CSF) from healthy human subjects and finds that metabolite and lipid data are generally able to predict chronological age within 10 years. We use these models to predict the age of a cohort of subjects with Alzheimer's and Parkinson's disease and find an increase in prediction error, potentially indicating that the relationship between the metabolome and chronological age differs with these diseases. However, evidence is not found to support the hypothesis that our models will consistently overpredict the age of these subjects. In our analysis of control subjects, we find the carnitine shuttle, sucrose, biopterin, vitamin E metabolism, tryptophan, and tyrosine to be the most associated with age. We showcase the potential usefulness of age prediction models in a small data set (n = 85) and discuss techniques for drift correction, missing data imputation, and regularized regression, which can be used to help mitigate the statistical challenges that commonly arise in this setting. To our knowledge, this work presents the first multivariate predictive metabolomic and lipidomic models for age using mass spectrometry analysis of CSF.

The extent to which the heterogeneity of gait and balance problems in PD may be explained by genetic variation is unknown. Variants in the glucocerebrosidase (GBA) gene are the strongest known genetic risk factor for PD and are associated with greater motor and cognitive severity. However, the impact of GBA variants on comprehensive measures of gait and balance and their relationship to cognition remains unknown. We aimed to determine differences in gait and balance impairments in those with and without GBA variants (mutation carriers and E326K polymorphism) and explore direct and indirect effects of GBA status on gait, balance, and cognition. 332 participants, 43 of whom had GBA variants, were recruited. Participants completed a comprehensive, objective assessment of gait and standing balance using body-worn inertial sensors. Group differences in gait and balance between PD with and without GBA variants were assessed with linear regression, adjusting for age, gender, clinical testing site, disease duration, and apolipoprotein E (APOE) ɛ4 status. Structural equation modeling (SEM) explored direct relationships between GBA status and gait and balance and indirect relationships between GBA status and gait and balance via cognition. The GBA variant group had more impaired gait (pace and variability) and balance (sway area/jerk and sway velocity), than the non-GBA variant group. SEM demonstrated cognition as a mediator of GBA status on gait and balance. The close relationships among GBA, gait/balance, and cognition suggest potential for novel therapeutics to target the GBA pathway and/or cognition to improve mobility in PD GBA variants.

In recent years, metabolomics has been used as a powerful tool to better understand the physiology of neurodegenerative diseases and identify potential biomarkers for progression. We used targeted and untargeted aqueous, and lipidomic profiles of the metabolome from human cerebrospinal fluid to build multivariate predictive models distinguishing patients with Alzheimer's disease (AD), Parkinson's disease (PD), and healthy age-matched controls. We emphasize several statistical challenges associated with metabolomic studies where the number of measured metabolites far exceeds sample size. We found strong separation in the metabolome between PD and controls, as well as between PD and AD, with weaker separation between AD and controls. Consistent with existing literature, we found alanine, kynurenine, tryptophan, and serine to be associated with PD classification against controls, while alanine, creatine, and long chain ceramides were associated with AD classification against controls. We conducted a univariate pathway analysis of untargeted and targeted metabolite profiles and find that vitamin E and urea cycle metabolism pathways are associated with PD, while the aspartate/asparagine and c21-steroid hormone biosynthesis pathways are associated with AD. We also found that the amount of metabolite missingness varied by phenotype, highlighting the importance of examining missing data in future metabolomic studies.

ObjectiveThe aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease.MethodsWe performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers.ResultsA variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset.InterpretationThis study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94.

Introduction: Parkinson's disease (PD) is associated with a range of cognitive deficits. Few studies have carefully examined the subtle impacts of PD on cognition among patients who do not meet formal criteria for MCI or dementia. The aim of the current study was thus to describe the impact of PD on cognition in those without cognitive impairment in a well-characterized cohort.Methods: Non-cognitively impaired participants (122 with PD, 122 age- and sex-matched healthy volunteers) underwent extensive cognitive testing. Linear regression analyses compared diagnostic group performance across cognitive measures. For cognitive tasks that were significantly different between groups, additional analyses examined group differences restricting the group inclusion to PD participants with mild motor symptoms or disease duration less than 10 years.Results: Processing speed and semantic verbal fluency were significantly lower in the PD group (B = -3.77, 95% CIs [-5.76 to -1.77], p

BackgroundReduced cortical sensorimotor inhibition is associated with mobility and cognitive impairments in people with Parkinson's disease (PD) and older adults (OAs). However, there is a lack of clarity regarding the relationships among sensorimotor, cognitive, and mobility impairments. The purpose of this study was to determine how cortical sensorimotor inhibition relates to impairments in mobility and cognition in people with PD and OAs.MethodCortical sensorimotor inhibition was characterized with short-latency afferent inhibition (SAI) in 81 people with PD and 69 OAs. Six inertial sensors recorded single- and dual-task gait and postural sway characteristics during a 2-minute walk and a 1-minute quiet stance. Cognition was assessed across the memory, visuospatial, executive function, attention, and language domains.ResultsSAI was significantly impaired in the PD compared to the OA group. The PD group preformed significantly worse across all gait and postural sway tasks. In PD, SAI significantly correlated with single-task foot strike angle and stride length variability, sway area, and jerkiness of sway in the coronal and sagittal planes. In OAs, SAI significantly related to single-task gait speed and stride length, dual-task stride length, and immediate recall (memory domain). No relationship among mobility, cognition, and SAI was observed.ConclusionsImpaired SAI related to slower gait in OA and to increased gait variability and postural sway in people with PD, all of which have been shown to be related to increased fall risk.

Cognitive impairment in Parkinson's disease (PD) is pervasive with potentially devastating effects. Identification of those at risk for cognitive decline is vital to identify and implement appropriate interventions. Robust multivariate approaches, including fixed-effect, mixed-effect, and multitask learning models, were used to study associations between biological, clinical, and cognitive factors and for predicting cognitive status longitudinally in a well-characterized prevalent PD cohort (n = 827). Age, disease duration, sex, and GBA status were the primary biological factors associated with cognitive status and progression to dementia. Specific cognitive tests were better predictors of subsequent cognitive status for cognitively unimpaired and dementia groups. However, these models could not accurately predict future mild cognitive impairment (PD-MCI). Data collected from a large PD cohort thus revealed the primary biological and cognitive factors associated with dementia, and provide clinicians with data to aid in the identification of risk for dementia. Sex differences and their potential relationship to genetic status are also discussed.

IntroductionCognitive dysfunction is common in Parkinson's disease (PD) and associated with reduced functional abilities and increased dependence. To date, however, little is known about the relationship between performance of instrumental activities of daily living (IADLs) and cognitive stages in PD, and there are conflicting reports as to whether declines in specific cognitive domains predict IADL impairment.MethodsParticipants with PD were drawn from the Pacific Udall Center and included in the study if both participant and study partner IADL ratings and cognitive tests were completed (n = 192). Logistic regression analyses were performed to determine whether participant and/or study partner rating predicted mild cognitive impairment or dementia. Correlations are reported for the relationship between participant/study partner IADL reports as well as for specific cognitive tests.ResultsAlthough both participant and study partner ratings of IADL performance were associated with a diagnosis of PD with dementia, only participant self-rating of functional ability was significantly associated with a diagnosis of PD with mild cognitive impairment. Functional ability correlated most strongly with measures of processing speed, auditory working memory, and immediate verbal recall for both the participant and study partner ratings.ConclusionFor participants with PD in the early stages of cognitive decline, self-rating may be more sensitive to the impact of cognitive changes on IADL function than ratings made by a knowledgeable study partner. Changes in executive function, processing speed, and learning may indicate a higher likelihood of IADL impairment. Careful assessment of cognition and IADL performance is recommended to permit individualized interventions prior to significant disability.

Neuropsychiatric symptoms are common in Parkinson's disease (PD). We investigated the relationship between neuropsychiatric symptoms and current and future diagnosis of PD dementia (PDD). Individuals with PD who had a study partner were enrolled (n = 696). Study partners were administered the Neuropsychiatric Inventory or Neuropsychiatric Inventory Questionnaire at baseline. Participants were assigned a cognitive diagnosis at baseline and follow up visits. Hallucinations were significantly associated with a diagnosis of PDD cross-sectionally (p

Background: Mobility and sensorimotor inhibition impairments are heterogeneous in Parkinson's disease (PD). Genetics may contribute to this heterogeneity since the apolipoprotein (APOE) ε4 allele and glucocerebrosidase (GBA) gene variants have been related to mobility impairments in otherwise healthy older adult (OA) and PD cohorts. The purpose of this study is to determine if APOE or GBA genetic status affects sensorimotor inhibition and whether the relationship between sensorimotor inhibition and mobility differs in genetic sub-groups of PD. Methods: Ninety-three participants with idiopathic PD (53 non-carriers; 23 ε4 carriers; 17 GBA variants) and 72 OA (45 non-carriers; 27 ε4 carriers) had sensorimotor inhibition characterized by short-latency afferent inhibition. Mobility was assessed in four gait domains (pace/turning, rhythm, trunk, variability) and two postural sway domains (area/jerkiness and velocity) using inertial sensors. Results: Sensorimotor inhibition was worse in the PD than OA group, with no effect of genetic status. Gait pace/turning was slower and variability was higher (p < 0.01) in PD compared to OA. Postural sway area/jerkiness (p < 0.01) and velocity (p < 0.01) were also worse in the PD than OA group. Genetic status was not significantly related to any gait or postural sway domain. Sensorimotor inhibition was significantly correlated with gait variability (r = 0.27; p = 0.02) and trunk movement (r = 0.23; p = 0.045) in the PD group. In PD non-carriers, sensorimotor inhibition related to variability (r = 0.35; p = 0.010) and trunk movement (r = 0.31; p = 0.025). In the PD ε4 group, sensorimotor inhibition only related to rhythm (r = 0.47; p = 0.024), while sensorimotor inhibition related to pace/turning (r = -0.49; p = 0.046) and rhythm (r = 0.59; p = 0.013) in the PD GBA group. Sensorimotor inhibition was significantly correlated with gait pace/turning (r = -0.27; p = 0.04) in the OA group. There was no relationship between sensorimotor inhibition and postural sway. Conclusion: ε4 and GBA genetic status did not affect sensorimotor inhibition or mobility impairments in this PD cohort. However, worse sensorimotor inhibition was associated with gait variability in PD non-carriers, but with gait rhythm in PD ε4 carriers and with gait rhythm and pace in PD with GBA variants. Impaired sensorimotor inhibition had a larger effect on mobility in people with PD than OA and affected different domains of mobility depending on genetic status.

IntroductionGait and balance impairments are cardinal features of Parkinson's disease (PD) that require cognitive input. However, the extent to which specific gait and balance characteristics relate to cognition in PD is unclear. In addition, independent models of gait and balance have not been developed from the same cohort. We aimed to i) develop models of gait and balance in a large PD cohort and ii) determine which gait and balance characteristics best related to cognition.MethodsOne hundred and ninety-eight people with PD were recruited to the Pacific Udall Center. Using six inertial sensors (APDM, Inc.), comprehensive gait measurements were collected over a 2-min continuous walk and comprehensive static balance measures were collected during a 60-second standing task. Six domains of cognition were assessed: global cognition, attention, executive function, language, memory, and visuospatial function. Correlations and hierarchical linear regression determined independent associations.ResultsPrincipal components analysis identified a gait model containing four domains accounting for 80.1% of total variance: pace/turning, rhythm, variability, and trunk. The balance model contained four independent domains accounting for 84.5% of total variance: sway area/jerkiness, sway velocity, sway frequency anteroposterior, and sway frequency mediolateral. Gait domains of pace/turning and variability were strongly associated with attention and executive function. Sway area and jerkiness of balance associated with attention and visuospatial function.ConclusionsGait and balance characteristics were associated with specific types of cognition. The specific relationships between gait or balance with cognitive functions suggests shared cerebral cortical circuitry for mobility and cognitive functions.

Introduction: Cognitive impairment is a common symptom of Parkinson's disease (PD) associated with reduced quality of life and a more severe disease state. Previous research has shown an association between visuospatial dysfunction and worse disease course; however, it is not clear whether this is separable from executive dysfunction and/or dementia. This study sought to determine whether distinct cognitive factors could be measured in a large PD cohort, and if those factors were differentially associated with other PD-related features, specifically to provide insight into visuospatial dysfunction. Methods: Non-demented participants with PD from the Pacific Udall Center were enrolled (n = 197). Co-participants (n = 104) completed questionnaires when available. Principal components factor analysis (PCFA) was utilized to group the neuropsychological test scores into independent factors by considering those with big factor loading (≥.40). Linear and logistic regression analyses were performed to examine the relationship between the cognitive factors identified in the PCFA and other clinical features of PD. Results: Six factors were extracted from the PCFA: 1) executive/processing speed, 2) visual learning & memory/visuospatial, 3) auditory working memory, 4) contextual verbal memory, 5) semantic learning & memory, and 6) visuospatial. Motor severity (p = 0.001), mood (p

The gold standard for a definitive diagnosis of Parkinson disease (PD) is the pathologic finding of aggregated α-synuclein into Lewy bodies and for Alzheimer disease (AD) aggregated amyloid into plaques and hyperphosphorylated tau into tangles. Implicit in this clinicopathologic-based nosology is the assumption that pathologic protein aggregation at autopsy reflects pathogenesis at disease onset. While these aggregates may in exceptional cases be on a causal pathway in humans (e.g., aggregated α-synuclein in SNCA gene multiplication or aggregated β-amyloid in APP mutations), their near universality at postmortem in sporadic PD and AD suggests they may alternatively represent common outcomes from upstream mechanisms or compensatory responses to cellular stress in order to delay cell death. These 3 conceptual frameworks of protein aggregation (pathogenic, epiphenomenon, protective) are difficult to resolve because of the inability to probe brain tissue in real time. Whereas animal models, in which neither PD nor AD occur in natural states, consistently support a pathogenic role of protein aggregation, indirect evidence from human studies does not. We hypothesize that (1) current biomarkers of protein aggregates may be relevant to common pathology but not to subgroup pathogenesis and (2) disease-modifying treatments targeting oligomers or fibrils might be futile or deleterious because these proteins are epiphenomena or protective in the human brain under molecular stress. Future precision medicine efforts for molecular targeting of neurodegenerative diseases may require analyses not anchored on current clinicopathologic criteria but instead on biological signals generated from large deeply phenotyped aging populations or from smaller but well-defined genetic-molecular cohorts.

BackgroundClinicians and researchers commonly use global cognitive assessments to screen for impairment. Currently there are no published studies directly comparing the sensitivity and specificity of the Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 in PD. The objective of this study was to identify the relative sensitivity and specificity of the Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 in PD.MethodsThe Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 were administered to training and validation cohorts. Cutoff scores were determined within the training cohort (n = 85) to optimize sensitivity and specificity for cognitive impairment and were applied to an independent validation cohort (n = 521).ResultsThe Montreal Cognitive Assessment was consistently sensitive across training and validation cohorts (90.0% and 80.3%, respectively), whereas the Mattis Dementia Rating Scale-2 was not (87.5% and 60.3%, respectively). In individual domains, the Montreal Cognitive Assessment remained sensitive to memory and visuospatial impairments (91.9% and 87.8%, respectively), whereas the Mattis Dementia Rating Scale-2 was sensitive to executive impairments (86.2%).ConclusionThe Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 demonstrated individual strengths. Future work should focus on developing domain-specific cognitive screening tools for PD. © 2018 International Parkinson and Movement Disorder Society.

Introduction:Cognitive impairment is a common complication of Parkinson's disease (PD) and identifying risk factors for progression to Parkinson's disease dementia (PDD) is important. However, little research has been done comparing the utility of commonly used cognitive screening tests in predicting cognitive progression in PD. Methods:We retrospectively reviewed data from patients with PD enrolled in the Pacific Udall Center who had baseline and longitudinal neuropsychological and global cognitive screening tests. The diagnostic accuracies of 3 common screening tests were compared: Montreal Cognitive Assessment (MoCA), Mattis Dementia Rating Scale (DRS-2), and Mini Mental Status Examination (MMSE). Cognitive diagnoses of PD with mild cognitive impairment (PD-MCI) and PDD were based on full neuropsychological testing and established Movement Disorder Society criteria. Logistic regression and Cox proportional hazards regression models were used to examine predictors of cognitive decline. Results:Four hundred seventy patients for whom scores on all 3 screening tests were available from the same assessment were included in a cross-sectional analysis. The MoCA demonstrated the best overall diagnostic accuracy for PD-MCI (AUC= 0.79, sensitivity= 76.4%) and for PDD (AUC= 0.89, sensitivity= 81.0%) compared to the DRS-2 and MMSE. A longitudinal analysis was performed on the subset of patients (316/470; 67.2%) who were nondemented at baseline and had undergone two or more assessments. After controlling for covariates, the MoCA was the only test associated with progression to PDD (OR= 1.27 95% CI 1.1 - 1.5, p=0.001) and faster time to dementia (HR = 1.3, 95% CI 1.1 - 1.4, p

BackgroundNumerous neuropsychological tests and test versions are used in Parkinson's disease research, but their relative capacity to detect mild cognitive deficits and their comparability across studies are unknown. The objective of this study was to identify neuropsychological tests that consistently detect cognitive decline in PD across studies.MethodsData from 30 normed neuropsychological tests across 20 international studies in up to 2908 nondemented PD patients were analyzed. A subset of 17 tests was administered to up to 1247 healthy controls. A 2-step meta-analytic approach using standardized scores compared performance in PD with normative data.ResultsPooled estimates of the differences between PD and site-specific healthy controls identified significant cognitive deficits in PD patients on 14 test scores across 5 commonly assessed cognitive domains (attention or working memory, executive, language, memory, and visuospatial abilities), but healthy control performance was statistically above average on 7 of these tests. Analyses based on published norms only, as opposed to direct assessment of healthy controls, showed high between-study variability that could not be accounted for and led to inconclusive results.ConclusionsNormed neuropsychological tests across multiple cognitive domains consistently detect cognitive deficits in PD when compared with site-specific healthy control performance, but relative PD performance was significantly affected by the inclusion and type of healthy controls versus the use of published norms only. Additional research is needed to identify a cognitive battery that can be administered in multisite international studies and that is sensitive to cognitive decline, responsive to therapeutic interventions, and superior to individual cognitive tests. © 2018 International Parkinson and Movement Disorder Society.

INTRODUCTION:Identification of factors associated with progression of cognitive symptoms in Parkinson's disease (PD) is important for treatment planning, clinical care, and design of future clinical trials. The current study sought to identify whether prediction of cognitive progression is aided by examining baseline cognitive features, and whether this differs according to stage of cognitive disease. METHODS:Participants with PD in the Pacific Udall Center Clinical Consortium who had longitudinal data available and were nondemented at baseline were included in the study (n = 418). Logistic and Cox regression models were utilized to examine the relationship between cognitive, demographic, and clinical variables with risk and time to progression from no cognitive impairment to mild cognitive impairment (PD-MCI) or dementia (PDD), and from PD-MCI to PDD. RESULTS:Processing speed (OR = 1.05, p = 0.009) and working memory (OR = 1.01, p = 0.03) were associated with conversion to PDD among those with PD-MCI at baseline, over and above demographic variables. Conversely, the primary predictive factor in the transition from no cognitive impairment to PD-MCI or PDD was male sex (OR = 4.47, p = 0.004), and males progressed more rapidly than females (p = 0.01). Further, among females with shorter disease duration, progression was slower than for their male counterparts, and poor baseline performance on semantic verbal fluency was associated with shorter time to cognitive impairment in females but not in males. CONCLUSIONS:This study provides evidence for sex differences in the progression to cognitive impairment in PD, while specific cognitive features become more important indicators of progression with impending conversion to PDD.

IntroductionIncreased plasma homocysteine (HC) is a risk factor for dementia in the general population. Levodopa therapy causes increased plasma HC, but it remains unclear whether elevated plasma HC is associated with cognitive impairment in Parkinson's disease (PD).MethodsThe study population includes all participants in the Pacific Northwest Udall Center (PANUC) Clinical cohort at the time of the study, consisting of 294 individuals with PD who had a standardized neuropsychological assessment and plasma collection for HC measurement. We tested the hypothesis that elevated plasma HC is inversely related to cognitive function in patients with PD.ResultsAs expected, plasma HC was positively associated with age, disease duration, disease severity, and levodopa usage, while cognitive function was associated with age, education, gender, and APOE genotype, so subsequent analyses controlled for these covariates. When plasma HC was dichotomized as normal (

Cognitive impairment is a common and disabling problem in Parkinson's disease (PD). Identification of genetic variants that influence the presence or severity of cognitive deficits in PD might provide a clearer understanding of the pathophysiology underlying this important nonmotor feature. We genotyped 1105 PD patients from the PD Cognitive Genetics Consortium for 249,336 variants using the NeuroX array. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), working memory/executive function (Letter-Number Sequencing and Trail Making Test [TMT] A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation [JoLO]), and global cognitive function (Montreal Cognitive Assessment). For common variants, we used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates. Rare variants were analyzed using the optimal unified sequence kernel association test. The significance threshold was defined as a false discovery rate-corrected p-value (PFDR) of 0.05. Eighteen common variants in 13 genomic regions exceeded the significance threshold for one of the cognitive tests. These included GBA rs2230288 (E326K; PFDR = 2.7 × 10-4) for JoLO, PARP4 rs9318600 (PFDR = 0.006), and rs9581094 (PFDR = 0.006) for HVLT-R total recall, and MTCL1 rs34877994 (PFDR = 0.01) for TMT B-A. Analysis of rare variants did not yield any significant gene regions. We have conducted the first large-scale PD cognitive genetics analysis and nominated several new putative susceptibility genes for cognitive impairment in PD. These results will require replication in independent PD cohorts.

BackgroundThere is mounting evidence for a connection between the gut and Parkinson's disease (PD). Dysbiosis of gut microbiota could explain several features of PD.ObjectiveThe objective of this study was to determine if PD involves dysbiosis of gut microbiome, disentangle effects of confounders, and identify candidate taxa and functional pathways to guide research.MethodsA total of 197 PD cases and 130 controls were studied. Microbial composition was determined by 16S rRNA gene sequencing of DNA extracted from stool. Metadata were collected on 39 potential confounders including medications, diet, gastrointestinal symptoms, and demographics. Statistical analyses were conducted while controlling for potential confounders and correcting for multiple testing. We tested differences in the overall microbial composition, taxa abundance, and functional pathways.ResultsIndependent microbial signatures were detected for PD (P = 4E-5), participants' region of residence within the United States (P = 3E-3), age (P = 0.03), sex (P = 1E-3), and dietary fruits/vegetables (P = 0.01). Among patients, independent signals were detected for catechol-O-methyltransferase-inhibitors (P = 4E-4), anticholinergics (P = 5E-3), and possibly carbidopa/levodopa (P = 0.05). We found significantly altered abundances of the Bifidobacteriaceae, Christensenellaceae, [Tissierellaceae], Lachnospiraceae, Lactobacillaceae, Pasteurellaceae, and Verrucomicrobiaceae families. Functional predictions revealed changes in numerous pathways, including the metabolism of plant-derived compounds and xenobiotics degradation.ConclusionPD is accompanied by dysbiosis of gut microbiome. Results coalesce divergent findings of prior studies, reveal altered abundance of several taxa, nominate functional pathways, and demonstrate independent effects of PD medications on the microbiome. The findings provide new leads and testable hypotheses on the pathophysiology and treatment of PD. © 2017 International Parkinson and Movement Disorder Society.

ObjectiveParkinson's disease (PD) presents clinically with several motor subtypes that exhibit variable treatment response and prognosis. Here, we investigated genetic variants for their potential association with PD motor phenotype and progression.MethodsWe screened 10 SNPs, previously associated with PD risk, for association with tremor-dominant (TD) versus postural-instability gait disorder (PIGD) motor subtypes. SNPs that correlated with the TD/PIGD ratio in a discovery cohort of 251 PD patients were then evaluated in a multi-site replication cohort of 559 PD patients. SNPs associated with motor phenotype in both cross-sectional cohorts were next evaluated for association with (1) rates of motor progression in a longitudinal subgroup of 230 PD patients and (2) brain alpha-synuclein (SNCA) expression in the GTEx (Genotype-Tissue Expression project) consortium database.ResultsGenotype at rs356182, near SNCA, correlated with the TD/PIGD ratio in both the discovery (Bonferroni-corrected P = 0.04) and replication cohorts (P = 0.02). The rs356182 GG genotype was associated with a more tremor-predominant phenotype and predicted a slower rate of motor progression (1-point difference in annual rate of UPDRS-III motor score change, P = 0.01). The rs356182 genotype was associated with SNCA expression in the cerebellum (P = 0.005).InterpretationOur study demonstrates that the GG genotype at rs356182 provides molecular definition for a clinically important endophenotype associated with (1) more tremor-predominant motor phenomenology, (2) slower rates of motor progression, and (3) decreased brain expression of SNCA. Such molecularly defined endophenotyping in PD may benefit both clinical trial design and tailoring of clinical care as we enter the era of precision medicine.

IntroductionAlzheimer's disease (AD) and Parkinson's disease (PD) involve tau pathology. Tau is detectable in blood, but its clearance from neuronal cells and the brain is poorly understood.MethodsTau efflux from the brain to the blood was evaluated by administering radioactively labeled and unlabeled tau intracerebroventricularly in wild-type and tau knock-out mice, respectively. Central nervous system (CNS)-derived tau in L1CAM-containing exosomes was further characterized extensively in human plasma, including by single molecule array technology with 303 subjects.ResultsThe efflux of Tau, including a fraction via CNS-derived L1CAM exosomes, was observed in mice. In human plasma, tau was explicitly identified within L1CAM exosomes. In contrast to AD patients, L1CAM exosomal tau was significantly higher in PD patients than controls and correlated with cerebrospinal fluid tau.ConclusionsTau is readily transported from the brain to the blood. The mechanisms of CNS tau efflux are likely different between AD and PD.

Mutations in the LRRK2 gene result in autosomal dominant, late onset Parkinson's disease (PD). Three such mutations (p.R1441C, p.R1441G, and p.R1441H) are known to occur within codon 1441, and haplotype analyses indicate that each one has arisen independently on multiple occasions. We sequenced the entire coding region of 18 casual genes for PD or other parkinsonian neurodegenerative disorders in the proband of a family with autosomal dominant PD. We discovered a new missense mutation in the LRRK2 gene, c.4321C>A (p.R1441S). The mutation was predicted to be highly deleterious in silico (Combined Annotation Dependent Depletion score of 25.5) and segregated with disease in the pedigree. The clinical characteristics of affected family members were similar to those described in PD families with other mutations in LRRK2 codon 1441 and included resting tremor, rigidity, bradykinesia, unilateral onset, and a good response to levodopa. Age at onset ranged from 41 to 76. Two of the affected members of the pedigree underwent detailed, longitudinal neuropsychological testing, and both displayed evidence of mild cognitive deficits at or slightly preceding the onset of motor symptoms. LRRK2 p.R1441S represents the fourth pathogenic mutation observed within codon 1441 and its discovery adds to the remarkable complexity of a mutational hotspot within the ROC domain of the LRRK2 protein. © 2016 Wiley Periodicals, Inc.

ImportanceParkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets.ObjectiveTo determine whether GBA mutations and the E326K polymorphism modify PD symptom progression.Design, setting, and participantsThe entire GBA coding region was screened for mutations and E326K in 740 patients with PD enrolled at 7 sites from the PD Cognitive Genetics Consortium. Detailed longitudinal motor and cognitive assessments were performed with patients in the on state.Main outcomes and measuresLinear regression was used to test for an association between GBA genotype and motor progression, with the Movement Disorder Society-sponsored version of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) score at the last assessment as the outcome and GBA genotype as the independent variable, with adjustment for levodopa equivalent dose, sex, age, disease duration, MDS-UPDRS III score at the first assessment, duration of follow-up, and site. Similar methods were used to examine the association between genotype and tremor and postural instability and gait difficulty (PIGD) scores. To examine the effect of GBA genotype on cognitive progression, patients were classified into those with conversion to mild cognitive impairment or dementia during the study (progression) and those without progression. The association between GBA genotype and progression status was then tested using logistic regression, adjusting for sex, age, disease duration, duration of follow-up, years of education, and site.ResultsOf the total sample of 733 patients who underwent successful genotyping, 226 (30.8%) were women and 507 (69.2%) were men (mean [SD] age, 68.1 [8.8] years). The mean (SD) duration of follow-up was 3.0 (1.7) years. GBA mutations (β = 4.65; 95% CI, 1.72-7.58; P = .002), E326K (β = 3.42; 95% CI, 0.66-6.17; P = .02), and GBA variants combined as a single group (β = 4.01; 95% CI, 1.95-6.07; P = 1.5 × 10-4) were associated with a more rapid decline in MDS-UPDRS III score. Combined GBA variants (β = 0.38; 95% CI, 0.23-0.53; P = .01) and E326K (β = 0.64; 95% CI, 0.43-0.86; P = .002) were associated with faster progression in PIGD scores, but not in tremor scores. A significantly higher proportion of E326K carriers (10 of 21 [47.6%]; P = .01) and GBA variant carriers (15 of 39 [38.5%]; P = .04) progressed to mild cognitive impairment or dementia.Conclusions and relevanceGBA variants predict a more rapid progression of cognitive dysfunction and motor symptoms in patients with PD, with a greater effect on PIGD than tremor. Thus, GBA variants influence the heterogeneity in symptom progression observed in PD.

BackgroundLoss-of-function mutations in the GBA gene are associated with more severe cognitive impairment in PD, but the nature of these deficits is not well understood and whether common GBA polymorphisms influence cognitive performance in PD is not yet known.MethodsWe screened the GBA coding region for mutations and the E326K polymorphism in 1,369 PD patients enrolled at eight sites from the PD Cognitive Genetics Consortium. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised), working memory/executive function (Letter-Number Sequencing Test and Trail Making Test A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation), and global cognitive function (MoCA). We used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates and accounted for multiple testing using Bonferroni's corrections.ResultsMutation carriers (n = 60; 4.4%) and E326K carriers (n = 65; 4.7%) had a higher prevalence of dementia (mutations, odds ratio = 5.1; P = 9.7 × 10(-6) ; E326K, odds ratio = 6.4; P = 5.7 × 10(-7) ) and lower performance on Letter-Number Sequencing (mutations, corrected P[Pc ] = 9.0 × 10(-4) ; E326K, Pc  = 0.036), Trail Making B-A (mutations, Pc  = 0.018; E326K, Pc  = 0.018), and Benton Judgment of Line Orientation (mutations, Pc  = 0.0045; E326K, Pc  = 0.0013).ConclusionsBoth GBA mutations and E326K are associated with a distinct cognitive profile characterized by greater impairment in working memory/executive function and visuospatial abilities in PD patients. The discovery that E326K negatively impacts cognitive performance approximately doubles the proportion of PD patients we now recognize are at risk for more severe GBA-related cognitive deficits.

ObjectiveTo identify the causal gene in a multi-incident U.S. kindred with Parkinson's disease (PD).MethodsWe characterized a family with a classical PD phenotype in which 7 individuals (5 males and 2 females) were affected with a mean age at onset of 46.1 years (range, 29-57 years). We performed whole exome sequencing on 4 affected and 1 unaffected family members. Sanger-sequencing was then used to verify and genotype all candidate variants in the remainder of the pedigree. Cultured cells transfected with wild-type or mutant constructs were used to characterize proteins of interest.ResultsWe identified a missense mutation (c.574G > A; p.G192R) in the RAB39B gene that closely segregated with disease and exhibited X-linked dominant inheritance with reduced penetrance in females. The mutation occurred in a highly conserved amino acid residue and was not observed among 87,725 X chromosomes in the Exome Aggregation Consortium dataset. Sequencing of the RAB39B coding region in 587 familial PD cases yielded two additional mutations (c.428C > G [p.A143G] and c.624_626delGAG [p.R209del]) that were predicted to be deleterious in silico but occurred in families that were not sufficiently informative to assess segregation with disease. Experiments in PC12 and SK-N-BE(2)C cells demonstrated that p.G192R resulted in mislocalization of the mutant protein, possibly by altering the structure of the hypervariable C-terminal domain which mediates intracellular targeting.ConclusionsOur findings implicate RAB39B, an essential regulator of vesicular-trafficking, in clinically typical PD. Further characterization of normal and aberrant RAB39B function might elucidate important mechanisms underlying neurodegeneration in PD and related disorders.

BackgroundAccurate diagnosis and early detection of complex diseases, such as Parkinson's disease, has the potential to be of great benefit for researchers and clinical practice. We aimed to create a non-invasive, accurate classification model for the diagnosis of Parkinson's disease, which could serve as a basis for future disease prediction studies in longitudinal cohorts.MethodsWe developed a model for disease classification using data from the Parkinson's Progression Marker Initiative (PPMI) study for 367 patients with Parkinson's disease and phenotypically typical imaging data and 165 controls without neurological disease. Olfactory function, genetic risk, family history of Parkinson's disease, age, and gender were algorithmically selected by stepwise logistic regression as significant contributors to our classifying model. We then tested the model with data from 825 patients with Parkinson's disease and 261 controls from five independent cohorts with varying recruitment strategies and designs: the Parkinson's Disease Biomarkers Program (PDBP), the Parkinson's Associated Risk Study (PARS), 23andMe, the Longitudinal and Biomarker Study in PD (LABS-PD), and the Morris K Udall Parkinson's Disease Research Center of Excellence cohort (Penn-Udall). Additionally, we used our model to investigate patients who had imaging scans without evidence of dopaminergic deficit (SWEDD).FindingsIn the population from PPMI, our initial model correctly distinguished patients with Parkinson's disease from controls at an area under the curve (AUC) of 0·923 (95% CI 0·900-0·946) with high sensitivity (0·834, 95% CI 0·711-0·883) and specificity (0·903, 95% CI 0·824-0·946) at its optimum AUC threshold (0·655). All Hosmer-Lemeshow simulations suggested that when parsed into random subgroups, the subgroup data matched that of the overall cohort. External validation showed good classification of Parkinson's disease, with AUCs of 0·894 (95% CI 0·867-0·921) in the PDBP cohort, 0·998 (0·992-1·000) in PARS, 0·955 (no 95% CI available) in 23andMe, 0·929 (0·896-0·962) in LABS-PD, and 0·939 (0·891-0·986) in the Penn-Udall cohort. Four of 17 SWEDD participants who our model classified as having Parkinson's disease converted to Parkinson's disease within 1 year, whereas only one of 38 SWEDD participants who were not classified as having Parkinson's disease underwent conversion (test of proportions, p=0·003).InterpretationOur model provides a potential new approach to distinguish participants with Parkinson's disease from controls. If the model can also identify individuals with prodromal or preclinical Parkinson's disease in prospective cohorts, it could facilitate identification of biomarkers and interventions.FundingNational Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Michael J Fox Foundation.

BackgroundIncreasing evidence suggests that genetic factors play a role in the variability associated with cognitive performance in Parkinson's disease (PD). Mutations in the LRRK2 gene are the most common cause of monogenic PD; however, the cognitive profile of LRRK2-related PD is not well-characterized.MethodsA cohort of 1,447 PD patients enrolled in the PD Cognitive Genetics Consortium was screened for LRRK2 mutations and completed detailed cognitive testing. Associations between mutation carrier status and cognitive test scores were assessed using linear regression models.ResultsLRRK2 mutation carriers (n = 29) demonstrated better performance on the Mini Mental State Examination (P = 0.03) and the Letter-Number Sequencing Test (P = 0.005). A smaller proportion of LRRK2 carriers were demented (P = 0.03).ConclusionsOur cross-sectional study demonstrates better performance on certain cognitive tests, as well as lower rates of dementia in LRRK2-related PD. Future longitudinal studies are needed to determine whether LRRK2 mutation carriers exhibit slower cognitive decline. © 2015 International Parkinson and Movement Disorder Society.

ImportanceCognitive 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.ObjectiveTo determine whether common variation in the APOE, MAPT, and SNCA genes is associated with cognitive performance in patients with PD.Design, setting, and participantsWe 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 measuresNine variables derived from 7 psychometric tests.ResultsThe 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 relevanceOur 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, including dementia, is common in Parkinson's disease (PD). The Mini-Mental State Examination (MMSE) has been recommended as a screening tool for Parkinson's disease dementia (PDD), with values below 26 indicative of possible dementia. Using a detailed neuropsychological battery, we examined the range of cognitive impairment in PD patients with an MMSE score of 26 or higher. In this multicenter, cross-sectional, observational study, we performed neuropsychological testing in a sample of 788 PD patients with MMSE scores of 26 or higher. Evaluation included tests of global cognition, executive function, language, memory, and visuospatial skills. A consensus panel reviewed results for 342 subjects and assigned a diagnosis of no cognitive impairment, mild cognitive impairment, or dementia. Sixty-seven percent of the 788 subjects performed 1.5 standard deviations below the normative mean on at least one test. On eight of the 15 tests, more than 20% of subjects scored 1.5 standard deviations or more below the normative mean. Greatest impairments were found on Hopkins Verbal Learning and Digit Symbol Coding tests. The sensitivity of the MMSE to detect dementia was 45% in a subset of participants who underwent clinical diagnostic procedures. A remarkably wide range of cognitive impairment can be found in PD patients with a relatively high score on the MMSE, including a level of cognitive impairment consistent with dementia. Given these findings, clinicians must be aware of the limitations of the MMSE in detecting cognitive impairment, including dementia, in PD.

Mild cognitive impairment in Parkinson's disease (PD-MCI) is common and increases the risk for dementia. Establishing distinct PD-MCI cognitive subtypes could be valuable for eventually predicting those most likely to convert to dementia. However, the study of PD-MCI subtypes has not yielded consistent results among cohorts. To determine whether there are distinct cognitive subtypes among participants diagnosed with PD-MCI in the Pacific Northwest Udall Center Clinical Consortium, we cognitively subtyped 95 patients with PD-MCI, using the Movement Disorders Society Task Force diagnostic guidelines. Psychometric test scores were then subjected to principle components factor analysis to determine whether similar cognitive subgroups could be identified using statistical methodology. Multiple-domain PD-MCI was diagnosed in 95% of the sample, and a range of cognitive impairments were noted. Factor analysis yielded seven factors and demonstrated overlap of phonemic verbal fluency on two factors, as well as the loading of verbal fluency on the same factor as a visuospatial measure; however, these factors did not partition the sample into distinct cognitive subtypes. Separation of cognitive subtypes based on the current PD-MCI criteria, or via statistical methods, may not provide sufficient information to describe distinct PD groups. Future efforts to validate the PD-MCI criteria and identify combinations of genetic or other risk factors for cognitive impairment are warranted.

Recently, α-synuclein (α-syn) and DJ-1, 2 proteins critically involved in Parkinson's disease (PD), have been shown to be present in saliva, suggesting their potential utility as biomarkers of PD. However, the origin and influence of demographic characteristics (e.g., age or sex) on these proteins are unknown. We identified cheek epithelium, which forms the majority of the cellular component of saliva and is readily accessible clinically, as 1 of several potential sources of salivary α-syn and DJ-1. However, no PD-related trend in the cellular component was present. In the supernatant collected from 198 healthy subjects, no correlation was seen between salivary DJ-1 or α-syn with age. When male and female subjects were analyzed separately, a weak age-dependent increase in DJ-1 level was present in male subjects, along with slightly increased α-syn in female subjects. These results, albeit largely negative, provide critical information for understanding the salivary gland pathology and saliva as a PD biomarker source, and must be considered in future investigations of salivary changes in PD.

BackgroundPrevious studies indicate that as many as six genes within the PARK10 region (RNF11, UQCRH, HIVEP3, EIF2B3, USP24, ELAVL4) might modify susceptibility or age at onset in Parkinson's disease (PD).MethodsWe sought to identify new PD susceptibility genes and to validate previously nominated candidate genes within the PARK10 region using a two-stage design. We used data from a large, publicly-available genome-wide association study (GWAS) in the discovery stage (n = 2000 cases and 1986 controls) and data from three independent studies for the replication stage (total n = 2113 cases and 2095 controls). Marker density was increased by imputation using HapMap 3 and 1000 Genomes reference panels, and over 40,000 single nucleotide polymorphisms (SNPs) were used in the final analysis. The association between each SNP and PD was modeled using logistic regression with an additive allele dosage effect and adjusted for sex, age, and axes of geographical variation.ResultsAlthough the discovery stage yielded promising findings for SNPs in several novel genes, including DAB1, none of the results were validated in the replication stage. Furthermore, in meta-analyses across all datasets no genes within PARK10 reached significance after accounting for multiple testing.ConclusionOur results suggest that common variation in the PARK10 region is not associated with PD risk. However, additional studies are needed to assess the role of PARK10 in modifying age at onset and to determine whether rare variants in this region might affect PD susceptibility.