Untargeted serum metabolic profiling of diabetes mellitus among Parkinson's disease patients.

Type 2 diabetes mellitus (T2DM) is a common comorbidity among Parkinson's disease (PD) patients. Yet, little is known about dysregulated pathways that are unique in PD patients with T2DM. We applied high-resolution metabolomic profiling in serum samples of 636 PD and 253 non-PD participants recruited from Central California. We conducted an initial discovery metabolome-wide association and pathway enrichment analysis. After adjusting for multiple testing, in positive (or negative) ion mode, 30 (25) metabolic features were associated with T2DM in both PD and non-PD participants, 162 (108) only in PD participants, and 32 (7) only in non-PD participants. Pathway enrichment analysis identified 17 enriched pathways associated with T2DM in both the PD and non-PD participants, 26 pathways only in PD participants, and 5 pathways only in non-PD participants. Several amino acid, nucleic acids, and fatty acid metabolisms were associated with T2DM only in the PD patient group suggesting a possible link between PD and T2DM.

Diet and the gut microbiome in patients with Parkinson's disease.

It has been suggested that gut microbiota influence Parkinson's disease (PD) via the gut-brain axis. Here, we examine associations between diet and gut microbiome composition and its predicted functional pathways in patients with PD. We assessed gut microbiota in fecal samples from 85 PD patients in central California using 16S rRNA gene sequencing. Diet quality was assessed by calculating the Healthy Eating Index 2015 (HEI-2015) based on the Diet History Questionnaire II. We examined associations of diet quality, fiber, and added sugar intake with microbial diversity, composition, taxon abundance, and predicted metagenomic profiles, adjusting for age, sex, race/ethnicity, and sequencing platform. Higher HEI scores and fiber intake were associated with an increase in putative anti-inflammatory butyrate-producing bacteria, such as the genera Butyricicoccus and Coprococcus 1. Conversely, higher added sugar intake was associated with an increase in putative pro-inflammatory bacteria, such as the genera Klebsiella. Predictive metagenomics suggested that bacterial genes involved in the biosynthesis of lipopolysaccharide decreased with higher HEI scores, whereas a simultaneous decrease in genes involved in taurine degradation indicates less neuroinflammation. We found that a healthy diet, fiber, and added sugar intake affect the gut microbiome composition and its predicted metagenomic function in PD patients. This suggests that a healthy diet may support gut microbiome that has a positive influence on PD risk and progression.

Untargeted serum metabolomics reveals novel metabolite associations and disruptions in amino acid and lipid metabolism in Parkinson's disease.

BACKGROUND: Untargeted high-resolution metabolomic profiling provides simultaneous measurement of thousands of metabolites. Metabolic networks based on these data can help uncover disease-related perturbations across interconnected pathways. OBJECTIVE: Identify metabolic disturbances associated with Parkinson's disease (PD) in two population-based studies using untargeted metabolomics. METHODS: We performed a metabolome-wide association study (MWAS) of PD using serum-based untargeted metabolomics data derived from liquid chromatography with high-resolution mass spectrometry (LC-HRMS) using two distinct population-based case-control populations. We also combined our results with a previous publication of 34 metabolites linked to PD in a large-scale, untargeted MWAS to assess external validation. RESULTS: LC-HRMS detected 4,762 metabolites for analysis (HILIC: 2716 metabolites; C18: 2046 metabolites). We identified 296 features associated with PD at FDR<0.05, 134 having a log2 fold change (FC) beyond ±0.5 (228 beyond ±0.25). Of these, 104 were independently associated with PD in both discovery and replication studies at p<0.05 (170 at p<0.10), while 27 were associated with levodopa-equivalent dose among the PD patients. Intriguingly, among the externally validated features were the microbial-related metabolites, p-cresol glucuronide (FC=2.52, 95% CI=1.67, 3.81, FDR=7.8e-04) and p-cresol sulfate. P-cresol glucuronide was also associated with motor symptoms among patients. Additional externally validated metabolites associated with PD include phenylacetyl-L-glutamine, trigonelline, kynurenine, biliverdin, and pantothenic acid. Novel associations include the anti-inflammatory metabolite itaconate (FC=0.79, 95% CI=0.73, 0.86; FDR=2.17E-06) and cysteine-S-sulfate (FC=1.56, 95% CI=1.39, 1.75; FDR=3.43E-11). Seventeen pathways were enriched, including several related to amino acid and lipid metabolism. CONCLUSIONS: Our results revealed PD-associated metabolites, confirming several previous observations, including for p-cresol glucuronide, and newly implicating interesting metabolites, such as itaconate. Our data also suggests metabolic disturbances in amino acid and lipid metabolism and inflammatory processes in PD.

Diet quality and Parkinson's disease: Potential strategies for non-motor symptom management.

INTRODUCTION: Parkinson's disease (PD) is now considered a systemic disease, and some phenotypes may be modifiable by diet. We will compare the diet quality and intake of specific nutrients and food groups of PD patients with household and community controls to examine how diet may influence PD clinical features. METHODS: We conducted a case-control study of 98 PD patients and 83 controls (household = 53; community = 30) in central California, assessing dietary habits over the past month and calculating the Healthy Eating Index (HEI)-2015. We employed multivariate logistic and linear regression analyses to assess associations between diet and PD status, PD symptom profiles, and medication, adjusting for relevant confounders. RESULTS: PD patients had a lower HEI score than controls, with an OR of 0.65 (95% CI: 0.45, 0.94) per 10-points increase in HEI. Lower-quality diet was characterized by higher intakes of carbohydrates, total and added sugars, and trans fats and lower intakes of fiber, folate, unsaturated fatty acids, protein, and fat. PD patients with chronic constipation had a 4.84 point lower HEI score than those without (ß per 10-point in HEI: -0.48; 95% CI: -0.97, -0.00). Furthermore, patients on high dopamine agonist doses consumed more sugar than those on lower doses. CONCLUSION: PD patients consume a lower-quality diet compared to household and community controls. Dietary modifications may alleviate non-motor symptoms like constipation, and promoting a healthy diet should become a part of routine care and disease management for PD patients, with special attention on agonist-treated and hyposmic patients.

A Wellness Prescription for Parkinson's: Mid to Late-Stage Disease.

The mid- to late-stages of Parkinson's disease (PD) bring increasing disability that may challenge independence and lower quality of life. Many people with PD struggle to remain hopeful and cope with an uncertain future due to the progression of the disease. Although disability in PD is due chiefly to motor impairment, nonmotor symptoms and psychosocial distress are also major contributors that are amenable to treatment. Interventions that address nonmotor symptoms and psychosocial distress can improve daily function and quality of life even as motor function worsens with disease progression. This manuscript proposes a patient-centered, proactive strategy to promote psychosocial adaptation to decrease the impact of motor, nonmotor, and psychosocial distress on quality of life and function in people with PD.

A Prescription for Wellness in Early PD: Just What the Doctor Ordered.

BACKGROUND: Being diagnosed with a neurodegenerative disease is a life-changing event and a critical time to help patients cope and move forward in a proactive way. Historically, the main focus of Parkinson's disease (PD) treatment has been on the motor features with limited attention given to non-motor and mental health sequelae, which have the most impact on quality of life. Although depression and anxiety have been described at the time of PD diagnosis, demoralization, intolerance of uncertainty, decreased self-efficacy, stigma and loneliness can also present and have negative effects on the trajectory of the disease. Hence, understanding the psychological impact of the diagnosis and how to provide better counselling at this critical time point may be the key to a better long-term trajectory and quality of life. FOCUS: There has been a paradigm shift in the treatment of chronic illness moving beyond the medical model, which focuses on fighting illness with the physician being in charge of the treatment process and the patient being the passive recipient, toward a more holistic (i.e., physical, psychological, social, and spiritual health) biopsychosocial approach that emphasizes behavioral factors with the patient being an active collaborator in their treatment. Hence, we propose that fostering resilience, social support, and psychological flexibility offer promise toward attenuating negative reactions and improving overall well-being. CONCLUSION: Through a proactive wellness approach incorporating lifestyle choices, people with PD (PwP) can not only achieve improved states of health, well-being, and quality of life, but actually thrive.

Ethnicity and Parkinson's Disease: Motor and Nonmotor Features and Disease Progression in Latino Patients Living in Rural California.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder among older adults worldwide. Currently, studies of PD progression rely primarily on White non-Latino (WNL) patients. Here, we compare clinical profiles and PD progression in Latino and WNL patients enrolled in a community-based study in rural Central California. METHOD: PD patients within 5 years of diagnosis were identified from 3 counties between 2001 and 2015. During up to 3 visits, participants were examined by movement disorders specialists and interviewed. We analyzed cross-sectional differences in PD clinical features severity at each study visit and used linear mixed models and Cox proportional hazards models to compare motor, nonmotor, and disability progression longitudinally and to assess time to death in Latinos compared to WNL patients. RESULTS: Of 775 patients included, 138 (18%) self-identified as Latino and presented with earlier age at diagnosis (63.6 vs 68.9) and death (78.6 vs 81.5) than WNL. Motor (hazard ratio [HR] = 1.17 [0.71, 1.94]) and nonmotor symptoms did not progress faster in Latino versus WNL patients after accounting for differences in baseline symptom severity. However, Latino patients progressed to disability stages according to Hoehn and Yahr faster than WNL (HR = 1.81 [1.11, 2.96]). Motor and nonmotor symptoms in Latino patients were also medically managed less well than in WNL. CONCLUSIONS: Our PD study with a large proportion of Latino enrollees and progression data reveals disparities in clinical features and progression by ethnicity that may reflect healthcare access and structural socioeconomic disadvantages in Latino patients with PD.

Proximity to residential and workplace pesticides application and the risk of progression of Parkinson's diseases in Central California.

BACKGROUND: Pesticide exposure has consistently been associated with Parkinson's disease (PD) onset. Yet, fewer epidemiologic studies have examined whether pesticides influence PD motor and non-motor symptom progression. OBJECTIVES: Using a geographic information system tool that integrates agricultural pesticide use reports and land use records to derive ambient exposures at residences and workplaces, we assessed associations between specific pesticides previously related to PD onset with PD symptom progression in two PD patient cohorts living in agricultural regions of California. METHODS: We calculated the pounds of pesticide applied agriculturally near each participant's residential or occupational addresses from 1974 to the year of PD diagnosis, using a geographic information system tool that links the California Pesticide Use Reports database to land use data. We examined 53 pesticides selected a priori as they have previously been associated with PD onset. We longitudinally followed two PD patient cohorts (PEG1 N = 242, PEG2 N = 259) for an average of 5.0 years (SD ± 3.5) and 2.7 years (SD ± 1.6) respectively and assessed PD symptoms using the movement disorder specialist-administered Unified Parkinson's disease Rating Scale part III (UPDRS), Mini-Mental State Examination (MMSE), and Geriatric Depression Scale (GDS). Weighted time-to-event regression models were implemented to estimate effects. RESULTS: Ten agricultural pesticides, including copper sulfate (pentahydrate), 2-methyl-4-chlorophenoxyacetic acid (MCPA) dimethylamine salt, tribufos, sodium cacodylate, methamidophos, ethephon, propargite, bromoxynil octanoate, monosodium methanearsonate (MSMA), and dicamba, were associated with faster symptom progression. Among these pesticides, residential or workplace proximity to higher amounts of copper sulfate (pentahydrate) and MCPA (dimethylamine salt) was associated with all three progression endpoints (copper sulfate: HRs = 1.22-1.36, 95 % CIs = 1.03-1.73; MCPA: HRs = 1.27-1.35, 95 % CIs = 1.02-1.70). CONCLUSIONS: Our findings suggest that pesticide exposure may not only be relevant for PD onset but also PD progression phenotypes. We have implicated ten specific pesticide active ingredients in faster PD motor and non-motor decline.

Parkinson's Disease and the Gut Microbiome in Rural California.

BACKGROUND: Increasing evidence connects the gut microbiome to Parkinson's disease (PD) etiology, but little is known about microbial contributions to PD progression and its clinical features. OBJECTIVE: We aim to explore the association between the gut microbiome with PD, and the microbial association with PD-specific clinical features. METHODS: In a community-based case-control study of 96 PD patients and 74 controls, microbiome data were obtained from 16S rRNA gene sequencing of fecal samples, and analyzed for microbial diversity, taxa abundance, and predicted functional pathways that differed in PD patients and controls, and their association with PD-specific features (disease duration, motor subtypes, L-DOPA daily dose, and motor function). RESULTS: PD patients' gut microbiome showed lower species diversity (p = 0.04) and were compositionally different (p = 0.002) compared to controls but had a higher abundance of three phyla (Proteobacteria, Verrucomicrobiota, Actinobacteria) and five genera (Akkermansia, Enterococcus, Hungatella, and two Ruminococcaceae) controlling for sex, race, age, and sequencing platform. Also, 35 Metacyc pathways were predicted to be differentially expressed in PD patients including biosynthesis, compound degradation/utilization/assimilation, generation of metabolites and energy, and glycan pathways. Additionally, the postural instability gait dysfunction subtype was associated with three phyla and the NAD biosynthesis pathway. PD duration was associated with the Synergistota phylum, six genera, and the aromatic compound degradation pathways. Two genera were associated with motor function. CONCLUSION: PD patients differed from controls in gut microbiome composition and its predicted metagenome. Clinical features were also associated with bacterial taxa and altered metabolic pathways of interest for PD progression.

Unmet Needs of Women Living with Parkinson's Disease: Gaps and Controversies.

Personalized medicine considering sex, gender, and cultural context has become the vanguard of delivery of care. However, women's issues in Parkinson disease (PD), especially from a psychosocial standpoint, have been an overlooked field. The key research areas include women-inclusive drug and device studies and genetic and hormonal considerations. Moreover, women with PD need to be educated and empowered on how to communicate their symptoms and needs, get engaged in research, get organized as a community, and support one another. Women with PD need tools to help track and convey their unique motor and nonmotor symptoms and psychological and social support needs. The management of PD needs to be customized to include the unique stages of women's lives, including menstrual cycles, pregnancy, perimenopause, menopause, and postmenopause. Specific guidelines for the use of hormonal treatments and customized dopamine replacement dosing need to be developed. Women need guidance on culturally sensitive wellness and self-care strategies that are customized for them. Basic core competencies in knowledge for all clinicians treating women with PD need to be established, including how to accurately diagnose, proactively identify, and treat the symptoms of PD in women and to ensure timely referral for specialty care, advanced therapies, and research studies. Caregivers and families need guidance on holistically supporting women with PD. The voices of women living with PD must be amplified to catalyze real change in this neglected field. This paper provides an overview of the current knowledge, gaps, and possible strategies to deal with the unmet needs of women living with PD with a focus on the clinical and psychosocial aspects. © 2022 International Parkinson and Movement Disorder Society.

DNA methylation-based surrogates of plasma proteins are associated with Parkinson's disease risk.

BACKGROUND: The epigenome may reflect Parkinson's disease (PD) risk, which serves as a point of convergence of genetic and environmental risk factors. Here, we investigate whether blood DNA methylation (DNAm) markers are associated with PD risk. METHODS: We selected 12 plasma proteins known as predictors of cardiovascular conditions and mortality to evaluate their effects on PD risk in a case-control study. In lieu of protein level measures, however, we assessed the influence of their DNAm surrogates. Primary analysis was restricted to 569 PD patients and 238 controls with DNAm data available. Using univariate logistic regression, we evaluated associations between the DNAm markers and PD. RESULTS: Of the 12 DNAm surrogates, the most robustly associated were DNAm EFEMP-1 and DNAm CD56, which were associated with PD with and without controlling for blood cell composition. DNAm EFEMP-1 was associated with a decreased risk of PD (OR = 0.83 per SD, 95% CI = 0.70, 0.98) whereas DNAm CD56 was associated with an increased risk of PD (OR = 1.41, 95% CI = 1.11, 1.79). CONCLUSIONS: Several DNAm markers, selected as part of a panel to track cardiovascular outcomes and mortality, were associated with PD risk. DNAm markers may inform of factors that are affected differentially in early PD patients compared with controls.

Increased Menopausal Age Reduces the Risk of Parkinson's Disease: A Mendelian Randomization Approach.

BACKGROUND: Studies of Parkinson's disease (PD) and the association with age at menarche or menopause have reported inconsistent findings. Mendelian randomization (MR) may address measurement errors because of difficulties accurately reporting the age these life events occur. OBJECTIVE: We used MR to assess the association between age at menopause and age at menarche with PD risk. METHODS: We performed inverse variant-weighted (IVW) MR analysis using external genome-wide association study (GWAS) summary data from the United Kingdom biobank, and the effect estimates between genetic variants and PD among two population-based studies (Parkinson's disease in Denmark (PASIDA) study, Denmark, and Parkinson's Environment and Gene study [PEG], United States) that enrolled 1737 female and 2430 male subjects of European ancestry. We, then, replicated our findings for age at menopause using summary statistics from the PD consortium (19 773 women), followed by a meta-analysis combining all summary statistics. RESULTS: For each year increase in age at menopause, the risk for PD decreased (odds ration [OR], 0.84; 95% confidence interval [CI], 0.73-0.98; P = 0.03) among women in our study, whereas there was no association among men (OR, 0.98; 95% CI, 0.85-1.11; P = 0.71). A replication using summary statistics from the PD consortium estimated an OR of 0.94 (95% CI, 0.90-0.99; P = 0.01), and we calculated a meta-analytic OR of 0.93 (95% CI, 0.89-0.98; P = 0.003). There was no indication for an association between age at menarche and PD (OR, 0.75; 95% CI, 0.44-1.29; P = 0.29). CONCLUSIONS: A later age at menopause was associated with a decreased risk of PD in women, supporting the hypothesis that sex hormones or other factors related to late menopause may be neuroprotective in PD. © 2021 International Parkinson and Movement Disorder Society.

Real-World Six-Year National Cost-Minimization Analysis of IncobotulinumtoxinA and OnabotulinumtoxinA in the VA/DoD Healthcare Systems.

PURPOSE: This study sought to perform a real-world, long-term cost-minimization analysis for incobotulinumtoxinA (Xeomin®) versus onabotulinumtoxinA (Botox®), given the established non-inferiority when utilized at similar doses. METHODS: The Department of Veterans Affairs (VA) and Department of Defense (DoD) national healthcare systems were included in this analysis. Real-world purchase data for incobotulinumtoxinA were used to estimate the direct drug costs between calendar years 2014 and 2019. Publicly available federal pharmaceutical prices (Federal Supply Schedule and Big 4) were used. The primary outcome was the difference in total direct costs nationally for incobotulinumtoxinA (real-world) versus having hypothetically utilized onabotulinumtoxinA (projected) for similar utilization. Sites utilizing ≥100 vials (of 100 Unit equivalents) of incobotulinumtoxinA annually were categorized as "major adopters". IncobotulinumtoxinA 50 Unit vials were assumed to be an alternative to a 100 Unit vial of onabotulinumtoxinA for 50% of such vial purchases in the base case scenario to account for differences in wastage. RESULTS: Over the six-year study time frame, 156 sites (76.8%) utilized incobotulinumtoxinA of the 203 total VA healthcare systems and DoD medical centers. Of these sites, 67 were major adopters for at least one year, with a mean of 3.4 years spent as a major adopter over the study period. Average annual savings per major adopter was $105,782. IncobotulinumtoxinA costs for all VA/DoD sites was $46.39 million for the six-year period versus a projected $71.92 million onabotulinumtoxinA cost-a total savings of $25.53 million (35.5% relative reduction). Approximately, 82.8% of savings stemmed from lower drug acquisition cost ($21.14 million) and 17.2% of savings ($4.39 million) was related to reduced wastage. It was estimated that a total of 9958 extra onabotulinumtoxinA 100 Unit vials would have been wasted during the six-year period, translating to the need for a 5.9% increase in vial purchases versus incobotulinumtoxinA. CONCLUSION: Meaningful cost savings were realized related to incobotulinumtoxinA adoption over a long-term time frame in the VA/DoD healthcare systems.

Genetic risk scores and hallucinations in patients with Parkinson disease.

OBJECTIVE: We examine the hypothesized overlap of genetic architecture for Alzheimer disease (AD), schizophrenia (SZ), and Parkinson disease (PD) through the use of polygenic risk scores (PRSs) with the occurrence of hallucinations in PD. METHODS: We used 2 population-based studies (ParkWest, Norway, and Parkinson's Environment and Gene, USA) providing us with 399 patients with PD with European ancestry and a PD diagnosis after age 55 years to assess the associations between 4 PRSs and hallucinations after 5 years of mean disease duration. Based on the existing genome-wide association study of other large consortia, 4 PRSs were created: one each using AD, SZ, and PD cohorts and another PRS for height, which served as a negative control. RESULTS: A higher prevalence of hallucinations was observed with each SD increase of the AD-PRS (odds ratio [OR]: 1.37, 95% confidence interval [CI]: 1.03-1.83). This effect was mainly driven by APOE (OR: 1.92, 95% CI: 1.14-3.22). In addition, a suggestive decrease and increase, respectively, in hallucination prevalence were observed with the SZ-PRS and the PD-PRS (OR: 0.77, 95% CI: 0.59-1.01; and OR: 1.29, 95% CI: 0.95-1.76, respectively). No association was observed with the height PRS. CONCLUSIONS: These results suggest that mechanisms for hallucinations in PD may in part be driven by the same genetic architecture that leads to cognitive decline in AD, especially by APOE.

Education Research: Evaluation of curriculum to teach resilience skills to neurology residents.

OBJECTIVE: To evaluate feasibility and acceptability of a health professional resilience skills training program with neurology residents. METHODS: The curriculum consists of five 1-hour-long modules that included the following skills: reflective narrative practices, emotion regulation, communication with highly distressed individuals, boundary management, and the identification of depression and trauma. Using a web-based survey tool, we administered the Brief Resilience Scale (BRS) and Abbreviated Maslach Burnout Inventory (aMBI) at baseline, in addition to a pre- and post-survey assessing change in beliefs and self-efficacy, as well as satisfaction with the intervention. Means were compared using the Wilcoxon rank-sum and signed rank tests. RESULTS: Twenty-two residents representing each year of training completed the pre-survey; 41% were women. Subscale scores on the aMBI revealed that 50% had moderate or high emotional exhaustion, 41% had moderate depersonalization, and 37% had moderate or low personal accomplishment, though 77.3% reported high career satisfaction. Female residents had lower scores on the BRS (mean 3.26 vs 3.88, p < 0.05), though scores on aMBI subscales did not differ by sex. Scores did not differ by year of training. Sixteen residents completed both the pre- and post-survey. Significant increases were detected in 4 of 9 self-efficacy statements. Seventy-one percent of residents were satisfied or extremely satisfied with the training. CONCLUSIONS: Residents were satisfied with the curriculum and reported improved ability to identify and cope with work-related stress. Further study is needed to evaluate the influence of skills adoption and practice on resilience and burnout.

Clinical progression in Parkinson's disease with features of REM sleep behavior disorder: A population-based longitudinal study.

INTRODUCTION: Rapid Eye Movement (REM) sleep behavior disorder (RBD) is characterized by dream enactment and is associated with incidence of neurodegenerative disorders, especially Parkinson's disease (PD). Whether PD with RBD constitutes a distinct subtype with unique progression is unknown. Here, we investigated motor and cognitive symptom progression in patients with self-reported RBD features in adult life. METHODS: We screened for RBD in a cohort of 776 PD patients whom we ascertained using a population-based strategy. Among participants with at least one follow-up (60%), we compared those with and without probable RBD (pRBD) estimating hazard rate ratios for progression events UPDRS-III≥ 35 and MMSE≤ 24. RESULTS: Prevalence of pRBD at baseline was 21%. In adjusted Cox regression models among patients with a Postural Instability and Gait Dysfunction (PIGD) phenotype, those with pRBD progressed faster to a UPDRS-III≥ 35 (HR = 1.92, 95% CI = 1.12; 3.27). Also, all patients with pRBD progressed twice as fast to a MMSE score≤ 24 (HR = 2.04, 95% CI = 1.13; 3.69). In sensitivity analyses, using alternative definition of pRBD and accounting for bias due to loss to follow-up results remained similar. DISCUSSION: Employing data from one of the largest population-based studies of PD, in which movement disorder specialists assessed patients, we confirm evidence that pRBD features are a clinical marker for faster cognitive decline and possibly also motor progression in PD patients, the latter for patients with a PIGD subtype early in disease.

Cognitive Impairment and Mortality in a Population-Based Parkinson's Disease Cohort.

BACKGROUND: Parkinson's disease (PD) is a heterogeneous disorder with variability in phenotype and progression. OBJECTIVE: We describe characteristics of PD patients in the largest population-based cohort followed for progression to date, and evaluate clinical risk factors for cognitive impairment and mortality. METHODS: We collected longitudinal data using the Unified Parkinson's Disease Rating Scale (UPDRS), Mini-Mental State Exam (MMSE), and Geriatric Depression Scale (GDS) in 242 new-onset PD patients followed for progression. We compared those who developed cognitive impairment (MMSE≤24) with those who did not, using t-tests, chi-square tests, and Cox proportional hazards regression. Mortality risk factors were assessed in all 360 patients enrolled at baseline. RESULTS: Thirty-four patients developed cognitive impairment during follow-up. Baseline characteristics predictive of faster time to cognitive impairment were older age at diagnosis, fewer years of education, and longer average sleep duration reported. The 197 patients who died were older at diagnosis, reported longer average sleep duration, had lower baseline MMSE scores, higher UPDRS-III scores, and a higher proportion were of the postural instability gait difficulty (PIGD) subtype. Patients with the tremor dominant (TD) subtype at baseline were less likely to develop cognitive impairment or die during follow-up. Progression of cognitive, depressive, and motor symptoms occurred in parallel. CONCLUSIONS: Motor symptom severity and subtype influence the incidence of cognitive impairment and mortality in PD, with the TD motor subtype being relatively protective. In addition, we newly found that longer average sleep duration at baseline predicts faster progression to cognitive impairment and mortality.