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.

Metformin Cessation and Dementia Incidence.

Importance: Prior studies suggested that metformin may be associated with reduced dementia incidence, but associations may be confounded by disease severity and prescribing trends. Cessation of metformin therapy in people with diabetes typically occurs due to signs of kidney dysfunction but sometimes is due to less serious adverse effects associated with metformin. Objective: To investigate the association of terminating metformin treatment for reasons unrelated to kidney dysfunction with dementia incidence. Design, Setting, and Participants: This cohort study was conducted at Kaiser Permanente Northern California, a large integrated health care delivery system, among a cohort of metformin users born prior to 1955 without history of diagnosed kidney disease at metformin initiation. Dementia follow-up began with the implementation of electronic health records in 1996 and continued to 2020. Data were analyzed from November 2021 through September 2023. Exposures: A total of 12 220 early terminators, individuals who stopped metformin with normal estimated glomerular filtration rate (eGFR), were compared with routine metformin users, who had not yet terminated metformin treatment or had terminated (with or without restarting) after their first abnormal eGFR measurement. Early terminators were matched with routine users of the same age and gender who had diabetes for the same duration. Main outcomes and measures: The outcome of interest was all-cause incident dementia. Follow-up for early terminators and their matched routine users was started at age of termination for the early terminator. Survival models adjusted for sociodemographic characteristics and comorbidities at the time of metformin termination (or matched age). Mediation models with HbA1c level and insulin usage 1 and 5 years after termination tested whether changes in blood glucose or insulin usage explained associations between early termination of metformin and dementia incidence. Results: The final analytic sample consisted of 12 220 early terminators (5640 women [46.2%]; mean [SD] age at start of first metformin prescription, 59.4 [9.0] years) and 29 126 routine users (13 582 women [46.6%]; mean [SD] age at start of first metformin prescription, 61.1 [8.9] years). Early terminators had 1.21 times the hazard of dementia diagnosis compared with routine users (hazard ratio, 1.21; 95% CI, 1.12 to 1.30). In mediation analysis, contributions to this association by changes in HbA1c level or insulin use ranged from no contribution (0.00 years; 95% CI, -0.02 to 0.02 years) for insulin use at 5 years after termination to 0.07 years (95% CI, 0.02 to 0.13 years) for HbA1c level at 1 year after termination, suggesting that the association was largely independent of changes in HbA1c level and insulin usage. Conclusions and Relevance: In this study, terminating metformin treatment was associated with increased dementia incidence. This finding may have important implications for clinical treatment of adults with diabetes and provides additional evidence that metformin is associated with reduced dementia risk.

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.

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.

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.

α-Synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes Parkinson's disease from multiple system atrophy.

The diagnosis of Parkinson's disease (PD) and atypical parkinsonian syndromes is difficult due to the lack of reliable, easily accessible biomarkers. Multiple system atrophy (MSA) is a synucleinopathy whose symptoms often overlap with PD. Exosomes isolated from blood by immunoprecipitation using CNS markers provide a window into the brain's biochemistry and may assist in distinguishing between PD and MSA. Thus, we asked whether α-synuclein (α-syn) in such exosomes could distinguish among healthy individuals, patients with PD, and patients with MSA. We isolated exosomes from the serum or plasma of these three groups by immunoprecipitation using neuronal and oligodendroglial markers in two independent cohorts and measured α-syn in these exosomes using an electrochemiluminescence ELISA. In both cohorts, α-syn concentrations were significantly lower in the control group and significantly higher in the MSA group compared to the PD group. The ratio between α-syn concentrations in putative oligodendroglial exosomes compared to putative neuronal exosomes was a particularly sensitive biomarker for distinguishing between PD and MSA. Combining this ratio with the α-syn concentration itself and the total exosome concentration, a multinomial logistic model trained on the discovery cohort separated PD from MSA with an AUC = 0.902, corresponding to 89.8% sensitivity and 86.0% specificity when applied to the independent validation cohort. The data demonstrate that a minimally invasive blood test measuring α-syn in blood exosomes immunoprecipitated using CNS markers can distinguish between patients with PD and patients with MSA with high sensitivity and specificity. Future optimization and validation of the data by other groups would allow this strategy to become a viable diagnostic test for synucleinopathies.

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.

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.