High-Throughput CSF Proteomics and Machine Learning to Identify Proteomic Signatures for Parkinson Disease Development and Progression.

BACKGROUND AND OBJECTIVES: This study aimed to identify CSF proteomic signatures characteristic of Parkinson disease (PD) and evaluate their clinical utility. METHODS: This observational study used data from the Parkinson's Progression Markers Initiative (PPMI), which enrolled patients with PD, healthy controls (HCs), and non-PD participants carrying GBA1, LRRK2, and/or SNCA pathogenic variants (genetic prodromals) at international sites. Study participants were chosen from PPMI enrollees based on the availability of aptamer-based CSF proteomic data, quantifying 4,071 proteins, and classified as patients with PD without GBA1, LRRK2, and/or SNCA pathogenic variants (nongenetic PD), HCs, patients with PD carrying the aforementioned pathogenic variants (genetic PD), or genetic prodromals. Differentially expressed protein (DEP) analysis and the least absolute shrinkage and selection operator (LASSO) were applied to the data from nongenetic PD and HCs. Signatures characteristics of nongenetic PD were quantified as a PD proteomic score (PD-ProS), validated internally and then externally using data of 1,556 CSF proteins from the LRRK2 Cohort Consortium (LCC). We further tested the PD-ProS in genetic PD and genetic prodromals and examined associations with clinical progression. RESULTS: Data from 279 patients with nongenetic PD (mean ± SD, age 62.0 ± 9.6 years; male 67.7%) and 141 HCs (age 60.5 ± 11.9 years; male 64.5%) were used for PD-ProS derivation. From 23 DEPs, LASSO determined weights of 14 DEPs for the PD-ProS (area under the curve [AUC] 0.83, 95% CI 0.78-0.87), validated in an independent internal validation cohort of 71 patients with nongenetic PD and 35 HCs (AUC 0.81, 95% CI 0.73-0.90). In the LCC, only 5 of the 14 DEPs were also measured. Notably, these 5 DEPs still distinguished 34 patients with nongenetic PD from 31 HCs with the same weights (AUC 0.75, 95% CI 0.63-0.87). Furthermore, the PD-ProS distinguished 258 patients with genetic PD from 365 genetic prodromals. Finally, regardless of genetic status, the PD-ProS independently predicted both cognitive and motor decline in PD (dementia, adjusted hazard ratio in the highest quintile [aHR-Q5] 2.8 [95% CI 1.6-5.0]; Hoehn and Yahr stage IV, aHR-Q5 2.1 [95% CI 1.1-4.0]). DISCUSSION: By integrating high-throughput proteomics with machine learning, we identified PD-associated CSF proteomic signatures crucial for PD development and progression. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov (NCT01176565). A link to the trial registry page is clinicaltrials.gov/ct2/show/NCT01141023. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the CSF proteome contains clinically important information regarding the development and progression of Parkinson disease that can be deciphered by a combination of high-throughput proteomics and machine learning.

Polygenic burden of Parkinson's disease risk stratifies the prognosis of isolated rapid-eye-movement disorder: A preliminary observational study.

BACKGROUND: Polygenic burden of Parkinson's disease (PD) risk single nucleotide polymorphisms (SNPs), is associated not only with PD development and age at onset, but also with higher PD penetrance in GBA and LRRK2 carriers. OBJECTIVES: To assess the impact of polygenic burden of PD risk SNPs in isolated rapid-eye-movement disorder (iRBD). METHODS: In this observational study using the data of the Parkinson's progression marker initiative, we retrospectively reviewed the records of iRBD patients of European-ancestry with genotype data for 90 PD risk SNPs available. We calculated the genetic risk score for PD (PD-GRS) as a weighted sum of those SNPs, and examined the association of PD-PRS with the subsequent course of iRBD patients. RESULTS: 37 IRBD patients (median age = 71.0 years, male = 65.4%) were included. Median follow-up years from the diagnosis was 6.8 years, and 14 patients (38.9%) developed overt α-synucleopathies during the follow-up period. PD-GRS was significantly associated with an increased phenoconversion risk [hazard ratio per +1 standard deviation (adjusted for age, sex, and baseline cognitive, motor, autonomic, and olfactory dysfunction as well as principal components 1 to 5 to account for the population stratification) = 7.4 (95% confidence interval, 1.6-34.6)]. Furthermore, iRBD patients with PD-GRS higher than the median showed an accelerated decline in motor function [standardized fixed-effects ß coefficients of the interaction term = 0.08 (95% confidence interval, 0.02-0.14)]. CONCLUSION: Our study showed the intriguing possibility that the disease course of iRBD patients differed according to the degree of polygenic burden of PD risk SNPs, although future validation is warranted.

Long-term Effect of Regular Physical Activity and Exercise Habits in Patients With Early Parkinson Disease.

BACKGROUND AND OBJECTIVES: Owing to the lack of long-term observations or comprehensive adjustment for confounding factors, reliable conclusions regarding long-term effects of exercise and regular physical activity in Parkinson disease (PD) have yet to be drawn. Here, using data from the Parkinson's Progression Markers Initiative study that includes longitudinal and comprehensive evaluations of many clinical parameters, we examined the long-term effects of regular physical activity and exercise habits on the course of PD. METHODS: In this retrospective, observational cohort study, we primarily used the multivariate linear mixed-effects models to analyze the interaction effects of their regular physical activity and moderate to vigorous exercise levels, measured with the Physical Activity Scale for the Elderly questionnaire, on the progression of clinical parameters, after adjusting for age, sex, levodopa equivalent dose, and disease duration. We also calculated bootstrapping 95% confidence intervals (CIs) and conducted sensitivity analyses using the multiple imputation method and subgroup analyses using propensity score matching to match for all baseline background factors. RESULTS: Two hundred thirty-seven patients with early PD (median [interquartile range] age, 63.0 [56.0-70.0] years, male 69.2%, follow-up duration 5.0 [4.0-6.0] years) were included. Regular physical activity and moderate to vigorous exercise levels at baseline did not significantly affect the subsequent clinical progression of PD. However, average regular overall physical activity levels over time were significantly associated with slower deterioration of postural and gait stability (standardized fixed-effects coefficients of the interaction term [ßinteraction] = -0.10 [95% CI -0.14 to -0.06]), activities of daily living (ßinteraction = 0.08 [95% CI 0.04-0.12]), and processing speed (ßinteraction = 0.05 [95% CI 0.03-0.08]) in patients with PD. Moderate to vigorous exercise levels were preferentially associated with slower decline of postural and gait stability (ßinteraction = -0.09 [95% CI -0.13 to -0.05]), and work-related activity levels were primarily associated with slower deterioration of processing speed (ßinteraction = 0.07 [95% CI 0.04-0.09]). Multiple imputation and propensity score matching confirmed the robustness of our results. DISCUSSION: In the long term, the maintenance of high regular physical activity levels and exercise habits was robustly associated with better clinical course of PD, with each type of physical activity having different effects. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT01176565. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that sustained increase in overall regular physical activity levels in patients with early PD was associated with slower decline of several clinical parameters.

Value of in vivo α-synuclein deposits in Parkinson's disease: A systematic review and meta-analysis.

Previous studies that have investigated the potential of in vivo abnormal α-synuclein deposits as a pathological biomarker for PD included few participants and reported different diagnostic accuracies. Here, we aimed to confirm the diagnostic value of in vivo α-synuclein deposits in PD through a systematic review and meta-analysis, with special emphasis on determining the tissue most suitable for examination and assessing whether anti-native α-synuclein or anti-phosphorylated α-synuclein antibodies should be used. Databases were searched on December 30, 2018. We finally included 41 case-control studies that examined in vivo tissue samples using anti-native α-synuclein or anti-phosphorylated α-synuclein antibody in PD patients and controls. Using a univariate random-effects model, pooled sensitivity and specificity (95% confidence interval) of anti-native α-synuclein antibody were 0.54 (0.49-0.60) and 0.72 (0.68-0.76) for the gastrointestinal tract and 0.76 (0.60-0.89) and 0.60 (0.43-0.74) for the skin. Pooled sensitivity and specificity (95% confidence interval) of anti-phosphorylated α-synuclein antibody were 0.43 (0.37-0.48) and 0.82 (0.78-0.86) for the gastrointestinal tract, 0.76 (0.69-0.82) and 1.00 (0.98-1.00) for the skin, 0.42 (0.26-0.59) and 0.94 (0.84-0.99) for the minor salivary glands, and 0.66 (0.51-0.79) and 0.96 (0.86-1.00) for the submandibular glands. Although ubiquitous heterogeneity between the included studies should be noted when interpreting our results, our analyses demonstrated the following: (1) in vivo α-synuclein immunoreactivity has the potential as a pathological biomarker for PD; (2) anti-phosphorylated α-synuclein antibody consistently has higher specificity than anti-native α-synuclein antibody; and (3) skin biopsy examination using anti-phosphorylated α-synuclein antibody has the best diagnostic accuracy, although feasibility remains an important issue. © 2019 International Parkinson and Movement Disorder Society.

Novel pathogenic VPS13A gene mutations in Japanese patients with chorea-acanthocytosis.

OBJECTIVE: To identify mutations in vacuolar protein sorting 13A (VPS13A) for Japanese patients with suspected chorea-acanthocytosis (ChAc). METHODS: We performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis of the VPS13A gene, and chorein Western blotting of erythrocyte ghosts. As the results of the analysis, 17 patients were molecularly diagnosed with ChAc. In addition, we investigated the distribution of VPS13A gene mutations and clinical symptoms in a total of 39 molecularly diagnosed Japanese patients with ChAc, including 22 previously reported cases. RESULTS: We identified 11 novel pathogenic mutations, including 1 novel CNV. Excluding 5 patients with the unknown symptoms, 97.1% of patients displayed various neuropsychiatric symptoms or forms of cognitive dysfunction during the course of disease. The patients carrying the 2 major mutations representing over half of the mutations, exon 60-61 deletion and exon 37 c.4411C>T (R1471X), were localized in western Japan. CONCLUSIONS: We identified 13 different mutations in VPS13A, including 11 novel mutations, and verified the clinical manifestations in 39 Japanese patients with ChAc.