Background and purpose: The identification of reliable diagnostic and prognostic biomarkers for Parkinson's disease (PD) is urgently needed. Here, we explored the potential use of a-synuclein (a-syn) in plasma neuronal exosomes as a biomarker for early PD diagnosis and disease progression. Methods: This study included both cross-sectional and longitudinal designs. The subjects included 36 patients with early-stage PD, 17 patients with advanced PD, 20 patients with idiopathic rapid eye movement sleep behavior disorder and 21 healthy controls (HCs). a-syn levels were measured by electrochemiluminescence immunoassay. A subgroup of patients with early-stage PD (n = 18) participated in a follow-up examination with repeated blood collection and clinical assessments after an average of 22 months. Results: The a-syn levels in plasma neuronal exosomes were significantly higher in patients with early-stage PD compared with HCs (P = 0.007). Differences in a-syn levels between patients with idiopathic rapid eye movement sleep behavior disorder and HCs did not reach statistical significance (P = 0.08). In addition, Spearman correlation analysis revealed that neuronal exosomal a-syn concentrations were correlated with Movement Disorders Society Unified Parkinson's Disease Rating Scale III/(I + II + III) scores, Non-Motor Symptom Questionnaire scores and Sniffin' Sticks 16-item test scores of patients with PD (P < 0.05). After a mean follow-up of 22 months in patients with earlystage PD, a Cox regression analysis adjusted for age and gender showed that longitudinally increased a-syn rather than baseline a-syn levels were associated with higher risk for motor symptom progression in PD (P = 0.039). Conclusions: Our results suggested that a-syn in plasma neuronal exosomes may serve as a biomarker to aid early diagnosis of PD and also as a prognostic marker for PD progression.

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Background: Genetic factors have a well-known influence on Parkinson's disease (PD) susceptibility; however, no previous studies have investigated the influence of SNCA mutations on the natural history of PD using a prospective follow-up study. The aim of this study was to assess the risk factors of variation of SNCA on the prognosis symptoms of PD patients. Methods: Fifty PD patients were recruited with 38 v-PSG confirmed PD+RBD patients, and the median follow-up period was 30 months. All patients underwent a comprehensive clinical evaluation at baseline and follow-up, and six SNPs of SNCA (rs356165, rs3857053, rs1045722, rs894278, rs356186, and rs356219) were analyzed. Cox proportional hazards regression models and Kaplan–Meier plot analysis were used to assess the associations between the SNCA variation and the primary and secondary progression outcomes. Results: Based on the clinical assessment, we found that hyposmia was substantially easier to aggravate. Regression analysis showed that patients with the T allele of rs1045722 and the G allele of rs356219 presented a 34 and 20% decreased risk of progression to the H-Y stage, respectively ( p = 0.022; p = 0.005). While for rs894278, G allele patients showed a 47% decreased risk of olfactory dysfunction ( p = 0.029). Further subgroup analysis showed that PD+RBD patients with rs356219/G exhibited a 30% and 20% decreased risk of progression on the H-Y stage and MoCA score ( p = 0.038; p = 0.045). Conclusions: Our results indicated that genetic variation in SNCA may contribute to variability natural progression of PD and could possibly be used as a prognostic marker.

A BS TRACT: Background: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is a prodromal stage of synucleinopathies. Patients with synucleinopathies frequently display eye movement abnormalities. However, whether patients with iRBD have eye movement abnormalities remains unknown. Objective: The aim of this study was to assess eye movement abnormalities and related gray matter alterations and explore whether such abnormalities can serve as biomarkers to indicate phenoconversion to synucleinopathies in iRBD. Methods: Forty patients with iRBD with early disease progression and 35 healthy control subjects participated in a 15-minute ocular-tracking task that evaluated their control of eye movement abilities. They also underwent clinical assessments for olfactory function, nonmotor symptoms, and autonomic symptoms, all of which are biomarkers to predict phenoconversion to synucleinopathies in iRBD. A subgroup of the participants (20 patients with iRBD and 20 healthy control subjects) also participated in structural magnetic resonance imaging. Results:The ocular-tracking ability in patients with iRBD was inferior to that of healthy control subjects in two aspects: pursuit initiation and steady-state tracking. Cortical thinning in the right visual area V4 in patients with iRBD is coupled with impaired pursuit initiation. Furthermore, prolonged pursuit initiation in patients with iRBD exhibits a trend of correlation with olfactory loss, the earliest biomarker that develops prior to other prodromal biomarkers. Conclusions: We found ocular-tracking abnormalities in patients with iRBD even early in their disease progression that have not been reported before. These abnormalities are coupled with atrophy of brain areas involved in the perception of object motion and might indicate phenoconversion to synucleinopathies in iRBD.