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.

Aims Age and sex are important individual factors modifying the clinical symptoms of patients with Parkinson's disease (PD). Our goal is to evaluate the effects of age and sex on brain networks and clinical manifestations of PD patients. Methods Parkinson's disease participants (n = 198) receiving functional magnetic resonance imaging from Parkinson's Progression Markers Initiative database were investigated. Participants were classified into lower quartile group (age rank: 0%~25%), interquartile group (age rank: 26%~75%), and upper quartile group (age rank: 76%~100%) according to their age quartiles to examine how age shapes brain network topology. The differences of brain network topological properties between male and female participants were also investigated. Results Parkinson's disease patients in the upper quartile age group exhibited disrupted network topology of white matter networks and impaired integrity of white matter fibers compared to lower quartile age group. In contrast, sex preferentially shaped the small‐world topology of gray matter covariance network. Differential network metrics mediated the effects of age and sex on cognitive function of PD patients. Conclusion Age and sex have diverse effects on brain structural networks and cognitive function of PD patients, highlighting their roles in the clinical management of PD.

Imaging markers sensitive to neurodegeneration in the substantia nigra are critically needed for future disease-modifying trials. Previous studies have demonstrated the utility of posterior substantia nigra free water as a marker of progression in Parkinson’s disease. In this study, we tested the hypothesis that free water is elevated in the posterior substantia nigra of idiopathic REM sleep behaviour disorder, which is considered a prodromal stage of synucleinopathy. We applied free-water imaging to 32 healthy control subjects, 34 patients with idiopathic REM sleep behaviour disorder and 38 patients with Parkinson’s disease. Eighteen healthy control subjects and 22 patients with idiopathic REM sleep behaviour disorder were followed up and completed longitudinal free-water imaging. Free-water values in the substantia nigra were calculated for each individual and compared among groups. We tested the associations between posterior substantia nigra free water and uptake of striatal dopamine transporter in idiopathic REM sleep behaviour disorder. Free-water values in the posterior substantia nigra were significantly higher in the patients with idiopathic REM sleep behaviour disorder patients than in the healthy control subjects, but were significantly lower in patients with idiopathic REM sleep behaviour disorder than in patients with Parkinson’s disease. In addition, we observed significantly negative associations between posterior substantia nigra free-water values and dopamine transporter striatal binding ratios in the idiopathic REM sleep behaviour disorder patients. Longitudinal free-water imaging analyses were conducted with a linear mixed-effects model, and showed a significant Group × Time interaction in posterior substantia nigra, identifying increased mean free-water values in posterior substantia nigra of idiopathic REM sleep behaviour disorder over time. These results demonstrate that free water in the posterior substantia nigra is a valid imaging marker of neurodegeneration in idiopathic REM sleep behaviour disorder, which has the potential to be used as an indicator in disease-modifying trials.