Oligomeric Alpha-Synuclein from neural-derived extracellular vesicles as possible biomarkers of non-motor symptoms in Parkinson's disease.

Non-motor symptoms (NMS) in Parkinson's disease (PD) are clinically impactful and lack reliable blood-based biomarkers. Neural-derived extracellular vesicles (NDEVs) enriched from serum may reflect central neurodegenerative processes. In this cross-sectional study, we examined associations between NMS burden and NDEV-associated proteins in 68 patients with PD. NDEVs were immunocaptured from serum using an anti-L1CAM approach and characterized according to MISEV guidelines. NDEV-associated oligomeric α-synuclein, SNARE complex proteins (SNAP-25, VAMP2, STX-1A), and neurotrophic factors (BDNF, GDNF, CDNF) were quantified by ELISA and related to NMS burden and PCA-derived non-motor domains, adjusting for age, sex, disease duration, MDS-UPDRS III, and levodopa equivalent daily dose (LEDD). Higher NDEV-associated oligomeric α-synuclein correlated with total NMSS score (partial Spearman's ρ = 0.252, p = 0.02) and with hallucinations (domain 4) and attention/memory (domain 5). These associations were confirmed by multivariable regression analyses. In domain-specific models, oligomeric α-synuclein was independently associated with worse cognitive and behavioral-psychotic scores, whereas higher STX-1A and lower CDNF were associated with greater affective-motivational symptom severity. No significant associations were observed for autonomic or sleep domains. These findings support NDEV-associated oligomeric α-synuclein as a candidate biomarker of non-motor symptom burden in PD and warrant longitudinal validation.