Differential Proteomic Landscape of Plasma Neuron-Derived Extracellular Vesicles in Parkinson's Disease with and...

Parkinson's disease (PD) is clinically heterogeneous, and the presence of rapid eye movement sleep behavior disorder (RBD) defines a distinct and aggressive subtype. There is an urgent need for molecular biomarkers to understand and identify these subtypes. Neuron-derived extracellular vesicles (nEVs) provide a window into brain pathology.

In this pilot study, we isolated plasma nEVs via L1CAM immunocapture from 28 subjects (PD-RBD, PD-noRBD, and controls). Proteomic analysis was performed using data-independent acquisition mass spectrometry (DIA-MS).

We quantified 1354 proteins. Comparative analysis revealed 239 differentially expressed proteins (DEPs) between PD-RBD and PD-noRBD. PD-RBD patients exhibited significantly higher levels of α-synuclein (SNCA) and showed pronounced enrichment in extracellular matrix remodeling (eg, NRGN, ELAV3) pathways. In contrast, PD-noRBD was characterized by dysregulated lipid metabolism (eg, APOE, CETP) and systemic inflammation. Specific DEPs correlated with motor severity, autonomic dysfunction, and brain iron deposition.

This pilot study reveals distinct proteomic profiles between the plasma nEVs of PD-RBD and PD-noRBD, suggesting divergent pathophysiological processes involving structural/extracellular matrix remodeling versus systemic metabolic-inflammatory pathways. These findings provide a prioritized panel of candidate nEV biomarkers for subtype-specific stratification in PD, which warrant further large-scale clinical and functional validation.