Plasma extracellular vesicle pathognomonic proteins as the biomarkers of the progression of Parkinson’s disease

SUMMARY: Parkinson’s disease (PD) is a progressive neurodegenerative disorder for which reliable blood biomarkers to predict disease progression remain elusive. Plasma extracellular vesicles (EVs) have gained attention as a promising biomarker platform due to their stability and ability to cross the blood-brain barrier. This study explored the potential of EV-cargo proteins, specifically α-synuclein, tau, and β-amyloid, as biomarkers of PD progression. A cohort of 55 people with PD (PwP) and 58 healthy controls (HCs) underwent annual assessments of plasma EV proteins, cognition, and motor symptoms. EVs were isolated and validated using standardized methods, with pathognomonic proteins quantified via immunomagnetic reduction assays. Associations between biomarker changes and clinical symptom progression were analyzed. Over an average of 3.96 visits for PwP and 2.25 visits for HCs, PwP exhibited a distinct pattern of plasma EV protein changes linked to motor symptom progression, particularly in the Unified PD Rating Scale (UPDRS) part II score. Notably, changes in plasma EV α-synuclein levels were significantly correlated with changes in motor and cognitive symptoms, suggesting its central role in disease progression. These findings highlight the potential of plasma EV biomarkers, especially α-synuclein, as indicators of ongoing pathogenesis and as candidates for evaluating α-synuclein-targeted therapies in PD.