Plasma Total and Phosphorylated α-Synuclein as Biomarkers in Multiple System Atrophy: A Multicenter Study

BACKGROUND: The diagnostic value and longitudinal dynamics of plasma α-synuclein (α-syn) and phosphorylated α-syn (p-α-syn) in multiple system atrophy (MSA) remain incompletely understood. This study aimed to investigate the potential of plasma α-syn and p-α-syn as biomarkers for clinical diagnosis and progression monitoring in MSA. METHODS: We quantified plasma α-syn and p-α-syn concentrations in a cross-sectional cohort comprising 228 MSA patients, 71 Parkinson's disease (PD) patients, and 218 healthy controls (HCs), as well as in a longitudinal cohort of 101 MSA patients. An independent validation cohort from another center (51 MSA, 52 HCs) was also included. RESULTS: Plasma levels of both α-syn and p-α-syn were significantly higher in MSA patients compared to HCs (both q<0.001), but not compared to PD patients. Both biomarkers excellently distinguished MSA from HCs (AUCs: α-syn=0.932, p-α-syn=0.909), which was validated in the independent cohort. Both proteins were positively correlated with the severity of autonomic dysfunction. Longitudinally, p-α-syn levels increased significantly, and lower baseline α-syn levels were associated with faster motor progression (p=0.031). DISCUSSION: Our study suggests that plasma α-syn and p-α-syn may have potential as supportive indicators for the clinical diagnosis and monitoring of disease progression in MSA. Their correlation with autonomic dysfunction and dynamic changes offers new insights into the pathophysiology and clinical monitoring in MSA Conclusion: Plasma α-syn and p-α-syn levels might be potential supportive indicators for clinical diagnosis and progression monitoring in MSA.