Age-dependent peripheral dissemination of α-synuclein seeds: mechanistic basis for blood-based early detection of Parkinson's disease.

Early diagnosis of Parkinson's disease (PD) before extensive neurodegeneration is a critical unmet need, largely due to the absence of sensitive, minimally or non-invasive biomarkers for the prodromal stage. Here, we primarily use α-synuclein (α-Syn) preformed fibril (PFF)-induced mouse models to investigate the mechanistic basis of peripheral α-Syn dissemination, and additionally perform a small exploratory analysis of a serum-based α-Syn seed amplification assay (SAA) in a prodromal human cohort as proof-of-concept. In the PFF model, misfolded α-Syn propagated broadly throughout the CNS and the periphery well before motor symptom onset, with middle-aged mice exhibiting exacerbated pathology, reflecting age-related vulnerability. Proteomic profiling linked α-Syn-induced neurodegeneration to neuroinflammatory signaling, while microglia depletion significantly reduced both central α-Syn accumulation and peripheral spread, implicating activated microglia as key contributors to disease progression. As an exploratory translational step, we applied serum α-Syn SAA to a small cross-sectional cohort of isolated REM sleep behavior disorder (iRBD; n = 25) individuals and matched healthy controls (n = 25). Combining the blood-brain barrier (BBB) integrity marker S100B with SAA yielded 64% sensitivity and 100% specificity versus healthy controls. Collectively, our findings delineate a mechanistic framework linking microglia-driven neuroinflammation, BBB disruption, and peripheral α-Syn dissemination, and provide preliminary evidence that serum α-Syn SAA combined with BBB biomarkers is a mechanistically plausible candidate strategy for early PD detection.