Serum α-Synuclein Seeding Amplification Assay: A Non-Invasive Biomarker for Early Detection of Parkinson's Disease

Introduction
Early diagnosis of Parkinson's disease (PD) remains challenging due to the lack of reliable, non-invasive biomarkers.

Objective
To assess the efficacy of serum α-synuclein seed amplification assay (α-Syn SAA) for early PD detection and to investigate the mechanisms underlying α-Syn propagation.

Methods
We utilized α-Syn preformed fibril (PFF) mouse models alongside clinical cohorts with isolated REM sleep behavior disorder (IRBD). Brain and serum samples were analyzed to measure α-Syn aggregation and seeding activity.

Results and Discussion
Aged mice exhibited accelerated brain α-Syn aggregation and earlier peripheral detection of α-Syn seeds compared to younger mice, with serum α-Syn seeds detectable as early as two months post-injection—prior to motor symptom onset. Proteomic analysis revealed age-related downregulation of lysosomal proteins alongside increased expression of inflammation-related genes. Following PFF injection, aged mice showed heightened microglial activation and oxidative stress, resulting in compromised blood-brain barrier (BBB) integrity. Pharmacological depletion of microglia significantly reduced α-Syn accumulation and its peripheral spread. In individuals with isolated REM sleep behavior disorder (IRBD), combining serum α-Syn SAA with S100B improved diagnostic specificity, highlighting their potential as non-invasive biomarkers for early Parkinson’s disease detection and offering valuable insight into the mechanisms driving α-Syn pathology. Serum α-Syn SAA shows promise as an early PD biomarker, influenced by aging and neuroinflammation. Further validation and therapeutic exploration targeting microglia are needed.

Conclusion
Serum α-Syn SAA is a promising non-invasive tool for early PD diagnosis with key clinical and therapeutic implications.