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Abstract: BACKGROUND: α-Synuclein aggregation is a pathological hallmark of synucleinopathies, including Parkinson's disease (PD) and multiple system atrophy (MSA). Although pathogenic α-synuclein seeds can be detected by real-time quaking-induced conversion (RT-QuIC), current assays primarily rely on cerebrospinal fluid, whose invasiveness limits repeated and large-scale applications. We therefore evaluated the feasibility of detecting pathogenic α-synuclein using urine-derived neuronal extracellular vesicles (NEVs). METHODS: Urine-derived NEVs were enriched by direct immunoprecipitation using L1CAM-conjugated magnetic beads. The RT-QuIC assay was performed in 26 patients with PD, 13 with MSA, and 25 disease controls, including 16 healthy controls (HC), 4 with progressive supranuclear palsy (PSP), and 5 with normal pressure hydrocephalus (NPH). RESULTS: Urine-derived NEVs exhibited characteristic neuronal and exosomal markers and a typical extracellular vesicle size distribution. The urine-based RT-QuIC assay distinguished PD from disease controls with 73.1% sensitivity and 84% specificity, and MSA from disease controls with 76.9% sensitivity and 84% specificity. When compared with HC alone, sensitivity and specificity were 73.1% and 93.8% for PD, and 76.9% and 93.8% for MSA, respectively. Kinetic analysis showed higher maximum fluorescence intensity and area under the curve (AUC) in PD compared with both disease controls and HC (P < 0.001 in all). MSA also demonstrated higher maximum fluorescence intensity than HC and increased AUC compared with both disease controls and HC (P < 0.05 in all). CONCLUSIONS: We developed and optimized a completely non-invasive urine-derived NEV α-synuclein RT-QuIC assay that demonstrates high specificity and moderate sensitivity for synucleinopathies. This approach warrants further validation in larger cohorts. © 2026 International Parkinson and Movement Disorder Society.