BACKGROUND: Parkinson's disease is characterized by intraneuronal α-synuclein aggregation. Currently there is no α-synuclein-based blood test in clinical practice. OBJECTIVES: Our aim was to assess by means of further testing and analysis whether α-synuclein measurements in serum L1CAM-immunocaptured exosomes can differentiate Parkinson's disease from related movement disorders. METHODS: We used poly(carboxybetaine-methacrylate)-coated magnetic beads to isolate L1CAM-positive exosomes and triplexed electrochemiluminescence to measure exosomal α-synuclein, clusterin, and syntenin-1 from 267 serum samples. Combined analysis of our current and previously published data from the Oxford, Kiel, Brescia, and PROSPECT cohorts consisting of individuals (total n = 735) with Parkinson's disease (n = 290), multiple system atrophy (MSA, n = 50), progressive supranuclear palsy (n = 116), corticobasal syndrome (n = 88), and healthy controls (n = 191) was done using 2-stage (training vs validation) receiver operating characteristic analysis. RESULTS: We established that α-synuclein level in L1CAM-immunocaptured exosomes above 14 pg/mL is a robust biomarker across cohorts that distinguishes Parkinson's disease from MSA (AUC, 0.90 vs 0.98) or 4-repeat tauopathies (AUC, 0.93 vs 0.94). We confirmed that exosomal clusterin is elevated in subjects with 4-repeat tauopathy, and when combined with α-synuclein, it improved the performance of the assay in differentiating Parkinson's disease from 4-repeat tauopathies to AUC, 0.98 versus 0.99. Correction for the generic exosomal protein syntenin-1 did not consistently improve the performance of the assay. CONCLUSIONS: α-Synuclein and clusterin in L1CAM-immunocaptured serum exosomes is a validated blood test for the molecular stratification of neuronal α-synucleinopathy (ie, Lewy body pathology) versus phenotypically related neurodegenerative movement disorders. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
L1CAM, biomarker, extracellular vesicles, neurodegeneration, synuclein