Validation of α‐Synuclein in L1CAM‐Immunocaptured Exosomes as a Biomarker for the Stratification of Parkinsonian Syndromes

Abstract 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