| Summary: | <p><strong>Background:</strong> Parkinson’s disease is characterised by intraneuronal α-synuclein aggregation.
Currently there is no α-synuclein-based blood test in clinical practice.</p>
<p><strong>Objectives:</strong> 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.</p>
<p><strong>Methods:</strong> We used poly(carboxybetaine-methacrylate) coated magnetic beads to isolate L1CAMpositive exosomes and triplexed electrochemiluminescence to measure exosomal a-synuclein, clusterin and syntenin-1 from 267 serum samples. Combined analysis of our current and previously
published data from Oxford, Kiel, Brescia and PROSPECT cohorts consisting of individuals (total n=735) with Parkinson’s disease (PD, n=290), Multiple system atrophy (MSA, n=50), Progressive supranuclear palsy (PSP, n=116), Corticobasal syndrome (CBS, n=88) and healthy controls (HC,
n=191) was done using two-stage (training vs validation) ROC analysis.</p>
<p><strong>Results:</strong> We established that α-synuclein levels 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 four-repeat tauopathies (AUC=0.93 vs 0.94). We confirmed that exosomal clusterin is elevated in subjects with four-repeat tauopathy and when combined with α-synuclein it
improved the performance of the assay in differentiating Parkinson’s disease from four-repeat tauopathies to AUC=0.98 vs 0.99. Correction for the generic exosomal protein syntenin-1 did not consistently improve the performance of the assay.</p>
<p><strong>Conclusions:</strong> α-Synuclein and clusterin in L1CAM-immunocaptured serum exosomes is a validated
blood test for the molecular stratification of neuronal α-synucleinopathy (i.e. Lewy body pathology)
versus phenotypically related neurodegenerative movement disorders.</p>
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