Abstract Details

EVs contain cell-state specific cargo and cross the blood-brain-barrier into the blood, providing a window into biochemical changes in the CNS. We showed previously that the level of total α-syn was significantly higher in neuronal- and oligodendroglial EVs (nEVs and oEVs, respectively) in the order HC < PD < MSA (Dutta et al. 2021). Separation of MSA from HC or PD was high whereas between PD and HC it was moderate. The level of pS129-α-syn in normal adult brain is ~4% but is substantially higher in PD/MSA brains. Tau aggregates are found in ~50% of PD brains but are rare in MSA.

To test whether pS129-α-synuclein and/or total tau measured in CNS-originating extracellular vesicles (EVs) improve the separation among healthy controls (HC), patients with Parkinson’s disease (PD) and patients with multiple system atrophy (MSA) when combined with total α-synuclein concentrations.

EVs were isolated from serum/plasma by an ExoQuick kit followed by immunoprecipitation of nEVs and oEVs separately. pS129-α-syn (32 HC, 46 PD, 30 MSA) was measured using an in-house developed electrochemilumiscence ELISA (ECLIA). Tau (54 HC, 51 PD, 41 MSA) was measured by a commercial ECLIA kit. Multinomial logistic regression with LASSO variable selection was used for ROC analysis. 

pS129-α-syn was significantly higher in the same order as total α-syn but only in oEVs. Addition of pS129-α-syn in oEVs to the discriminative formula increased the separation among all the groups, particularly between HC and PD. Total tau was significantly lower in nEVs and oEVs in MSA compared to HC and PD though did not increase the separation power.

The accuracy of an algorithm comprising total α-syn in nEVs, oEV:nEV α-syn concentration ratio, pS129-α-syn in oEVs, and total EV concentration is ~80% for discriminating HC from PD, ~99% for separating HC from MSA, and ~93% for distinguishing between PD and MSA.