The diagnosis of Parkinson’s disease (PD) and atypical parkinsonian syndromes is difficult due to the lack of reliable, easily accessible biomarkers. Multiple system atrophy (MSA) is a synucleinopathy whose symptoms often overlap with PD. Exosomes isolated from blood by immunoprecipitation using CNS markers provide a window into the brain’s biochemistry and may assist in distinguishing between PD and MSA. Thus, we asked whether α-synuclein (α-syn) in such exosomes could distinguish among healthy individuals, patients with PD, and patients with MSA. We isolated exosomes from the serum or plasma of these three groups by immunoprecipitation using neuronal and oligodendroglial markers in two independent cohorts and measured α-syn in these exosomes using an electrochemiluminescence ELISA. In both cohorts, α-syn concentrations were significantly lower in the control group and significantly higher in the MSA group compared to the PD group. The ratio between α-syn concentrations in putative oligodendroglial exosomes compared to putative neuronal exosomes was a particularly sensitive biomarker for distinguishing between PD and MSA. Combining this ratio with the α-syn concentration itself and the total exosome concentration, a multinomial logistic model trained on the discovery cohort separated PD from MSA with an AUC = 0.902, corresponding to 89.8% sensitivity and 86.0% specificity when applied to the independent validation cohort. The data demonstrate that a minimally invasive blood test measuring α-syn in blood exosomes immunoprecipitated using CNS markers can distinguish between patients with PD and patients with MSA with high sensitivity and specificity. Future optimization and validation of the data by other groups would allow this strategy to become a viable diagnostic test for synucleinopathies.

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Background Synucleinopathies are diseases characterized by aggregation and deposition of α‐synuclein in different brain cells. Diagnosis of these neurological disorders is challenging due to overlapping complex clinical symptoms. Developing reliable biomarkers that can distinguish among the synucleinopathies is an urgent public health need. Recently, α‐synuclein was shown to transfer via exosomes between different brain cells suggesting that measuring α‐synuclein in brain‐derived exosomes could serve as a potential biomarker for synucleinopathies. Method In this study, we used antibody‐coated magnetic beads to immunochemically isolate specific exosomes released by neurons or oligodendrocytes from serum/plasma of healthy individuals and patients with Parkinson’s disease and Multiple System Atrophy and measured biomarker concentration in them by a sensitive electro‐chemiluminescence ELISA. Oligodendroglial and neuronal exosomes were isolated from serum of 101 patients with MSA, 104 patients with PD and 100 healthy controls. Result Significantly higher concentrations of α‐synuclein were found in both neuronal and oligodendroglial exosomes from patients than in controls. The absolute values of α‐synuclein in neuronal and oligodendroglial exosomes provided moderate separation between the MSA and PD groups, yet the ratio between the two cell types allowed separating the two disease groups with 90.0% sensitivity and 90.0% specificity. Conclusion α‐Synuclein in brain‐derived blood exosomes provides a sensitive biomarker for distinguishing patients with MSA from healthy controls and from patients with PD using a blood test and suggest that the method can be expanded further for other neurodegenerative diseases.

Background: Synucleinopathies are neurodegenerative diseases characterized by aggregation and deposition of α-synuclein in different brain cells. Diagnosis of these neurological disorders is very challenging due to overlapping complex clinical symptoms. Developing reliable biomarkers that can distinguish among the synucleinopathies is an urgent public health need. Recently, α-synuclein was shown to transfer via exosomes between different brain cells suggesting that measuring α-synuclein in specific brain cell-derived exosomes could serve as a potential biomarker for synucleinopathies. Method: In this study, we used antibody-coated magnetic dynabeads to immunochemically enrich specific exosomes released by neurons or oligodendrocytes from serum of healthy individuals and patients with Parkinson's disease (PD) and Multiple System Atrophy (MSA) and measured biomarker concentration in them by a sensitive electrochemiluminescence ELISA. CNS exosomes were isolated from serum/plasma from a discovery cohort and a validation cohort containing 50 patients with MSA, 50 patients with PD and 50 healthy controls in each cohorts.Result: Significantly higher concentrations of α-synuclein were observed in both neuronal and oligodendroglial exosomes from patients than in controls. The absolute values of α-synuclein in neuronal and oligodendroglial exosomes provided moderate separation between the MSA and PD groups, yet the ratio between the two cell types derived exosomal α-synuclein allowed separating the two disease groups with 90.0% sensitivity and specificity. Conclusion:α-Synuclein in CNS-derived blood exosomes provides a sensitive biomarker for distinguishing these two synucleinopathies using a blood test and suggest that the method can be expanded further for other neurodegenerative diseases.