Abstract
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.
Highlights
Synucleinopathies are neurodegenerative diseases characterized by abnormal accumulation of intracellular α-syn aggregates
We used a different marker from the one chosen by Yu et al, myelin oligodendrocyte glycoprotein (MOG), for isolation of oligodendroglial exosomes. We found in both diseases a significant elevation of α-syn concentration in putative oligodendroglial exosomes compared to healthy controls. α-Syn concentrations were high in the multiple system atrophy (MSA) group compared to the control and Parkinson’s disease (PD) groups
Analysis of biomarkers in CNS-originating exosomes allows comparison among exosomes from different cell types, offering an additional advantage compared to cerebrospinal fluid (CSF) analysis
Summary
Synucleinopathies are neurodegenerative diseases characterized by abnormal accumulation of intracellular α-syn aggregates. In Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), α-syn accumulates in intraneuronal Lewy bodies and Lewy neurites, whereas in multiple system atrophy (MSA), α-syn deposits primarily as glial cytoplasmic inclusions (GCIs) in oligodendrocytes [8, 45, 67]. Accumulation and deposition of α-syn occur in other neurodegenerative diseases and conditions, such as Alzheimer’s disease (AD), pure autonomic failure, rapid eye movement sleep behavioral disorders, traumatic brain injury, and neuroaxonal dystrophies [29, 41, 44]. The rates of misdiagnosis are higher for the rarer synucleinopathies [57, 62]. A retrospective post-mortem study found that about one in four patients
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