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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Synucleinopathies are neurodegenerative diseases characterized by accumulation of misfolded α-synuclein (α-syn) inclusions in neuronal and/or glial cells. Different synucleinopathies may affect different brain regions and cell types. In Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), α-syn deposits predominantly in neuronal Lewy bodies (LBs) and Lewy neurites (LNs), whereas in multiple system atrophy (MSA), α-syn-rich glial cytoplasmic inclusions (GCIs) are found in oligodendrocytes (1). Despite differences in the underlying pathophysiology, synucleinopathies often are misdiagnosed, especially by non-experts in the early-stages, due to the overlapping clinical symptoms (2, 3). Several studies have demonstrated the utility of measuring α-syn in neuronal EVs (nEVs) as a diagnostic biomarker for PD and atypical parkinsonian disorders (4). Recently, our group has shown that α-syn measured in both nEVs and oligodendroglial EVs (oEVs) in the same samples, and in particular the oEV:nEV α-syn concentration ratio, yielded a discriminative model distinguishing between PD and MSA with 89.8% sensitivity and 86.0% specificity and between healthy controls (HC) and MSA with 96.0% sensitivity and 84.3% specificity. In contrast, the model offered moderate separation between PD and HC – 71.4% sensitivity and 62.7% specificity (5).

Background: DNA methylation studies in Parkinson’s disease (PD) thus far have focused on disease susceptibility but not progression. Objective: In this epigenome-wide association study (EWAS), we aim to identify methylation markers associated with faster cognitive decline or motor progression in PD. Methods: We included 232 PD patients from the Parkinson’s Environment and Gene follow-up study who provided blood samples at enrolment. Information on cognitive and motor function was collected using the Mini-Mental State Examination (MMSE) and Unified Parkinson’s Disease Rating Scale (UPDRS). For EWAS analyses, we used a robust measure of correlation: biweight midcorrelations, t-tests, and Cox proportional hazard models. We also conducted weighted correlation network analysis (WGCNA) to identify CpG modules associated with cognitive decline or motor progression in PD. Results: Among 197 individuals of European ancestry, with our EWAS approach we identified 7 genome-wide significant CpGs associated with a MMSE 4-point decline and 8 CpGs associated with faster motor progression (i.e., rate of UPDRS increase ≥5-point/year). The most interesting CpGs for cognitive decline include cg17445913 in KCNB1 (cor = 0.36, p = 6.85 × 10−7) and cg02920897 in DLEU2 (cor = 0.34, p = 3.23 × 10−6), while for motor progression it was cg01754178 in PTPRN2 (cor = −0.34, p = 2.07 × 10−6). In WGCNA, motor progression related modules were enriched for genes related to neuronal synaptic functions, Wnt signaling pathway, and mitochondrial apoptosis. Conclusions: Our study provides the first epigenetic evidence that differential methylation in genes previously identified as being associated with cognitive impairment, neuronal synaptic function, Wnt signaling pathway, and mitochondrial apoptosis is associated with cognitive and motor progression in PD.