Toward a biomarker panel measured in CNS-originating extracellular vesicles for improved differential diagnosis of Parkinson’s disease and multiple system atrophy

Abstract 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).