UCLA

Synucleinopathies are a group of neurodegenerative diseases including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). These diseases are characterized by the aggregation and deposition of α-synuclein (α-syn) in Lewy bodies (LBs) in PD and DLB or as glial cytoplasmic inclusions in MSA. Current antemortem differential diagnosis of Parkinson’s disease (PD) and multiple system atrophy (MSA) is challenging due to the overlap of Parkinsonian symptoms, especially in the early stages. Analysis of biomarkers in CNS-originating extracellular vesicles (EVs) isolated from blood is a promising strategy for these diseases. EVs are released by all cell types and pass through the blood-brain barrier, providing a proxy of the brain’s biochemistry. We have shown previously that α-synuclein (α-syn) concentration in neuronal- and oligodendroglial-EVs (nEVs and oEVs, respectively) isolated from the serum or plasma of healthy controls (HC), and patients with PD or MSA allowed separating MSA from both HC and PD with high sensitivity and specificity. In healthy brains, only ∼4% of α-syn is phosphorylated at Ser129 (pS129-α-syn), whereas >90% pS129-α-syn may be found in LBs, suggesting that pS129-α-syn could be a helpful biomarker for synucleinopathies. Further, tau is implicated in patients with PD but not MSA. Here, I describe the development of a novel electrochemiluminescence ELISA for the measurement of pS129-α-syn in nEVs and oEVs based on the Meso Scale Discovery platform. Using this in-house assay and other commercial assays, we measured α-syn phosphorylated at Ser 129 (pS129-α-syn), total tau, and neurofilament light chain (NfL) in subsets of patients with PD, MSA or HCs to test if they improved the diagnostic power.The findings may suggest that a biomarker panel compromising nEVs α-syn, oEVs:nEVs α-syn, oEVs pS129-α-syn and exosome concentration may help distinguish patients with PD from MSA. However, many limitations currently exist with issues related to preanalytical variables, the need for independent validation and replication, differing postmortem diagnosis from the antemortem diagnosis, assay matrix effects, and issues with the L1CAM antibody, among others. Several notable limitations are associated with the current state of research in this area. These limitations encompass various factors such as preanalytical variables, the necessity for independent validation and replication, discrepancies between postmortem and antemortem diagnoses, assay matrix effects, challenges related to the L1CAM antibody, and other related issues.