Biomarkers for parkinsonian disorders in CNS-originating extracellular vesicles

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Summary Many cases of Parkinson’s disease, and even more so atypical parkinsonian disorders, are misdiagnosed. Misdiagnosis not only causes high stress and anxiety to patients, their families, and their caregivers, but also is a major impediment to development of effective therapy for these diseases. Recently, we have demonstrated that the α-synuclein concentration in extracellular vesicles (EVs) immunoprecipitated from serum or plasma using oligodendroglial and neuronal markers, and in particular the ratio between the α-synuclein concentrations in the two types of EVs, is a sensitive biomarker for distinguishing between Parkinson’s disease and multiple system atrophy. This liquid biopsy approach requires only a minimally invasive blood draw and could lead to a major advancement in developing diagnostic tests for these diseases. Here, we propose to build upon these recent findings by constructing a biomarker panel, including several additional candidate markers, and apply the panel to two additional atypical parkinsonian syndromes—progressive supranuclear palsy and corticobasal syndrome. Serum samples for the study will be obtained from several national biorepositories as well as collected locally, prospectively, in expert clinics. The study design emphasizes biomarker analysis within the first two years of diagnosis, and in prodromal synucleinopathy, to test the utility of the biomarker panel when it is most needed. An additional goal of the project is to develop methodology for validating the cellular origin of the EVs, an urgent unmet need in the field. Success of the project will lead both to an advancement of research on biomarkers for CNS diseases using a minimally invasive liquid biopsy that can be translated into clinical use in the near future.