Detecting Misfolded α‐Synuclein in Blood Years before the Diagnosis of Parkinson's Disease

Background Identifying individuals with Parkinson's disease (PD) already in the prodromal phase of the disease has become a priority objective for opening a window for early disease‐modifying therapies. Objective The aim was to evaluate a blood‐based α‐synuclein seed amplification assay (α‐syn SAA) as a novel biomarker for diagnosing PD in the prodromal phase. Methods In the TREND study (University of Tuebingen) biennial blood samples of n = 1201 individuals with/without increased risk for PD were taken prospectively over 4 to 10 years. We retrospectively analyzed blood samples of 12 participants later diagnosed with PD during the study to detect and amplify pathological α‐syn conformers derived from neuronal extracellular vesicles using (1) immunoblot analyses with an antibody against these conformers and (2) an α‐syn‐SAA. Additionally, blood samples of n = 13 healthy individuals from the TREND cohort and n = 20 individuals with isolated rapid eye movement sleep behavior disorder (iRBD) from the University Hospital Cologne were analyzed. Results All individuals with PD showed positive immunoblots and a positive α‐syn SAA at the time of diagnosis. Moreover, all PD patients showed a positive α‐syn SAA 1 to 10 years before clinical diagnosis. In the iRBD cohort, 30% showed a positive α‐syn SAA. All healthy controls had a negative SAA. Conclusions We here demonstrate the possibility to detect and amplify pathological α‐syn conformers in peripheral blood up to 10 years before the clinical diagnosis of PD in individuals with and without iRBD. The findings of this study indicate that this blood‐based α‐syn SAA assay has the potential to serve as a diagnostic biomarker for prodromal PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.