α-Synuclein Conformations in Plasma Distinguish Parkinson's Disease from Dementia with Lewy Bodies

Aggregation of misfolded α-synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Evidence exists for aSyn "strains" - conformations with distinct biological properties. However, biomarkers for PD vs. DLB, including potential aSyn strain differences, are lacking. Here, we used two monoclonal antibodies selective for different in vitro aSyn species - termed Strain A and B - to evaluate human brain tissue, cerebrospinal fluid (CSF), and plasma. Surprisingly, levels of Strain A and B aSyn species differed in plasma from individuals with PD vs. DLB in two independent cohorts. Lower plasma aSyn Strain A species also predicted subsequent PD cognitive decline. Strain A and Strain B aSyn species were undetectable in CSF, but plasma aSyn species could template aSyn fibrillization, particularly in PD. Our findings suggest that aSyn strains may impact LBD clinical presentation and originate outside the brain.