2024 American Academy of Neurology Abstract Website

George Kannarkat¹, Rebecca Zack⁴, Robert Skrinak⁴, James Morley⁵, Roseanne Davila-Rivera⁴, Sanaz Arezoumandan⁴, Katherine Dorfman⁴, Kelvin Luk², Daniel Weintraub³, Thomas Tropea⁴, Edward Lee⁴, Virginia Lee⁴, David Irwin⁴, Rizwan Akhtar⁶, Alice Chen-Plotkin⁴
¹Neurology, ²Pathology, ³Psychiatry, University of Pennsylvania, ⁴University of Pennsylvania, ⁵Parkinson's Disease Research, Education and Clinical Center, Corporal Michael J. Crescenz VA Medical Center, ⁶Northwestern University

Objective:

This study tested whether monoclonal antibodies generated against in vitro alpha-synuclein (aSyn) strains can serve as biomarkers in human biofluids.

Background:

Neurodegenerative disease caused by the misfolding and aggregation of aSyn is clinically heterogeneous. Recent studies have shown that “strains”, conformations of aSyn with distinct biochemical properties, may underlie the diversity of motor and non-motor symptoms in Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple systems atrophy (MSA).

Design/Methods:

Strain-selective antibodies were tested by immunohistochemistry, western blotting, ELISA, and immunoprecipitation in human tissue and biofluids. Extracellular vesicles (EVs) were isolated by size-exclusion chromatography.

Results:

These strain-selective antibodies recognize different subsets of aSyn pathology in human brain tissue but do not readily detect aSyn in cerebrospinal fluid by ELISA. Rather, they are enriched in plasma EVs. Remarkably, plasma levels of aSyn species recognized by strain-selective antibodies using ELISA reliably differentiated individuals with DLB from PD in two independent cohorts (AUC up to 0.83, n = 25-115 / group). Levels of plasma aSyn detected in MSA patients were similar to those in PD. Furthermore, elevated plasma levels of aSyn recognized by one of these antibodies predicted a slower rate of cognitive decline in individuals with PD. However, levels of plasma aSyn species did not reflect brain levels within two years of autopsy and the biochemical properties of plasma aSyn species isolated by immunoprecipitation differed from those in brain. Finally, aSyn species isolated by from PD plasma but not brain were able to induce fibrillization of aSyn in vitro.

Conclusions:

There are conformations of aSyn enriched in human plasma that correlate with cognitive outcomes and differentiate PD from DLB. With the increasing identification of aSyn strains outside of the brain, understanding the source and pathologic relevance of circulating plasma aSyn strains will help improve our understanding of these diseases which lack FDA-approved disease modifying therapies.