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Abstract Details

Alpha-Synuclein Strains in Plasma Distinguish Parkinson's Disease from Dementia with Lewy Bodies
Movement Disorders
S26 - Movement Disorders: Basic Science (4:30 PM-4:42 PM)
006

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).

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

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.

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.

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.
Authors/Disclosures
George Kannarkat
PRESENTER
Dr. Kannarkat has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint Global.
No disclosure on file
No disclosure on file
James Morley Dr. Morley has nothing to disclose.
No disclosure on file
Sanaz Arezoumandan (University of Pennsylvania) Ms. Arezoumandan has nothing to disclose.
Katherine Dorfman Ms. Dorfman has nothing to disclose.
No disclosure on file
Daniel Weintraub Daniel Weintraub has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Clintrex. Daniel Weintraub has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Daniel Weintraub has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Daniel Weintraub has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sage. Daniel Weintraub has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Scion. Daniel Weintraub has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Signant. Daniel Weintraub has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sunovion. Daniel Weintraub has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Modality.ai. Daniel Weintraub has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cerevel. Daniel Weintraub has received personal compensation in the range of $500-$4,999 for serving as a Consultant for CuraSen. Daniel Weintraub has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Takeda. Daniel Weintraub has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Boehringer Ingelheim. Daniel Weintraub has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Daniel Weintraub has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Acadia. Daniel Weintraub has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Movement Disorder Society. The institution of Daniel Weintraub has received research support from NIH. The institution of Daniel Weintraub has received research support from Fox Foundation. The institution of Daniel Weintraub has received research support from IPMDS. Daniel Weintraub has received intellectual property interests from a discovery or technology relating to health care.
Thomas Tropea (University of Pennsylvania) Dr. Tropea has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bial. The institution of Dr. Tropea has received research support from NINDS. The institution of Dr. Tropea has received research support from Parkinson Foundation. The institution of Dr. Tropea has received research support from Michael J Fox Foundation.
No disclosure on file
Virginia Lee (University of Pennsylvania) Virginia Lee, PhD has nothing to disclose.
David Irwin (University of Pennsylvania) The institution of Dr. Irwin has received research support from NIH. The institution of Dr. Irwin has received research support from Prevail. The institution of Dr. Irwin has received research support from Passage Bio. The institution of Dr. Irwin has received research support from Alector. The institution of Dr. Irwin has received research support from Transposon. The institution of Dr. Irwin has received research support from Denali.
Rizwan Akhtar (Northwestern University) The institution of Dr. Akhtar has received research support from Vanqua Bio.
Alice Chen-Plotkin Dr. Chen-Plotkin has received intellectual property interests from a discovery or technology relating to health care.