2025 American Academy of Neurology Abstract Website

Objective:

This study investigates the source and pathogenic potential of blood-based alpha-synuclein (aSyn) using conformation-selective antibodies.

Background:

Monoclonal antibodies raised against different conformations or “strains” of recombinant aSyn have been shown to recognize differential but overlapping subsets of Lewy brain pathology. These antibodies can also recognize aSyn conformations enriched in blood that differentiate individuals with Parkinson’s disease (PD) from dementia with Lewy bodies and that correlate with rates of cognitive decline in PD. The source and pathologic potential of these species remain uncharacterized.

Design/Methods:

To investigate the source of these aSyn conformations in blood, we measured levels by strain-selective ELISA in blood cells and in plasma fractions separated by size exclusion chromatography. Concurrently, we applied these blood-derived aSyn strains to seed amplification assays (SAAs) and in vitro cellular models to test their pathogenic potential.

Results:

In blood, the aSyn conformation identified by these strain-selective antibodies are most enriched in fractions that correlate with extracellular vesicles. Plasma aSyn strain levels do not correlate with levels in blood cells. In SAA, aggregation of monomeric aSyn was induced by plasma derived aSyn in a strain-selective and a disease-specific manner. Cellular models also reflected a strain-selective induction of aSyn pathology.

Conclusions:

Overall, these strain-selective antibodies that correlate with cognitive status and trajectory in Lewy body disease are enriched in blood-derived extracellular vesicles and have pathogenic properties when tested in SAA and in vitro cellular models. These aSyn conformations outside of the brain could serve as disease biomarkers and lead to a better understanding of the origin and spread of pathogenic aSyn pathology.