α-Synuclein Strain Dynamics Correlate with Cognitive Shifts in Parkinson's Disease
-Synuclein (-syn) strains can serve as discriminators between Parkinsons disease (PD) from other -synucleinopathies. The relationship between -syn strain dynamics and clinical performance as patients transition from normal cognition (NC) to cognitive impairment (CI) is not known. Here, we show that the biophysical properties and neurotoxicity of -syn strains change as PD cognitive status transitions from NC to mild cognitive impairment (PD-MCI) and dementia (PD-D). Both cross-sectional and longitudinal analyses reveal distinct -syn strains in PD patients correlating to their level of cognitive impairment. This study presents evidence that individuals with PD have different -syn strains that change in accordance with their cognitive status and highlights the potential of -syn strain dynamics to guide future diagnosis, management, and stratification of PD patients.

One Sentence SummaryDistinct features of -syn strains change with cognitive decline in Parkinsons disease.