Alpha-Synuclein Pre-Formed Fibrils Injected into Prefrontal Cortex Primarily Spread to Cortical and Subcortical Structures

Background: Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are characterized by diffuse spread of alpha-synuclein (alpha-syn) throughout the brain. Patients with PDD and DLB have a neuropsychological pattern of deficits that include executive dysfunction, such as abnormalities in planning, timing, working memory, and behavioral flexibility. The prefrontal cortex (PFC) plays a major role in normal executive function and often develops alpha-syn aggregates in DLB and PDD. Objective: To investigate the long-term behavioral and cognitive consequences of alpha-syn pathology in the cortex and characterize pathological spread of alpha-syn. Methods: We injected human alpha-syn pre-formed fibrils into the PFC of wild-type male mice. We then assessed the behavioral and cognitive effects between 12- and 21-months post-injection and characterized the spread of pathological alpha-syn in cortical, subcortical, and brainstem regions. Results: We report that PFC PFFs: 1) induced alpha-syn aggregation in multiple cortical and subcortical regions with sparse aggregation in midbrain and brainstem nuclei; 2) did not affect interval timing or spatial learning acquisition but did mildly alter behavioral flexibility as measured by intraday reversal learning; and 3) increased open field exploration. Conclusions: This model of cortical-dominant pathology aids in our understanding of how local alpha-syn aggregation might impact some symptoms in PDD and DLB.