TBI-related polyproteinopathy and the role of multiple neurodegenerations in cognitive decline and parkinsonism

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Multiple pathologies can contribute to cognitive impairment, dementia and parkinsonism, particularly in the setting of advanced age. A history of chronic traumatic brain injury (cTBI) or repetitive head impacts (RHI) increases the risk for dementia, although the relative contributions of chronic traumatic encephalopathy (CTE), Alzheimer disease (AD), Lewy body disease (LBD), frontotemporal lobar degeneration, amyotrophic lateral sclerosis (ALS) and other pathologies to post-traumatic dementia are unknown. In this project we will use the 8 cohorts of the Brain Bank Core that are separately focused on RHI, TBI, AD, ADRD, ALS, PTSD, and community- aging to systematically evaluate the precise neuropathology of RHI and TBI-related neurodegeneration. These combined brain banks contain over 2500 cases, and include the largest neuropathologically-confirmed autopsy cohort of CTE subjects (n= 361) as well as >50 cases of remote, moderately-severe TBI with a chronic cavitary lesion (cTBI). We and others have reported the clinical, neuroimaging, and neuropathologic characteristics of subjects who developed early onset dementia after sustaining a single moderate-severe TBI many years earlier and developed multiple unique pathologies. Furthermore, our preliminary data examining the pathology in hundreds of participants with and without RHI demonstrate that the type and distribution of beta-amyloid plaques are altered in CTE; neocortical LBD is common in CTE and associated with RHI, and 50% of participants with a history of cTBI had CTE in an ALS cohort. In addition, we show that RHI is associated with altered microglial and astrocyte phenotypes that are differentially associated with comorbid pathology in CTE. Our hypothesis, based on our preliminary data, is that RHI and cTBI are associated with increased frequency of multiple neurodegenerative pathologies and that the distribution of pathology is altered to reflect the pattern of injury. We further hypothesize that these multiple RHI and cTBI-related pathologies, including CTE, contribute to the development of dementia and parkinsonism in various brain bank cohorts. Our long-term goal is to uncover the relative risk, heterogeneity, and cellular mechanisms of cTBI-related neurodegeneration that underlie the development of dementia and parkinsonism. The immediate goal of this research project is to determine the prevalence and pathological distribution of RHI and cTBI-related disease in a variety of neurodegenerative brain banks. This research is critical to understanding how trauma triggers or accelerates multiple neuropathologies. Overall, we aim to determine prevalence and heterogeneity of multiple pathologies in subjects exposed to RHI and cTBI and to determine the relative contributions of these pathologies to cognitive decline and parkinsonism.