Late Pathologies of Exposure to Repetitive Head Impacts from Contact Sports: White Matter and Vascular Contributions to Cognitive Impairment, Dementia, and Neuropsychiatric Symptoms

Each year, millions of Americans are exposed to repetitive head impacts (RHI) through contact sport participation and may be at risk for chronic traumatic encephalopathy (CTE). The clinical presentation of CTE is ill-defined and includes deficits in executive function and memory, dementia, neurobehavioral dysregulation and depression. While these clinical features have been attributed to phosphorylated tau (p-tau) pathology, our data show p-tau is not related to neuropsychiatric symptoms and does not account for all cognitive deficits in CTE. The etiology of these clinical features is thus unclear and likely multifactorial. Our data in small samples of male football players show that white matter (WM) degeneration and cerebrovascular disease (CBVD) are common and affect cognition. Yet, the vascular contributions to neuropsychiatric syndromes and cognitive impairment and dementia (VCID) in former contact sport athletes are unknown and a topic that our existing studies do not address. This R01 will conduct sophisticated in vivo and ex vivo assessments of WM integrity and CBVD and examine risk factors for, and the cognitive and neuropsychiatric effects of WM degeneration and CBVD in living and deceased former contact sport athletes. In a collaborative effort between the Boston University (BU) and Univ. of California, San Francisco (UCSF) Alzheimer's Disease Research Centers (ADRCs), we will recruit 200 former contact sport athletes (>50 years), males and females from different sports, and 100 age- and race- matched people with no history of RHI or traumatic brain injury (TBI). Groups will span the cognitive continuum. Participants will enroll into the BU or UCSF ADRC to complete cognitive and neuropsychiatric tests, advanced MRI protocols of WM integrity and CBVD, and blood draw for plasma biomarker analysis of WM integrity and CBVD. A subgroup (50 former contact sport athletes, 25 non-RHI/TBI) will undergo lumbar puncture to test plasma-CSF analyte concordance and examine novel CSF microvascular markers. We will expand our U54 of 7 harmonized brain banks studying RHI and AD/ADRD risk by adding novel ELISA, multiplex immunofluorescence, and CLARITY pathological assessments of WM integrity (myelin integrity and thickness, oligodendrocyte and axonal loss) and CBVD (vessel density, size, and branch points) on 200 deceased contact sport athletes (varying in RHI exposure and age) and 100 age-/race-matched non-RHI/TBI donors. Harmonized pathological protocols, informant interviews and clinicopathological conferences are done across all brain banks. Data from this R01 will be used to test our hypotheses that RHI exposure is associated with WM degeneration and CBVD; these pathologies independently contribute to executive dysfunction, neurobehavioral dysregulation and depression; and RHI (e.g., type of sport played) and non-RHI (e.g., vascular risk) factors are effect modifiers. This R01 will lead to unprecedented data sets to increase understanding of the risk for cognitive and neuropsychiatric impairment from WM degeneration and CBVD in former contact sport athletes. Data will inform on symptom etiology and open the door to intervention and preventative targets for the millions exposed to RHI.