Tau Pathology in Motor Regions and Parkinsonism in Chronic Traumatic Encephalopathy: A Comparison to Progressive Supranuclear Palsy and Corticobasal Degeneration

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Abstract: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head trauma and characterized by accumulation of hyperphosphorylated tau protein (p-tau). The p- tau pathology of CTE is enhanced by post-traumatic neuroinflammation and microvascular damage. Common clinical symptoms of CTE include cognitive impairment, mood and behavior changes, and parkinsonism. Other p-tau based neurodegenerative disorders associated with parkinsonism include progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), two distinct sporadic tauopathies with no known association with head trauma, neuroinflammation, or microvascular damage. CTE, PSP, and CBD are definitively diagnosed only at postmortem examination. CTE p-tau contains tau isoforms with three repeats (3R) and four repeats (4R) while PSP and CBD are exclusively 4R tauopathies. In PSP and CBD, p-tau pathology in motor regions (MRs) correlates with parkinsonism, but parkinsonism in CTE is less well understood. This knowledge gap led us to hypothesize that microvascular injury and inflammation play critical roles in accumulation of 3R and 4R p-tau in MRs in CTE, and that MR p-tau burden will be associated with parkinsonism in CTE. We further hypothesize that MR p-tau burden in CTE will be positively associated with duration and dose of previous head trauma (measured as repetitive head impacts (RHI)) in CTE. To address our hypotheses, we will use postmortem tissue from neuropathologically confirmed cases of CTE, PSP, and CBD for immunohistological and proteomic analysis, as well as corresponding clinical data. The role of RHI exposure in the development of MR p-tau pathology in CTE will be definitively established through the inclusion of RHI-naïve controls, RHI-exposed controls that did not develop CTE, and cases of PSP and CBD. In Aim 1, we will quantitate 3R and 4R MR p-tau burden in CTE compared to PSP and CBD, and characterize disease-specific cytopathology with multiplex immunofluorescent staining to determine increased MR p-tau pathology in CTE. In Aim 2, we will quantitate MR neuroinflammation and microvascular pathology and nigral dopaminergic cells in CTE compared to PSP, CBD, RHI-naïve and RHI-exposed controls using immunohistochemistry, tissue clearing, and protein immunoassay to establish increased MR inflammation, microvascular pathology and loss of dopaminergic cells in CTE. In Aim 3, we will use available clinical data to assess associations among RHI exposure, MR p-tau pathology, and antemortem parkinsonism in CTE. Previous work by the McKee Lab and BU CTE Center (Sponsor and Co- Sponsor) and preliminary data have validated the proposed techniques. We will delineate the unique inflammatory features, microvascular alterations, and p-tau pathology in MRs in CTE that are distinct from PSP and CBD, and the correlation between MR p-tau pathology and parkinsonism in CTE, in order to help identify diagnostic biomarkers and therapeutic targets for CTE and other tauopathies.