Pathological correlates of psychiatric phenotypes across brain regions in chronic traumatic encephalopathy

Abstract

BACKGROUND Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease with cognitive, behavioral, and psychiatric symptoms, with depression and suicidality present in a large proportion of CTE cases. Pathologically CTE is defined by a distinctive accumulation of hyperphophorylated tau (pTau) predominately involving the frontal and temporal cortices, medial temporal lobe, and brainstem. However, the association between pathology in particular brain regions and psychiatric CTE symptoms is unknown. METHODS AND RESULTS Human postmortem brains from CTE cases and controls were obtained from the VA-BU-CLF Brain Bank. Trained neuropathologists examined each brain for gross and microscopic pathology, and provided semi-quantitative assessments. Regions of interest (including frontal, temporal, limbic, and brainstem structures) were sectioned and stained for pathological markers of interest (e.g. pTau, β-amyloid, α-synuclein, pTDP43, etc). Stained slides were scanned and traced digitally, with staining quantified using a Leica Aperio system. Preliminary analyses suggest alterations in specific cortical, limbic, midbrain, and white matter structures may associate with depressive and suicidal features in CTE. In particular, cortical white matter loss as well as hippocampal and midbrain pathology were associated with psychiatric features. We have also found myelination and inflammation-associated changes in the anterior cingulate cortex of depressed CTE cases. CONCLUSIONS This investigation is the first to explore associations between neuropathology in particular brain regions and specific psychiatric features in CTE. Preliminary results suggest neurodegenerative pathology, loss of white matter, neuroinflammation, and gliosis could underlie psychiatric phenotypes in CTE.