Research Project 2 SUMMARY There is growing concern over the association between traumatic brain injury (TBI) and progressive neurodegenerative changes, in particular those described as chronic traumatic encephalopathy (CTE). First recognized in boxers, it was not until later reports of similar pathologies in non-boxer athletes that the long-term consequences of TBI attracted widespread attention. Recent and preliminary consensus criteria propose CTE as a distinct neurodegenerative pathology, although the associated clinical consequences of this pathology remain unclear. Importantly, there is growing consensus that there is a high prevalence of comorbidity across neurodegenerative diseases including AD, Lewy body disease, and frontotemporal lobar degeneration. While, current reporting in CTE largely focuses on proposed “pathognomonic” tau pathologies, the heterogeneity of neurodegenerative disease neuropathology associated with chronic survival from TBI (cTBI) is not well described. Here we will evaluate the spectrum of neuropathologic change that is shared or unique between TBI- related neurodegeneration (TReND) versus other neurodegenerative diseases including Alzheimer’s disease (AD), Lewy body disease, and frontotemporal lobar degeneration. Specifically, by evaluating a neurodegenerative disease autopsy cohort of 275 cases, matched to the cTBI cohort studied in research project 1, we will examine for the presence and distribution of neuropathologies including Aβ amyloid, tau, α-synuclein and TDP-43 aggregates. Importantly, by examining a further cohort of 450 cases, we will also determine whether TReND pathology, like other neurodegenerative disease processes, can also be observed in neurodegenerative disease cases without any history of TBI.