Research Project 1 SUMMARY There is growing concern over the association between traumatic brain injury (TBI) and progressive neurodegenerative changes, in particular those that are characterized as chronic traumatic encephalopathy (CTE). First recognized in boxers, it was not until descriptions of CTE pathology in non-boxer athletes attracted widespread attention. However, reflecting the paucity of cases described, current consensus criteria for the neuropathological assessment of CTE remain preliminary, with the associated clinical consequences of this pathology unclear. Furthermore, the narrow focus on CTE and its characteristic tau pathologies has come at the cost of characterizing many other neuropathologies that have also been observed in CTE cases and in all forms of TBI. Current reporting in CTE largely focuses on p-tau pathologies, which are thought to define its pathognomonic neuropathology. However, rather than a single proteinopathy, wider, unbiased autopsy reporting of TBI related neurodegeneration (TReND) in chronic TBI (cTBI) survivors across a full spectrum of injury severities documents far more varied complex neuropathologies. Furthermore, the pathologies encountered in cTBI patients often are mixed, with multiple proteinopathies, particularly in aged patients. As such, there is growing recognition that TReND in TBI survivors is a complex polypathology, just one element of which might be described by current definitions of CTE. We propose to characterize the extent, distribution and range of pathologies contributing to TReND in cTBI patients across a spectrum TBI types and severities. In addition, we will develop and validate operational criteria for the neuropathological diagnosis of TReND pathologies using established protocols that have proven successful for wider neurodegenerative disease.