Abstract

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder that can only be diagnosed post-mortem and has been retrospectively linked to a history of neurotrauma involving repeated concussive and subconcussive head injuries. Such a pattern of neurotrauma is commonly found among military veterans and athletes participating in contact sports. A post-mortem diagnosis depends on the detection of abnormal hyperphosphorylated-tau (p-tau) neuropathology that is characterized by an irregular, focal, perivascular distribution largely localized to cortical sulci. Although p-tau is not unique to CTE, this distribution pattern helps distinguish it from other degenerative tauopathies. High molecular weight p-tau proteins tend to accumulate in neurons and glia as pretangles, neurofibrillary tangles, extracellular tangles and neuropil threads. Supportive non-p-tau pathologies include TDP-43 and β-amyloid in neuronal cytoplasmic inclusions and dot-like structures in the tangles. Progressive tauopathies can share a broad range of neuropsychiatric sequelae, which for CTE are identified through next-of-kin interviews or verbal autopsies. A better understanding of how CTE relates to other neuropsychiatric and neurodegenerative disorders will require carefully controlled prospective studies involving both in vitro and in vivo model systems as well as parallel efforts to develop and validate fluid biomarkers and tau-specific neuroimaging technologies. Such an approach will improve the odds of advancing multiple, targeted therapies from preclinical studies to clinical trials. This chapter covers etiology, pathophysiology, experimental model systems, biomarkers and potential therapeutic strategies pertaining to CTE.