Pathology of Chronic Traumatic Encephalopathy

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease found in contact sport athletes and military veterans exposed to repetitive mild traumatic brain injury, including concussive and blast injuries. In 2015, a NINDS consensus conference defined the preliminary neuropathological criteria to diagnose CTE as the accumulation of hyperphosphorylated tau as neurofibrillary tangles and neurites around small blood vessels at the sulcal depths of the cerebral cortex. The pathology of CTE has been stratified into stages I to IV of increasing pathological severity that, in football players, are associated with the age of the subject at death and the number of years of exposure to football. Evidence suggests that the physics of traumatic injury dictates the localization of early CTE lesions to the regions around small blood vessels at the depths of the cerebral sulci. With advancing age, CTE pathology spreads to involve wide regions of the cerebral cortex, diencephalon, and brainstem. How the tau pathology spreads throughout the brain in the absence of further trauma is not known, but hypotheses include a prion templating mechanism of intraneuronal tau propagation, abnormal glymphatic clearance that impedes the removal of hyperphosphorylated tau from the nervous system, or persistent neuroinflammation. Current research is focused on early detection of the CTE pathological lesions in living subjects using fluid biomarkers and neuroimaging, as well as identification of unique components of the pathology that can be targeted therapeutically.