Chronic traumatic encephalopathy: A paradigm in search of evidence?

Chronic traumatic encephalopathy (CTE) has been in the medical literature since the 1920s. It is characterized clinically by diverse neuropsychiatric symptoms, and pathologically by variable degrees of phosphorylated tau accumulation in the brain. The evolving paradigm for the pathogenesis of CTE suggests that concussion or subconcussion from athletic participation initiates a cascade of pathologic events, encompassing neuroinflammation and protein templating with trans-synaptic neurotoxicity. The end result is neurologic and neurobehavioral deterioration, often with self-harm. Although these concepts warrant further investigation, the available evidence permits no conclusions as regards the pathogenesis of the reported findings. Investigations into the role of premorbid or co-morbid neurodegenerative diseases has been limited to date, and in-depth genetic analyses have not been performed. The role of concussion or subconcussion if any, whether and how the condition progresses over time, the extent of phosphorylated tau in clinically normal athletes, the role of phosphorylated tau as a toxic species versus an inert disease response, and whether protein templating has any in vivo relevance remain to be elucidated.