The neuropathology of chronic traumatic encephalopathy

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head trauma, including concussion and subconcussion. CTE was first recognized in boxers nearly a century ago as "dementia pugilistica" or "punch drunk," but has been recently identified in contact sports athletes (including American football, ice hockey, soccer, baseball, rugby, boxing, and wrestling) and military veterans exposed to blast. Similar to many other neurodegenerative diseases, CTE is diagnosed conclusively only by neuropathologic examination of brain tissue. CTE is characterized by the buildup of hyperphosphorylated tau as neurofibrillary tangles, abnormal neurites, and inclusions in astrocytes around small blood vessels with a tendency to occur in clusters at the sulcal depths of the cortex. Using the McKee criteria, a consensus panel of expert neuropathologists confirmed CTE as a unique neurodegenerative disease with a pathognomonic CTE lesion that has only been found in individuals exposed to brain trauma. Recently, 177 instances of CTE were reported in a convenience sample of 202 former American football players, including 110 of 111 former National Football League players (99%), 48 of 53 former college football players (91%), and 3 of 14 former high school players (21%), by far the largest case series ever reported. Significant increases in active microglia and inflammation also occur after repetitive head impact injury and in CTE. A preliminary study showed that inflammatory cytokines were elevated in the brain tissue and cerebrospinal fluid of individuals with pathologically confirmed CTE compared to controls and individuals with Alzheimer disease, which may some day be useful in diagnosis of CTE during life. Although many fundamental questions remain to be answered regarding CTE, postmortem analysis of tissue from brain donors and tissue-based research have accelerated and expanded our current understanding of CTE and its pathogenesis. Guided by the neuropathologic findings, current research efforts are underway to develop biomarkers to diagnose CTE and effective ways to treat the disorder during life.