Chronic traumatic encephalopathy (CTE) is a
neurodegenerative disease associated with repetitive mild impact
traumatic brain injury from contact sports. Recently, a consensus panel defined the pathognomonic lesion for CTE as accumulations of abnormally hyperphosphorylated tau (p-tau) in neurons (neurofibrillary tangles), astrocytes and cell processes distributed around small blood vessels at sulcal depths in irregular patterns within the cortex. The pathophysiological mechanism for this lesion is unknown. Moreover, a subset of CTE cases harbors cortical β-
amyloid plaques. In this study, we analyzed postmortem brain tissues from five institutionalized patients with
schizophrenia and history of surgical
leucotomy with subsequent survival of at least another 40 years. Because
leucotomy involves severing axons bilaterally in prefrontal cortex, this
surgical procedure represents a human model of single
traumatic brain injury with severe axonal damage and no external impact. We examined cortical tissues at the
leucotomy site and at both prefrontal cortex rostral and frontal cortex caudal to the
leucotomy site. For comparison, we analyzed brain tissues at equivalent neuroanatomical sites from non-leucotomized patients with
schizophrenia, matched in age and gender. All five
leucotomy cases revealed severe white matter damage with dense
astrogliosis at the
axotomy site and also neurofibrillary tangles and p-tau immunoreactive neurites in the overlying gray matter. Four cases displayed p-tau immunoreactivity in neurons, astrocytes and cell processes encompassing blood vessels at cortical sulcal depths in irregular patterns, similar to CTE. The three cases with
apolipoprotein E ε4 haplotype showed scattered β-
amyloid plaques in the overlying gray matter, but not the two cases with
apolipoprotein E ε3/3 genotype. Brain tissue samples from prefrontal cortex rostral and frontal cortex caudal to the
leucotomy site, and all cortical samples from the non-leucotomized patients, showed minimal p-tau and β-
amyloid pathology. These findings suggest that chronic axonal damage contributes to the unique pathology of CTE over time.