Prolonged Repetitive Head Trauma Induces a Singular Chronic Traumatic Encephalopathy–Like Pathology in White Matter Despite Transient Behavioral Abnormalities

Abstract

Repetitive mild traumatic brain injury (rmTBI), resulting from insults caused by an external mechanical force that disrupts normal brain function, has been linked to the development of neurodegenerative diseases, such as chronic traumatic encephalopathy and Alzheimer disease; however, neither the severity nor frequency of head injury required to trigger adverse behavioral outcomes is well understood. In this study, the administration of 30 head impacts using two different weights to lightly anesthetized, completely unrestrained mice established a paradigm that simulates the highly repetitive nature of sports- and military-related head injury. As the number of head impacts increases, the time to recover consciousness diminishes; however, both the sensorimotor function and behavioral outcomes of impacted mice evolve during the ensuing weeks. Postmortem analyses reveal robust Alzheimer disease and chronic traumatic encephalopathy-like conditions that manifest in a singular manner throughout the white matter concomitant with evidence of chronic oligodendrogenesis. Our data suggest that latency to recover the righting reflex may be an inadequate measure of injury severity and imply that exposure to repeated head impacts may mask the severity of an underlying and developing neuropathologic condition that does not manifest itself until long after head collisions cease. In addition, our data indicate that there is a cumulative and dose-dependent effect of repetitive head impacts that induces the neurobehavioral and neuropathologic outcomes seen in humans with a history of rmTBI.