Sections from two brains used in the current BU-led study. The left sample comes from a 17-year-old American male high school football player who died by suicide two days after a closed-head impact injury. The brown stain indicates a widespread immune response, pointing to an abnormal increase in the number of astrocytes, a type of helper cell in the brain, due to the destruction of nearby neurons. The sample on the right, from the control group, shows the brain of a 22-year-old American male former high school football player who also died by suicide, with no history of recent head injury. Images courtesy of BU School of Medicine

The latest chronic traumatic encephalopathy (CTE) research has drawn a line between concussions, traumatic brain injury and CTE, for the first time ever. Results from a Boston University-led study published recently in Brain suggest the neurological conditions are each promoted by different biological mechanisms. The research explains why 20 percent of athletes who exhibited the early stages of progressive brain illness postmortem never had a diagnosed concussion.

“In order to reduce CTE risk, there must be a reduction in the number of head impacts,” says Ann McKee, director of the CTE Center at Boston University and study coauthor. “The continued focus on concussion and symptomatic recovery does not address the fundamental danger these activities pose to human health.”

McKee and her team examined the postmortem brains of eight young adult male athletes—four with recent (1 day to 4 months) sports-related impact injuries, and four without history of symptomatic impact head injuries.

Of the four brains with recent impact injuries, one showed pathologies associated with early-stage CTE, while two others showed abnormal tau accumulations. Upon examination, the researchers noticed broken blood vessels, leading them to hypothesize that these brain blood vessels leak proteins into brain tissue, causing inflammation—a possible trigger for CTE.

To test this theory, the researchers exposed mice to two CTE events: repeated head impact and blast exposure, commonly seen in soldiers.

Virtually all the mice subjected to impact testing during experimentation demonstrated neurobehavioral deficits “strikingly” similar to that of concussion-related responses in humans, according to the study. Electron microscopic analysis of the mice brains two weeks post-injury revealed “microglial cells, dystrophic nerve fibers and dark neurons” close to small blood vessels—all of which shouldn’t be there. These warning signs were not found in the brains of the uninjured mice controls.

“These findings provide direct evidence that experimental closed-head impact injury damages small blood vessels and induces persistent focal traumatic microvascular injury,” the authors explain in their study.

Rather surprisingly, the mice exposed to blast did not exhibit the same deficits as those exposed to impact injuries. Subsequent computational simulations confirmed these findings, revealing dramatic differences in the evolution of shear stress in the head and brain. This suggests that trauma-induced disturbances in brain function may occur even in the absence of overt structural brain pathology—again threading the line between neurological condition and its associated biomechanism.

“Specifically, our results point to differences in shear stress as the primary driver of acute neurobehavioral impairments triggered by impact injury,” the authors explain in their study. “Our data suggest that exposure to focal shear stress may also be associated with structural brain injury and its aftermath.”

Overall, McKee’s research suggests there are different pathobiological mechanisms and triggers to concussions, CTE and TBI. That being said, these different mechanisms can still, ultimately, trigger the same brain pathologies and end result.

“From this perspective, concussion can be viewed as an observable clinical manifestation that reflects a spectrum of altered neurological functional states that may or may not be associated with antecedent structural brain injury,” the authors conclude in their study.