Chronic traumatic encephalopathy (CTE) is a disease of the dead. Clinical features suggestive of the degenerative brain disorder — memory loss, decision-making impairments, attention and behavior issues — are seen in former athletes and soldiers and are linked to repetitive head impacts, but a definitive diagnosis is only possible postmortem, through the detection of a buildup of tau protein around brain blood vessels.
A paper published Wednesday, however, could aid efforts to identify biomarkers of the disease before symptoms emerge, so that protective measures can be adopted. Research on CTE over the last several decades, and its diagnosis in star professional athletes, has raised awareness about the risks of concussions and other head injuries, but how they cause brain damage is unclear.
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It is disproportionately diagnosed in athletes who have played contact sports such as football — who are typically male, and often young. The prevalence of CTE in the general population is unknown, though a 2023 study published in JAMA Neurology looked at about 150 athletes who participated in sports such as football, hockey, or rugby and died before 30. It found that over 40% of them had early-stage CTE.
The new study from the Boston University Chobanian & Avedisian School of Medicine and published in Nature shows that damage to brain cells begins long before tau protein accumulations are found in the brain.
The researchers looked at a small sample of 28 brain tissue samples of individuals aged 51 or younger at the time of death, divided into three groups: the first — a control — of individuals not exposed to repetitive head impacts (RHI); the second, of RHI-exposed individuals whose brains didn’t show CTE markers; the third, RHI-exposed individuals with early-stage CTE.
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Through single-cell RNA sequencing, a technique that allows researchers to characterize gene activity in individual cells, they found that the group who sustained repeated impact but didn’t yet have CTE pathology showed some of the inflammatory response, vascular dysfunction, and cell damage that is seen with CTE, even without the tau protein buildup. RHI-exposed individuals showed an average 56% loss of certain frontal neocortex neurons compared to the control, and their overall brain damage was comparable with that of early-stage CTE.
This suggests that the damage caused by RHI is significant even when it does not bear the markers of CTE, said Jonathan Cherry, an assistant professor of pathology and laboratory medicine at Boston University.
“Not everybody who plays these sports and has these repetitive head injuries will get CTE,” said Cherry, who is the paper’s corresponding author. But, he said, “the study is showing that it doesn’t always matter if you do get CTE, because the damage is still present.”
Kevin Bieniek, a professor of pathology & laboratory Medicine at the University of Texas in San Antonio who was not involved with the research, said the study was “elegant” and “unbiased,” and that it “shows shows disease pathophysiology goes beyond the tau protein benchmark that is used to neuropathologically define the disease.” He also noted that by focusing on the frontal neocortex of young individuals, the authors were able to limit the noise of other age-related brain pathologies.
Though the study is small, the authors believe it could point to the possibility of identifying new biomarkers to diagnose RHI-related brain damage. Further, said Bieniek, the findings point toward two potential treatment routes: one that targets, or protects against, the neuron cell loss, and the other that modulates the inflammatory immune response following RHI.
When it comes to strategies to manage risk of brain damage in contact sports, the study adds evidence that it is not simply severe injuries that need to be avoided. Many of the individuals in the CTE and RHI groups never reported concussions (that is, they didn’t have symptoms after impact), but developed the damage as a result of repeated lower-impact incidents.
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“There are people that have been diagnosed with CTE that have never had a single reported concussion,” said Cherry. “Non-concussive, sub-concussive injuries are what we think is really driving this.”