New research reveals early brain cell changes in young athletes exposed to head impacts

A new study has found that repeated head impacts from contact sports can lead to lasting and measurable changes in the brains of young and middle-aged athletes. These alterations, which include inflammation and the loss of specific brain cells, can appear years before the development of the hallmark protein clumps associated with chronic traumatic encephalopathy. The research, supported by the National Institutes of Health, was published in the scientific journal Nature.

Scientists have long known that repetitive head impacts, such as those sustained in sports like American football, are the primary risk factor for a neurodegenerative disease called chronic traumatic encephalopathy. A major challenge for researchers and clinicians is that this condition can only be definitively diagnosed by examining brain tissue after a person has died. The initial biological events that set the disease in motion have remained unclear, making it difficult to detect or treat in its early stages.

Many young individuals with a history of head impacts report symptoms that are not fully explained by the known pathology of the disease, pointing to a gap in understanding the earliest consequences of these injuries.

To investigate these early changes, a team of scientists from the Boston University CTE Center and the U.S. Department of Veterans Affairs Boston Healthcare System, along with other collaborating institutions, designed a study to look at the brain at a single-cell level. They analyzed postmortem brain tissue from 28 deceased individuals who were younger than 51 years old.

The individuals were divided into three groups: a control group with no history of contact sports or head impacts, a group of athletes with a history of repetitive head impacts but no evidence of chronic traumatic encephalopathy pathology, and a group of athletes with diagnosed early-stage chronic traumatic encephalopathy. The majority of the athletes had played American football.

The researchers used a sophisticated technique known as single-nucleus RNA sequencing. This method allowed them to isolate individual cells from the brain tissue and analyze their genetic activity. By reading which genes were turned on or off in each cell, the scientists could determine the cell’s state and function. For example, they could distinguish between a healthy, resting immune cell and one that had become activated and inflammatory. This detailed approach provided a snapshot of the cellular landscape of the brain in response to head impacts. They then used other imaging and staining techniques to confirm their findings directly within the brain tissue.

One of the most significant findings concerned the brain’s resident immune cells, known as microglia. In the brains of individuals with a history of head impacts, both with and without the formal disease diagnosis, the microglia showed a distinct shift. There was a significant decrease in the population of healthy, “homeostatic” microglia, which are responsible for maintaining a stable brain environment. In their place, the researchers identified new subtypes of microglia that were in an inflammatory state. The proportion of these inflammatory microglia was directly associated with the number of years an athlete had played contact sports.

The analysis of these inflammatory microglia revealed that they were expressing genes related to immune signaling, oxygen deprivation, and metabolism. To validate this observation, the team used specialized staining methods on a larger set of 37 brain samples. This analysis confirmed that as the years of football play increased, the number of healthy microglia decreased. These changes were most prominent in the deep folds of the brain’s outer layer, or cortex, a region known to be particularly vulnerable to the mechanical forces of head trauma.

The study also identified changes in the cells that line the brain’s blood vessels, called endothelial cells. In the athletes’ brains, these cells showed signs of an inflammatory response. They were also activating genes associated with angiogenesis, the process of forming new blood vessels. This suggests that the brain’s vascular system is actively responding to the trauma, potentially as part of a repair process that may become dysfunctional over time. These changes in the blood vessels may contribute to the breakdown of the blood-brain barrier, a protective lining that is often compromised in chronic traumatic encephalopathy.

Perhaps the most striking result was the discovery of specific neuron loss. The researchers found a substantial reduction in a particular type of nerve cell located in the upper layers of the cortex. These neurons, identified by the genes they express, were significantly depleted in the brains of individuals exposed to repetitive head impacts, regardless of whether they had developed the protein deposits of chronic traumatic encephalopathy. On average, athletes with a history of impacts had 56 percent fewer of these specific neurons compared to the control group.

This loss of brain cells was directly linked to the duration of an athlete’s exposure to contact sports. The more years a person played football, the fewer of these neurons were present in the vulnerable sulcal regions of the brain. The finding that this neurodegeneration occurs before the appearance of the disease’s classic protein pathology is profound. It suggests that brain damage and cell death may be an early and direct consequence of repetitive head impacts, and could help explain the cognitive and mood symptoms reported by young athletes. This neuronal loss was confirmed using staining methods on a larger cohort of 86 individuals, again showing a clear link between years of football play and reduced neuron density in that specific brain region.

In an effort to understand how these different cell types might be communicating with each other to drive the disease process, the team performed a computational analysis of signaling pathways. They identified a potential communication link between the inflammatory microglia and the altered endothelial cells. It appears that microglia may be sending signals that activate the endothelial cells, contributing to the vascular changes. One molecule, TGFB1, was identified as a key component of this signaling pathway, which was more active in individuals with early-stage disease.

The study does have some limitations. The number of brain samples available from young individuals is small, which is an inherent challenge in this type of research. Chronic traumatic encephalopathy is also a disease that can appear in patches, meaning the tissue samples taken might not have captured every aspect of the pathology. Future work with larger and more diverse groups of individuals will be needed to build on these findings and explore changes in other brain regions.

This research offers a new window into the earliest stages of brain injury following repetitive head impacts. The findings suggest that significant damage at the cellular level is happening long before chronic traumatic encephalopathy can be diagnosed with current methods. By identifying specific types of cells and molecular pathways involved in this early response, the study provides potential targets for developing new diagnostic tools and therapeutic interventions. Such advances could one day help detect brain injury in living athletes and prevent the progression to severe neurodegeneration.

“This study underscores that many changes in the brain can occur after repetitive head impacts,” said Walter Koroshetz, director of the National Institute of Neurological Disorders and Stroke, a part of the National Institutes of Health. “These early brain changes might help diagnose and treat CTE earlier than is currently possible now.”

The research shifts the focus from the advanced stages of the disease in older individuals to the very first cellular signs of damage in younger people. Richard Hodes, director of the National Institute on Aging at the National Institutes of Health, commented on the importance of this work. “What’s striking is the dramatic cellular changes, including significant, location-specific neuron loss in young athletes who had no detectable CTE,” he said. “Understanding these early events may help us protect young athletes today as well as reduce risks for dementia in the future.”

The study, “Repeated head trauma causes neuron loss and inflammation in young athletes,” was authored by Morgane L. M. D. Butler, Nida Pervaiz, Kerry Breen, Samantha Calderazzo, Petra Ypsilantis, Yichen Wang, Julia Cammasola Breda, Sarah Mazzilli, Raymond Nicks, Elizabeth Spurlock, Marco M. Hefti, Kimberly L. Fiock, Bertrand R. Huber, Victor E. Alvarez, Thor D. Stein, Joshua D. Campbell, Ann C. McKee, and Jonathan D. Cherry.