In Former Football Players, Inflammation Tracks with White Matter Damage and Poorer Memory

The connection between repetitive head impacts and long-term cognitive decline has been established in principle for years. What has remained unclear is the chain of events that links a career of subconcussive hits to the memory problems and cognitive changes that some former players experience decades later. A study published in Neurology offers one potential pathway: inflammation.

Using data from the DIAGNOSE CTE Research Project - a dedicated study of chronic traumatic encephalopathy - researchers examined 223 male participants: 170 former college or professional football players with an average age of 57, and 53 men with no history of contact sports or concussion with an average age of 59. The team measured three inflammation biomarkers in blood and spinal fluid, imaged participants' brains to assess white matter microstructure, and tested their cognitive function.

The Biomarkers and What They Measured

The three inflammation markers analyzed were interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and glial fibrillary acidic protein (GFAP). All three have been implicated in neuroinflammatory processes associated with brain injury. GFAP is released by astrocytes when activated by injury or stress, and elevated blood levels indicate breakdown of the blood-brain barrier. IL-6 and TNF-alpha are pro-inflammatory cytokines with roles in both acute and chronic neuroinflammation.

Brain structure was assessed using two diffusion tensor imaging metrics: fractional anisotropy, which measures the directionality of water movement through white matter (lower values indicate damage), and mean diffusivity, which measures how freely water moves (higher values indicate disrupted tissue).

The Association: Inflammation to Brain Structure to Memory

Among football players, higher levels of all three inflammation biomarkers were associated with worse white matter microstructure specifically in the limbic system - a network of brain structures governing emotion, motivation, memory formation, and behavioral regulation. The association between inflammation and worse brain microstructure was stronger in football players than in non-football players.

A second-order association then connected worse brain microstructure to poorer memory performance. Crucially, the researchers found no direct link between inflammation levels and cognitive performance - the effect appeared to be mediated through the brain structural changes. When the analysis was restricted to 57 players considered most likely to have CTE based on symptom severity, most of the associations strengthened.

What the Study Does Not Establish

This is an observational, cross-sectional analysis. It cannot determine whether inflammation caused the white matter changes seen in football players, or whether some underlying vulnerability produces both inflammation and structural damage through independent pathways. CTE itself can only be confirmed at autopsy; living participants were evaluated for traumatic encephalopathy syndrome rather than confirmed CTE.

The study included only male athletes who played football at the college or professional level. Whether the inflammation-structure-cognition pathway applies to female athletes, players at lower levels, or athletes in other contact sports is unknown. The DIAGNOSE CTE Research Project was supported by the National Institute of Neurological Disorders and Stroke.

"Because the limbic system influences both cognition and behavior, targeting inflammation could offer a way to potentially reduce the risk for developing brain changes that lead to worsening symptoms associated with repetitive head injuries," said study author Breton Asken, PhD, of the University of Florida.