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What MRI-Derived Data and Other Factors Reveal About White Matter Hyperintensity in Former Football Players

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New research shows that higher total lesion volume in the brain for former football players is directly associated with higher vascular risks and changes in white matter hyperintensity-associated biomarkers of Alzheimer’s disease.

Higher phosphorylated tau (p-tau181) and lower fractional anisotropy (FA) are associated with higher total lesion volume (TLV) detected on fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) in former football players, according to new research.

For the study, recently published in Neurology, researchers compared biological correlates of white matter hyperintensities (WMH) in 180 former college and professional football players (mean age of 57) to 60 asymptomatic men (mean age of 59.3) who did not play football. The researchers specifically assessed associations between log-transformed TLV and MRI-based measurements of cortical thickness and fractional anisotropy (FA), the cerebrospinal fluid (CSF) level of p-tau181, and the revised Framingham stroke risk profile (rFSRP), according to the study.

The researchers found strong positive associations between higher TLV and rFSRP and CSF p-tau181 in former football players in comparison to study participants with no history of playing football. The study authors also pointed out a strong negative association between FA and log TLV in football players in contrast to the unexposed group.

While lower systolic and diastolic blood pressure measurements contributed to a lower overall vascular risk for former football players, the researchers noted that higher body mass index (BMI), sleep apnea and unhealthy alcohol use were more common among former football players. The study authors emphasized that the association between elevated WMH and higher vascular risk was “more pronounced” for former football players.

“ … (Sleep apnea, alcohol use and high cholesterol) remain important modifiable factors for consideration in the treatment of former football players because of their effects on cognitive and neuropsychiatric symptoms and their relationships with elevated WMH burden,” wrote study co-author Michael L. Alosco, Ph.D., an associate professor of neurology at the Chobanian and Avedisian School of Medicine at Boston University and co-director of the university’s Alzheimer’s Disease Research Center Clinical Core, and colleagues.

Three Key Takeaways

  1. Biomarkers and imaging. Elevated phosphorylated tau (p-tau181) in former football players' cerebrospinal fluid is associated with increased total lesion volume (TLV) on MRI, while lower fractional anisotropy (FA) suggests potential neurocognitive impact.
  2. Vascular risk and white matter changes. Former football players exhibit a pronounced link between TLV and vascular risk, emphasizing the role of cardiovascular factors. Modifiable factors like sleep apnea and alcohol use are crucial considerations for cognitive health.
  3. Repetitive head impact and white matter hyperintensity. Repetitive head impact in football is associated with white matter hyperintensities (WMH) and altered fractional anisotropy, suggesting persistent axonal injury and emphasizing the importance of assessing exposure proxies.


In contrast to study participants with no exposure to playing football, the researchers noted that former football players had an association between WMH and CSF p-tau181, an association that may be linked to repetitive head impact (RHI) exposure in football. The study authors also found that an association between WMH and lower average whole brain FA was more prominent in former football players.

“Lower FA in several white matter tracts has been reported in athletes after subconcussive impacts. Exposure to RHI might lead to axonal injury that persists or worsens with age,” noted Alosco and colleagues.

“Proxies of exposure to RHI (e.g. age of first exposure, years of football play, and a quantitative measure based on football history and helmet accelerometer studies) have been associated with altered corpus callosum microstructure in former professional football players and greater white matter rarefaction in autopsy-confirmed CTE.”

Increased levels of football play also contributed to a stronger association between log(TLV) and lower FA. The researchers noted an 86 percent difference between unexposed participants and former college football players, and a 319 percent difference between the unexposed group and former professional football players.

(Editor’s note: For related content, see “Could Structural MRI Findings Help Detect CTE During Life?”)

In regard to study limitations, the researchers acknowledged a lack of participant enrollment criteria specific to symptomatology in former football players and that the cohort was comprised of self-identified volunteers. The study authors also noted unbalanced sample sizes with former college and professional football players. They also conceded that the study did not examine associations between RHI and first exposure to football or total years of playing football.

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