White matter hyperintensities may help study repetitive head impacts

White matter hyperintensities (WMH) on MRI were linked to years of exposure to repetitive head trauma and post-mortem pathology changes, a cross-sectional exploratory study found.

Of 75 brain donors, including 67 American football players and eight men who had been involved in other contact sports or who had been military veterans, 70.7% had (chronic traumatic encephalopathy) CTE at autopsy. All had fluid attenuated inversion recovery (FLAIR) MRI scans as part of clinical care while living.

The log-total lesion volume (log-TLV) of WMH on MRI was associated with white matter rarefaction (OR 2.32 per unit difference in log-TLV, 95% CI 1.03-5.24, P=0.04), arteriolosclerosis (OR 2.38, 95% CI 1.02-5.52, P=0.04), CTE stage (OR 2.58, 95% CI 1.17-5.71, P=0.02), and dorsolateral frontal p-tau severity (OR 3.03, 95% CI 1.32-6.97, P=0.01) at autopsy, reported Michael Alosco, PhD, of Boston University, and co-authors in Neurology. There was no association with amyloid-beta.

More years of football play was associated with log-TLV (unstandardized beta=0.04, 95% CI 0.01-0.06, P=0.01). Greater log-TLV correlated with worse scores on a functional measure (unstandardized beta=4.94, 95% CI 0.42-8.57, P=0.03), and subjective cognitive difficulty scores (unstandardized beta=15.35, 95% CI −0.27 to 30.97, P=0.05).

“Our results are exciting because they show that white matter hyperintensities might capture long-term harm to the brain in people who have a history of repetitive head impacts,” Alosco said in a statement. “White matter hyperintensities on MRI may indeed be an effective tool to study the effects of repetitive head impacts on the brain’s white matter while the athlete is still alive.”

“There are key limitations to the study, and we need more research to determine the unique risk factors and causes of these brain lesions in people with a history of repetitive head impact,” he added.

The etiologies of WMH are multifactorial but often are interpreted as markers of cerebral small vessel disease due to vascular risk factors, the researchers noted. “WMH can also reflect axonal degeneration from Alzheimer’s disease neuropathologic changes and are correlates of disease severity in behavioral variant frontotemporal dementia,” they wrote. In addition, WMH may capture white matter degeneration and microvascular pathologies associated with repetitive head impacts, they added.

In this analysis, Alosco and co-authors included symptomatic brain donors from the Understanding Neurologic Injury in Traumatic Encephalopathy (UNITE) study. All in the UNITE database had been exposed to repetitive head injury.

All 75 donors in the current analysis were men with mean age at death of 66.7. All had MRI done antemortem for a clinical reason (most often—64%—for questions of dementia or neurodegenerative disease) and 67 men (89.3%) had played American football for an average of 12.2 years. Mean time from last clinically obtained MRI to death was 4.84 years.

Informant interviews provided information for the Functional Activities Questionnaire (FAQ, which assesses activities of daily living; higher scores indicate greater functional impairment) and the Cognitive Difficulties Scale (CDS, with higher scores indicating more cognitive complaints). Brain autopsy assessed white matter rarefaction, cerebrovascular disease, p-tau severity with CTE stage in the dorsolateral frontal cortex, and amyloid-beta.

A total of 53 of the 75 brain donors had CTE at autopsy; 22 had severe (stage IV) CTE. There was no correlation between log-TLV and atherosclerosis, cerebral amyloid angiopathy, remote infarcts, or microinfarcts.

Repetitive head impacts have been associated with multiple pathologies, among them white matter degeneration and microvascular injury that contribute to neurocognitive impairment. In addition to marking cerebral small vessel disease, WMHs have been implicated as a possible marker for repetitive head trauma.

A 2013 study that compared 26 former professional U.S. football players with 26 controls found cognitive deficits and depression correlated with white matter changes. A 2018 study of former professional U.S. football players examined white matter signal abnormalities and found that increased volume of signal abnormality was associated with higher cumulative head impact scores and worse psychomotor speed and executive function.

“A novel finding of the present study was the statistically significant association between WMH and white matter rarefaction independent of vascular risk factors,” Alosco and co-authors noted. “White matter rarefaction is a measure of overall white matter integrity and reflects myelin loss, axonal loss, tissue attenuation around small blood vessels, and reactive astrocytosis.”

“Although white matter rarefaction can be a consequence of vascular risk factors, our previous study among 180 older deceased American football players with autopsy-confirmed CTE showed that white matter rarefaction was not associated with atherosclerosis, arteriolosclerosis, or vascular risk factors, yet there was a significant association between years of football play and white matter rarefaction severity,” they wrote. “We hypothesized that white matter rarefaction can reflect chronic and diffuse white matter neuropathologies (e.g., axonal and myelin loss, astrocytosis, neuroinflammation) associated with exposure to repetitive head impacts.”

“These late white matter neuropathologies related to exposure to repetitive head impacts, particularly myelin and axonal loss, could be visualized on clinically routine FLAIR scans,” they added.

Limitations of the analysis included a sample that likely was enriched for WMH and was most representative of former American football players who presented to a clinic due to concerns related to their cognition. There was too little representation of other contact sports and military veterans to draw conclusions about those populations, Alosco and co-authors acknowledged.

“This study provides Class IV evidence of associations between FLAIR white matter hyperintensities, and neuropathological changes (white matter rarefaction, arteriolosclerosis, p-tau accumulation), years of American football play, and reported cognitive symptoms in symptomatic brain donors exposed to repetitive head impacts,” the researchers noted.

  1. White matter hyperintensities (WMH) on MRI were linked to years of exposure to repetitive head trauma and post-mortem pathology changes, a cross-sectional exploratory study found.

  2. The study included 67 American football players and eight men who had been involved in other contact sports or who had been military veterans; most had (chronic traumatic encephalopathy) CTE at autopsy.

Paul Smyth, MD, Contributing Writer, BreakingMED™

The study was supported by National Institute on Aging, National Institute of Neurological Disorders and Stroke, Boston University Alzheimer’s Disease Research Center, Department of Veterans Affairs, the Nick and Lynn Buoniconti Foundation, and Boston University Clinical and Translational Science Institute.

Alosco had no disclosures.

Cat ID: 474

Topic ID: 82,474,730,474,192,925