It turns out that white matter matters. Researchers have found greater white matter changes in association with more years of playing American football — a novel finding that paints a more complete picture of dementia risk beyond tau protein and other factors known to contribute to dementia.
A post mortem study of 180 former football players who donated their brains supports previous findings that a greater amount of phosphorylated tau protein in the brain is associated with dementia and duration of play.
The research advances the field with findings of a direct association between severity of white matter changes, number of years of playing football, and risk for dementia in these former athletes who had been diagnosed with chronic traumatic encephalopathy (CTE).
Another new finding emerged — that a factor not associated with repetitive head impacts (RHIs) contributed equally to dementia risk — atherosclerosis associated with aging and cardiovascular disease.
“The findings underscore that the etiology of dementia and other clinical signs and symptoms among older, former American football players is multifaceted and likely related to tau and non-tau pathologies,” lead author Michael L. Alosco, PhD, assistant professor of neurology and clinical care and co-director of the Boston University Alzheimer’s Disease Center and the Boston University CTE Center at Boston University School of Medicine, told Medscape Medical News.
“It is therefore critical that treating physicians consider these multifaceted etiologies of the clinical signs and symptoms when treating and coordinating care for symptomatic individuals who have been exposed to repetitive head impacts,” he said.
The study was published online August 5 in JAMA Neurology.
Arteriosclerosis an Equal Contributor
The association between phosphorylated tau and dementia “is consistent with what we see in other neurodegenerative disease fields, like Alzheimer’s disease,” Alosco added. “However, it was quite notable that white matter rarefaction and arteriosclerosis equally contributed to dementia in this sample.”
Previous research suggests that tau and non-tau pathways, including cerebrovascular disease, are related to the delayed effects of repetitive head injury with respect to dementia among individuals with CTE.
However, the contribution of phosphorylated tau pathologic changes, comorbid neurodegenerative disease, or other pathologic conditions to dementia in CTE remains unclear, the researchers note.
To learn more, the investigators studied 180 men who were aged 40 years or older at the time of death and who had played US football. Each person had been neuropathologically diagnosed with CTE.
Their brains were donated to the Veterans Affairs–Boston University–Concussion Legacy Foundation brain bank as part of the ongoing Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) study.
The investigators performed semiquantitative assessment of white matter rarefaction and arteriolosclerosis. Rarefaction reflects overall white matter integrity, including degree of myelin loss, extent of tissue attenuation or vacuolization around small blood vessels, and the density of reactive astrocytes.
They also conducted telephone interviews with informants and recorded medical and clinical histories, including the presence, nature, and timeline of symptoms associated with cognition, behavior, or mood and daily functioning.
The number of years playing football was a proxy for experiencing RHIs.
Of the 180 donors with CTE, 120 had dementia prior to death.
The investigators linked increasing age with more severe white matter rarefaction (β, 0.37; 95% confidence interval [CI], 025 – 0.50), high CTE stage (β, 0.32; 95% CI, 0.19 – 0.45), and increased likelihood for dementia (β, 0.27; 95% CI, 0.13 – 0.42). All of these differences were statistically significant (P
Race did not significantly affect white matter rarefaction, CTE stage, dorsolateral frontal cortex neurofibrillary tangles burden, or dementia.
Adjusted analysis showed that compared to participants with a lower burden of dorsolateral frontal cortex neurofibrillary tangles, those with a high burden had a 2.65 greater increased risk for dementia (odds ratio [OR], 2.65; 95% CI, 1.24 – 5.70; P = .01).
Although arteriolosclerosis was not associated with number of years playing football, it was independently associated with dementia (β, 0.21; 95% CI, 0.07 – 0.35; P = .003).
Alosco and colleagues note that white matter rarefaction and arteriosclerosis “seemed to be a result of different causes, with white matter rarefaction related to repetitive head impact exposure…and arteriolosclerosis from cardiovascular disease.
“The findings speak to the diverse pathologies found in CTE and how they each uniquely contribute to clinical signs and symptoms, including dementia,” they add.
Future research is warranted, Alosco said. Longitudinal studies in living individuals exposed to repetitive head impacts that use various in vivo biomarkers to estimate white matter and cerebrovascular disease and other pathologies “are essential to determine how these pathologies might contribute to the clinical course and presentation of CTE or other neurological disorders associated with repetitive head impacts.
“Along these lines, we are continuing to investigate risk factors and biomarkers for CTE in order to facilitate the ability to diagnose this disease during life,” he added. “This is the critical next step.”
New Insights, Intriguing Data
“The authors uncovered several important and new insights into the pathologic pathways to dementia in deceased individuals who had played football and had had CTE,” Julie A. Schneider, MD, of the Rush Alzheimer’s Disease Center, Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, notes in an accompanying editorial.
The researchers showed that the number of years of playing football was associated with severity of tau pathology independently of other neurodegenerative disorders, she noted.
“More intriguing was a second white matter pathway, which connected years of play with dementia via the severity of white matter rarefaction independent of the tau pathway,” Schnieder writes.
Therefore, “the authors provide intriguing data regarding the importance of both the white matter and tau pathways,” said Schneider, who is also affiliated with the Department of Pathology at Rush University Medical Center.
Furthermore, the study is noteworthy because the investigators also “found that small-vessel disease in the form of arteriolosclerosis provides a third and distinct pathway to dementia in football players with CTE,” she writes.
Comprehensive neuropathologic examinations, advanced statistical techniques, and multiple sensitivity analyses are strengths of the study, Schneider notes.
Selection bias is an “important limitation.” The researchers assessed a convenience sample of individuals who had played football, were deceased, had opted in or been opted in for brain donation, and were found to have CTE.
“Thus, the frequency of pathologic characteristics in this group should not be generalized to estimate the prevalence of neuropathologic conditions in living individuals who have played or are playing US football,” she writes. Recall bias is an additional potential limitation, she notes.
“In spite of these limitations, the authors should be applauded for elegant work and compelling support for multiple pathologic pathways to dementia in football players with CTE,” Schneider states.
The study was supported by grants from the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, the Department of Veterans Affairs Merit Award, the Nick and Lynn Buoniconti Foundation, and the National Center for Advancing Translational Sciences. The study authors’ relevant financial relationships are listed in the original article. Schneider has been an expert consultant for the National Football League and the National Hockey League.
Follow Damian McNamara on Twitter: @MedReporter