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Dementia in chronic traumatic encephalopathy (CTE) was tied to neuropathologic changes associated with exposure to repetitive head impact -- including white matter rarefaction and phosphorylated tau -- but also with changes not associated with head trauma, such as arteriolosclerosis, a study of American football players showed.

Moreover, years of play correlated with more severe white matter rarefaction and a greater phosphorylated tau burden in the dorsolateral frontal cortex, reported Ann McKee, MD, of the Boston University School of Medicine, and coauthors in .

"The findings underscore that the etiology of dementia and other clinical signs and symptoms among older, former American football players is multifaceted and related to tau and non-tau pathologies," said first author Michael Alosco, PhD, also of Boston University.

"The association between phosphorylated tau and dementia is consistent with what we see in other neurodegenerative disease fields, like Alzheimer's disease," Alosco told 番茄社区app.

While ties between and phosphorylated tau severity have been reported previously, this study identified a link between years of American football play and severity of white matter rarefaction, he added. "It was quite notable that white matter rarefaction, as well as arteriosclerosis likely from cardiovascular disease and aging, equally contributed to dementia in this sample," he said.

The findings were based on data from 180 deceased American football players who were diagnosed at autopsy with mild to severe CTE in the ongoing Understanding Neurologic Injury and Traumatic Encephalopathy () Study, which included brain donors to the Concussion Legacy Foundation brain bank, from 2008 to 2017.

In their pathology exam, McKee and colleagues looked at the stage of CTE-associated tau pathology, density of tau neurofibrillary tangles in the dorsolateral frontal cortex, severity of white matter rarefaction, and arteriolosclerosis. They assessed phosphorylated tau density of the dorsolateral frontal cortex because it is an initial site of tau deposition in CTE that becomes severely affected with disease advancement and has been . They also conducted retrospective clinical interviews with informants to determine dementia diagnoses and used the number of years of football play as a proxy for repetitive head impacts.

Mean age at death for ex-players was 68. Most (67%) had played professional football; about 25% stopped after college, and the remaining either played semi-professionally or stopped after playing high school or youth football. Overall, 120 players were diagnosed with ante-mortem dementia.

Dorsolateral frontal cortex neurofibrillary tangle burden was moderate to severe in 130 players (72%). Moderate to severe white matter rarefaction (84 players, 46.6%) and arteriolosclerosis (85 players, 47.2%) also were common; infarcts, microinfarcts, and microbleeds were not.

More years of play were tied to both an increased likelihood of more severe white matter rarefaction (β 0.16, 95% CI 0.02-0.29; P=0.02) and greater phosphorylated tau accumulation in the dorsolateral frontal cortex (β 0.15, 95% CI 0.004-0.30; P=0.04), after controlling for age and race. More severe white matter rarefaction (β 0.16; 95% CI 0.02-0.29; P=0.03) and greater neurofibrillary tangle burden (β 0.16, 95% CI 0.03-0.28; P=0.01) corresponded with an increased likelihood of dementia.

Arteriolosclerosis was independently associated with dementia (β 0.21, 95% CI 0.07-0.35; P=0.003), but was not associated with years of football play.

In this study, "the association between years of play and dementia was completely mediated by the white matter rarefaction and tauopathy," noted Julie Schneider, MD, MS, of Rush University in Chicago, in an . "Moreover, the magnitude of the association on dementia from the white matter injury and tauopathy was similar across these two pathways. These findings underscore the importance of studying the risk factors and mechanisms for the white matter rarefaction, in addition to the tauopathy in individuals who have played U.S. football and have CTE."

The research also shows that small-vessel disease provides a third and distinct pathway to dementia in football players with CTE, she added.

This study was limited by selection bias: it involved only American football players who had their brains donated for research and were found to have CTE. The findings do not represent the prevalence of neuropathologic conditions in other people, including living football players, the researchers noted. In addition, the diagnosis of dementia was made retrospectively and may be subject to recall bias.

"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 -- as well as objective measures of clinical function -- 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," Alosco said.

"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."

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