From the Journals

Researchers examine potential causes of dementia in CTE

View on the News

Data provide compelling support for pathologic origins of dementia in CTE

The study by Alosco et al. provides new insights into the pathogenesis of dementia in deceased former football players with chronic traumatic encephalopathy (CTE), Julie A. Schneider, MD, professor of neuropathology at Rush University, Chicago, wrote in an accompanying editorial (JAMA Neurol. 2019 Aug 5. doi: 10.1001/jamaneurol.2019.1089).

Significant and widespread white matter injury is an established result of head trauma resulting from acceleration-deceleration injuries. In addition, studies of single and repetitive traumatic brain injury have shown disruption of axons and white matter. The findings of Alosco et al. “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,” Dr. Schneider wrote.

The comprehensive neuropathologic examinations, advanced statistical techniques, and multiple sensitivity analyses that the investigators performed are among the study’s strengths. An important limitation, however, is selection bias. “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 U.S. football,” Dr. Schneider wrote. “Moreover, individuals who played football who were selected for autopsy and found to have CTE may differ in other important ways from those who did not undergo autopsy or did not have CTE.” Recall bias could alter associations between years of play and dementia diagnosis, and the study’s semiquantitative assessments could result in decreased power to observe relevant associations, she said.

“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,” Dr. Schneider concluded.

Dr. Schneider is with the Rush Alzheimer’s Disease Center at Rush University, Chicago. She has been an expert consultant for the National Football League and the National Hockey League.



In patients with chronic traumatic encephalopathy (CTE), dementia likely results from neuropathologic changes associated with repetitive head impact (e.g., white matter rarefaction and tau accumulation) and pathologic changes unrelated to head trauma (e.g., arteriolosclerosis), according to a cross-sectional study published online Aug. 5 in JAMA Neurology.

A graphic illustration of the brain of an American football player. solar22/Thinkstock

The study of older, deceased former American football players with CTE showed that more years of play were associated with more severe white matter rarefaction and greater burden of neurofibrillary tau tangles in the dorsolateral frontal cortex, wrote Michael L. Alosco, PhD, assistant professor of neurology at Boston University’s CTE Center, and colleagues.

An analysis of donated brains

Repetitive head impacts are associated with CTE. The clinical presentation of CTE includes cognitive, behavioral, and mood changes that can progress to dementia. The contributions of pathologic changes in phosphorylated tau, white matter degeneration, and cerebrovascular disease to dementia in the context of CTE are poorly understood. Dr. Alosco and colleagues examined arteriosclerosis, infarcts, microinfarcts, microbleeds, and white matter rarefaction in donated brains to illuminate these contributions.

The researchers examined data from the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Study and Veterans Affairs–Boston University–Concussion Legacy Foundation brain bank. The population included deceased men who had played football and had received a neuropathologic diagnosis of CTE. Eligible participants had a history of repetitive head impacts. Brains that had been donated after a prolonged time postmortem and those with poor tissue quality were excluded.

Neuropathologists blinded to clinical data analyzed patients’ CTE stage and severity of neurofibrillary tangle burden in the dorsolateral frontal cortex as semiquantitative scales of phosphorylated tau severity. Neurofibrillary tangle burden was dichotomized as none or mild versus moderate or severe. The neuropathologists also rated white matter rarefaction and arteriolosclerosis severity using a scale of 0 points (i.e., none) to 3 points (i.e., severe changes). The investigators obtained clinical data through online surveys and retrospective telephone interviews with informants. They adjudicated consensus diagnoses of dementia based on modified criteria from DSM-IV.

White matter rarefaction was common

Dr. Alosco and colleagues included 180 individuals in their analysis, excluding those aged younger than 40 years because of low pathologic burden and minimal presence of dementia. Mean age at death was nearly 68 years. Fifty patients had no or mild neurofibrillary tangle burden, and 130 had moderate to severe burden. Thirty-five patients had CTE at stage I or II, and 145 had CTE at stage III or IV. In all, 120 patients were determined to have had dementia. About 47% of the sample had moderate to severe white matter rarefaction, and about 47% had arteriolosclerosis. Infarcts, microinfarcts, and microbleeds were uncommon.

When the investigators created a simultaneous equations regression model and controlled for age and race, they found that more years of play was associated with more severe white matter rarefaction, greater phosphorylated tau accumulation, and high CTE stage. Furthermore, white matter rarefaction and dorsolateral frontal cortex neurofibrillary tangles were associated with dementia. The association of years of play with dementia was mediated by white matter rarefaction and neurofibrillary tangle burden. Arteriolosclerosis was not associated with years of play, but arteriolosclerosis was independently associated with dementia.

The odds ratio for dementia was 1.69 among participants with more severe white matter rarefaction and 1.81 among patients with arteriolosclerosis. After the researchers controlled for age and race, the odds ratio of dementia was 2.65 among participants with a high neurofibrillary tangle burden, compared with participants with a low burden.

“Studies that include direct cardiovascular disease and repetitive head impacts metrics and refined measures of white matter integrity are needed to improve understanding of the pathogenesis of white matter rarefaction and cerebral small vessel changes in CTE,” Dr. Alosco and colleagues wrote.

The study was funded by grants from the National Institute on Aging, National Institute of Neurological Disorders and Stroke, the Department of Veterans Affairs, the Nick and Lynn Buoniconti Foundation, and the National Center for Advancing Translational Sciences. Some of the authors reported financial ties to the pharmaceutical industry and serving on professional sports committees.

SOURCE: Alosco ML et al. JAMA Neurol. 2019 Aug 5. doi: 10.1001/jamaneurol.2019.2244.

Next Article: