People who sustain repeated head injuries are at risk for developing chronic traumatic encephalopathy (CTE) many years later, but what causes the clinical symptoms of the disease? At least three kinds of neuropathology, according to a paper in the August 5 JAMA Neurology. Researchers led by Ann McKee at Boston University reported that among former American football players who were confirmed to have CTE upon autopsy, the number of years they played football correlated with their burden of tau tangles, as well as loss of white-matter integrity. Both of these pathological hallmarks contributed to dementia. Arteriolosclerosis, a hardening and thickening of teeny arterioles, also raised their chances of dementia, regardless of time spent on the football field.
- Among NFL players with CTE, career length correlated with tau tangles and white-matter loss.
- Both pathologies correlated with dementia risk.
- Arteriolosclerosis associated with dementia in people with CTE, regardless of how long they played football.
People with CTE develop a combination of cognitive, behavioral, and mood symptoms that can progress to dementia. Though the disease is best known as a tauopathy, white-matter degeneration and cerebrovascular disease are also common (McKee et al., 2013; Jan 2013 news). The causal relationships between these different pathologies, and how each contributes to the clinical manifestation of CTE, remain unclear.
To investigate how tau tangles, white-matter damage, and arteriolosclerosis contribute to clinical symptoms of CTE, first author Michael Alosco and colleagues measured these pathologies in postmortem brain samples from the Veterans Affairs-Boston University-Concussion Legacy Foundation brain bank, which includes brains donated from people with a history of repeated head injury. As part of the ongoing Understanding Neurologic Injury and Traumatic Encephalopathy study, the researchers selected samples from 180 former football players who were at least 40 years of age at death, and who had neuropathologically confirmed CTE upon autopsy, based on established criteria (McKee et al., 2015). Thirty-five had CTE in stages I and II, while the remaining 145 had CTE stage III and IV. One hundred and twenty of them had been diagnosed with dementia.
Alosco found that years of football play correlated with tau tangle burden in the dorsolateral prefrontal cortex, a region known to shoulder early and severe burden of tau pathology in people with CTE. Men who played longer also had more severe white-matter rarefaction—a combination of white-matter loss and gliosis. Tau burden and white-matter pathology each contributed similarly, and independently, to the chances of a dementia diagnosis. People with moderate to severe levels of white-matter loss or tau pathology had 1.69 and 2.65 times the odds of dementia, respectively, than their counterparts with mild amounts either pathology.
The researchers also took stock of brain arteriolosclerosis. They found that while years of football play had no bearing on the arterioles, the severity of this condition correlated with the likelihood of dementia. It did so to a similar extent as white-matter loss. People with more severe arteriolosclerosis had 1.81 times the odds of developing dementia than did people who had a lower burden.
Road to Dementia. In footballers with CTE, years of play boosted tau tangles and white-matter damage, each of which associated with dementia. Arteriolosclerosis correlated with dementia independent of playing years. [Courtesy of Alosco et al., JAMA Neurology, 2019.]
Adjusting for comorbid pathologies, including AD-like Aβ/tau, prion disease, or motor neuron disease, had no bearing on the outcomes.
Interestingly, though the researchers reported that broader signs of cardiovascular disease, including atherosclerosis and hypertension, associated with brain arteriolosclerosis, these cardiovascular problems did not correlate with white-matter loss or with dementia in the CTE cohort. Arteriolosclerosis did not correlate with white-matter pathology either, suggesting the axonal damage arises independently. “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,” wrote Julie Schneider of Rush University in Chicago, in an accompanying editorial.
The authors concluded that dementia in people with CTE results from repeated head injuries that cause neuropathological conditions—including tau tangles and white-matter loss—as well as cerebrovascular disease, which arises independently of head injury.
Peter Nelson of the University of Kentucky in Lexington said that the findings support the idea that malfunctions in small vessels of the brain contribute to dementia. Nelson’s group previously reported that arteriolosclerosis hastened cognitive decline, and other groups have implicated cerebrovascular disease (Ighodaro et al., 2016; Aug 2014 news; Aug 2017 news). Controlling hypertension has been found to reduce dementia incidence by almost 20 percent in the SPRINT trial (Aug 2018 news). Nelson said the current findings align with the idea that people predisposed to arteriolosclerosis might be more likely to develop dementia due to CTE, or other neurodegenerative pathologies.
“Arteriolosclerosis has been shown to increase the likelihood of not only vascular dementia but also Alzheimer dementia,” Schneider wrote in her editorial (Arvanitakis et al., 2016). “Whether these vascular changes result in additive injury to the brain or interact with pathologic proteins to further neurodegenerative and white-matter changes is a major area of research.”
Schneider also called out selection bias of the cohort as a limitation of the study. The samples came from former U.S. football players who had opted in for brain donation, a possible indication that they sensed something was amiss, and were later 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 U.S. football,” she wrote. “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.”—Jessica Shugart
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Brain Bank Citations
- McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC. The spectrum of disease in chronic traumatic encephalopathy. Brain. 2013 Jan;136(Pt 1):43-64. PubMed.
- McKee AC, Cairns NJ, Dickson DW, Folkerth RD, Keene CD, Litvan I, Perl DP, Stein TD, Vonsattel JP, Stewart W, Tripodis Y, Crary JF, Bieniek KF, Dams-O'Connor K, Alvarez VE, Gordon WA, TBI/CTE group. The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol. 2016 Jan;131(1):75-86. Epub 2015 Dec 14 PubMed.
- Ighodaro ET, Abner EL, Fardo DW, Lin AL, Katsumata Y, Schmitt FA, Kryscio RJ, Jicha GA, Neltner JH, Monsell SE, Kukull WA, Moser DK, Appiah F, Bachstetter AD, Van Eldik LJ, Alzheimer's Disease Neuroimaging Initiative (ADNI), Nelson PT. Risk factors and global cognitive status related to brain arteriolosclerosis in elderly individuals. J Cereb Blood Flow Metab. 2016 Jan 6; PubMed.
- Arvanitakis Z, Capuano AW, Leurgans SE, Bennett DA, Schneider JA. Relation of cerebral vessel disease to Alzheimer's disease dementia and cognitive function in elderly people: a cross-sectional study. Lancet Neurol. 2016 Aug;15(9):934-43. Epub 2016 Jun 14 PubMed.
- Alosco ML, Stein TD, Tripodis Y, Chua AS, Kowall NW, Huber BR, Goldstein LE, Cantu RC, Katz DI, Palmisano JN, Martin B, Cherry JD, Mahar I, Killiany RJ, McClean MD, Au R, Alvarez V, Stern RA, Mez J, McKee AC. Association of White Matter Rarefaction, Arteriolosclerosis, and Tau With Dementia in Chronic Traumatic Encephalopathy. JAMA Neurol. 2019 Aug 5; PubMed.