Association of White Matter Rarefaction, Arteriolosclerosis, and Tau With Dementia in Chronic Traumatic Encephalopathy

Abstract

Importance: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head impacts, including those from US football, that presents with cognitive and neuropsychiatric disturbances that can progress to dementia. Pathways to dementia in CTE are unclear and likely involve tau and nontau pathologic conditions.

Objective: To investigate the association of white matter rarefaction and cerebrovascular disease with dementia in deceased men older than 40 years who played football and had CTE.

Design, setting, and participants: This cross-sectional study involves analyses of data from the ongoing Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Study, which is conducted via and included brain donors from the Veterans Affairs-Boston University-Concussion Legacy Foundation brain bank between 2008 and 2017. An original sample of 224 men who had played football and were neuropathologically diagnosed with CTE was reduced after exclusion of those younger than 40 years and those missing data.

Exposures: The number of years of football play as a proxy for repetitive head impacts.

Main outcomes and measures: Neuropathological assessment of white matter rarefaction and arteriolosclerosis severity (on a scale of 0-3, where 3 is severe); number of infarcts, microinfarcts, and microbleeds; and phosphorylated tau accumulation determined by CTE stage and semiquantitative rating of dorsolateral frontal cortex (DLFC) neurofibrillary tangles (NFTs) (none or mild vs moderate or severe). Informant-based retrospective clinical interviews determined dementia diagnoses via diagnostic consensus conferences.

Results: A total of 180 men were included. The mean (SD) age of the sample at death was 67.9 (12.7) years. Of 180, 120 [66.7%]) were found to have had dementia prior to death. Moderate to severe white matter rarefaction (84 of 180 [46.6%]) and arteriolosclerosis (85 of 180 [47.2%]) were common; infarcts, microinfarcts, and microbleeds were not. A simultaneous equations regression model controlling for age and race showed that more years of play was associated with more severe white matter rarefaction (β, 0.16 [95% CI, 0.02-0.29]; P = .03) and greater phosphorylated tau accumulation (DLFC NFTs: β, 0.15 [95% CI, 0.004-0.30]; P = .04; CTE stage: β, 0.27 [95% CI, 0.14-0.41]; P < .001). White matter rarefaction (β, 0.16 [95% CI, 0.02-0.29]; P = .03) and DLFC NFTs (β, 0.16 [95% CI, 0.03-0.28]; P = .01) were associated with dementia. Arteriolosclerosis and years of play were not associated, but arteriolosclerosis was independently associated with dementia (β, 0.21 [95% CI, 0.07-0.35]; P = .003).

Conclusions and relevance: Among older men who had played football and had CTE, more years of football play were associated with more severe white matter rarefaction and greater DLFC NFT burden. White matter rarefaction, arteriolosclerosis, and DLFC NFTs were independently associated with dementia. Dementia in CTE is likely a result of neuropathologic changes, including white matter rarefaction and phosphorylated tau, associated with repetitive head impact and pathologic changes not associated with head trauma, such as arteriolosclerosis.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Goldstein is a paid consultant to Johnson & Johnson, Janssen Research & Development LLC, and Rebiscan Inc and has received funding from the WWE (World Wrestling Entertainment) and Ivivi Health Sciences. Dr Stern has received research funding from Avid Radiopharmaceuticals Inc, is a member of the Mackey-White Committee of the National Football League Players Association, is a paid consultant to Biogen and Eli Lilly, receives royalties for published neuropsychological tests from Psychological Assessment Resources Inc, and is a member of the Board of Directors of King-Devick Technologies. Dr Cantu is a paid consultant to the National Football League Head Neck and Spine Committee, a vice president and chair of the scientific advisory committee of the National Operating Committee on Standards for Athletic Equipment, and a consultant to the Concussion Legacy Foundation; he also receives royalties from Houghton Mifflin Harcourt and compensation for expert legal opinion to the National Collegiate Athletic Association and National Hockey League and is a member of the Mackey-White Committee of the National Football League Players Association. Dr McKee is a member of the Mackey-White Committee of the National Football League Players Association and reports receiving grants from the National Institutes of Health and Department of Veteran Affairs and other funding from Buoniconti Foundation during the conduct of the study. Dr Alosco reported grants from National Institutes of Health/National Institute of Neurological Disorders and Stroke during the conduct of the study. Dr Katz reported grants from Boston University School of Medicine Department of Neurology during the conduct of the study. Dr Au reported grants from Cohen Veterans Bioscience, Pfizer, Biogen, and Evidation Health and personal fees from Optum Health, outside the submitted work. Dr Stern reported grants from the National Institutes of Health during the conduct of the study; personal fees from Biogen and Eli Lilly outside the submitted work; membership on the board of directors for King-Devick Technologies, with stock options; and royalties for published neuropsychological tests from Psychological Assessment Resources Inc. Dr Mez reported grants from the National Institutes of Health, Department of Defense, Alzheimer’s Association, and Concussion Legacy Foundation during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. Cross-Sectional Model on the Contributions of White Matter Rarefaction, Arteriolosclerosis, and Phosphorylated Tau to Dementia in Chronic Traumatic Encephalopathy (CTE)

Simultaneous equations regression models tested the association of pathological markers of cerebrovascular disease with dementia in older deceased individuals who had played football and had CTE. The Figure provides an illustrative conceptual summary of the primary significant findings. Not all variables or pathways are displayed for ease of presentation. See eMethods 3 and 4 in the Supplement for a summary of all variables included in the model and associated pathways estimated. The β values shown are standardized estimates, and each path shown is significant at an α less than .05. Standardized estimates are interpreted as changes in SD units. For instance, there was a 0.16-SD change in dementia per unit SD increase in white matter rarefaction and dorsolateral frontal cortex neurofibrillary tangles of hyperphosphorylated tau. Standardized estimates permit direct comparison of the effect sizes across pathways. The dashed line between years of football play and dementia denotes a significant indirect effect in which the association of years of football play with dementia was mediated by dorsolateral frontal cortex neurofibrillary tangles and severity of white matter rarefaction. Arteriolosclerosis and white matter rarefaction were rated on a scale of 0 to 3 points, with 3 indicating severe pathologic changes. Dorsolateral frontal cortex neurofibrillary tangles was a binary variable, with 0 indicating a low burden of neurofibrillary tangles and 1 a high burden.

Figure 2.. White Matter Rarefaction, Arteriolosclerosis, and Dorsolateral Frontal Cortex Tau Pathologic Changes in Participants With Chronic Traumatic Encephalopathy

A, Luxol fast blue with hemotoxylin-eosin histochemical staining shows robust myelin staining (blue) in a former US football college player in his early 40s who was neuropathologically diagnosed with chronic traumatic encephalopathy (CTE) (stage I/II) who was not determined to have had antemortem dementia. B and C, In a man who had played professional US football, was in his mid-80s, had been neuropathologically diagnosed with CTE (stage III/IV), and was determined by consensus to have dementia, there was severe loss (3+) of myelinated fibers (B), as well as marked arteriolosclerosis with hyalinization of the vessel wall (C, arrowhead). D-F, Immunohistochemical staining for tau pathologic changes (antibody AT8) in the dorsolateral frontal cortex shows perivascular accumulations of abnormal tau at the sulcal depths within neurons and cell processes (asterisks indicate the lumen of cortical vessels; arrowheads, examples of pretangles and tangles within neurons). The scale bar for A-C and F is 100 μm; for D and E, 150 μm.