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 PARTICIPANTSThis 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 MEASURESNeuropathological 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...

Chronic Traumatic Encephalopathy and Neuropathological Comorbidities

“…A recent study found that moderate to severe WM rarefaction (46.6%) and arteriolosclerosis (47.2%) are common in 180 deceased football players with autopsy-confirmed CTE (Table 1). 81 Simultaneous equations regression model controlling for age and race showed more years of play corresponded to more severe WM rarefaction and greater tau pathology accumulation. Arteriolosclerosis and years of play were not related, but arteriolosclerosis was independently associated with dementia.…”

“…Among older football players with CTE, more years of football participation corresponded to more severe WM rarefaction and greater burden of tau pathology. 81 Overall, dementia in CTE may result from multiple neuropathologies linked to RHI, including WM rarefaction and tau pathology, as well as pathologies not related to TBI or RHI, such as arteriolosclerosis and other age-related disease (►Fig. 1).…”

Clinical Presentation of Chronic Traumatic Encephalopathy

“…The hypothesis that the tau pathology may not on its own be responsible for diverse clinical symptoms reported to be associated with CTE is supported by a recent postmortem study of 180 former American football players with neuropathological diagnoses of CTE, 120 of who had dementia prior to death. 92 The authors examined dorsolateral frontal cortex (DLFC) NFT burden (a measure of CTE-related tau pathology), as well as white matter rarefaction (a marker of non-tau pathologic changes possibly associated with RHI exposure), and arteriolosclerosis (a marker of pathology not related to RHI exposure that can lead to clinical impairments). Results showed that the greater number of years of football play was associated with greater DLFC NFT burden and greater severity of white matter rarefaction but not arteriolosclerosis.…”

“…The authors stated that these findings indicate that dementia in CTE is a result of neuropathologic changes, including p-tau and white matter rarefaction, associated with RHI exposure as well as pathologic changes, such as arteriolosclerosis, unrelated to head trauma. 92…”

Altered oligodendroglia and astroglia in chronic traumatic encephalopathy

“…However, white matter atrophy, white matter rarefaction, myelin and axonal loss, astrocytic degeneration, and ptau pathology in the cortical white matter have also been described (McKee et al 2013;Holleran et al 2017;Hsu et al 2018). Furthermore, white matter rarefaction is independently associated with dementia in CTE in addition to p-tau pathology and inflammation (Alosco et al 2019;Cherry et al 2016).…”