Alosco Michael L, Stein Thor D, Tripodis Yorghos, Chua Alicia S, Kowall Neil W, Huber Bertrand Russell, Goldstein Lee E, Cantu Robert C, Katz Douglas I, Palmisano Joseph N, Martin Brett, Cherry Jonathan D, Mahar Ian, Killiany Ronald J, McClean Michael D, Au Rhoda, Alvarez Victor, Stern Robert A, Mez Jesse, McKee Ann C
Boston University Alzheimer's Disease Center and CTE Center, Department of Neurology, Boston University School of Medicine, Boston, Massachusetts.
Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts.
JAMA Neurol. 2019 Nov 1;76(11):1298-1308. doi: 10.1001/jamaneurol.2019.2244.
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.
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.
The number of years of football play as a proxy for repetitive head impacts.
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.
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).
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.
慢性创伤性脑病（CTE）是一种与重复性头部撞击相关的神经退行性疾病，包括来自美式橄榄球运动中的撞击，其表现为认知和神经精神障碍，可发展为痴呆症。CTE中导致痴呆症的途径尚不清楚，可能涉及tau蛋白和非tau蛋白的病理状况。
研究40岁以上曾踢足球且患有CTE的已故男性中，白质稀疏和脑血管疾病与痴呆症之间的关联。
设计、背景和参与者：这项横断面研究涉及对正在进行的“理解神经损伤与创伤性脑病（UNITE）研究”数据的分析，该研究通过退伍军人事务部-波士顿大学-脑震荡遗产基金会脑库进行，并纳入了2008年至2017年间的脑捐赠者。最初的224名曾踢足球且经神经病理学诊断患有CTE的男性样本，在排除40岁以下和数据缺失者后数量减少。
以踢足球的年数作为重复性头部撞击的替代指标。
对白质稀疏和小动脉硬化严重程度进行神经病理学评估（范围为0至3级，3级为严重）；梗死灶、微梗死灶和微出血灶的数量；以及通过CTE分期和背外侧前额叶皮质（DLFC）神经原纤维缠结（NFTs）的半定量评分确定的磷酸化tau蛋白积累情况（无或轻度与中度或重度）。通过基于信息提供者的回顾性临床访谈，经诊断共识会议确定痴呆症诊断。
共纳入180名男性。样本死亡时的平均（标准差）年龄为67.9（12.7）岁。180名中，120名（66.7%）在死亡前被发现患有痴呆症。中度至重度白质稀疏（180名中的84名[46.6%]）和小动脉硬化（180名中的85名[47.2%]）很常见；梗死灶、微梗死灶和微出血灶则不常见。控制年龄和种族的联立方程回归模型显示，踢足球年数越多，白质稀疏越严重（β，0.16[95%置信区间，0.02 - 0.29]；P = 0.03），磷酸化tau蛋白积累越多（DLFC NFTs：β，0.15[95%置信区间，0.004 - 0.30]；P = 0.04；CTE分期：β，0.27[95%置信区间，0.14 - 0.41]；P < 0.001）。白质稀疏（β，0.16[95%置信区间，0.02 - 0.29]；P = 0.03）和DLFC NFTs（β，0.16[95%置信区间，0.03 - 0.28]；P = 0.01）与痴呆症相关。小动脉硬化与踢足球年数无关，但小动脉硬化与痴呆症独立相关（β，0.21[95%置信区间，0.07 - 0.35]；P = 0.003）。
在曾踢足球且患有CTE的老年男性中，踢足球年数越多，白质稀疏越严重，DLFC NFT负担越大。白质稀疏、小动脉硬化和DLFC NFTs与痴呆症独立相关。CTE中的痴呆症可能是神经病理变化的结果，包括与重复性头部撞击相关的白质稀疏和磷酸化tau蛋白，以及与头部创伤无关的病理变化，如小动脉硬化。
