Late neuropathologies of repetitive head impacts from contact sports can include chronic traumatic encephalopathy (CTE) and white matter degeneration. White matter hyperintensities (WMH) on fluid-attenuated inversion recovery (FLAIR) MRI scans are often viewed as microvascular disease from vascular risk, but might have unique underlying pathologies and risk factors in the setting of repetitive head impacts. We investigated the neuropathologic correlates of antemortem WMH in brain donors exposed to repetitive head impacts. The association between WMH and repetitive head impact exposure and informant-reported cognitive and daily function were tested.

This imaging–pathologic correlation study included symptomatic male decedents exposed to repetitive head impacts. Donors had antemortem FLAIR scans from medical records and were without evidence of CNS neoplasm, large vessel infarcts, hemorrhage, or encephalomalacia. WMH were quantified using log-transformed values for total lesion volume (TLV), calculated using the lesion prediction algorithm from the Lesion Segmentation Toolbox. Neuropathologic assessments included semiquantitative ratings of white matter rarefaction, cerebrovascular disease, hyperphosphorylated tau (p-tau) severity (CTE stage, dorsolateral frontal cortex), and β-amyloid (Aβ). Among football players, years of play was a proxy for repetitive head impact exposure. Retrospective informant-reported cognitive and daily function were assessed using the Cognitive Difficulties Scale (CDS) and Functional Activities Questionnaire (FAQ). Regression models controlled for demographics, diabetes, hypertension, and MRI resolution. Statistical significance was defined as p ≤ 0.05.

The sample included 75 donors: 67 football players and 8 nonfootball contact sport athletes or military veterans. Dementia was the most common MRI indication (64%). Fifty-three (70.7%) had CTE at autopsy. Log TLV was associated with white matter rarefaction (odds ratio [OR] 2.32, 95% confidence interval [CI] 1.03, 5.24; p = 0.04), arteriolosclerosis (OR 2.38, 95% CI 1.02, 5.52; p = 0.04), CTE stage (OR 2.58, 95% CI 1.17, 5.71; p = 0.02), and dorsolateral frontal p-tau severity (OR 3.03, 95% CI 1.32, 6.97; p = 0.01). There was no association with Aβ. More years of football play was associated with log TLV (unstandardized β 0.04, 95% CI 0.01, 0.06; p = 0.01). Greater log TLV correlated with higher FAQ (unstandardized β 4.94, 95% CI 0.42, 8.57; p = 0.03) and CDS scores (unstandardized β 15.35, 95% CI –0.27, 30.97; p = 0.05).

WMH might capture long-term white matter pathologies from repetitive head impacts, including those from white matter rarefaction and p-tau, in addition to microvascular disease. Prospective imaging–pathologic correlation studies are needed.

This study provides Class IV evidence of associations between FLAIR white matter hyperintensities and neuropathologic changes (white matter rarefaction, arteriolosclerosis, p-tau accumulation), years of American football play, and reported cognitive symptoms in symptomatic brain donors exposed to repetitive head impacts.

接触性运动造成的重复性头部撞击导致的晚期神经病理学包括慢性创伤性脑病 (CTE) 和白质变性。液体衰减反转恢复 (FLAIR) MRI 扫描中的白质高信号 (WMH) 通常被视为血管风险引起的微血管疾病，但在重复头部撞击的情况下可能具有独特的潜在病理和危险因素。我们研究了遭受重复性头部撞击的大脑捐献者生前 WMH 的神经病理学相关性。测试了 WMH 与重复性头部撞击暴露以及知情者报告的认知和日常功能之间的关联。

这项影像学病理相关性研究包括暴露于重复头部撞击的有症状的男性死者。捐赠者进行了生前 FLAIR 医疗记录扫描，没有中枢神经系统肿瘤、大血管梗塞、出血或脑软化的证据。使用总病灶体积 (TLV) 的对数转换值对 WMH 进行量化，使用病灶分割工具箱中的病灶预测算法进行计算。神经病理学评估包括白质稀疏、脑血管疾病、过度磷酸化 tau (p-tau) 严重程度（CTE 阶段、背外侧额叶皮层）和 β-淀粉样蛋白 (Aβ) 的半定量评级。对于足球运动员来说，比赛年限是头部反复受到撞击的代表。使用认知困难量表（CDS）和功能活动问卷（FAQ）评估回顾性知情者报告的认知和日常功能。回归模型控制了人口统计、糖尿病、高血压和 MRI 分辨率。统计显着性定义为p ≤ 0.05。

样本包括 75 名捐赠者：67 名足球运动员和 8 名非足球接触运动运动员或退伍军人。痴呆症是最常见的 MRI 指征 (64%)。五十三名 (70.7%) 尸检时出现 CTE。Log TLV 与白质稀疏（比值比 [OR] 2.32，95% 置信区间 [CI] 1.03, 5.24；p = 0.04）、动脉硬化（OR 2.38，95% CI 1.02, 5.52；p = 0.04）、CTE相关分期（OR 2.58，95% CI 1.17，5.71；p = 0.02）和背外侧额叶 p-tau 严重程度（OR 3.03，95% CI 1.32，6.97；p = 0.01）。与 Aβ 没有关联。更长的足球比赛年限与 log TLV 相关（非标准化 β 0.04，95% CI 0.01，0.06；p = 0.01）。较大的对数 TLV 与较高的 FAQ（非标准化 β 4.94，95% CI 0.42，8.57；p = 0.03）和 CDS 评分（非标准化 β 15.35，95% CI –0.27，30.97；p = 0.05）相关。

除了微血管疾病之外，WMH 还可以捕获重复性头部撞击引起的长期白质病理，包括白质稀疏和 p-tau 蛋白引起的病理。需要进行前瞻性影像-病理相关性研究。

这项研究提供了 FLAIR 白质高信号与神经病理变化（白质稀疏、动脉硬化、p-tau 积累）、美式橄榄球比赛年限以及暴露于重复头部撞击的有症状大脑捐赠者的认知症状之间的关联的 IV 级证据。