From the Boston University Alzheimer's Disease Research Center and CTE Center, Department of Neurology (M.U., R.J.K., Y.T., D.H.D., B.D., L.G., D.K., C.N., R.C., N.K., B.R.H., R.A.S., V.E.A., T.D.S., A.M., J.M., M.L.A.), Department of Anatomy and Neurobiology (R.J.K., R.A.S.), Center for Biomedical Imaging (R.J.K.), Department of Radiology (A.Z.M., C.F.), Framingham Heart Study (C.F., T.D.S., A.M., J.M.), Department of Pathology and Laboratory Medicine (L.G., N.K., T.D.S., A.M.), Department of Psychiatry (L.G.), Department of Ophthalmology (L.G.), and Department of Neurosurgery (R.C., R.A.S.), Boston University School of Medicine; Department of Psychiatry, Psychiatry Neuroimaging Laboratory (S.B.), Brigham and Women's Hospital, Harvard Medical School; Department of Biostatistics (Y.T.) and Biostatistics and Epidemiology Data Analytics Center (B.M., J.P.), Boston University School of Public Health; Departments of Radiology (K.B.) and Physical Medicine & Rehabilitation (D.H.D.), Massachusetts General Hospital, Boston; Braintree Rehabilitation Hospital (B.D., D.K.); Department of Biomedical, Electrical & Computer Engineering (L.G.), Boston University College of Engineering; Concussion Legacy Foundation (C.N., R.C.), Boston; Department of Neurosurgery (R.C.), Emerson Hospital, Concord; VA Boston Healthcare System (B.R.H., V.E.A., T.D.S., A.M.), US Department of Veterans Affairs, Jamaica Plain; National Center for PTSD (B.R.H., V.E.A.), VA Boston Healthcare, Jamaica Plain; and Department of Veterans Affairs Medical Center (V.E.A., T.D.S., A.M.), Bedford, MA.
Neurology. 2022 Jan 4;98(1):e27-e39. doi: 10.1212/WNL.0000000000013012. Epub 2021 Nov 24.
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 ≤ 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; = 0.04), arteriolosclerosis (OR 2.38, 95% CI 1.02, 5.52; = 0.04), CTE stage (OR 2.58, 95% CI 1.17, 5.71; = 0.02), and dorsolateral frontal p-tau severity (OR 3.03, 95% CI 1.32, 6.97; = 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; = 0.01). Greater log TLV correlated with higher FAQ (unstandardized β 4.94, 95% CI 0.42, 8.57; = 0.03) and CDS scores (unstandardized β 15.35, 95% CI -0.27, 30.97; = 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.
接触性运动中反复头部撞击的迟发性神经病理学改变包括慢性创伤性脑病（CTE）和白质退化。液体衰减反转恢复（FLAIR）MRI 扫描上的白质高信号（WMH）通常被认为是血管风险引起的微血管疾病，但在反复头部撞击的情况下，可能存在独特的潜在病理学和危险因素。我们研究了暴露于反复头部撞击的脑捐献者的生前 FLAIR 扫描中 WMH 的神经病理学相关性。测试了 WMH 与反复头部撞击暴露以及报告认知和日常功能的知情人之间的关联。
这项影像学-病理学相关性研究包括有症状的男性死者，他们暴露于反复头部撞击。供体有来自病历的生前 FLAIR 扫描，且没有中枢神经系统肿瘤、大动脉梗死、出血或脑软化的证据。WMH 使用来自病变分割工具箱的病变预测算法计算的总病变体积（TLV）的对数变换值进行量化。神经病理学评估包括白质稀疏度、脑血管疾病、磷酸化 tau（p-tau）严重程度（CTE 分期，额侧皮质）和β-淀粉样蛋白（Aβ）的半定量评分。在足球运动员中，参赛年限是反复头部撞击暴露的替代指标。使用认知困难量表（CDS）和功能活动问卷（FAQ）评估回顾性报告的认知和日常功能。回归模型控制了人口统计学、糖尿病、高血压和 MRI 分辨率。定义统计学意义为≤0.05。
该样本包括 75 名供体：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。痴呆是最常见的 MRI 指征（64%）。53 人（70.7%）尸检时患有 CTE。TLV 与白质稀疏（比值比[OR]2.32，95%置信区间[CI]1.03，5.24； = 0.04）、小动脉硬化（OR 2.38，95% CI 1.02，5.52； = 0.04）、CTE 分期（OR 2.58，95% CI 1.17，5.71； = 0.02）和额侧皮质 p-tau 严重程度（OR 3.03，95% CI 1.32，6.97； = 0.01）相关。与 Aβ 无关。更多年的足球比赛与 TLV 呈正相关（未标准化β0.04，95%CI 0.01，0.06； = 0.01）。更大的 TLV 与更高的 FAQ（未标准化β4.94，95%CI 0.42，8.57； = 0.03）和 CDS 评分（未标准化β15.35，95%CI -0.27，30.97； = 0.05）相关。
WMH 可能反映了反复头部撞击的长期白质病理学改变，包括白质稀疏和 p-tau 以及微血管疾病。需要前瞻性影像学-病理学相关性研究。
这项研究提供了 IV 级证据，表明 FLAIR 白质高信号与神经病理学变化（白质稀疏、小动脉硬化、p-tau 积聚）、美式足球比赛年限以及报告的认知症状之间存在关联，这些关联存在于暴露于反复头部撞击的有症状脑捐献者中。
