Repetitive Head Impact Exposure and Later-Life White Matter Signal Abnormalities: An Investigation in Former NFL Players, Subjects with Alzheimer's Disease, and Cognitively Normal Controls

重复性头部撞击（RHI）与神经退行性疾病慢性创伤性脑病（CTE）有关。根据CTE的研究诊断标准，即创伤性脑病综合征（TES）， CTE表现为行为、情绪和/或认知症状。由于病理和受影响的大脑区域的差异，症状存在多样性，RHI晚年临床缺陷的机制尚不明确。因此，目前无法发现由RHI引起的长期神经系统疾病（例如CTE）。白质信号异常（WMSA）是非特异性磁共振成像（MRI）的病理标记，可能与RHI相关，并影响CTE的临床表现。WMSA预测阿尔茨海默病（AD）的风险增加，WMSA的病理相关因素在CTE中很常见。我们发表的数据将T1 WMSA与前国家橄榄球联盟（NFL）球员的RHI和执行缺陷联系起来，独立于血管状况。然而，需要对照和比较（如AD）组的多模态神经影像学研究来阐明前NFL球员中WMSA的存在、性质和影响。该K23将使用液体衰减反转恢复（FLAIR）和弥散MRI来检查与AD不同的RHI的WMSA长期后果，并影响后期临床功能。来自波士顿大学（BU）的跨学科科学家团队将解决Alosco博士在CTE研究关键领域（暴露科学，神经成像，神经病理学）的知识空白，从而启动他自己的研究项目。K23将包括30名有症状的前NFL男性球员（45-74岁），30名同龄且血管风险匹配的男性正常对照（NC），以及30名同龄且血管风险匹配的AD男性。NC和AD受试者均无头部外伤史。前NFL球员和NC将来自Stern博士（主要导师）NINDS U01检查CTE生物标志物。AD受试者将来自BU AD和CTE中心（ADCTEC）注册中心。ADCTEC外联核心将确保包括年轻的AD男性（45-55岁）。所有受试者完成医学、认知、行为/情绪、神经影像学评估（T1、FLAIR、弥散、PET）、腰椎穿刺和抽血。FreeSurfer和受底层解剖约束的束将评估大叶体积和纤维路径。WMSA将通过贝叶斯概率结构来估计。我们将测试前NFL球员是否有相对于NC和AD的不同的脑叶和纤维路径WMSA模式，以及区域WMSA是否预测认知、行为和情绪功能。我们将研究RHI是否预测WMSA和纤维通路不完整。在前NFL球员中，我们将测试WMSA是否与大叶体积损失和纤维通路不完整相对应，并探讨WMSA是否与tau的液体和PET标志物相关。数以百万计的美国人接触到RHI，这项研究将通过提高对RHI神经系统后遗症的了解，对公共卫生产生重大影响，这对于促进CTE等脑部疾病的诊断、治疗和预防研究是必不可少的。

Repetitive head impacts (RHI) are associated with the neurodegenerative disease, chronic traumatic encephalopathy (CTE). According to research diagnostic criteria for CTE, known as Traumatic Encephalopathy Syndrome (TES), CTE presents with behavior, mood, and/or cognitive symptoms. There is diversity in the presence of symptoms due to differences in pathology and brain regions affected, and mechanisms of the later-life clinical deficits from RHI are ill-defined. As a result, long-term neurological diseases from RHI (e.g., CTE) cannot be detected at this time. White matter signal abnormalities (WMSA) are non-specific magnetic resonance imaging (MRI) markers of pathologies that may be associated with RHI and affect the clinical presentation of CTE. WMSA predict increased risk for Alzheimer's disease (AD) and pathological correlates of WMSA are common in CTE. Our published data linked T1 WMSA with RHI and executive deficits in former National Football League (NFL) players, independent of vascular status. However, multi-modal neuroimaging studies with control and comparison (e.g., AD) groups are needed to clarify the presence, nature, and effects of WMSA in former NFL players. This K23 will use fluid attenuated inversion recovery (FLAIR) and diffusion MRI to examine WMSA as a long-term consequence of RHI that are distinct from AD and affect later-life clinical function. A team of transdisciplinary scientists from Boston University (BU) will address Dr. Alosco's knowledge gaps in areas key for the study of CTE (exposure science, neuroimaging, neuropathology), leading to an R01 to launch his own research program. The K23 will include 30 male symptomatic former NFL players (45-74 years), 30 same-age and vascular risk-matched male normal controls (NC), and 30 same-age and vascular-risk matched males with AD. NC and AD subjects will be without head trauma history. Former NFL players and NC will be from Dr. Stern's (primary mentor) NINDS U01 examining CTE biomarkers. AD subjects will be from the BU AD and CTE Center (ADCTEC) Registry. The ADCTEC outreach core will ensure inclusion of young AD males (45-55 years). All subjects complete medical, cognitive, behavior/mood, neuroimaging evaluations (T1, FLAIR, diffusion, PET), and lumbar puncture, and blood draw. FreeSurfer and Tracts Constrained by Underlying Anatomy will assess lobar volumes and fiber paths. WMSA will be estimated via a Bayesian probability structure. We will test if former NFL players have a distinct pattern of lobar and fiber path WMSA relative to NC and AD, and if regional WMSA predict cognitive, behavior, and mood function. We will examine whether RHI predicts WMSA and fiber path dysintegrity. In the former NFL players, we will test whether WMSA correspond to lobar volume loss and fiber path dysintegrity and explore if WMSA are related to fluid and PET markers of tau. Millions of Americans are exposed to RHI and this study will have a major public health impact by improving knowledge on the neurological sequelae of RHI, which is imperative to facilitate research on the diagnosis, treatment, and prevention of brain diseases, like CTE.