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

重复头部撞击暴露和晚年白质信号异常：对前 NFL 球员、阿尔茨海默氏病受试者和认知正常对照的调查

• 批准号: 9921499
• 负责人: Michael Alosco
• 金额: $ 16.25万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921499
• 关键词: Address; Affect; Age; Aggressive behavior; Aging; Algorithms; Alzheimer' s Disease; Alzheimer' s disease risk; American; Amyloid; Anatomy; Anisotropy; Area; Attenuated; Axon; Behavior; Behavioral; Biological Assay; Biological Markers; Blood; Blood Vessels; Boston; Brain Diseases; Brain region; Cardiovascular Diseases; Cerebrospinal Fluid; Chronic; Clinical; Cognition; Cognition Disorders; Cognitive; Cognitive deficits; Craniocerebral Trauma; Data; Diagnosis; Diagnostic; Diagnostics Research; Diffuse; Diffusion; Diffusion Magnetic Resonance Imaging; Elderly; Ensure; Evaluation; Exposure to; Fiber; Forcep; Gold; Heterogeneity; Image; Imaging Techniques; Impaired cognition; Impairment; Impulsivity; Investigation; Knowledge; Lead; Link; Liquid substance; Lobar; Magnetic Resonance Imaging; Manufactured football; Medical; Memory; Mental Depression; Mentors; Minor; Moods; National Institute of Neurological Disorders and Stroke; Nature; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurologic; Outcome Study; Parietal; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Plasma; Positron-Emission Tomography; Prevention; Probability; Protocols documentation; Public Health; Publishing; Radial; Recording of previous events; Recovery; Registries; Research; Risk; Sampling; Science; Scientist; Severities; Signal Transduction; Spinal Puncture; Sports; Structure; Symptoms; Syndrome; Temporal Lobe; Testing; Thinking; Time; Tissues; Universities; Variant; chronic traumatic encephalopathy; comorbidity; executive function; experience; frontal lobe; head impact; imaging biomarker; improved; male; mood symptom; multimodality; nervous system disorder; neuroimaging; neuropathology; outreach; prevent; programs; tau Proteins; tau-1; uptake; white matter; white matter change

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.

重复的头部影响（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，称为创伤性脑病综合征（TES），CTE表现出行为，情绪和/或认知症状。由于病理学和大脑区域的差异而存在症状的存在，而RHI的后期临床缺陷的机制也很不明确。结果，目前无法检测到RHI（例如CTE）的长期神经疾病。白质信号异常（WMSA）是可能与RHI相关并影响CTE临床表现的病理学的非特异性磁共振成像（MRI）。 WMSA预测，阿尔茨海默氏病（AD）的风险增加，WMSA的病理相关性在CTE中很常见。我们发表的数据将T1 WMSA与RHI和前国家橄榄球联盟（NFL）球员的执行缺陷联系起来，独立于血管状态。但是，需要对控制和比较（例如AD）组进行多模式神经影像学研究，以阐明WMSA在以前的NFL参与者中的存在，性质和影响。该K23将使用衰减反转恢复（FLAIR）和扩散MRI的流体来检查WMSA，这是与AD不同的RHI的长期后果，并影响了后期寿命的临床功能。来自波士顿大学（BU）的跨学科科学家团队将解决Alosco博士在研究CTE（暴露科学，神经影像学，神经病理学）关键领域的知识差距，从而启动了R01启动自己的研究计划。 K23将包括30名男性症状的前NFL球员（45-74岁），30个年龄和血管风险匹配的男性正常对照（NC），以及30名与AD的同龄男性和血管风险匹配的男性。 NC和AD主题将没有头部创伤历史。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。广告主题将来自BU AD和CTE中心（ADCTEC）注册表。 ADCTEC外展核心将确保包括年轻的AD男性（45-55岁）。所有受试者都完成医学，认知，行为/情绪，神经影像学评估（T1，FLAIR，扩散，PET）和腰椎穿刺和抽血。通过基础解剖结构限制的自由卷和裂纹将评估小叶体积和纤维路径。 WMSA将通过贝叶斯概率结构估算。我们将测试以前的NFL玩家是否相对于NC和AD具有独特的LOBAR和FIBER PATH WMSA模式，以及区域WMSA是否预测认知，行为和情绪功能。我们将检查RHI是否预测WMSA和纤维路径取积分。在以前的NFL播放器中，我们将测试WMSA是否对应于Lobar量损失和纤维路径取向障碍，并探索WMSA是否与Tau的流体和宠物标记有关。数以百万计的美国人暴露于RHI，这项研究将通过改善RHI神经后遗症的知识来产生重大的公共卫生影响，这对于促进对CTE等脑部疾病的诊断，治疗和预防的研究至关重要。