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: 10176610
• 负责人: Michael Alosco
• 金额: $ 15.28万
• 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/10176610
• 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; Structure; Symptoms; Syndrome; Temporal Lobe; Testing; Thinking; Time; Tissues; Universities; Variant; chronic traumatic encephalopathy; comorbidity; contact sports; 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。根据被称为创伤性脑病综合征(TES)的CTE的研究诊断标准，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不同，症状的存在存在多样性，RHI引起的后世临床缺陷的机制尚不清楚。因此，目前无法检测到RHI引起的长期神经疾病(例如CTE)。白质信号异常(WMSA)是一种非特异性磁共振成像(MRI)病理标志物，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在一起，与血管状况无关。然而，需要对对照和对照(例如AD)组进行多模式神经成像研究，以澄清WMSA在前NFL球员中的存在、性质和影响。这款K23将使用液体衰减反转恢复(FLAIR)和弥散磁共振成像来检查WMSA作为RHI的长期后果，这些结果与AD不同，并影响以后的临床功能。来自波士顿大学(BU)的一个由跨学科科学家组成的团队将解决Alosco博士在CTE研究的关键领域(暴露科学、神经成像、神经病理学)的知识空白问题，从而导致R01启动他自己的研究计划。K23将包括30名有症状的前NFL球员(45-74岁)，30名同龄和血管风险匹配的男性正常对照组(NC)，以及30名同龄和血管风险匹配的AD男性。NC和AD受试者将没有头部创伤病史。前NFL球员和NC将来自斯特恩博士的(主要导师)NINDS U01检查CTE生物标记物。广告主题将来自BU AD和CTE中心(ADCTEC)注册。ADCTEC外联核心将确保纳入年轻的AD男性(45-55岁)。所有受试者完成医学、认知、行为/情绪、神经成像评估(T1、FLAIR、弥散、PET)、腰椎穿刺术和抽血。受基础解剖学限制的自由游动和纤维束将评估叶体积和纤维路径。WMSA将通过贝叶斯概率结构进行估计。我们将测试前NFL球员是否具有相对于NC和AD的叶和纤维路径WMSA的独特模式，以及区域性WMSA是否预测认知、行为和情绪功能。我们将检查RHI是否可以预测WMSA和光纤路径不完整性。在前NFL球员中，我们将测试WMSA是否与肺叶体积损失和纤维路径不完整相对应，并探索WMSA是否与tau的液体和PET标记物有关。数以百万计的美国人暴露在RHI中，这项研究将通过提高对RHI神经后遗症的了解，对公共健康产生重大影响，这对于促进CTE等脑部疾病的诊断、治疗和预防的研究至关重要。