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.

重复性头部撞击 (RHI) 与神经退行性疾病、慢性创伤性脑病 (CTE) 相关。根据 CTE（称为创伤性脑病综合征 (TES)）的研究诊断标准，CTE 会出现行为、情绪和/或认知症状。由于病理学和受影响的大脑区域的差异，症状存在多样性，并且 RHI 导致晚年临床缺陷的机制尚不明确。因此，目前无法检测到 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) 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，并且 WMSA 的病理相关性在 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，与血管状况无关。然而，需要对对照组和比较组（例如 AD）进行多模式神经影像学研究，以阐明前 NFL 球员中 WMSA 的存在、性质和影响。 K23 将使用液体衰减反转恢复 (FLAIR) 和扩散 MRI 来检查 WMSA，将其作为 RHI 的长期后果，与 AD 不同并影响以后的临床功能。来自波士顿大学 (BU) 的跨学科科学家团队将解决 Alosco 博士在 CTE（暴露科学、神经影像学、神经病理学）研究关键领域的知识空白，从而促使 R01 启动自己的研究计划。 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 受试者没有头部外伤史。前 NFL 球员和 NC 将从 Stern 博士（主要导师）NINDS U01 检查 CTE 生物标志物。 AD 科目将来自 BU AD 和 CTE 中心 (ADCTEC) 注册处。 ADCTEC 外展核心将确保年轻 AD 男性（45-55 岁）的参与。所有受试者均完成医学、认知、行为/情绪、神经影像学评估（T1、FLAIR、弥散、PET）以及腰椎穿刺和抽血。 FreeSurfer 和 Tracts Constrained by Underlying Anatomy 将评估肺叶体积和纤维路径。 WMSA 将通过贝叶斯概率结构进行估计。我们将测试前 NFL 球员相对于 NC 和 AD 是否具有独特的脑叶和纤维路径 WMSA 模式，以及区域 WMSA 是否可以预测认知、行为和情绪功能。我们将检查 RHI 是否可以预测 WMSA 和纤维路径不完整性。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完整性不相关，并探讨 WMSA 是否与 tau 液体和 PET 标记物相关。数以百万计的美国人接触过 RHI，这项研究将通过提高对 RHI 神经系统后遗症的了解而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、治疗和预防研究至关重要。