Subconcussive neurodegenerative progression in adolescent athletes

青少年运动员的亚震荡神经退行性进展

• 批准号: 10049757
• 负责人: Keisuke Kawata
• 金额: $ 55.16万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10049757
• 关键词: Acute; Address; Adolescence; Adolescent; Adult; American; Autoimmune Responses; Awareness; Axon; Biological Markers; Blood; Brain; Brain Concussion; Brain Diseases; Chronic; Clinical; Clinical Research; Corpus Callosum; Data; Development; Diffuse; Dose; Elderly; Exhibits; Exposure to; Eye; Functional Magnetic Resonance Imaging; Glial Fibrillary Acidic Protein; Goals; Guidelines; Head; Health; Ice Hockey; Image; Impairment; Light; Limbic System; Long-Term Effects; Longitudinal Studies; Manufactured football; Measures; Microglia; Molecular; Nerve Degeneration; Neurocognitive Deficit; Neurofilament-L; Neuroglia; Neurologic; Neurons; Ophthalmology; Participant; Pathologic; Performance; Physiological; Play; Positioning Attribute; Prefrontal Cortex; Prospective Studies; Proteomics; Protocols documentation; Public Health; Research; Research Personnel; Rest; Risk; Safety; Seasons; Sensory; Serum; Signs and Symptoms; Site; Soccer; Speed; Sports; Structure; Teenagers; Testing; Time; United States; Work; axon injury; biobehavior; brain cell; brain health; career; catalyst; concussive symptom; contact sports; evidence based guidelines; exosome; experience; gaze; glial activation; head impact; high school; innovation; kinematics; mechanical force; motor impairment; multimodality; neurodevelopment; neurofilament; neuroimaging; neuroinflammation; oculomotor; prevent; progressive neurodegeneration; relating to nervous system; response; sensor; subconcussion; synaptic pruning; tau Proteins; ubiquitin C-terminal hydrolase; white matter; white matter change

PROJECT SUMMARY/ABSTRACT Every year, nearly 2.5 million U.S. high school athletes participate in contact sports. Each of these athletes sustains an average of 650 subconcussive head impacts (SHI) in a single season, with some athletes exceeding 1,000 hits from, for example, football tackles and soccer headings. A subconcussive head impact is defined as an impact that does not trigger the clinically detectable signs and symptoms of concussion. However, these mechanical forces, if applied repeatedly, can trigger subclinical cellular and molecular disruptions in brain cells. Adolescence is an especially vulnerable time for neurodevelopment, because of (a) arborization of white matter tracts within the prefrontal cortex (PFC) and between the PFC and limbic structures and (b) synaptic pruning. Our clinical studies suggest that both acute and chronic exposure to SHI can impair neuro-ophthalmologic functions, increase the levels of brain-derived proteomic (NF-L, Tau, UCH-L1, GFAP, S100B) and exosome (7 neuron/glia-specific exosomes) biomarkers in blood, and trigger changes in the microstructural integrity of white matter. Despite these serious public health implications, no empirical basis exists for establishing a safety protocol or predicting who may develop cumulative pathologic sequelae from SHI, and to what extent, during a 4-year high school football career. The overall goal of this study is to determine the longitudinal effects of SHI on neural integrity and function in adolescents throughout their high school football careers and to identify the dose and intensity of SHI that induce chronic, progressive neurodegeneration. Our central hypothesis is that SHIs in adolescents will gradually degrade neuronal cellular and functional integrity across multiple football seasons in a head-impact-dependent manner. There are three related, hypothesis-driven aims. We hypothesize (1) that a panel of brain-derived proteomic (NF-L, Tau, UCH-L1, GFAP) and exosome markers will increase in blood in response to SHI; (2) that chronic exposure to SHI will disrupt neuro-ophthalmologic function, as reflected in increased variability in smooth eye pursuit and slower King-Devick performance; and (3) that repetitive SHI will lead to disruption in white matter microstructure and changes in resting-state fMRI connectivity. We further hypothesize that with repetitive SHI these changes may not return to baseline and may carry over and accumulate from one season to the next. By tracking SHI exposure and neurologic health in the same athletes for 4 years, the proposed study will help to establish safety guidelines for adolescent athletes. The long-term goal is to prevent neurocognitive deficits in competitive sports athletes.

项目概要/摘要 每年，近 250 万美国高中运动员参加接触性运动。这些运动员中的每一位 在一个赛季中平均承受 650 次头部震荡 (SHI)，其中一些运动员超过 例如，来自足球铲球和足球头球的 1,000 次命中。次脑震荡头部撞击定义为 不会引发临床上可检测到的脑震荡体征和症状的撞击。然而，这些 如果重复施加机械力，可能会引发脑细胞的亚临床细胞和分子破坏。 青春期是神经发育特别脆弱的时期，因为 (a) 白质树状化 前额皮质 (PFC) 内以及 PFC 和边缘结构之间的纤维束；(b) 突触修剪。 我们的临床研究表明，急性和慢性接触 SHI 都会损害神经眼科 功能，增加脑源性蛋白质组（NF-L、Tau、UCH-L1、GFAP、S100B）和外泌体（7 神经元/胶质细胞特异性外泌体）血液中的生物标志物，并引发白细胞微观结构完整性的变化 事情。尽管存在这些严重的公共卫生影响，但不存在建立安全性的经验基础 方案或预测谁可能因 SHI 而产生累积性病理后遗症，以及在治疗期间达到什么程度 4年高中橄榄球生涯。本研究的总体目标是确定 SHI 的纵向效应 研究青少年在整个高中足球生涯中的神经完整性和功能，并确定 诱导慢性进行性神经变性的 SHI 剂量和强度。我们的中心假设是 青少年的 SHI 将逐渐降低多个足球场的神经元细胞和功能完整性 以头部影响依赖的方式季节。存在三个相关的、假设驱动的目标。我们假设 (1) 一组脑源性蛋白质组（NF-L、Tau、UCH-L1、GFAP）和外泌体标记物将在 SHI 反应的血液； (2) 长期暴露于 SHI 会破坏神经眼科功能，如所反映的 平滑眼球追踪的变异性增加，King-Devick 表现变慢； (3) 重复的 SHI 将导致白质微观结构的破坏和静息态功能磁共振成像连接的变化。我们进一步 假设通过重复的 SHI，这些变化可能不会返回到基线，并且可能会延续并 从一个季节积累到下一个季节。通过追踪同一运动员的 SHI 暴露和神经系统健康状况 为期4年的拟议研究将有助于为青少年运动员制定安全指南。长期来看 目标是预防竞技体育运动员的神经认知缺陷。