Subconcussive neurodegenerative progression in adolescent athletes

项目摘要/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个 在一个赛季中平均遭受650次头部亚震荡撞击(SHI)，有些运动员超过 例如，来自足球铲球和足球标题的1000个点击量。亚震荡头部撞击的定义为 这种冲击不会引发临床上可检测到的脑震荡迹象和症状。然而，这些 如果反复施加机械力，可能会引发脑细胞的亚临床细胞和分子破坏。 青春期是神经发育的一个特别脆弱的时期，因为(A)白质的树枝状分布 前额叶皮质(PFC)内以及PFC和边缘结构之间的束和(B)突触修剪。 我们的临床研究表明，无论是急性还是慢性暴露于石灰都会损害神经眼科。 功能，增加脑源性蛋白质组(核因子-L、牛磺酸、UCH-L1、胶质纤维酸性蛋白、S100B)和外体(7 神经元/神经胶质细胞特异性外切体)，并引发白血球微结构完整性的改变。 物质。尽管存在这些严重的公共健康影响，但尚不存在建立安全性的经验基础 方案或预测谁可能发展为SHI的累积病理后遗症，以及在多大程度上，在一个 4年的高中足球生涯。这项研究的总体目标是确定SHI的纵向效应 关于青少年在高中足球生涯中的神经完整性和功能，并确定 SHI的剂量和强度会导致慢性进行性神经变性。我们的中心假设是 青少年的SHIS会在多个足球比赛中逐渐降低神经细胞和功能的完整性 以头部撞击依赖的方式进行季节转换。有三个相互关联的、受假设驱动的目标。我们假设 (1)一组脑源性蛋白质组(核因子-L、牛磺酸、UCH-L1、胶质纤维酸性蛋白)和外体标志物将在 血应史氏；(2)慢性接触史氏会扰乱神经眼科功能，如所反映。 在流畅的眼球追逐和较慢的King-Devick表现上的变异性增加；以及(3)重复的Ship 将导致脑白质微观结构的破坏和静息状态功能磁共振连通性的改变。我们进一步 假设对于重复的史，这些变化可能不会回到基线，而可能会延续和 从一个季节到下一个季节积累。通过跟踪同一运动员的石英年暴露和神经健康 在4年内，这项拟议的研究将有助于为青少年运动员建立安全指南。长期的 目标是预防竞技体育运动员的神经认知缺陷。

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.