Subconcussive neurodegenerative progression in adolescent athletes

项目总结/摘要 每年有近250万美国高中运动员参加接触性运动。这些运动员 在一个赛季中平均承受650次亚震荡头部撞击（SHI），有些运动员超过 1,000次命中，例如，足球铲球和足球头球。亚震荡性头部撞击的定义是 撞击不会引发临床上可检测到的脑震荡体征和症状。但这些 如果反复施加机械力，则可触发脑细胞中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）白色物质的树枝状化 前额叶皮层（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，急性和慢性暴露于SHI可损害神经眼科学， 功能，增加脑源性蛋白质组（NF-L，Tau，UCH-L1，GFAP，S100 B）和外泌体的水平（7 神经元/胶质细胞特异性外泌体）生物标志物，并触发白色 所谓了尽管存在这些严重的公共卫生影响，但没有建立安全性的经验基础。 协议或预测谁可能发展累积病理后遗症SHI，以及在何种程度上，在一个 4-高中足球生涯本研究的总体目标是确定SHI的纵向效应 对青少年在高中足球生涯中的神经完整性和功能的影响，并确定 剂量和强度的SHI诱导慢性进行性神经变性。我们的核心假设是， 青少年的SHI将逐渐降低神经元细胞和功能的完整性， 季节以头部撞击依赖的方式。有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 （2）慢性暴露于SHI会破坏神经眼科功能，如反映的那样， 在平滑的眼睛追踪和较慢的King-Devick性能中增加的可变性;和（3）重复的SHI 将导致白色物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 假设在重复SHI的情况下，这些变化可能不会恢复到基线， 从一个季节到下一个季节。通过跟踪同一运动员的SHI暴露和神经健康， 这项为期四年的研究将有助于为青少年运动员制定安全指南。长期 目的是防止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.