The effects of cumulative concussion, repetitive head impacts, and comorbid cardiovascular risk factors on MRI metrics of pathological aging and neurobehavioral functioning across the lifespan

项目概要/摘要（1页） 在参与体育运动期间暴露于轻度创伤性脑损伤（mTBI）和重复性头部撞击（RHI）， 与不良的长期后果有关（例如，认知能力下降）。研究这些 相关性仅限于在生命周期的单个点进行横断面研究，而不考虑 影响这些关联的因素。更大的mTBI/RHI病史与脑血流量相关 (CBF)和白色物质（WM）异常，甚至在年轻运动员中。CBF和WM异常是两种 一般人口的病理老化和纵向衰退指标。年龄与心血管风险 整个生命周期中的各种因素都会影响这些异常。该提案的科学目标是 确定mTBI/RHI对病理性衰老和神经行为功能的MRI指标的影响， 寿命我们的中心假设是mTBI/RHI将与神经行为功能相关， CBF/WM异常，并且这种关联的强度独立地受年龄增加的影响 以及心血管危险因素的存在。这个项目的基本原理是， mTBI/RHI对病理性衰老和神经行为功能的MRI指标的影响，以及 影响这种关系的因素，将提供深入了解累积性脑损伤的过程 和神经功能衰退。我们的假设将通过两个具体目标和一个探索性目标进行测试： 1)确定mTBI/RHI与整个生命周期的神经行为功能之间的关联， 共病心血管危险因素的影响; 2）确定mTBI/RHI和MRI之间的相关性 整个生命周期的病理性衰老指标和共病心血管风险因素的影响; 探索性）检查病理性老化的MRI指标是否介导累积老化与 mTBI/RHI和整个生命周期的神经行为功能。建立一个独立的研究项目 确定了mTBI/RHI可导致长期神经系统疾病负担的机制， 本建议书的培训目标是接受以下方面的专家培训/指导：a）分析和解释 神经影像学数据，B）衰老和心血管危险因素对长期大脑健康的累积影响 和功能，以及c）神经病理学的分子机制和进展， mTBI/RHI。我们将采用一种创新的寿命方法，利用来自四个大规模， 对运动员几十年来的前瞻性多中心研究。几位导师的协调- 运动员的定向的、大规模的多地点数据集将允许混合的前瞻性、横截面设计。我们 将利用先进的分析方法来研究衰老和共病的潜在影响， 心血管危险因素对mTBI/RHI与病理性衰老的MRI指标之间的相关性， 长期的神经行为变化。这项工作的重要性在于，它将为确定那些在 降低风险，改善长期结果的风险估计，并为干预的治疗目标提供信息。

Project Summary/Abstract (1 page) Exposure to mild traumatic brain injury (mTBI) and repetitive head impacts (RHI) during sport participation has been associated with adverse long-term consequences (e.g., cognitive decline). Research investigating these associations has been limited to cross-sectional studies at single points of the lifespan without consideration of factors that can influence these associations. Greater mTBI/RHI history is associated with cerebral blood flow (CBF) and white matter (WM) abnormalities, even within younger athletes. CBF and WM abnormalities are two indicators of pathological aging and longitudinal decline in the general population. Age and cardiovascular risk factors across the lifespan can influence these abnormalities. The scientific objective of this proposal is to determine the influence of mTBI/RHI on MRI metrics of pathological aging and neurobehavioral function across the lifespan. Our central hypothesis is that mTBI/RHI will be associated with neurobehavioral function and CBF/WM abnormalities, and that the strength of this association is independently influenced by increasing age and the presence of cardiovascular risk factors. The rationale for this project is that determining the influence of mTBI/RHI on MRI metrics of pathological aging and neurobehavioral function across the lifespan, as well as factors that influence this relationship, will provide insight into the process underlying cumulative head injury and neurological decline later in life. Our hypothesis will be tested with two specific and one exploratory aims: 1) Determine the associations between mTBI/RHI and neurobehavioral function across the lifespan and the influence of comorbid cardiovascular risk factors; 2) Determine the associations between mTBI/RHI and MRI metrics of pathological aging across the lifespan and the influence of comorbid cardiovascular risk factors; Exploratory) Examine if MRI metrics of pathological aging mediate the association between cumulative mTBI/RHI and neurobehavioral function across the lifespan. To establish an independent research program that identifies the mechanisms by which mTBI/RHI can result in long-term neurological disease burden, the training objective of this proposal is to receive expert training/mentorship in a) the analysis and interpretation of neuroimaging data, b) the cumulative effects of aging and cardiovascular risk factors on long-term brain health and function, and c) the molecular mechanisms and progression of neuropathology as a consequence of mTBI/RHI. We will employ an innovative lifespan approach by leveraging data from four large-scale, prospective, multi-center studies of athletes across several decades of life. Harmonization of several mentor- directed, large-scale multisite datasets of athletes will allow a hybrid prospective, cross-sectional design. We will utilize advanced analytical approaches to examine the potential influence of aging and comorbid cardiovascular risk factors on the associations between mTBI/RHI with MRI metrics of pathological aging and long-term neurobehavioral changes. This work is significant in that it will inform methods for identifying those at risk for decline, improve risk estimates of long-term outcomes, and inform therapeutic targets for intervention.