The neuropathology of mild traumatic brain injury in Alzheimer's disease

重复性头部撞击（RHI）是一种轻度创伤性脑损伤，可导致严重的认知和 行为症状和慢性创伤性脑病（CTE）的进行性神经退行性变。 创伤也是阿尔茨海默病（AD）的一个已知危险因素，我们假设长期创伤 RHI在AD和CTE的发生发展中起着重要作用。此外，脑血管疾病是 一个众所周知的贡献者认知障碍;然而，血管变化的作用，在发展中的 CTE和AD病理学尚未得到很好的理解。脑血管的完整性对于正常的新陈代谢和 大脑的灌注。大的脑动脉的顺应性允许这些动脉抑制搏动， 保护微循环和血脑屏障免受损害。因此， 功能障碍可能对大脑产生有害影响，包括增加对脉压的敏感性， 血脑屏障破坏和tau病理学、β-淀粉样蛋白和其他有毒物质的无效清除 代谢物。本项目的总体目标是确定RHI是否与 脑血管重塑和CTE的进展，并比较脑血管重塑的作用。 AD中的重塑 基于我们在血管机械生物学，精密质谱， 先进的光学成像，免疫组织化学，血管生物学和神经病理学的CTE和AD，我们 将在三个目标中检验该假设：目标1）确定脑血管重塑（生物力学， 结构和成分变化）;目的2）确定CTE中额叶 脑血管重塑与CTE和AD病理改变的关系;目的3）研究CTE和AD病理改变与脑血管重塑的关系。 脑血管重塑与RHI病史和死前认知状态之间的关系。我们将使用no或low 来自NIH的80名年龄和性别匹配的脑捐赠者的动脉粥样硬化脑血管和脑组织， VA资助的BU阿尔茨海默病和CTE研究中心，1）无RHI病史且无病理学，2）RHI 无CTE病史，3）低CTE病理，和4）高CTE病理。这些大脑捐赠者经历了 医疗审查和知情人进行了广泛的结构化访谈/问卷调查，使用修改后的 来自国家阿尔茨海默病协调中心（NACC）统一数据集（UDS）的问题，包括 认知功能（包括记忆、语言、注意力、执行功能）的死后评估 视觉空间功能）。 该提案旨在利用现有资源进行新的发现。匹配和平行 脑血管和脑组织的研究将提供新的理解的时间发展， 脑血管重塑。了解血管重塑在CTE中的作用可能会导致 发现新的治疗选择和干预方向，以避免我们的认知障碍， 退伍军人。

Repetitive head impacts (RHI) are a form of mild traumatic brain injury that can lead to severe cognitive and behavioral symptoms and the progressive neurodegeneration of chronic traumatic encephalopathy (CTE). Trauma is also a known risk factor for Alzheimer disease (AD), and we hypothesize that a prolonged period of RHI can play a causative role in the development of AD as well as CTE. In addition, cerebrovascular disease is a well-known contributor to cognitive impairment; however, the role of vascular changes in the development of CTE and AD pathology are not well understood. Cerebrovascular integrity is critical for proper metabolism and perfusion of the brain. Compliance of large cerebral arteries allows these arteries to dampen the pulsatile pressure and protect the microcirculation and blood brain barrier from damage. Thus, cerebrovascular dysfunction can have detrimental impacts on the brain, including increased susceptibility to pulse pressure, blood brain barrier breakdown and ineffective clearance of tau pathology, beta-amyloid, and other toxic metabolites. The overall goal of this project is to determine whether RHI is associated with cerebrovascular remodeling and the progression of CTE and compare to the role of cerebrovascular remodeling in AD. Building upon our multidisciplinary expertise in vascular mechanobiology, precision mass spectrometry, advanced optical imaging, immunohistochemistry, vascular biology and neuropathology of CTE and AD, we will test this hypothesis in three aims: Aim 1) to determine cerebrovascular remodeling (biomechanical, structural, and compositional changes) in the frontal lobe in CTE; Aim 2) to determine the association between cerebrovascular remodeling and CTE and AD pathological changes; and Aim 3) to examine the association between cerebrovascular remodeling and RHI history and antemortem cognitive status. We will use no or low atherosclerotic cerebrovascular and brain tissue from 80 age- and sex-matched brain donors from the NIH and VA-funded BU Alzheimer Disease & CTE Research Center with 1) no RHI history and no pathology, 2) RHI history with no CTE, 3) low CTE pathology, and 4) high CTE pathology. These brain donors have undergone medical review and informants are given extensive structured interview/questionnaires using modified questions from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS), including postmortem assessments of cognitive functioning (including memory, language, attention, executive function and visuospatial function). This proposal is designed to leverage existing resources to make new discoveries. The matched and parallel studies of cerebral vessels and brain tissue will provide new understandings of the temporal development of cerebrovascular remodeling in CTE. Understanding the role of vascular remodeling in CTE may lead to the discovery of new treatment options and directions for interventions to stave off cognitive impairment in our military Veterans.