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

重复性头部撞击(RHI)是一种轻微的创伤性脑损伤，可导致严重的认知和 慢性创伤性脑病(CTE)的行为症状与进行性神经变性 创伤也是阿尔茨海默病(AD)的已知危险因素，我们假设长期的 RHI在AD和CTE的发生发展中可能起到致病作用。此外，脑血管疾病 一个众所周知的认知障碍的贡献者；然而，血管变化在糖尿病发展中的作用 CTE和AD的病理还不是很清楚。脑血管的完整性对于正常的新陈代谢和 大脑的灌流。大脑大动脉的顺应性使这些动脉能够抑制脉搏 并保护微循环和血脑屏障免受损害。因此，脑血管 功能障碍可能会对大脑产生有害影响，包括增加对脉压的敏感性， 血脑屏障的破坏和tau病理、β-淀粉样蛋白和其他毒性物质的无效清除 代谢物。该项目的总体目标是确定RHI是否与 脑血管重塑与CTE的进展及与脑血管病变作用的比较 公元后的重塑。 基于我们在血管机械生物学、精密质谱学、 CTE和AD的先进光学成像、免疫组织化学、血管生物学和神经病理学 我将从三个方面检验这一假说：目的1)确定脑血管重塑(生物力学， CTE患者额叶的结构和成分变化)；目的2)确定 脑血管重塑与CTE和AD的病理改变；目的3)研究两者之间的关系 脑血管重塑与RHI病史及生前认知状态的关系。我们将使用no或low 来自NIH和NIH的80名年龄和性别匹配的脑捐赠者的动脉粥样硬化性脑血管和脑组织 弗吉尼亚大学资助的BU阿尔茨海默病和CTE研究中心，1)无RHI病史和病理，2)RHI 无CTE病史，3)低CTE病理，4)高CTE病理。这些脑捐赠者经历了 医学审查和告密者使用修改后的 来自国家阿尔茨海默氏症协调中心(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 和视觉空间功能)。 这项提议旨在利用现有资源进行新的发现。匹配的和平行的 对脑血管和脑组织的研究将对脑梗塞的时间发育提供新的理解。 CTE中的脑血管重构。了解血管重塑在CTE中的作用可能导致 发现新的治疗选择和干预方向以延缓我们的认知障碍 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.