Longitudinal Sub-thalamic Structure and Functional Alterations in Mild Traumatic Brain Injury

摘要/项目摘要 一些临床前和临床研究表明，加速/减速作用于大脑 超过一定的阈值会导致轴突微管和血管的破坏 内皮细胞。这种损伤的后果包括弥漫性轴索损伤和一过性血液。 急性期的血流障碍和有毒蛋白质的积累，如 随着时间的推移，磷酸化tau是血管认知障碍发展的关键因素 和痴呆症。此外，人们认为阿尔茨海默病相关的tau细胞骨架病理位于丘脑。 最有可能导致神经精神症状、注意力缺陷、睡眠 精神障碍、眼球运动功能障碍和痛觉改变。一个全脑的“淋巴系统”， 由动脉搏动性驱动，由血管旁通路和脑膜淋巴通道组成 现在被认为是这些蛋白质从大脑中清除的主要途径。这条小路，紧紧地 在时间上与睡眠相关，最近显示受到脑外伤的影响。丘脑起着很好的作用- 已知在睡眠调节中的作用。因此，我们假设存在一种可能的“恶性循环”，在这种恶性循环中， 受脑外伤干扰的通路无法清除丘脑中的有毒蛋白质，从而影响其结构 和功能，导致睡眠失调，从而损害淋巴外流。作为补充 到母基金，该基金专注于研究结构和结构的纵向变化 对于脑外伤后丘脑的功能连接，我们希望利用先进的磁共振技术来检查， 脑损伤的症状是否源于丘脑损伤和淋巴功能受损的相互作用 外流。我们假设，脑外伤后的血管损伤不仅包括内皮损伤 但也延伸到淋巴中断和脑膜淋巴损伤，这种中断将 不同地影响丘脑结构和功能的连通性。使用先进的成像技术， 我们建议通过以下两个目标来解决这个问题：(1)我们希望使用MRI在体内进行检查， 跨越血管周围的人类淋巴系统的结构和功能的差异 轻度颅脑损伤患者与年龄和性别匹配的对照组之间脑膜淋巴管的间隙 受试者在损伤早期(~6个月)和晚期(初始损伤后~5年)。在《目标2》中我们将 评估淋巴功能障碍对整体丘脑和单个丘脑核团的影响 结构和丘脑皮质结构和功能的连通性以及在 神经心理评估。这项研究的结果将提供一个统一的框架，以 了解不仅导致脑外伤相关痴呆、血管认知障碍的机制 损伤和阿尔茨海默病，但也包括有毒蛋白质积累引起的损伤和阿尔茨海默病 如额颞叶痴呆症和路易体病等。

ABSTRACT/PROJECT SUMMARY Several preclinical & clinical studies have implicated that acceleration/deceleration forces to the brain beyond a certain threshold can lead to disruption of both axonal microtubules and vascular endothelium. The consequences of such injury include diffuse axonal injury and transitory blood flow impairment at the acute stage and the accumulation of toxic protein species such as phosphorylated tau over time, a key factor in the development of vascular cognitive impairment and dementia. In addition, it is thought that the AD-related tau cytoskeletal pathology in the thalamus most likely contributes substantially to the neuropsychiatric symptoms, attention deficits, sleep disturbances, oculomotor dysfunctions and altered pain perception. A brain wide “glymphatic system”, driven by arterial pulsatility, comprised of paravascular pathways and meningeal lymphatic channels is now recognized as a major pathway of clearance of these proteins from the brain. This pathway, tightly temporally correlated to sleep, has recently shown to be affected by TBI. The thalamus plays a well- known role in sleep regulation. We therefore posit that a likely “vicious cycle” exists wherein glymphatic pathways disrupted by TBI fail to clear toxic protein species from the thalamus, affecting its structure and function, resulting in sleep dysregulation and thereby, impaired glymphatic efflux. As a supplement to the parent grant which is focused on examining the longitudinal changes in the structural and functional connectivity of the thalamus after TBI, we wish to examine, using advanced MRI techniques, whether symptoms of TBI arise from an interplay between thalamic injury and impaired glymphatic efflux. We hypothesize that vascular impairments following TBI include not only endothelial damage but also extend to glymphatic disruption and meningeal lymphatic injury and that such disruption will differentially affect thalamic structural and functional connectivity. Using advanced imaging techniques, we propose to address this using the following two aims: (1) we wish to examine in vivo, using MRI, differences in the structure and function of the human glymphatic system spanning the perivascular space to the meningeal lymphatics between patients with mild TBI and age and gender matched control subjects both at the early (~6mo) and late stages of injury (~5y after initial injury). In Aim 2 we will assess the influence of glymphatic dysfunction upon global thalamic and individual thalamic nuclear structure and thalamocortical structural and functional connectivity and upon performance on neuropsychological assessments. The results from this study will provide a unified framework to understand mechanisms that lead to not only TBI related dementia, vascular cognitive impairment and Alzheimer’s disease but also those that arise from toxic protein accumulation such as Frontotemporal dementia and Lewy Body Disease among others.