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

摘要/项目总结 一些临床前和临床研究表明，加速/减速力对大脑 超过一定阈值可导致轴突微管和血管 内皮细胞这种损伤的后果包括弥漫性轴索损伤和短暂性出血 急性期的血流障碍和毒性蛋白质种类的积累， 随着时间的推移，tau蛋白磷酸化，这是血管性认知障碍发展的关键因素 和痴呆症。此外，认为丘脑中AD相关的tau细胞骨架病理学 最有可能导致神经精神症状，注意力缺陷，睡眠 障碍、眼功能障碍和疼痛感知改变。一个大脑范围的“胶质淋巴系统”， 由血管旁通路和脑膜淋巴管组成的动脉搏动驱动， 现在被认为是从大脑中清除这些蛋白质的主要途径。这条路紧紧地 时间上与睡眠相关，最近显示受到TBI的影响。丘脑扮演着一个很好的角色- 在睡眠调节中的作用因此，我们认为存在一种可能的“恶性循环”， TBI破坏的通路不能清除丘脑中的有毒蛋白，影响其结构 和功能，导致睡眠失调，从而损害胶质淋巴流出。作为补充 父母补助金的重点是审查结构和 TBI后丘脑的功能连接，我们希望使用先进的MRI技术， TBI的症状是否源于丘脑损伤和受损的胶质淋巴细胞之间的相互作用， 流出我们假设创伤性脑损伤后的血管损伤不仅包括内皮损伤 而且还扩展到胶质淋巴破坏和脑膜淋巴损伤，并且这种破坏将 不同地影响丘脑结构和功能连接。利用先进的成像技术， 我们建议使用以下两个目标来解决这个问题：（1）我们希望使用MRI在体内检查， 跨越血管周围的人类胶质淋巴系统的结构和功能的差异 轻度TBI患者与年龄和性别匹配的对照组之间的脑膜炎间隙 受试者在损伤的早期（约6个月）和晚期（初始损伤后约5年）。在目标2中， 评估胶质淋巴功能障碍对整体丘脑和个体丘脑核的影响 结构和丘脑皮质结构和功能连接，以及 神经心理学评估这项研究的结果将提供一个统一的框架， 了解机制，不仅导致TBI相关的痴呆症，血管认知 以及由毒性蛋白质积累引起疾病 例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.