Axonal Pathology and TBI-Related Neurodegeneration (TReND)

轴突病理学和TBI相关神经变性（TReND） 在过去的十年里，人们对创伤性脑损伤（TBI）与脑损伤之间的联系产生了极大的兴趣。 晚期神经退行性病变的发展，特别是慢性创伤性脑病 神经病理学改变（CTE-NC）及其与不良认知结果风险增加的相关性， 包括阿尔茨海默病和阿尔茨海默病相关痴呆（AD/ADRD）。但 对CTE-NC中神经元缠结的强烈关注是以牺牲对更广泛的神经元缠结的研究为代价的。 所有形式的TBI后发现的病理学谱。因此，为了更好地反映复杂的神经病理 TBI后出现，包括AD/ADRD的许多常见病理，我们采用了 概念框架，“TBI相关的神经变性”（TReND），其中CTE-NC只是一种形式。我们 我建议在有单一中度或重度（sTBI）或重复性TBI病史的患者中检查TReND的演变。 轻度TBI（rTBI），我们将直接与“正常”衰老和更广泛的病理学进行比较。 神经退行性疾病，包括AD/ADRD。此外，我们建议在以下背景下审查这些变化： 弥漫性轴索损伤（DAI），在所有严重程度的TBI中发现的最常见的病理之一，其中 我们假设一些轴突可能经历修复，而另一些轴突则被驱使退化。值得注意的是， 通过这项拨款，我们已经证明，轴突变性持续数十年后，TBI导致 淀粉样β肽的持续释放和tau蛋白的磷酸化。我们假设这种阴燃 TBI后晚期轴突变性是TReND病理学的驱动因素和底物库 以及相关的AD/ADRD结局。我们还发现，TBI诱导的tau星形胶质细胞病变与 与衰老相关的tau星形胶质细胞病（ARTAG）有关，但其模式和分布与 衰老和AD/ADRD，可能需要重新评估目前对CTE-NC中tau病理学的理解。最后， 初步数据表明，女性TBI患者的DAI比男性更广泛，这表明性别- 基于轴突病理学演变的差异。重要的是要注意，对于此提案，我们将利用 独特和无与伦比的临床数据集和组织档案的CONNECT-TBI，一个NIH U 54支持的中心 没有墙，这是从目前的赠款周期出现。具体而言，我们建议：1）记录 以及在所有严重程度和TBI存活后轴突变性和修复的分布; 2） 表征轴突病理的程度、分布和进展及其与TReND的关联; 3） 记录复杂的星形胶质细胞和小胶质细胞神经炎症反应的时间进程和分布 TBI后，以及它们与正在进行的轴突变性、白色物质萎缩和 TReND和AD/ADRD;以及4）鉴定轴突形态和分布的性别相关差异， TBI后轴突和相关TReND病理学的进展。

Axonal Pathology and TBI-Related Neurodegeneration (TReND) Over the last decade there has been an explosion of interest in the link between traumatic brain injury (TBI) and the development of late neurodegenerative pathologies, particularly chronic traumatic encephalopathy neuropathologic change (CTE-NC) and their association with increased risk of adverse cognitive outcomes, including Alzheimer’s disease and Alzhemier’s disease related dementias (AD/ADRD). However, the intense focus on neurofibrillary tangles in CTE-NC has come at the expense of investigation of the broader spectrum of pathologies found after all forms of TBI. Accordingly, to better reflect the complex neuropathology emerging after TBI, which includes many of the common pathologies of AD/ADRD, we have adopted the conceptual framework, “TBI-related neurodegeneration” (TReND), of which CTE-NC is just one form. We propose to examine the evolution of TReND in those with history of single moderate or severe (sTBI) or repetitive mild TBI (rTBI), which we will directly compare to the pathologies of both ‘normal’ aging and wider neurodegenerative disease, including AD/ADRD. Further, we propose to examine these changes in context of diffuse axonal injury (DAI), one of the most common pathologies found across all severities of TBI, in which we hypothesize that some axons may undergo repair, while others are driven towards degeneration. Notably, through this grant award, we have demonstrated that axon degeneration persists for decades after TBI leading to ongoing release of amyloid-beta peptides and phosphorylation of tau. We hypothesize that this smoldering axonal degeneration late after TBI presents both a driver of and a substrate pool for TReND pathology and associated AD/ADRD outcomes. We have also found that TBI induces a tau astrogliopathy with similarity to aging-related tau astrogliopathy (ARTAG) but with a pattern and distribution that is distinct from that seen in aging and AD/ADRD and may demand reappraisal of current understanding of tau pathology in CTE-NC. Finally, preliminary data indicate that females with TBI have more extensive DAI than males, suggesting there are sex- based differences in evolution of axonal pathology. It is important to note that for this proposal we will leverage the unique and unrivalled clinical datasets and tissue archives of CONNECT-TBI, an NIH U54-supported Center Without Walls, which emerged from the current grant cycle. Specifically, we propose to: 1) Document the extent and distribution of axonal degeneration and repair following all severities of and survivals from TBI; 2) Characterize the extent, distribution and progression of axonal pathology and its association with TReND; 3) Document the time course and distribution of the complex astroglial and microglial neuroinflammatory responses following TBI and their relation to ongoing axonal degeneration, white matter atrophy and the pathologies of TReND and AD/ADRD; and 4) Identify sex-associated differences in axonal morphology and the distribution and progression of axonal and related TReND pathologies following TBI.