Axonal Pathology and TBI-Related Neurodegeneration (TReND)

轴突病理学与颅脑损伤相关神经退行性变(趋势) 在过去的十年里，人们对创伤性脑损伤(TBI)和脑损伤之间的联系的兴趣激增。 晚期神经退行性病变的发展，特别是慢性创伤性脑病 神经病理改变(CTE-NC)及其与认知不良结局风险增加的关系 包括阿尔茨海默病和阿尔兹迈尔氏病相关痴呆(AD/ADRD)。然而， 在CTE-NC中，对神经原纤维缠结的强烈关注是以牺牲更广泛的调查为代价的 各种形式的颅脑损伤后发现的病理图谱。因此，为了更好地反映复杂的神经病理 在包括AD/ADRD的许多常见病理的创伤性脑损伤后出现，我们采用了 概念框架“脑损伤相关神经变性”(Trend)，CTE-NC只是其中的一种形式。我们 建议研究有单一、中度或重度(STBI)或重复病史的人的趋势演变 轻度脑外伤(RTBI)，我们将直接将其与正常衰老和更广泛的衰老的病理进行比较 神经退行性疾病，包括AD/ADRD。此外，我们建议在以下情况下研究这些变化 弥漫性轴索损伤(DAI)是各种程度的颅脑损伤中最常见的病理之一，其中 我们假设一些轴突可能会经历修复，而另一些轴突则被驱使走向退化。值得注意的是， 通过这项授予，我们证明了轴突变性在脑外伤后持续了几十年。 与淀粉样β蛋白多肽的持续释放和tau的磷酸化有关。我们假设这场阴燃 颅脑损伤后晚期轴突变性既是趋势病理的驱动因素，也是底物池 以及相关的AD/ADRD结果。我们还发现，脑外伤可引起类似的tau星形胶质细胞病变。 与衰老相关的tau星形胶质病(ARTAG)，但其模式和分布与 衰老和AD/ADRD，可能需要重新评估CTE-NC中目前对tau病理的理解。最后， 初步数据显示，患有颅脑损伤的女性比男性有更广泛的DAI，这表明有性行为- 基于轴突病理演变的差异。值得注意的是，对于这项建议，我们将利用 NIH U54支持的中心CONNECT-TBI独特且无与伦比的临床数据集和组织档案 没有围墙，这是在当前的赠款周期中出现的。具体地说，我们建议：1)记录程度 以及各种程度的颅脑损伤和存活后轴突变性和修复的分布；2) 描述轴突病变的范围、分布、进展及其与趋势的关系；3) 记录复杂的星形胶质和小胶质神经炎性反应的时间进程和分布 颅脑损伤后与正在进行的轴突变性、白质萎缩和脑损伤病理的关系 趋势和AD/ADRD；以及4)确定轴突形态和分布的性别差异和 颅脑损伤后轴突的进展及相关趋势病理学。

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.