The neuropathology of mild traumatic brain injury in Alzheimer disease

反复头部撞击(RHI)会导致严重的认知和行为症状，并 慢性创伤性脑病(CTE)的神经变性。创伤也是一个已知的风险因素 阿尔茨海默病(AD)，我们假设长期的RHI可能在 AD和CTE的发展。目前，还没有针对CTE或AD的疾病修正治疗，并且 只有在尸检时才能做出CTE的诊断。此外，对遗传和分子方面的知识知之甚少 在RHI暴露设置中CTE或AD的变化。这在很大程度上是因为没有 到目前为止，系统地收集了几个CTE病例。我们的翻译方法是 系统地解决世界上最大的神经病理证实的尸检队列中的神经变性问题 CTE和CTE与AD(CTE-AD)受试者在DNA、RNA和蛋白质水平上的比较，目的是识别 可作为药物发现靶点的新的遗传风险因素、生物标记物和机制。我们有 结果表明，在CTE受试者中，β淀粉样蛋白的沉积加速，与机械性脑损伤相关 压力最大，并且受载脂蛋白E等位基因状态的影响。此外，基因组变异可以发挥一种 在疾病进展中的重要作用，基于载脂蛋白E等位基因ε4状态的分层发现了其他 根据潜在的遗传学，风险等位基因和预测改变的病理。我们的初步数据显示， TMEM106B基因变异与CTE的小胶质细胞激活、tau病理和临床症状相关 APOEε4阴性受试者。TMEM106B基因变异与FTLD-TDP和TO的发生有关 原颗粒蛋白(PRGN)水平与炎症通路的调节。许多其他基因与阿尔茨海默病有关 遗传风险也与大脑的炎症反应/免疫系统有关。我们已经证明了 小胶质细胞激活是CTE的早期改变，并已证明改变了神经炎性 在CTE和AD中，细胞因子与tau病理的发展不同。我们的假设是， 根据我们的初步数据，APOE和TMEM106B的变体富含CTE和CTE-AD 受试者与细胞因子改变和β-淀粉样蛋白、tau和 疾病的发展。我们进一步假设，已知AD基因的基因组变异将预测风险或 RHI暴露后CTE和CTE-AD进展以及β-淀粉样蛋白、tau和 神经炎性细胞因子可作为创伤后神经退行性变的生物标志物。我们的长期合作 目的是揭示阿尔茨海默病发生的遗传和分子机制 多处轻微创伤性脑损伤。这项研究项目的直接目标是发现 基因组变异和神经炎性标志物可作为识别这些个体的生物标志物 在创伤背景下发展为AD的风险。这项研究对于理解创伤是如何 引起或加速阿尔茨海默病，开发评估接触体育运动和服兵役风险的方法，以及 告知合理的药物设计。在这里，我们建议采用跨学科的方法，将专业知识和 神经病理学、遗传学和数据分析方面的新技术，以发现新的风险致病途径 评估、生物标记物开发和治疗学。

Repetitive head impacts (RHI) 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. Currently, there are no disease modifying treatments for CTE or AD, and diagnosis of CTE can only be made at autopsy. Furthermore, little is known about the genetic and molecular changes in CTE or in AD in the setting of RHI exposure. This is largely because there has not been a systematic collection of more than a handful of cases of CTE, until now. Our translational approach is to systematically address neurodegeneration in the world's largest neuropathologically-confirmed autopsy cohort of CTE and CTE with AD (CTE-AD) subjects on the DNA, RNA, and protein levels, with the goal of identifying novel genetic risk factors, biomarkers, and mechanisms that can be targeted for drug discovery. We have shown that in CTE subjects beta-amyloid deposition is accelerated, related to areas where mechanical stresses are greatest, and influenced by APOE allele status. Furthermore, genomic variation can play an important role in disease progression, and stratification based on APOE allele ε4 status uncovers additional risk alleles and predicts altered pathologies based on the underlying genetics. Our preliminary data shows that variation in TMEM106B is associated with microglia activation, tau pathology, and clinical symptoms in CTE in APOE ε4-negative subjects. Variation in TMEM106B is related to the development of FTLD-TDP and to progranulin (PRGN) levels and modulation of inflammatory pathways. Many other genes implicated in AD genetic risk are also involved in the brain's inflammatory response/immune system. We have shown that microglial activation is an early change in CTE and have demonstrated that altered neuroinflammatory cytokines are related to the development of tau pathologies disparately in CTE versus AD. Our hypothesis, based on our preliminary data, is that variants of APOE and TMEM106B are enriched in CTE and CTE-AD subjects and are associated with altered cytokines and increased levels of beta-amyloid and tau and progression of disease. We further hypothesize that genomic variation in known AD genes will predict risk or progression of CTE and CTE-AD following RHI exposure and that levels of beta-amyloid, tau, and neuroinflammatory cytokines may serve as biomarkers for trauma-induced neurodegenerations. Our long-term goal is to uncover genetic and molecular mechanisms underlying the development of AD in the setting of multiple mild traumatic brain injuries. The immediate goal of this research project is to discover differences in genomic variation and neuroinflammatory markers that may serve as biomarkers to identify those individuals at risk for developing AD in the setting of trauma. This research will be critical for understanding how trauma may cause or accelerate AD, developing ways to assess risk in contact sports play and military service, and for informing rational drug design. Here we propose a cross-disciplinary approach that combines expertise and novel techniques in neuropathology, genetics, and data analysis to discover new pathogenic pathways for risk assessment, biomarker development, and therapeutics.