The neuropathology of mild traumatic brain injury in Alzheimer disease

阿尔茨海默病轻度创伤性脑损伤的神经病理学

• 批准号: 10294950
• 负责人: Thor Stein
• 金额: --
• 依托单位: EDITH NOURSE ROGERS MEMORIAL VETERANS HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10294950
• 关键词: Address; Affect; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease risk; Amyloid beta-Protein; Area; Autopsy; Behavioral Symptoms; Biochemical; Biological Markers; Blast Injuries; Brain; CCL2 gene; Clinical; Collection; Craniocerebral Trauma; DNA; Data; Data Analyses; Development; Diagnosis; Disease; Disease Progression; Drug Design; Drug Targeting; Gene Expression; Gene Expression Alteration; Genes; Genetic; Genetic Risk; Genetic Variation; Genotype; Goals; Histologic; Immune response; Individual; Inflammatory; Inflammatory Response; Injury; Interferon Type II; Interleukin-1; Interleukin-6; Lead; Link; Logistic Regressions; Measurement; Measures; Mechanical Stress; Meta-Analysis; Methodology; Methods; Microglia; Molecular; Nerve Degeneration; Neurobehavioral Manifestations; Neurodegenerative Disorders; Outcome; PGRN gene; Pathogenicity; Pathologic; Pathology; Pathway interactions; Pattern; Play; Prevention; Proteins; RNA; Recording of previous events; Research; Research Project Grants; Risk; Risk Assessment; Risk Factors; Role; Severity of illness; Soldier; Stratification; Symptoms; TNF gene; Techniques; Testing; Therapeutic; Transcript; Translating; Trauma; Variant; Veterans; abeta deposition; apolipoprotein E-4; base; biomarker development; brain tissue; chronic traumatic encephalopathy; cohort; contact sports; cost; cytokine; density; disorder control; drug discovery; experience; genetic analysis; genetic risk factor; genetic variant; genome-wide; genomic variation; head impact; human subject; inflammatory modulation; mild traumatic brain injury; military service; military veteran; neuroinflammation; neuropathology; novel; polygenic risk score; progressive neurodegeneration; risk variant; tau Proteins; transcriptome; transcriptome sequencing; translational approach

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.

重复头部撞击（RHI）导致严重的认知和行为症状， 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可以发挥致病作用， AD和CTE的发展。目前，没有CTE或AD的疾病修饰治疗，并且 CTE的诊断只能在尸检时做出。此外，对遗传和分子生物学知之甚少。 在RHI暴露的情况下CTE或AD的变化。这在很大程度上是因为， 到目前为止，系统收集了超过少数CTE病例。我们的翻译方法是 在世界上最大的神经病理学证实的尸检队列中系统地解决神经变性问题 CTE和CTE伴AD（CTE-AD）受试者的DNA、RNA和蛋白质水平，目的是识别 新的遗传风险因素，生物标志物和机制，可以作为药物发现的目标。我们有 显示在CTE受试者中，β-淀粉样蛋白沉积加速，与机械 压力最大，受APOE等位基因状态的影响。此外，基因组变异可以发挥作用， 在疾病进展中的重要作用，基于APOE等位基因ε4状态的分层揭示了额外的 风险等位基因，并根据潜在的遗传学预测改变的病理。我们的初步数据显示， TMEM 106 B的变异与CTE中的小胶质细胞活化、tau病理学和临床症状相关。 APOE ε4阴性受试者。TMEM 106 B的变化与FTLD-TDP的发展有关， 颗粒蛋白前体（PRGN）水平和炎症途径的调节。与AD有关的许多其他基因 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 小胶质细胞活化是CTE的早期变化，并且已经证明改变的神经炎症 细胞因子与CTE与AD中tau病理学的发展密切相关。我们的假设， 基于我们的初步数据，APOE和TMEM 106 B的变体在CTE和CTE-AD中富集， 受试者并与细胞因子改变以及β-淀粉样蛋白和tau水平升高相关， 疾病进展。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的进展以及β-淀粉样蛋白、tau和 神经炎性细胞因子可作为创伤诱导的神经退行性变的生物标志物。我们的长期 目的是揭示遗传和分子机制的发展，AD的背景下， 多处轻度脑外伤本研究项目的直接目标是发现 基因组变异和神经炎症标记物，可以作为生物标志物，以确定这些人在 在创伤环境中发展AD的风险。这项研究对于理解创伤如何 导致或加速AD，开发评估接触性体育运动和兵役风险的方法， 合理的药物设计。在这里，我们提出了一个跨学科的方法，结合专业知识和 神经病理学、遗传学和数据分析方面的新技术，以发现新的致病途径， 评估、生物标志物开发和治疗。

项目成果

Case records of the Massachusetts General Hospital. Case 40-2011. A 52-year-old man with weakness, infections, and enlarged adrenal glands.

马萨诸塞州总医院的病例记录。

• DOI: 10.1056/nejmcpc1100919
• 发表时间: 2011
• 期刊: The New England journal of medicine
• 作者: Tritos,NicholasA;Schaefer,PamelaW;Stein,ThorD
• 通讯作者: Stein,ThorD

Circulating autoantibodies recognize and bind dying neurons following injury to the brain.

大脑受伤后，循环自身抗体会识别并结合垂死的神经元。

• DOI: 10.1093/jnen/61.12.1100
• 发表时间: 2002
• 期刊: Journal of neuropathology and experimental neurology
• 影响因子: 3.2
• 作者: Stein,ThorD;Fedynyshyn,JosephP;Kalil,RonaldE
• 通讯作者: Kalil,RonaldE

Genetic programming by the proteolytic fragments of the amyloid precursor protein: somewhere between confusion and clarity.

淀粉样前体蛋白的蛋白水解片段的遗传编程：介于混乱和清晰之间。

• DOI: 10.1515/revneuro.2003.14.4.317
• 发表时间: 2003
• 期刊: Reviews in the neurosciences
• 影响因子: 4.1
• 作者: Stein,ThorD;Johnson,JeffreyA
• 通讯作者: Johnson,JeffreyA

Functional connectivity in the thalamus and hippocampus studied with functional MR imaging.

• 发表时间: 2000-09
• 期刊: AJNR. American journal of neuroradiology
• 作者: T. Stein;C. Moritz;Michelle Quigley;D. Cordes;V. Haughton;Elizabeth Meyerand

Nrf2, a multi-organ protector?

• DOI: 10.1096/fj.04-2591hyp
• 发表时间: 2005-07-01
• 期刊: FASEB JOURNAL
• 影响因子: 4.8
• 作者: Lee, JM;Li, J;Johnson, JA
• 通讯作者: Johnson, JA