Alzheimer-Like Pathologies Following Traumatic Brain Injury in Older Individuals

老年人脑外伤后出现类似阿尔茨海默病的病理

• 批准号: 8260281
• 负责人: Douglas Hamilton Smith
• 金额: $ 6.56万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260281
• 关键词: Acceleration; Accounting; Acute; Affect; Age; Aging; Alzheimer like pathology; Alzheimer' s Disease; American; Amyloid; Amyloid beta-Protein; Apolipoprotein E; Archives; Automobile Driving; Brain; Cause of Death; Cessation of life; Chronic Phase; Clinical; Clinical Management; Commit; Coupled; Data; Development; Disease; Elderly; Enzymes; Epidemiology; Genes; Genetic Polymorphism; Health; High Prevalence; Hour; Human; Immunohistochemistry; Incidence; Individual; Life; Link; Literature; Neprilysin; Nerve Degeneration; Neurocognitive; Neurocognitive Deficit; Neurofibrillary Tangles; Outcome; Pathogenesis; Pathologic; Pathology; Patients; Play; Population; Process; Recording of previous events; Recovery; Risk; Risk Factors; Role; Subgroup; Therapeutic; Therapeutic Intervention; Time; Trauma; Traumatic Brain Injury; aged; aging brain; aging population; base; brain tissue; disability; experience; falls; functional outcomes; high risk; improved; normal aging; novel; older patient; public health relevance; young adult

DESCRIPTION (provided by applicant): Mounting evidence suggests a history of traumatic brain injury (TBI) can increase the risk of developing Alzheimer's disease (AD). A pathological clue linking these two disease states came with the observation that amyloid-beta (A2) plaques, a hallmark pathology of AD, could be found in patients within hours following TBI. Furthermore, excessive plaques can be observed, persisting even decades after the initiating trauma. More recently, we have identified that the A2- degrading enzyme, neprilysin, may play an important role in the emergence of plaques. It has also been demonstrated that just a single TBI can induce the delayed emergence of neurofibrillary tangles (the other hallmark pathology of AD) and stands as important evidence in the link between these two disease states. While AD-like pathologies after TBI have been studied primarily in younger adults, little is known about how the aged brain responds to trauma with regard to these pathologies. Using a unique human brain archive based in Glasgow, UK, we propose to examine post-mortem brain tissue of elderly individuals for AD-like pathologies following TBI. Specifically, we aim to 1. Examine for the hallmark pathologies of Alzheimer's disease (A2 plaques and NFTs) in individuals aged 60+ who have sustained a TBI. 2. Examine of A2 degrading enzyme, neprilysin, in individuals aged 60+ who have sustained a TBI, using immunohistochemistry and 3. Examine of the influence of polymorphisms of both the neprilysin gene Apolipoprotein E (ApoE) gene in predicting amyloid-2 plaque formation in individuals aged 60+ who have sustained a TBI. As AD is predominantly a disease of ageing, we hypothesize that older individuals will be have increased vulnerability to developing AD-like pathology post-TBI. Exploration of these mechanisms may provide an important basis for improving the clinical management and developing therapeutic opportunities for this unique subgroup of individuals. ) PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a risk factor for Alzheimer's disease (AD). Both Hallmark pathologies of AD - A2 plaques and neurofibrillary tangles, have been found following TBI. Preliminary data suggests older individuals may be an increased risk of these TBI-induced pathologies. Using a unique human brain archive, we propose to examine older individuals for AD-like pathologies following TBI. Potential findings may explain the worsened neurocognitive outcomes observed following TBI in older patients. Understanding the mechanistic basis of these processes is vital in the drive towards targeted therapeutic intervention - particularly as novel AD-therapies emerge into the clinical forum. )

描述（由申请人提供）：越来越多的证据表明，创伤性脑损伤病史（TBI）可以增加患阿尔茨海默氏病（AD）的风险。将这两种疾病状态联系起来的病理线索与观察到，淀粉样蛋白β（A2）斑块是AD的标志性病理，在TBI后几个小时内可以在​​患者中找到。此外，可以观察到过多的斑块，即使在创伤创伤后几十年才持续存在。最近，我们确定A2降解酶Neprilysin可能在斑块的出现中起重要作用。还证明，只有一个TBI可以诱导神经原纤维缠结的延迟出现（AD的另一个标志性病理），并且在这两种疾病状态之间的联系中是重要的证据。尽管主要在年轻人中研究了TBI后类似AD的病理学，但对这些病理学对创伤的反应方式鲜为人知。我们建议使用英国格拉斯哥的独特的人脑存档，我们建议检查老年人的验尸后脑组织，以了解TBI之后的广告样病理学。具体而言，我们的目标是1。检查患有TBI的60岁以上的个体中阿尔茨海默氏病（A2斑块和NFTS）的标志性病理。 2. Examine of A2 degrading enzyme, neprilysin, in individuals aged 60+ who have sustained a TBI, using immunohistochemistry and 3. Examine of the influence of polymorphisms of both the neprilysin gene Apolipoprotein E (ApoE) gene in predicting amyloid-2 plaque formation in individuals aged 60+ who have sustained a TBI.由于AD主要是衰老的疾病，因此我们假设老年人将增加对TBI后发展类似AD样病理学的脆弱性。对这些机制的探索可能为改善临床管理和为这个独特的个人子组开发治疗机会提供了重要的基础。 ） 公共卫生相关性：创伤性脑损伤（TBI）是阿尔茨海默氏病（AD）的危险因素。 TBI之后，发现了AD A2斑块和神经原纤维缠结的两个标志性病理。初步数据表明，老年人可能会增加这些TBI诱导的病理的风险。使用独特的人脑存档，我们建议检查老年人在TBI之后是否有类似广告的病理。潜在的发现可能解释了老年患者TBI后观察到的神经认知结果恶化。了解这些过程的机械基础对于朝着有针对性的治疗干预的推动至关重要 - 尤其是随着新型的广告速度出现在临床论坛中。 ）