Alzheimer-Like Pathologies Following Traumatic Brain Injury in Older Individuals

描述（由申请人提供）：越来越多的证据表明，创伤性脑损伤（TBI）史可增加患阿尔茨海默病（AD）的风险。将这两种疾病状态联系起来的病理学线索来自于以下观察结果，即淀粉样蛋白β（A2）斑块，AD的标志性病理学，可以在TBI后数小时内在患者中发现。此外，可以观察到过多的斑块，甚至在初始创伤后持续数十年。最近，我们已经确定，A2-降解酶，脑啡肽酶，可能在斑块的出现中发挥重要作用。也已经证明，仅仅一次TBI就可以诱导神经元缠结（AD的另一个标志性病理学）的延迟出现，并且是这两种疾病状态之间联系的重要证据。虽然TBI后的AD样病理主要在年轻人中进行了研究，但对老年人的大脑如何对这些病理的创伤做出反应知之甚少。使用一个独特的人脑档案馆设在英国格拉斯哥，我们建议检查死后的脑组织的老年人的AD样病变TBI。具体来说，我们的目标是1。检查阿尔茨海默病的标志性病理（A2斑块和NFT）在60岁以上的人谁持续TBI。2.检查A2降解酶，脑啡肽酶，在60岁以上的人谁持续TBI，使用免疫组化和3。研究脑啡肽酶基因和载脂蛋白E（ApoE）基因多态性对预测60岁以上TBI患者淀粉样蛋白2斑块形成的影响。由于AD主要是一种衰老性疾病，我们假设老年人在TBI后将更容易发生AD样病理。这些机制的探索可能会提供一个重要的基础，改善临床管理和开发治疗机会，这一独特的亚组的个人。) 公共卫生相关性：创伤性脑损伤（TBI）是阿尔茨海默病（AD）的危险因素。在TBI后发现了AD-A2斑块和神经元缠结的标志性病理学。初步数据表明，老年人可能是这些TBI诱导的病理风险增加。使用一个独特的人类大脑档案，我们建议检查老年人的AD样病变TBI。潜在的发现可能解释老年患者TBI后观察到的神经认知结果恶化。了解这些过程的机制基础对于靶向治疗干预至关重要-特别是当新型AD疗法出现在临床论坛时。)

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. )