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)史会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线索来自观察，即AD的标志性病理--淀粉样β蛋白(A2)斑块可以在脑损伤后几小时内在患者身上发现。此外，可以观察到过多的斑块，甚至在最初的创伤后持续数十年。最近，我们发现A2降解酶，neprilysin，可能在斑块的出现中发挥重要作用。研究还表明，仅一次脑外伤就可以导致神经原纤维缠结的延迟出现(AD的另一种标志性病理)，并作为这两种疾病状态之间联系的重要证据。虽然脑外伤后类似AD的病理研究主要在年轻人身上进行，但关于老年大脑对这些病理变化的反应却知之甚少。利用位于英国格拉斯哥的一个独特的人脑档案，我们建议检查老年人死后脑组织中是否存在脑外伤后AD样病理。具体地说，我们的目标是1.在60岁以上遭受脑外伤的人中检查阿尔茨海默病的标志性病理(A2斑块和NFT)。2.用免疫组织化学方法检测60岁以上脑外伤患者A2降解酶--Neprilysin的含量；3.检测Neprilysin基因载脂蛋白E(ApoE)基因多态性对预测60岁以上脑外伤患者淀粉样蛋白-2斑块形成的影响。由于阿尔茨海默病主要是一种老年病，我们假设老年人在脑外伤后更容易发生类似AD的病理变化。对这些机制的探索可能会为改善临床管理和为这一独特的个体亚群开发治疗机会提供重要的基础。) 公共卫生相关性：创伤性脑损伤(TBI)是阿尔茨海默病(AD)的危险因素。颅脑损伤后发现了AD-A2斑块和神经原纤维缠结的Hallmark病理改变。初步数据表明，年龄较大的人患上这些由脑外伤引起的病理的风险可能会增加。使用独特的人脑档案，我们建议检查老年人在脑损伤后的AD样病理。潜在的发现可能解释了老年患者脑外伤后观察到的神经认知结果恶化的原因。了解这些过程的机制基础对于推动有针对性的治疗干预至关重要--特别是在新的AD疗法进入临床论坛的情况下。)

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. )