Pharmaconeuropathology of Brain Aging and Dementia

描述（由申请人提供）：老年痴呆症是一种具有多种原因的慢性综合征，已经成为主要的公共卫生负担，并对生物医学研究人员提出了明确的治疗要求。考虑到专注于预防或延迟痴呆症事件的随机临床试验（RCT）的时间和费用，公共卫生迫切需要快速而有力地验证疗法，以确保最佳候选人进入RCT。该申请是脑老化和痴呆症的药物神经病理学的竞争性更新，其利用了成人思维变化研究的巨大和独特的资源，这是一项针对老年人脑老化和痴呆症事件的大型基于人群的纵向研究，以确定潜在有效的治疗方法，用于推进临床试验。在这次竞争性更新中，我们建议确定以下中年和晚年暴露或活动与老年痴呆症的神经病理学，结构和生化特征之间的关联：“心脏保护”剂量的阿司匹林，女性激素替代疗法，两种具有神经保护作用的抗高血压药物（钙通道阻滞剂和血管紧张素转换酶抑制剂）和体育锻炼水平。这些观察性数据将提供一个独特的视角，了解常用处方药或运动抑制疾病的特定机制，从而指导比较有效性的研究，并帮助选择在RCT中追求的方案。

DESCRIPTION (provided by applicant): Dementia in the elderly is a chronic syndrome with multiple causes that is already major public health burden and presents a clear therapeutic imperative to biomedical researchers. Given the time and expense of randomized clinical trials (RCTs) focused on preventing or delaying incident dementia, there is a critical public health need to validate therapies quickly and robustly to insure that the best possible candidates advance to RCTs. This application is a competitive renewal of Pharmaco- neuropathology of Brain Aging and Dementia that exploits the tremendous and unique resources of the Adult Changes in Thought Study, a large population-based longitudinal study of brain aging and incident dementia in older individuals, to identify potentially effective therapeutics for advancement to clinical trials. In this competitive renewal, we propose to determine the associations between the following mid- and late-life exposures or activities and neuropathologic, structural, and biochemical features of dementia in the elderly: "cardioprotective" doses of aspirin, hormone replacement therapy in women, two subclasses of antihypertensive drugs with proposed neuroprotective actions (calcium channel blockers and angiotensin-converting enzyme inhibitors), and level of physical exercise. These observational data will provide a unique perspective on which commonly prescribed drugs or exercise suppress specific mechanisms of disease, thereby guiding research on comparative effectiveness and aiding in the selection of regimens to pursue in RCTs.