A Proinflammatory Endophenotype to Predict NSAID Treatment Response Alzheimer's Disease Clinical Trials

项目总结 我们的假设是阿尔茨海默病(AD)和轻度认知障碍(MCI)是不同的 因此，需要转变范式，以确定目标人群的具体亚群。 干预措施。这种方法在其他复杂疾病上取得了巨大的成功，如癌症和 心血管疾病。在这方面的一个关键机会是确定那些最有可能受益于 非类固醇抗炎(NSAID)药物和其他抗炎化合物。两者之间的关系 炎症与AD、MCI和认知功能减退的发展已经引起了极大的关注 基础科学和观察性人体研究表明，它对防止认知丧失有保护作用。 同样，在我们的工作中，炎症一直是生物学特征中的一个关键机制，它表明 疾病的存在。基于大量文献(流行病学、横断面、病理生物学和动物 模型)，已经进行了多项临床试验，以确定非类固醇抗炎药在治疗或 预防AD(阿尔茨海默病合作研究[ADCS]AD和MCI抗炎试验； 阿尔茨海默病抗炎预防试验[ADAPT])；然而，这些研究中的每一项都未能 表现出治疗效果，事实上，一些患者的认知能力可能会恶化 接受治疗。我们的初步数据表明，这些试验中的特定患者亚组确实受益于 我们的血液促炎症内表型可以识别阳性和不良反应 这些试验中的应答者。 在这里，我们建议利用之前进行的三项临床试验来测试我们的假设，即我们的血液- 基于促炎症内表型可以确定受益于这些疾病的患者亚群 此前曾进行过临床试验。通过从现有的生物信息库进行蛋白质组分析 ADC和适应，我们将解决以下具体目标：具体目标1.展示 促炎内表型作为患者选择非甾体抗炎药治疗和 预防阿尔茨海默病；具体目标2。确定促炎症内表型评分随时间的变化是否 治疗反应的生物标记物。 通过利用高度创新的方法和大量现有资源，目前的项目解决了 在寻找新的阿尔茨海默病疗法方面的重大需求。当前项目的意义在于 确定将经历临床上显著认知益处的特定患者子集 非甾体抗炎药的管理。如果成功，目前的项目将为一项新的临床试验奠定基础 它专门根据基础促炎症内表型评分登记患者，用于给药 非甾体抗炎药治疗。从长远来看，这一系列研究的目的是建立以人为中心(即个性化) 阿尔茨海默病的治疗方法。

PROJECT SUMMARY It is our hypothesis that Alzheimer's disease (AD) and mild cognitive impairment (MCI) are heterogeneous conditions and, therefore, a paradigm shift is required to identify specific subpopulations for targeted interventions. This approach has generated significant success in other complex diseases such as cancer and cardiovascular disease. A key opportunity in this context is the identification of those most likely to benefit from non-steroidal anti-inflammatory (NSAID) drugs and other anti-inflammatory compounds. The relation between inflammation and the development of AD, MCI, and cognitive decline has received a great deal of attention with basic science and observational human studies demonstrating a protective effect against cognitive loss. Likewise, in our work, inflammation has been a key mechanism in the biological profile that is indicative of disease presence. Based on a wealth of literature (epidemiological, cross-sectional, pathobiological and animal model), multiple clinical trials have been conducted to determine the utility of NSAID compounds in treating or preventing AD (Alzheimer's Disease Cooperative Study [ADCS] AD and MCI anti-inflammatory trials; Alzheimer's Disease Anti-inflammatory Prevention Trial [ADAPT]); however, each of these studies failed to demonstrate therapeutic benefit, in fact some patients may have exhibited worsening cognitive performance with treatment. Our preliminary data suggests that particular subsets of patients in these trials did benefit from treatment and that our blood-based proinflammatory endophenotype can identify both positive and adverse responders within these trials. Here we propose to leverage three previously conducted clinical trials to test our hypothesis that our blood- based proinflammatory endophenotype can identify the subsets of patients who benefited from these previously conducted clinical trials. By conducting proteomic assays from existing biorepositories from the ADCS and ADAPT, we will address the following Specific Aims: Specific Aim 1. Demonstrate the utility of the proinflammatory endophenotype as a means for patient selection into NSAID therapy for treating and preventing AD; Specific Aim 2. To determine if change in proinflammatory endophenotype scores over time is a biomarker of therapeutic response. By leveraging a highly innovative method and substantial existing resources, the current project addresses a significant need in the search for novel approaches AD therapeutics. The significance of the current project is the identification of a specific subset of patients who will experience clinically significant cognitive benefit from administration of NSAID medication. If successful, the current project will set the stage for a novel clinical trial that enrolls patients specifically based on baseline proinflammatory endophenotype scores for administration of NSAID therapy. In the long-term, this line of research is designed to build a person-centered (i.e. personalized) approach to the treatment of Alzheimer's disease.