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

预测 NSAID 治疗反应的促炎症内表型阿尔茨海默病临床试验

基本信息

批准号：
9888293
负责人：
CONSTANTINE G LYKETSOS
金额：
$ 68.16万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9888293
关键词：
Address Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Alzheimer&apos s disease therapy Animal Model Anti-Inflammatory Agents Attention Basic Science Biological Biological Assay Biological Markers Blood Cardiovascular Diseases Clinical Clinical Trials Cognition Cognitive Complex Conduct Clinical Trials Data Development Disease Disease Progression Elderly Enrollment Epidemiology Exhibits Future Generations Health Care Costs Human IL18 gene IL5 gene IL6 gene IL7 gene Impaired cognition Inflammation Inflammatory Interleukin-10 Intervention Literature Malignant Neoplasms Methods Modeling Monitor Naproxen Non-Steroidal Anti-Inflammatory Agents Outcome Participant Patient Selection Patient-Focused Outcomes Patients Pharmaceutical Preparations Placebos Plasma Prevention trial Proteins Proteomics Public Health Randomized Research Resources Sampling Subgroup TNF gene Testing Therapeutic Time Validation Work adverse outcome arm base biobank clinically significant cognitive benefits cognitive performance cohort cooperative study design endophenotype experience innovation mild cognitive impairment non-demented novel novel strategies novel therapeutics overtreatment patient subsets person centered personalized approach precision medicine prevent protective effect response success support vector machine targeted treatment treatment response

项目摘要

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.

项目摘要我们假设阿尔茨海默病（AD）和轻度认知障碍（MCI）是异质性的因此，需要转变模式，以确定特定的亚群，干预措施。这种方法在其他复杂疾病中取得了重大成功，如癌症和心血管疾病这方面的一个关键机会是确定那些最有可能受益于非甾体抗炎药（NSAID）和其他抗炎化合物。的关系炎症与AD、MCI和认知功能下降的发展受到了极大的关注基础科学和观察性人类研究证明了对认知丧失的保护作用。同样，在我们的工作中，炎症是生物学特征中的一个关键机制，疾病的存在。根据大量文献（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NSAID化合物在治疗或治疗中的效用。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显示出治疗益处，事实上，一些患者可能表现出认知能力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子集确实受益于我们的血液促炎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，我们建议利用三个以前进行的临床试验来测试我们的假设，我们的血液- 基于促炎性内表型的研究可以识别从这些疾病中受益的患者亚群，以前进行的临床试验。通过从现有的生物储存库进行蛋白质组学测定， ADCS和ADAPT，我们将解决以下具体目标：具体目标1。演示促炎性内表型作为选择患者接受NSAID治疗的手段，预防AD;具体目标2。为了确定促炎性内表型评分随时间的变化是否治疗反应的生物标志物。通过利用高度创新的方法和大量现有资源，目前的项目解决了一个在寻找AD治疗的新方法方面存在显著需求。本项目的意义在于识别将经历以下临床显著认知益处的特定患者子集：服用NSAID药物。如果成功，目前的项目将为一项新的临床试验奠定基础。其特别基于基线促炎性内表型评分招募患者，非甾体抗炎药治疗。从长远来看，这条研究路线旨在建立一个以人为中心的（即个性化）阿尔茨海默病的治疗方法。