Prostaglandins & Oxidative Damage in ADAPT Participants

几项大型流行病学研究表明，阿尔茨海默氏症的发病率显著降低 服用非类固醇抗炎药(NSAIDs)时间超过 2年。然而，在已确诊的AD患者中进行的非类固醇抗炎药的临床试验并未显示出疗效。这有 导致假设非类固醇抗炎药抑制对AD的启动至关重要的病理过程，并且这些 这一过程可能与抑制环氧合酶和随后的前列腺素(PG)有关。 制作。我们建议通过量化受试者内源性二十烷类化合物的产生来检验这一假说。 参加由NIA赞助的阿尔茨海默病抗炎预防试验(Adapt) 非甾体抗炎药在预防阿尔茨海默病中的作用。具体地说，我们将1)确定选择性和非选择性的疗效 选择性非甾体类抗炎药抑制1种定量标记物的系统和临床应用 适应受试者的中枢神经系统；2)确定非类固醇抗炎药抑制 系统性氧化损伤和适应性中枢神经系统氧化损伤的定量生物标志物 参与者；以及3)PG产生的生物标志物水平的变化与氧化损伤的相关性 认知功能减退的速度在适应中确定。我们已经开发出高度精确和精确的 对前列腺素、前列腺素代谢产物和脂质过氧化产物进行定量的质谱分析是常规的 在我们的实验室进行这些检测。这些研究将为了解这些机制提供重要的见解。 非甾体类抗炎药通过它来预防AD。

Several large epidemiological studies have associated a profound reduction in the incidence of Alzheimer's Disease (AD) in older individuals who took non-steroidal anti-inflammatory drugs (NSAIDs) for longer than 2 years. However, clinical trials of NSAIDs in patients with established AD failed to show efficacy. This has led to the hypothesis that NSAIDs suppress pathologic processes critical to the initiation of AD and that these processes may be related to inhibition of the cyclooxygenase enzymes and subsequent prostaglandin (PG) production. We propose to test this hypothesis by quantifying endogenous eicosanoid production in subjects enrolled in the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT), an NIA-sponsored study of NSAIDs in the prevention of AD. Specifically, we will 1) determine the efficacy of selective and non- selective NSAIDs t o suppress 1 evels o f quantitative b iomarkers o f P G p reduction systemically and in t he central nervous system of ADAPT participants; 2) determine the efficacy of NSAIDs to suppress levels of quantitative biomarkers of oxidative damage systemically and in the central nervous system of ADAPT participants; and 3) correlate changes in the levels of biomarkers of PG production and oxidative damage with rates of cognitive decline as determined in ADAPT. We have developed highly accurate and precise mass spectrometric assays to quantify PGs, PG metabolites, and lipid peroxidation products and are routinely performing these assays in our laboratory. These studies will provide important insights into the mechanisms by which NSAIDs prevent AD.