Prostaglandins & Oxidative Damage in ADAPT Participants

几项大型流行病学研究表明， 老年人服用非甾体类抗炎药（NSAID）时间超过 2年然而，NSAID在已确诊AD患者中的临床试验未能显示疗效。这 这导致了一种假设，即NSAID抑制了对AD起始至关重要的病理过程， 这些过程可能与抑制环氧合酶和随后的前列腺素（PG）有关 生产我们建议通过量化受试者体内内源性类二十烷酸的产生来验证这一假设 参加了阿尔茨海默病抗炎预防试验（ADAPT），这是一项由NIA赞助的研究 NSAIDs在预防AD中的作用具体来说，我们将1）确定选择性和非选择性的有效性， 选择性非甾体类抗炎药可抑制PGp降低的全身和全身定量B标记物水平， ADAPT参与者的中枢神经系统; 2）确定NSAID抑制 ADAPT全身和中枢神经系统中氧化损伤的定量生物标志物 参与者;和3）PG产生和氧化损伤的生物标志物水平的相关变化 与ADAPT中确定的认知下降率。我们已经开发出了高度准确和精确的 质谱分析，以定量PG，PG代谢物和脂质过氧化产物，并常规 在我们的实验室里进行这些检测。这些研究将提供重要的见解的机制 非甾体类抗炎药预防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.