CLINICAL STUDIES OF NSAIDSs AS y-SECRETASE MODULATORS IN ALZHEIMER'S DISEASE

减少Abeta的产生可能有益于阿尔茨海默病（AD）的治疗。基本 通过项目1和2进行的研究先前确定，γ- 分泌酶选择性地降低Abeta 42，而不影响Notch加工，并筛选了几种非甾体类药物。 抗炎药（NSAIDS）作为候选药物。我们设计并进行了一项临床试验， ：R-氟比洛芬在健康老年人中的安全性、耐受性和药代动力学。这些数据被用于 Myriad Pharmaceuticals，Inc.，计划和实施第2阶段和正在进行的第3阶段临床试验计划， R-氟比洛芬治疗AD的临床试验在项目3的更新中，我们的目标是优化生物标志物测量， CSF中的Abeta，以表征R-氟比洛芬的Abeta降低作用。我们还旨在测试布洛芬， 具有γ-分泌酶调节活性和抗炎作用的NSAID， 在遗忘型轻度认知障碍（aMCI）患者中进行的临床试验， AD的阶段。这是针对早期干预，在患者发生广泛的淀粉样蛋白沉积之前 以及神经元和突触的损伤。我们推测，AD早期降低A β 42可能 对成像和生物化学生物标志物的有益作用。我们有两个目的：（1）评估CSF水平， 在健康成年人中，使用腰椎间盘突出症，以1600 mg高剂量R-氟比洛芬急性治疗后的A β 42 CSF导管在24小时内获得CSF样品，稳定同位素标记技术用于 计算Abeta合成速率。这将表征Abeta降低作用的时间和持续时间。（二） 在100例aMCI患者中评价CSF和MRI脑萎缩指标的生物标志物变化， 将随机接受布洛芬800 mg每日三次治疗（+奥美拉唑20 mg/天， 胃保护）或安慰剂，持续12个月。将在基线和12个月时获得CSF和MRI 并在基线、6和12时进行简短的神经心理测试组合（NTB）和IADL问卷调查 个月主要结果测量将是海马和总脑体积（MRI）的变化; 总tau、磷酸化tau 181、A β 42和A β 38以及F2-异前列烷（CSF）的浓度。二次 结果测量将是NTB和ADCS ADL-MCI评分的变化。意义：未接受治疗 已被证明对AD具有改善疾病的作用。脑脊液生物标志物和核磁共振检查可以让我们监测 以调节γ-分泌酶为目标的治疗是否会（1）选择性降低人体中的A β 42 急性治疗后;（2）对与Abeta相关的生物标志物和由Abeta引起的损伤具有有益作用。 导致aMCI（AD可被诊断的最早临床阶段）中的病理级联。这些 结果将支持进一步努力开发用于早期临床使用的γ-分泌酶调节剂。

Decreasing the production of Abeta may be beneficial in the treatment of Alzheimer's Disease (AD). Basic research carried out through Projects 1 and 2 previously identified that allosteric modulators of gamma- secretase selectively lower Abeta42, without affecting Notch processing, and screened several Nonsteriodal anti-inflammatory drugs (NSAIDS) as candidates. We designed and conducted'a clinical trial to determine :he safety, tolerability and pharmacokinetics of R-flurbiprofen in healthy older adults. The data was used by Myriad Pharmaceuticals, Inc.,to plan and implement phase 2 and an ongoing program of phase 3 clinical trials of R-flurbiprofen in AD. In this renewal of Project 3, we aim to optimize biomarker measurements of Abeta in CSF to characterize Abeta lowering effects of R-flurbiprofen. We also aim to test ibuprofen, an NSAID with gamma-secretase modulating activity and anti-inflammatory actions, by carrying out a controlled clinical trial in patients with amnestic Mild Cognitive Impairment (aMCI), the earliest clinically diagnosable stage of AD. This targets early intervention, before patients have developed extensive amyloid deposition and damage to neurons and synapses. We hypothesize that lowering Abeta42 very early in AD may have beneficial effects on imaging and biochemical biomarkers. We have 2 aims: (1) To evaluate CSF levels of Abeta42 after acute treatment with R-flurbiprofen at a high dose of 1600mg in healthy adults, using a lumbar CSF catheter to obtain CSF samples during 24 hours, and the technique of stable isotopic labeling to calculate Abeta synthesis rates. This will characterize the timing and duration of Abeta lowering actions. (2) To evaluate biomarker changes in CSF and brain atrophy measures on MRI,in 100 patients with aMCI who will be randomized to treatment with ibuprofen 800 mg three times per day (+ omeprazole 20 mg/day for gastroprotection), or to placebo, for 12 months. CSF and MRI will be obtained at baseline and 12 months and a brief neuropsychological test battery (NTB) and lADL-questionnaire will be given at baseline, 6 and 12 months. Primary outcome measures will be change in hippocampal and total brain volume (MRI); concentrations of total tau, phosphotau 181,Abeta42 and Abeta38, and F2-isoprostanes (CSF). Secondary outcome measures will be change in NTB and ADCS ADL-MCI scores. Significance: No treatment has been shown to have disease-modifying effects in AD. CSF biomarkers and MRI measures allow us to monitor whether treatment that targets modulation of gamma-secretase will (1) selectively lower Abeta42 in humans following acute treatment; (2) have beneficial effects on biomarkers related to Abeta and to damage from the resulting cascade of pathology in aMCI, the earliest clinical stage at which AD can be diagnosed. These results will support further efforts to develop gamma-secretase modulators for early clinical use.