Prevention of Alzheimer Dementia and Cognitive Decline

预防阿尔茨海默氏痴呆和认知能力下降

• 批准号: 7916459
• 负责人: John C S Breitner
• 金额: $ 286.98万
• 依托单位: SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7916459
• 关键词: Age-associated memory impairment; Alzheimer disease prevention; Alzheimer' s Disease; Anti-Inflammatory Agents; Anti-inflammatory; Cardiovascular system; Clinical; Cognitive; Data; Data Set; Dementia; Disease; Elderly; Employee Strikes; Enrollment; Epidemiology; Event; Follow-Up Studies; Funding; Future; Generations; Human; Impaired cognition; Incidence; Individual; Inflammatory; Interruption; Intervention; Laboratories; Masks; Mediating; Methods; Naproxen; Nerve Degeneration; Non-Steroidal Anti-Inflammatory Agents; Outcome; PTGS2 gene; Paper; Participant; Pathogenesis; Pathology; Pathway interactions; Placebo Control; Placebos; Prevention; Prevention strategy; Primary Prevention; Process; Prostaglandins; Publishing; Request for Applications; Research Personnel; Risk; Safety; Screening procedure; Signal Transduction; Specific qualifier value; Staging; Telephone; Testing; Time; cardiovascular risk factor; celecoxib; cognitive function; cohort; cyclooxygenase 1; design; expectation; follow-up; hazard; inhibitor/antagonist; mortality; neuroprotection; primary outcome; programs; randomized placebo controlled trial; response; secondary outcome; treatment effect; trend

DESCRIPTION (provided by applicant): The dementia of Alzheimer's disease (AD) follows years of pre-symptomatic neurodegeneration. An ideal AD intervention would therefore reduce the occurrence of dementia by slowing or stopping the disease process in its pre-symptomatic stages. Laboratory results suggest that prostaglandin-dependent inflammatory or signaling mechanisms may be important in AD pathogenesis, and epidemiologic evidence suggests that conventional NSAIDs that inhibit COX-1 or COX-2 activation of the prostaglandin pathway can reduce AD dementia incidence. The masked, placebo-controlled Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) was therefore designed to test whether the dual-inhibitor NSAID naproxen or the COX-2 selective agent celecoxib can reduce the incidence of AD dementia and mitigate age-related cognitive decline. Expectations for informative results from ADAPT were diminished when its treatments were stopped after an average 21 months of treatment assignment. Indeed, recently published results from ADAPT showed no benefit from NSAID exposure, but instead suggested an early increase in the incidence of dementia with treatment. Over the past 22 months, however, the naproxen-assigned group has shown reduced AD dementia incidence, and the contrast between the earlier and later direction of effects with naproxen is striking. Unfortunately, interruption of funding has necessitated an end of data gathering and the unmasking of ADAPT just when its predicted treatment effects seem to be emerging. This application therefore proposes to follow up the ADAPT cohort over an interval of 30 months, using the telephone to screen for cognitive difficulty and then evaluating screen-positive individuals for new dementia outcomes. We will then repeat this process a year later and combine the new results with those of ADAPT to accrue some 180 total AD dementia "events" as well as an extensive array of longitudinal cognitive test scores. Our Specific Aim 1 is thus to extend observations on the ADAPT outcomes of incident AD dementia and age-related cognitive decline in relation to treatment assignment. We seek in particular to discover whether naproxen can cause a long-term reduction in the incidence of AD dementia. Also (as permitted by the data) we seek to characterize a "bi-directional" or "bi-phasic" response of elderly people to naproxen (or, if any, to celecoxib) with a brief interval of increased incidence followed by a more substantial epoch of diminished risk. Specific Aim 2 is to determine whether the limited exposures in ADAPT to either of the two NSAID treatments produced long-term change in age-related cognitive decline as a possible early manifestation of AD pathology. Although safety concerns will probably negate the utility of current generation NSAIDs for prevention of AD dementia, the elucidation of their effects on the disease in humans is of great importance as an indicator of AD pathogenetic mechanisms and future prevention strategies.

描述(由申请人提供)：阿尔茨海默病(AD)痴呆症(AD)是在多年的无症状神经变性之后发生的。因此，理想的阿尔茨海默病干预将通过延缓或停止症状前期的疾病过程来减少痴呆症的发生。实验室结果提示前列腺素依赖的炎症或信号机制可能在AD的发病机制中起重要作用，流行病学证据表明，传统的抑制前列腺素途径COX-1或COX-2激活的非甾体抗炎药可以降低AD痴呆的发生率。因此，这项蒙面、安慰剂对照的阿尔茨海默病抗炎预防试验(ADAPT)旨在测试双重抑制剂NSAID纳普生或COX-2选择性药物塞来昔布是否可以降低AD痴呆的发生率和缓解与年龄相关的认知能力下降。当在平均21个月的治疗分配后停止治疗时，对Adapt的信息结果的期望降低。事实上，最近发表的来自Adapt的结果显示，接触非类固醇抗炎药并没有带来好处，相反，它表明接受治疗后痴呆症的发病率会早期增加。然而，在过去的22个月里，分配给萘普生的那一组显示出阿尔茨海默病的发病率降低了，而且使用萘普生的早期和后期疗效方向之间的对比是显著的。不幸的是，资金的中断导致了数据收集的结束，并在Adapt的预期治疗效果似乎正在显现时揭开了它的面纱。因此，该应用程序建议在30个月的间隔内对Adapt队列进行跟踪，使用电话筛查认知困难，然后评估筛查阳性的个体是否出现新的痴呆症结果。一年后，我们将重复这一过程，并将新的结果与Adapt的结果结合起来，累积大约180个AD痴呆症“事件”以及一系列广泛的纵向认知测试分数。因此，我们的具体目标1是扩大对阿尔茨海默病事件的适应结果的观察，以及与治疗分配相关的与年龄相关的认知能力下降。我们特别寻求发现，萘普生是否可以导致AD痴呆发病率的长期降低。此外(在数据允许的情况下)，我们试图描述老年人对萘普生(或，如果有的话，对塞来昔布)的“双向”或“双相”反应，伴随着短暂的发病率增加和更实质性的风险降低时期。具体目标2是确定适应两种非甾体抗炎药疗法中的任何一种的有限暴露是否产生了作为AD病理可能的早期表现的与年龄相关的认知衰退的长期变化。尽管安全性问题可能会否定当代非类固醇抗炎药在预防AD痴呆方面的作用，但阐明它们对人类疾病的影响对于AD的发病机制和未来的预防策略具有重要意义。

项目成果

Celecoxib or naproxen treatment does not benefit depressive symptoms in persons age 70 and older: findings from a randomized controlled trial.

• DOI: 10.1097/jgp.0b013e318227f4da
• 发表时间: 2012-06
• 期刊: The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry
• 作者: Fields C;Drye L;Vaidya V;Lyketsos C;ADAPT Research Group
• 通讯作者: ADAPT Research Group

APOE ε4 specific imbalance of arachidonic acid and docosahexaenoic acid in serum phospholipids identifies individuals with preclinical Mild Cognitive Impairment/Alzheimer's Disease.

• DOI: 10.18632/aging.101203
• 发表时间: 2017-03-23
• 期刊: Aging
• 作者: Abdullah L;Evans JE;Emmerich T;Crynen G;Shackleton B;Keegan AP;Luis C;Tai L;LaDu MJ;Mullan M;Crawford F;Bachmeier C
• 通讯作者: Bachmeier C

Results of a follow-up study to the randomized Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT).

• DOI: 10.1016/j.jalz.2012.11.012
• 发表时间: 2013-11
• 期刊: Alzheimer's & dementia : the journal of the Alzheimer's Association
• 作者: Alzheimer's Disease Anti-inflammatory Prevention Trial Research Group

Alzheimer's Disease Anti-inflammatory Prevention Trial: design, methods, and baseline results.

• DOI: 10.1016/j.jalz.2008.09.004
• 发表时间: 2009-03
• 期刊: ALZHEIMERS & DEMENTIA
• 影响因子: 14
• 作者: Meinert, Curtis L.;McCaffrey, Lee D.;Breitner, John C. S.
• 通讯作者: Breitner, John C. S.

Follow-up evaluation of cognitive function in the randomized Alzheimer's Disease Anti-inflammatory Prevention Trial and its Follow-up Study.

• DOI: 10.1016/j.jalz.2014.03.009
• 发表时间: 2015-02
• 期刊: Alzheimer's & dementia : the journal of the Alzheimer's Association
• 作者: ADAPT-FS Research Group