INtervention for Cognitive Reserve Enhancement in delaying the onset of Alzheimer’s Symptomatic Expression: The INCREASE study

阿尔茨海默病(AD)是当今社会面临的最重要的公共卫生问题之一。 据估计，美国目前有500万65岁及以上的人患有阿尔茨海默病，而这 到2050年，这一数字可能会增加近两倍。为了解决这一阻碍人口负担的问题，国家阿尔茨海默氏症项目 ACT(国家适应行动方案)2015年报告强调需要确定能够延缓症状的预防战略 疾病发作。虽然人们非常重视开发和测试有效的疾病修改 针对这一无症状的AD临床前阶段(PAD)的策略，很少被重视 目前可用的针对认知储备的策略，导致(1)延迟症状出现，(2)缩短 症状疾病的总病程，以及(3)显著减少AD的经济和社会影响。 我们假设，有针对性地减少不适当的药物使用(Beers Criteria 2015)将支持 阿尔茨海默病高危人群的认知储备，延迟临床症状的出现，降低患病率 以及症状性疾病的持续时间。这一战略的影响，如果成功，包括大幅减少 通过推迟疾病的症状阶段为数百万受阿尔茨海默病影响的人提供的总体医疗保健支出 与国家适应行动方案的目标一致。我们的具体目标是： 具体目标1.进行为期12个月的随机、安慰剂对照试验，以评估我们的患者- 以药剂师-医生团队为中心的MTM干预，减少不必要和不适当的药物治疗 用于社区居住、老年人、非精神错乱的对象。主要结果衡量标准将包括事前到事后 干预措施：(1)以用药适当性衡量的不当用药 指数(MAI)；2)认知储备改变评分(CRCS)，定义为东莨菪碱- 有挑战和无挑战的神经认知得分。 具体目标2评估临床前淀粉样蛋白负荷对认知储备缺陷和下降的影响 (以CRCs衡量)以评估延缓PAD症状性疾病进展的疗效。 虽然没有消除阿尔茨海默病或缩短生物性疾病的持续时间，但症状出现和 减少不适当用药导致的功能衰退可以减轻AD 不仅与AD相关，而且可能与所有形式的AD相关的医疗支出显著减少 涉及前驱症状无症状期的痴呆。研究结果将使更大范围的实施 临床实践中类似的用药管理策略，以满足多方面预防的需要 在老龄化人口中维持认知健康的策略。

Alzheimer's disease (AD) represents one of the most important public health issues our society is facing today. An estimated 5 million people age 65 and older in the United States (US) are currently living with AD, and this number may nearly triple by 2050. To address this impeding population burden, the National Alzheimer's Project Act (NAPA) 2015 report emphasized the need for identifying preventive strategies that can delay symptomatic disease onset. While much emphasis has been placed on developing and testing effective disease-modifying strategies targeting this asymptomatic preclinical phase of AD (pAD), little emphasis has been placed on currently available strategies that target cognitive reserve, resulting in (1) delaying symptom onset, (2) shortening the overall course of symptomatic disease, and (3) substantially reducing the financial and societal impact of AD. We hypothesize that targeted reductions in inappropriate medication use (Beers Criteria 2015), will bolster cognitive reserve in subjects at risk for AD, delaying the onset of clinical symptoms, and reducing the prevalence and duration of symptomatic disease. The impact of this strategy, if successful, includes a dramatic reduction in overall health care expenditures for the millions affected by AD by delaying the symptomatic phase of disease in accord with NAPA aims. Our specific aims are: Specific Aim 1. Conduct a 12-month, randomized, placebo-controlled trial to evaluate the impact of our patient- centered, pharmacist-physician team MTM intervention in reducing unnecessary and inappropriate medication use in community-dwelling, elderly, non-demented subjects. Primary outcome measures will include pre- to post- intervention measures of: (1) use of inappropriate medications as measured by the Medication Appropriateness Index (MAI); 2) Cognitive Reserve Change Score (CRCS) defined as the difference in the scopolamine- challenged vs unchallenged measures on the neurocognitive score. Specific Aim 2 Evaluate the impact of preclinical amyloid burden on cognitive reserve deficits and decline (measured as CRCS) to evaluate efficacy of delaying symptomatic disease progression in pAD. While not eliminating AD or shortening duration of biological disease, the delay in symptom onset and progression to functional decline resulting from reduction in inappropriate medication use could lessen AD prevalence and significantly reduce healthcare expenditures related to not only AD, but potentially all forms of dementia involving a prodromal asymptomatic period. Study results would enable the larger implementation of similar medication management strategies in clinical practice to address the need for multifaceted preventive strategies to maintain cognitive health in the aging population.