Neural Effects of Exercise, Cognitive, or Combined Training in AD At-Risk Elders

描述(由申请人提供)：这项ARRA挑战资助申请涉及广泛的挑战领域(05)-比较有效性研究和特定挑战主题05-AG-105-针对包括神经退行性疾病在内的老龄化疾病和症状的比较干预试验。老年人的认知能力下降与丧失独立性、日常生活活动功能下降、养老院安置和死亡率有关。认知衰退是作为正常衰老过程的一部分出现的，还是由于阿尔茨海默病(AD)高危老年人亚临床疾病活动的结果，这是一个科学争论的问题。目前，高龄、AD家族史(FH)和APOE e4等位基因的存在是预测非痴呆个体未来认知功能下降的最好的(如果不完美的)指标。我们的初步研究表明，使用语义激活任务的功能磁共振成像(FMRI)可以区分认知完好的AD风险老年人和非AD风险老年人，并可以预测其他健康老年人未来的认知能力下降。已发表的试验表明，短期认知训练(CT)和有氧运动训练(ET)干预对健康老年人的认知能力有积极影响。尽管有这些积极的结果，(1)没有公开发表的研究直接比较CT和ET在改善认知功能方面的疗效，(2)没有研究探讨联合治疗(CT+ET)是否优于单一干预(CT或ET)，(3)干预试验的主要结果指标神经心理测试没有提供与调节认知改善的潜在神经变化有关的信息，以及(4)干预措施针对非特定老年人群体，而不是针对患阿尔茨海默病的风险较高的老年人。为了解决我们知识中的这些差距，我们提出了一个具体的目标，即进行一项为期12周的四臂随机对照临床试验，以比较CT、ET和联合训练(CT+ET)相对于主动对照(AC)的疗效，AC包括教育和灵活性训练。主要的结果衡量标准是任务激活功能磁共振成像，次要结果通过认知、ADL和健康评估进行评估。目标干预人群将包括认知完好但身体不活跃的老年人，基于FH和APOE e4阳性状态，有发展为AD的风险。该项目将首次(1)比较CT、ET和联合干预的相对有效性；(2)使用功能神经成像来评估干预效果；(3)对有患AD风险的老年人进行干预。长期目标是评估有效、低风险和相对廉价的干预措施，以解决认知能力下降的问题，并对控制与向美国不断增长的老龄化人口提供医疗保健相关的成本产生巨大影响。 公共卫生相关性：已发表的试验表明，短期认知训练(CT)和有氧运动训练(ET)干预对健康老年人的认知能力有积极影响。尽管有这些积极的结果，我们不知道CT和ET在改善认知功能方面的相对疗效，也不知道联合治疗(CT+ET)是否优于单一干预。我们也不知道大脑的变化是调节认知改善的，也不知道这种治疗方法是否对有患阿尔茨海默病(AD)风险的健康老年人有效。在这项为期12周的随机临床试验中，我们将比较CT、ET和联合训练(CT+ET)与积极对照(包括教育和灵活性训练)的疗效。主要的结果衡量标准是任务激活功能磁共振成像，次要结果通过认知、日常生活能力和健康评估进行评估。目标干预人群将包括认知完好、但身体不活跃、有患AD风险的老年人。总体目标是评估低风险和相对廉价的干预措施在解决老年人认知能力下降问题上的有效性。

DESCRIPTION (provided by applicant): This ARRA Challenge Grant application addresses Broad Challenge Area (05) - Comparative Effectiveness Research and Specific Challenge Topic 05-AG-105 - Comparative Intervention Trials for Diseases and Syndromes of Aging Including Neurodegenerative Diseases. Cognitive decline in older age is associated with loss of independence, functional decline in activities of daily living, nursing home placement, and mortality. Whether cognitive declines occur universally as part of the normal aging process or are the result of subclinical disease activity in a subgroup of elders at-risk for developing Alzheimer's disease (AD) is a matter of scientific debate. At present, older age, family history (FH) of AD, and the presence of the APOE e4 allele are the best, if imperfect, predictors of future cognitive decline in non-demented individuals. Our preliminary studies indicate that functional MRI (fMRI), using a semantic activation task, differentiates cognitively intact elders at-risk for AD from those not at-risk and can predict future cognitive decline in otherwise healthy older individuals. Published trials have demonstrated positive effects of short-term cognitive training (CT) and aerobic exercise training (ET) interventions on cognitive abilities in healthy elders. Despite these positive results, (1) there exist no published studies directly comparing the efficacy of CT to ET in improving cognitive function, (2) no study examining whether a combined treatment (CT+ET) would be superior to a single intervention (CT or ET alone), (3) neuropsychological testing, the primary outcome measure of intervention trials, does not provide information pertaining to the underlying neural changes that mediate cognitive improvement, and (4) interventions have been aimed at non-specific groups of elders rather than targeting elders at-risk for developing AD. To address these gaps in our knowledge, we propose a single specific aim, namely to conduct a 12-week, four-arm, randomized, controlled, clinical trial to compare the efficacy of CT, ET, and Combined Training (CT+ET) relative to an Active Control (AC), consisting of educational and flexibility training. The primary outcome measure is task-activated fMRI, with secondary outcomes assessed with cognitive, ADL, and fitness assessments. The target intervention population will consist of cognitively intact, but physically inactive, older adults at-risk for developing AD based on a positive FH and APOE e4 status. This project will be the first to (1) compare the relative efficacy of CT, ET, and a combined intervention; (2) use functional neuroimaging to assess intervention efficacy; and (3) intervene in older individuals at risk for developing AD. The long-range goal is to evaluate effective, low-risk, and relatively inexpensive interventions for addressing cognitive decline, with enormous implications for containing costs associated with health-care delivery to the ever increasing aging population of the United States. PUBLIC HEALTH RELEVANCE: Published trials have demonstrated positive effects of short-term cognitive training (CT) and aerobic exercise training (ET) interventions on cognitive abilities in healthy elders. Despite these positive results, we do not know the relative efficacy of CT and ET in improving cognitive function or whether a combined treatment (CT+ET) would be superior to a single intervention. We also do not understand the brain changes that mediate cognitive improvement or whether the treatments would work in healthy elders at-risk for developing Alzheimer's disease (AD). In this 12-week, randomized, clinical trial, we will compare the efficacy of CT, ET, and Combined Training (CT+ET) relative to an Active Control, consisting of educational and flexibility training. The primary outcome measure is task-activated fMRI, with secondary outcomes assessed with cognitive, activities of daily living, and fitness assessments. The target intervention population will consist of cognitively intact, but physically inactive, older adults at-risk for developing AD. The overall goal is to evaluate the efficacy of low-risk and relatively inexpensive interventions for addressing cognitive decline in older age.