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

描述（由申请人提供）：本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的挑战主题05-AG-105 -包括神经退行性疾病在内的衰老疾病和Syndrome的比较干预试验。老年认知功能下降与独立性丧失、日常生活活动功能下降、养老院安置和死亡率有关。认知能力下降是否作为正常衰老过程的一部分普遍发生，或者是处于发展阿尔茨海默病（AD）风险的老年人亚组中亚临床疾病活动的结果，这是一个科学争论的问题。目前，年龄较大，AD家族史（FH）和APOE e4等位基因的存在是非痴呆个体未来认知能力下降的最佳预测因素，如果不完美的话。我们的初步研究表明，功能磁共振成像（fMRI），使用语义激活任务，区分认知完整的老年人的风险，为AD从那些没有风险，可以预测未来的认知能力下降，否则健康的老年人。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）没有发表的研究直接比较CT与ET在改善认知功能方面的疗效，（2）没有研究检查联合治疗（CT+ET）是否优于单一干预措施（上级）（单独CT或ET），（3）神经心理学测试，干预试验的主要结局指标，没有提供有关的信息，潜在的神经变化，介导认知改善，和（4）干预措施已针对非特定群体的老年人，而不是针对老年人的风险，为发展AD。为了解决我们知识中的这些差距，我们提出了一个单一的具体目标，即进行一项为期12周的四组随机对照临床试验，以比较CT，ET和联合训练（CT+ET）相对于主动对照（AC）的疗效，包括教育和灵活性训练。主要结果测量是任务激活的fMRI，次要结果评估与认知，ADL和健身评估。目标干预人群将包括认知功能完整但身体活动不活跃的老年人，这些老年人基于FH和APOE e4阳性状态而有发生AD的风险。该项目将是第一个（1）比较CT，ET和联合干预的相对有效性;（2）使用功能性神经成像来评估干预有效性;（3）干预有发展AD风险的老年人。长期目标是评估有效，低风险和相对便宜的干预措施，以解决认知能力下降，对控制与美国不断增加的老龄化人口的医疗保健提供相关的成本具有巨大的影响。 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，或者联合治疗（CT+ET）是否上级单一干预。我们也不了解介导认知改善的大脑变化，或者这些治疗方法是否适用于有患阿尔茨海默病（AD）风险的健康老年人。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）相对于主动对照（包括教育和灵活性训练）的疗效。主要结果测量是任务激活的功能磁共振成像，次要结果评估与认知，日常生活活动和健身评估。目标干预人群将包括认知功能完整但身体活动不活跃的老年人，这些老年人有患AD的风险。总体目标是评估低风险和相对便宜的干预措施对解决老年认知能力下降的有效性。

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.