Investigating Gains in Neurocognition in an Intervention Trial of Exercise

1摘要。 2在这一相互竞争的修订中，我们建议扩大目前资助的多地点 3第三阶段临床试验，IGNITE（调查在神经认知的干预试验中的收益， 4运动），包括12个月体力活动（PA）干预后的Aβ测量。 5尽管认识到Aβ积累在AD中的重要性，但目前没有 6种有效的治疗方法来减缓或逆转沉积。中等强度PA是最常见的 7种有前途的非药物方法，用于减轻与年龄相关的认知能力下降， 8降低神经退行性疾病如AD的风险。然而，PA的有效性 由于缺乏控制良好的第三阶段， 10临床试验为了解决这种持续的怀疑，我们的团队开发了一项III期临床试验， IGNITE（Investigating Gains in Neurocognition in an Intervention Trial of Exercise，运动干预试验中神经认知的研究）这 2016年资助的12项研究旨在明确PA是否能改善认知和 13脑健康IGNITE研究旨在解决几个主要问题，包括 14 Aβ的存在是否缓和了运动干预对认知或 15其他大脑结果（例如，海马体积）。IGNITE研究还旨在 16研究运动对大脑的潜在机制。我们有一个独特的机会， 在正在进行的IGNITE研究的随访中，17例PET Aβ，这将使我们能够测试一些关键的 18个目标因此，该竞争性翻修将利用IGNITE试验的规模和严格性（N = 639） 19检查12个月的中等强度PA是否改变了Aβ病理学， 20名认知健康的老年人。具体而言，我们将测试：（a）12个月的PA是否 与非有氧对照组相比，干预减弱了Aβ水平，以及（B）是否 22种变化以剂量依赖性方式发生。我们还将检测Aβ的变化是否介导了 23运动引起的认知变化，并将测试是否运动引起的变化， 24种心脏代谢、炎症和神经营养因子在统计学上介导Aβ的变化 25负担这一建议是解决是否可以适用PA的独特机会 26作为一种低成本、易于推广的方法来缓解Aβ蓄积。的成果 IGNITE将对我们治疗和预防糖尿病的方式产生巨大影响。 28 AD，并有潜力推进老年学，神经科学和公共卫生领域。 29 30 31 32

1 Abstract. 2 In this competing revision we propose to expand the scope of the currently funded multi-site 3 Phase III clinical trial, IGNITE (Investigating Gains in Neurocognition in an Intervention Trial of 4 Exercise) to include measurement of Aβ following a 12-month physical activity (PA) intervention. 5 Despite an appreciation for the importance of Aβ accumulation in AD, there are currently no 6 effective treatments to slow or reverse deposition. Moderate intensity PA is one of the most 7 promising non-pharmaceutical approaches for mitigating age-related cognitive decline and 8 reducing risk for neurodegenerative conditions like AD. Unfortunately, the effectiveness of PA 9 remains a matter of continued skepticism because of the lack of a well-controlled Phase III 10 clinical trial. To address this continued skepticism, our team developed a Phase III clinical trial 11 called IGNITE (Investigating Gains in Neurocognition in an Intervention Trial of Exercise). This 12 study, funded in 2016, was designed to definitively address whether PA improves cognitive and 13 brain health. The IGNITE study was designed to address several major questions including 14 whether the presence of Aβ moderates the impact of the exercise intervention on cognitive or 15 other brain outcomes (e.g., hippocampal volume). The IGNITE study was also designed to 16 examine potential mechanisms of exercise on the brain. We have a unique opportunity to add 17 PET Aβ at follow-up to the ongoing IGNITE study which will allow us to test a number of critical 18 aims. Thus, this competing revision will leverage the size and rigor of the IGNITE trial (N = 639) 19 to examine whether 12 months of moderate intensity PA modifies Aβ pathology among 20 cognitively healthy older adults. Specifically, we will test: (a) whether a 12-month PA 21 intervention attenuates Aβ levels compared to a non-aerobic control group and (b) whether 22 changes occur in a dose-dependent manner. We will also test whether changes in Aβ mediate 23 exercise-induced changes in cognition and will test whether exercise-induced changes in 24 cardiometabolic, inflammatory, and neurotrophic factors statistically mediate changes in Aβ 25 burden. This proposal represents a unique opportunity to resolve whether PA could be applied 26 as a low cost, easily disseminated approach to mitigate Aβ accumulation. The outcomes of 27 IGNITE will have enormous implications for the way we approach treatment and prevention of 28 AD, and has the potential to advance the fields of gerontology, neuroscience, and public health. 29 30 31 32