Efficacy and Mechanisms of Combined Aerobic Exercise and Cognitive Training in MCI (The ACT Trial)

因为几乎所有治疗阿尔茨海默病(AD)的药物试验都失败了，开发出了非药理学的 有很大潜力在高危人群中预防或推迟AD发病的干预措施(例如， 轻度认知障碍[MCI])至关重要。有氧运动和认知训练是两个很有前途的 预防AD的干预措施。有氧运动增加有氧健身，进而改善大脑 结构和功能，而认知训练则密集地改善选择性神经功能。因此，组合在一起 有氧运动和认知训练(ACT)很可能对认知有相加或协同作用 通过不同神经功能的互补强化。很少有研究测试ACT的效果，而且 这些研究报告了不同的发现，很大程度上是由于ACT计划的不同。这样做的目的是 单盲、2×2析因II期随机对照试验 为期6个月的联合循环和处理速度(SOP)训练干预的相加/协同效应 关于认知和相关机制(有氧适应、AD信号皮质厚度和功能 遗忘性MCI(AMCI)的老年人的默认模式网络中的连通性。我们的预赛 研究表明，增强的有氧体能与更好的认知和休息状态有关 AD患者DMN中的功能连接，以及约20小时的SOP培训可改善执行功能和 在aMCI中维护DMN中的功能连接。这项随机对照试验将128名参与者平均随机分配到4名 手臂：行动，仅骑自行车，仅SOP训练，或6个月的注意力控制，然后跟随他们另一个月 12个月。将在基线、3个月、6个月、12个月和18个月评估认知和有氧适应能力；AD签名 在基线、6个月、12个月和18个月时，DMN的皮质厚度和功能连接性；在3个月时， 6个月、12个月和18个月。具体目标是：目标一.确定药物的功效和相加/协同作用 对认知采取行动超过6个月。H1：ACT将对执行功能和插曲产生最大影响 与其他组的记忆进行比较。目的II.研究ACT在6个月内的潜在机制。H_2A： ACT将对AD信号的皮质厚度、DMN中的功能连接性产生最大影响，以及 与其他组的有氧健身进行比较。H2B：机制措施的变化与以下方面有关 认知变化。H_2c：AD信号皮质厚度的变化和DMN介导有氧健身的影响 关于认知。目标三(探索性)。计算ACT对认知和临床的远期效应大小 病理性AD转换以通知未来的III期RCT。分析将使用意向处理和线性 混合效果建模。这项试验将首次测试在认知和机制上的协同效应 (与AD相关的神经退行性变相关)中独特的概念化和严格设计的ACT 患有急性心肌梗塞的老年人。它将通过提供准确的效果大小估计来推进AD预防研究 采取干预措施。我们的长期目标是延缓AD的发病和进展。

Because almost all drug trials for Alzheimer's disease (AD) have failed, developing non-pharmacological interventions with strong potential to prevent or delay the onset of AD in high-risk populations (e.g., those with mild cognitive impairment [MCI]) is critically important. Aerobic exercise and cognitive training are 2 promising interventions for preventing AD. Aerobic exercise increases aerobic fitness, which in turn improves brain structure and function, while cognitive training improves selective neural function intensively. Hence, combined Aerobic exercise and Cognitive Training (ACT) may very well have an additive or synergistic effect on cognition by complementary strengthening of different neural functions. Few studies have tested ACT's effects, and those studies have reported discrepant findings, largely due to varying ACT programs. The purpose of this single-blinded, 2×2 factorial Phase II randomized controlled trial (RCT) is to test the efficacy and additive/synergistic effects of a 6-month combined cycling and speed of processing (SOP) training intervention on cognition and relevant mechanisms (aerobic fitness, AD signature cortical thickness, and functional connectivity in the default mode network [DMN]) in older adults with amnestic MCI (aMCI). Our preliminary studies have shown that enhanced aerobic fitness is associated with better cognition and resting-state functional connectivity in the DMN in AD, and ~20 hours of SOP training improves executive function and maintains functional connectivity in the DMN in aMCI. This RCT will randomize 128 participants equally to 4 arms: ACT, cycling only, SOP training only, or attention control for 6 months, and then follow them for another 12 months. Cognition and aerobic fitness will be assessed at baseline, 3, 6, 12, and 18 months; AD signature cortical thickness and functional connectivity in the DMN at baseline, 6, 12, and 18 months; AD conversion at 3, 6, 12, and 18 months. The specific aims are to: Aim I. Determine the efficacy and additive/synergistic effects of ACT on cognition over 6 months. H1: ACT will have the greatest effects on executive function and episodic memory compared with other groups. Aim II. Examine the underlying mechanisms of ACT over 6 months. H2a: ACT will have the greatest effects on AD signature cortical thickness, functional connectivity in the DMN, and aerobic fitness compared with other groups. H2b: Changes in the mechanistic measures are related to cognitive changes. H2c: Changes in AD signature cortical thickness and DMN mediate aerobic fitness' effects on cognition. Aim III (exploratory). Calculate the long-term effect sizes of ACT on cognition and clinical and pathological AD conversion to inform future Phase III RCTs. Analysis will use intention-to-treat and linear mixed-effect modeling. This trial will be the first to test the synergistic effects on cognition and mechanisms (relevant to AD-associated neurodegeneration) of a uniquely conceptualized and rigorously designed ACT in older adults with aMCI. It will advance AD prevention research by providing precise effect-size estimates of the ACT intervention. Our long-term goal is to delay AD onset and slow AD progression.