Blood Biomarkers as Surrogate Endpoints of Treatment Responses to Aerobic Exercise and/or Cognitive Training in Amnestic Mild Cognitive Impairment

项目摘要 阿尔茨海默病(AD)是一种具有巨大公共卫生影响的流行病，无法预防或 治愈了。用于预防AD的随机对照试验(RCT)通常使用临床终点，这些终点需要数年时间才能 显示(例如，事件AD)或昂贵或侵入性(例如，磁共振)的代理终端 成像[核磁共振成像]或脑脊液生物标志物)。血液生物标记物代表了一种临床适用的替代方案 RCT的替代终点，既经济有效，又具有最小的侵入性。重要证据 支持血液生物标记物在流行病学中作为认知功能下降和AD风险的预后指标 研究，但对它们作为AD预防治疗反应的替代终点的价值知之甚少。 我们研究的长期目标是建立可用于个性化AD的血液生物标记物 预防和治疗。本研究的目的是研究血液中神经病理和神经营养。 生物标志物作为3种干预措施对老年人轻度遗忘症治疗反应的替代终点 认知障碍(aMCI，AD的前驱阶段)：有氧运动；认知训练；以及综合 有氧运动和认知训练(ACT)。我们选择这些生物标记物是因为它们独特的机制 与脑淀粉样变性、神经退行性变和神经发生的关系。我们的中心假设是 血液生物标志物因这三种干预措施而发生不同的变化，并预测认知反应 这些干预措施。本研究建立在ACT试验(1R01AG055469)的基础上，该试验为单盲、多点、2×2 析因第二阶段随机对照试验，考察为期6个月的ACT干预对认知和 MRI生物标志物(AD标志物皮质厚度和海马体积)(n=128)。ACT审判将 将患有aMCI的老年人随机分为4组(有氧运动、认知训练、ACT和 注意力控制)6个月，然后再跟踪他们12个月。认知能力评估将在 基线、3、6、12和18个月，AD标志性皮质厚度和海马体体积将为 在基线、6个月、12个月和18个月时进行MRI评估。在这项辅助血液生物标记物研究中，我们将招募120名 在基线、3个月、6个月、12个月和18个月时，执行试验参与者并测量血液生物标记物。具体目标 包括：(1)确定干预措施对aMCI患者6个月内血液生物标记物的影响；(2)评估血液 生物标记物作为预测18个月以上急性MCI患者干预后认知反应的替代终点； 以及(3)探索性地检查血液变化和MRI生物标记物之间的对应关系 在AMCI的18个月以上的干预。我们已经确定了招生、留校和抽血的可行性 在我们正在进行的有氧运动对AD影响的随机对照试验中，收集辅助血液生物标记物的研究。通过 检测ACT对血液生物标记物的协同作用及其作为 作为治疗反应的替代终点，我们的工作将告知并推进预防和治疗策略 阿尔茨海默病的认知功能下降，这可以用来改善受阿尔茨海默病影响的人的健康。

Project Summary Alzheimer’s disease (AD) is an epidemic with tremendous public health impacts, and cannot be prevented or cured. Randomized controlled trials (RCTs) for AD prevention often use clinical endpoints that take years to manifest (e.g., incident AD) or surrogate endpoints that are costly or invasive (e.g., magnetic resonance imaging [MRI] or cerebrospinal fluid biomarkers). Blood biomarkers represent a clinically applicable alternative surrogate endpoint for RCTs that would be both cost-effective and minimally invasive. Significant evidence supports blood biomarkers as prognostic indicators of cognitive decline and risk of AD in epidemiological studies, but little is known about their value as surrogate endpoints for treatment responses in AD prevention. The long-term goal of our research is to establish blood biomarkers that can be used to personalize AD prevention and treatment. The objective of this study is to investigate blood neuropathological and neurotrophic biomarkers as surrogate endpoints for treatment responses to 3 interventions in older adults with amnestic mild cognitive impairment (aMCI, a prodromal stage of AD): aerobic exercise; cognitive training; and combined aerobic exercise and cognitive training (ACT). We chose these biomarkers for their unique mechanistic associations with cerebral amyloidosis, neurodegeneration and neurogenesis. Our central hypothesis is that blood biomarkers change differently as a result of these 3 interventions and predict cognitive responses to these interventions. This study is built on the ACT Trial (1R01AG055469), a single-blinded, multi-site, 2×2 factorial Phase II RCT that examines the synergistic effects of a 6-month ACT intervention on cognition and MRI biomarkers (AD-signature cortical thickness and hippocampal volume) (n=128). The ACT Trial will randomize older adults with aMCI equally to 1 of 4 groups (aerobic exercise, cognitive training, ACT, and attention control) for 6 months and then follow them for another 12 months. Cognition will be assessed at baseline, 3, 6, 12, and 18 months, and AD-signature cortical thickness and hippocampal volume will be assessed by MRI at baseline, 6, 12, and 18 months. In this ancillary blood biomarker study, we will enroll 120 ACT Trial participants and measure blood biomarkers at baseline, 3, 6, 12, and 18 months. The specific aims are: (1) Determine the effects of interventions on blood biomarkers over 6 months in aMCI; (2) Evaluate blood biomarkers as surrogate endpoints for predicting cognitive responses to interventions over 18 months in aMCI; and (3; exploratory) Examine the correspondence between changes in blood and MRI biomarkers in response to interventions over 18 months in aMCI. We have established the feasibility of enrollment, retention, and blood collections in an ancillary blood biomarker study in our ongoing RCT of aerobic exercise effects in AD. By examining the synergistic effects of ACT on blood biomarkers and the potential of blood biomarkers as surrogate endpoints for treatment responses, our work will inform and advance strategies to prevent and treat cognitive decline in AD, which can be used to improve the health of those impacted by AD.