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，无法预防或治疗。 痊愈了预防AD的随机对照试验（RCT）通常使用需要数年时间才能完成的临床终点。 清单（例如，事件AD）或昂贵或侵入性的替代端点（例如，磁共振 成像[MRI]或脑脊液生物标志物）。血液生物标志物代表了临床适用的替代方法 替代终点的随机对照试验，这将是成本效益和微创。重要证据 支持血液生物标志物作为流行病学中认知能力下降和AD风险的预后指标 研究，但很少有人知道他们的价值作为替代终点的治疗反应，在AD预防。 我们研究的长期目标是建立可用于个性化AD的血液生物标志物 预防和治疗。本研究的目的是探讨血液神经病理和神经营养 生物标志物作为3种干预措施治疗轻度遗忘症老年人的替代终点 认知功能障碍（aMCI，AD的前驱期）：有氧运动;认知训练;以及 有氧运动和认知训练（ACT）。我们选择这些生物标志物是因为它们独特的机制， 与脑淀粉样变性、神经变性和神经发生相关。我们的核心假设是， 这3种干预措施导致血液生物标志物发生不同变化，并预测对 这些干预。本研究建立在ACT试验（1 R 01 AG 055469）的基础上，ACT试验是一项单盲、多中心、2×2 析因II期RCT，检查6个月ACT干预对认知的协同作用， MRI生物标志物（AD特征皮质厚度和海马体积）（n=128）。ACT试验将 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。认知能力将在 基线、3个月、6个月、12个月和18个月，AD特征皮质厚度和海马体积将被 在基线、6、12和18个月时通过MRI进行评估。在这项辅助血液生物标志物研究中，我们将招募120名 ACT试验参与者在基线、3、6、12和18个月时测量血液生物标志物。具体目标 （1）确定干预措施对aMCI患者6个月内血液生物标志物的影响;（2）评估血液生物标志物的影响。 作为替代终点的生物标志物，用于预测aMCI患者在18个月内对干预措施的认知反应; 和（3;探索性）检查血液变化与MRI生物标志物之间的对应关系 在aMCI中进行了18个月的干预。我们已经建立了可行性的招生，保留，血液 在我们正在进行的关于有氧运动对AD影响的随机对照试验的辅助血液生物标志物研究中，通过 检查ACT对血液生物标志物的协同作用以及血液生物标志物作为 作为治疗反应的替代终点，我们的工作将为预防和治疗 AD的认知下降，可用于改善受AD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.