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

血液生物标志物作为遗忘性轻度认知障碍有氧运动和/或认知训练治疗反应的替代终点

• 批准号: 9752399
• 负责人: Danni Li
• 金额: $ 49.61万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752399
• 关键词: Aerobic Exercise; Affect; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Ancillary Study; Animals; Biological Markers; Blood; Brain; Brain-Derived Neurotrophic Factor; Cerebrospinal Fluid; Clinical; Cognition; Cognitive; Collection; Educational Intervention; Elderly; Enrollment; Epidemic; Future; Goals; Growth Factor; Health; Hippocampus (Brain); Impaired cognition; Insulin; Intervention; Light; Link; Magnetic Resonance Imaging; Measures; Multiple Sclerosis; Nerve Degeneration; Neurologic; Neuronal Injury; Outcome Measure; Participant; Pathology; Phase; Prevention strategy; Prognostic Marker; Public Health; Randomized; Randomized Controlled Trials; Research; Research Personnel; Single-Blind Study; Site; Structure; Surrogate Endpoint; Testing; Thick; Time; Treatment Protocols; Work; acylcarnitine; amnestic mild cognitive impairment; arm; attentional control; cerebral amyloidosis; clinical application; cognitive change; cognitive training; cost; cost effective; epidemiology study; exercise training; improved; intervention effect; magnetic resonance imaging biomarker; minimally invasive; neurofilament; neurogenesis; prevent; public health relevance; response; tau Proteins; tau-1; treatment response; treatment strategy; trial design

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.

项目概要 阿尔茨海默病 (AD) 是一种对公共卫生影响巨大的流行病，无法预防或预防 AD 预防的随机对照试验 (RCT) 通常使用需要数年时间才能达到的临床终点。 昂贵或侵入性的事件（例如 AD）或替代终点（例如磁共振清单） 成像 [MRI] 或脑脊液生物标志物）代表了临床上适用的替代方案。 随机对照试验的替代终点既具有成本效益又具有微创性。 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，但人们对其作为 AD 预防治疗反应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 的血液生物标志物 本研究的目的是研究血液神经病理学和神经营养学。 生物标志物作为轻度遗忘症老年人对 3 种干预措施的治疗反应的替代终点 认知障碍（aMCI，AD 的前驱阶段）：有氧运动和综合训练； 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的关联我们的中心假设是 血液生物标志物因这 3 种干预措施而发生不同的变化，并预测认知反应 这些干预措施基于 ACT 试验 (1R01AG055469)，这是一项单盲、多中心、2×2 的试验。 析因 II 期随机对照试验，检验 6 个月的 ACT 干预对认知和认知能力的协同效应 MRI 生物标志物（AD 特征皮质厚度和海马体积）（n=128）。 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 12 个月，评估认知能力。 基线、3、6、12 和 18 个月，AD 特征皮质厚度和海马体积将 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 名受试者。 ACT 试验参与者并测量基线、3、6、12 和 18 个月时的血液生物标志物。 是： (1) 确定 6 个月内干预措施对 aMCI 中血液生物标志物的影响； (2) 评估血液； 生物标志物作为替代终点，用于预测 aMCI 中 18 个月以上干预措施的认知反应； (3;探索性)检查血液变化和生物标志物 MRI 响应之间的对应关系 在 aMCI 中进行超过 18 个月的干预措施 我们已经确定了入组、保留和血液的可行性。 我们正在进行的有氧运动对 AD 影响的随机对照试验中，收集了辅助血液生物标志物研究中的数据。 检查 ACT 对血液生物标志物的协同效应以及血液生物标志物作为药物的潜力 作为治疗反应的替代终点，我们的工作将为预防和治疗策略提供信息和推进 AD 中的认知能力下降，可用于改善受 AD 影响的人的健康。