Curcumin and Yoga Exercise Effects in Veterans at Risk for Alzheimer's Disease

姜黄素和瑜伽运动对有阿尔茨海默病风险的退伍军人的影响

• 批准号: 8976082
• 负责人: SALLY ANN FRAUTSCHY
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8976082
• 关键词: Activities of Daily Living; Admission activity; Aerobic; Aerobic Exercise; Age; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antihypertensive Agents; Antioxidants; Apolipoprotein E; Attention; Behavioral; Biochemical; Biological Assay; Biological Availability; Biological Markers; Blood; Blood specimen; Brain; Brain imaging; Brain-Derived Neurotrophic Factor; Caring; Cause of Death; Cerebrum; Clinical; Clinical Trials; Cognition; Cognitive; Complement; Control Groups; Curcumin; Data; Degenerative Disorder; Disease Progression; Documentation; Dose; Double-Blind Method; Dropout; Drug Formulations; Early Intervention; Ensure; Epidemiologic Studies; Epidemiology; Evaluation; Exercise; Feedback; Future; Gender; Genetic; Genotype; Heart Rate; Home environment; Human; Impaired cognition; Inflammatory; Insulin; Insulin-Like Growth Factor I; Intervention; Lead; Longitudinal Studies; Maximum Heart Rate; Measurement; Measures; Medical; Memory; Memory Loss; Mental Depression; Methods; Monitor; Neurologic; Neuropsychological Tests; Nursing Homes; Onset of illness; Oral; Outcome; Outcome Study; Participant; Pathogenesis; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phase II Clinical Trials; Physical activity; Placebo Control; Placebos; Plasma; Population; Positron-Emission Tomography; Post-Traumatic Stress Disorders; Prevention trial; Proteins; Quality of life; Questionnaires; Randomized; Rehabilitation therapy; Relative (related person); Reporting; Resistance; Risk; Role; Social Interaction; Staging; Supplementation; Sweat; Sweating; Tauopathies; The Sun; Therapeutic; Time; Training; Training Programs; Translations; Treadmill Tests; Treatment outcome; Veterans; Work; Yoga; apolipoprotein E-4; base; cohort; cost; design; disability; executive function; exhaustion; glucose metabolism; imaging biomarker; improved; indexing; instructor; meetings; mild cognitive impairment; multi-site trial; neuropathology; neuropsychological; neurotrophic factor; novel; patient population; phase 2 study; phase II trial; pre-clinical; programs; response; strength training; sustained attention; synergism; tau Proteins; treatment response; trial design; uptake

DESCRIPTION (provided by applicant): This 12-month randomized double-blind placebo-controlled early Phase II study of older veterans with mild cognitive impairment (MCI) seeks to investigate the role of curcumin for the prevention of Alzheimer's Disease (AD). MCI often represents incipient AD, as underlying AD neuropathology is common in MCI. Over the first 6 months of the study, we will assess curcumin effects on blood-based biomarkers, brain glucose metabolism, and cognitive and functional parameters predictive of AD risk. Preclinical data suggest curcumin targets early and late steps in AD pathogenesis through its anti-oxidant, anti-inflammatory, and anti-tau/A� aggregate activities. Prior studies of curcumin in AD were limited by poor uptake, but we will use a novel curcumin formulation to achieve previously established target free curcumin blood levels, facilitating delivery to the brain. Over the second 6 months of this study, we will assess the potential for synergism between curcumin treatment and aerobic exercise on our biomarker and clinical indices of AD risk. Exercise improves some aspects of cognition and increases IGF-1 and BDNF levels in the brain. These effects are likely to be potentiated by curcumin, which, in addition to its other effects, reduces insulin/neurotrophic factor resistance. General Design: We will examine the effects of 12 months of curcumin supplementation on a panel of plasma biomarkers identified in both the UCLA and ADNI MCI cohorts as indicative of AD risk. Plasma will be collected at 0, 6 and 12 months. Additional endpoints include neuropsychological, behavioral, and functional assessments at 0, 6 and 12 months and FDG-PET brain imaging at 0 and 6 months. Since physical activity levels may independently modulate rates of progression to AD, the second half of the trial will assess for potential additive benefits derived from an aerobi exercise enrichment program. We have chosen Yoga instead of typical treadmill exercise because it includes both resistance training and aerobic poses in specific sequences that may help sustain attention and reduce attrition. Standard Yoga sequences (Sun Salutations) are equivalent to moderate aerobic exercise, and Yoga studies have lower dropout rates than other comparable exercise trials. In the aerobic yoga class, by one month of training, instructors will increase intensity of practice to ensure target heart rates (60-80% of maximum heart rate) are met and subjects are sweating prior to beginning of cool-down sequence. The non-aerobic yoga group controls for potential confounds such as social interaction and active participation and may improve indices of quality of life and depression (compared to baseline), but is unlikely to provide sufficient exercise to improve biomarker or MCI-relevant clinical indices. Objectives: The specific aims are to determine the impact of 12 months of curcumin supplementation on potential plasma biomarkers of AD, brain glucose metabolism, and cognitive, behavioral, and functional endpoints in older veterans with MCI (Aim 1), and to determine whether the addition of an aerobic exercise program can further potentiate the effects of curcumin supplementation (Aim 2). Hypotheses: We hypothesize that curcumin supplementation will improve cerebral glucose metabolism at 6 months, modify blood-based biomarkers of AD risk at 6 and 12 months, and improve cognitive, behavioral, and functional endpoints at 12 months. We further hypothesize that more substantial biomarker and clinical improvements will be seen in the curcumin + aerobic Yoga treatment group relative to the other treatment groups. Potential Outcomes: This work will help evaluate impact of curcumin dosing on selective biomarker changes associated with conversion to AD to establish whether there is sufficient rationale for larger prevention trials (ADCS or VA). This study also develops a new paradigm for assessing the effects of physical activity on AD risk. Both interventions may be more broadly applied to other medical conditions that are prevalent in the larger VA population such as TBI and PTSD. This proposal complements existing longitudinal studies at UCLA that examine biochemical and imaging biomarkers in untreated MCI subjects relative to progressive cognitive decline.

描述（由申请人提供）： 这项为期 12 个月的随机双盲安慰剂对照早期 II 期研究针对患有轻度认知障碍 (MCI) 的老年退伍军人，旨在研究姜黄素在预防阿尔茨海默病 (AD) 中的作用。 MCI 通常代表早期 AD，因为潜在的 AD 神经病理学在 MCI 中很常见。在研究的前 6 个月中，我们将评估姜黄素对血液生物标志物、脑葡萄糖代谢以及预测 AD 风险的认知和功能参数的影响。临床前数据表明，姜黄素通过其抗氧化、抗炎和抗 tau/A� 聚集活性，针对 AD 发病机制的早期和晚期步骤。此前姜黄素在 AD 中的研究因吸收不良而受到限制，但我们将使用一种新型姜黄素配方来实现先前设定的目标游离姜黄素血液水平，从而促进向大脑的输送。在本研究的后 6 个月中，我们将评估姜黄素治疗和有氧运动对 AD 风险生物标志物和临床指数的协同潜力。运动可以改善认知的某些方面，并增加大脑中 IGF-1 和 BDNF 的水平。姜黄素可能会增强这些作用，除了其他作用外，姜黄素还可以降低胰岛素/神经营养因子抵抗。 总体设计：我们将检查补充 12 个月的姜黄素对 UCLA 和 ADNI MCI 队列中确定的一组血浆生物标志物的影响，这些生物标志物可指示 AD 风险。血浆将在 0、6 和 12 个月时收集。其他终点包括 0、6 和 12 个月时的神经心理学、行为和功能评估以及 0 和 6 个月时的 FDG-PET 脑成像。由于体力活动水平可能独立调节 AD 的进展速度，因此试验的后半部分将评估有氧运动强化计划带来的潜在附加益处。我们选择瑜伽而不是典型的跑步机运动，因为它包括阻力训练和特定顺序的有氧姿势，这可能有助于维持注意力并减少消耗。标准瑜伽序列（拜日式）相当于适度的有氧运动，并且瑜伽研究的退出率比其他类似的运动试验要低。在有氧瑜伽课程中，通过一个月的训练，教练将增加练习强度，以确保达到目标心率（最大心率的60-80%），并且受试者在开始冷却序列之前出汗。非有氧瑜伽组控制了潜在的混杂因素，例如社交互动和积极参与，并可能改善生活质量和抑郁指数（与基线相比），但不太可能提供足够的锻炼来改善生物标志物或 MCI 相关临床指数。目标：具体目标是确定补充 12 个月的姜黄素对患有 MCI 的老年退伍军人的 AD 潜在血浆生物标志物、脑葡萄糖代谢以及认知、行为和功能终点的影响（目标 1），并确定添加有氧运动计划是否可以进一步增强姜黄素补充的效果（目标 2）。假设：我们假设补充姜黄素将改善 6 个月时的脑葡萄糖代谢，改变 6 个月和 12 个月时 AD 风险的血液生物标志物，并改善 12 个月时的认知、行为和功能终点。我们进一步假设，相对于其他治疗组，姜黄素+有氧瑜伽治疗组将看到更实质性的生物标志物和临床改善。潜在结果：这项工作将有助于评估姜黄素剂量对与 AD 转化相关的选择性生物标志物变化的影响，以确定是否有足够的理由进行更大规模的预防试验（ADCS 或 VA）。这项研究还开发了一种新的范式来评估体力活动对 AD 风险的影响。这两种干预措施可能更广泛地应用于更多退伍军人群体中普遍存在的其他医疗状况，例如创伤性脑损伤和创伤后应激障碍。该提案补充了加州大学洛杉矶分校现有的纵向研究，该研究检查了未经治疗的 MCI 受试者与进行性认知衰退相关的生化和影像生物标志物。