Dietary Effects on Imaging and Fluid-based Biomarkers of the Adipose-Brain Axis in Alzheimers Disease

饮食对阿尔茨海默病脂肪脑轴成像和基于液体的生物标志物的影响

• 批准号: 10133495
• 负责人: Tina E Brinkley
• 金额: $ 68.53万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10133495
• 关键词: Abdomen; Address; Adipose tissue; Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American Heart Association; Amyloid; Amyloid beta-42; Ancillary Study; Area; Attenuated; Biological Markers; Blood; Blood specimen; Body Weight; Body fat; Body mass index; Brain; Carbohydrates; Cerebral small vessel disease; Cerebrospinal Fluid; Clinical Trials Design; Cognition; Collection; Complement; Complement Factor D; Data; Deposition; Diet; Dietary Intervention; Disease; Disease Progression; Drug or chemical Tissue Distribution; Elderly; Fat-Restricted Diet; Functional Magnetic Resonance Imaging; Functional disorder; Generations; Genotype; Goals; Health; Hormone secretion; Image; Impairment; Infiltration; Insulin Resistance; Intervention; Leptin; Link; Liquid substance; Liver; Magnetic Resonance Imaging; Measures; Mediating; Memory; Metabolic; Metabolic Marker; Metabolism; MicroRNAs; Molecular; Muscle; Nerve Degeneration; Obesity; Organ; Overweight; PET/CT scan; Parents; Participant; Pathway interactions; Peripheral; Phase; Play; Positron-Emission Tomography; Procedures; Process; Randomized Clinical Trials; Research; Risk; Role; Sampling; Skeletal Muscle; Structure; Testing; Therapeutic Agents; Therapeutic Intervention; Thigh structure; Time; Tissue imaging; Visceral; White Matter Hyperintensity; X-Ray Computed Tomography; adipokines; adiponectin; aged; amnestic mild cognitive impairment; base; brain health; cost effective; cytokine; density; dietary; effective therapy; exosome; fluorodeoxyglucose positron emission tomography; glucose uptake; glycemic control; improved; innovation; insight; interest; ketogenic diet; lipid metabolism; middle age; nervous system disorder; neuroinflammation; neuropathology; novel; novel therapeutics; prevent; resistin; response; subcutaneous; tau Proteins; tau-1

PROJECT SUMMARY The present proposal, in response to PAR-17-029, seeks to advance our understanding of how crosstalk between adipose tissue (AT) and the brain may contribute to the pathophysiology of Alzheimer's disease (AD). The scientific premise is based on the fact that while body mass index (BMI) is an independent predictor of AD in both mid- and late-life, the association with this crude global measure of obesity is confounded by aging- related changes in AT distribution and function. Although the underlying mechanisms remain to be elucidated, it is clear that BMI is not sufficient to fully understand the obesity-associated risks for AD. Diet influences the risk of both obesity and AD, and investigating dietary interventions that can modulate both AT and the brain may provide critical insight into the overlapping molecular pathways linking these diseases. Our preliminary data suggest that greater amounts of AT in central / visceral (VAT) depots and lower amounts of AT in peripheral / subcutaneous (SAT) depots are associated with a cerebrospinal fluid (CSF) biomarker profile indicative of increased AD pathology. Moreover, minimizing the loss of protective SAT depots following a ketogenic diet may favorably impact AD pathology. To confirm and extend these findings, we propose to conduct an ancillary study to the Brain Energy for Amyloid Transformation in AD (BEAT-AD) trial, a phase 2 randomized clinical trial designed to examine the effects of a 4-month Modified Mediterranean Ketogenic (MMK) diet versus an American Heart Association (AHA) low-fat diet on brain health in 120 adults (age: 55 to 85 years) with amnestic mild cognitive impairment (aMCI) (R01AG055122; PI: Craft). The proposed study will leverage ongoing study procedures, data, and samples to generate new data on AT distribution and function, including their relationship with AD biomarkers and their modulation by diet. Specifically, CT imaging will be leveraged to quantify changes in the cross-sectional area and density of VAT, SAT, and intermuscular AT in the abdomen and thigh, as well as fatty infiltration of liver and skeletal muscle. FDG-PET imaging will also be leveraged to quantify changes in glucose uptake (i.e., metabolic activity) in AT depots of interest. Finally, stored blood and CSF will be used to assess changes in circulating adipokines and AT-derived exosomes. To complement the ongoing collection of CSF, FDG-PET, amyloid PET, and structural/functional MRI, the proposed study will also add 18F-AV-1451 tau PET in a subset of participants (n=60), which will enhance the categorization of participants across the AD spectrum as defined by the NIA-AA Research Framework. This timely, cost-effective, and innovative study will not only expand the scope and impact of the parent trial, but will also address important gaps in the field. Investigating AT distribution and function in the context of the MMK diet may reveal novel targets that are amenable to intervention and new therapeutic agents that can alter the trajectory of AD.

项目概要 本提案是针对 PAR-17-029 的回应，旨在加深我们对串扰如何产生的理解。 脂肪组织（AT）和大脑之间的相互作用可能与阿尔茨海默病（AD）的病理生理学有关。 科学前提基于以下事实：虽然体重指数 (BMI) 是 AD 的独立预测因子 在中年和晚年，与这种粗略的全球肥胖衡量标准的关联受到衰老的影响—— AT分布和功能的相关变化。尽管潜在的机制仍有待阐明， 显然，BMI 不足以充分了解与肥胖相关的 AD 风险。饮食影响 肥胖和 AD 的风险，并研究可以调节 AT 和大脑的饮食干预措施 可能为连接这些疾病的重叠分子途径提供重要的见解。我们的初步 数据表明，中央/内脏 (VAT) 仓库中的 AT 数量较多，而 外周/皮下 (SAT) 储库与脑脊液 (CSF) 生物标志物谱相关 表明 AD 病理增加。此外，最大限度地减少 SAT 保护站的损失 生酮饮食可能会对 AD 病理产生有利的影响。为了确认并扩展这些发现，我们建议 对 AD 中淀粉样蛋白转化的脑能量 (BEAT-AD) 试验进行辅助研究，这是第二阶段 旨在检验 4 个月改良地中海生酮效果的随机临床试验 (MMK) 饮食与美国心脏协会 (AHA) 低脂饮食对 120 名成年人（年龄：55 岁至 85 岁）患有遗忘性轻度认知障碍（aMCI）（R01AG055122；PI：Craft）。拟议的研究将 利用正在进行的研究程序、数据和样本来生成有关 AT 分布和功能的新数据， 包括它们与 AD 生物标志物的关系以及饮食的调节。具体而言，CT 成像将 用于量化 VAT、SAT 和肌间 AT 的横截面积和密度的变化 腹部和大腿，以及肝脏和骨骼肌的脂肪浸润。 FDG-PET 成像也将 用于量化感兴趣的 AT 库中葡萄糖摄取（即代谢活动）的变化。最后， 储存的血液和脑脊液将用于评估循环脂肪因子和 AT 衍生的外泌体的变化。到 补充了正在进行的 CSF、FDG-PET、淀粉样蛋白 PET 和结构/功能 MRI 收集， 拟议的研究还将在一部分参与者 (n=60) 中添加 18F-AV-1451 tau PET，这将增强 根据 NIA-AA 研究框架的定义，对 AD 范围内的参与者进行分类。这 及时、具有成本效益且创新的研究不仅会扩大母体试验的范围和影响，而且将 还解决了该领域的重要差距。在 MMK 背景下研究 AT 分布和功能 饮食可能会揭示适合干预的新目标和可以改变的新治疗药物 AD的轨迹。