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

项目总结 本提案是对PAR-17-029的回应，旨在增进我们对串扰 脂肪组织(AT)和脑之间的相互作用可能参与阿尔茨海默病(AD)的病理生理过程。 科学前提是基于这样一个事实：虽然身体质量指数(BMI)是AD的独立预测因子 在中年和晚年，与这一粗略的全球肥胖指标的联系因年龄增长而变得混乱。 AT分布和功能的相关变化。尽管其潜在的机制仍有待阐明， 很明显，BMI还不足以完全了解肥胖与AD相关的风险。饮食影响 肥胖和AD的风险，并调查可以调节AT和大脑的饮食干预 可能对连接这些疾病的重叠的分子通路提供关键的洞察力。我们的预赛 数据表明，在中央/内脏(VAT)仓库中AT含量较高，而在 外周/皮下(SAT)储存库与脑脊液(CSF)生物标记物特征相关 预示着AD病理的增加。此外，将保护SAT仓库的损失降至最低 生酮饮食可能有利于AD的病理改变。为了证实和扩大这些研究结果，我们建议 对阿尔茨海默病中淀粉样蛋白转化的大脑能量进行辅助研究(BEAT-AD)试验，2期 一项随机临床试验，旨在检查为期4个月的改良地中海生酮药物的疗效 (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55岁)脑健康的影响 85岁)患有遗忘性轻度认知障碍(AMCI)(R01AG055122；PI：CRATURE)。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对它们的调节。具体来说，CT成像将是 利用来量化VAT、SAT和肌间AT横截面面积和密度的变化 腹部和大腿，以及肝脏和骨骼肌的脂肪渗透。FDG-PET成像也将 用来量化AT感兴趣仓库中葡萄糖摄取(即代谢活动)的变化。最后， 储存的血液和脑脊液将被用来评估循环脂肪因子和AT衍生的外切体的变化。至 补充脑脊液、FDG-PET、淀粉样蛋白PET和结构/功能磁共振成像的持续收集， 拟议的研究还将在一组参与者(n=60)中添加18F-AV-1451tau 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、经济、创新的研究不仅将扩大家长试验的范围和影响，而且将 还应解决该领域的重要差距。在MMK背景下考察AT的分布和功能 饮食可能揭示出易于干预的新靶点，以及可以改变心脏功能的新治疗剂 公元后的轨迹。

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.