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

项目摘要 目前的建议，在响应PAR-17-029，旨在促进我们的理解，如何串扰 脂肪组织（AT）和大脑之间的相互作用可能有助于阿尔茨海默病（AD）的病理生理学。 科学的前提是基于这样一个事实，即虽然身体质量指数（BMI）是AD的独立预测因子， 在中年和晚年，与这种粗略的全球肥胖衡量标准的关联被衰老所混淆- AT分布和功能的相关变化。尽管潜在的机制仍有待阐明， 很明显，BMI不足以完全了解AD的肥胖相关风险。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 可能提供关键的洞察重叠的分子途径连接这些疾病。我们的初步 数据表明，在中央/内脏（VAT）库中AT的量较大， 外周/皮下（SAT）贮库与脑脊液（CSF）生物标志物谱相关 表明AD病理学增加。此外，为了尽量减少在爆炸后保护性SAT仓库的损失， 生酮饮食可能有利地影响AD病理学。为了证实和扩展这些发现，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， 一项随机临床试验，旨在检查4个月的改良地中海生酮 (MMK)饮食与美国心脏协会（AHA）低脂肪饮食对120名成年人（年龄：55岁至 85岁），患有遗忘型轻度认知功能障碍（aMCI）（R 01 AG 055122; PI：Craft）。拟定的研究将 利用正在进行的研究程序、数据和样本生成关于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它们通过饮食的调节。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成像也将在 用来量化葡萄糖摄取的变化（即，代谢活性）。最后， 储存的血液和CSF将用于评估循环脂肪因子和AT衍生的外来体的变化。到 补充正在进行的收集CSF，FDG-PET，淀粉样蛋白PET和结构/功能MRI， 拟议的研究还将在一个参与者子集（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，对整个AD谱的参与者进行分类。这 及时、具有成本效益和创新性的研究不仅会扩大母试验的范围和影响，而且会 并解决实地的重大差距。在MMK背景下研究AT分布和功能 饮食可能揭示新的目标，是服从干预和新的治疗剂，可以改变 AD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.