Imaging cerebral metabolic impairment in AD using Deuterium MRI

项目总结/摘要 本项目将研究氘（2 H）代谢成像（氘）作为一种定量的稳定同位素MR 分子影像学方法探测阿尔茨海默病（AD）的脑代谢损伤。AD和 相关痴呆代表了日益增长的公共卫生问题，对患者及其 家庭有效治疗AD的努力部分地被关于其起始的不同假设所混淆 和进展，这反映了用于研究AD的一系列高信息量成像方法，包括 正电子发射断层扫描（PET）和先进的磁共振成像（MRI）。功能失调性葡萄糖 代谢是疾病进展的早期和关键决定因素， [18 F]氟脱氧葡萄糖（FDG）已被广泛用于探测AD患者的脑代谢。虽然这 可能反映了葡萄糖需求的减少，但它并不反映新陈代谢本身。此外，FDG-PET具有 在可及性、成本和准确性方面存在重大限制，并且没有提供关于代谢过程的信息 除了葡萄糖摄取和磷酸化。因此，虽然FDG-PET显示了代谢生物标志物的潜力， 迫切需要一种灵敏且实用的成像方法。 氘磁共振成像是一种新的定量代谢成像方法，提供直接可视化的代谢， 葡萄糖在时间尺度和灵敏度上的摄取和代谢命运，这是1H或 超极化13 C磁共振波谱成像。我们在AD的J20小鼠模型中使用BMPs的初始数据显示， 与年龄相比，可以观察到降低的葡萄糖代谢为乳酸盐和降低的HDO富集。 匹配的健康对照。在这些结果的基础上，我们建议开发新的评估方法 的葡萄糖代谢的活脑，并验证这些技术在健康和AD小鼠，以及在 健康志愿者在目标1中，我们将研究三种不同的策略来评估2 H葡萄糖代谢 MRI：使用[6，6 '-2H]葡萄糖进行代谢，使用[U-2 H]葡萄糖进行HDO富集，使用[2，2'-2 H]葡萄糖进行蓄积。 2 H 2]2-脱氧葡萄糖。在目标2中，我们将这三种方法应用于AD的临床前模型，并比较 FDG-PET结果在目标3中，我们将开发用于7 T人类翻译的硬件，并将描述大脑 使用[6，6 '-2H]葡萄糖和[U-2 H]葡萄糖在健康志愿者中进行代谢。成功完成该项目 将提高我们对AD糖代谢的理解，为未来的临床研究提供基础， AD患者，改善临床管理，帮助完善治疗方案，并最终导致更好的 结果和生活质量的人生活与AD。

Project Summary/Abstract This project will investigate deuterium (2H) metabolic imaging (DMI) as a quantitative, stable-isotope MR molecular imaging approach to probe cerebral metabolic impairment in Alzheimer’s Disease (AD). AD and related dementias represent a growing public health concern with tremendous impact on patients and their families. Efforts to treat AD effectively are partially confounded by different hypotheses regarding its initiation and progression, as reflected by the range of highly informative imaging methods used to study AD, including positron emission tomography (PET) and advanced magnetic resonance imaging (MRI). Dysfunctional glucose metabolism is both an early and critical determinant of disease progression, and the glucose derivative [18F]Fluorodeoxyglucose (FDG) has been widely used to probe cerebral metabolism in AD patients. While this may reflect a decrease in glucose demand, it does not inform on metabolism itself. Furthermore, FDG-PET has significant limitations in accessibility, cost and accuracy, and provides no information on metabolic processes beyond glucose uptake and phosphorylation. Thus, while FDG-PET shows the potential of a metabolic biomarker, a sensitive and practical imaging method is critically needed. Deuterium MRI is a novel and quantitative metabolic imaging approach that provides direct visualization of the uptake and meteabolic fate of glucose on timescales and sensitivities that are not achievable with 1H or hyperpolarized 13C MR spectroscopic imaging. Our initial data using DMI in a J20 mouse model of AD show that reduced glucose metabolism to lactate and reduced HDO enrichment can be observed compared to age- matched healthy controls. Building on these results, we propose to develop new DMI approaches for assessment of glucose metabolism in the live brain, and validate these techniques in healthy and AD mice, as well as in healthy volunteers. In Aim 1, we will investigate three separate strategies to assess glucose metabolism with 2H MRI: metabolism using [6,6’-2H]glucose, HDO enrichment using [U-2H]glucose, and accumulation using [2,2’- 2H2]2-deoxyglucose. In Aim 2, we will apply these three approaches to preclinical models of AD and compare results to FDG-PET. In Aim 3, we will develop hardware for human translation at 7T and will characterize brain metabolism in healthy volunteers using [6,6’-2H]glucose and [U-2H]glucose. Successful completion of this project will improve our understanding of glucose metabolism in AD, provide a foundation for future clinical studies in patients with AD, improve clinical management, help refine therapy regimens and, ultimately lead to better outcome and quality of life for people living with AD.