Imaging cerebral metabolic impairment in AD using Deuterium MRI

项目摘要/摘要 本项目将研究氢(2H)代谢成像(Dmi)作为一种定量的、稳定的同位素mr。 阿尔茨海默病(AD)脑代谢损害的分子成像研究广告和 相关痴呆症是一个日益严重的公共卫生问题，对患者及其 家人。有效治疗阿尔茨海默病的努力在一定程度上受到了关于其启动的不同假设的混淆 和进展，这反映在用于研究AD的一系列高信息量的成像方法，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 代谢既是疾病进展的早期和关键决定因素，也是葡萄糖的衍生物 [18F]氟脱氧葡萄糖(FDG)已被广泛应用于AD患者的脑代谢研究。虽然这件事 可能反映了葡萄糖需求的减少，但它本身并不影响新陈代谢。此外，FDG-PET具有 在可获得性、成本和准确性方面存在重大限制，并且没有提供有关代谢过程的信息 超越了葡萄糖摄取和磷酸化。因此，虽然FDG-PET显示了代谢生物标记物的潜力， 迫切需要一种灵敏实用的成像方法。 氘核磁共振是一种新的定量代谢成像方法，它提供了直接的可视化 葡萄糖在时间尺度和敏感性上的摄取和代谢去向，这是1H或 超极化13C磁共振波谱成像。我们在AD的J20小鼠模型中使用DMI的初始数据显示 与年龄相比，可以观察到葡萄糖代谢减少为乳酸，HDO增加减少。 与健康对照组相匹配。在这些结果的基础上，我们建议开发新的DMI评估方法 并在健康和AD小鼠身上验证这些技术，以及在 健康的志愿者。在目标1中，我们将研究用2H评估葡萄糖代谢的三种不同策略。 MRI：使用[6，6‘-2H]葡萄糖代谢，使用[U-2H]葡萄糖浓缩HDO，使用[2，2’-]葡萄糖积累 2H2]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 结果转至FDG-PET。在目标3中，我们将在7T开发用于人工翻译的硬件，并将表征大脑 [6，6‘-2H]葡萄糖和[U-2H]葡萄糖在健康志愿者体内的代谢。本项目圆满完成 将提高我们对AD糖代谢的认识，为今后AD的临床研究提供基础 AD患者，改善临床管理，帮助改进治疗方案，并最终导致更好的 阿尔茨海默病患者的结局和生活质量。

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.