Imaging cerebral metabolic impairment in AD using Deuterium MRI

使用氘 MRI 对 AD 中的脑代谢损伤进行成像

• 批准号: 10608908
• 负责人: Myriam Marianne Chaumeil
• 金额: $ 71.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608908
• 关键词: 3-Dimensional; APP-PS1; Acetates; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Automobile Driving; Biological Markers; Brain; Cerebrum; Chemical Shift Imaging; Clinical; Clinical Management; Clinical Research; Data; Deoxyglucose; Detection; Deuterium; Disease; Disease Progression; Evaluation; Family; Foundations; Fumarates; Future; Glucose; Glutamates; Glutamine; Goals; Human; Human Volunteers; Hydrogen; Image; Imaging Phantoms; Impairment; Intervention; Ionizing radiation; J20 mouse; Label; Lead; Magnetic Resonance Imaging; Measures; Metabolic; Metabolism; Methods; Monitor; Mus; Outcome; Pathogenesis; Patients; Persons; Phosphorylation; Physiologic pulse; Play; Positron-Emission Tomography; Pre-Clinical Model; Process; Public Health; Quality of life; Regimen; Research; Role; Safety; System; Techniques; Therapeutic; Translations; Visualization; Water; Wild Type Mouse; brain metabolism; clinical translation; clinically relevant; cost; experimental study; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; glucose metabolism; glucose uptake; healthy volunteer; imaging approach; imaging modality; improved; in vivo; metabolic imaging; metabolomics; molecular imaging; mouse model; nervous system disorder; novel; patient stratification; personalized therapeutic; pre-clinical; precision medicine; response; sex; spectroscopic imaging; stable isotope; success; therapy development; tool; treatment response; uptake

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.

项目摘要/摘要 该项目将研究氘（2H）代谢成像（DMI）作为定量，稳定的同位素MR 探测阿尔茨海默氏病（AD）探测大脑代谢损害的分子成像方法。广告和 相关的痴呆症代表了公共卫生的日益关注，对患者及其患者的影响很大 家庭。有效治疗广告的努力部分被有关其启动的不同假设所困扰 和进步，如用于研究AD的一系列信息丰富的成像方法所反映的，包括 正电子发射断层扫描（PET）和晚期磁共振成像（MRI）。功能失调的葡萄糖 代谢既是疾病进展的早期和关键决定剂，又是葡萄糖衍生物 [18F]氟脱氧葡萄糖（FDG）已被广泛用于探测AD患者的脑代谢。同时 可能反映了葡萄糖需求的减少，它不会告知新陈代谢本身。此外，FDG-PET具有 可访问性，成本和准确性的重大限制，没有提供有关代谢过程的信息 超越葡萄糖摄取和磷酸化。虽然FDG-PET显示了代谢生物标志物的潜力，但 需要一种敏感且实用的成像方法。 氘MRI是一种新颖的定量代谢成像方法，可直接可视化 葡萄糖对时间尺度和灵敏度的吸收和蛋白酶命运，而1H或1H无法实现 超极化13C MR光谱成像。我们在AD的J20鼠标模型中使用DMI使用DMI的初始数据表明 与年龄相比 匹配的健康对照。在这些结果的基础上，我们建议开发新的DMI评估方法 活大脑中的葡萄糖代谢，并在健康和AD小鼠中验证这些技术 健康的志愿者。在AIM 1中，我们将研究三种单独的策略，以评估2H的葡萄糖代谢 MRI：使用[6,6'-2H]葡萄糖，使用[U-2H]葡萄糖的HDO富集以及使用[2,2'--- 2H2] 2-脱氧葡萄糖。在AIM 2中，我们将将这三种方法应用于AD的临床前模型并进行比较 结果为FDG-PET。在AIM 3中，我们将在7T处开发用于人类翻译的硬件，并将表征大脑 使用[6,6'-2H]葡萄糖和[U-2H]葡萄糖的健康志愿者中的代谢。成功完成该项目 将提高我们对AD中葡萄糖代谢的理解，为将来的临床研究奠定了基础 AD患者，改善临床管理，帮助精炼治疗方案，并最终导致更好 享有广告的人的结果和生活质量。