Integrating 1H MRS with 2H-Labeled Glucose to Characterize Dynamic Glutamate Metabolism in Major Depressive Disorder

将 1H MRS 与 2H 标记的葡萄糖相结合来表征重度抑郁症的动态谷氨酸代谢

基本信息

批准号：
10668075
负责人：
TIFFANY CHEING HO
金额：
$ 21.15万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668075
关键词：
Adult Affect Age Agreement Anterior Antidepressive Agents Astrocytes Benchmarking Blood Glucose Brain Carbon Citric Acid Cycle Data Depressed mood Detection Deuterium Disease Dose Enzymes Exhibits Functional disorder Future Glucose Glutamate Metabolism Pathway Glutamates Glutamine Goals Image Individual Intake Isotopes Ketamine Kinetics Label Magnetic Resonance Spectroscopy Magnetism Major Depressive Disorder Measures Mental Depression Metabolic Metabolism Methodology Methods Mitochondria Modeling Nature Neurons Neurotransmitters Noise Oral Oral Administration Patients Persons Protocols documentation Protons Reproducibility Research Resolution Sampling Scanning Signal Transduction Spectrum Analysis Techniques Testing Theoretical model Time Tricarboxylic Acids brain based cingulate cortex clinical application depressed patient gamma-Aminobutyric Acid imaging modality innovation insight magnetic field metabolic imaging metabolic rate mitochondrial dysfunction neurotransmission novel recruit sex temporal measurement tool

项目摘要

PROJECT SUMMARY/ABSTRACT Major depressive disorder (MDD) is a brain-based disorder that affects nearly 300 million people worldwide. Recent theoretical models and empirical studies have highlighted glutamate (Glu) as a key neurotransmitter in the pathophysiology of MDD that may be an important target for novel antidepressants. Using proton magnetic spectroscopy (1H MRS), several studies have identified lower concentrations of Glu and other related metabolites (e.g., glutamine, Gln) in depressed patients in anterior cingulate cortex (ACC). However, given the dynamic nature of the Glu–Gln cycle (Glu can be metabolized in neurons as part of the tricarboxylic acid [TCA] cycle or synthesized into Gln, which is a precursor to both GABA and Glu, in astrocytes), it is critical to generate novel imaging methods that will clarify which aspects of Glu metabolism underlie MDD. Doing so will advance our understanding of MDD and elucidate the mechanisms underlying fast-acting antidepressants targeting glutamatergic neurotransmission (e.g., ketamine). In this context, carbon-13 (13C) MRS with 13C-labeled substrates has been the only method to evaluate the Glu–Gln cycle, but this method has limited clinical applications due to significant technical challenges. Deuterium (2H) metabolic imaging has also been recently presented as a tool for detecting Glx (Glu+Gln) following oral administration of deuterated glucose (2H-glucose), as this method contains higher overall sensitivity compared to 13C MRS but is unable to resolve Glu from Gln. Thus, the goal of the present proposal is to develop an interleaved 1H/2H MRS acquisition combined with 2H- glucose on a 7T scanner to establish the reliable detection of Glu metabolism in patients with MDD. In Aim 1, we will develop the dynamic imaging protocol to obtain reliable measures of Glu metabolism following oral 2H- glucose intake. Our benchmarks for determining the optimal dynamic acquisition protocol will be based on maximizing signal-to-noise ratios of 1H Glu, 1H Gln, and 2H Glx and temporal resolution (time per block of 1H or 2H MRS) and determining the time course when kinetic curves for label exchange reaches steady-state. We will validate our optimized protocol in an independent sample of patients with MDD and age- and sex-matched healthy controls and hypothesize that both groups will exhibit comparable test-retest reliability (repeatability coefficient > 0.95). In Aim 2, we will develop methods to fit a simplified kinetic metabolic model to estimate the rates of TCA and Glu–Gln cycling, and will test the hypothesis that MDD is characterized lower baseline (as measured during the pre-glucose acquisition) levels of Glu and Gln, and slower Glu metabolism (as measured by the metabolic cycling rates) in ACC. The novel imaging protocol and the metabolic metrics we develop will stimulate innovative research on elucidating the mechanisms of fast-acting antidepressants targeting glutamatergic neurotransmission (e.g., ketamine).

项目摘要/摘要重度抑郁症（MDD）是一种基于脑部疾病，影响了全球近3亿人。最近的理论模型和经验研究突出了谷氨酸（GLU）作为关键的神经递质 MDD的病理生理可能是新型抗抑郁药的重要靶标。使用质子磁光谱法（1H MRS），几项研究确定了较低浓度的GLU和其他相关代谢物（例如，谷氨酰胺，GLN）在前扣带回皮层（ACC）的抑郁症患者中。但是，给定动态 GLU -GLN循环的性质（GLU可以在神经元中代谢，作为三核酸[TCA]循环的一部分或合成成GLN，这是GABA和GLU的前体，在星形胶质细胞中），生成新颖的是至关重要的成像方法将阐明MDD基础GLU代谢的哪些方面。这样做会推动我们的了解MDD并阐明靶向快速作用抗抑郁药的机制谷氨酸能神经传递（例如氯胺酮）。在这种情况下，具有13C标记的碳13（13C）MRS 底物是评估GLU -GLN周期的唯一方法，但是该方法有限由于巨大的技术挑战，应用程序。氘（2H）的代谢成像最近也是在口服氘化葡萄糖（2H-葡萄糖），用于检测GLX（GLU+GLN）的工具，由于该方法与13C MRS相比含有更高的总体灵敏度，但无法从GLN中解析GLU。这是本提案的目的是开发一个交错的1H/2H MRS收购与2H-的相结合 7T扫描仪上的葡萄糖在MDD患者中建立了对GLU代谢的可靠检测。在AIM 1中，我们将开发动态成像方案，以获得口服2H-之后GLU代谢的可靠测量。葡萄糖摄入量。我们确定最佳动态采集协议的基准将基于最大化1H GLU，1H GLN和2H GLX和临时分辨率的信噪比最大化（每块1H或1H或 2H MRS）并确定标签交换的动力学曲线达到稳态时的时间过程。我们将在独立的MDD患者以及年龄和性别匹配的患者的独立样本中验证我们优化的方案健康对照和假设，两组将暴露可比测试可靠性（可重复性核心> 0.95）。在AIM 2中，我们将开发适合简化动力学代谢模型的方法以估计 TCA和GLU – GLN循环的速率，并将检验MDD表征较低基线的假设（AS 在GLU和GLN的葡萄糖含量中测量，以及GLU代谢较慢（如测量通过代谢循环速率）在ACC中。我们开发的新型成像协议和代谢指标将刺激有关阐明靶向抗抑郁药的机制的创新研究谷氨酸能神经传递（例如氯胺酮）。