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

项目摘要/摘要 严重抑郁障碍(MDD)是一种以大脑为基础的疾病，全球有近3亿人受到影响。 最近的理论模型和实证研究强调谷氨酸(Glu)是一种关键的神经递质 MDD的病理生理学可能是新型抗抑郁药物的重要靶点。使用质子磁铁 光谱学(1HMRS)，一些研究已经确定了较低浓度的谷氨酸和其他相关代谢物 抑郁症患者在前扣带回皮质(ACC)使用谷氨酰胺、谷氨酰胺。然而，考虑到动态 谷氨酸-谷氨酰胺循环的性质(谷氨酸可以作为三羧酸[TCA]循环的一部分在神经元中代谢，或者 在星形胶质细胞中合成谷氨酰胺(GLN)，这是GABA和Glu的前体)，对于产生新的 成像方法将阐明MDD背后的谷氨酸代谢的哪些方面。这样做将促进我们的 了解MDD并阐明快速抗抑郁药靶向作用的机制 谷氨酸能神经传递(如氯胺酮)。在这种情况下，具有13C标记碳-13(13C)MRS 底物一直是评估Glu-Gln循环的唯一方法，但这种方法在临床上受到了限制。 由于重大的技术挑战而导致的应用。氘(2H)代谢成像也是最近进行的 作为口服二氢葡萄糖(2H-葡萄糖)后检测GLX(Glu+Gln)的工具， 由于该方法与13C-MRS相比具有更高的总体灵敏度，但不能从谷氨酰胺中分离出谷氨酸。 因此，本方案的目标是开发结合2H-MRS的交织1H/2H MRS捕获。 在7T扫描仪上检测葡萄糖，以建立可靠的检测MDD患者谷氨酸代谢的方法。在目标1中， 我们将开发动态成像方案以获得口服2H-GMT后谷氨酸代谢的可靠指标。 葡萄糖摄入量。我们确定最优动态采集协议的基准将基于 最大限度地提高1H Glu、1H Gln和2H Glx的信噪比和时间分辨率(1H或 2HMRS)，并确定标记交换动力学曲线达到稳定状态的时间过程。我们会 在年龄和性别匹配的MDD患者的独立样本中验证我们的优化方案 健康对照和假设两组将表现出相当的重测可靠性(重复性 系数为0.95)。在目标2中，我们将开发方法来拟合简化的动力学代谢模型来估计 TCA和Glu-Gln循环率，并将检验MDD以较低基线(AS)为特征的假设 在葡萄糖获取前测量)谷氨酸和谷氨酰胺水平，以及较慢的谷氨酸代谢(测量 新陈代谢循环率)。我们开发的新的成像方案和代谢指标将 激发创新研究阐明速效抗抑郁药靶向作用机制 谷氨酸能神经传递(如氯胺酮)。

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).