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:
- 金额:$ 21.15万
- 依托单位:
- 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:
- 关键词:AdultAffectAgeAgreementAnteriorAntidepressive AgentsAstrocytesBenchmarkingBlood GlucoseBrainCarbonCitric Acid CycleDataDepressed moodDetectionDeuteriumDiseaseDoseEnzymesExhibitsFunctional disorderFutureGlucoseGlutamate Metabolism PathwayGlutamatesGlutamineGoalsImageIndividualIntakeIsotopesKetamineKineticsLabelMagnetic Resonance SpectroscopyMagnetismMajor Depressive DisorderMeasuresMental DepressionMetabolicMetabolismMethodologyMethodsMitochondriaModelingNatureNeuronsNeurotransmittersNoiseOralOral AdministrationPatientsPersonsProtocols documentationProtonsReproducibilityResearchResolutionSamplingScanningSignal TransductionSpectrum AnalysisTechniquesTestingTheoretical modelTimeTricarboxylic Acidsbrain basedcingulate cortexclinical applicationdepressed patientgamma-Aminobutyric Acidimaging modalityinnovationinsightmagnetic fieldmetabolic imagingmetabolic ratemitochondrial dysfunctionneurotransmissionnovelrecruitsextemporal measurementtool
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)是一种以大脑为基础的疾病,影响着全球近3亿人。
最近的理论模型和实证研究强调谷氨酸(Glu)是神经系统中的一种关键神经递质。
抑郁症的病理生理学可能是新型抗抑郁药的重要靶点。质子磁
通过核磁共振波谱(1H MRS),几项研究已经确定了较低浓度的Glu和其他相关代谢产物
(e.g.,谷氨酰胺(Gln)在抑郁症患者前扣带皮层(ACC)的表达。然而,鉴于动态
Glu-Gln循环的性质(Glu可以作为三羧酸[TCA]循环的一部分在神经元中代谢,或
在星形胶质细胞中合成为Gln,其是GABA和Glu两者的前体),产生新的
成像方法,将澄清哪些方面的谷氨酸代谢的基础MDD。这样做将促进我们的
了解MDD并阐明快速作用抗抑郁药靶向的机制
交感神经能神经传递(例如,氯胺酮)。在这种情况下,使用13 C标记的碳-13(13 C)MRS
底物法一直是评价Glu-Gln循环的唯一方法,但这种方法在临床上受到限制,
由于重大技术挑战,应用程序面临挑战。氘(2 H)代谢成像最近也已
作为检测口服氘代葡萄糖(2 H-葡萄糖)后Glx(Glu+Gln)的工具,
因为该方法与13 C MRS相比具有更高的总灵敏度,但不能从Gln中分辨Glu。
因此,本提议的目标是开发与2 H-MRS相结合的交织1H/2 H MRS采集。
在7 T扫描仪上测量血糖,以建立MDD患者中Glu代谢的可靠检测。在目标1中,
我们将开发动态成像方案,以获得口服2 H-
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2 H Glx的信噪比和时间分辨率(1H或2 H Glx的每个块的时间),
2 H MRS)并确定标记交换动力学曲线达到稳态的时间过程。我们将
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
健康对照并假设两组将表现出相当的重测可靠性(重复性
系数> 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,以估计
TCA和Glu-Gln循环的速率,并将检验MDD的特征在于较低的基线(作为
在葡萄糖采集前测量的)Glu和Gln水平,以及较慢的Glu代谢(如测量的
我们开发的新的成像方案和代谢指标将
鼓励创新研究,阐明快速作用的抗抑郁药的靶向机制
交感神经能神经传递(例如,氯胺酮)。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('TIFFANY CHEING HO', 18)}}的其他基金
Inflammatory and Glutamatergic Mechanisms of Sustained Threat in Adolescents with Depression: Toward Predictors of Treatment Response and Clinical Course
抑郁症青少年持续威胁的炎症和谷氨酸机制:治疗反应和临床过程的预测因子
- 批准号:
10755122 - 财政年份:2022
- 资助金额:
$ 21.15万 - 项目类别:
Inflammatory and Glutamatergic Mechanisms of Sustained Threat in Adolescents with Depression: Toward Predictors of Treatment Response and Clinical Course
抑郁症青少年持续威胁的炎症和谷氨酸机制:治疗反应和临床过程的预测因子
- 批准号:
10622580 - 财政年份:2022
- 资助金额:
$ 21.15万 - 项目类别:
Inflammatory and Glutamatergic Mechanisms of Sustained Threat in Adolescents with Depression: Toward Predictors of Treatment Response and Clinical Course
抑郁症青少年持续威胁的炎症和谷氨酸机制:治疗反应和临床过程的预测因素
- 批准号:
10445166 - 财政年份:2022
- 资助金额:
$ 21.15万 - 项目类别:
The Roles of Inflammatory and Glutamatergic Processes in the Neurodevelopmental Mechanisms Underlying Adolescent Depression
炎症和谷氨酸能过程在青少年抑郁症神经发育机制中的作用
- 批准号:
10756332 - 财政年份:2018
- 资助金额:
$ 21.15万 - 项目类别:
The Roles of Inflammatory and Glutamatergic Processes in the Neurodevelopmental Mechanisms Underlying Adolescent Depression
炎症和谷氨酸能过程在青少年抑郁症神经发育机制中的作用
- 批准号:
10551423 - 财政年份:2018
- 资助金额:
$ 21.15万 - 项目类别:
The Roles of Inflammatory and Glutamatergic Processes in the Neurodevelopmental Mechanisms Underlying Adolescent Depression
炎症和谷氨酸能过程在青少年抑郁症神经发育机制中的作用
- 批准号:
10094020 - 财政年份:2018
- 资助金额:
$ 21.15万 - 项目类别:
The Roles of Inflammatory and Glutamatergic Processes in the Neurodevelopmental Mechanisms Underlying Adolescent Depression
炎症和谷氨酸能过程在青少年抑郁症神经发育机制中的作用
- 批准号:
9933235 - 财政年份:2018
- 资助金额:
$ 21.15万 - 项目类别:
The Roles of Inflammatory and Glutamatergic Processes in the Neurodevelopmental Mechanisms Underlying Adolescent Depression
炎症和谷氨酸能过程在青少年抑郁症神经发育机制中的作用
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10165829 - 财政年份:2018
- 资助金额:
$ 21.15万 - 项目类别:
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