Novel High-field MRS Study of CNS Neurotransmitter Function in Schizophrenia

精神分裂症中枢神经递质功能的新型高场 MRS 研究

• 批准号: 8192034
• 负责人: Changho Choi
• 金额: $ 23.78万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-08 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8192034
• 关键词: Acids; Age; Agonist; Animal Model; Anterior; Antipsychotic Agents; Astrocytes; Autopsy; Autoreceptors; Benzodiazepines; Biological Markers; Brain; Brain region; Carboxy-Lyases; Characteristics; Choline; Clinical; Cognition; Cognitive; Control Groups; Creatine; DSM-IV; Data; Development; Diagnosis; Disease; Documentation; Enrollment; Enzymes; Functional disorder; Future; GABA Agonists; Glutamates; Glutamine; Glutathione; Glycine; Grant; Human; Image; Imaging Techniques; Influentials; Inositol; Interneurons; Interview; Ketamine; Knowledge; Life; Magnetic Resonance Spectroscopy; Measurement; Measures; Mediating; Metabotropic Glutamate Receptors; Methodology; Methods; Modeling; Molecular; N-Methylaspartate; N-acetylaspartate; NMDA receptor antagonist; Neurons; Neurotransmitters; Outcome; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Phencyclidine; Phenotype; Prefrontal Cortex; Process; Protons; Recruitment Activity; Reproducibility; Research; Resolution; Scanning; Schizophrenia; Signal Transduction; Subcategory; Symptoms; Syndrome; System; Testing; Time; base; cingulate cortex; cost; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; improved; in vivo; metabotropic glutamate receptor 2; molecular pathology; neurochemistry; neurotransmission; novel; postsynaptic; presynaptic; receptor; relating to nervous system; research study; response; reuptake; trafficking; transmission process; transport inhibitor; volunteer

DESCRIPTION (provided by applicant): Convergent lines of evidence indicate that schizophrenia may involve alterations in glutamate neurotransmission. While human postmortem and animal-model studies have been critical in achieving this understanding, any definitive testing of existing models requires in vivo demonstration in humans of neurotransmitter system pathology. Glutamatergic hypofunction in schizophrenia may be reflected by alterations in brain metabolite levels, as suggested in prior studies. In this exploratory grant request, we aim to create novel methodologies to measure glutamate-related neurochemical profiles in schizophrenia using proton magnetic resonance spectroscopy (MRS) at 7 T, taking advantage of the high field benefits of signal gain and spectral resolution enhancement. We have developed new 7 T MRS methods recently that allow precise measurements of several experimentally-challenging brain metabolites, including glutamate, glutamine, GABA, glycine, N-acetylaspartyl-glutamate, glutathione, and myo-inositol, which were achieved by means of echo time optimization of standard MRS sequences. We will measure the concentrations of these brain metabolites, in addition to other major signals in brain MRS (i.e., N-acetylaspartate, creatine and choline), in anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) in volunteers with schizophrenia (SZ) and normal controls (NC). ACC and DLPFC are the brain regions most critically involved in SZ and thus this study will create a focus coincident with a number of prior studies. We will enroll 40 SZ volunteers (20 on- antipsychotic drugs, SZ-ON, and 20 off-medication, SZ-OFF) and 20 age-matched controls. Each patient will undergo a complete workup with a research diagnosis (SCID) interview, cognitive characterization (MATRIC Battery), and symptom assessment (PANSS). MRS data from the groups will be analyzed for differences, then correlated with patient characteristics. We will test whether any of the MRS group differences are associated with specific phenotypes in schizophrenia. Test-retest MRS scans will be conducted with a 2-week interval on 15 subjects (5 SZ-ON, 5 SZ-OFF, and 5 controls) in order to assess the reproducibility of the MRS data. PUBLIC HEALTH RELEVANCE: The pathophysiology of schizophrenia may be reflected by abnormalities in neurochemical concentrations which reflect the activity of cellular transmission. Recently, we have developed new imaging techniques for precise measurements of experimentally-challenging brain metabolites in vivo. We propose, using these methods, to find biomarkers of molecular pathology in schizophrenia, to define the effect of antipsychotic treatment and to examine the correlation between metabolite levels and phenotypic expression of symptoms. This is an essential step toward establishing this new methodology and, ultimately, to better understanding the pathophysiology of the disorder. Eventually, data on altered levels of neurotransmitters and their metabolites, as long as they can be measured with precision, will provide important pieces of data that can be utilized for development of new treatments in schizophrenia.

描述（由申请人提供）：趋同的证据线表明精神分裂症可能涉及谷氨酸神经传递的改变。虽然人类死后和动物模型研究对于实现这一理解至关重要，但对现有模型的任何明确测试都需要在人体内证明神经递质系统的病理。先前的研究表明，精神分裂症的谷氨酸能功能减退可能通过脑代谢物水平的改变来反映。在这个探索性的资助申请中，我们的目标是创造新的方法，利用质子磁共振波谱（MRS）在7 T下测量精神分裂症中谷氨酸相关的神经化学特征，利用信号增益和光谱分辨率增强的高场优势。我们最近开发了新的7 T MRS方法，可以精确测量几种具有实验挑战性的脑代谢物，包括谷氨酸、谷氨酰胺、GABA、甘氨酸、n -乙酰天冬氨酸谷氨酸、谷胱甘肽和肌醇，这些方法是通过对标准MRS序列的回声时间优化实现的。我们将测量这些脑代谢物的浓度，以及脑MRS中的其他主要信号（即n -乙酰天冬氨酸、肌酸和胆碱）、前扣带皮层（ACC）和背外侧前额叶皮层（DLPFC）中精神分裂症志愿者（SZ）和正常对照组（NC）的浓度。ACC和DLPFC是参与SZ最关键的大脑区域，因此本研究将与先前的一些研究建立一致的焦点。我们将招募40名SZ志愿者（20名服用抗精神病药物，SZ- on， 20名停药，SZ- off）和20名年龄匹配的对照组。每位患者将接受完整的检查，包括研究诊断（SCID）访谈、认知特征（matrix Battery）和症状评估（PANSS）。各组的MRS数据将进行差异分析，然后与患者特征相关联。我们将测试MRS组的差异是否与精神分裂症的特定表型有关。将对15名受试者（5名SZ-ON、5名SZ-OFF和5名对照）每隔2周进行复测-复测磁共振扫描，以评估磁共振数据的可重复性。