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: 8298136
• 负责人: Changho Choi
• 金额: $ 19.86万
• 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 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8298136
• 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.

描述（由申请人提供）：一致的证据表明精神分裂症可能涉及谷氨酸神经传递的改变。虽然人类尸检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类体内演示神经递质系统病理学。正如先前的研究表明的那样，精神分裂症的谷氨酸功能减退可能通过大脑代谢水平的改变反映出来。在这项探索性拨款申请中，我们的目标是创建新的方法，利用 7 T 的质子磁共振波谱 (MRS) 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-乙酰天冬氨酰-谷氨酸、谷胱甘肽和肌醇，这是通过标准 MRS 序列的回波时间优化实现的。除了脑 MRS 中的其他主要信号（即 N-乙酰天冬氨酸、肌酸和胆碱）、精神分裂症志愿者 (SZ) 和正常对照 (NC) 的前扣带皮层 (ACC) 和背外侧前额叶皮层 (DLPFC) 中，我们还将测量这些脑代谢物的浓度。 ACC 和 DLPFC 是与 SZ 关系最密切的大脑区域，因此本研究将建立与许多先前研究一致的焦点。我们将招募 40 名 SZ 志愿者（20 名正在服用抗精神病药物的志愿者，SZ-ON，20 名未服药的志愿者，SZ-OFF）和 20 名年龄匹配的对照者。每位患者都将接受完整的检查，包括研究诊断 (SCID) 访谈、认知表征 (MATRIC Battery) 和症状评估 (PANSS)。将分析各组的 MRS 数据的差异，然后与患者特征相关联。我们将测试 MRS 组差异是否与精神分裂症的特定表型相关。将每隔 2 周对 15 名受试者（5 名 SZ-ON、5 名 SZ-OFF 和 5 名对照）进行重测 MRS 扫描，以评估 MRS 数据的再现性。

项目成果

Measurement of glycine in gray and white matter in the human brain in vivo by 1H MRS at 7.0 T.

• DOI: 10.1002/mrm.24368
• 发表时间: 2012-08
• 期刊: MAGNETIC RESONANCE IN MEDICINE
• 影响因子: 3.3
• 作者: Banerjee, Abhishek;Ganji, Sandeep;Hulsey, Keith;Dimitrov, Ivan;Maher, Elizabeth;Ghose, Subroto;Tamminga, Carol;Choi, Changho
• 通讯作者: Choi, Changho

Measurement of regional variation of GABA in the human brain by optimized point-resolved spectroscopy at 7 T in vivo.

• DOI: 10.1002/nbm.3170
• 发表时间: 2014-10
• 期刊: NMR IN BIOMEDICINE
• 影响因子: 2.9
• 作者: Ganji, Sandeep K.;An, Zhongxu;Banerjee, Abhishek;Madan, Akshay;Hulsey, Keith M.;Choi, Changho
• 通讯作者: Choi, Changho