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

基本信息

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
项目类别：
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

项目摘要

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）：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，这些都是通过回波实现的标准 MRS 序列的时间优化。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。 SZ) 和正常对照 (NC)。 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。公共卫生相关性：精神分裂症的病理生理学可能通过神经化学浓度的异常来反映，而神经化学浓度的异常反映了细胞传递的活动。最近，我们开发了新的成像技术，用于精确测量体内具有实验挑战性的大脑代谢物。我们建议使用这些方法寻找精神分裂症分子病理学的生物标志物，以确定抗精神病药物治疗的效果并检查代谢物水平与症状表型表达之间的相关性。这是建立这种新方法并最终更好地了解该疾病的病理生理学的重要一步。最终，只要能够精确测量，有关神经递质及其代谢物水平变化的数据将提供重要的数据，可用于开发精神分裂症的新疗法。