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）：融合的证据线表明，精神分裂症可能涉及谷氨酸神经传递的改变。尽管人类验尸和动物模型研究对于实现这种理解至关重要，但对现有模型的任何确定测试都需要在神经递质系统病理学人类中进行体内演示。如先前的研究中所示，精神分裂症的谷氨酸能功能功能低下可能会反映出脑代谢物水平的改变。在此探索性赠款请求中，我们旨在创建新的方法，以利用信号增益和光谱分辨率增强的高场益处，利用质子磁共振光谱（MRS）在7 t下使用质子磁共振光谱（MRS）来测量精神分裂症中与谷氨酸相关的神经化学特征。我们最近开发了新的7 T MRS方法，可以精确测量几种实验挑战的脑代谢物，包括谷氨酸，谷氨酰胺，GABA，甘氨酸，甘氨酸，N-乙酰基甲基谷氨酸，谷胱甘肽，谷胱甘肽和肌醇，并通过通过ECHO时间优化的eCho Time Outitions来实现。除脑MRS中的其他主要信号（即N-乙酰天冬氨酸，肌酸和胆碱）中，我们还将测量这些脑代谢产物的浓度，在具有精神分裂症（SZSZ）和正常对照的志愿者中的前扣带回皮层（ACC）和背外侧前额叶皮层（DLPFC）和背外侧前额叶皮层（DLPFC）中。 ACC和DLPFC是大脑区域中最重要的SZ区域，因此这项研究将与许多先前的研究创造焦点。我们将招募40名SZ志愿者（20名抗精神病药，SZ-ON和20个过度药物，SZ-OFF）和20个年龄匹配的对照。每个患者将通过研究诊断（SCID）访谈，认知表征（矩阵电池）和症状评估（PANSS）进行完整的检查。将分析来自组的MRS数据的差异，然后与患者特征相关。我们将测试任何MRS组差异是否与精神分裂症的特定表型有关。重新测试MRS扫描将在15名受试者（5 sz-on，5 sz-off和5个对照中）进行2周的间隔进行，以评估MRS数据的可重复性。公共卫生相关性：精神分裂症的病理生理学可以反映出反映细胞传播活性的神经化学浓度的异常。最近，我们开发了新的成像技术，用于在体内进行实验挑战的脑代谢物的精确测量。我们建议使用这些方法来找到精神分裂症中分子病理学的生物标志物，以定义抗精神病药物治疗的作用，并检查代谢物水平与症状的表型表达之间的相关性。这是建立这种新方法的重要一步，最终是更好地理解该疾病的病理生理学。最终，关于神经递质及其代谢产物水平变化水平的数据，只要可以精确测量它们，就将提供重要的数据，可用于开发精神分裂症的新疗法。