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

描述（由申请人提供）：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在实现这一理解方面至关重要，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病理学。精神分裂症的谷氨酸能功能减退可能反映在脑代谢物水平的改变，如先前的研究所建议的。在这项探索性资助申请中，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）来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，可以精确测量几种实验上具有挑战性的脑代谢物，包括谷氨酸、谷氨酰胺、GABA、甘氨酸、N-乙酰基-谷氨酸、谷胱甘肽和肌醇，这些代谢物是通过标准MRS序列的回波时间优化实现的。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）在前扣带皮层（ACC）和背外侧前额叶皮层（DLPFC）中的表达。ACC和DLPFC是SZ中最关键的脑区，因此本研究将创建一个与先前研究一致的焦点。我们将招募40名SZ志愿者（20名服用抗精神病药物（SZ-ON）和20名停用药物（SZ-OFF））和20名年龄匹配的对照。每例患者将接受一次完整的检查，包括研究诊断（SCID）访谈、认知表征（MATRIC组合）和症状评估（PANSS）。将分析各组的MRS数据的差异，然后将其与患者特征相关联。我们将测试是否有任何MRS组间差异与精神分裂症的特定表型相关。将对15例受试者（5例SZ-ON、5例SZ-OFF和5例对照）进行2周间隔的重新测试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通过反映细胞传递活性的神经化学物质浓度的异常来反映。最近，我们开发了新的成像技术，用于精确测量体内实验性脑代谢物。我们建议，使用这些方法，找到精神分裂症的分子病理学生物标志物，确定抗精神病药物治疗的效果，并检查代谢物水平和症状表型表达之间的相关性。这是建立这种新方法学的重要一步，最终是更好地理解这种疾病的病理生理学。最终，神经递质及其代谢物水平变化的数据，只要能够精确测量，将提供重要的数据，可用于开发精神分裂症的新疗法。

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.