Glutamate in OCD: a magnetic resonance spectroscopy study.

描述(申请人提供)：强迫症影响2%的人口，并在世界范围内产生相当大的发病率。即使对最佳的心理治疗和药物治疗也常常没有反应。迫切需要对这种疾病的神经生物学及其可能导致的药理学策略有新的见解。一致的证据表明，神经递质谷氨酸的失调可能导致强迫症；因此，在标准治疗无效的30%的病例中，谷氨酸调节药物可能是有益的。我们小组和其他人已经报道了支持这一假说的遗传关联和脑脊液(CSF)发现。磁共振波谱(MRS)允许在定义的解剖区域对谷氨酸进行非侵入性测量，从而提供了独特的能力来研究与强迫症症状相关的特定回路中神经递质的调节失调。MRS研究表明，前扣带回皮质(ACC)、纹状体和眶前叶皮质存在谷氨酸异常。然而，这些研究是在低场强下进行的，无法将谷氨酸从谷氨酰胺中分离出来(相反，报告了一种复合测量，GLX，并且通常没有相互复制)。在更高的场强下，通过最先进的谷氨酸测量可能实现的清晰度是迫切需要的，以完善我们对强迫症谷氨酸失调的理解。我们在此报告一项初步研究，测量前扣带回皮质中的谷氨酸和谷氨酰胺。在4TMRS扫描仪中，对从ACC上的单个中线体素收集的数据进行模拟基组的光谱拟合，结果显示谷氨酸减少，但谷氨酰胺正常，仅在心境良好的强迫症患者中。抑郁的强迫症患者谷氨酸水平正常。这一意想不到的效果表明，这些经常并存的疾病之间存在着病理生理上的相互作用。它也可能是导致GLX已发表报告复制失败的一个变异性来源。我们建议复制和扩大这些发现。首先，我们将在更大的队列中重复我们的先导性研究，这段时间也包括未用药的抑郁症患者作为对照组，以更好地阐明诊断之间的相互作用。其次，我们将在纹状体进行谷氨酸和谷氨酰胺的测量，纹状体是与强迫症有关的另一个结构，在这种情况下，GLX异常(在这种情况下是升高的)被不一致地报告。然后，我们将调查这些脑神经化学测量方法预测药物治疗反应的能力；这样的关联将确定谷氨酸测量方法为一种潜在的临床有用的生物标记物，以帮助指导治疗选择。这一系列最先进的光谱研究将阐明强迫症患者兴奋性神经传递的区域特异性失调，重要的是加深我们对该疾病的神经化学的理解，同时探索一种新的、具有潜在临床实用价值的生物标志物的潜在用途。

DESCRIPTION (provided by applicant): Obsessive-compulsive disorder affects 2% of the population and produces substantial morbidity worldwide. It is often unresponsive even to optimal psychotherapy and pharmacotherapy. New insights into the neurobiology of the disorder, and the pharmacological strategies to which they may lead, are urgently needed. Convergent evidence suggest that dysregulation of the neurotransmitter glutamate may contribute to OCD; glutamate-modulating medications may therefore be of benefit in some of the 30% of cases refractory to standard treatment. Genetic associations and cerebrospinal fluid (CSF) findings supporting this hypothesis have been reported, by our group and others. Magnetic resonance spectroscopy (MRS) allows noninvasive measurement of glutamate in defined anatomical regions and thus offers the unique capacity to investigate dysregulation of the neurotransmitter in the specific circuit associated with OCD symptomatology. MRS studies have suggested glutamate abnormalities in the anterior cingulate cortex (ACC), the striatum, and the orbitofrontal cortex. However, these studies have been performed at low field strength and have been unable to dissociate glutamate from glutamine (reporting instead a compound measure, Glx, and have not generally replicated one another. The clarity possible through state-of-the-art glutamate measures at higher field strength is badly needed to refine our understanding of glutamate dysregulation in OCD. We here report a pilot study measuring glutamate and glutamine in the anterior cingulate cortex. Spectral fitting using a simulated basis set on data collected from a single midline voxel over the ACC in a 4T MRS scanner revealed reduced glutamate, but normal glutamine, only in euthymic OCD patients. Depressed OCD patients had normal glutamate levels. This unexpected effect suggests a pathophysiological interaction between these frequently comorbid disorders. It also may be a source of variability contributing to the failures of replication among published reports of Glx. We propose to replicate and expand these findings. First, we will replicate our pilot study in a larger cohort, tis time also including unmedicated depressed patients as a comparison group to better elucidate the interaction between diagnoses. Second, we will perform glutamate and glutamine measures in the striatum, another structure implicated in OCD in which Glx abnormalities (elevations, in this case) have been inconsistently reported. We will then investigate the ability of these measurements of brain neurochemistry to predict the response to pharmacotherapy; such an association would identify glutamate measures as a potential clinically useful biomarker to help guide therapeutic choices. This series of state-of-the-art spectroscopic investigations will elucidate the region-specific dysregulation of excitatory neurotransmission in OCD, importantly refining our understanding of the neurochemistry of the disorder while probing the potential utility of a novel and potentially clinically useful biomarker.