Neurotransmitters in Schizophrenia using high-field MR Spectroscopy

描述(申请人提供)：精神分裂症，一种致残的精神障碍，影响大约1%的人口。这种疾病给社会造成的代价很高尽管进行了广泛的研究，但精神分裂症的潜在生化原因仍然难以捉摸，有证据表明，多巴胺、谷氨酸和GABA能神经递质系统都在症状的发展中发挥作用。提高对局部神经递质水平的了解是设计新疗法的第一步。在过去的几年里，人们对谷氨酸(Glu)、N-乙酰天冬氨酸(NAAG)和β-氨基丁酸(GABA)在精神分裂症中的作用特别感兴趣。谷氨酸和GABA分别是人脑中主要的兴奋性和抑制性神经递质.NAAG是谷氨酸的前体，也与谷氨酸能系统中的受体结合。高场(7Telsa)磁共振波谱(MRS)与光谱编辑技术相结合，具有比低场强下更高的灵敏度和特异度，能够在活体内测量人脑中的各种神经递质，包括Glu和GABA。因此，这项建议的目的是(1)确定7T MRS可以可靠地测量精神分裂症患者大脑多个区域的谷氨酸、NAAG和GABA的‘神经递质谱’，(2)调查健康志愿者、早期和晚期精神分裂症患者之间的神经递质水平的差异，以及也测量表现出与精神分裂症患者相同特征的精神分裂症患者的一级亲属的相同化合物。患者还将接受神经心理测试的彻底评估，并将检查神经递质水平与精神分裂症阳性和阴性症状的相关性。研究一级亲属的一个重要原因是，他们将不会服用药物，从而可以观察与疾病相关的神经化学变化，而不会受到药物可能产生的混淆影响。本研究的长期目标是确定Glu、NAAG和GABA(以及其他代谢物)在精神分裂症的病理生理学中的作用，并探讨它们与症状严重程度的关系。这些知识将有助于设计未来的治疗试验。我们还期望高场磁共振波谱建立这些非侵入性生物标志物将在未来评估精神分裂症患者的疾病严重程度、进展和治疗反应方面有用。

DESCRIPTION (provided by applicant): Schizophrenia a disabling psychiatric disorder that affects approximately 1% of the population. The cost to society resulting from this illness is high Despite extensive research, the underlying biochemical causes of schizophrenia remain elusive, with evidence to suggest that the dopaminergic, glutamatergic and GABAergic neurotransmitter systems all play a role in the development of symptoms. An improved understanding of regional neurotransmitter levels is a first step towards the design of new treatments. Over the last few years, there has been particular interest in the roles of glutamate (Glu), N-acetyl aspartyl glutamate (NAAG) and ?-aminobutyric acid (GABA) in schizophrenia. Glu and GABA the primary excitatory and inhibitory neurotransmitters in the human brain, respectively. NAAG is a precursor of Glu and also binds to receptors involved in the glutamatergic system. High field (7 Telsa) magnetic resonance spectroscopy (MRS), in conjunction with spectral editing techniques, has the potential to measure various neurotransmitters in vivo in the human brain, including Glu and GABA, with higher sensitivity and specificity than at lower field strengths. We have also recently demonstrated that it is possible to reliably determine NAAG in the brain using MRS. The aims of this proposal are therefore to (1) to establish that 7T MRS can reliably measure a 'neurotransmitter profile' of Glu, NAAG and GABA in multiple brain regions in patients with schizophrenia, (2) investigate the differences in neurotransmitter levels between healthy volunteers, early-stage, and later stage patients with schizophrenia, and to also measure the same compounds in first degree relatives of subjects with schizophrenia who demonstrate some of the same traits as patients with schizophrenia. Patients will also be thoroughly evaluated with neuropsychological testing, and neurotransmitter levels will be examined for correlations with both positive and negative symptoms of schizophrenia. An important reason for studying first degree relatives is that they will be unmedicated, allowing observation of disease related neurochemical changes free from the possible confounding effects of medication. The long term goal of this study is to firmly establish the role of Glu, NAAG and GABA (as well as other metabolites) in the pathophysiology of schizophrenia, and investigate their relationship to symptom severity. This knowledge will aid in the design of future treatment trials. We also expect that the establishment of these noninvasive biomarkers by high-field MRS will be useful in the future for evaluating disease severity, progression and treatment response in patients with schizophrenia.