Investigating the relationships between risk factors and brain glutamate in schizophrenia

研究精神分裂症危险因素与脑谷氨酸之间的关系

• 批准号: 2749198
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2749198
• 关键词: Investigating; relationships; between; risk; factors

Glutamate is a key neurotransmitter implicated in the neurobiology of schizophrenia. Within the living human brain, the concentration of glutamate can be measured within pre-selected brain areas using the MRI-based technique of proton magnetic resonance spectroscopy (1H-MRS). There are now over 80 1H-MRS studies of glutamate in schizophrenia. These individual studies have observed various results, finding increases, decreases or no change in glutamate levels. Amongst other factors, this may relate to differences in patient characteristics, the brain regions investigated and measurement variability within the relatively small sample sizes of individual studies. Knowledge can be developed by studies examining larger, well-characterised patient samples or by applying mega- or meta- analytical techniques to combine data from individual studies. For example, recent meta and mega-analyses led by Prof Egerton's group have shown elevations in glutamate in schizophrenia in distinct brain regions (Merritt et al., 2018), and that elevations may be most marked shortly after onset of psychosis, or patients who have highest symptom burden (Merritt et al., 2021). Our most recent meta-analysis (Merritt et al., in preparation) shows that glutamate levels in schizophrenia are more variable than in healthy volunteers. The causes and clinical consequences of this variability are currently unclear. Understanding these processes may have translational implications, as it could indicate patient subgroups for whom glutamate-acting therapeutics may have greatest efficacy, and thus inform stratified medicine approaches. This PhD will extend this work in three ways. 1. Our group and others have also shown that elevations in glutamate in the anterior cingulate cortex (ACC) are more marked in patients who have not responded well to antipsychotic treatment (Egerton et al., 2012, 2018, 2020; Iwata et al., 2018; Tarumi et al., 2021), although some other studies have not detected the same finding (Goldstein et al., 2015; Horne et al., 2021). The first study of the PhD will consist of a meta-analysis and participant level mega-analysis, to determine whether glutamate is elevated in treatment-non-responsive schizophrenia when all the existing information is considered. The translational implication is that this could indicate that glutamate-lowering drugs may have efficacy in those who have not responded well to existing antipsychotics. 2. It is not clear how specific abnormalities in glutamate are to schizophrenia. Glutamate is the major excitatory neurotransmitter in the brain and is thus intricately involved in all aspects of heathy cognition, thus abnormalities in glutamate have been suggested across the psychiatric disorders. In addition to meta-analyses from our group (Merritt et al., 2018; Merritt et al., in prep) and others (Nakahara et al., 2022 ) in schizophrenia, meta-analysis have shown decreases in MFC glutamate in major depressive disorder (Moriguchi et al, 2019), increases in glutamate across brain regions in bipolar disorder (Gigante et al., 2012) and no difference in alcohol use disorder (Kirkland et al., 2022). The second study of the PhD will use meta-analytical approaches to compare brain glutamate abnormalities across two or more psychiatric disorders. This will provide initial, novel information on the extent to which glutamate dysfunction may represent a shared or distinct mechanism, in a transdiagnostic approach. 3. Third, several environmental and genetic risk factors have been associated with the development of psychosis and with more severe forms of schizophrenia, but the biological mechanisms are unclear. Our group has recently shown that polygenetic risk for pathways involving NMDA receptor dysfunction are associated with ACC glutamate levels (Griffiths et al., submitted). The third study of the PhD will investigate whether the presence of other risk factors, including family history, early...

谷氨酸是精神分裂症神经生物学中的关键神经递质。在活体人脑内，可以使用基于MRI的质子磁共振波谱（1H-MRS）技术在预先选择的脑区域内测量谷氨酸盐的浓度。现在有超过80个谷氨酸在精神分裂症中的1H-MRS研究。这些单独的研究观察到了各种结果，发现谷氨酸水平增加，减少或没有变化。除其他因素外，这可能与患者特征的差异、研究的大脑区域以及个体研究相对较小样本量内的测量变异性有关。知识可以通过检查更大的、充分表征的患者样本的研究或通过应用大分析或Meta分析技术来联合收割机结合来自个体研究的数据来开发。例如，最近由Egerton教授的小组领导的Meta和大型分析显示，精神分裂症患者不同脑区的谷氨酸盐升高（Merritt et al.，2018），并且在精神病发作后不久或具有最高症状负担的患者中，升高可能最显著（Merritt et al.，2021年）。我们最近的荟萃分析（Merritt et al.，精神分裂症患者的谷氨酸水平比健康志愿者更易变。这种变异性的原因和临床后果目前尚不清楚。理解这些过程可能具有翻译意义，因为它可以指示谷氨酸作用疗法可能具有最大疗效的患者亚组，从而为分层医学方法提供信息。本博士将以三种方式扩展这项工作。 1.我们的小组和其他人还表明，前扣带皮层（ACC）中谷氨酸盐的升高在对抗精神病药物治疗反应不佳的患者中更明显（Egerton等人，2012，2018，2020;岩田等人，2018; Tarumi等人，2021），尽管其他一些研究没有发现相同的发现（Goldstein等人，2015; Horne等人，2021年）。博士的第一项研究将包括荟萃分析和参与者水平的大型分析，以确定在考虑所有现有信息时，谷氨酸是否在治疗无反应精神分裂症中升高。翻译的含义是，这可能表明，降低谷氨酸盐的药物可能对那些对现有抗精神病药物反应不佳的人有效。2.目前尚不清楚谷氨酸异常对精神分裂症的具体影响。谷氨酸是大脑中主要的兴奋性神经递质，因此复杂地参与健康认知的各个方面，因此在精神疾病中已经提出了谷氨酸的异常。除了我们小组的荟萃分析（Merritt et al.，2018; Merritt等人，准备中）和其他人（Nakahara等人，2022），荟萃分析显示，在重度抑郁症中MFC谷氨酸盐减少（Moriguchi等人，2019），在双相情感障碍中跨脑区谷氨酸盐增加（Gigante等人，2012）和酒精使用障碍无差异（柯克兰等人，2022年）。博士的第二项研究将使用荟萃分析方法来比较两种或多种精神疾病的脑谷氨酸异常。这将提供初步的，新的信息在何种程度上谷氨酸功能障碍可能代表一个共享的或不同的机制，在transdiagnosis方法。3.第三，一些环境和遗传风险因素与精神病的发展和更严重形式的精神分裂症有关，但生物学机制尚不清楚。我们的小组最近表明，涉及NMDA受体功能障碍的途径的多基因风险与ACC谷氨酸水平相关（Griffiths et al.，提交）。博士的第三项研究将调查是否存在其他风险因素，包括家族史，早期诊断和治疗。