MRI Studies of Brain Function and Metabolism

脑功能和代谢的 MRI 研究

• 批准号: 8158086
• 负责人: Daniel Weinberger
• 金额: $ 206.17万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8158086
• 关键词: Brain; Magnetic Resonance Imaging; Metabolism

Identifying genes associated with risk for schizophrenia has allowed us to generate hypotheses about molecular and neural system mechanisms related to biologic aspects of the illness. By using a convergent validation strategy of cognitive, neuroimaging and basic science offers the ability to identify new approaches to treatment based on confirmed mechanisms and may lead to potentially new therapeutic targets within molecular pathways and networks. Our aim for biological validation of genetic association with schizophrenia is to provide biologic evidence of the effect of schizophrenia associated risk alleles on relevant measures of brain development and function assayed with cognitive and neuroimaging approaches in healthy and ill subjects. Accomplishing this will require refinement of brain functional intermediate phenotypes based on novel cognitive paradigms and analytic strategies in imaging. Phenotypes that derive from finely targeting brain information processing dynamics may result in stronger gene effects that interfere with these processes. Lemaitre et al. (Journal of Neuroscience, 2010) examined the effect of the fibroblast growth factor (FGF20) gene polymorphism associated with risk for Parkinsons disease on brain structure and function in a large sample of young and elderly male subjects. Incorporating the convergent biologic validation strategy, we used voxel-based morphometry to analyze high-resolution anatomical magnetic resonance images and FGF20 mRNA expression was measured in human postmortem brain tissue. Our results showed subjects carrying the T allele had larger hippocampal volume, reduced verbal episodic memory and demonstrated a sharp decline in hippocampal volume with normal aging. The T carriers also had greater expression of hippocampal FGF20 mRNA which is consistent with previously reported data. Individuals carrying the C allele matched the expected microRNA binding domain, whereas the T carriers disrupt the binding ability of microRNA resulting in an increase in FGF20 protein. Lastly, FGF receptor 1 is found most abundantly in the human hippocampus and is thought to mediate the strong genetic effects of FGF20 in the hippocampus. Altogether the convergent evidence in healthy subjects of Parkinsons disease risk association, mRNA expression, brain morphology, cognitive deficits and an interaction with aging confirmed the role of FGF20 in human brain structure and function during development and aging. Another aspect of our research is in imaging genetics, which plays an important role in our overall convergent validation strategy for confirming neural mechanisms implicated in neuropsychiatric disorders. Schizophrenia is complex, heritable and genetically heterogeneous. Schizophrenia susceptibility genes are associated with a myriad of symptoms by affecting the development and function of neural systems that mediate expression of behavior, cognition and executive function. This dysfunction of the human brain remains to be well understood. Imaging genetics plays a role in integrating the basic biology of putative disease mechanisms with physiological correlated traits in the living brain. Specifically, the aim of this approach is to test whether alleles that are statistically associated with clinical diagnosis predict deviations in brain structure and function that are related to findings in patients with schizophrenia and their healthy siblings. Tan et al. (Cognitive Neuropsychiatry, 2009) reviewed how imaging genetics elucidates prefrontal brain systems associated with working memory and executive function beginning with genetic variation in the dopamine system via catechol-O-methyltransferase (COMT) and modulation of prefrontal brain networks during active cognitive processing. There is also evidence of variation of dopamine-related expression downstream on AKT1 (an intracellular signaling molecule). These genetic variants are evidence of epistasis on neuroimaging measures, suggesting that a non-additive combination of multiple genes modulate active cognitive brain mechanisms. Imaging genetics has added to our knowledge of genetic mechanisms of human cognitive brain processes related to neuropsychiatric disorders. There are published reports of convergent evidence implicating the reelin gene (RELN) in neurodevelopmental deficits associated with an increased risk for schizophrenia. RELN encodes for the glycoprotein reelin, a secretory protease which plays a pivotal role in the molecular processes that subserve neuronal migration and synaptic plasticity. The convergent evidence of schizophrenia pathogenesis is from genetic association and gene expression studies showing a reduction in mRNA and protein levels in postmortem brain tissue of patients with schizophrenia. There have also been inconsistent findings regarding these measures. Tost et al. (Biological Psychiatry, 2010) evaluated brain structure using voxel-based morphometry and diffusion tensor imaging. Brain function was studied using fMRI during working memory tasks, and gene expression was measured in both prefrontal cortex and hippocampus in postmortem brain tissue. These analyses did not show evidence of a significant effect of the gene or a gene-sex interaction, which had been reported. We concluded that the tested and other related polymorphisms do not affect brain measures related to the neurobiology of schizophrenia.

识别与精神分裂症风险相关的基因使我们能够产生有关疾病生物学方面的分子和神经系统机制的假设。通过使用认知的收敛验证策略，神经影像学和基础科学提供了基于确认的机制识别新方法的能力，并可能导致分子途径和网络中潜在的新治疗靶标。我们对精神分裂症遗传关联的生物学验证的目的是提供精神分裂症相关风险等位基因对脑发育相关的措施的影响的生物学证据。实现这一目标将需要基于新颖的认知范例和成像中的分析策略来改进大脑功能性中间表型。源自精细靶向大脑信息处理动力学的表型可能会导致更强的基因作用，从而干扰这些过程。 Lemaitre等。 （神经科学杂志，2010年）研究了与帕金森氏病风险有关的成纤维细胞生长因子（FGF20）基因多态性对大量年轻男性和老年男性受试者的脑结构和功能的影响。结合了收敛的生物学验证策略，我们使用基于体素的形态计量学来分析高分辨率的解剖磁共振图像和FGF20 mRNA表达在人类后尸体后脑组织中测量。我们的结果表明，携带T等位基因的受试者的海马体积较大，言语记忆减少，并且表现出正常衰老的海马体积急剧下降。 T载体也具有更大的海马FGF20 mRNA表达，这与先前报道的数据一致。携带C等位基因的个体与预期的microRNA结合结构域相匹配，而T载体破坏了microRNA的结合能力，从而导致FGF20蛋白增加。最后，在人海马中发现FGF受体1最丰富，被认为可以介导Hippocampus中FGF20的强遗传作用。总的来说，帕金森氏病风险关联，mRNA表达，脑形态，认知缺陷以及与衰老的相互作用的健康受试者的收敛证据证实了FGF20在发育和衰老过程中人类脑结构和功能中的作用。 我们研究的另一个方面是成像遗传学，它在我们的整体收敛验证策略中起着重要作用，以确认与神经精神疾病有关的神经机制。精神分裂症是复杂的，可遗传的且遗传性异质的。精神分裂症的敏感性基因通过影响介导行为，认知和执行功能表达的神经系统的发展和功能，与无数症状有关。人脑的这种功能障碍尚待理解。成像遗传学在将假定疾病机制的基本生物学与活大脑中的生理相关性状结合在一起。具体而言，这种方法的目的是测试与临床诊断统计相关的等位基因是否可以预测与精神分裂症患者及其健康兄弟姐妹的发现有关的大脑结构和功能的偏差。 Tan等。 （认知神经精神病学，2009年）回顾了成像遗传学如何阐明与工作记忆和执行功能相关的前额叶脑系统，从多巴胺系统中的遗传变异开始，通过儿茶素-O-甲基转移酶（COMT）和在主动认知过程中的前额叶脑网络的调节。也有证据表明在AKT1（细胞内信号分子）下游多巴胺相关的表达变异。 这些遗传变异是对神经影像措施的上毒症的证据，表明多个基因的非添加结合调节了主动认知脑机制。成像遗传学增加了我们对与神经精神疾病有关的人类认知脑过程的遗传机制的了解。 有关于收敛证据的报道，暗示了与精神分裂症风险增加有关的神经发育缺陷中的reelin基因（RELN）。 RELN编码糖蛋白reelin，这是一种分泌蛋白酶，在分子过程中起着关键作用，可提供神经元迁移和突触可塑性。精神分裂症发病机理的收敛证据来自遗传缔合和基因表达研究，表明精神分裂症患者死后脑组织中mRNA和蛋白质水平的降低。关于这些措施也有不一致的发现。 Tost等。 （生物精神病学，2010年）使用基于体素的形态计量学和扩散张量成像评估了大脑结构。在工作记忆任务期间，使用fMRI研究了脑功能，并在冠状脑组织中的前额叶皮层和海马中测量了基因表达。这些分析没有显示出据报道的基因或基因性相互作用的显着作用的证据。 我们得出的结论是，经过测试和其他相关的多态性不会影响与精神分裂症神经生物学有关的脑测量。