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与疾病生物学方面相关的分子和神经系统机制的假设。通过使用认知、神经影像学和基础科学的融合验证策略，提供了基于已证实的机制确定新的治疗方法的能力，并可能导致分子通路和网络内的潜在新治疗靶点。我们的目的是生物学验证与精神分裂症的遗传关联是提供生物学证据的影响，精神分裂症相关的风险等位基因的相关措施的大脑发育和功能测定与认知和神经影像学方法在健康和患病的主题。实现这一目标将需要基于新的认知范式和成像分析策略的脑功能中间表型的细化。源自精细靶向大脑信息处理动力学的表型可能导致干扰这些过程的更强的基因效应。 Lemaitre等人（Journal of Neuroscience，2010）在大量年轻和老年男性受试者样本中检查了与帕金森病风险相关的成纤维细胞生长因子（FGF 20）基因多态性对脑结构和功能的影响。结合收敛生物验证策略，我们使用基于体素的形态测量法分析高分辨率解剖磁共振图像，并测量了人死后脑组织中的FGF 20 mRNA表达。我们的研究结果表明，携带T等位基因的受试者海马体积较大，言语情景记忆减少，海马体积随着正常年龄的增长而急剧下降。T细胞携带者海马FGF 20 mRNA的表达也更高，这与先前报道的数据一致。携带C等位基因的个体匹配预期的microRNA结合结构域，而T携带者破坏microRNA的结合能力，导致FGF 20蛋白的增加。最后，FGF受体1在人类海马体中最丰富，并且被认为介导海马体中FGF 20的强遗传效应。总之，帕金森病风险关联、mRNA表达、脑形态、认知缺陷和与衰老的相互作用的健康受试者中的会聚证据证实了FGF 20在发育和衰老期间在人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，它在我们确认神经精神疾病所涉及的神经机制的整体收敛验证策略中起着重要作用。精神分裂症是一种复杂的、可遗传的、遗传异质性的疾病。精神分裂症易感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育和功能与无数症状相关。人类大脑的这种功能障碍仍有待深入了解。成像遗传学在整合推定疾病机制的基础生物学与活脑中的生理相关性状方面发挥作用。具体来说，这种方法的目的是测试是否等位基因与临床诊断统计学相关预测偏差的大脑结构和功能，与精神分裂症患者和他们的健康同胞的发现。Tan et al.（Cognitive Neuropsychiatry，2009）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，首先是多巴胺系统的遗传变异，通过儿茶酚-O-甲基转移酶（COMT）和主动认知过程中前额叶脑网络的调节。也有证据表明AKT 1（一种细胞内信号分子）下游多巴胺相关表达的变化。 这些遗传变异是神经影像学测量上位性的证据，表明多个基因的非加性组合调节活跃的认知脑机制。成像遗传学增加了我们对人类认知脑过程与神经精神疾病相关的遗传机制的认识。 有发表的报告，收敛的证据表明，reelin基因（reelin基因）在神经发育缺陷与精神分裂症的风险增加。Reelin是一种分泌性蛋白酶，在神经元迁移和突触可塑性的分子过程中起着关键作用。精神分裂症发病机制的趋同证据来自遗传关联和基因表达研究，显示精神分裂症患者死后脑组织中mRNA和蛋白质水平降低。关于这些措施的调查结果也不一致。Tost等人（Biological Psychiatry，2010）使用基于体素的形态测量和扩散张量成像评价了大脑结构。在工作记忆任务中使用功能磁共振成像研究脑功能，并在死后脑组织中测量前额叶皮层和海马的基因表达。这些分析没有显示出基因或基因-性别相互作用的显著影响的证据，这已经报道过了。 我们的结论是，测试和其他相关的多态性不影响大脑的措施有关的精神分裂症的神经生物学。