MRI Studies of Brain Function and Metabolism

识别与精神分裂症风险相关的基因使我们能够产生与该疾病的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、神经影像和基础科学的聚合验证策略，能够根据已证实的机制确定新的治疗方法，并可能在分子途径和网络中产生潜在的新治疗靶点。我们对精神分裂症遗传关联进行生物学验证的目的是提供生物学证据，证明精神分裂症相关风险等位基因对健康和患病受试者的大脑发育和功能相关测量指标的影响，并通过认知和神经影像方法进行测定。实现这一目标需要基于新的认知范式和成像分析策略来完善大脑功能中间表型。源自精细靶向大脑信息处理动态的表型可能会导致更强的基因效应，从而干扰这些过程。 勒梅特等人。 （Journal of Neuroscience，2010）研究了与帕金森病风险相关的成纤维细胞生长因子 (FGF20) 基因多态性对大量年轻和老年男性受试者的大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来分析高分辨率解剖磁共振图像，并测量人类死后脑组织中的 FGF20 mRNA 表达。我们的结果显示，携带 T 等位基因的受试者的海马体积较大，言语情景记忆减少，并且随着正常衰老，海马体积急剧下降。 T 携带者的海马 FGF20 mRNA 表达也较高，这与之前报道的数据一致。携带 C 等位基因的个体与预期的 microRNA 结合域相匹配，而 T 携带者破坏了 microRNA 的结合能力，导致 FGF20 蛋白增加。最后，FGF 受体 1 在人类海马体中含量最丰富，被认为介导海马体中 FGF20 的强大遗传效应。健康受试者中帕金森病风险关联、mRNA 表达、大脑形态、认知缺陷以及与衰老的相互作用的综合证据证实了 FGF20 在发育和衰老过程中人类大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涉及的神经机制的整体收敛验证策略中发挥着重要作用。精神分裂症是复杂的、可遗传的和遗传异质性的。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，与多种症状相关。人脑的这种功能障碍仍有待深入了解。影像遗传学在将假定疾病机制的基础生物学与活体大脑的生理相关特征相结合方面发挥着重要作用。具体来说，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相关的大脑结构和功能的偏差。谭等人。 （认知神经精神病学，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大脑系统，首先是通过儿茶酚-O-甲基转移酶（COMT）在多巴胺系统中发生遗传变异，并在主动认知处理过程中调节前额叶大脑网络。还有证据表明 AKT1（一种细胞内信号分子）下游的多巴胺相关表达存在变化。 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大脑机制。成像遗传学增加了我们对与神经精神疾病相关的人类认知大脑过程的遗传机制的了解。 已发表的报告显示，reelin 基因 (RELN) 与神经发育缺陷有关，并与精神分裂症风险增加相关。 RELN 编码糖蛋白 reelin，这是一种分泌性蛋白酶，在促进神经元迁移和突触可塑性的分子过程中发挥着关键作用。精神分裂症发病机制的集中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。托斯特等人。 （生物精神病学，2010）使用基于体素的形态测量和扩散张量成像评估大脑结构。在工作记忆任务期间使用功能磁共振成像研究大脑功能，并测量死后脑组织中前额叶皮层和海马体的基因表达。这些分析没有显示出该基因或基因与性别相互作用的显着影响的证据，而这一点已被报道。 我们的结论是，测试的多态性和其他相关的多态性不会影响与精神分裂症神经生物学相关的大脑测量。

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.