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对与该疾病的生物学方面相关的分子和神经系统机制产生假设。通过使用认知、神经影像学和基础科学的聚合验证策略，可以根据已确认的机制确定新的治疗方法，并可能在分子途径和网络中找到潜在的新治疗靶点。我们对精神分裂症遗传关联进行生物学验证的目的是为精神分裂症相关风险等位基因对健康和疾病受试者大脑发育和功能的相关测量的影响提供生物学证据。要实现这一目标，需要基于新的认知范式和成像分析策略来改进脑功能中间表型。来自精细靶向大脑信息处理动态的表型可能导致干扰这些过程的更强的基因效应。

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.