Multimodal imaging: genetic and environmental effects in neuropsychiatry

多模态成像：神经精神病学中的遗传和环境影响

基本信息

批准号：
8745762
负责人：
Stefano Marenco
金额：
$ 141.37万
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
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/8745762
关键词：
7q11.23 Address Adult Affect Alleles Aminobutyric Acids Amygdaloid structure Anatomy Anger Anisotropy Anterior Antipsychotic Agents Architecture Area Axon Biological Preservation Biological Process Biology Birth Order Brain Brain region Brain-Derived Neurotrophic Factor Cells Characteristics Choline Chromosomes Clinical Code Collaborations Complement Computer software Conflict (Psychology)Creatine Cues Data Data Analyses Data Set Deformity Detection Development Diffusion Magnetic Resonance Imaging Distant Emotional Environmental Risk Factor Equipment Etiology Face Female Fiber Functional Magnetic Resonance Imaging Genes Genetic Genetic Materials Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Genomics Glutamates Growth Cones Hippocampus (Brain)Homozygote Image Individual Inferior Insula of Reil International LIMK1 gene Link Literature Magnetic Resonance Spectroscopy Magnetism Maps Measures Memory Mental disorders Methods Metric Molecular Abnormality Mood Disorders Multimodal Imaging Mutation Myelin N-acetylaspartate Neurons Oligodendroglia Paper Parietal Participant Paternal Age Patients Performance Peripheral Pharmaceutical Preparations Phenotype Physiological Prefrontal Cortex Pregnancy Process Promoter Regions Property Psychotic Disorders Publications Publishing Regulation Relaxation Research Research Personnel Rest Risk Role Schizophrenia Short-Term Memory Siblings Structure Susceptibility Gene Suspension substance Suspensions Synapses System Technical Expertise Techniques Thalamic structure Time Tissues Variant Williams Syndrome Work axon guidance base brain tissue cell motility cell type cingulate cortex computerized data processing data acquisition data integration design gamma-Aminobutyric Acid genetic variant gray matter healthy volunteer imaging modality in vivo indexing inhibitor/antagonist male meetings migration myelination neurochemistry neuroimaging neuropsychiatry novel response serotonin transporter sex trafficking treatment response trend valylvaline white matter

7q11.23 Address Adult Affect Alleles Aminobutyric Acids Amygdaloid structure Anatomy Anger Anisotropy Anterior Antipsychotic Agents Architecture Area Axon Biological Preservation Biological Process Biology Birth Order Brain Brain region Brain-Derived Neurotrophic Factor Cells Characteristics Choline Chromosomes Clinical Code Collaborations Complement Computer software Conflict (Psychology)Creatine Cues Data Data Analyses Data Set Deformity Detection Development Diffusion Magnetic Resonance Imaging Distant Emotional Environmental Risk Factor Equipment Etiology Face Female Fiber Functional Magnetic Resonance Imaging Genes Genetic Genetic Materials Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Genomics Glutamates Growth Cones Hippocampus (Brain)Homozygote Image Individual Inferior Insula of Reil International LIMK1 gene Link Literature Magnetic Resonance Spectroscopy Magnetism Maps Measures Memory Mental disorders Methods Metric Molecular Abnormality Mood Disorders Multimodal Imaging Mutation Myelin N-acetylaspartate Neurons Oligodendroglia Paper Parietal Participant Paternal Age Patients Performance Peripheral Pharmaceutical Preparations Phenotype Physiological Prefrontal Cortex Pregnancy Process Promoter Regions Property Psychotic Disorders Publications Publishing Regulation Relaxation Research Research Personnel Rest Risk Role Schizophrenia Short-Term Memory Siblings Structure Susceptibility Gene Suspension substance Suspensions Synapses System Technical Expertise Techniques Thalamic structure Time Tissues Variant Williams Syndrome Work axon guidance base brain tissue cell motility cell type cingulate cortex computerized data processing data acquisition data integration design gamma-Aminobutyric Acid genetic variant gray matter healthy volunteer imaging modality in vivo indexing inhibitor/antagonist male meetings migration myelination neurochemistry neuroimaging neuropsychiatry novel response serotonin transporter sex trafficking treatment response trend valylvaline white matter

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项目摘要

The past year has seen a number of published papers and new data presented at national and international meetings. In Tost et al. 2013, an association of variation in the gene coding for the brain derived neurotrophic factor (BDNF; Val66Met polymorphism) with white matter microstructure was assessed. This polymorphism has been associated with various psychiatric conditions, including schizophrenia. It is known that the variant changes the trafficking of BDNF within neural cells, resulting in changes in hippocampal neurochemistry, fMRI activation and performance on memory tasks. Besides affecting neuronal phenotypes, BDNF has effects on other cell types, including oligodendrocytes, represented more prominently in white matter. Several studies have addressed the effect of the BDNF Val66Met polymorphism on white matter structure, with conflicting results. Our results are in line with the largest study in the literature in finding that white matter anisotropy (a measure of the coherent spatial organization of white matter bundles) was increased in Met carriers as compared to Val homozygotes. We also found that this effect was mostly due to a decrease in a measure that is usually considered a measure of myelination; however, there is no evidence supporting increased myelination in Met carriers and it is more likely that these changes reflect alterations in the architecture of white matter fibers. We also showed in this publication that in Val/Val individuals white matter microstructure (anisotropy) was positively correlated with verbal and working memory performance, while in Met carriers, the opposite was true. Along similar lines of inquiry, we found an effect of a polymorphism in the serotonin transporter promoter region (5HTT-LPR) on the white matter microstructure of the uncinate fasciculus. This polymorphism has been implicated in the causation of mood disorders and has been associated with changes in white matter microstructure in previous literature, though the results have been conflicting. We implemented a novel method to define the uncinate fasciculus that allows for automatic delineation of multiple white matter tracts and extraction of tract metrics. In Radulescu et al. 2013, genetic variants in GPR85 that were previously found to increase risk for schizophrenia, were associated with brain activation studied with fMRI. Tasks designed to produce activation in hippocampus (encoding of scenes) and amygdala (presentation of anxious or angry faces), both regions where this gene in highly expressed in adulthood, showed association with the two variants studied. The association in the amygdala was sex specific. Moreover, one of the studied gene variants was associated in a sex specific manner to brain activation during a working memory task. A similar trend occurred in our clinical, where the G allele at locus rs56080411 appeared to increase risk for schizophrenia mainly in males, while it was protective in females. Although the functions of GPR85 are still unknown, these results obtained in healthy individuals support a role of this gene in emotional and mnemonic processing, both functions that are altered in schizophrenia. The work on obstetrical complications as an environmental risk factor for schizophrenia generated a publication (Jaffe et al. 2013, Mol. Psych.) showing that it is unlikely that de novo mutations are the main cause for the known association of paternal age and schizophrenia. Obstetrical complications were associated with increased risk for schizophrenia especially for lower birth order, consistent with the fact that initial pregnancies are more likely to be problematic than later ones. In collaboration, advances have also been made in detailing the effects on white matter microstructure of the 7q11.23 hemideletion associated with Williams Syndrome, leading to the observation that white matter tracts connecting the insula to other important stations of the emotional regulation system (such as amygdala and prefrontal cortex) may be altered in this condition (Jabbi et al. 2012). Moreover, studies in this domain have revealed that people with atypical deletions of the Williams Syndrome chromosome region have an overall alteration of white matter microstructure as compared to controls. Because all the atypical deletions involved the gene LIMK1, which is important in neuronal migration and maturation, it is possible that this gene controls multiple aspects of white matter architecture. Confirmation of this hypothesis was obtained in healthy volunteers, where a genetic variant in the promoter region of LIMK1 was found to be associated with reduced gray matter volume in the intra-parietal sulcus (a characteristic of Williams Syndrome) and a global alteration of white matter microstructure with the same directionality as found in partial and full deletions of the Williams Syndrome chromosome region. Consistent with a role of LIMK1 in regulating white matter microstructure are its known biological functions, which include regulation of growth cone motility in response to axon guidance cues, synapse maturation and plasticity, axon response to myelin associated inhibitors, and appropriate myelination of peripheral nervous cells. Connected to this research, is a more methodological line of work, where we laid the groundwork for determination of white matter tract volume in large datasets of individuals for genetic studies. We focused on the inferior fronto-occipital fasciculus because preliminary work indicated that this might be the white matter tract particularly reduced in volume in participants with short deletions of the Williams syndrome chromosome region. We have also studied GABA and glutamate levels in the anterior cingulate cortex of patients with schizophrenia as compared to controls and have found that GABA levels do not differ between patients and controls, whereas glutamate levels appear to be reduced. We also found that the suspension of neuroleptic medication had no effect on GABA levels in patients with schizophrenia.

在过去的一年中，国家和国际会议上介绍了许多已发表的论文和新数据。在Tost等人中。 2013年，评估了对脑衍生的神经营养因子（BDNF; Val66met多态性）与白质微结构的基因差异的关联。这种多态性与包括精神分裂症在内的各种精神疾病有关。众所周知，这种变体会改变BDNF在神经细胞中的运输，从而导致海马神经化学，fMRI激活和记忆任务上的性能的变化。除影响神经元表型外，BDNF还对包括少突胶质细胞在内的其他细胞类型具有影响，在白质中更为突出。几项研究已经解决了BDNF Val66met多态性对白质结构的影响，结果矛盾。我们的结果符合文献中最大的研究，即发现白质各向异性（对白质捆绑包的连贯空间组织的量度）与Val纯合子相比增加了。我们还发现，这种效果主要是由于通常认为是髓鞘量度的度量的减少。但是，没有证据支持MET载体中髓鞘促进的增加，这些变化更有可能反映了白质纤维结构的变化。我们在本出版物中还表明，在Val/Val个体中，白质微观结构（各向异性）与言语和工作记忆表现呈正相关，而在MET载体中，情况恰恰相反。沿着类似的探究线，我们发现了5-羟色胺转运蛋白启动子区域（5HTT-LPR）中多态性的影响对未筋膜的白质微观结构。这种多态性与情绪障碍的因果关系有关，并且与以前文献中的白质微观结构的变化有关，尽管结果矛盾。我们实施了一种新的方法来定义不符合筋膜，该方法允许自动描述多个白质区域和萃取道指标。在Radulescu等。 2013年，以前发现GPR85中的遗传变异与通过fMRI研究的脑激活相关。旨在在海马中产生激活（场景编码）和杏仁核（焦虑或愤怒面的表现）的任务，这两个区域在成年后高度表达的基因都与研究的两个变体相关。杏仁核的关联是特定于性别的。此外，在工作记忆任务期间，研究的一种基因变体以性别方式与大脑激活相关联。在我们的临床上也发生了类似的趋势，在该基因座的G等位基因rs56080411似乎增加了精神分裂症的风险，主要是男性，而女性则具有保护性。尽管GPR85的功能仍然未知，但在健康个体中获得的这些结果支持该基因在情绪和助记符处理中的作用，这两个功能在精神分裂症中都发生了改变。作为精神分裂症作为环境风险因素的产科并发症的工作引起了出版物（Jaffe等，2013，Mol。Psych。），表明从头突变不太可能是已知的父亲时代和精神分裂症相关的主要原因。产科并发症与精神分裂症的风险增加有关，尤其是对于较低的出生顺序，这与初次怀孕比以后的怀孕更有可能是有问题的事实。在合作中，还取得了进步，详细介绍了与威廉姆斯综合征相关的7q11.23半骨架的效果，导致观察到，与情绪调节系统的其他重要站相连的白质区域（例如，amygdala和therefortal corortex）可能会在这种情况下（jabbi等）改变。此外，该领域的研究表明，与对照组相比，威廉姆斯综合征染色体区域非典型缺失的人的白质微观结构的总体改变。因为所有非典型缺失涉及基因limk1，这在神经元迁移和成熟中很重要，所以该基因可能控制白质结构的多个方面。在健康志愿者中获得了这一假设的证实，在健康志愿者中，发现Limk1的启动子区域的遗传变异与灰质体内的灰质体积减少有关（威廉姆斯综合征的特征）和白质微观结构的全球变化，其方向与Williams Syndrome的部分方向相同。与Limk1在调节白质微观结构中的作用一致的是其已知的生物学功能，其中包括响应轴突引导提示，突触成熟和可塑性的调节生长锥运动，对髓磷脂相关抑制剂的反应以及适当的外周神经细胞的髓鞘化。与这项研究相关的是一种更具方法论的工作，我们为确定大型个体数据集中的白质量的基础奠定了基础，以进行遗传研究。我们专注于下额枕骨肌，因为初步工作表明，这可能是Williams综合征染色体区域缺失的参与者的白质界，尤其减少了体积。与对照组相比，我们还研究了精神分裂症患者的前扣带回皮层中的GABA和谷氨酸水平，并发现患者和对照组之间的GABA水平没有差异，而谷氨酸水平似乎降低。我们还发现，精神分裂症患者的GABA水平没有影响。