White Matter Abnormalities in the Schizophrenia Spectrum

精神分裂症谱系中的白质异常

• 批准号: 8698390
• 负责人: Larry J Siever
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698390
• 关键词: Accounting; Affective; Alleles; Anisotropy; Anterior; Antipsychotic Agents; Brain; Brain region; Brodmann' s area; Caring; Characteristics; Chronic; Chronic Schizophrenia; Clinical; Cognitive; Communication; DNA; Data; Development; Diagnosis; Diagnostic; Diffusion Magnetic Resonance Imaging; Dimensions; Disease; Environment; Fiber; Forcep; Functional disorder; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Goals; Gray unit of radiation dose; Health Care Costs; Impaired cognition; Individual; Inferior; Institutionalization; Internal Capsule; Intervention; Lead; Limb structure; Magnetic Resonance Imaging; Maps; Measurable; Measures; Mediating; Minor; Modeling; Molecular Abnormality; Morphologic artifacts; Myelin; Neuregulin 1; Neuregulins; Neuromodulator; Occupational; Oligodendroglia; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Population; Psychophysiology; Psychotic Disorders; Research; Sampling; Schizophrenia; Schizotypal Personality Disorder; Series; Severity of illness; Susceptibility Gene; Symptoms; Temporal Lobe; Translations; Variant; base; cingulate cortex; cognitive function; frontal lobe; functional disability; genetic association; genetic variant; gray matter; interest; myelination; perceptual organization; pre-clinical; psychotic symptoms; risk variant; trait; white matter

DESCRIPTION (provided by applicant): Project Summary In order to identify promising new targets for intervention in schizophrenia, a better understanding of its pathologic circuitry and underlying genetic susceptibilities is required. A promising pathophysiologic model of schizophrenia is the white matter hypothesis which posits oligodendrocyte abnormalities resulting in defective myelination and ultimately disordered white matter tracts impair effective communication between brain regions contributing to the cognitive, affective, perceptual, and interpersonal deficits/disorganization characteristics of schizophrenia. A number of susceptibility genes are implicated in white abnormalities and schizophrenia including neuregulin 1 (NRG1) and ERBB4. In this series of studies, we propose to investigative a model of white matter disorganization in schizophrenia driven by genetic susceptibilities in NRG1 and ERBB4 as well as other white matter related genes in interaction with adverse environments during brain development in which white matter disorder would partially mediate the genetic effects on the schizophrenic phenotype and particularly its deficit and disorganization symptoms. We have selected schizotypal personality disorder (SPD) subjects as our choice of phenotype as they represent a form of schizophrenia without the confounding artifacts of chronic neuroleptic treatment, long term psychosis, and even institutionalization, and offers an opportunity to parse the underlying dimensions of schizophrenia. The proposed studies aim to evaluate white matter organization through fractional anisotropy (FA) as evaluated by diffusion tensor imaging (DTI) and grey and white matter volumes in the schizophrenia spectrum by structural MRI and their relationship to allelic variation in two underlying susceptibility genes NRG1 and ERBB4. It is hypothesized that reduced FA in temporal and frontal white matter tracts is association with SPD, the prototypic schizophrenia spectrum disorder minimizing the confounding artifacts associated with chronic schizophrenia, as well as the deficit and disorganization symptom dimensions of SPD. Both reduced FA and SPD are hypothesized to be associated with alleles in NRG1 and ERBB4. It is also hypothesized that reduced gray matter volume in temporal lobe is associated with SPD. Exploratory path analysis will evaluate to what extent the association of alleles of NRG1 and ERBB4 with SPD are mediated through white matter abnormalities. Other analyses will explore the relationship of regions of interest to these genes' alleles, the possible association of these genetic alleles with temporal grey matter volume, and the relationship of FA and associated genetic alleles to the deficit and disorganization symptoms of SPD.

描述（由申请人提供）： 为了确定有希望的精神分裂症干预目标的项目摘要，需要更好地了解其病理电路和潜在的遗传敏感性。精神分裂症的有前途的病理生理模型是白质假说，它提出了少突胶质细胞异常，导致骨髓缺陷并最终导致白质区域障碍损害大脑区域之间有效的有效沟通，从而有助于认知，情感，感知，感知和人际关系缺乏/跨性别障碍和人性化的特征。许多敏感性基因与白色异常和精神分裂症有关，包括神经调节蛋白1（NRG1）和ERBB4。在这一系列研究中，我们建议研究一种由NRG1和ERBB4中遗传敏感性以及其他白质相关的基因与大脑发育过程中白质障碍相互作用的精神分裂症中的白质混乱模型，在该模型中，白质疾病与不良环境相互作用，其中白质障碍会部分介导对精神分裂症的遗传效应，尤其是其遗传现象和疾病的遗传效果。我们选择了精神型人格障碍（SPD）作为我们对表型的选择，因为它们代表了一种精神分裂症的形式，而没有慢性神经疗法治疗，长期精神病甚至制度化的混杂伪像，并提供了一个机会来解析精神分裂症的潜在维度。 拟议的研究旨在通过分数各向异性（FA）通过结构MRI及其与两个潜在的易感基因NRG1和ERBB4的等位基因变异的关系评估，通过分数各向异性（FA）评估了精神分裂症谱的扩散张量成像（DTI）和灰质和白质体积。假设在时间和额叶白质区域中的FA降低是与SPD相关的，SPD是原型精神分裂症谱系障碍最小化与慢性精神分裂症相关的混杂伪影，以及SPD的缺陷和混乱症状。假设FA和SPD的降低都与NRG1和ERBB4中的等位基因相关。还假设颞叶中的灰质体积减小与SPD相关。探索性路径分析将评估NRG1和ERBB4等位基因与SPD的相关性在多大程度上是通过白质异常介导的。其他分析将探索感兴趣区域与这些基因等位基因的关系，这些遗传等位基因与时间灰质体积的可能关联，以及FA与相关遗传等位基因与SPD的不足和混乱症状的关系。