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)： 为了确定治疗精神分裂症的有希望的新靶点，需要更好地了解其病理回路和潜在的遗传易感性。白质假说是一种很有前途的精神分裂症病理生理学模型，该假说假设少突胶质细胞异常导致髓鞘形成缺陷，最终白质束紊乱损害大脑区域之间的有效沟通，导致精神分裂症的认知、情感、知觉和人际关系缺陷/混乱特征。许多易感基因与白色畸形和精神分裂症有关，包括神经调节蛋白1(NRG1)和ERBB4。在这一系列研究中，我们建议研究精神分裂症中白质紊乱的模型，该模型由NRG1和ERBB4以及其他白质相关基因的遗传易感性驱动，在大脑发育过程中与不利环境相互作用，其中白质障碍将部分中介精神分裂症表型的遗传效应，特别是其缺陷和紊乱症状。我们选择分裂型人格障碍(SPD)患者作为我们的表型选择，因为他们代表了一种精神分裂症，没有慢性抗精神病药物治疗、长期精神病甚至住院治疗等令人困惑的人工制品，并提供了一个解析精神分裂症潜在维度的机会。这些研究旨在通过扩散张量成像(DTI)评估的分数各向异性(FA)和结构MRI评估精神分裂症谱系中的灰质和白质体积来评估白质组织及其与两个潜在易感基因NRG1和ERBB4的等位基因变异的关系。假设颞叶和额叶白质束FA减少与SPD有关，SPD是一种典型的精神分裂症谱系障碍，最大限度地减少了与慢性精神分裂症相关的混杂伪影，以及SPD的缺陷和组织紊乱症状维度。推测FA和SPD的降低都与NRG1和ERBB4的等位基因有关。还假设颞叶灰质体积减少与SPD有关。探索性路径分析将评估NRG1和ERBB4等位基因与SPD的关联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与这些基因等位基因的关系，这些遗传等位基因与颞叶灰质体积的可能关联，以及FA和相关遗传等位基因与SPD缺陷和组织紊乱症状的关系。