White Matter Abnormalities in the Schizophrenia Spectrum

描述（由申请人提供）： 为了确定有希望的新目标，干预精神分裂症，需要更好地了解其病理电路和潜在的遗传易感性。精神分裂症的一个有希望的病理生理学模型是白色物质假说，该假说假定少突胶质细胞异常导致髓鞘形成缺陷，并且最终紊乱的白色物质束损害脑区域之间的有效通信，从而导致精神分裂症的认知、情感、知觉和人际交往缺陷/紊乱特征。许多易感基因与白色异常和精神分裂症有关，包括神经调节蛋白1（NRG 1）和ERBB 4。在这一系列的研究中，我们建议调查的精神分裂症的白色物质紊乱的NRG 1和ERBB 4以及其他白色物质相关基因的遗传易感性驱动的模型在大脑发育过程中与不利的环境，其中白色物质障碍将部分介导的精神分裂症的表型，特别是其赤字和紊乱症状的遗传效应。我们选择了典型人格障碍（SPD）作为我们选择的表型，因为他们代表了一种形式的精神分裂症，没有长期精神抑制剂治疗，长期精神病，甚至制度化的混淆工件，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弥散张量成像（DTI）评估的各向异性分数（FA）评估白色物质组织，通过结构MRI评估精神分裂症谱系中的灰色和白色物质体积，以及它们与两个潜在易感基因NRG 1和ERBB 4等位基因变异的关系。据推测，减少FA在颞叶和额叶白色物质束是与SPD，原型精神分裂症谱系障碍，最大限度地减少与慢性精神分裂症，以及缺陷和混乱的SPD症状维度的混淆工件。假设FA和SPD的降低均与NRG 1和ERBB 4中的等位基因相关。也有人假设颞叶灰质体积减少与SPD有关。探索性路径分析将评估NRG 1和ERBB 4等位基因与SPD的关联在多大程度上是通过白色物质异常介导的。其他分析将探索感兴趣的区域与这些基因的等位基因的关系，这些遗传等位基因与时间灰质体积的可能关联，以及FA和相关遗传等位基因与SPD的缺陷和紊乱症状的关系。

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.