White Matter Abnormalities in Schizophrenia

描述(由申请人提供)：建议的Mt.西奈孔特精神疾病神经科学中心(CCNMD)旨在高度集中的努力阐明白质、少突胶质细胞和髓鞘在精神分裂症中的作用。这一建议是因为越来越多的证据表明，精神分裂症患者在各种科学探索领域中存在白质异常。连接失败已被证明在精神分裂症中起到了作用。髓鞘形成和那些影响髓鞘形成的因素，如少突胶质细胞的功能，是可能深刻影响神经元连接的关键过程，特别是考虑到少突胶质细胞的弥漫分布和与精神分裂症有关的脑区的广泛分布。现在，多条证据汇聚在一起，证明精神分裂症与少突胶质细胞和髓鞘有关。影像和神经细胞化学证据、与脱髓鞘疾病的相似性、白质的年龄相关性变化、髓鞘相关基因异常以及精神分裂症脑中显示的少突胶质细胞的形态异常，都有助于提出一种假设，即少突胶质细胞功能障碍甚至死亡，以及随后的髓鞘维护和修复异常，都会导致精神分裂症综合征(有关详细参考资料，请参阅概述和具体项目)。将在CCNMD将追求的问题上运用一系列广泛的方法和专业知识，包括神经解剖学、神经成像、分子生物学、分子遗传学、神经心理学、现象学、统计学和数据管理。CCNMD由4个核心组成：核心A：行政；核心B：临床；核心C：脑库；核心D：数据管理和统计。CCNMD的项目包括：项目1，将量化精神分裂症患者大脑中少突胶质细胞的数量和空间分布的变化，重点是皮质、丘脑和主要是白质区域。项目2是基于Buxbaum博士实验室的微阵列发现，在相对治疗难治性患者的亚组中，6个髓鞘相关基因在背侧前额叶皮质中的表达减少。项目3检查与髓鞘形成有关的基因，寻找影响蛋白质序列和表达的DNA序列变异，以评估其中一些变异参与决定精神分裂症易感性的可能性。项目4将强大的神经成像技术--扩散张量成像(DTI)和磁化转移成像(MTI)--引入精神分裂症白质的研究。项目5将质子磁共振波谱(1MRS)应用于精神分裂症患者大脑中的白质区域。

DESCRIPTION (provided by applicant): The proposed Mt. Sinai Conte Center for the Neuroscience of Mental Disorders (CCNMD) is designed to be a highly focused effort to elucidate the role of white matter, oligodendrocytes and myelin in schizophrenia. This proposal is informed by increasing evidence of white matter abnormalities in schizophrenia in a variety of areas of scientific exploration. A failure in connectivity has been demonstrated to have a role in schizophrenia. Myelination and those factors that affect myelination, such as the function of oligodendroglia, are critical processes that could profoundly affect neuronal connectivity, especially given the diffuse distribution of oligodendrocytes and the widespread distribution of brain regions that have been implicated in schizophrenia. Multiple lines of evidence now converge to implicate oligodendroglia and myelin in schizophrenia. Imaging and neurocytochemical evidence, similarities with demyelinating diseases, age-related changes in white matter, myelin-related gene abnormalities, and morphological abnormalities in the oligodendroglia demonstrated in schizophrenic brains, all contribute to a hypothesis that oligodendroglial dysfunction and even death, with subsequent abnormalities in myelin maintenance and repair, contribute to the schizophrenic syndrome (see overview and specific projects for detailed references). A broad set of methodologies and expertise will be brought to bear on the questions the CCNMD will pursue, including neuroanatomy, neuroimaging, molecular biology, molecular genetics, neuropsychology, phenomenology, statistics, and data management. The CCNMD is comprised of 4 Cores: Core A: Administrative; Core B: Clinical; Core C: Brain Bank; Core D: Data Management and Statistics. The projects of the CCNMD include: Project 1 which will quantify alterations in both numbers of and spatial distribution of oligodendroglia in the brains of schizophrenic patients, focusing on cortical, thalamic, and predominantly white matter areas. Project 2 is based on microarray findings by the laboratory of Dr. Buxbaum of decreased expression of 6 myelin-related genes in the dorsolateral prefrontal cortex of a subgroup of relatively treatment refractory patients. Project 3 examines genes involved in myelination for DNA sequence variation affecting protein sequence and expression in order to assess the possibility that some of these variants are involved in determining susceptibility to schizophrenia. Project 4 brings powerful neuroimaging techniques- diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI)- to the study of white matter in schizophrenia. Project 5 applies proton magnetic resonance spectroscopy (1 MRS) to white matter areas in the brains of schizophrenic patients.