PROJECT 4: VULNERABILITY TO WHITE MATTER PROGRESSION IN SCHIZOPHRENIA

最近的核磁共振研究显示颞叶和额叶皮质的灰质进行性改变。 在精神分裂症发作后。然而，对白质异常的了解要少得多，尤其是 额颞部连接，长期以来被认为在精神分裂症中是不正常的。此外，尸检 研究表明，星形胶质细胞和少突胶质细胞可能是异常的。因为神经胶质细胞扮演着重要的角色 在神经元迁移和突触功能中的作用，它们的功能障碍可能导致神经元体积缩小， 突触蛋白水平降低以及神经传递和功能异常 连接障碍。更值得注意的是，最近的遗传学研究指出少突胶质细胞和髓鞘相关(OMR) 异常现象。综上所述，这些发现表明，对白质的调查可能导致 对精神分裂症神经病理学的进一步认识。这个项目的主要目的是调查 精神分裂症不同阶段白质异常进展易感性的证据 疾病(即发病之前、发病后很久)，以便描述可能的推定标志物。 研究对象为：(1)75名有前驱症状的高危受试者，在研究开始时和一年随访时，以及 转换为精神分裂症的第一个发作，也是在进入第一个发作研究的时候；(2)80个首先 发病精神分裂症，以首次住院定义，在研究开始时，在6个月和18个月后；(3) 42例诊断为慢性精神分裂症患者。正常对照组将在年龄、性别、 等等，到每个队列。我们将使用扩散张量成像来评估额颞白质纤维 联系(钩状束、扣带束、弓状束和穹隆)、胼胝体、前部 连合和内囊前肢，我们预测慢性病患者的各向异性降低 精神分裂症患者的首发症状在18个月后发生变化，首发症状在6个月时发生变化 转换&>；不转换的前身。我们还预测了与OMR基因的关联，我们将在那里进行测试 用于6个OMR的基因序列变异(单核苷酸多态-SNPs)之间的关联 基因(NRG1、ERBBS、MAG、CNP、MOG、GRM3)。(另请参阅死后核心以从4个细胞中分离出mRNA OMR基因-ErbB3、MAG、CNP、MOG)。这项提议将提供与白质相关的新发现。 精神分裂症的进展，这可能会导致新的治疗和预防策略。

Recent MRI studies demonstrate progressive changes in gray matter in temporal and frontal cortices following onset of schizophrenia. Far less, however, is known about white matter abnormalities, particularly fronto-temporal connections, long thought to be abnormal in schizophrenia. Additionally, post-mortem studies indicate that astrocytes and oligodendrocytes may be abnormal. Since glial cells play an important role in neuronal migration and in synaptic function, their dysfunction could lead to reduced neuronal size, reduced levels of synaptic proteins, as well as to abnormalities in neurotransmission and functional dysconnectivity. Of further note, recent genetic studies point to oligodendrocyte and myelin related (OMR) abnormalities. Taken together, these findings indicate that an investigation of white matter may lead to a further understanding of the neuropathology of schizophrenia. The main aim of this project is to investigate evidence for vulnerability to progression of white matter abnormalities in schizophrenia, at various stages of the illness (i.e., before, at first onset, long after illness onset), in order to delineate possible putative markers. Subjects will be: (1) 75 prodrome at risk subjects at study entry and at 1-year follow-up, and for those who convert to a first episode of schizophrenia, also at time of entry into the first episode study; (2) 80 first episode schizophrenia, defined by first hospitalization, at study entry.and followed at 6-mths and 18-mths; (3) 42 patients diagnosed with chronic schizophrenia. Normal controls will be group matched for age, gender, etc., to each cohort. We will use Diffusion Tensor Imaging to evaluate fronto-temporal white matter fiber connections (uncinate fasciculus, cingulate bundle, arcuate fasciculus, and fornix), corpus callosum, anterior commissure, and anterior limb of internal capsule, where we predict decreased anisotropy in chronic schizophrenics>first episode with changes at 18 months>first episode changes at 6 months>prodromes who convert>prodromes who do not convert. We also predict associations with OMR genes, where we will test for association between gene sequence variants (single nucleotide polymorphisms-SNPs) for six OMR genes (NRG1, ErbBS, MAG, CNP, MOG, GRM3). (See also Postmortem Core for isolation of mRNA from 4 OMR genes-ErbB3, MAG, CNP, MOG). This proposal will provide new discoveries relevant to white matter progression in schizophrenia, which will likely lead to new treatment and preventative strategies.