PROJECT 4: VULNERABILITY TO WHITE MATTER PROGRESSION IN SCHIZOPHRENIA

项目 4：精神分裂症患者白质进展的脆弱性

• 批准号: 8136029
• 负责人: Martha E. Shenton
• 金额: $ 41.59万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8136029
• 关键词: Acute Erythroblastic Leukemia; Age; Amygdaloid structure; Anisotropy; Anterior; Area; Astrocytes; Autopsy; Biological Markers; Biological Neural Networks; Brain; Brain region; Caliber; Candidate Disease Gene; Cell Nucleus; Cells; Chronic; Chronic Schizophrenia; Clinical; Cognitive; Communication; Complex; Corpus Callosum; Cyclic Nucleotides; Data; Databases; Development; Diagnosis; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Dorsal; Etiology; Fiber; Functional disorder; Gender; Gene Expression; Genes; Genetic; Genetic Variation; Glycoproteins; Hippocampus (Brain); Homologous Gene; Hospitalization; Human; Image; Immigration; Individual; Inferior; Internal Capsule; Investigation; Lead; Left; Lesion; Limb structure; Link; Literature; Lobule; Magnetic Resonance Imaging; Matched Group; Measures; Medial; Memory; Messenger RNA; Metabolism; Myelin; Myelin Associated Glycoprotein; N-Methylaspartate; NRG1 gene; Neuroglia; Neurons; Oligodendroglia; Onset of illness; Parietal; Pathologic Processes; Pathology; Patients; Play; Proteins; Recording of previous events; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Schizophrenia; Signal Transduction; Single Nucleotide Polymorphism; Source; Staging; Structure of supramarginal gyrus; Suggestion; Superior temporal gyrus; Susceptibility Gene; Symptoms; Synapses; Temporal Lobe; Testing; Thalamic structure; Thick; Time; Transcript; Variant; Viral Oncogene; anterior commissure; base; cohort; density; first episode schizophrenia; follow-up; frontal lobe; genetic association; gray matter; insight; interest; laser capture microdissection; metabotropic glutamate receptors type 3; neuroimaging; neuropathology; neurotransmission; oligodendrocyte-myelin glycoprotein; phosphoric diester hydrolase; progression marker; synaptic function; white matter

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.

最近的MRI研究表明，颞叶和额叶皮质的灰质渐进性变化 精神分裂症发作。然而，关于白质异常的了解要少得多，尤其是 额叶连接，长期以来被认为是精神分裂症异常的。另外，验尸 研究表明，星形胶质细胞和少突胶质细胞可能异常。由于神经胶质细胞起着重要的作用 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的大小降低， 突触蛋白的水平降低，以及神经传递和功能的异常 功能障碍。另外，最近的遗传研究表明少突胶质细胞和髓磷脂相关（OMR） 异常。综上所述，这些发现表明对白质的调查可能导致 进一步了解精神分裂症的神经病理学。该项目的主要目的是调查 在精神分裂症的白质异常进展的证据，在各个阶段 为了描述可能的推定标记，这种疾病（即，首先，首次发作之前，在疾病发作后很长时间）。 受试者将是：（1）75个原生物在研究条目和1年的随访中处于风险的风险对象，对于那些人 转换为精神分裂症的第一集，也是在进入第一集研究时； （2）80首先 精神分裂症是由第一次住院定义的，在研究条目中定义的，紧随其后的是第6个和第18个中。 （3） 42例诊断为慢性精神分裂症的患者。正常控件将与年龄，性别， 等，每个队列。我们将使用扩散张量成像来评估额叶白质纤维 连接（无筋膜，扣带束，弓形筋膜和福尼克斯），callosum callosum，前 连合胶囊和内囊的前肢，我们预测慢性的各向异性降低 精神分裂症患者>第一集在18个月时变化>第一次情节在6个月时变化> 转换>不转换的前驱物。我们还预测了与OMR基因的关联，我们将在其中测试 对于六个OMR的基因序列变体（单核苷酸多态性-SNP）之间的关联 基因（NRG1，ERBBS，MAG，CNP，MOG，GRM3）。 （另请参见验尸核心，以分离4个mRNA OMR Genes-ERBB3，MAG，CNP，MOG）。该建议将提供与白奇有关的新发现 精神分裂症的进展可能会导致新的治疗和预防策略。