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: 7920844
• 负责人: Martha E. Shenton
• 金额: $ 49.63万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7920844
• 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.

最近的磁共振成像研究表明，在颞叶和额叶皮质的灰质进行性变化 精神分裂症发作后然而，对白色物质异常的了解要少得多， 额颞连接长期以来被认为是精神分裂症的异常另外，死后 研究表明星形胶质细胞和少突胶质细胞可能是异常的。由于神经胶质细胞在 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尺寸减小， 突触蛋白水平降低，以及神经传递和功能异常 连接障碍值得进一步注意的是，最近的遗传研究指出，少突胶质细胞和髓鞘相关（OMR） 异常总之，这些发现表明，对白色物质的研究可能会导致 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 在精神分裂症的不同阶段，白色异常易受进展影响的证据 疾病（即，在发病前、首次发病时、发病后很长时间），以便描绘可能的推定标记物。 受试者将是：（1）75名在研究入组时和1年随访时有前驱症状风险的受试者， 转换为精神分裂症的首次发作，也是在进入首次发作研究时;（2）80例首次发作 精神分裂症发作，定义为研究入组时首次住院，并在6个月和18个月时随访;（3） 42例诊断为慢性精神分裂症的患者。正常对照将在年龄、性别、 等等，每个队列。我们将使用扩散张量成像来评估额颞白色纤维 连接（钩束、扣带束、弓状束和穹窿）、胼胝体、前 连合和内囊的前肢，我们预测在慢性关节炎中各向异性降低。 精神分裂症患者>首次发作18个月时发生变化>首次发作6个月时发生变化> “皈依”的人，不皈依。我们还预测与OMR基因的关联，我们将测试 用于六种OMR的基因序列变体（单核苷酸多态性-SNP）之间的关联 基因（NRG 1、ErbBS、MAG、CNP、MOG、GRM 3）。(See也用于从4个组织中分离mRNA的尸检核心 OMR基因ErbB 3、MAG、CNP、MOG）。这个提议将提供与白色物质有关的新发现 精神分裂症的进展，这可能会导致新的治疗和预防策略。