Prospective Studies of the Pathogenesis of Schizophrenia

描述(申请人提供)：精神分裂症与MRI上大脑结构的细微异常有关，包括侧脑室扩大，皮质灰质体积减少，海马体体积减少，以及白质中异常的扩散特性。虽然有人假设这些大脑异常出现在大脑发育的早期，但几乎没有直接证据支持这一观点。在这个康特中心项目的第一个资助期，我们开发了磁共振图像(MRI)采集和图像分析工具，以研究精神分裂症高危儿童的非常早期的大脑发育。其中包括一组遗传高危人群--患有精神分裂症妇女的后代，以及一组“结构性”高危人群--患有产前孤立的轻度脑室肿大的儿童。我们的结果对数据表明，与正常对照组相比，精神分裂症母亲的后代在新生儿MRI上皮质灰质体积减少。这是第一个确凿的证据表明，早期皮质发育受到遗传脆弱性的影响。围产期和出生后早期是皮质连通性发展的关键时期之一，这是突触快速生长的时期，也是Conte中心的重点。此外，我们还发展了一大批正常对照。在第二个资助期，我们建议继续我们对正常和高危儿童早期大脑发育的研究，应用我们的新图像分析方法来研究不断扩大的队列中的灰质和白质发育，并研究随着我们的队列进入童年中期，大脑发育的纵向变化。具体地说，我们将使用3T MRI(包括扩散张量成像)和0、1、2、4和6岁的神经发育评估来研究精神分裂症高危儿童的纵向大脑发育。我们还将研究患有双相情感障碍母亲的后代的早期大脑发育，作为药物和慢性病的非特异性影响的对照组。最后，我们已经获得了一大组正常新生儿的DNA和核磁共振成像，并将确定危险基因的多态是否会影响生命最早阶段的皮质发育。

DESCRIPTION (as provided by applicant): Schizophrenia is associated with subtle abnormalities of brain structure on MRI, including enlarged lateral ventricles, reduced cortical gray matter volumes, reduced hippocampal volumes, as well as abnormal diffusion properties in white matter. While it has been hypothesized that these brain abnormalities arise during early brain development, there has been little direct evidence to support this idea. In the first funding period of this Conte Center project, we developed the magnetic resonance image (MRI) acquisition and image analysis tools to study very early brain development in children at high risk for schizophrenia. These included a genetic high risk group - the offspring of women with schizophrenia, and a "structural" high risk group - children with prenatal isolated mild ventriculomegaly. Our results to data indicate that compared to normal controls, the offspring of mothers with schizophrenia have reduced cortical gray matter volumes on neonatal MRI. This is the first concrete evidence that early cortical development is compromised by genetic vulnerability. The perinatal and early postnatal period is one of the critical periods in the development of cortical connectivity - a time of rapid synapse growth - one that is a focus of this Conte Center. In addition, we have developed a large cohort of normal controls. In the second funding period, we propose to continue our study of every early brain development in normal and high risk children, applying our novel image analysis methodologies to study gray and white matter development in an expanding cohort, and to study longitudinal brain developmental changes as we follow our cohort into mid childhood. Specifically we will study longitudinal brain development in children at high risk for schizophrenia with 3T MRI (including diffusion tensor imaging) and neurodevelopmental assessments at ages 0, 1, 2, 4, and 6 years of age. We will also study early brain development in the offspring of mothers with bipolar illness as a comparison group for non-specific effects of medication and chronic illness. Finally, we have obtained DNA and MRIs on a large group of normal neonates and will determine if polymorphisms of risk genes influence cortical development at this earliest stage of life.