The impact of prenatal maternal infection and inflammation on human brain development and psychopathology during adolescence

项目摘要 母体免疫激活（MIA）是指妊娠期间母体免疫系统的触发， 感染或慢性疾病。这会导致胎儿发生一系列免疫学改变， 对大脑发育的影响。大规模的、基于人群的研究表明，MIA与许多 神经精神障碍，包括自闭症谱系障碍、双相情感障碍和精神分裂症。此外，委员会认为， 啮齿类动物的研究一致表明，妊娠早期的MIA导致结构性 以及后代的大脑功能异常和行为障碍。在人类中，最近的成像研究 报道了MIA对儿童大脑结构和行为的类似影响。然而，这些研究受到以下限制： 适度的样本量和相对较短的随访期。 本研究的总体目的是研究妊娠期间母体免疫激活对妊娠期高血压疾病的影响。 青少年神经发育我们将使用世界上唯一的队列，即R世代， 联合收割机尺寸和纵向随访（i）手术期间感染和炎症的详细信息 妊娠，（ii）后代脑成像和（iii）行为和精神结果。在目标1a中，我们将定义 我们的暴露变量母体免疫激活（MIA）。我们将使用详细的三个月具体信息， 感染，并确定感染的类型，以及严重程度。我们将测量一组著名的专家， 炎症标志物（CRP、IL-1β、IL-6、IL-8、TNF-α），以计算慢性低级别 妊娠13周和20周时血清中的炎症。在目标1b中，我们将研究 MIA、胎儿生长和出生时胎龄。在目标2中，我们将研究MIA对后代大脑的影响 14岁时的结构和连接。为了验证MIA导致非典型皮质发育的假设， 我们将为3，757名青少年提供MRI测量。这些包括全脑，白色 皮质灰质和皮质下体积。在目标3中，我们将确定MIA是否会增加以下风险： 认知缺陷、行为障碍和精神病理学也在14岁时发生。 该项目将提供一个全面的定义产妇免疫激活，包括具体方面， 感染的类型和时间，检查其对神经发育的影响，并阐明假定的机制 迄今为止最大的出生队列中的这些影响。总的来说，这些产出将提出预防目标 并协助努力及早发现高危妊娠。

PROJECT SUMMARY Maternal immune activation (MIA) refers to the triggering of the maternal immune system during pregnancy by infections or chronic conditions. This leads to a series of immunologic alterations in the fetus, which can have an impact on brain development. Large-scale, population-based studies have implicated MIA in a number of neuropsychiatric disorders, including autism spectrum disorders, bipolar disorder and schizophrenia. Moreover, studies in rodents have consistently demonstrated that MIA during early phases of pregnancy leads to structural and functional brain abnormalities and behavioral dysfunction in the offspring. In humans, recent imaging studies reported similar effects of MIA on child brain structure and behavior. However, these studies were limited by modest sample sizes and relatively short follow-up periods. The overall aim of this study is to investigate the impact of maternal immune activation during pregnancy on adolescent neurodevelopment. We will use the only cohort in the world, Generation R, with both sufficient sample size and longitudinal follow-up to combine (i) detailed information on infection and inflammation during pregnancy, with (ii) offspring brain imaging and (iii) behavioral and psychiatric outcomes. In aim 1a we will define our exposure variable Maternal Immune Activation (MIA). We will use detailed trimester-specific information on infections and determine the type of infection, as well as severity. We will measure a panel of well-known pro- inflammatory markers (CRP, IL-1β, IL-6, IL-8, TNF-α) to calculate an inflammatory index of chronic low-grade inflammation in serum at 13 and 20 weeks of gestation. In aim 1b we will investigate the association between MIA, fetal growth and gestational age at birth. In aim 2, we will investigate the impact of MIA on offspring brain structure and connectivity at age 14 years. To test the hypothesis that MIA leads to atypical cortical development, we will include MRI measures available and ready to use for 3,757 adolescents. These include total brain, white matter, cortical gray and subcortical volumes. In aim 3 we will determine whether MIA increases the risk for cognitive deficits, behavioral impairments and psychopathology also at age 14 years. This project will provide a comprehensive definition of maternal immune activation, including specific aspects of infection such as type and timing, examine its effects on neurodevelopment, and elucidate putative mechanisms for these effects in the largest birth cohort to date. Collectively, these outputs will suggest targets for prevention and aid the efforts towards early identification of high-risk pregnancies.