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

产前母体感染和炎症对青春期人脑发育和精神病理学的影响

• 批准号: 10468261
• 负责人: Veerle Bergink
• 金额: $ 70.9万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-11 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10468261
• 关键词: 14 year old; Adolescence; Adolescent; Animal Model; Anisotropy; Behavior; Behavioral; Biological Markers; Bipolar Disorder; Birth; Body mass index; Brain; Brain imaging; COVID-19 pandemic; Child; Child Behavior Checklist; Chronic; Clinical; Cognition; Cognitive; Cognitive deficits; Data; Development; Diffuse; Diffusion Magnetic Resonance Imaging; Early identification; Equipment and supply inventories; Family; Fetal Growth; Fetus; Functional disorder; Generations; Gestational Age; High-Risk Pregnancy; Human; IL8 gene; Immune response; Immune system; Immunologics; Infection; Infectious Pregnancy Complications; Inflammation; Inflammatory; Intelligence; Interleukin-1 beta; Interleukin-17; Interleukin-6; Lead; Left; Long-Term Effects; Longterm Follow-up; Magnetic Resonance Imaging; Measures; Mediating; Mediator of activation protein; Negative Finding; Outcome; Output; Phase; Population Study; Pre-Eclampsia; Pregnancy; Pregnant Women; Premature Birth; Prevention; Psychopathology; Reporting; Risk; Rodent; SARS-CoV-2 infection; Sample Size; Sampling; Schizophrenia; Series; Serum; Severities; Structure; TNF gene; Temporal Lobe; Testing; Thick; Virus; adolescent offspring; adverse outcome; aggressive therapy; autism spectrum disorder; base; behavioral impairment; boys; brain abnormalities; brain behavior; clinically relevant; cohort; cytokine; executive function; follow-up; girls; graph theory; imaging study; immune activation; indexing; inflammatory marker; maternal serum; neurodevelopment; neuropsychiatric disorder; next generation; offspring; prehypertension; prenatal; social; tractography; ultrasound; white matter

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.

项目摘要 母体免疫激活（MIA）是指怀孕期间触发母体免疫系统 感染或慢性病。这导致胎儿的一系列免疫学改变，可以 对大脑发育的影响。大规模，基于人群的研究已在许多人中实施了MIA 神经精神疾病，包括自闭症谱系障碍，躁郁症和精神分裂症。而且， 啮齿动物的研究一直表明，在怀孕早期阶段的MIA导致结构性 后代的功能性脑异常和行为功能障碍。在人类中，最近的成像研究 报道了MIA对儿童脑结构和行为的类似影响。但是，这些研究受到 样本量适中，随访期相对较短。 这项研究的总体目的是研究怀孕期间母体免疫激活对 青少年神经发育。我们将使用世界上唯一的人群，这两个都足够样本 大小和纵向随访，以结合（i）有关感染和注射的详细信息 怀孕，（ii）后代大脑成像以及（iii）行为和精神病结果。在AIM 1A中，我们将定义 我们的暴露变量产生免疫激活（MIA）。我们将使用详细的妊娠特定信息 感染并确定感染的类型以及严重程度。我们将测量一个众所周知的亲 炎症标记（CRP，IL-1β，IL-6，IL-8，TNF-α）计算慢性低级炎症指数 妊娠13和20周的血清炎症。在AIM 1B中，我们将调查 MIA，胎儿的生长和出生时的胎龄。在AIM 2中，我们将研究MIA对后代大脑的影响 14岁的结构和连通性。为了检验MIA导致非典型皮质发育的假设， 我们将提供3,757名青少年的MRI措施，并准备使用。这些包括整个大脑，白色 物质，皮质灰色和皮质下体积。在AIM 3中，我们将确定MIA是否增加了 认知缺陷，行为障碍和心理病理学也有14岁。 该项目将为母体免疫激活提供全面的定义，包括 感染（例如类型和计时），检查其对神经发育的影响并阐明推定的机制 这些影响在迄今为止最大的出生队列中。总的来说，这些输出将提出预防目标 并有助于早期识别高危妊娠的努力。