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: 10296635
• 负责人: Veerle Bergink
• 金额: $ 77.33万
• 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/10296635
• 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; Ultrasonography; 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; 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.

项目概要 母体免疫激活（MIA）是指在怀孕期间通过以下方式触发母体免疫系统： 感染或慢性疾病会导致胎儿发生一系列免疫改变，从而导致胎儿死亡。 大规模、以人群为基础的研究表明，MIA 与许多疾病有关。 神经精神疾病，包括自闭症谱系障碍、双相情感障碍和精神分裂症。 对啮齿类动物的研究一致表明，怀孕早期阶段的 MIA 会导致结构性 最近的影像学研究表明，人类后代的功能性大脑异常和行为功能障碍。 报道了 MIA 对儿童大脑结构和行为的类似影响，但这些研究受到以下因素的限制。 适度的样本量和相对较短的随访期。 本研究的总体目的是调查妊娠期间母体免疫激活对胎儿的影响。 我们将使用世界上唯一一个拥有足够样本的群体——R 世代。 大小和纵向随访结合（i）有关感染和炎症的详细信息 怀孕，以及 (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) 我们将使用详细的妊娠期特定信息。 感染并确定感染的类型以及严重程度。 炎症标志物（CRP、IL-1β、IL-6、IL-8、TNF-α）计算慢性低度炎症的炎症指数 在目标 1b 中，我们将研究妊娠 13 周和 20 周时血清中的炎症。 MIA、胎儿生长和出生胎龄 在目标 2 中，我们将研究 MIA 对后代大脑的影响。 14 岁时的结构和连接性 为了检验 MIA 导致非典型皮质发育的假设， 我们将为 3,757 名青少年提供可用的 MRI 测量，其中包括全脑、白人。 在目标 3 中，我们将确定 MIA 是否会增加风险。 认知缺陷、行为障碍和精神病理学也在 14 岁时出现。 该项目将提供母体免疫激活的全面定义，包括以下具体方面 感染，例如类型和时间，检查其对神经发育的影响，并阐明假定的机制 总的来说，这些成果将为迄今为止最大的出生队列中的这些影响提出预防目标。 并协助早期识别高风险妊娠。