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.

项目总结