Infection, fever and immunity and offspring ADHD in a population-based pregnancy/birth cohort

基于人群的妊娠/出生队列中的感染、发烧和免疫以及后代多动症

• 批准号: 10174976
• 负责人: Marisa N Spann
• 金额: $ 41.6万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10174976
• 关键词: 3 year old; Address; Affect; Allergic; Analgesics; Animal Model; Antibiotics; Antibody Response; Attention deficit hyperactivity disorder; Attenuated; Autoimmune; Biological; Biological Markers; Birth; Blood specimen; Brain; Breast Feeding; Child; Clinical; Clinical assessments; Cohort Studies; Collection; Cytomegalovirus; Data; Development; Diet; Disease; Early Diagnosis; Early Intervention; Economic Burden; Environmental Exposure; Epidemiology; Event; Exposure to; Fathers; Fever; Funding; Genetic Predisposition to Disease; Heritability; Herpesvirus 1; Hypersensitivity; Immune; Immune System Diseases; Immune response; Immunity; Immunoassay; Immunology procedure; Immunoprecipitation; Individual; Individual Differences; Infant; Infection; Infectious Agent; Inflammatory; Inflammatory Response; Innate Immune Response; Intake; Intervention; Learning Disabilities; Life; Luciferases; Maternal antibody; Measures; Mediating; Mental disorders; Microbe; Micronutrients; Modeling; Mothers; Neuraxis; Neurodevelopmental Disability; Non-Steroidal Anti-Inflammatory Agents; Norway; Outcome; Pathogenesis; Pharmaceutical Preparations; Plasma; Pregnancy; Pregnant Women; Prevention; Preventive measure; Questionnaires; Registries; Reporting; Resources; Retrieval; Risk; Risk Factors; Role; Sample Size; Sampling; Serology; Serology test; Study models; Symptoms; System; Teratogens; Testing; Time; Toxoplasma gondii; Umbilical Cord Blood; United States; United States National Institutes of Health; Universities; Vitamin D; Zinc; adaptive immune response; antipyretic; cohort; comorbidity; data access; design; developmental disease; disorder control; disorder risk; epidemiological model; fighting; high throughput screening; immune activation; immunoregulation; influenzavirus; insight; nervous system development; neurogenesis; novel; offspring; pathogen; population based; postnatal; prospective; psychosocial; public health relevance; substance use; synaptogenesis; systems research

ABSTRACT Growing evidence from epidemiologic, clinical and animal model studies of attention-deficit/hyperactivity disorder (ADHD) supports a role for pre- and postnatal immune and infectious factors in the pathogenesis of this common, disabling and frequently persistent disorder. ADHD is a major contributor to the psychosocial and economic burden of neurodevelopmental disabilities globally, affecting 5% of children in the United States, and is frequently complicated by comorbidity with substance use and other psychiatric disorders, learning disabilities and criminality. Associations of ADHD with exposure of mothers during pregnancy and infants in early life to specific pathogens and fever episodes are reported, but individual differences in innate and adaptive immune responses, and concomitant exposures to medications and immunity-regulating micronutrients, have not been rigorously and prospectively addressed. This project will leverage the unique data and biological sample resources of the Norwegian Mother and Child Cohort Study (MoBa) and the Center for Infection and Immunity at Columbia University for insights into the role of infection and immunity in ADHD through pursuit of three complementary aims that address not only maternally-reported infection, fever and immune/inflammatory disease but also quantitative measures of immune activation and pathogen-directed antibody responses. Because MoBa mothers report illness events and symptoms as well as medication use in 4-week intervals throughout pregnancy, unusually rich information is available to relate the timing of these phenomena, rather than gestation per se, to ADHD outcomes. In Aim 1 we will investigate the relationship of maternal and child infection, fever and immune disorders to ADHD risk using prospective MoBa questionnaire data, controlling for medication use (antipyretics, analgesics, antibiotics) and intake of micronutrients with immunomodulatory potential (vitamin D, zinc). In Aim 2 we will define the immune signatures in plasma from mothers and children during pregnancy and at birth and determine their association with ADHD risk using multiplexed immunoassays (Luminex) to compare levels of 60 immune/inflammatory molecules with known or suspected effects on neurogenesis and synaptogenesis broadly as well as ADHD-relevant dopaminergic circuitry more specifically. In Aim 3 we will examine the role of specific infectious agents implicated in ADHD by measuring maternal antibodies at mid-gestation and birth to ToRCH pathogens Toxoplasma gondii, rubellavirus, cytomegalovirus and herpes simplex viruses 1 and 2 using multiplexed immunoassays (Luminex) and to influenza viruses using luciferase immunoprecipitation systems (LIPS). In concert, these aims have the potential to identify novel factors and biomarkers for ADHD risk that could facilitate early diagnosis and intervention and guide the development of preventive measures.

抽象的 来自注意力缺陷/多动的流行病学、临床和动物模型研究的越来越多的证据 多动症 (ADHD) 支持产前和产后免疫和感染因素在 这种常见、致残且经常持续的疾病的发病机制。 ADHD 是一个主要贡献者 全球神经发育障碍造成的社会心理和经济负担，影响了 5% 在美国，儿童经常因药物滥用和其他疾病的合并症而变得复杂。 精神疾病、学习障碍和犯罪。 ADHD 与接触 据报告，怀孕期间的母亲和生命早期的婴儿感染特定病原体并出现发烧症状， 但先天性和适应性免疫反应以及伴随暴露的个体差异 药物和免疫调节微量营养素尚未得到严格和前瞻性的研究 已解决。该项目将利用挪威独特的数据和生物样本资源 母婴队列研究 (MoBa) 以及哥伦比亚大学感染与免疫中心 通过追求三个互补的目标，深入了解感染和免疫在多动症中的作用 不仅解决孕产妇报告的感染、发烧和免疫/炎症性疾病，还解决 免疫激活和针对病原体的抗体反应的定量测量。因为MoBa 母亲每隔 4 周报告一次疾病事件和症状以及药物使用情况 怀孕时，可以获得异常丰富的信息来关联这些现象的时间，而不是 妊娠本身对多动症的结果。在目标 1 中，我们将调查母子关系 使用前瞻性 MoBa 问卷数据，感染、发烧和免疫紊乱对 ADHD 风险的影响， 控制药物使用（退烧药、镇痛药、抗生素）和微量营养素的摄入 免疫调节潜力（维生素 D、锌）。在目标 2 中，我们将定义血浆中的免疫特征 来自母亲和儿童在怀孕和出生期间的数据，并确定它们与 ADHD 风险的关系 使用多重免疫分析 (Luminex) 比较 60 种免疫/炎症分子的水平 已知或怀疑对神经发生和突触发生以及 ADHD 相关的广泛影响 更具体地说，是多巴胺能电路。在目标 3 中，我们将研究特定传染源的作用 通过测量妊娠中期和出生时 ToRCH 病原体的母体抗体，发现与 ADHD 有关 使用多重检测弓形虫、风疹病毒、巨细胞病毒和单纯疱疹病毒 1 型和 2 型 免疫测定（Luminex）和使用荧光素酶免疫沉淀系统（LIPS）的流感病毒。 总之，这些目标有可能确定 ADHD 风险的新因素和生物标志物， 可以促进早期诊断和干预，并指导预防措施的制定。