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

摘要 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 注意力缺陷多动障碍（ADHD）支持产前和产后免疫和感染因素在 这种常见的，致残的和经常持续的疾病的发病机制。ADHD是导致 全球神经发育障碍的心理社会和经济负担，影响到5%的 儿童在美国，并经常并发症与物质使用和其他 精神障碍、学习障碍和犯罪。ADHD与暴露于 报告了怀孕期间的母亲和生命早期的婴儿对特定病原体的感染和发烧发作， 但先天性和适应性免疫反应的个体差异，以及伴随的暴露于 药物和免疫调节微量营养素，还没有严格和前瞻性地 处理。该项目将利用挪威的独特数据和生物样本资源， 母亲和儿童队列研究（MoBa）和哥伦比亚大学感染和免疫中心 通过追求三个互补的目标，深入了解感染和免疫在ADHD中的作用 这不仅涉及产妇报告感染、发烧和免疫/炎症疾病， 免疫激活和病原体导向的抗体应答的定量测量。因为MoBa 母亲报告疾病事件和症状以及药物使用在4周的时间间隔， 怀孕期间，异常丰富的信息可用于这些现象的时间，而不是 妊娠本身与ADHD的结果有关。在目标1中，我们将调查母亲和孩子的关系 感染、发热和免疫紊乱与ADHD风险的关系， 控制药物使用（退烧药、止痛药、抗生素）和微量营养素摄入， 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 从母亲和儿童在怀孕期间和出生时，并确定其与ADHD风险的关联 使用多重免疫测定（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有广泛的影响，以及ADHD相关的 更确切地说是多巴胺能回路在目标3中，我们将研究特定感染因子的作用 通过测量妊娠中期和出生时ToRCH病原体的母体抗体与ADHD有关 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）检测流感病毒。 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。

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.