Maternal Inflammation During Pregnancy: Clinical and Neurocognitive Outcomes in Adult Offspring

项目摘要/摘要 这是重新提交的一项申请，该申请旨在调查怀孕期间的母体炎症 中年晚期对成年后代的临床、神经认知和神经特征的影响 句号。越来越多的证据表明，孕妇在怀孕期间的炎症和感染会增加 子女患精神分裂症和抑郁症的风险，以及精神分裂症更严重的后果 案子。然而，还没有研究确定困难是否会持续到发育的后期，以及 从现有研究中得出推论的能力受到各种因素的限制，例如选择 受试者根据子女的精神障碍状况。由于这些局限性，以前的研究一直是 无法控制组内暴露于炎症水平的可变性，控制潜在的 混杂因素，包括可能与炎症比精神疾病更直接相关的结果 诊断。拟议的项目旨在从之前的出生队列中随机选择参与者 分析细胞因子数据以确定胎儿暴露于炎症中的可变性是否与特定的 跨障碍发生的神经和症状结果，这可能提供与 一系列神经发育后遗症。这项拟议的研究是基于一个非常独特的队列--儿童 健康与发展研究(CHDS)，在怀孕期间收集生物样本，持续跟踪 通过青春期的后代，以及对大量潜在的出生前和出生后协变量的评估。 具体地说，从1959年到1966年，对20,000名妇女在整个怀孕期间进行了跟踪调查；这是其后代的一个子集 在从出生到青春期的多个时间点接受了一系列评估。之前的发现来自我们的 研究小组表示，妊娠中期炎症和感染与后代风险增加之间存在一致的联系 抑郁，以及童年的困难(例如，内化)。拟议的项目将收集详细的 临床(问卷、半结构化访谈和实验室任务)、神经认知和大脑(多 在子宫内暴露于不同程度炎症的子代的模式磁共振成像)指标。具体目标如下 以下是：为了调查胎儿暴露在更高水平的炎症中是否会增加1)特定疾病的风险 子女之间的症状维度(例如，精神病症状、奖励功能、抑郁)和/或 2)子代的特定神经认知和神经结果(使用多模式大脑评估 成像和神经心理测试)，以及3)以确定胎儿暴露于 炎症和儿童/青少年的结局一直持续到中年。这项拟议的研究是独一无二的 能够回答有关妊娠期母体炎症如何导致 子代在不同发育阶段的神经认知、大脑和临床障碍具有潜在的 影响干预和预防战略的发展，并有助于澄清 在神经发育和各种精神障碍中的炎症。

Project Summary/Abstract This is a resubmission of an application that aims to investigate how maternal inflammation during pregnancy influences clinical, neurocognitive, and neural characteristics in adult offspring during the late middle-age period. Accumulating evidence suggests that maternal inflammation and infection during pregnancy increase risk for schizophrenia and depression in offspring, as well as for more severe outcomes among schizophrenia cases. However, no studies have determined whether difficulties persist into later periods of development, and the ability to draw inferences from existing studies has been limited by a variety of factors, such as selecting participants based on mental disorder status of offspring. Due to these limitations, previous studies have been unable to control variability in the level of exposure to inflammation within groups, control for potential confounding factors, and include outcomes that may be more directly linked to inflammation than psychiatric diagnoses. The proposed project aims to randomly select participants from a birth cohort with previously analyzed cytokine data to determine whether variability in fetal exposure to inflammation is related to specific neural and symptomatic outcomes that occur across disorders, which could provide findings pertinent to a range of neurodevelopmental sequelae. The proposed study is based on a very unique cohort, the Child Health and Development Study (CHDS), with biosamples collected during pregnancy, continual follow-up of offspring through adolescence, and assessment of a multitude of potential pre- and postnatal covariates. Specifically, 20,000 women were followed throughout their pregnancies from 1959-1966; a subset of offspring were given a range of assessments at multiple points from birth to adolescence. Previous findings from our group indicated consistent links between 2nd trimester inflammation and infection to increased risk of offspring depression, as well as childhood difficulties (e.g., internalization). The proposed project will collect detailed clinical (questionnaires, semi-structured interviews, and laboratory tasks), neurocognitive, and brain (multi- modal MRI) indices for offspring exposed to varying levels of inflammation in utero. The specific aims are as follows: to investigate whether fetal exposure to higher levels of inflammation increases risk for 1) specific symptom dimensions among offspring (e.g., psychotic symptoms, reward functioning, depression), and/or for 2) specific neurocognitive and neurological outcomes among offspring (assessed using multi-modal brain imaging and neuropsychological testing), and 3) to determine whether links between fetal exposure to inflammation and childhood/adolescent outcomes persist into middle-age. The proposed study is uniquely positioned to answer key questions about how maternal inflammation during pregnancy contributes to neurocognitive, brain, and clinical disturbances in offspring at various periods of development, has the potential to influence the development of intervention and prevention strategies, and could help clarify the role of inflammation in neurodevelopment and in a variety of mental disorders.