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

项目概要/摘要 这是一份申请的重新提交，该申请旨在调查孕妇在怀孕期间的炎症是如何发生的。 影响中年后期成年后代的临床、神经认知和神经特征 期越来越多的证据表明，母亲在怀孕期间的炎症和感染增加 后代患精神分裂症和抑郁症的风险，以及精神分裂症患者更严重的结局 例然而，没有研究确定这些困难是否会持续到发育后期， 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 参与者基于后代的精神障碍状况。由于这些局限性，以前的研究已经 无法控制组内炎症暴露水平的变异性， 混杂因素，包括可能与炎症比精神疾病更直接相关的结局 诊断。拟议的项目旨在从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的变异性是否与特异性 神经和症状的结果，发生在疾病，这可能会提供相关的发现， 一系列神经发育后遗症。这项研究是基于一个非常独特的队列，儿童 健康与发育研究（CHDS），妊娠期间采集生物样本， 通过青春期的后代，并评估大量潜在的产前和产后协变量。 具体来说，从1959年到1966年，在整个怀孕过程中跟踪了20，000名妇女; 在从出生到青春期的多个时间点进行了一系列评估。从我们以前的发现 研究表明，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 抑郁症，以及童年困难（例如，内化）。该项目将收集详细的 临床（问卷调查，半结构化访谈和实验室任务），神经认知和大脑（多功能） 模态MRI）指数。具体目标如下： 以下：为了研究胎儿暴露于较高水平的炎症是否会增加以下风险：1）特定的 后代中的症状维度（例如，精神病症状、奖赏功能、抑郁症），和/或 2)后代中特定的神经认知和神经学结局（使用多模态脑评估） 成像和神经心理学测试），以及3）确定胎儿暴露于 炎症和儿童/青少年的结果持续到中年。这项研究是独一无二的。 能够回答关于怀孕期间母体炎症如何有助于 神经认知，大脑和临床障碍的后代在不同时期的发展，有可能 影响干预和预防战略的制定，并有助于澄清 炎症在神经发育和各种精神障碍中的作用。

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.