Neuroimaging epigenetics of prospective postpartum depression biomarkers

前瞻性产后抑郁症生物标志物的神经影像表观遗传学

• 批准号: 9067505
• 负责人: Zachary Aaron Kaminsky
• 金额: $ 51.22万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9067505
• 关键词: Affect; Amygdaloid structure; Biological Markers; Birth; Blood; Blood Tests; Brain; Brain imaging; Brain region; Classification; Clinic; Clinical; DNA Methylation; Data; Depression screen; Diagnosis; Discipline of obstetrics; Disease; Emotional; Epigenetic Process; Estrogens; Etiology; Evaluation; Female; Functional Imaging; Functional Magnetic Resonance Imaging; General Population; Genes; Gonadal Hormones; Gynecology; Health; High Risk Woman; Hippocampus (Brain); Hormones; Image; Individual; Infanticide; Longitudinal Studies; Measures; Mediating; Mental Depression; Mental Health; Modeling; Mood Disorders; Mothers; Outcome; Oxytocin; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phenotype; Population; Postpartum Depression; Postpartum Period; Pregnancy; Process; Progesterone; Recording of previous events; Recruitment Activity; Research Design; Research Personnel; Rest; Risk; Sampling; Series; Serum; Short-Term Memory; Synaptic plasticity; Talents; Testing; Third Pregnancy Trimester; Time; Translating; Woman; base; cognitive performance; cohort; comparison group; depressive symptoms; endophenotype; epigenetic marker; epigenetic variation; epigenomics; experience; follow-up; genome-wide analysis; high risk; hippocampal subregions; improved; methylation biomarker; molecular pathology; neurogenesis; neuroimaging; novel; offspring; postnatal; predictive marker; prospective; psychologic; research study; response; sample collection; screening; single episode major depressive disorder; therapeutic target; trait

DESCRIPTION (provided by applicant): This is a application to implement blood based screening for postpartum depression (PPD) using a novel epigenetic biomarker we have developed, enabling the longitudinal evaluation of PPD specific neuroimaging phenotypes in the postpartum period in individuals at risk and in matched controls. The project will take advantage of the talents of a leader in the field of women's mental health and PPD, a highly experienced DNA methylation and biomarker researcher, and an accomplished neuroimager. Through a recent cross species translational experiment investigating hippocampal epigenetic responses to estrogen and epigenomic profiling in a prospective sample of women at risk for PPD, we identified a set of epigenetic marks functionally related to modulating synaptic plasticity and capable of predicting PPD with >85% accuracy. Our results indicated that risk to PPD is mediated by an increased sensitivity to estrogen. The availability of peripheral biomarkers opens novel opportunities to perform imaging epigenetics in the PPD population. While there is some consistency across MDD and PPD specific neuroimaging phenotypes, it is unclear if these findings represent disease etiology or the state of depression and requires longitudinal study in spontaneous and previous mood disorder diagnosed cases to elucidate. The central hypothesis is that PPD risk may arise due to an altered sensitivity of the epigenetic reprogramming machinery in response to gonadal hormones and that peripherally measured epigenetic variation at these loci will be associated with longitudinally progressive depression associated neuroimaging phenotypes including resting state functional connectivity alterations of corticolimbic pathways, emotional processing, working memory, and hippocampal subregion specific activity changes in the postpartum period. In Aim 1, we will use standard third trimester blood draws to perform PPD prediction and generate a sample of women at risk for PPD from the general population and from women with a previous history of mood disorder. In Aim 2, we will perform a series of fMRI tests to assess resting state functional connectivity, emotional response, working memory, and hippocampal subregion specific alterations at both a pre-depression time point of two weeks at six weeks during major depressive episodes. A within groups comparison will identify trait associated endophenotypes that will be integrated with epigenetic, serum hormone, and psychological data in Aim 3. The analyses performed will identify novel brain endophenotypes susceptible to hormone and epigenetic interaction that will aid in our understanding of the molecular pathology of PPD and hold the potential to act as novel and modifiable therapeutic targets.

描述（由申请人提供）：这是一项使用我们开发的新型表观遗传生物标志物实施产后抑郁症（PPD）血液筛查的申请，能够纵向评价高危个体和匹配对照中产后期PPD特异性神经影像学表型。该项目将利用女性心理健康和PPD领域的领导者，经验丰富的DNA甲基化和生物标志物研究人员以及成就卓著的神经成像师的才能。通过最近的一项跨物种翻译实验，研究了海马对雌激素的表观遗传反应以及具有PPD风险的女性前瞻性样本的表观基因组分析，我们确定了一组与调节突触可塑性功能相关的表观遗传标记，并且能够以>85%的准确度预测PPD。我们的研究结果表明，PPD的风险是由雌激素敏感性增加介导的。外周生物标志物的可用性为在PPD人群中进行成像表观遗传学提供了新的机会。虽然MDD和PPD特异性神经影像学表型之间存在一定的一致性，但尚不清楚这些发现是否代表疾病病因或抑郁状态，需要对自发性和既往心境障碍诊断病例进行纵向研究以阐明。中心假设是PPD风险可能由于表观遗传重编程机制响应于性腺激素的敏感性改变而出现，并且这些基因座处的外周测量的表观遗传变异将与纵向进行性抑郁相关的神经影像学表型相关，包括皮质边缘通路的静息状态功能连接改变、情绪处理、工作记忆、产后海马亚区比活性变化。在目标1中，我们将使用标准的妊娠晚期抽血进行PPD预测，并从一般人群和既往有情绪障碍病史的女性中产生PPD风险女性样本。在目标2中，我们将进行一系列的功能磁共振成像测试，以评估静息状态下的功能连接，情绪反应，工作记忆，和海马亚区的具体改变在两个抑郁症前的时间点，两个星期，在6周的抑郁症发作。组内比较将鉴定性状相关的内表型，其将与目标3中的表观遗传、血清激素和心理数据整合。所进行的分析将确定对激素和表观遗传相互作用敏感的新型脑内表型，这将有助于我们理解PPD的分子病理学，并有可能成为新型和可修改的治疗靶点。