Genetic and hemodynamic effects on prenatal cortical development in congenital heart disease

遗传和血流动力学对先天性心脏病产前皮质发育的影响

• 批准号: 10594404
• 负责人: Kiho Im
• 金额: $ 58.59万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594404
• 关键词: Affect; Alleles; Aorta; Area; Birth; Brain; Brain region; Cardiovascular system; Cerebrovascular Circulation; Cerebrum; Child; Congenital Disorders; Development; Early Intervention; Early identification; Elderly; Fetal Development; Fetus; Foundations; Future; Gene Expression; Genes; Genetic; Growth; Heart; Hypoplastic Left Heart Syndrome; Impairment; Individual; Injury; Intervention; Live Birth; Lung; Magnetic Resonance Imaging; Measures; Methods; Monitor; Neurodevelopmental Disability; Obstruction; Oxygen; Patients; Pattern; Perfusion; Prefrontal Cortex; Risk; Role; Second Pregnancy Trimester; Single ventricle congenital heart disease; Site; Socioeconomic Status; Surface; Therapeutic Intervention; Thick; Third Pregnancy Trimester; Time; Treatment Efficacy; Variant; Vascular blood supply; aortic arch; brain abnormalities; brain magnetic resonance imaging; brain volume; cerebral hemodynamics; cerebral oxygenation; cognitive function; cohort; congenital heart disorder; exome sequencing; fetal; frontal lobe; genetic variant; hemodynamics; high risk; hypoperfusion; imaging study; in utero; insight; large datasets; magnetic resonance imaging biomarker; neonatal period; neurogenesis; neuroprotection; prenatal; prospective; resilience; sex; success

PROJECT SUMMARY/ABSTRACT Congenital heart disease (CHD) is one of the most common congenital disorders, affecting about 1% of all live births. More than half of children with moderate or severe CHD have neurodevelopmental disabilities (NDD) that persist into later life. Quantitative methods that can objectively identify subjects at high risk for NDD as early as possible are needed to allow for characterization of the mechanisms underlying NDD and monitor the success of potential therapeutic interventions. Brain magnetic resonance imaging (MRI) studies provide evidence for a prenatal origin of NDD by detecting reduced global brain volumes and gyrification in fetuses with CHD. However, these whole-brain measures do not provide insight into regional brain vulnerabilities or second trimester differences in brain development. In addition, no studies have yet explored the potential role of genetic variants and attempted to disentangle the relative contributions of genetic and hemodynamic factors on prenatal brain development in CHD. Since patients with single-ventricle (SV) CHD suffer high rates of NDD and show both severe in utero reduction in oxygenated cerebral blood supply and frequent damaging genetic variants, fetal SV CHD cohort is an ideal group in which to explore markers of altered early brain development influenced by genetic and/or cerebral hemodynamic factors. This study will examine sulcal patterns and regional cortical growth (thickness and surface area) to indicate the effects of genetic variants and altered cerebral hemodynamics respectively using a large dataset of retrospective and prospective longitudinal MRIs from the second trimester to birth with three time points in 175 SV CHD and 260 typically developing (TD) subjects. Sulcal pattern development will be compared between SV CHD and TD subjects and correlated with rare damaging variants in high heart expression (HHE) genes and presence of neuroprotective APOE allele in SV CHD. We will also develop surface-based regional analysis of fetal cortical thickness and surface area. Regional cortical thickness and surface area will be compared between SV CHD and TD subjects and correlated with different types of cerebral blood flow in SV CHD. We hypothesize that sulcal pattern alterations will be detected in SV CHD in the second trimester and more abnormal in SV CHD subjects with rare damaging variants in HHE and/or neuroresilience APOE genes. Differences in cortical thickness and surface area between SV CHD and TD subjects may be regionally inhomogeneous and more severe in the frontal regions. Regional cortical growth will be more reduced in SV CHD subjects with aortic outflow obstruction and retrograde aortic arch flow compared to the subjects with pulmonary obstruction with anterograde arch flow or unobstructed outflow tracts. This project would allow early identification of the relative roles of altered genetics and cerebral perfusion and lay the foundation for early selection and optimization of individual therapy and deciding the efficacy of the interventions in CHD.

项目总结/摘要 先天性心脏病（CHD）是最常见的先天性疾病之一，影响约1%的所有生活 出生超过一半的中度或重度CHD儿童患有神经发育障碍（NDD） 一直延续到晚年定量方法可以客观地识别NDD高风险受试者， 需要尽早描述NDD的潜在机制并监测 潜在治疗干预的成功。脑磁共振成像（MRI）研究提供了 通过检测胎儿的全脑体积减少和脑回形成，为NDD的产前起源提供证据， 冠心病然而，这些全脑测量并不能提供对区域性大脑脆弱性的洞察力， 三个月的大脑发育差异。此外，尚未有研究探讨 遗传变异，并试图解开遗传和血液动力学因素对 先天性心脏病的产前脑发育由于单心室（SV）CHD患者的NDD发生率较高， 并显示子宫内含氧脑血供严重减少和频繁的遗传损伤 胎儿SV CHD队列是探索早期脑发育改变标志物的理想组 受遗传和/或脑血流动力学因素的影响。本研究将检查脑沟模式， 区域皮质生长（厚度和表面积），以表明遗传变异和改变的影响 分别使用回顾性和前瞻性纵向MRI的大数据集进行脑血流动力学研究 175例SV CHD和260例典型发育（TD）中从孕中期到出生的三个时间点 科目将比较SV CHD和TD受试者之间的脑沟模式发展，并与 心脏高表达（HHE）基因中罕见的损伤性变体和神经保护性APOE等位基因的存在， 心脏瓣膜病。我们还将开发胎儿皮质厚度和表面积的基于表面的区域分析。 将比较SV CHD和TD受试者的局部皮质厚度和表面积， 与不同类型的脑血流有关。我们假设脑沟模式的改变 在妊娠中期的SV CHD中检测到，在罕见的SV CHD受试者中更异常， HHE和/或神经弹性APOE基因的破坏性变体。皮质厚度和表面差异 SV CHD和TD受试者之间的区域可能是区域不均匀的，并且在额叶更严重 地区在主动脉流出道阻塞的SV CHD受试者中，区域皮质生长将更多地减少， 逆行主动脉弓血流与肺阻塞伴顺行主动脉弓血流的受试者相比， 流出道通畅。该项目将允许早期识别改变的遗传学的相对作用 为早期选择和优化个体化治疗方案奠定基础， 决定冠心病干预措施的有效性。