Exploring the relationship between advanced multimodal brain MRI phenotypes, genes and cognitive outcome in adults with CHD

探索成人先心病患者高级多模态脑 MRI 表型、基因和认知结果之间的关系

• 批准号: 10371086
• 负责人: Patricia Ellen Grant
• 金额: $ 78.37万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371086
• 关键词: Address; Adult; Affect; Alleles; Apolipoprotein E; Birth; Boston; Brain; Cardiac; Cardiovascular system; Caring; Child; Cognitive; Complex; Data; Development; Diffusion; Elderly; Equilibrium; Executive Dysfunction; Functional Magnetic Resonance Imaging; Future; Genes; Genotype; Goals; Hematocrit procedure; Hypoxia; Image Analysis; Impairment; Independent Living; Individual; Intervention; Knowledge; Life; Live Birth; Magnetic Resonance Imaging; Measures; Medical; Mental Health; Methods; Neurocognitive; Neurodevelopmental Disability; Neuropsychology; Operative Surgical Procedures; Organizational Change; Outcome; Pathway interactions; Patients; Pattern; Peripheral; Phenotype; Rest; Risk; Role; Services; Testing; Therapeutic Intervention; Time; United States; Variant; brain magnetic resonance imaging; cohort; congenital heart disorder; d-transposition of the great arteries; disability; executive function; genetic testing; genetic variant; high risk; improved; improved outcome; in utero; infancy; multimodality; novel; operation; postnatal; prenatal; prenatal therapy; resilience; response

Congenital heart disease (CHD) affects ~1% of all live births in the United States. Over 85% of individuals with CHD now live well into adulthood1–4, exposing a burden of non-cardiac disabilities, such as neurodevelopmental disabilities. In fact, over half of all children with moderate or complex CHD suffer from neuropsychological deficits, with impaired executive functions (EF) the most common. EF are critical higher-order neurocognitive functions important for independent living and mental health. However, predicting who will be more impaired and in need of intervention is challenging, as routinely measured patient and medical factors explain only one-third of the variance in outcomes. Because impaired EF is particularly amenable to treatment, better predictors of EF are needed to appropriately allocate services and improve outcomes. To develop such methods, we first focus on dextro-transposition of the great arteries (d-TGA). Among the severe forms of CHD, d-TGA is the more common, occurring in 3/10,000 live births. d-TGA leads to severe in utero hypoxia that is corrected soon after birth with an arterial switch operation. Additional surgery and cardiovascular sequelae are rare. Thus d-TGA patients have the most uniform postnatal course of all CHDs but, like other CHDs, is associated with hypoxia and has significant yet variable impairment in EF. This project leverages adult d-TGA subjects being studied under R01HL135061 and d-TGA patients involved in prior Boston trials to create the largest, best characterized d-TGA cohort to date. We propose to perform sophisticated image analysis on brain MRI data and add genetic testing focused on neuroresilience and hypoxia response genes. First, we will employ our sulcal pattern analysis to determine the extent of in utero alterations in brain development, as sulcal patterns are determined prenatally and remain stable into adult life. Second, we will explore the rich club structural and functional networks to separate highly connected central hubs (rich club) that form early in life from less connected peripheral regions which are thought to be adaptive. The overarching goal of this study is to use novel MRI analyses to determine the brain organizational changes associated with altered EF and the modulating role of neuroresilience and hypoxia response genes in adults with d-TGA. Toward these ends, we propose the following specific aims: Aim 1. Determine the relationship between sulcal patterns and executive function in adults with d-TGA and if this relationship is modified by (a) presence of neuro-resilience gene ApoE ε2 or ε4 alleles, or (b) variants in hypoxia response genes. Aim 2/3. Determine the relationship between structural/functional connectivity using rich club and executive function in adults with d-TGA and if this relationship is modified by (a) presence of neuro-resilience gene ApoE ε2 or ε4 alleles or (b) variants in hypoxia response genes. Successful completion would help determine brain changes associated with altered EF and the potential modulating role of neuroresilience and hypoxia response genes as well as inform the balance of in utero versus adaptive changes. This knowledge is relevant to the larger CHD group and will inform the need for prenatal versus postnatal interventions.

先天性心脏病（CHD）影响美国所有活产的约1％。超过85％的人 CHD现在生活在成年期1-4，暴露了非心脏疾病的伯恩（例如神经发育） 残疾。实际上，所有中度或复杂冠心病患有神经心理学缺陷的儿童中有一半以上， 由于执行功能受损（EF）最常见。 EF是关键的高阶神经认知功能 对于独立的生活和心理健康很重要。但是，预测谁将受到更大的障碍和有需要的 挑战干预的挑战，因为常规测量的患者和医学因素仅解释了三分之一的三分之一 结果的差异。由于EF受损受损特别适合治疗，因此EF的更好预测指标是 需要适当分配服务并改善结果。为了开发这种方法，我们首先关注 大动脉（D-TGA）的右旋转移。在严重的冠心病形式中，D-TGA更常见， 发生在3/10,000个活生生中。 D-TGA导致子宫缺氧严重，出生后不久就被纠正 动脉开关操作。其他手术和心血管后遗症很少见。 D-TGA患者有 所有CHD中最均匀的产后过程，但与其他CHD一样，与缺氧有关，并且具有显着的 EF中的可变障碍。该项目利用R01HL135061研究的成人D-TGA受试者 和D-TGA患者涉及先前的波士顿试验，以创建迄今为止最大，最佳的D-TGA队列。 我们建议对大脑MRI数据进行复杂的图像分析，并添加关注的基因测试 神经性和缺氧反应基因。首先，我们将采用我们的沟道模式分析来确定 子宫发育中子宫内变化的程度，因为沟的模式是在产前确定的，并且保持稳定 进入成人生活。其次，我们将探索丰富的俱乐部结构和功能网络，以高度分开 互联的中央集线器（Rich Club），从较不连接的周围地区形成了早期的互联俱乐部 自适应。这项研究的总体目标是使用新颖的MRI分析来确定大脑 与EF改变相关的组织变化以及神经和缺氧的调节作用 D-TGA成人的反应基因。对于这些目的，我们提出以下特定目标：目标1。 确定D-TGA成人成人的沟渠模式与执行功能之间的关系，如果这是 关系通过（a）存在神经释放能力基因apoEε2或ε4等位基因，或（b）缺氧的变体。 反应基因。目标2/3。使用Rich Club确定结构/功能连接之间的关系 以及D-TGA成年人的执行功能，如果（a）存在这种关系 缺氧反应基因中的基因APOEε2或ε4等位基因或（B）变体。成功完成会有所帮助 确定与EF改变相关的大脑变化以及神经性的潜在调节作用和 缺氧反应基因以及为子宫与自适应变化的平衡提供了信息。这些知识是 与较大的CHD组相关，并将告知产前与产后干预的需求。