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.

在美国，先天性心脏病(CHD)影响了大约1%的活产婴儿。超过85%的人患有 CHD现在可以活到成年1-4岁，暴露出非心脏功能障碍的负担，如神经发育 残疾人士。事实上，所有患有中度或复杂冠心病的儿童中，超过一半的人患有神经心理障碍， 最常见的是执行功能受损(EF)。EF是关键的高级神经认知功能 对独立生活和精神健康很重要。然而，预测谁将受到更大的伤害和更有需要 的干预是具有挑战性的，因为常规测量的患者和医疗因素只解释了三分之一的 结果的差异。因为EF受损特别容易接受治疗，所以EF更好的预测因素是 需要适当分配服务和改善成果。为了开发这样的方法，我们首先专注于 右旋大动脉转位(d-TGA)。在严重的冠心病中，d-TGA更为常见， 发生在万分之三的活产儿中。D-TGA导致严重的宫内缺氧，出生后不久即可纠正 动脉调换手术。额外的手术和心血管后遗症很少见。因此，d-TGA患者有 所有先天性心脏病中最均匀的出生后病程，但与其他先天性心脏病一样，与缺氧有关，并具有显著的 然而，EF的可变性损害。该项目利用R01HL135061正在研究的成人d-TGA对象 和d-TGA患者参与之前的波士顿试验，以创建迄今为止规模最大、特征最好的d-TGA队列。 我们建议对脑MRI数据进行复杂的图像分析，并增加专注于 神经弹性和低氧反应基因。首先，我们将使用我们的槽型分析来确定 大脑发育中宫内变化的程度，因为脑沟模式是在产前确定的，并保持稳定 进入成年人的生活。第二，我们将探索丰富的俱乐部结构和功能网络，以高度分离 连接的中心枢纽(富俱乐部)，在生命早期从连接较少的外围区域形成，这些区域被认为 适应能力强。这项研究的首要目标是使用新的核磁共振分析来确定大脑 与EF改变相关的组织改变及神经弹性和低氧的调节作用 成年d-TGA患者的反应基因。为此，我们提出了以下具体目标：目标1。 确定患有d-TGA的成年人的脑沟类型与执行功能之间的关系 (A)神经弹性基因载脂蛋白Eε2或ε4等位基因的存在，或(B)低氧中的变异 反应基因。目标2/3：使用RICH俱乐部确定结构/功能连接之间的关系 患有d-TGA的成年人的执行功能，如果这种关系被(A)神经弹性的存在所改变 载脂蛋白E基因ε2或ε4等位基因或(B)低氧反应基因变异。如果成功完成，将会有所帮助 确定与EF改变相关的脑变化以及神经弹性和 低氧反应基因以及通知子宫内和适应性变化的平衡。这一知识是 与更大的CHD群体相关，并将告知产前和产后干预的必要性。