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: 10579297
• 负责人: Patricia Ellen Grant
• 金额: $ 78.26万
• 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/10579297
• 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; 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; protective pathway; 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）影响美国所有活产婴儿的约1%。超过85%的人 CHD现在可以很好地生活到成年期1 -4，暴露出非心脏残疾的负担，如神经发育障碍。 残疾。事实上，超过一半的中度或复杂CHD儿童患有神经心理缺陷， 执行功能受损（EF）最为常见。EF是重要的高阶神经认知功能 对独立生活和心理健康很重要。然而，预测谁会更受损，更需要 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能解释三分之一的 结果的差异。由于EF受损特别容易治疗，因此更好的EF预测因子是 需要适当分配服务和改善成果。为了开发这种方法，我们首先关注 大动脉转位（d-TGA）。在CHD的严重形式中，d-TGA更常见， 发生率为3/10，000活产。d-TGA导致严重的子宫内缺氧，出生后不久即被纠正， 动脉转换手术额外的手术和心血管后遗症是罕见的。因此，d-TGA患者具有 所有CHD中最一致的出生后病程，但与其他CHD一样，与缺氧有关， 但EF受损程度不同。本项目利用R 01 HL 135061下研究的成人d-TGA受试者 和参与先前波士顿试验的d-TGA患者，以创建迄今为止最大、最佳表征的d-TGA队列。 我们建议对大脑MRI数据进行复杂的图像分析，并增加基因检测，重点是 神经恢复和缺氧反应基因。首先，我们将使用我们的脑沟模式分析，以确定 脑发育的子宫内变化程度，因为脑沟模式在产前确定并保持稳定 进入成年生活二是探索丰富的俱乐部结构与功能网络的高度分离 连接的中心枢纽（富人俱乐部），在生命早期从连接较少的外围区域形成，这些区域被认为是 to be adaptive适应.这项研究的首要目标是使用新的MRI分析来确定大脑 与EF改变相关的组织变化以及神经弹性和缺氧的调节作用 d-TGA成人中的反应基因。为此，我们提出以下具体目标：目标1。 确定脑沟模式和d-TGA成人执行功能之间的关系，如果这 这种关系被（a）神经弹性基因ApoE ε2或ε4等位基因的存在，或（B）缺氧中的变体所改变 反应基因瞄准2/3。使用rich club确定结构/功能连接之间的关系 和执行功能，如果这种关系被（a）神经弹性的存在所改变， 基因ApoE ε2或ε4等位基因或低氧应答基因中的（B）变体。成功完成将有助于 确定与EF改变相关的大脑变化以及神经弹性的潜在调节作用， 缺氧反应基因以及通知子宫内与适应性变化的平衡。这种知识是 与较大的CHD组相关，并将告知产前与产后干预的必要性。