A Longitudinal MRI Study Characterizing Very Early Brain Development in Infants with Down Syndrome

脑发育极早期的纵向MRI特征 患有唐氏综合症的婴儿 项目摘要/摘要 唐氏综合症(DS)是导致智力残疾的最常见的遗传原因，与不同程度的 认知和行为障碍。药物疗法和基因调节剂正在涌现，如果 早期与传统疗法结合使用，显示出改善发育结果的希望 对于患有DS的儿童。然而，DS患者早期神经发育知识的明显缺乏阻碍了这些 努力。这项提案的主要目标是开发生物标记物，作为未来特定疗法的靶点，基于 仔细描述早期异常神经发育模式。这项研究将是与 吴作为协调中心和其他六个研究小组：北卡罗来纳大学、密歇根大学、CHOP、MNI、纽约大学和芝加哥大学 明尼苏达州。这些小组包括ACE-IBIS(自闭症卓越中心婴儿脑成像研究) Network，一个久负盛名、经验丰富的团队，已经在MRI领域进行了8年的富有成效的合作 自闭症高危婴儿、健康典型婴儿(TYP)和 患有脆性X的婴儿。这项建议的目的是：1)确定早期大脑的纵向特征 患有DS的婴儿(3~24个月)与TYP型婴儿和其他类型婴儿的发育比较 使用三种不同类型的神经成像(MRI、DTI、rsfMRI)的发育性残疾(ASD和脆性X)；2) 根据纵向结构或结构建立DS婴儿发育结局的预测模型 功能磁共振特征；以及3)表征与协调多模式相关的大脑行为 描述纵向网络成像参数与婴儿期影像的关系 使用复杂多变量支持向量机的认知、行为和神经发育结果 (支持向量机)分析策略。对120名患有DS的婴儿和40名TYP对照组的婴儿进行纵向随访，从3岁到40岁 24个月。核磁共振扫描将在自然睡眠期间获得，以及一系列经过充分验证的发育和 行为评估将在每次访问时完成。这个项目将是第一个定义自然和 DS婴儿脑发育改变的时间。拟议的项目解决了几个关键问题 “NICHD 2014--美国国立卫生研究院唐氏综合症研究计划”的研究建议。这项研究旨在 与基于早期脑发育成像的定量特征的推荐相匹配 以及认知、行为和社会发育与DS早期异常神经发育的关系。 该项目还将针对DS合并ASD的调查提出建议，这可能会高达 5%-10%。IBIS网络是唯一有资格检查早期神经发育模式的网络，利用 ASD、TYP和FRAX婴儿数据集，以更好地表征和检查DS早期发育的特异性 包括社会发展中的自闭症特征和障碍的模式。很明显，量化 DS婴儿的神经发育轨迹将是确定个性化干预的关键 策略和评估早期生活的疗效，有针对性的，高度新颖的和机械特异性的DS 干预措施。

Longitudinal MRI Characterization of Very Early Brain Development in Infants with Down Syndrome Project Summary/Abstract Down syndrome (DS), the most common genetic cause of intellectual disability, is associated with varying degrees of cognitive and behavioral impairments. Pharmacologic therapies and genetic modulators are emerging which, if administered early in conjunction with traditional therapies, show promise for improving developmental outcomes in children with DS. However, the stark absence of early neurodevelopment knowledge in DS hampers these efforts. The main goal of this proposal is to develop biomarkers as future targets for specific therapies based on careful characterization of early aberrant neurodevelopmental patterns. This study will be a combined effort with WU as the coordinating center and six other research groups: UNC, UW, CHOP, MNI, NYU, and University of Minnesota. These groups comprise the ACE-IBIS (Autism Center of Excellence Infant Brain Imaging Study) network, a well-established and experienced group that has been productively collaborating for 8 years on MRI imaging and behavioral characterization of infants at high risk for autism, healthy typical infants (TYP), and infants with Fragile X. The aims of this proposal are: 1) Define the longitudinal characteristics of early brain development in infants (3 to 24 months) with DS in comparison to TYP infants and infants with other developmental disabilities (ASD and Fragile X) using three different types of neuroimaging (MRI, DTI, rsfMRI); 2) Develop predictive models for developmental outcomes in infants with DS based on longitudinal structural or functional MRI characteristics; and 3) Characterize brain-behavior correlates with coordinated multimodal imaging in infancy characterizing the interrelationship between longitudinal network imaging parameters and cognitive, behavioral and neurodevelopmental outcomes using sophisticated multivariate support vector machine (SVM) analytic strategies. 120 infants with DS and 40 TYP control infants will be followed longitudinally from 3 to 24 months. MRI scans will be obtained during natural sleep and a series of well-validated developmental and behavioral assessments will be completed at each visit. This project will be the first to define the nature and timing of alterations in brain development in infants with DS. The proposed project addresses several key research recommendations from the “NICHD 2014-The NIH Research Plan on Down Syndrome.” The study aims match the recommendation for the quantitative characterization based on imaging of early brain development and the relationship of cognitive, behavioral and social development to early aberrant neurodevelopment in DS. This project will also address recommendations for investigation of comorbid ASD in DS, which could be as high as 5-10%. The IBIS network is uniquely qualified to examine early neurodevelopmental patterns, utilizing the ASD, TYP and FraX infant data sets to better characterize and examine specificity of DS early developmental patterns including ASD qualities and impairments in social development. It is clear that quantification of neurodevelopmental trajectories in infants with DS will be critical to identification of personalized intervention strategies and to assess the efficacy of early life, targeted, highly novel and mechanistically specific DS interventions.