LONGITUDINAL OUTCOMES & NEUROIMAGING OF FRAGILE X SYND

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 脆性X综合征(FRAX)是遗传性精神障碍的最常见原因，在美国有超过10万人受到影响。FMR1基因的突变会导致一种临床表型，包括认知、行为和情绪功能异常的风险增加。本申请中提出的为期5年的研究的主要重点是对当前赠款期间完成的工作的前瞻性、纵向扩展，在此期间，从美国和加拿大的120个家庭收集了关键的认知、行为、神经内分泌、遗传和环境数据，每个家庭都有一个患有FRAX的儿童先证者和一个典型的发育中的兄弟姐妹。据我们所知，这项研究将是第一次对影响临床结果的生物和环境因素进行前瞻性评估的大型学龄期FRAX队列的纵向调查。我们还建议使用先进的脑成像技术来扩大我们对这种疾病的神经生物学的研究。具体地说，纵向成像研究将被用来阐明与关键控制组相比，患有FRAX儿童的大脑结构和功能的发展轨迹。具体目标：1)使用纵向、前瞻性实验设计(“时间1”和“时间2”评估)来阐明与其同性同胞相比，患有FRAX先证者的认知、行为和情绪发育的发展轨迹；2)明确FRAX先证者的下丘脑-垂体-肾上腺(HPA)功能的纵向发展轨迹以及FMR1基因表达的测量；以及3)利用神经成像技术确定FRAX先证者与特定年龄、性别、利手、SES和IQ匹配的对照组儿童的大脑结构和功能的发展轨迹。尽管在过去的20年里，患有FRAX的儿童和成人对认知、行为和大脑的了解有了很大的增长，但来自患有这种疾病的学龄儿童的纵向数据是有限的。到目前为止，横断面研究结果和有限的纵向数据支持这样一种假设，即患有FRAX的学龄儿童的标准化认知和适应行为得分随年龄的下降而下降。然而，关于这一现象的许多问题仍然没有得到回答，特别是与范围、时机和神经基础有关的问题。这些悬而未决的问题提供了一个令人信服的理由，可以对本申请中提议的一大批患有FRAX的学龄儿童进行纵向研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Fragile X syndrome (fraX) is the most common known cause of inherited mental impairment with well over 100,000 individuals affected in the U.S. Mutations in the FMR1 gene give rise to a clinical phenotype that includes increased risk for aberrant cognitive, behavioral and emotional function. The major emphasis of the 5-year study proposed in this application is a prospective, longitudinal extension of the work completed during the current grant period, during which key cognitive, behavioral, neuroendocrinological, genetic and environmental data were collected from 120 families across the U.S. and Canada, each having a child proband affected with fraX and a typically developing sibling. To the best of our knowledge, this study would be the first longitudinal investigation of a large, school-age fraX cohort in which both biological and environmental factors contributing to clinical outcome were assessed on a prospective basis. We also propose to extend our investigation into the neurobiology of this disorder using advanced brain imaging techniques. Specifically, longitudinal imaging studies will be used to explicate the developmental trajectory of brain structure and function in children with fraX as compared to key control groups. Specific Aims: 1) To use a longitudinal, prospective experimental design (with "Time 1" and "Time 2" assessments) to elucidate the developmental trajectory of cognitive, behavioral and emotional development in probands with fraX compared to their like-gender siblings; 2)to specify the longitudinal trajectory of hypothalamic-pituitary-adrenal (HPA) function and measures of FMR1 gene expression in probands with fraX; and 3)to utilize neuromaging techniques to specify the trajectory of brain structure and function in children with fraX compared to specific age-, gender-, handedness-, SES- and IQ-matched control groups. Although knowledge of cognition, behavior and the brain in children and adults with fraX has grown considerably over the past 20 years, longitudinal data from school-age children with this condition are limited. Cross-sectional findings and limited longitudinal data to date support the hypothesis that an age-related decline in standardized cognitive and adaptive behavioral scores occurs among school-age children with fraX. However, many questions remain unanswered regarding this phenomenon, in particular as related to extent, timing and neural basis. These unanswered questions offer a compelling rationale for conducting a longitudinal study of a large group of school-age boys and girls with fraX as proposed in this application.