A Longitudinal 3-D MRSI Study of Infants at High Risk for Autism

描述(由申请人提供)：这项建议的目的是扩大NIH资助的项目“自闭症高危婴儿的纵向MRI研究”(RO1 HD055741-IBIS网络)的范围，通过增加三维质子回声平面光谱成像(3D Pepsi)来测量被诊断为自闭症(高风险)的儿童的6个月大的兄弟姐妹以及没有自闭症家族史(低风险)的年龄匹配的婴儿(低风险)，这些婴儿然后在12个月时重新扫描，并在12个月和24个月时进行临床评估。具体地说，我们计划将3D Pepsi纳入我们正在进行的MRI/DTI结构成像方案中(到目前为止，有29名6个月高风险婴儿被研究，71名正在等待母项目的100项6个月研究)，并扫描更多的婴儿(在拟议的2年项目中，每年额外预算20次扫描-总共90名高风险婴儿和40名低风险6个月婴儿)，以补充父母资助的目标招募目标，并在另一个晚上重复失败的研究。这项建议的第二个目标是开发自动化的3D外体积饱和频带放置技术和QC程序，以便在我们的成像财团所涉及的其他地点实施百事可乐技术，这些地点包括北卡罗来纳大学教堂山分校、宾夕法尼亚大学/CHOP大学、华盛顿大学和蒙特利尔神经研究所(DCC)，以便对这一纵向队列进行多地点3D百事后续研究。我们资助的项目是调查大脑结构发育和自闭症症状发作之间的关系，自闭症症状通常出现在12到24个月大的婴儿身上。拟议的附录将增加补充的大脑化学信息，以评估MRI/DTI测量的假想的脑生长异常(区域、组织、结构和纤维束)的潜在机制以及与临床特征的关系。3D百事可乐最近在我们的3T西门子Tim Trio扫描仪上开发和实施，提供高分辨率的可量化化学图像，具有更好的解剖覆盖范围，特别适合在正常睡眠期间对婴儿进行快速扫描。我们的研究团队除了在儿科成像研究方面非常熟练外，还走在开发和临床应用化学成像技术的前沿，并开发了专门为高效、可靠和有效地处理3D大脑化学数据而设计的分析工具。这些结果将为自闭症的大脑发育、行为表型和潜在的神经生物学提供重要的见解。 公共卫生相关性：这项赠款建议的研究针对机构间自闭症协调委员会(IACC)自闭症谱系障碍(ASD)研究战略计划(2009年1月)概述的挑战。具体地说，该项目将解决6个月大的ASD高危婴儿的异质性，因为受影响的兄弟姐妹年龄较大，他们在6个月、12个月和24个月时进行纵向成像，然后在24个月时进行诊断，并在3岁时得到确认。作为该项目的一部分，收集的脑化学测量有可能帮助识别具有特定预后和治疗意义的ASD的不同临床亚型。脑化学测量将提供可能识别不同ASD内表型的生物标记物，例如，可能患有微小线粒体功能障碍的婴儿，并有助于阐明导致自闭症脑发育异常的潜在病理生理机制。

DESCRIPTION (provided by applicant): The aim of this proposal is to expand the scope of a funded NIH project "A longitudinal MRI Study of Infants at Risk for Autism," (RO1 HD055741- IBIS network) through adding 3-D Proton Echo Planar Spectroscopic Imaging (3D PEPSI) to allow measurements of brain chemistry in 6 month-old siblings of children diagnosed with autism (high risk) and age-matched infants without a family history of autism (low risk) who then are rescanned at 12 months and clinically assessed at 12 and 24 months. Specifically, we plan to incorporate 3D PEPSI into our ongoing MRI/DTI structural imaging protocol (29 6 month high risk infants studied to date, 71 pending for the parent project total of 100 6mo studies), and scan additional infants (20 additional scans budgeted per year during the proposed 2-year project- for a total of 90 high-risk and 40 low-risk 6 month infants) to supplement target recruitment goals of the parent grant and repeat failed studies on another night. A secondary aim of this proposal is to develop automated 3D outer volume saturation band placement techniques and QC procedures for implementation of PEPSI technology at other sites involved in our imaging consortium, UNC- Chapel Hill, U Penn/ CHOP, Wash U, and Montreal Neurological Institute (DCC), to allow multi-site 3D PEPSI follow-up studies of this longitudinal cohort. Our funded project is investigating relationships between brain structural development and autism symptom onset that typically presents between 12 and 24 months of age. The proposed supplement will add complementary brain chemical information to assess mechanisms underlying hypothesized abnormalities of brain growth (regions, tissues, structures and fiber tracts) measured by MRI/ DTI and relationships to clinical features. 3D PEPSI, recently developed and implemented on our 3T Siemens TIM Trio scanner, provides highly resolved quantifiable chemical images with improved anatomical coverage and is particularly well suited for rapid scanning of infants during normal sleep. Our research team, in addition to being highly skilled at pediatric imaging studies, is at the forefront for developing and clinically applying chemical imaging techniques and has developed analytical tools specifically designed for highly efficient, reliable, and valid processing of 3D brain chemical data. These results will provide important insights into brain development, behavioral phenotypes and the underlying neurobiology of autism. PUBLIC HEALTH RELEVANCE: Research proposed in this grant targets challenges outlined by the Interagency Autism Coordinating Committee (IACC) Strategic Plan for Autism Spectrum Disorder (ASD) Research (January 2009). Specifically, the project will address heterogeneity in 6 month-old infants at high risk for ASD due to an older affected sibling, who are imaged longitudinally at 6, 12 and 24 months, then diagnosed at 24 months that is confirmed at age 3. Brain chemical measures collected as part of this project have the potential to help identify distinct clinical subtypes of ASD having specific prognostic and treatment implications. Brain chemical measurements will provide biomarkers that may identify distinct ASD endophenotypes, for example, infants potentially having subtle mitochondrial dysfunction, and help elucidate underlying pathophysiological mechanisms responsible for brain developmental abnormalities in autism.