DEVELOPMENTAL CHARACTERISTICS OF MRI DIFFUSION TENSOR PATHWAY CHANGES IN AUTISM

描述(由申请人提供)：自闭症谱系障碍是影响儿童和成人的主要公共健康问题，在过去15年中，美国的病例数量增加了两倍，发病率为每10,000人中有67人。自闭症是一种终生衰弱的发育性大脑疾病，其特征是社交和语言/非语言交流方面的障碍。在使用磁共振扩散张量跟踪(DTT)对青少年和年轻自闭症患者进行的研究中，我们先前观察到独特的扩散变化，表明用于识别面孔和面孔情绪(社交和非语言交流的关键方面)的白质通路内神经纤维的微观水运动(扩散)放缓。由于这些功能通常在儿童和成人自闭症患者中受到影响，而这种独特的扩散变化通常在后天或成人发病的疾病中看不到，我们解释这些DTT发现表明了一种初级的、早期的发育变化。扩散的异常减慢尤其与自闭症参与者识别面孔的能力较低有关。这种关系表明，该通路在显微镜下是由小直径神经纤维(轴突)组成的，这将使神经传导速度较慢，功能较差。为了确定这些变化是否是自闭症中发生在婴儿发育早期的基本的、原发的异常，我们将使用DTT和扩散敏感方法来：1)测试自闭症高危婴儿(与低风险婴儿相比)在相同面部加工路径上的这些水扩散变化；以及2)测试高风险婴儿和低风险婴儿语言路径的类似变化。我们计划研究20名高风险婴儿和20名单独匹配的低风险婴儿，根据自闭症兄弟姐妹的存在来分配风险。DTT结果的功能意义将通过与为婴儿设计的相关面部处理和语言测试进行比较来确定。结果将确定在青少年和年轻人的面部加工途径中看到的异常在婴儿中是更严重、相似还是不那么严重；这种扩散模式是否延伸到其他可能与自闭症核心特征相关的途径；以及婴儿是否在患有自闭症的年轻人中看到的其他途径中表现出非特异性的扩散变化，这些途径似乎是继发性的。我们的长期目标是：1)更好地了解自闭症的潜在生物学机制和病因；2)改进自闭症的早期诊断、筛查、风险评估、亚型鉴定以及早期治疗和干预的设计/规划；以及3)提供自闭症非常早期的脑变化的安全、非侵入性测量(生物标记物)，可在婴儿期和儿童期使用，以确定遗传/免疫/环境事件(例如免疫)与可测量的微观脑变化的开始之间的关系。 公共卫生相关性：在使用磁共振扩散张量跟踪(DTT)对自闭症年轻人进行的一项研究中，我们先前观察到的变化表明，白质通路中涉及面部和面部情绪识别的小直径神经纤维(社交和非语言交流的关键方面，通常在自闭症中受到影响)。为了确定这种变化是否是婴儿发育早期发生的基本异常，我们将使用DTT和新的扩散敏感磁共振方法来：1)与低风险婴儿(风险基于受影响的兄弟姐妹的存在)相比，测试自闭症高风险婴儿的这些通路变化，以及2)测试高风险婴儿和低风险婴儿语言通路的类似变化。我们的长期目标是1)更好地了解自闭症的生物学原因，2)改进自闭症的早期诊断、筛查和治疗，3)提供自闭症非常早期的脑变化的测量(生物标记物)，可用于研究遗传、免疫和环境事件(例如免疫)与可测量的脑变化开始之间的时间关系。

DESCRIPTION (provided by applicant): Autism spectrum disorder is a major public health problem affecting children and adults, with the number of cases having tripled in the US in the past 15 years, and with an incidence of 67 in 10,000 people. Autism is a lifelong debilitating developmental brain disorder characterized by impairments in social interaction and verbal/non-verbal communication. In a study of adolescents and young adults with autism using MRI diffusion tensor tracking (DTT), we previously observed unique diffusion changes indicating a slowing of microscopic water movements (diffusion) across nerve fibers within white matter pathways used for recognizing faces and face emotions (critical aspects of social interaction and non-verbal communication). Because these functions are often affected in young children as well as adults with autism, and such unique diffusion changes are usually not seen in acquired or adult-onset disorders, we interpreted these DTT findings to indicate a primary, early-developmental change. The unusual slowing of diffusion was particularly associated with a lower ability of the autism participants to recognize faces. This relation suggests that the pathway is microscopically composed of small-diameter nerve fibers (axons), which would have a slower neural conduction speed and lower function. To determine whether such changes are a fundamental, primary abnormality in autism that occurs early in infant development, we will use DTT and diffusion-sensitive methods to: 1) test for these water diffusion changes in the same face processing pathways in infants at high-risk for autism (compared to low-risk infants); and 2) test for similar changes in language pathways in high-risk versus low-risk infants. We plan to study 20 high-risk infants and 20 individually-matched low-risk infants, where risk is assigned based on existence of a sibling with autism. The functional significance of DTT results will be determined by comparison to relevant face-processing and language tests designed for infants. The results will determine if the abnormalities seen in face-processing pathways in adolescents and young adults are more severe, similar, or less severe in infants; whether this diffusion pattern extends to other pathways potentially related to the core features of autism; and if infants exhibit non-specific diffusion changes in other pathways seen in young adults with autism that appear to be secondary in nature. Our long-term goals are to: 1) provide a better understanding of the underlying biological mechanisms and causes of autism; 2) improve the early diagnosis, screening, risk assessment, subtype characterization, and design/planning of early treatments and interventions; and 3) provide safe, non-invasive measures (biomarkers) of very early brain changes in autism that can be used during infancy and childhood to determine relationships between genetic/immunological/environmental events (e.g., immunization) and the onset of measurable microscopic brain changes. PUBLIC HEALTH RELEVANCE: In a study of young adults with autism using MRI diffusion tensor tracking (DTT), we previously observed changes suggesting small-diameter nerve fibers in the white matter pathways involved in the recognition of faces and facial emotions (critical aspects of social interaction and non-verbal communication often affected in autism). To determine whether such changes are a fundamental abnormality that occurs early in infant development, we will use DTT and new diffusion-sensitive MRI methods to: 1) test for these pathway changes in infants at high-risk for autism compared to infants at low risk (where risk is based on the existence of an affected sibling), and 2) test for similar changes in language pathways in high-risk versus low-risk infants. Our long-term goal is to 1) provide a better understanding of the biological causes of autism, 2) improve the early diagnosis, screening, and treatment of autism, and 3) provide measures (biomarkers) of very early brain changes in autism that can be used to study the time relation between genetic, immunological, and environmental events (e.g., immunization) and the onset of measurable brain changes.