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卫生问题，在过去的15年中，美国的病例数量增加了两倍，发病率为10,000人中有67人。自闭症是一种以社会交往和语言/非语言交流障碍为特征的终身衰弱性脑发育障碍。在一项使用MRI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，我们之前观察到独特的扩散变化，表明用于识别面部和面部情绪（社交互动和非语言交流的关键方面）的白质通路内的神经纤维中的微观水运动（扩散）减慢。由于这些功能在幼儿和成人自闭症患者中经常受到影响，而且这种独特的扩散变化通常在获得性或成人发病的疾病中没有看到，因此我们将这些DTT的发现解释为原发性的早期发育变化。这种不寻常的扩散速度减缓与自闭症患者识别面孔的能力下降密切相关。这种关系表明，该通路微观上由直径较小的神经纤维（轴突）组成，其神经传导速度较慢，功能较低。为了确定这些变化是否是发生在婴儿发育早期的自闭症的基本、原发性异常，我们将使用DTT和扩散敏感方法来：1)测试自闭症高风险婴儿（与低风险婴儿相比）相同面部加工通路中的这些水扩散变化；2)测试高危婴儿和低危婴儿在语言通路上的相似变化。我们计划研究20名高风险婴儿和20名个体匹配的低风险婴儿，其中风险是根据是否存在患有自闭症的兄弟姐妹来分配的。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的比较来确定。研究结果将决定，在青少年和年轻人中看到的面部处理通路异常，在婴儿中是更严重、相似还是较轻；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；如果婴儿在其他途径中表现出非特异性的扩散变化，就像在患有自闭症的年轻人身上看到的那样，这似乎是继发性的。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原因；2)改善早期诊断、筛查、风险评估、亚型表征以及早期治疗和干预措施的设计/规划；3)为自闭症患者早期大脑变化提供安全、无创的测量方法（生物标志物），可以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）与可测量的微观大脑变化的发生之间的关系。

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.