Biomarkers of Autism at 12 months: From Brain Overgrowth to Genes

自闭症是一种发育障碍，但人们对最重要的东西知之甚少：发展。什么是早期大脑异常？它们破坏了哪些神经功能？自闭症风险的第一个行为指标是什么？在第一次诊断时，幼儿或儿童的预后如何？哪些可能对已知的有效治疗有反应，哪些没有？他们的大脑或其他生物标志物是否可以预测无反应者，以便治疗研究可以针对发现可以帮助他们的治疗方法？哪些基因和基因通路导致早期脑缺陷？ 每个问题的答案都有一个共同点：早期识别方法。除非有一种方法来识别有自闭症风险的婴儿，否则这些关键问题无法解决。最流行的方法是婴儿兄弟姐妹法。现在很多人都在尝试这种方法。最早使用这种方法的两个实验室在五年前和七年前开始了他们的研究，并发表了两篇原创论文，一篇是关于7名自闭症谱系（ASD）婴儿的，另一篇是关于27名ASD婴儿的。他们发现6个月时与典型发育没有差异，但12个月时有差异。他们没有提供ASD婴儿的大脑，神经功能，遗传或其他生物学数据。 婴儿兄弟姐妹的方法有主要的成本，实用性和方法的局限性，这是在我们的补助金详细。虽然流行和进展了很长一段时间，迄今为止，使用这种方法的研究没有提供任何上述提出的主要问题的答案。 一种更简单，更快速，更灵活，更具成本效益和临床相关性和实用性的方法是研究医生推荐的个体，因为他们显示出表明ASD风险的行为症状。在20世纪90年代，这种方法可以识别出3岁及以上的高危儿童。到21世纪初，由于医生提高了认识和新的诊断工具，转诊的风险年龄为2岁。在每个“时代”，其他人和我们都能够积极研究ASD年轻时的大脑和行为异常以及新的治疗方法。正是通过这种简单的转诊方法，我们实验室发现了ASD早期大脑过度生长的重大发现。正是通过这种方法，我们已经能够在2岁时对ASD进行首次fMRI激活研究。 现在，通过这种已被证明有效的前瞻性方法的新变体（见核心B），在我们的ACE中心，我们将使用先进的生物学和行为方法研究12个月大的ASD风险婴儿、发育迟缓风险婴儿和典型婴儿。每名婴儿将间隔纵向研究，并在36个月时进行最终最佳估计诊断，为统计学分组提供最后一步

Autism is a developmental disorder, but the least is known about what is most important: Development. What are the early brain abnormalities? What neural functions do they disrupt? What the first behavioral indicators of risk for autism? What is the prognosis for the toddler or child at first diagnosis? Which are likely to respond to known effective treatment and which not? Are their brain or other biological markers that could predict non-responders so that treatment research could be targeted towards discovery of treatments that could help them? What genes and gene pathways are responsible for early brain defects? The answer to each question comes to the same point: Early identification methods. These sorts of crucial questions cannot be addressed unless there is a way to identify infants at risk for autism. The most popular method is the infant sibling method. Now many groups are trying this method. The first two laboratories to use this method began their research five and seven years ago, and have published two original papers, one on 7 autism spectrum (ASD) infants and one on 27 ASD infants. They found no differences from typical development at 6 months, but did by 12 months. They provided no brain, neurofunctional, genetic or other biological data on the ASD infants. The infant sibling method has major cost, practicality and methodological limitations, which are detailed in our grant. Although popular and in progress for a long time, to date, studies using this method have provided no answer any of the major questions posed above. A simpler, quicker, more flexible, cost-effective and more clinically relevant and practical method is to study individuals referred by physicians because they display behavioral symptoms indicating risk for an ASD. In the 1990s, this method resulted in identification of mostly at-risk 3 year olds and up. By the early 2000s, the at-risk age for referral was age 2 years because of heightened awareness by physicians and new diagnostic tools. In each "era", others and we were able to vigorously investigate brain and behavior abnormalities and new treatment approaches at young ages in ASD. It was via this simple referral method that major discoveries about early brain overgrowth in ASD occurred in our laboratory. It was via this method that we have been able to perform the first fMRI activation studies on ASD at age 2-years. Now, via a novel variant of this proven effective prospective method (see Core B), in our ACE Center we will study 12-month old infants at-risk for ASD, infants at-risk for developmental delay and typical infants using advanced biological and behavioral methods. Each infant will be studied at intervals longitudinally and a final best estimate diagnosis made at 36 months providing a final step for group assignment for statistical