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

自闭症是一种发育障碍，但人们对最重要的事情却知之甚少：发育。早期大脑异常有哪些？它们会破坏哪些神经功能？自闭症风险的第一个行为指标是什么？初诊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记是否可以预测无反应者，以便治疗研究可以有针对性地发现可以帮助他们的治疗方法？哪些基因和基因途径导致早期大脑缺陷？ 每个问题的答案都指向同一点：早期识别方法。除非有办法识别有自闭症风险的婴儿，否则这些关键问题就无法得到解决。最流行的方法是婴儿兄弟姐妹法。现在很多团体都在尝试这种方法。最早使用这种方法的两个实验室于五年前和七年前开始研究，并发表了两篇原创论文，一篇针对 7 名自闭症谱系 (ASD) 婴儿，另一篇针对 27 名 ASD 婴儿。他们发现 6 个月时的发育与典型发育没有差异，但到 12 个月时却发现了差异。他们没有提供自闭症谱系障碍婴儿的大脑、神经功能、遗传或其他生物学数据。 婴儿兄弟姐妹方法具有重大成本、实用性和方法学局限性，这些都在我们的资助中详细说明。尽管这种方法很流行并且已经进行了很长时间，但迄今为止，使用这种方法的研究尚未回答上述提出的任何主要问题。 一种更简单、更快速、更灵活、更具成本效益且更具临床相关性和实用性的方法是研究由医生推荐的个人，因为他们表现出表明存在自闭症谱系障碍风险的行为症状。在 20 世纪 90 年代，这种方法识别出了大多数 3 岁及以上的高危儿童。到 2000 年代初期，由于医生意识的提高和新诊断工具的出现，转诊的危险年龄为 2 岁。在每个“时代”，其他人和我们都能够积极研究自闭症谱系障碍（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，我们的实验室才取得了关于自闭症谱系障碍早期大脑过度生长的重大发现。正是通过这种方法，我们能够在 2 岁时对 ASD 进行首次功能磁共振成像激活研究。 现在，通过这种经过验证有效的前瞻性方法的新变体（参见核心 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有 ASD 风险的 12 个月大婴儿、有发育迟缓风险的婴儿和典型婴儿。每个婴儿将纵向间隔一段时间进行研究，并在 36 个月时做出最终的最佳估计诊断，为统计分组提供最后一步

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