Neuroimmunologic Investigations of Autism Spectrum Disorders (ASD)

自闭症谱系障碍 (ASD) 的神经免疫学研究

• 批准号: 8158154
• 负责人: Susan Swedo
• 金额: $ 38.53万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8158154
• 关键词: Investigation; autism spectrum disorder

Autism is defined by its behavioral manifestations: social deficits, impairments in communication and the presence of restricted or repetitive behaviors. The cause of these abnormalities is unknown, but it is strongly suspected that autism spectrum disorders (ASD) result from a combination of genetic and environmental factors. The rising prevalence rates of ASD (last reported to affect as many as 1 in 100 children) and the life-long, often debilitating nature of the symptoms combine to make autism spectrum disorders a major public health problem. Research that increases our understanding of the causes and nature of the symptoms, and studies that investigate the potential role for novel therapeutic interventions hold the promise of benefit for millions of American families. A growing literature supports a role for neuroimmune dysfunction in autism spectrum disorders (ASD), including observations of abnormal patterns of CSF cytokines and chemokines, and pathological reports of chronic neuroinflammatory changes among individuals with ASD. Neuroimmune dysfunction is considered to be a potential etiologic factor in regressive autism where there is a significant loss of social and communication skills. The clinical course suggests that there may be a unique alteration in immune function among children with regressive autism. Children with this pattern of onset are part of the focus of a large, phenotyping study underway in the PDN Branch. We expect to find that at least some children with developmental regression and ASD have demonstrable abnormalities in immune function. These abnormalities are not expected to be found among autistic children without a regressive course nor will they be found among typically developing children or children with developmental delays (without autism symptoms). In the phenotyping study, part of the cohort includes children first evaluated between 12-48 months of age and then followed forward to look at changes over time in a variety of measures, including comprehensive behavioral, neuropsychological, medical and neurological evaluations, as well as assessments of CSF cytokines and chemokines, brain structure (using magnetic resonance imaging or MRI) and history of environmental exposures that might trigger immune dysfunction. The study also evaluates children with autism without a history of regression, children with developmental delays, and children with typical development, in order to determine the specificity of the findings in the children with regressive autism. For example, when researchers reported a potential link between XMRV (a retrovirus) and autism, PDN could provide investigators interested in replicating the report with samples from children with regressive autism and non-regressive autism, as well as typically developing controls. The phenotyping study is still recruiting young children to participate -- interested parties are invited to learn more about the study at: http://clinicalstudies.info.nih.gov/detail/A_2006-M-0102.html One of hypotheses related to immune dysfunction led us to investigate microbial translocation (MT), which results from permeation of bacteria or microbial byproducts from the lumen of mucosal barriers such as the gastrointestinal, respiratory or urinary tract into the bloodstream. It is believed that abnormalities of the gastrointestinal tract during enteropathies and/or inflammatory disorders increase permeability of the mucosa or a leaky gut that facilitate MT and it is thought to cause systemic immune activation. From analyses of children in the phenotyping study, circulating levels of MT markers did not differ significantly between children with autism and age-matched typical controls or children with regressive vs. non-regressive features. These observations suggest that MT is not a common pathophysiological response in children with autism and do not support the hypothesis that autistic symptoms are uniformly related to a "leaky gut". However, it is possible that a subgroup of children might develop autistic symptoms in response to GI-neuro-immune dysfunction and that our cohort didn't include such children. Therefore, we are planning to further expand the phenotyping study to study children with autism who also have significant gastrointestinal symptoms Finding new and effective treatments for autism is one of PDN's highest research priorities. A 2005 study by D. Vargas et al (Johns Hopkins) demonstrated that individuals with autism and a history of neurodevelopmental regression had evidence of chronic brain neuroinflammation, as exemplified by activation of microglia and astroglia and the abnormal production of inflammatory cytokine and growth factors assayed in both tissue samples and CSF. The authors remarked that chronic microglia activation appeared to be responsible for a sustained neuroinflammatory response that facilitated the production of a number of neurotoxic mediators. Alternatively, neuroglial activation could occur in response to a secondary neurotoxic factor(s) and thus represent the result, rather than the cause, of the injury. Neuroglial activation requires the nuclear translocation of the pro-inflammatory transcription factor NF-kappaB. A small pilot study of minocycline, an antibiotic with known effects on NF-kappaB was undertaken in an effort to determine if the drug might have an effect on autistic behaviors or change patterns of distribution for the CSF or serum cytokines or chemokines. At the doses used in the pilot investigation, no clinically meaningful improvements were seen in behavior nor in the pattern of distribution of the CSF or serum cytokines or chemokines. Thus, no further investigations are planned for minocycline, but the search for novel therapeutic agents continues through the phenotyping study, where longitudinal assessments provide the opportunity to identify biomarkers of neuroinflammation in serial CSF and serum samples and to correlate the results of the assays with clinical symptomatology.

自闭症由其行为表现形式定义：社会缺陷，沟通障碍以及存在受限制或重复行为的存在。 这些异常的原因尚不清楚，但强烈怀疑自闭症谱系障碍（ASD）是由于遗传和环境因素的组合引起的。 ASD的患病率上升（上次据报道会影响100名儿童中多达1个），症状的终身性，常常使人衰弱的性质结合在一起，使自闭症谱系成为一个主要的公共卫生问题。 提高了我们对症状原因和性质的理解以及研究新型治疗干预措施的潜在作用的研究使人对数百万美国家庭有利。 越来越多的文献支持自闭症谱系障碍（ASD）中神经免疫功能障碍的作用，包括观察到CSF细胞因子和趋化因子异常模式，以及ASD患者中慢性神经炎性变化的病理报道。 神经免疫性功能障碍被认为是回归自闭症的潜在病因因素，在社会和沟通技巧上丧失了重大丧失。 临床课程表明，回归自闭症儿童的免疫功能可能会发生独特的改变。 具有这种发作模式的儿童是PDN分支中进行的大型表型研究的重点的一部分。 我们希望至少一些患有发育回归和ASD的儿童在免疫功能方面具有明显的异常。预计不会在没有回归病程的自闭症儿童中发现这些异常，也不会在通常发育延迟的儿童或儿童中发现这些异常（没有自闭症症状）。 在表型研究中，该队列的一部分包括首先评估12-48个月之间的儿童，然后遵循以各种措施中的时间的变化，包括全面的行为，神经心理学，医学和神经学评估，以及对CSF细胞因子和趋化因子，脑结构，大脑结构，脑结构的评估（使用磁性共振剂的磁性或MRI触发环境）和MRI触发性能，并将其评估。 这项研究还评估了没有回归史，发育延迟的儿童和典型发育的儿童的自闭症儿童，以确定回归自闭症儿童的发现的特异性。 例如，当研究人员报告了XMRV（逆转录病毒）与自闭症之间的潜在联系时，PDN可以为有兴趣复制该报告的研究人员提供回归自闭症和非退休自闭症儿童的样本，以及通常开发控制措施。 该表型研究仍在招募幼儿参加 - 邀请感兴趣的各方了解有关该研究的更多信息： http://clinicalstudies.info.nih.gov/detail/a_2006-m-0102.html 与免疫功能障碍相关的假设之一使我们研究了微生物易位（MT），这是由于细菌或微生物副产品的渗透而导致的，这些粘膜或微生物副产品来自粘膜屏障的腔内，例如胃肠道，呼吸道或尿路进入血液流进入血液。 据认为，肠道病和/或炎症性疾病期间胃肠道的异常增加了粘膜的渗透性或促进MT的渗漏的肠道，并被认为会引起系统性免疫激活。 从表型研究中的儿童分析中，自闭症儿童和年龄匹配的典型对照组或具有回归性与非回归特征的儿童之间的MT标记水平没有显着差异。 这些观察结果表明，MT在自闭症儿童中不是常见的病理生理反应，并且不支持自闭症症状与“漏水肠道”一致相关的假设。 但是，可能会因响应gi-neuro-smmune功能障碍而产生自闭症症状，而我们的队列不包括这样的孩子。 因此，我们计划进一步扩大表型研究，以研究自闭症儿童，这些儿童也患有明显的胃肠道症状 为自闭症寻找新的有效治疗方法是PDN的最高研究重点之一。 D. Vargas等2005年的一项研究（Johns Hopkins）表明，自闭症患者和神经发育回归的病史具有慢性脑神经炎症的证据，这是通过小胶质细胞和阿斯特罗格尼亚的激活以及在炎症细胞因子和生长因素中的异常产生和CSSF中的炎症性细胞因子和生长因素的异常。 作者指出，慢性小胶质细胞活化似乎是导致持续的神经炎症反应，从而促进了许多神经毒性介质的产生。 或者，神经元激活可能是响应继发性神经毒性因子而发生的，因此代表了损伤的结果，而不是原因。 神经激活需要促炎性转录因子NF-kappab的核转运。 一项针对米诺环素的小型试点研究，是一种对NF-kappab的已知作用的抗生素，以确定该药物是否可能对CSF或血清细胞因子或趋化因子或趋化因子或趋化因子或趋化因子或变化的分布模式产生影响。 在试点调查中使用的剂量时，在行为或CSF分布或血清细胞因子或趋化因子的分布方面没有看到临床意义的改善。 因此，没有计划进一步研究米诺环素，但是对新型治疗剂的搜索继续通过表型研究继续进行，在该研究中，纵向评估为鉴定连续CSF和血清样本中神经炎症的生物标志物提供了机会，并将鉴定结果与临床症状学相关联。