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.

自闭症的定义是其行为表现：社交缺陷、沟通障碍以及受限或重复行为的存在。 这些异常的原因尚不清楚，但强烈怀疑自闭症谱系障碍（ASD）是遗传和环境因素共同作用的结果。 自闭症谱系障碍（ASD）患病率的上升（据最新报道，影响多达百分之一的儿童）和终生且常常使人衰弱的症状结合在一起，使自闭症谱系障碍成为一个主要的公共卫生问题。 增进我们对症状原因和性质的理解的研究，以及调查新型治疗干预措施潜在作用的研究，有望为数百万美国家庭带来好处。 越来越多的文献支持神经免疫功能障碍在自闭症谱系障碍 (ASD) 中的作用，包括对脑脊液细胞因子和趋化因子异常模式的观察，以及 ASD 个体慢性神经炎症变化的病理报告。 神经免疫功能障碍被认为是退行性自闭症的潜在病因，导致社交和沟通技能显着丧失。 临床过程表明，退行性自闭症儿童的免疫功能可能存在独特的改变。 PDN 部门正在进行一项大型表型分析研究，重点关注具有这种发病模式的儿童。 我们期望发现至少一些患有发育退化和自闭症谱系障碍的儿童存在明显的免疫功能异常。这些异常预计不会出现在没有退行过程的自闭症儿童中，也不会出现在正常发育的儿童或发育迟缓（无自闭症症状）的儿童中。 在表型分析研究中，部分队列包括首先对 12-48 个月大的儿童进行评估，然后观察各种指标随时间的变化，包括综合行为、神经心理学、医学和神经学评估，以及对脑脊液细胞因子和趋化因子、大脑结构（使用磁共振成像或 MRI）以及可能引发免疫功能障碍的环境暴露史的评估。 该研究还评估了没有退行史的自闭症儿童、发育迟缓的儿童和典型发育的儿童，以确定退行自闭症儿童研究结果的特异性。 例如，当研究人员报告 XMRV（一种逆转录病毒）与自闭症之间存在潜在联系时，PDN 可以为有兴趣复制该报告的研究人员提供来自退行自闭症和非退行自闭症儿童的样本，以及通常开发的对照。 表型研究仍在招募幼儿参与——欢迎感兴趣的人士通过以下网址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促使我们研究微生物易位（MT），这是由于细菌或微生物副产物从胃肠道、呼吸道或泌尿道等粘膜屏障的内腔渗透到血液中造成的。 据信，肠病和/或炎症性疾病期间胃肠道的异常会增加粘膜的通透性或肠漏，从而促进 MT，并被认为会导致全身免疫激活。 从表型研究中对儿童的分析来看，自闭症儿童和年龄匹配的典型对照儿童或具有退行特征与非退行特征的儿童之间的 MT 标记物循环水平没有显着差异。 这些观察结果表明，MT 并不是自闭症儿童常见的病理生理反应，并且不支持自闭症症状与“肠漏”一致相关的假设。 然而，有可能一部分儿童可能因胃肠道神经免疫功能障碍而出现自闭症症状，而我们的队列不包括此类儿童。 因此，我们计划进一步扩大表型研究，以研究也有明显胃肠道症状的自闭症儿童 寻找新的有效的自闭症治疗方法是 PDN 的最高研究重点之一。 D. Vargas 等人（约翰·霍普金斯大学）2005 年的一项研究表明，患有自闭症且有神经发育退化史的个体存在慢性脑神经炎症的证据，例如在组织样本和脑脊液中检测到的小胶质细胞和星形胶质细胞的激活以及炎症细胞因子和生长因子的异常产生。 作者指出，慢性小胶质细胞激活似乎导致了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，神经胶质细胞的激活可能是对继发性神经毒性因素的反应而发生的，因此代表了损伤的结果，而不是原因。 神经胶质细胞的激活需要促炎转录因子 NF-κB 的核转位。 对米诺环素（一种已知对 NF-κB 有影响的抗生素）进行了一项小型试点研究，以确定该药物是否可能对自闭症行为产生影响或改变脑脊液或血清细胞因子或趋化因子的分布模式。 在试点研究中使用的剂量下，行为以及脑脊液或血清细胞因子或趋化因子的分布模式均未发现有临床意义的改善。 因此，没有计划对米诺环素进行进一步的研究，但通过表型研究继续寻找新型治疗药物，其中纵向评估提供了识别连续脑脊液和血清样本中神经炎症生物标志物的机会，并将测定结果与临床症状学相关联。