Neuroimmunologic Investigations of Autism Spectrum Disorders (ASD)

自闭症是通过其行为表现来定义的：社交缺陷，沟通障碍以及限制或重复行为的存在。这些异常的原因尚不清楚，但人们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）的患病率不断上升（据最新报道，每100名儿童中就有1名受其影响），加上这些症状的终生性，往往使人虚弱，使自闭症谱系障碍成为一个主要的公共卫生问题。增加我们对症状的原因和性质的理解的研究，以及调查新型治疗干预的潜在作用的研究，为数百万美国家庭带来了受益的希望。

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.