Neuroimmunologic Investigations of Autism Spectrum Disorders (ASD)

自闭症是由其行为表现来定义的：社交缺陷，沟通障碍以及存在限制或重复行为。 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。 自闭症谱系障碍的患病率不断上升（最近报告约每150名儿童中就有1名患病），加上这些症状的终生性、往往使人衰弱的性质，联合收割机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，以及调查新的治疗干预措施的潜在作用的研究，有望使数百万美国家庭受益。 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CSF细胞因子和趋化因子异常模式的观察，以及ASD患者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一个潜在病因因素，其中一个典型的发展时期之后是社交和沟通技能的丧失。 临床过程表明，可能有一个独特的改变免疫功能的儿童与倒退自闭症。 这些儿童是PDN分支正在进行的一项大型表型研究的重点。 我们预计会发现至少一些发育倒退和自闭症谱系障碍的儿童存在明显的免疫功能异常。这些异常预计不会在没有退化过程的自闭症儿童中发现，也不会在发育正常的儿童或发育迟缓的儿童（没有自闭症症状）中发现。 在表型研究中，首先对12-48个月大的儿童进行评估，然后进行随访，以观察各种措施随时间的变化，包括全面的行为，神经心理学，医学和神经学评估，以及CSF细胞因子和趋化因子的评估，大脑结构（使用磁共振成像或MRI）和可能引发免疫功能障碍的环境暴露史。 该研究还评估了没有回归史的自闭症儿童，发育迟缓的儿童和典型发育的儿童，以确定回归自闭症儿童的发现的特异性。 受试者招募正在进行中，请感兴趣的各方通过以下方式了解有关研究的更多信息： http://clinicalstudies.info.nih.gov/detail/A_2006-M-0102.html 寻找新的有效的自闭症治疗方法也是PDN研究的优先事项。2005年，D. Vargas等人（Johns霍普金斯）证明，患有自闭症和有神经发育退化史的个体有慢性脑神经炎症的证据，如在组织样本（脑库）和CSF中测定的小胶质细胞和星形胶质细胞的激活以及炎性细胞因子和生长因子的异常产生所例示。 作者指出，慢性小胶质细胞活化似乎是导致持续神经炎症反应的原因，这种反应促进了许多神经毒性介质的产生。 慢性神经胶质激活可能是胎儿发育模式异常持续的结果。 在这种情况下，神经胶质细胞激活可能在启动和维持自闭症的神经病理学中发挥作用。 或者，神经胶质细胞激活可能是对继发性神经毒性因子的反应，因此代表了损伤的结果，而不是损伤的原因。 神经胶质细胞活化需要促炎转录因子NF-κ B的核转位。 抗生素米诺环素似乎能够阻断NF-κ B核转位，从而抑制小胶质细胞活化。 这种抑制已经显示在肌萎缩侧索硬化（ALS）和亨廷顿病的小鼠模型中具有神经保护作用，并且已经报道在人类中稳定病程2年（Bonelli，R.M.等人（2004）。 为了确定米诺环素是否对自闭症有类似的有益作用，进行了一项两阶段研究。 第一阶段是一项为期6个月的开放标签研究，旨在评估10名儿童（年龄4至12岁）的剂量安全性和药物效应，这些儿童的主要诊断为自闭症和发育退化史。 在6个月治疗期之前和之后，将通过诊断/行为评估和通过CSF细胞因子/趋化因子谱判断的神经炎症程度来评价受试者。 CSF细胞因子/趋化因子谱的变化是这项小型开放标签试验的主要结局变量。 如果I期研究中出现预测性特征，则将在30例额外受试者中实施双盲、安慰剂对照试验。 该研究的主要结果变量将是随着时间的推移行为的变化-二甲胺四环素给药是否产生有意义的行为改善或发育进展的进展？ 最后一名儿童在报告期间完成了开放标签试验。 目前正在分析I期数据，然后将决定II期研究的效用。 关于米诺环素研究的其他信息可以在以下网站找到：http://clinicalstudies.info.nih.gov/detail/A_2007-M-0024.html

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 approximately 1 in 150 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 a period of typical development is followed by a 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. These children are 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, children are 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. Subject recruitment is ongoing and interested parties are invited to learn more about the study at: http://clinicalstudies.info.nih.gov/detail/A_2006-M-0102.html Finding new and effective treatments for autism is also a priority for PDN's research. 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 (brain banks) 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. Chronic neuroglial activation could be the result of an abnormal persistence of a fetal development pattern. In this scenario, neuroglial activation could play a role in initiating and in maintaining the neuropathology in autism. 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. The antibiotic minocycline appears to be able to block NF-kappaB nuclear translocation and consequently, inhibit microglial activation. This inhibition has been shown to be neuroprotective in mouse models of amyotrophic lateral sclerosis (ALS) and Huntingtons disease, and has been reported to stabilize the course of illness in humans for a 2-year period (Bonelli, R.M. et al. (2004). To determine if minocycline will have similar beneficial effects in autism, a two-phase study was undertaken. The first stage is a 6-months long, open-label study to evaluate dose safety and drug effects in 10 children, (ages 4 to 12 years), with a primary diagnosis of autism and a history of developmental regression. The subjects will be evaluated by a diagnostic/behavioral assessment and the extent of neuroinflammation judged by CSF cytokine/chemokine profiles before and after the 6-month treatment phase. Changes in CSF cytokine/chemokine profiles are the primary outcome variable for this small, open-label trial. If a predictive profile emerges from the Phase 1 investigation, then a double-blind, placebo-controlled trial will be implemented with 30 additional subjects. The primary outcome variable of that study will be behavioral change over time -- does minocycline administration produce meaningful behavioral improvements or advances in developmental progression? The last child finished the open-label trial during the reporting period. The Phase 1 data are currently being analyzed and a decision will then be made about the utility of the Phase 2 study. Additional information about the minocycline study can be found at: http://clinicalstudies.info.nih.gov/detail/A_2007-M-0024.html