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: 7969477
• 负责人: Susan Swedo
• 金额: $ 34.81万
• 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/7969477
• 关键词: Affect; Age; Age-Months; American; Amyotrophic Lateral Sclerosis; Antibiotics; Astrocytes; Autistic Disorder; Behavior; Behavior assessment; Behavioral; Biological Assay; Biological Markers; Brain; Cerebrospinal Fluid; Child; Chronic; Clinical; Communication; Data; Development; Developmental Delay Disorders; Diagnosis; Diagnostic; Dose; Environmental Exposure; Environmental Risk Factor; Evaluation; Family; Fetal Development; Functional disorder; Genetic; Goals; Growth Factor; Human; Huntington Disease; I-kappa B Proteins; Immune System Diseases; Impairment; Individual; Inflammatory; Injury; Investigation; Learning; Life; Literature; Magnetic Resonance Imaging; Measures; Mediator of activation protein; Medical; Microglia; Minocycline; NF-kappa B; Nature; Neurologic; Nuclear Translocation; Pattern; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phenotype; Play; Prevalence; Production; Public Health; Recording of previous events; Reporting; Research; Role; Safety; Specificity; Staging; Structure; Symptoms; Time; Tissue Sample; autism spectrum disorder; autistic children; chemokine; cytokine; design; double-blind placebo controlled trial; effective therapy; immune function; interest; mouse model; neurobehavioral; neuroinflammation; neuropathology; neuropsychological; neurotoxic; novel therapeutic intervention; open label; placebo controlled study; primary outcome; response; skills; social; social communication; suspected autism; transcription factor; treatment effect; treatment trial

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

自闭症是通过其行为表现来定义的：社交缺陷、交流障碍以及存在受限或重复的行为。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。自闭症患病率的上升(最近一次报告影响到大约每150名儿童中就有1人受到影响)，以及这些症状的终生、往往使人虚弱的性质，共同使自闭症谱系障碍成为一个主要的公共卫生问题。增加我们对症状原因和本质的理解的研究，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，包括观察脑脊液细胞因子和趋化因子的异常模式，以及ASD患者慢性神经炎性改变的病理报告。神经免疫功能障碍被认为是退行性自闭症的一个潜在的病因，在一段典型的发育期之后，社交和沟通技能的丧失。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变化。这些儿童是PDN分部正在进行的一项大型表型研究的重点。我们希望发现至少一些患有发育退化和自闭症的儿童在免疫功能方面存在明显的异常。这些异常预计不会在没有倒退病程的自闭症儿童中发现，也不会在典型的发育中儿童或有发育迟缓(没有自闭症症状)的儿童中发现。 在表型研究中，首先对12-48个月大的儿童进行评估，然后向前跟踪观察各种指标随时间的变化，包括综合行为、神经心理、医学和神经学评估，以及对脑脊液细胞因子和趋化因子、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的评估。这项研究还评估了无退化史的自闭症儿童、发育迟缓的儿童和具有典型发育的儿童，以确定退行性自闭症儿童研究结果的特异性。受试者招募工作正在进行中，有兴趣的团体可通过以下网址了解更多有关这项研究的信息： 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。D.Vargas等人(Johns Hopkins)2005年的一项研究表明，患有自闭症并有神经发育退化史的人有慢性脑神经炎症的证据，例如在组织样本(脑库)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性细胞因子和生长因子的异常产生。作者评论说，慢性小胶质细胞的激活似乎是导致持续的神经炎性反应的原因，这种反应促进了许多神经毒性介质的产生。慢性神经胶质细胞激活可能是胎儿发育模式异常持续的结果。在这种情况下，神经胶质细胞的激活可能在启动和维持自闭症的神经病理中发挥作用。或者，神经胶质细胞的激活可能是对继发性神经毒性因子(S)的反应，因此，它代表了损伤的结果，而不是损伤的原因。 神经胶质细胞的激活需要促炎转录因子NF-kappaB的核转位。抗生素米诺环素似乎能够阻止核因子-kappaB核转位，从而抑制小胶质细胞的激活。这种抑制已被证明在肌萎缩侧索硬化症(ALS)和亨廷顿病的小鼠模型中具有神经保护作用，并已被报道在两年内稳定人类的病程(Bonelli，R.M.等人)。(2004)。为了确定米诺环素是否对自闭症有类似的益处，进行了两个阶段的研究。第一阶段是一项为期6个月的开放标签研究，以评估10名儿童(4至12岁)的剂量安全性和药物效果，这些儿童最初被诊断为自闭症，有发育退化史。受试者将在6个月的治疗阶段之前和之后通过诊断/行为评估和脑脊液细胞因子/趋化因子图谱判断神经炎症的程度来进行评估。脑脊液细胞因子/趋化因子图谱的变化是这项小型开放试验的主要结果变量。如果从第一阶段研究中出现预测性特征，那么将实施一项双盲、安慰剂对照试验，另外还有30名受试者。这项研究的主要结果变量将是随着时间的推移而发生的行为变化--米诺环素的应用是否产生了有意义的行为改善或发育进展？最后一名儿童在本报告所述期间完成了开放标签试验。目前正在分析第一阶段的数据，然后将就第二阶段研究的效用做出决定。有关米诺环素研究的更多信息，请访问：http://clinicalstudies.info.nih.gov/detail/A_2007-M-0024.html。