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: 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:

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U.S. National Institute of Mental Health
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Burbelo, Peter D; Swedo, Susan E; Thurm, Audrey et al. (2013) Lack of serum antibodies against Borrelia burgdorferi in children with autism. Clin Vaccine Immunol 20:1092-3
Pardo, Carlos A; Buckley, Ashura; Thurm, Audrey et al. (2013) A pilot open-label trial of minocycline in patients with autism and regressive features. J Neurodev Disord 5:9