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. 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 particularly likely 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. We are evaluating this hypothesis through a combination of phenotyping investigations and treatment trials.? ? The current phenotyping investigation is evaluating children with regressive autism and expects to find that at least some children have demonstrable abnormalities in immune function. These abnormalities will not be found among autistic children without a regressive course nor will they be found among typically developing children. ? ? The specific aims of the study are: ? Specific Aim #1: To characterize the immune response in children with autism.? Working Hypothesis 1a: Distinct immunologic responses and cytokines abnormalities will be evident in children in the regressive autism sample, but not in the non-regressive autism or typically developing samples.? Working Hypothesis 1b: MRI scans will reveal regional neuroinflammation among children in the regressive autism sample, but not in the non-regressive autism or typically developing samples.? ? Specific Aim #2: To identify neurobiologic markers for autism through the techniques of metabolomics, proteomics and genomics (e.g. gene expression profiles).? Working hypothesis: These neurobiologic markers will reliably differentiate between children with autism and typically developing children.? ? The phenotyping investigation is a natural history study in which children are first evaluated between 12-48 months of age and then followed forward to look at changes in symptom presentation over time. The baseline evaluations include 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. 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 recent study by Vargas and co-workers at Johns Hopkins has demonstrated that the regressive subtype of autism is associated with 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 these responses were similar to those seen in some neurodegenerative disorders such as amyotrophic lateral sclerosis, and that chronic microglia activation appears to be responsible for a sustained neuroinflammatory response that facilitates the production of multiple 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 may only be a secondary response to the initiating causal factor(s) and not a direct effector of injury. Since neuroglial activation requires the nuclear translocation of the pro-inflammatory transcription factor NF-kappaB, and since inhibitors of NF-kappaB with good CNS penetrance are available, the role of neuroinflammation in initiating and sustaining the autistic condition can be probed. ? ? The antibiotic minocycline is a powerful inhibitor of microglial activation, apparently through blockade of NF-kappaB nuclear translocation. Minocycline is 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 evaluate the potential for benefit of minocycline treatment of autistic children, we are conducting an open-label trial. The trial is a 6-months long, open-label study that will evaluate dose safety and efficacy 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. If the results of this open-label trial are encouraging, we will conduct a double-blind, placebo-controlled 6-month trial in 30 additional subjects. ? ? Subjects are currently being enrolled in the open-label phase of the investigation. Additional information about the study can be found at: http://clinicalstudies.info.nih.gov/detail/A_2007-M-0024.html
