Autism is defined by its behavioral manifestations: social-communication deficits 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 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. Evidence thus far supports that neuroimmune dysfunction may play prominent role in certain cases of autism, including those with a history of significant regression. If this hypothesis is correct, we would expect to find that at least some autistic children, particularly those with a history of regression, will have demonstrable abnormalities in immune function. Thus, we are continuing to collect data on a cohort of young children with autism that have been well-characterized and studied longitudinally. We are exploring immune markers in the CNS as well as peripherally. Finding new and effective treatments for autism is one of PDN's highest research priorities. One potential target was provided by a paper from Johns Hopkins University (D. Vargas et al, 2005) reporting that autopsy material from individuals with autism showed evidence of chronic brain neuroinflammation, as exemplified by activation of microglia and astroglia. The authors remarked that chronic microglia activation appeared to be responsible for a sustained neuroinflammatory response which could be producing neurotoxic factors. (Alternatively, neuroglial activation could occur in response to the presence of neurotoxins and thus represent the result, rather than the cause, of the injury.) The neuroinflammatory changes associated with neuroglial activation can be prevented by blocking nuclear translocation of the pro-inflammatory transcription factor NF-kappaB. Having completed an open-label trial of minocycline, an agent shown to inhibit NF KappaB, wherein neither immune markers (e.g. CSF and serum cyotkines and chemokines) nor behavioral status changed, we continue to explore targets for further pharmaceutical intervention. The phenotyping study (NCT 00298246) is also continuing efforts to identify individuals with evidence of ongoing neuroinflammation as a potential cohort for targeted therapeutic efforts. Markers under investigation include those that relate to direct evidence of immune dysfunction in relation to core symptoms of autism, as well as in relation to associated features, such as gastro-intestinal problems in a subset of children. Previously collected samples have also been used to demonstrate that, contrary to a highly publicized report, children with autism do not have circulating antibodies against Borrelia burgdorferi (as would be seen in Lyme Disease);nor was there any evidence of microbial translocation, which had been proposed as an etiologic factor in autism (the so-called "leaky gut" hypothesis). In both studies, there were no discernable differences between samples obtained from typically developing children and those from children with autism. More recently, serum samples have been obtained from mothers of children with autism or typical development in order to evaluate recent reports that maternal antibodies play a role in the etiology of autism. The antibody assays, and others, will commence when sample collection is completed over the next few months.

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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