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 as many as 1 in 100 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 children are reported to have had a period of normal development and then began losing social and communication skills. The clinical course of regressive autism (particularly when it occurs acutely or semi-acutely) is consistent with alterations in immune function that are impacting on the central nervous system. If this hypothesis is correct, we would expect to find that at least some autistic children with a history of regression will have demonstrable abnormalities in immune function. These abnormalities are not expected to be found among autistic children without a regressive course;nor should they be present in the contrast groups of typically developing children or children with non-autistic developmental delays. 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. Minocycline has been shown to inhibit NF-kappaB production and has been used with modest benefit in a number of neuroinflammatory disorders. We undertook an open-label trial of minocycline to determine if the drug might have an effect on autistic behaviors or change patterns of distribution for the CSF or serum cytokines or chemokines. Minocycline produced no discernable improvements in the children's developmental trajectory or overall behavior;it also failed to significantly change the patterns of cytokines or chemokines in CSF or serum. Thus, no further investigations are planned for minocycline, but the search for novel therapeutic agents continues in other PDN projects. The phenotyping study is also continuing efforts to identify individuals with evidence of ongoing neuroinflammation as a potential cohort for targeted therapeutic efforts. A number of anecdotal reports have linked autism with gastrointestinal (GI) dysfunction;most notable among these are reports that autism is associated with """"""""leaky gut"""""""" syndrome. Microbial translocation (MT) is the process by which bacteria or microbial byproducts permeate through the wall of the GI tract (or other abnormally porous mucosal barriers) into the bloodstream. The microbial byproducts would then stimulate the immune system, which could have secondary effects on CNS functioning, or the byproducts could have a direct neurotoxic effect. We conducted assays of MT products in children with autism (from blood and CSF), as well as typically developing children (blood samples only). MT markers were not found in the blood or CSF of children with autism and there were no overall differences found between children with autism and the age-matched typically developing children who served as their controls. Although these results would appear to rule out the """"""""leaky gut"""""""" syndrome as a cause of autism, GI dysfunction was not a major problem for any of the children studied. Therefore, it is possible that our results were negative only because our sample didn't include patients with GI-neuro-immune dysfunction. Our ongoing phenotyping studies will be used to identify a cohort of children with autism who also have significant gastrointestinal symptoms in order to address this potentially important subgroup of patients.
| 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 |
