The Autism Research Institute (ARI) conducts, sponsors, and supports research on the underlying causes of, and treatments for, Autism Spectrum Disorders (ASDs). In order to provide parents and professionals with an independent, unbiased assessment of causal and treatment efficacy issues, ARI seeks no financial support from government agencies or drug manufacturers.

We therefore rely on the generosity of donors so that we may continue to advance autism research. Our founder Dr. Bernard Rimland would often say, ‘Research that makes a difference!’ to remind us of the need to focus on what might be beneficial here and now for people with ASDs.

Elevated urinary p-cresol in small autistic children: causes and consequences

Antonio M. Persico, M.D.
Child and Adolescent Neuropsychiatry Unit Laboratory of Molecular Psychiatry & Neurogenetics University Campus Bio-Medico, Rome, Italy

The purpose of the study is to investigate the origin of elevated urinary p-cresol in small autistic children. This elevation in urinary p-cresol could be due to several causes, such as gut infection with C. difficile or other cresol-producing microorganism, frequent antibiotic use selecting cresol-producing bacteria, slow intestinal transit time, and/or enhanced environmental exposure. We also plan to study the behavioral effects of acute p-cresol administration in BTBR mice as well as the effects of p-cresol and p-cresylsulfate at the cellular level.

Durability and Neuroplasticity Changes From Cognitive Enhancement Therapy in Adults with Autism Spectrum Disorders

Shaun M. Eack, Ph.D., David E. Epperson Associate Professor, School of Social Work and Department of Psychiatry, University of Pittsburgh

The purpose of this study is to perform durability neuroimaging assessments, preprocessing, and analysis in 17 adults with autism from our clinical trial of Cognitive Enhancement Therapy (CET). Early results are showing significant neuroplasticity changes in the prefrontal cortex associated with CET, and provide the first evidence that long-term cognitive remediation can improve brain function in adult autism.

Study of Vitamin D during Pregnancy to Prevent the Recurrence of Autism in Newborn Siblings

Eugene Stubbs, M.D., Professor Emeritus, Oregon Health Sciences University

This study was based upon Dr. John Cannell’s article in Medical Hypotheses in 2008 suggesting that Vitamin D deficiency during pregnancy may contribute to autism. This is a single arm prospective study using vitamin D during pregnancy of mothers who already have one or more children with autism to prevent the recurrence of autism in newborn siblings.  Data analysis is ongoing.

Detection of a toxin-producing Clostridium in the gut flora of autistic children

Sydney M. Finegold, M.D., Staff Physician, Infectious Diseases Section, VA Greater Los Angeles Healthcare System, Emeritus Professor of Medicine, UCLA School of Medicine, Emeritus Professor of Microbiology, Immunology, & Molecular Genetics, UCLA

Microbiological studies revealed a higher incidence and higher counts of clostridia in autism samples compared to control samples and a significantly reduced overall bacterial diversity in the feces of the autistic group children. Research includes quantitative, selective anaerobic culture from stool specimens of 22 children diagnosed with autism and 12 control children.

Biorepository of Blood, Stool and Mucosal Samples from the Gastrointestinal Tracts of Persons with Autism

Harland Winter, M.D., Director, Pediatric Inflammatory Bowel Disease Center, Masachusettss General Hospital for Children

Autism Research Institute has supported the collection of samples of blood, stool and mucosal samples from the gastrointestinal tract of children with autism.  The biorepository currently has biological specimens from over 1200 children with various gastrointestinal disorders including over 100 children with autism.  These samples are being used by investigators who are studying: (i) specific metabolic pathways that could contribute to causes of autism; (ii) genetic markers; (iii) the microbiome in both the colon and the upper gastrointestinal tract; (iv) serologic markers that might lead to diagnostic indicators of disease; and (v) the effects of gluten- and casein-free diets on behavior, metabolic pathways, and the intestinal microbiome.  This biorepository with samples from children with autism would not be possible without the support of ARI.

MIG-6 tumor suppressor gene protein and ERK 1 and 2 and their association with EGF and EGFR in autistic children

AJ Russo, Visiting Assistant Professor of Biology, Hartwick College

There is compelling evidence, including data that the EGFR/ERK pathway, associated with cell growth, differentiation and division, may be associated with the etiology of autism. In some cancers, the MIG-6 suppressor gene protein is decreased, resulting in high EGFR levels and high ERK. This results in increased and unregulated cell division. Preliminary data has resulted in the following paper: Russo AJ Decreased Mitogen Inducible Gene 6 (MIG-6) Associated with Symptom Severity in Children with Autism Biomarker Insights 2014 Oct 6;9:85-9. doi: 10.4137/BMI.S15218. eCollection 2014. Free PMC Article

Neuregulin 1 (NRG1) in autistic children

AJ Russo, Visiting Assistant Professor of Biology, Hartwick College

This study is measuring NRG1 in the plasma of autistic children and controls. We will compare these levels with EGF, EGFR and ERK 1 and 2 levels, as well as symptom severity, already established in these same individuals in earlier studie; the previous studies detected decreased levels of EGF and increased plasma EGFR in children diagnosed with autism. Because of the potential relationship of NRG1 with EGF and EGFR, and the significance of these relationships in the etiology of Parkinson’s and Schizophrenia, as well as the significance of the therapeutic potential of NRG1 in these disorders, the researchers hypothesize that NRG1 may play an important role in the etiology of autism, and may become a potential therapeutic modality.

Anti-GAD antibodies in autism

AJ Russo, Visiting Assistant Professor of Biology, Hartwick College

There is evidence suggesting that Glutamic acid decarboxylases (GAD65 and GAD67)  may serve as an autoantigen in anti-GAD associated diseases. GAD may be a presynaptic autoantigen, and is generally thought to play a key role in Stiff Person Syndrome. Researchers are using ELISAs to measure the presence of anti-GAD65 and 67 antibodies in another younger group (mean age 2-3 years) of children with autism, non-autistic siblings, as well as in their mothers, from 10 families. If antibodies are detected, western blot analysis will be used to confirm specificity to either GAD65 or GAD67. We expect to confirm a relationship between GAD in mothers and anti-GAD in their children with autism.

Elevated serum neurotensin and CRH levels in children with autistic spectrum disorders and tail-chasing Bull Terriers with a phenotype similar to autism.

Principal Investigator, Theo Theoharides, M.D., Department of Psychiatry, Tufts University School of Medicine and Tufts Medical Center, Boston, MA, USA

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by defects in communication and social interactions, as well as stereotypic behaviors. Symptoms typically worsen with anxiety and stress. ASD occur in early childhood, often present with regression and have a prevalence of 1 out of 68 children. The lack of distinct pathogenesis or any objective biomarkers or reliable animal models hampers our understanding and treatment of ASD. Neurotensin (NT) and corticotropin-releasing hormone (CRH) are secreted under stress in various tissues, and have proinflammatory actions. We had previously shown that NT augments the ability of CRH to increase mast cell (MC)-dependent skin vascular permeability in rodents. CRH also induced NT receptor gene and protein expression in MCs, which have been implicated in ASD. Here we report that serum of ASD children (4-10 years old) has significantly higher NT and CRH levels as compared with normotypic controls. Moreover, there is a statistically significant correlation between the number of children with gastrointestinal symptoms and high serum NT levels. In Bull Terriers that exhibit a behavioral phenotype similar to the clinical presentation of ASD, NT and CRH levels are also significantly elevated, as compared with unaffected dogs of the same breed. Further investigation of serum NT and CRH, as well as characterization of this putative canine breed could provide useful insights into the pathogenesis, diagnosis and treatment of ASD.

Abnormalities in signal transduction in autism

Principal Investigator: Ved Chauhan, Ph.D.

G-proteins and several protein kinases such as protein kinase C (PKC), phosphatidyl inositol 3-kinase/phosphoinositide-dependent kinase/Akt have been implicated in the synaptic plasticity and in neuropsychiatric disorders such as mood disorder, depression, and suicide. This study’s authors suggest that complexity of behavioral domains in autism may be associated with altered cellular signaling. Considering the upstream role played by protein kinases and phosphoinositides in synaptic plasticity, the aim of this study is to investigate the hypothesis that the development of autism may be due to a defect in G-protein-coupled receptor-mediated intracellular signal involving protein kinases. The primary goal is to study signal transduction pathways involving G-proteins-coupled protein kinases in the frontal cortex of children with autism/regressive autism, and age-matched control subjects, and to investigate if these changes in behavioral parameters are associated with autism.

Neuropathology of the Shank3 mouse model for autism

Casanova MF, Sokhadze E, Opris I, et al.

Researchers, working in collaboration with Drs. Guoping Feng and Yang Zhou, both from MIT, are studying the neuropathology of their Shank3 mouse model for autism. The Shank3 mutation is associated with the Phelan-McDermid Syndrome which has a high prevalence of syndromic autism.Some of the more exciting findings of our research thus far indicate significant differences in the autism models in lamination thickness of the upper layers 2/3 and of cell density within minicolumns (i.e., a basic arrangement of circuits within the cerebral cortex) in those layers. In addition, in the homozygous autism mutant model, in which both alleles of Shank3 are impaired, we found that layer 4 was also significantly thinner compared to wild-type control. Significant differences were not noted in the schizophrenia models so far, although there was a trend towards increased cell density within minicolumns in layers 2/3. Overall, these results suggest that there are indeed disturbances to neocortical development in the Shank3 autism models, a finding not yet reported in the literature, and that these disturbances likely occur early in development. There are some features consistent in the autism models with focal cortical dysplasia type 1, a neuropathological finding often associated with epilepsy and/or intellectual disability. These include features such as the laminar thinning, as well as extensive overlap of cell bodies to the extent not seen in wild-type layers 2/3. Features of focal cortical malformations of various types have been consistently noted in postmortem findings in those with autism. Our hope is to be able to translate the findings into a potential therapeutic intervention for individuals with the Phelan-McDermid Syndrome using Transcranial Magnetic Stimulation just as we did for autism (Casanova et al., 2015). Depending on the mutation the Shank3 mutant mouse has been labeled a model for either autism or schizophrenia. Casanova MF, Sokhadze E, Opris I, et al. Autism spectrum disorders: linking neuropathological findings to treatment with transcranial magnetic stimulation. Acta Paediatr [Epub ahead of print] doi: 10.1111/apa.12943

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