Research

ARI Funded Research Studies (2007)

The Autism Research Institute (ARI) conducts, sponsors, and supports research on the underlying causes of and treatments for Autism Spectrum Disorder (ASD).

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 to 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 for people with ASDs here and now.

ARI is the only national autism organization to receive a four-star rating for fiscal responsibility from Charity Navigator.

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ARI funded the following research grant proposals in 2007:

MeHG/D-Penicillamine Experiment

This study involves two sets of experiments. The first set is designed to confirm a previous finding, that D-penicillamine reduces brain mercury, and to examine whether organic or inorganic mercury are excreted from an animal brain. The second set of experiments will be similar to the first set, except the animals will be autopsied at 1 day, 2 days, and 32 days of D-penicillamine treatment to determine if there is an initial increase in brain mercury, as is often observed with some chelating agents. In both sets of experiments, mercury levels will be measured in brain and kidney.

(PI: Vas Aposhian, Ph.D., Dept. of Molecular & Cellular Biology, University of Arizona.)

Autistic Enterocolitis: microscopic ileo-colitis in childhood and ileo-colonic Crohn’s disease in adulthood. Confirmation of endoscopical and histological evidence of a progressive inflammatory involvement of the bowel.

This two-year study aims: (1) to evaluate the prevalence of Autistic Enterocolitis with microscopic pattern in patients with regressive autism under 14 years of age, and to evaluate the prevalence of Autistic Enterocolitis with Crohn’s disease pattern in 40 consecutive patients over 14 years old with regressive autism; (2) to identify and evaluate a group of routine blood tests that could correlate with the intestinal disease and to evaluate the IBD serological and faecal markers in the two subgroups of patients; and (3) to evaluate any variations in the routine blood tests and IBD serological and faecal markers in the groups of patients who submitted to pharmacological therapy after 6 and 12 months of follow-up.

(PI: Federico Balzola M.D., Gastro-Epatologia Dipartimento Medico-Chirurgico delle Malattie dell’Apparato Digerente e della Nutrizione Azienda Ospedaliera Molinette C.so Bramante 86 10126 Torino, Italy.)

Improving the quality of life for people with autism and their families by integrating biomedical and behavioral approaches to address pain and illness.

Presently the field is undergoing a transformation to a “whole-body approach” to ASD in which biomedical factors, particularly those involving physical illness, are being closely examined for their impact on individuals’ functioning, and their families. Our research program at Developmental Disabilities Institute suggests that the integration of biomedical and behavioral approaches can result in benefits beyond those achieved by using either approach alone.

(PI: Edward Carr, Ph.D. , State University of New York at Stony Brook and Developmental Disabilities Institute.)

Markers of Inflammation and Oxidative Damage in Autism

The aim of this project is two-fold: (1) to study markers of oxidative stress in autism; and (2) to study whether anti-inflammatory response and/or immunological response is abnormal in autism.

To ascertain oxidative stress, we will analyze levels of ROS (free radicals) in the serum, levels of markers of oxidative damage to proteins and DNA in the plasma, and total antioxidant status in serum. With regard to anti-inflammatory responses, we will study inflammatory markers in autism by measuring (a) levels of acute phase proteins such as C-reactive protein, haptoglobin, alpha 1-antitrypsin, and also a2-macroglobulin in the serum from children with autism and controls; (b) complement cascade pathways of activation, i.e., classical, alternate and lectin pathways, and levels of different components of complement cascade (C3A, iC3b, C4a, C4d, C5A), membrane-attack complex (SC5b6789), and complement C1q- and C3d-containing circulating immune complexes will be studied in the serum of autism and controls; and (c) levels of different cytokines and chemokines in the plasma will be studied using Luminex technology. With regard to an imbalance in immune response, we will compare in the serum of autistic and non-autistic siblings the levels of different immunoglobulins and their subclasses: IgG subclasses (IgG1, IgG2, IgG3, IgG4), IgA subclasses (IgA1, IgA2) and IgM.

We will also examine the relationship between oxidative stress/ inflammation/ immune response and severity, and/or behavior and language problems in low-functioning and high-functioning autistic children. Analysis of levels of ROS, oxidative markers, APP, immunoglobulins, complement proteins and cytokines in relation to severity and behavior/ language abnormalities in different cohorts of autism will suggest whether the measurement of these parameters can be of value in supporting the behavioral diagnosis of autism. The relationship, if any, between these abnormalities and low- or high-functioning autism groups, as well as severity of behavior deficits in autism, will also be studied.

(PI: Abha Chauhan, Ph.D., Developmental Neuroscience Laboratory, NYS Institute for Basic Research in Developmental Disabilities.)

Enhancement of Tissue Procurement from Autistic Individuals

The focus of the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland is to retrieve brain tissue from individuals with developmental disorders, including autistic children, and matching controls. Our goal is to recruit four or five additional medical examiners. These tissue donations are critical to shorten the time until the causes of autism and other pervasive developmental disorders are known.

(PI: Kathleen M. Currey, M.D. and H. Ronald Zielke, Ph.D., University of Maryland, Baltimore, NICHD Brain and Tissue Bank for Developmental Disorders.)

Measuring HCY Thiolactone in autism

Homocysteine thiolactone (HcyTL) is a cyclic form of homocysteine (Hcy) that is produced as a “by-product” of the loading of amino acids onto transfer RNA (tRNA) during protein synthesis. There are two components of this research project: (1) develop a novel GC-MS or LC-MS-based assay for HcyTL; and (2) measurement of plasma HcyLT levels in autistic and normal control subjects.

(PI: Richard Deth, Ph.D. , Northeastern University.)

Methionine Synthase Status as an Oxidative Stress Biomarker

Initial studies will utilize cultured lymphoblasts to validate the utility of measuring methionine synthase modifications as indicators of oxidative stress status. Methionine synthase status in 8 pairs of lymphoblasts from autistic subjects and same-sex neurotypical siblings under normal growth conditions will be compared before and after induction of oxidative stress by blocking the synthesis of glutathione with buthionine sulfoxide (BSO) treatment. We will measure cellular levels of glutathione to confirm that they are lower after BSO treatment, and then use PCR to evaluate methionine synthase mRNA. We will utilize primer pairs directed against each of the five domains to determine if they are all present, or whether the Cap domain is absent. Primers directed against individual exons within the Cap domain will allow us to learn which specific exons are being removed by alternative splicing. Based upon our preliminary findings we hypothesize that the Cap domain will be partially spliced under normal growth conditions, but more extensively spliced under conditions of oxidative stress. In addition to providing information about alternative splicing of mRNA, the PCR assay will also indicate the overall amount of mRNA, a reflection of the level of transcription. If we did indeed observe changes in methionine synthase mRNA status, it would strongly suggest that alternative splicing of methionine synthase mRNA in blood cells might be a useful marker of oxidative stress status. In addition to mRNA analyses, we will assess the molecular size of methionine synthase in the 8 sib-pairs of lymphoblasts, to confirm absence of domains from alternative mRNA splicing, but also to determine whether additional domain deletion occurs at the level of the protein.

(PI: Richard Deth, Ph.D. , Northeastern University.)

Pilot test of Actos in autistic children: A double-blinded, placebo-controlled, crossover study on the effects of Actos on behavioral and metabolic measures in children with ASD

The goals of this study are: (1) to determine if treatment with Actos reduces behavioral abnormalities as assessed using the Aberrant Behavior Checklist (ABC) exam in children diagnosed with ASD; (2) to determine whether Actos will normalize plasma cytokine profiles; and (3) to determine if any measured improvements in behavior or cytokine levels are maintained for up to three months after stopping Actos treatment.

(PI: Douglas Feinstein, Ph.D., Department of Anesthesiology, University of Illinois.)

Impact of Innate Immunity on Regressive Autism

This study focuses on the dissection of intrinsic abnormalities of innate immune cells, and their effects on adaptive immunity and tolerance induction. Identification of innate immune abnormalities that might be biomarkers for identifying ASD children in whom development of ASD is strongly associated with neuro-immune interactions. This will include (1) an assessment of responses to TLR stimulants by isolated innate immune cells from ASD children; and (2) an assessment of cellular immune reactivity to common luminal Ags in ASD children.

(PI: Harumi Jyonouchi, M.D., Department of Pediatrics, UMDNJ-New Jersey Medical School.)

Rising Glutathione Levels in Children with Autism

The proposed study will examine the use of two supplemental programs to determine their efficacy in raising GSH levels in children with autism. These are: (1) Oral Lipoceutical GSH; and (2) Transdermal N-acetyl L-cysteine (NAC) + oral Vitamin B6 + oral Vitamin C. The aim is (a) to measure the change in GSH levels after a 6-week trial, (b) to examine tolerance and side-effect, (c) to monitor any changes in the symptoms of autism while on the supplemental programs.

(PI: Janet Kern, Ph.D. , Autism Treatment Center, Dallas, Texas.)

Neuronal Oxidative Stress in Autism; Characterization of CEP-modification as an oxidative stress marker in autistic brain

This study investigates whether episodic or sustained oxidative stress contributes to altered brain development and function, which then manifest as autistic behavior. The goal is: (1) to determine the differential content of CEP in various brain regions (both inside and outside of blood brain barrier) from autistic patients and to correlate alterations with morphological abnormalities, behavioral deficits or onset of autism; (2) to determine the association of CEP with abnormal systems in autism by double-staining for GABA-ergic, glutamatergic, cholinergic, and oxytocin receptors, as well as glutamic acid decarbosylase (GAD) and reelin; and (3) to determine the proteins modified by CEP in autistic brain.

(PIs: Woody McGinnis, M.D. , Ashland, Oregon, and Xiongwei Zhu, Ph.D. , Dept of Pathology, Case Western University, Cleveland, Ohio.)

Support for Several Studies

These studies include: (1) a pilot study examining methylation abnormalities and oxidative stress in children undergoing hyperbaric therapy; (2) a study comparing metabolic organic acid profiles in urine of children with Autism Spectrum Disorder to 50 control (healthy, non-autistic) children; and (3) a study to compare the prevalence of Rh-negativity in mothers of children with neurodevelopmental disorders vs. children with normal development.

(PI: Elizabeth Mumper, M.D., The Rimland Center, Lynchburg, Virginia.)

Brain region-specific oxidative stress in autism: standardization of tissue protocols and evaluation of potential artifacts

The proposed studies will test the hypothesis that elevated oxidative stress in autism is brain-region specific. By measuring oxidative-stress markers in diverse regions of brain, we will begin the first quantitative mapping of oxidative changes in autistic brains. The hypothesis will be tested using both postmortem human brain tissue from autistic and control cases, and rat brain tissue isolated from neonates exposed to neurotoxins (LPS, MSG, and Hg) during the critical developmental period (postnatal days 4-7) corresponding to the last trimester of human pregnancy. The specific aims are: (1) to standardize tissue protocols for measuring oxidative stress markers; (2) to evaluate potential artifacts in assessing oxidative stress markers in brain tissue; and (3) to compare the region-specific distribution of oxidative-stress markers in autistic and control brains, and in animals exposed to neurotoxins known to exert oxidative effects in brain.

(PI: Elizabeth Sajdel-Sulkowska, D.Sc. , Assistant Professor of Biochemistry, Dept. of Psychiatry, Harvard Medical School, Boston, Mass.)

Use of Probiotics to prevent the recurrence of autism in sibpairs

This is a pilot study using a comparison of reported recurrence of autism in families (7-10%) versus those who have at least one child with autism whose newborn sibling gets treatment in our study with probiotics (VSL#3). Probiotics have been used safely in infants to prevent allergy onset. These products have been used safely anecdotally in children with autism who have abnormal bowel symptoms. VSL#3 has been studied in ulcerative colitis, Crohn’s Disease, and Irritable Bowel Disease, and shown to be safe and effective. VSL#3 has been shown to colonize the gut microflora during the period of time it is taken.

(PI: Gene Stubbs, M.D., Professor Emeritus of Psychiatry and Pediatrics, Oregon Health & Sciences University.)

Efficacy of neuromodulation technique with children diagnosed with autism.

The purpose of this study is to determine whether neuromodulation technique (NMT) is effective in reducing maladaptive behaviors and increasing adaptive behaviors in children diagnosed with autism. This is a pilot, Phase I Study: Treatment, Randomized, Wait-list Control. This is project is part of an international (US, Canada, Mexico), multi-site and interdisciplinary study.

(PI: Robert H. Weiner, Ph.D. , Dallas, Texas.)