2012:
- Novel Probiotic Therapies for Autism
- Intranasal Oxytocin for the Treatment of Children and Adolescents with Autism Spectrum Disorders (ASD)
2011:
2010:
2009:
- Reliability and Validity of Autism Assessments and Diagnosis Using Telemedicine
- Autism and Associated Neuro-Behavioral Functioning Among Patients in a Psychiatric Hospital
2012
Novel Probiotic Therapies for Autism
Posted October 9, 2012
Paul Patterson, Ph.D., California Institute of Technology
Interplay between the immune system and autism spectrum disorders (ASD) has been shown by a variety of studies, including epidemiological surveys and analyses of postmortem brains of individuals with ASD. This connection was successfully reproduced in an animal model of an ASD risk factor, maternal infection. In mice, maternal immune activation (MIA) during pregnancy leads to offspring with ASD features. Dr. Paul Patterson at the California Institute of Technology recently published a paper in PNAS, on a project led by graduate student Ms. Elaine Hsiao, reporting that offspring in the MIA model not only have ASD features (such as repetitive or stereotyped behaviors, decreased social interactions, and impaired communication) but also have indicators of inflammation that persist through adulthood. When these mice are given bone marrow transplants from typical mice (a process that should restore immune functioning), a reduction is seen in the behavioral impairments. These observations support the idea that the immune system may be a novel therapeutic target for individuals with ASD.
The Autism Research Program awarded Dr. Patterson and collaborator Dr. Sarkis Mazmanian an Idea Development Award in Fiscal Year 2010 to evaluate gastrointestinal (GI) changes in mice in the MIA model and to explore the potential for manipulation of the GI system with probiotics ("healthy" bacteria, here Bacteroides fragilis) to reduce inflammation and ameliorate ASD-like behaviors. In fact, the offspring of immune-activated mothers appear to display a striking GI pathology believed to be also found in many ASD children, "leaky gut syndrome." In this condition, the barrier of the gut lining allows molecules to leak from the gut into the bloodstream. In a paper currently under review, Ms. Hsiao, Drs. Patterson and Mazmanian, and their collaborators report that probiotic treatment (through food) of newly weaned MIA offspring restores GI function and results in significantly fewer ASD-like behaviors. Current work involves identifying the molecules that leak from the gut into the blood in MIA offspring, and testing whether any of these might be responsible for inducing the abnormal behaviors. Altering gut bacteria as a potential therapy to mediate ASD severity is an exciting possibility, one that has been anecdotally tried by individual families. Performing this study in a controlled environment is one of the first steps in better understanding if and how this type of treatment affects individuals with ASD behaviors.Links:
Public and Technical Abstracts: Novel Probiotic Therapies for Autism
Intranasal Oxytocin for the Treatment of Children and Adolescents with Autism Spectrum Disorders (ASD)
Posted April 5, 2012
Evdokia Anagnostou, MD, Holland Bloorview Kids Rehabilitation Hospital, Toronto, CA
Significant deficits in social cognitive skills, language and repetitive behaviors are prominent characteristics of children with Autism Spectrum Disorders (ASD). Furthermore, in comparison with other neurodevelopmental disorders, individuals with autism are much less likely to attend or orient their attention to social stimuli in their environment such as having eye-to-eye gaze, facial expression, and pointing gestures, that lack of which are considered early signs of autism.
There has not been any pharmacological treatment for mitigating the deficits in social cognition and related social functioning in children with ASD. The hormone oxytocin, originally known to help stimulate childbirth and breast-feeding, is a neurotransmitter and neuromodulator; it has a spectrum of central and peripheral effects. Animal studies and preliminary human studies have indicated oxytocin may play a role in social bonding, emotion regulation, repetitive and affiliated behaviors, and anxiety modulation. Furthermore, blood oxytocin levels are reported to be lower in children with ASD compared to those of typically developing children. The blood oxytocin levels in children with ASD remain unchanged, while those in typically developing children increase. In addition, recent research indicates an association between a single nucleotide polymorphism (SNP) in the oxytocin receptor gene (OXTR) and autism.
Dr. Evdokia Anagnostou, whose preliminary data suggested therapeutic potential of intranasal oxytocin (IN-OXT) for social cognition/functioning and repetitive behaviors in adults with autism, received a Fiscal Year 2009 Autism Research Program (ARP) Clinical Trial Award to determine the effects of IN-OXT on social cognition and related functions in older children and adolescent (ages 12-17) with ASD in a two-phase study.
Phase I is a 12-week prospective open label, randomized, dose finding study to examine safety and tolerability of 15 to 24 high functioning ASD individuals. Phase II is a randomized, double-blinded, placebo-controlled trial to evaluate the safety and efficacy of IN-OXT in 60 participants with ASD on social cognition and function. It is being conducted at two sites: Holland Bloorview Kids Rehabilitation and University of Illinois, Chicago, and is currently in progress with all regulatory documents being completed, and recruitment is ongoing (ClinicalTrial.gov Identifier of NCT01256060).
Dr. Anagnostou and her coinvestigator Dr Jacob hypothesize that the oxytocin treatment may be effective in children and adolescents in improving social cognition deficits. They will also test the hypothesis that those who have lower blood oxytocin levels before treatment but show an increase in oxytocin levels and dose-related tolerability during treatment, would be most likely to respond. Since there are no medications yet available to treat and improve the core symptoms of autism (social cognition and social functioning), the trial may have tremendous therapeutic impact for social deficits of ASD.
2011
Mechanisms of Mitochondrial Dysfunction in Autism
Posted March 31, 2011
John Shoffner, M.D., Georgia State University, Atlanta, Georgia, and Medical Neurogenetics, LLC, Atlanta, GeorgiaIn order to detect adenosine triphosphate (ATP) production within cells,
HEK293 cells were transfected with luciferase that is targeted to the cytoplasm
(pCyto-Luc) or is targeted to the mitochondria (pMito-Luc). Luciferase
targeted to these locations within the cells allows quantitation of ATP production with
the cytoplasm or the mitochondria. This technique is being used to quantitate
ATP production within the cytoplasm and within the mitochondia of cells from
patients with autistic spectrum disorders. These cells can be used to understand
cellular energetics defects in patients with ASD as well as to screen new drugs for their
ability to increase mitochondrial ATP production.
Localization of luciferase was detected using anti-luciferase antibody. Immunofluorescence
detection used confocal microscopy (63x magnification).Although all individuals with autism spectrum disorders (ASD) share difficulties in social interaction, communication, and behavior, the complex genetic and phenotypic variability that is observed may indicate the existence of multiple subgroups. Defining these subgroups is the first step to understanding the causes of ASD, developing effective treatments, and eventually finding a cure. One subset of individuals with ASD has defects in oxidative phosphorylation genes, resulting in mitochondrial disease. Oxidative phosphorylation is the process that produces energy for cellular function. Mitochondrial disease, which can affect all systems in the body, presents very differently from individual to individual. Organs that have high energy requirements and low energy reserves, such as the brain, are particularly susceptible to oxidative phosphorylation defects.
Although the cause is unknown, neurologic regression occurs in approximately 25% of children with ASD. Patients with mitochondrial disease are at increased risk for neurologic regression during periods of fever. As a recipient of a Fiscal Year 2008 (FY08) Autism Research Program (ARP) Concept Award, Dr. John Shoffner has used this funding to evaluate links to mitochondrial dysfunction and ASD regression. Performing a retrospective chart review of 28 patients who met the diagnostic criteria for both ASD and mitochondrial disease, Dr. Shoffner found that autistic regression occurred in 17 out of 28 patients (60.7%). Of those with autistic regression, 12 out of 17 patients had regressed with fever (70.6%), while 5 out of 17 patients with autistic regression could not be linked to a febrile event (29.4%). While the study was small and could not account for factors such as dehydration and other metabolic effects of fever, Dr. Shoffner demonstrated that a subgroup of individuals with mitochondrial defects may be at increased risk of autistic regression. Screening for oxidative phosphorylation defects in individuals with ASD may be necessary to further characterize this subset of the ASD population and to develop treatments for the dysfunction. Dr. Shoffner is currently working to develop a minimally invasive screening test to identify key indicators of oxidative phosphorylation defects in children with ASD. The test uses luciferase, an oxidative enzyme that converts ATP into light, targeted to the cytoplasm and mitochondria, to detect ATP production within the cells of patients with autism spectrum disorders caused by mitochondrial defects. This personalized medicine approach to ASD could allow rapid discovery of novel treatments for these children. Dr. Shoffner has received an FY09 ARP Idea Award to continue his research into the relationship between oxidative phosphorylation defects and ASD.
Autism Speaks voted Dr. Shoffner's research, published in the Journal of Child Neurology, as one of the top ten accomplishments in autism research for 2009.Publications:
Shoffner J, Hyams L, Niedziela-Langley G, Cossette S, Mylacraine L, Dale J, Ollis L, Kuoch S, Bennett K, Aliberti A, and Hyland K. 2010. Fever plus mitochondrial disease could be risk factors for autistic regression. Journal of Child Neurology 25: 429-34.
Links:
Public and Technical Abstracts: Mitochondrial Defects in Autism
Public and Technical Abstracts: Mechanisms of Mitochondrial Dysfunction in Autism
2010
Gestational Neuro-Immuno-Pathology Hypothesis
Posted October 29, 2010
Robert Vogt, Ph.D., Centers for Disease Control and Prevention (CDC)
Data and epidemiologic evidence from animal model studies indicate that predisposing genetic factors and aberrant brain development during gestation may contribute to autism spectrum disorders (ASD) pathogenesis. Neuroimmunomodulatory factors have been associated with the prenatal pathogenic process. Dr. Robert Vogt, recipient of an Idea Development Award from the FY07 Autism Research Program, and his team in the Newborn Screening Translational Laboratory at CDC are developing and evaluating assays to search for biomarkers of increased risk for ASD in newborn dried blood spot (DBS) samples. The researchers are testing the Gestational Neuro-Immuno-Pathology hypothesis, which proposes that autoimmune or cross-reactive antibodies in pregnant women transverse the placenta to the fetus and may disrupt normal development by reacting with brain tissue. To date, the assay that Dr. Vogt developed has been used to measure nerve tissue antigen-specific IgG antibodies in over 390 DBS samples from children who developed ASD, over 390 children with mental retardation, and over 625 matched (birth year, sex, and gestational age) controls. Unexpectedly, the researchers found that higher levels of the nerve tissue antigen-specific IgG antibodies were associated with a reduced risk of ASD. Specifically, this trend was observed in brain-derived neurotropic factor, glial fibrillary axonal protein, and myelin basic protein IgG antibodies. These findings may be attributed to the placentally transferred IgG acting as a blocking antibody and highlight the need for further studies.
Link:
2009
Reliability and Validity of Autism Assessments and Diagnosis Using Telemedicine
Posted August 14, 2009
R. Matthew Reese, Ph.D., University of Kansas Medical Center, Kansas City, Kansas
Autism is a complex developmental disorder that affects approximately 1 in 150 children. In order to initiate treatment as early as possible, it is extremely important to have the most accurate and appropriate diagnostic assessment tools available to qualified professionals. Evaluations for autism spectrum disorders (ASD) are particularly needed in rural communities as these areas have fewer qualified specialists. Dr. Matthew Reese, from the University of Kansas Medical Center Research Institute, received a fiscal year 2007 Autism Research Program Concept Award through the Department of Defense to explore the innovative use of telemedicine (interactive TV) to diagnose ASD in children. Dr. Reese will study the reliability and validity of autism assessments and diagnosis using telemedicine. This project highlights the need to empirically evaluate use of telemedicine for delivery of services to children with autism living in underserved areas. Telemedicine overcomes several barriers, including traveling for appointments, missing work, and accessing services from qualified specialists.
The proposed project will determine whether young children can receive an appropriate diagnosis through telemedicine. The American Academy of Neurology practice parameters for diagnosing autism indicate that adequate diagnosis includes a parent interview, such as the Autism Diagnostic Interview (ADI), and a structured observation of the child using a validated instrument such as the Autism Diagnostic Observation Schedule (ADOS; Filipek et al. 2000). The ADI and ADOS are considered gold standards instruments for use in diagnosing autism. These measures, along with a medical history and review of record, are used to determine whether the child meets the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), criteria for autism.
In this study, two clinicians will evaluate the children and participate in the parent interview through telemedicine, and two clinicians will conduct observations in the same room as the parents and child. For half of the families, the assessment will be directed by the two clinicians in the room. The other half of the assessments will be directed by the two clinicians via telemedicine. The reliability of autism measures (ADOS and ADI) will then be compared for those scored live versus those scored by telemedicine. Accuracy of diagnosis as well as patient satisfaction will also be evaluated. Dr. Reese hypothesizes that the reliability of measures, diagnostic accuracy, and patient satisfaction will not be significantly different when comparing telemedicine and live assessments, thus making telemedicine a viable option for assessing autism.
Publications:
Nesbitt TS, Rogers SJ, Rich BA, et al. 2006. Enhancing Mental Health Services to Children with Autism in Rural Communities. VC Davis Center for Health and Technology, Sacramento, California.
Marcin JP, Ellis J, Mawis R, et al. 2004. Using Telemedicine to Provide Pediatric Subspecialty Care to Children with Special Health Care Needs in an Underserved Rural Community. Pediatrics 113:1-6.
Filipek PA, Accardo PJ, Ashwal S, et al. 2000. Practice Parameter: Screening and Diagnosis of Autism: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society. Neurology 55:468-479.
Links:
Autism and Associated Neuro-Behavioral Functioning Among Patients in a Psychiatric Hospital
Posted June 29, 2009
David S. Mandell, Sc.D., University of Pennsylvania, Philadelphia
Published studies have estimated the prevalence of autism in adult psychiatric patients to be between 0.6% and 5.3%, with an even higher prevalence in those more severely affected. In psychiatric patients, fewer than 10% of cases were diagnosed with autism; most cases were commonly diagnosed with schizophrenia instead. Researchers speculate that autism is overrepresented and underdiagnosed because many hospitalized individuals received their diagnosis before advanced or updated criteria were in place. Current psychiatric patients are more clinically complex with fewer community alternatives to evaluation and treatment. In previous work, Dr. Mandell and colleagues have evaluated 350 state hospital patients for autism, using the Social Responsiveness Scale (SRS). Twenty-one percent (21%) received a score highly specific for autism spectrum disorder. While these findings are highly thought-provoking, more information is needed to determine whether these individuals truly meet criteria for autism or are experiencing the social and communication deficits sometimes associated with other psychiatric and developmental disorders. To this end, Dr. Mandell received a fiscal year 2007 Concept Award through the U.S. Department of Defense Autism Research Program to study autism and associated neuro-behavioral functioning among patients in a psychiatric hospital. Dr. Mandell will determine the prevalence of autism among psychiatric inpatients; validate a screening instrument for autism in an adult, psychiatrically impaired sample; and identify clinical and neurobehavioral characteristics that discriminate between adults with autism and other psychiatric disorders.
Publications:
Chang H, Juang Y, Wang W, Huang C, Chen C, Hwang Y. 2003. Screening for autism spectrum disorder in adult psychiatric outpatients in a clinic in Taiwan. General Hospital Psychiatry 25:284-288.
Nylander L and Gillberg C. 2001. Screening for autism spectrum disorders in adult psychiatric outpatients: A preliminary report. Acta Psychiatria Scandinavia 103:428-434.
Links:
