Fifth-Annual IMFAR: The Full Report

Families continually ask how we can push research forward, that is, how we can make progress faster. Six years ago, having scientists who were studying autism from all different perspectives meet in one place at one time, and having them share their findings, was considered

a dream. Today, this occurs on an annual basis and is called The International Meeting for Autism Research (IMFAR), which convened for the fifth time June 1 through June 3 in Montreal, Canada. There were 21 presentations by Cure Autism Now grant recipients as well as 27 presentations regarding research conducted using data from CAN's Autism Genetic Resource Exchange (AGRE). Overall, a record 936 people attended the 2006 IMFAR. This year the conference organizers implemented a new structure to encourage even more interaction and learning opportunities among participants. The change allowed for fewer overlapping symposia and keynote speakers highlighting different areas of autism research to open each day of the conference.

Keynote Speakers Set the Tone

The first keynote speaker was Thomas Insel, M.D., Director of the National Institute of Mental Health. Dr. Insel reviewed the landscape of autism research and set the tone for the conference by stressing the need for a greater sense of urgency in the field of autism. At the outset of his address, Dr. Insel stated that autism is currently recognized as a developmental brain disorder. Although it is accepted that genetics play a role in the development of autism, no genuine candidate genes have yet been identified and environmental factors are also likely involved in the development of the disease.
Because autism is a developmental brain disorder, Dr. Insel called for the expansion of the field of autism research to include developmental neurobiologists, stating that the tools of developmental neurobiology had not yet been applied to autism. Dr. Insel then addressed some of the roadblocks to autism research including the lack of a good understanding of the pathogenic mechanisms that lead to the disorder. Understanding what's broken on a systems level is complicated by the diversity of the autism phenotypes. In addressing this phenotypic heterogeneity, he stated that autism may actually be many disorders with one final common pathway, thus highlighting the importance of knowing when and how development goes off track. Dr. Insel pointed to the use of the Human HapMap, part of the Human Genome Project, as a method that researchers can apply to recognize genomic lesions specific to autism. Identifying genomic lesions, Dr. Insel stated, gets to the root of the biochemical pathways that are malfunctioning in autism and may ultimately provide targets for treatment.

Finally, Dr. Insel discussed a research vision for autism and referred to the
Autism Matrix [1]
(click on the link for the PDF of the report on the Autism Matrix). Currently autism is diagnosed psychologically by observation of atypical behaviors, and treatment begins well after onset of the disease. The research vision includes identifying the pathogenic mechanisms involved in autism, developing a biological diagnostic tool, treatment of the core pathology of autism, and ultimately strategic prevention and therapeutics. At the end of his address, Dr. Insel encapsulated the goal and direction of autism research, “We need to make the research work to alleviate the burden of disease.”

In her presidential address on the second day, International Society for Autism Research (INSAR) governing board president, and CAN grantee, Sally Rogers, Ph.D. from the M.I.N.D. Institute and UC Davis summarized what the field has learned about one of the earliest features seen in autism: imitation difficulties. Dr. Rogers highlighted that evidence indicates that imitation difficulties are not likely due to motor or memory impairments. She pointed out that children with autism are able to imitate when they are consciously aware of the goal of the task. What autistic children seem to have difficulty with is automatic social mimicry, a type of imitation that both children and adults do unconsciously when they are speaking to others. This has important implications for therapies—if children are able to imitate, they can be taught how to use imitation for social purposes in conversations. Dr. Rogers also drew attention to how current research in the area of mirror neurons, recently found to be abnormally functioning in autism, could provide insight into potential mechanisms for mimicry, allowing us to better understand the biological underpinnings of the disorder.
The final day's keynote speaker, Conrad Gilliam, Ph.D., professor from the University of Chicago, and AGRE Advisory Board Member, described an interesting new technology that could provide a new direction in genetics research—studying genes as a network instead of just studying single genes in isolation. Dr. Gilliam suggested that such an approach could be quite profitable for a disorder such as autism which most likely has multigenic origins. This technique may also provide a promising way in the future to bring together and integrate the emerging findings from genetic studies. Ultimately, understanding the pathways that are targeted by genetic susceptibilities would also allow us to search for the potential environmental contributors that can affect the presentation of the disorder.

Key Themes Highlighted in Symposia and Presentations

The themes highlighted in Dr. Insel's opening keynote speech were reflected in the focus of the symposia and scientific presentations during the three day conference. Scientific presentations at various sessions throughout the meeting addressed topics in the areas of early diagnosis/detection, diagnostic assessments, services, early development, brain structure and neurophysiology, fMRI, cognition/perception, genetics, biomedical issues and repetitive behaviors. The educational symposia, intended to help young researchers and others from outside the field become familiar with autism science, this year included sessions on: early detection, psychopharmacology, psychosocial interventions, genetics, neuroimaging, and animal models. This year for the first time, there was also a special symposium on Epidemiology which included a presentation by Marshalyn Yeargin-Allsop, M.D. from the Centers for Disease Control. Both the educational symposia and research presentation sessions offered a vast array of new findings. Some of the intriguing new findings and perspectives are highlighted below.

The psychopharmacology symposium provided a useful analysis of currently available pharmaceutical treatments for autism. Lawrence Scahill, Ph.D. of the Yale University Child Study Center provided an overview of the currently available pharmaceutical treatments that have been used to treat the core symptoms of autism. Dr. Scahill addressed limitations of clinical trials using pharmaceutical interventions for autism. Most of the reported clinical trials have had small sample sizes. To date clinical trials have examined the efficacy of treatment vs. no treatment or placebo. Although at times it appears that the treatment is effective, Dr. Scahill noted that in some trials of drug treatments for autism the placebo group also shows improvement. Dr. Scahill stressed that for pharmaceuticals to be developed more rapidly, the methods for measuring improvement should be sufficiently sensitive to detect the improvement in symptoms that occur as a result of the medication.
Michael Aman, Ph.D. a psychologist from Ohio State University presented an overview of the use of methylphenidate for the treatment of autism. Dr. Aman and colleagues have now conducted a trial using methylphenidate with a larger group of children than in previous studies. Their results supported what has been shown previously with this medication–roughly half of the children taking it showed improvement in symptoms. The main side effect reported in Dr. Aman's study was irritability. Dr. Aman recommended that future trials of pharmaceutical interventions for autism need to incorporate methods for comparing clinical phenotypes of children who respond to medication to children who do not respond. Such comparisons may help resolve questions of why some autistic children show improvement with medication while others do not.

CAN Treatment Advisory Board member, Evdokia Anagnostou, M.D., from Mount Sinai School of Medicine ended the psychcopharmacology symposium with an overview of the available pharmaceutical treatments for autism. Much of Dr. Anagnostou's talk centered on the drug memantine which is commercially known as Namenda and currently used as a treatment for Alzheimer's disease. Memantine acts to partially block a particular type of nerve cell receptor when they are over stimulated by the excitatory neurotransmitter glutamate. Too many excitatory signals can be harmful to nerve cells and may result in excitotoxicity, which can lead to nerve cell dath. While there is a clear role for excitotoxicity in the pathogenesis of Alzheimer's disease, it is unclear whether or not excitotoxicity is involved in the pathogenesis of autism. Yet, Dr. Anagnostou described reports of improved compliance behaviors in children who have tried memantine although the efficacy of memantine for ameliorating symptoms of autism has not yet been studied in a controlled clinical trial. Fortunately, several clinical trials studying different features of memantine action on autism are slated to begin this year, including a multi-site trial sponsored by CAN in which the effects of memantine on motor planning and expressive language will be specifically examined by investigators participating in CAN's new autism Clinical Trials Network.

The usefulness of animal models as a means to study features of autism was the focus of an entire symposium. Any animal model designed for the study of autism must confront the difficulty of generalizing a limited set of atypical behaviors in animals to the complex variety of atypical behaviors seen in people living with the disorder. Historically, the field of autism has lacked an adequate animal model for study of the disorder. More recently, mouse models have been designed to specifically reflect some of the neurological abnormalities observed in autism. Emanuel DiCicco-Bloom, Ph.D. from NAAR and the University of Medicine and Dentistry, New Jersey (UMDNJ) presented data from the Engrailed 2 knock-out mouse model. Engrailed 2 (En2) is a gene that is found on chromosome 7 and is believed to be involved in the proper development of the cerebellum. A previous study using samples from the AGRE database by Benayed and colleagues found that the En2 gene was associated with autism. An intriguing finding reported from Dr. DiCicco-Bloom's mouse model was that mice lacking the En2 gene developed abnormalities in the cerebellum similar to those seen in autism. Dr. DiCicco-Bloom's group cultured cells from the En2 knock-out mice and found that cerebellar granular cells lacking the En2 gene appeared to undergo excessive cell division. Dr. DiCicco-Bloom suggested that any alterations in the En2 gene may lead to improper regulation of the activity of cellular growth factors that may impact the development of the cerebellum.

One of the current gaps in the field of autism addressed during the conference was the need to establish an early biological diagnostic marker of the disease. During the Early Detection symposium Sally Ozonoff, Ph.D. from the University of California, Davis and M.I.N.D. Institute presented findings from the Infant Sibling Study and discussed the limitations of using behavioral markers as predictors of the disease. The Infant Sibling Study examined the reliability of behavior patterns observed during the first year of life (eye gaze, pointing, and response to name) as predictors for an autism diagnosis. Dr. Ozonoff reported that within the first year many children on the autism spectrum have normal language and social interaction. Among the different behaviors studied, only “response to name” adequately differentiated children with autism from typically developing children. Dr. Ozonoff cautioned that response to name, if used as a screening tool, is not a perfect predictive marker of autism in the first year of life, thus highlighting the need for biological markers.

One method currently being investigated for use as an early diagnostic marker for autism is analysis of maternal blood for the presence of antibodies to fetal brain proteins. During the Biomedical Aspects of Autism session, Daniel Braunschweig, Immunology Ph.D. candidate in the laboratory of Dr. Judy Van de Water at UC Davis, presented preliminary findings from analysis of blood samples of mothers of children with autism compared to those of mothers of typically developing children. Mothers of children with autism were more likely to have antibodies to fetal brain proteins than mothers of typically developing children. Detection of maternal antibodies to fetal brain proteins during pregnancy could potentially serve as an early biological marker for autism.

Another presentation in this session focused on environmental issues. Irva Hertz-Picciotto, Ph.D., M.P.H. of the M.I.N.D. Institute and UC Davis, reported findings on mercury levels in 2-5 year-old children with autism, developmental delay, and controls who were part of a larger study of Childhood Autism Risk from Genetics and Environment (CHARGE). So far this study has found there are no differences in mercury levels between the children with autism or developmental delay, and the control group. However, since these measurements were made after the development and diagnosis of autism and reflect recent exposure, they are not informative in regard to causative factors. A future analysis of newborn blood spots by Dr. Hertz-Picciotto will shed light on whether prenatal exposures to mercury could be related to autism. The CHARGE study also demonstrated the validity of questionnaires to collect information on sources of exposure. For example, fish consumption strongly predicted the levels of total mercury in the children's blood samples. CAN is also supporting an add-on to Dr. Hertz-Picciotto's CHARGE study with a 2006 grant to examine the blood levels of chemicals used in flame retardants (polybrominated diphenyl ether-PBDEs).
In addition to the symposia and scientific lectures, researchers presented results from on-going research at the poster session. A few highlights included:

• Judy Reaven, Ph.D. and Susan Hepburn, Ph.D. of the University of Colorado at Denver Health Sciences Center reported promising initial findings from a family-based, group Cognitive Behavioral Treatment which showed it may be effective at reducing parent-reported and self-reported anxiety in children with autism. With funding from CAN, the treatment will continue to be tested using independent measures of anxiety contrasted to a wait-list control group.
• CAN grantees Carlos Pardo, M.D. and Andrew Zimmerman, M.D. and their colleagues from Kennedy Krieger Institute and John's Hopkins University presented a poster on a novel animal model for neuroinflammation in which animals are exposed to terbutaline, a drug used to prevent pre-term labor that acts by stimulating beta-2 adrenergic receptors. The researchers found that the neonatal rats exposed to terbutaline developed increased levels of activated microglia similar to those seen in autism. This model has potential for further examination of the effects of environmental factors and their interaction with genetic predispositions. It may also demonstrate the specific role of neuroinflammation in autism and possibilities for its treatment.
• CAN grantee Darragh Devine, Ph.D. from the University of Florida used an animal model to examine the effectiveness of memantine as well as MK-801, topiramate, and valprorate in reducing self-injurious behavior. Using this model, topiramate seemed to have the best potential for therapeutic use in autism. While memantine was not shown to reduce the severity of self-injurious behavior in this model, comparison of the effects of the different drugs may be useful in understanding the mechanisms for blocking self-injurious behavior.
• Paul Ashwood, Ph.D. and Judy Van de Water, Ph.D. of the M.I.N.D. Institute reported findings from their study on the immune system demonstrating that children with autism have decreased plasma levels of an immune regulator called Transforming Growth Factorß1. This finding may suggest immune dysregulation in autism that could have adverse effects in early development. Dr. Ashwood has received a CAN grant to continue his characterization of immune responses in autism.
• Given that there is a higher prevalence of autism in males, researchers have been interested in the role of the X chromosome in autism. Focusing on the X chromosome, CAN grant recipient, Zohreh Talebizadeh, Ph.D. of the University of Missouri-Kansas City School of Medicine, used AGRE families to examine X inactivation in autistic females. Since females have two X chromosomes while males only have one, one of their X chromosomes must be inactivated during development to prevent females from having twice as much X-related gene activity as males. X inactivation should happen randomly. However, Dr. Talebizadeh's study found that autistic females had a high degree of X inactivation irregularity ("skewness") which may allow unequal expression of X-linked genes. She also found that the degree of X inactivation was associated with certain subset scores on the ADI-R, suggesting that females showing abnormal X inactivation may represent one subgroup of autism.

Events like IMFAR contribute to the expansion of the field of autism research by bringing scientists from different areas of research together to promote integrated thinking about the disorder. Research in autism has continued to progress immensely in the years since IMFAR's inception, and the field is at a critical time of discovery. Near the end of his address Dr. Insel declared, “we are at a tipping point in autism.” As an attendee it was certainly easy to see the impact of CAN's drive to accelerate the pace of science and bring the field of autism research to the tipping point. From the growth of the IMFAR conference, to the increased number of student attendees just entering the field, to the broad range of research questions addressed in the symposia, there is an inescapable sense that autism researchers are already reaching beyond the tipping point so that their work will soon impact the treatment of the disease, an important goal for all parents.

Cure Autism Now recognizes the importance of the IMFAR conference for creating an interdisciplinary venue for the sharing of ideas by providing continued sponsorship of the event. The International Society for Autism Research (INSAR) has invited CAN Science Director, Sophia Colamarino, Ph.D., to serve on the Scientific Program Committee for the 2007 IMFAR conference. As a committee member Dr. Colamarino will assist with the direction and expansion of next year's conference which will be held in Seattle, WA. For more details about IMFAR 2006 and 2007 go to
www.IMFAR.org [2].