Researchers, Scientists Share New Autism Research Findings

October 14, 2007

Nearly 900 researchers, scientists, students, parents and others were on hand in Montreal on June 1-3, 2006, at the International Meeting for Autism Research, the largest-ever of leading autism researchers from around the world. Autism Speaks was among the sponsors.

Recent groundbreaking findings in autism research were outlined at six separate poster sessions, with a 40% increase in abstract submissions from the previous year. The three-day event provided a unique opportunity to share results from different areas of research, including the fields of epidemiology, genetics, neuroanatomy and neurobiology, and treatment paradigms.

In addition to the poster sessions, each morning began with a special address by a leading researcher. On June 1, Tom Insel, M.D., director of the National Institute of Mental Health at the National Institutes of Health, opened the meeting by outlining the current landscape of autism research and highlighting the most pressing issues. He noted a growing sense of urgency that despite the fact that autism is well established as a developmental brain disorder, researchers have made little impact on unraveling the basis of the disorder to date.

Insel discussed the needs for solving the puzzle of autism: characterizing subgroups, identifying biological markers of autism, finding the underlying cause – including genetic predispositions and environmental triggers, treatments and strategies for prevention, and finally establishing a common measure for diagnosis and outcome. Breakthroughs have been made in the discovery of the pathophysiological genes underlying Fragile X and Rett Syndromes; and these discoveries should be exploited and applied to autism research.

Dr. Insel pointed out that the work of Autism Speaks has made major contributions to these efforts through research funding, coordination of large scale collaborations between researchers in the US and around the world, public awareness, the Autism Tissue Program and the Interactive Autism Network.

Early Detection Leads to Better Interventions

On June 2, Sally Rogers, a member of the High Risk Baby Siblings Research Consortium, or BSRC, presented the most current research findings studying infant siblings as young as 6 months of age. While autism is not reliably diagnosed at 6 months of age, these children show subtle signs of impairment. This includes spending more time looking at the mouth than the eyes of their parents.

Later that day, other members of the BSRC, including Wendy Stone, Dr. Lonnie Zwaigenbaum, Sally Ozonoff, Deborah Fein, Susan Bryson, and Catherine Lord, discussed methods of screening these children as early as possible so diagnosis can be made (or not made) as early as possible. Specifically, Dr. Zwaigenbaum and Bryson, along with Peter Szatmari, reported that the Autism Observation Scale in Infants (AOSI) could distinguish siblings with ASD from undiagnosed siblings and controls by 12 months of age – however this is not yet consider a clinical diagnosis.

Both the Early Autism Screening Tool and the Screening Tool for Autism in Two-year Olds were shown by presenters as effective methods of screening high-risk infants and toddlers for early intervention prior to a full diagnosis. It was agreed that while some signs of autism, including a change in social engagement, can be observed as early as 12 months, a stable diagnosis can not be made until 2 years. Early identification of individuals at high risk, however, is becoming better and better. That means that the capacity of community service providers to work with these children will need to be expanded.

Role of Genetics Studied from Many Angles

Together with early detection, the role of genetics was a prominent theme at the meeting. The role of genetics in the cause of autism was highlighted by basic and clinical researchers, along with investigators studying autism in families. On June 3, Conrad Gilliam's presented a keynote address entitled “Genomic and Bioinformatic Approaches“. Gilliam reviewed current research pointing to over a dozen genes of interest using different methods of genetic screening. These include areas on chromosomes 2, 7 and 15.

While mutations of genes on regions of these chromosomes have been associated with autism, simple mis-expression of one more genes may not hold the entire answer. Rather, an interaction of genetic signals may hold the clue to deciphering the effects of mutations of multiple genes which control specific functions, like expression of a single receptor or more widespread functions, like how neurons know where to travel during brain development. Determining how these genes interact will require novel analysis techniques as well as a new emphasis on neuroinformatic techniques to decipher these possible interactions.

Gilliam also emphasized the need for large scale, multisite studies which will be able to identify with a relative degree of certainty the different genes of interest. Multiple genes of interest were presented for discussion at the meeting, including those which control the direction of how brain cells migrate during development (neuroligins, semaphorins, and ephrins) and receptors which turn on or turn off neuron activity (GABA receptors).

Multiple studies investigating the neurobiological and behavioral function of mutations of another gene associated with autism, engrailed-2, were highlighted by Emanuel Dicicco-Bloom, M.D. Dr. Dicicco-Bloom reviewed evidence that mutations alter how cells develop into neurons and how animals behave during development. This behavioral phenotype includes a delay in major behavioral milestones and an increased susceptibility to seizures.

Other researchers are approaching the role of genetics in autism by looking at the correspondence of language and social skills in individuals in a family affected by autism. For example, parents of children with pervasive developmental disorder showed a greater degree of impairment identifying their emotions than parents of children with Prader Willi Syndrome.

There is also evidence from multiple groups, including researchers in the United States, Canada and the United Kingdom, which demonstrated that impairments in language ability or a language delay clustered in families with autism. That is, there was a similar relationship between scores for language and social communication abilities in twins, non-twin siblings, parents and those of the affected individual.

These results support the importance of genetic factors in the etiology of autism spectrum disorder and suggest the presence of a ‘broader autism phenotype' in families.

The Autism Genome Project, or AGP, presented its preliminary results from the recently completed genome scan. Dr. Jim Sutcliffe, a molecular geneticist from Vanderbilt University and one of the principle investigators of the AGP shared data providing support for two previously identified chromosomal regions as well as three novel sites in the genome that may harbor autism susceptibility genes. As the largest autism genome scan ever attempted, results that are starting to emerge from the consortium could potentially impact the direction of the field for years to come.

Autism Epidemiology: Who Counts and How Do We Count Them?

Another area of research that has immediate implications for public policy and awareness is epidemiology. Monitoring the prevalence in autism in different areas around the world will serve two purposes: 1) to determine if there are differences in the number of affected individuals and what factors account for those differences and 2) to inform policymakers in countries where there is little or no infrastructure on the need for services.

Different genetic makeup of individuals from different races and ethic backgrounds together with variations in environmental conditions make this sort of study ideal for examining gene/environment interactions. In fact, Eric Fombonne presented evidence of a Native-American population in Canada which has not shown a single case of autism in 20 years – supporting the value of epidemiological approaches to study genetic and environmental influences.

Research in China, the United Kingdom, Iceland, and Canada was also presented during the course of the three days. While determining the regional differences in prevalence is an important task, developing and conducting this type of research is also challenging. Differences in ascertainment procedures and the current level of support and services for individuals may play a role in the differences as well. Tony Charman from the University College London described different prevalence rates of autism in the same group based on how children were identified and how they were diagnosed. This points out the importance of common screening and diagnostic procedures when designing new studies.

Understanding Brain Structure, Function in Autism Spectrum Disorders

Findings of researchers studying the neurobiology, neuroanatomy and neuropathology of autism will help researchers find better treatments, interventions, and may lead to better diagnosis.

Recently, Cynthia Schumann and David Amaral at the MIND Institute at UC Davis reported that the size of the amygdala (an area of the brain that regulates emotion, anxiety and fear) was larger in young children but not adults with autism. These studies were then followed up with investigations of the size and number of neurons in this area using post-mortem brain tissue in adolescents and adults. Using a technique called “unbiased stereological analysis” on tissue distributed from the Autism Tissue Program, Dr. Schumann saw fewer neurons in the lateral amygdala in individuals with autism. This study was recently published in the Journal of Neuroscience (click here to read more). Further studies will examine the size and complexity of connections that these neurons make with each other and also study other brain regions which connect with these amygdala cells.

Neurochemical studies conducted by Gene Blatt implicate two neurotransmitter systems: the GABA system and the serotonin system. GABA stands for 4-aminobutyrate; this neurochemical is known to slow down the firing of neurons, and drugs which target the GABA system are used to treat epilepsy and anxiety disorders.

These two chemicals are especially interesting because multiple genetic analyses have also pointed to disturbances in genes coding for GABA and serotonin receptors. A dysregulation in these two systems was found in the cerebellum and the cingulate cortex of individuals with autism, the consequences of which may be an inability of neurons to “talk” to each other effectively.

Other genetic mutations were also investigated and presented at the meeting – including a defect in the expression of a protein named “MeCP2”. MeCP2 acts to slow down expression of certain genes in the brain, and full coding mutations of MeCP2 are found in girls with Rett Syndrome. Research conducted in the labs of Janine LaSalle and Arthur Beaudet, M.D. reported that while individuals with autism rarely show these same deletions of this gene, MeCP2 is not expressed properly in the brain of individuals with autism and also does not work correctly. This suggests that genes under the control of MeCP2 regulation are also affected as well.

The “underconnectivity” theory –or idea that different brain regions are not able to signal to each other sufficiently in individuals with autism- was also discussed by the neuroimaging expert Marcel Just. Just suggested that while different areas of the cortex may be ‘activated' normally in individuals with autism, different brain areas may not be working together effectively, leading to a lower degree of integration of information from sensory and motor inputs.

Researchers investigating brain activity using both functional MRI and electroencephalograms report a reduction in the activity of “mirror neurons” in individuals with autism. Mirror neurons normally fire when someone is imitating the actions of someone else, and neuroscientists believe it is the neural basis by which the actions of another person can be interpreted accurately. This deficit may explain many of the core symptoms of autism – and may also serve to better diagnose and distinguish individuals with autism in the future.

Research Leads to Better Treatments

The ultimate goal of studies into the cause and contributing factors of autism is to both find a cure and to develop effective treatments. A session was held on review ongoing and upcoming studies which utilized pharmacological agents.

Mike Aman noted a rise in medications used by individuals with autism from 1995 to 2001. As there are no FDA “approved” medications for autism, all of these compounds are being used off label, indicating the need for vigorous clinical trials to determine which is effective and for what symptoms.

One medication shown to be effective is Risperdal, which is used to treat aggressive behaviors in individuals with autism. Currently, new studies are being conducted which combine Risperdal with other compounds to offset some of its side effects or improve cognitive function. While Risperdal acts on the serotonin and dopamine systems, there is reason to believe that other neurotransmitter systems, including glutamine and GABA are affected as well. GABA is a neurotransmitter of interest from both genetic studies and studies by Blatt which implicate a misexpression of GABAergic signaling in the cerebellum.

As individuals with autism frequently suffer from epileptic seizures, drugs which control these seizures including lamotrigine, D-cycloserine and valproic acid have been shown to be effective. In addition, an ongoing trial using a glutaminergic agent called memantine is being conducted to determine the effectiveness of this agent.

Scientific discoveries in autism research highlight the need for multiple areas of study to determine the cause, developmental trajectory, identify high risk individuals who could benefit from intervention, and develop new pharmacological or behavioral interventions to treat the symptoms of autism. The International Meeting for Autism Research provides scientists the opportunity to learn from other researchers so that major discoveries and advances can be made even faster. Scientists cannot conduct research without the ongoing collaboration, input and updates of the most current findings in all areas of autism research, and this meeting makes these advancements possible.