NIH Multisite Network Aims To Aid Understanding Of Autism

The cause of autism has baffled researchers since 1943, when the late American psychiatrist Leo Kanner first described the disorder in 11 children. Once thought to be a result of poor upbringing or a psychological disorder, autism has come to be understood as a biologically based disruption in mental functioning that makes it difficult for those with the disease to process information about the world around them. Recent studies have focused on identifying brain abnormalities and the genetic defects that may trigger autism. A five-year, $27 million National Institutes of Health project will help fill in the wide gaps in understanding of autism. "At this time, there is no reliable biological marker [for autism]," says Marie Bristol, head of the autism program at the National Institute of Child Health and Human Development. Finding a marker is just one goal of NIH's International Network on Biology and Brain Development in Autism. According to the National Institute of Neurological Disorders and Stroke (NINDS), autism affects about one in 1,000 people. Bristol says if the whole spectrum of autism-like disorders is included, that number rises to about one in 700. Three times as many boys suffer from autism as girls. She adds that "we don't have good data" on whether autism is actually increasing in prevalence. Characteristics and symptoms of autism are varied. Almost three quarters of patients have IQs below 70, although some have quite high IQs, and about 10 percent show savant abilities. Symptoms include impaired social interaction and problems with verbal and nonverbal communication. Higher-functioning autistic people tend to have a very narrow range of interests and are obsessive about the things that do interest them. While the cause of the disorder remains elusive, one candidate gene has already been identified as possibly playing a role in its development. Edwin H. Cook, Jr., an associate professor of psychiatry at the University of Chicago, found autistic children are more likely to have a shortened form of the serotonin transporter gene, which codes for a protein that reabsorbs serotonin into the neuron that has released it (Molecular Psychiatry, 2:247-50, 1997). Interestingly, fluoxetine (Prozac), a serotonin enhancer, has been found to suppress the repetitive and ritualistic behaviors of autism. "In terms of genetics, we're almost at square one," says Geraldine Dawson, a professor of psychology at the University of Washington. "We've got lots and lots of hints, but in some ways we're really kind of at the beginning of this process of discovery." Autism Society of America 7910 Woodmont Ave., Suite 650 Bethesda, Md. 20814-3015 (301) 657-0881 - Fax: (301) 657-0869 http://www.autism-society.org Cure Autism Now Foundation 5225 Wilshire Blvd., Suite 503 Los Angeles, Calif. 90036 (213) 549-0500 - Fax: (213) 549-0547 http://www.canfoundation.org National Institute of Child Health and Human Development Building 31, Room 2A32 Bethesda, Md. 20857 (301) 496-5133 http://www. nichd.nih.gov Cook's findings may be corroborated by some of the 24 universities participating in NIH's International Network on Biology and Brain Development in Autism. The network, launched in May, is being led by NICHD and the National Institute on Deafness and other Communication Disorders. It involves more than 65 scientists at sites in the United States, Canada, Britan, France, and Germany who will study the neurobiology and genetics of autism. Several patient advocacy groups, including the San Diego-based Autism Research Institute, the Bethesda, Md.- based Autism Society of America, and the Los Angeles-based Cure Autism Now Foundation, are helping to recruit 1,000 people with autism. All the studies, involving scientists from various disciplines, use a common diagnosis and shared procedures, such as a standardized family history, that will allow data from the different groups to be compared in later genetic analyses. FOCUS ON THE BRAIN: Helen Tager-Flusberg of the Shriver Center hopes to pinpoint areas affected in autism. Helen Tager-Flusberg, a senior scientist at the Behavioral Sciences Division of the Waltham, Mass.-based Eunice Kennedy Shriver Center, is heading up the project there. She is planning to pinpoint which areas of the brain might be affected in autism, particularly those areas of the frontal cortex and limbic system associated with language. She also intends to examine the role of autistic people's apparent inability to form ideas about other people's motivations and knowledge: "Is it a theory-of-mind deficit that underlies language impairment, or is it language impairment that underlies the theory-of-mind deficit, or is it a more complex interrelation between the two?" she asks. She adds that the last of these "is what we suspect." She plans to use tone recognition in lower-functioning, nonverbal autistic patients to examine whether they can transfer that ability to speech-like stimuli. Via funtional magnetic resonance imaging (MRI) tests, she hopes to determine which areas of the brain the subjects are using. Tager-Flusberg also is planning a longitudinal study of children moving from preadolescence to postadolescence, when final cortical development takes place, to compare brain images over time. NEURAL SYSTEM ASSESSMENT: Pittsburgh's Nancy Minshew and her team are studying brain function. Researchers at the University of Pittsburgh site also are studying brain function. "It looks like what's happening is that the neural system for language, memory, and reasoning in autism [is] not developing well," comments Nancy J. Minshew, a child neurologist who directs the project. Her hope is to assess whether deficits in highly functioning autistic people occur in attention, working memory, verbal reasoning, nonverbal reasoning, or executive function. One study, for instance, will use functional MRI to look at the development of these abilities over time in subjects aged eight to 16 and adults 16 to 40, and compare that to subjects' performance on behavioral tests. Eye movement is linked to particular cortical circuitry, and another study will perform eye- movement tests on autistic people to see if there's a difference in the brain circuitry they use. Minshew and her colleagues, John Sweeney and Patricia A. Carpenter, psychologists at Carnegie Mellon University, hypothesize that neural connections within systems and between systems are somehow impaired in autism. Their hope is that if those impairments can be identified, they can be linked with genes involved in development of specific areas (N. Minshew et al., Journal of the International Neuropsychological Society, 3:303-16, 1997). Patricia M. Rodier, a teratologist who heads the project at the University of Rochester, is studying the possibility that brain injury early in gestation is responsible for some cases of autism. Studies in Europe have linked exposure to thalidomide, a teratogen that has been banned in the U.S., to autism. Thalidomide is known to affect the fetal brain at between 20 and 24 days of age, before the neural tube has closed. That narrows down the parts of the brain that could be damaged, because some parts don't exist that early, although early damage could affect later development. Rodier has found that by exposing rats to valproic acid, she can duplicate damage found in human brains, yet produce a rat that, like autistic children, is outwardly healthy and normal in appearance. Of course, there's no reliable way to say whether such rats are in any way "autistic" (P. Rodier et al., Journal of Comparative Neurology, 370:247-61, 1996). Unlike, say, Down syndrome, there are no obvious physical signs of autism that have been widely accepted. Rodier, however, has looked at autistic children from Nova Scotia and found, in an unpublished study, that 42 percent had a malformation of their external ears, much higher than the percentage in either children without any problems or children with other forms of mental retardation. Previous studies had linked ear defects with thalidomide exposure, and ears are formed at about the same time Rodier was targeting in her studies. Now, she's looking at genes that are active at that point in gestation to see if she can identify some that may be defective in autism. VIRAL ASSOCIATION: Utah's Reed Warren is looking for an immunogenic cause. Meanwhile, Reed P. Warren, a professor of immunology and an adjunct professor of psychiatry who heads the University of Utah group, is looking for an immunogenic cause for autism: "There have been at least 20 reports of viral association with autism, and it's kind of hard to ignore that." Autism has been associated with rubella, cytomegalovirus, and meningitis. Warren has found an amino acid sequence in the genes of the major histocompatibility complex that is expressed more frequently in autistic subjects than in controls. This sequence is responsible for the development of antibody responses to antigens, and this general area has been linked to other autoimmune disorders. In addition, eight mothers in the study expressed another sequence that they did not pass on to their autistic children. Warren says there are two ways immune system genes may lead to autism. One is that antibodies may bind weakly or not at all to certain pathogens, leaving the pathogens free to produce damage in the brain. The other is that the pathogens may trigger an overzealous immune response, leading to autoimmune damage to the central nervous system. And it could be that mothers with the expressed sequence either fail to provide their fetuses with adequate immune protection or mount an attack on the fetal brain (R. Warren et al., Journal of Neuroimmunology, 67:97-102, 1996). A project between the University of Washington and the Veterans Affairs Medical Center in Seattle will look at both genetic aspects and brain studies in an attempt to identify subtypes of autism. "In some disorders, like Alzheimer's disease, subtypes have been critical in trying to discover the genetic basis," notes principal investigator Dawson, who heads the University of Washington project. One part of the University of Washington project will be a genetic linkage analysis. Another study will use magnetic resonance spectroscopy on autistic adults to measure chemicals like sodium and choline that affect the density of neurons. Research suggests that disruptions in brain growth may lead to autism. Dawson and coinvestigator Andrew Meltzoff will use event-related potential analysis of electrical activity in the brain to study very young, nonverbal children to see if they are performing face recognition and emotion recognition, which normally appear almost instinctively. The researchers also will create brain maps of where the electrical activity occurs. "We believe that some of these children will show very basic subcortical abnormalities that are responsible for processing some of this very basic information," Dawson comments. Dawson is also trying to improve early diagnosis. For the most part, autistic children are identified behaviorally at about two or three years old. Dawson has examined videotapes of first birthday parties to see if she can identify symptoms in children later diagnosed as autistic. A decade or so ago, conventional wisdom was that little could be done for children with autism. While many autistic children respond well to behavioral therapy and medication, it's unknown what treatments are best and why many children don't appear to be helped by these conventional therapies. NIH's Bristol would like to see more work done in psychopharmacology and rationally designed drugs. "Psychopharmacological research in autism has a great deal of difficulty getting funded," she says. She also thinks that more study needs to be done on behavioral treatment. Bristol is hoping that more funding will soon be available for autism research. The projected NIH budget for the next fiscal year includes $21.4 million for the study of autism, double the amount spent two years ago. "We're really looking for good research, particularly innovative research and particularly [in] molecular biology," she states. NIH is making a commitment to study autism, and this is a good time for scientists from a variety of disciplines who want to do research, according to Bristol. "There were more outstanding scientists than we were able to fund, so we're hoping even though the RFA [request for applications] period has passed that they will keep applying." l Neil Savage is a writer based in Boston.

NIH Multisite Network Aims To Aid Understanding Of Autism

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