AUTISM RESEARCH BEGINS TO BEAR FRUIT

BY EVE JACOBS

The California study on autism incidence, released last fall, caused multiple aftershocks, like an earthquake felt miles from the epicenter. In the four-year period from 1999 to 2002, the state's newly diagnosed cases of "full spectrum autism" doubled from 10,360 to 20,377; and perhaps even more shocking, increased 634 percent in the 15 years from 1987 (when the count was 2,778) to 2002.

California is adding 11 new children diagnosed with autism to its rosters every day, seven days a week, making autism a looming giant that can’t be ignored.

The increase has been so precipitous that the interpretation of the statistics themselves have been called into question. Are heightened parent and physician awareness–or changes in diagnostic criteria-responsible for what appears to be an epidemic? Can the upsurge be explained by changing demographics? Or have the documented beneficial effects of early intervention encouraged many parents to come forward? The higher than expected numbers-and the many questions raised by the climbing figures-are stirring up heated debates among experts in the field.

Although California is the only state to have documented its numbers, the CDC recently completed two prevalence studies–one in Atlanta and one in Brick Township, New Jersey–that count considerably more cases than previously thought. In the Brick Township study, published in June 2001, the prevalence of all autism spectrum disorders was documented at an alarming 6.7 cases per 1,000 in the target population of children ages 3 to 10.

California is 2,800 miles away, but the Garden State may be its twin in autism figures. Pioneering research in the state is looking at the epidemiology, as well numerous other facets of a disorder that is mysterious and profound.

Does New Jersey have an epidemic?

How do New Jersey’s rates compare with California’s? Were the Brick Township figures a fluke, a cluster or reflective of autism numbers around the entire state? Are there identifiable trends related to geographic location, heredity, medical history, dietary or other factors?

Researchers at New Jersey Medical School headed by Franklin Desposito, MD, and Walter Zahorodny, PhD, are conducting a multi-million dollar, CDC-supported, autism surveillance study to establish the baseline prevalence of autism in the state. The “New Jersey Autism Study” is now working to identify every child with autism born in 1992 and residing in four New Jersey counties—Essex, Union, Hudson and Ocean. The study team is uncovering this information by reviewing medical and school-based records. As part of the investigation, they will also create an autism monitoring network which will be used to update the prevalence estimates yearly, so changes in the occurrence or expression of this disorder can be identified quickly.

Zahorodny and his team are also well on the way to creating the nation’s first comprehensive biomedical database on autism. Enrollment in the “New Jersey Answers for Autism Survey” is proceeding statewide and will be used to identify patterns, trends, subgroups and risk factors, and to track the efficacy of medical treatments and educational interventions for autism.

The researchers are seeking to enlist as many persons with autism of every age as possible. With the carefully-elaborated information provided by many parents of autistic children and by persons who are self-identified with the disorder (those with milder forms may grow up, hold jobs and never have been diagnosed with autism by a physician), the researchers hope to start answering some important questions and raise new issues which will advance care and lead to prevention or cure.

“At that time, we will start analyzing the information people have shared. Rather than just compiling an ocean of data, we’ll use the information to test a handful of specific hypotheses and then go on to build case-control studies,” Zahorodny says. The survey project is supported by the New Jersey Governor’s Council on Autism, as part of its mission to advance biomedical research.

The 23-page “New Jersey Answers for Autism Survey” takes 30 to 60 minutes to fill out, according to Zahorodny, and is available in English and Spanish. Areas addressed by the survey include: family medical and developmental history; pregnancy and birth information, including maternal health and pre-natal conditions; birth complications and treatments given the newborn; developmental history and medical profile of the affected person; and information about the skills, abilities and needs of the person with autism.

“Since autism is a complex disorder, asking only a handful of questions is not likely to advance fundamental understanding,” the researcher says.

"Too much of what is said to be known about autism is based on piecemeal or anecdotal reports," he continues. "We need detailed, current, reliable information that will be updated regularly, so that the causes and courses of autism can be understood scientifically."

Although the investigators' initial goal is to enroll 1,000 participants by year’s end, Zahorodny says the survey will continue recruiting new participants for the foreseeable future. “The more complete the survey population and the more effective the follow-up, the more likely it is that the survey answers important questions about autism,” he explains.

So far, the “New Jersey Answers for Autism Survey” has been completed by more than 800 participants. They constitute a very diverse population, come from every part of the state, represent all major ethnic groups and range in age from 2 to 65.

Want to participate? Your response is needed. The number to call is 1-888-699-8038.

Will the canary sing?

The story goes that in the 19th century, miners lowered canaries into the mine shafts before going down themselves. If the canaries died, that signaled a toxic build-up of odorless and colorless gases-a red flag for imminent danger.

“Children may be our society’s canaries,” says George Lambert, MD, director of the Center of Childhood Neurotoxicology and Exposure Assessment, located at the Environmen-tal and Occupational Health Sciences Institute, a joint venture of UMDNJ-Robert Wood Johnson Medical School (RWJMS) and Rutgers. “They may be more sensitive, and so react more quickly or strongly, to contaminants that have not yet affected the majority of us.”

That's food for thought. What if these kids are exposed in utero, or during their early years, to environmental chemicals that their young bodies cannot handle?

The Center received a $5 million, five-year grant from the National Institute of Environmental Health Sciences and the U.S. Environmental Protection Agency in November 2001 to investigate how exposure to toxins influences the neurological health and development of children. Lambert, a developmental toxicologist, says they will focus on children with autism who lose function or regress between ages 12 and 30 months to determine if exposure to environmental chemicals is contributing to the loss of function.

“We know that lead, mercury, dioxin, PCBs and other chemicals alter neurodevelopment,” he says, “but we don’t really know the critical cut-off point. Look at lead, for instance. We’ve lowered the acceptable levels over the years from 60 to 30 to 10 micrograms per deciliter. We now know that 7 to 10 micrograms per deciliter can cause a child to lose as much as seven IQ points.”

Because children with autism often repeat actions over and over again, and toddlers with and without autism explore their environments and often put things into their mouths, the researchers are considering that what’s called “repetitive mouthing” could be contributing to environmental toxins getting into the children’s systems. Lambert says: “The kids with this genetic susceptibility may not be able to get rid of the toxins as well, or not as fast, or their brains may be more vulnerable.

“And the losses are more precious,” he explains. “If a child is mildly affected with autism and loses 10 IQ points, that could be critical. He may be facing another set of insults that he just can’t handle.”

The Center is conducting a large clinical trial looking at the role of environment in autism. They will enroll 100 2- and 3-year-olds with autism that has been diagnosed by a physician. Following an assessment by Audrey Mars, MD, a developmental pediatrician at RWJMS who participated in the Brick Township study and has done a lot of work with children with autism, the child can participate in the study if three major criteria are met: he has lived in the same home his whole life; is essentially healthy; and spends most of his day at home, not in day care.

A team from the Center will make a home visit during which they will take samples of dust, air, bathing and drinking water, as well as hair, blood and urine from the child. They are looking for sources of contaminants such as heavy metals and volatile organic chemicals in the home.

Results will be reported back to the families if an environmental contaminant is found in the home, and the studies will be repeated two years later. He says creating each child’s profile will cost $15,000 to $20,000, for a total of $2 to $3 million.

The team will also videotape the child, and collect photos and videotapes from the family. “You know, when the canary died, the miners realized that the mine was dangerous,” says Lambert. “These children may have a major story to tell and we’re just not listening carefully enough.”

Call 732-445-0174 for further information on this study.

First birthday parties yield vital clues

A child's first birthday party is a time of great joy, and family members often record the event for posterity. It is these very videotapes that can provide crucial clues for researchers trying to pinpoint when a child first showed signs of autism.

Audrey Mars has been involved in studying the behaviors associated with autism spectrum disorder for most of a decade. Early in her career, she worked with a team studying home movies of the happy first birthdays of children later diagnosed with autism or another developmental disorder. In this look backwards into children’s lives, she says investigators pinpointed telltale signs of autism long before the disorder was actually recognized. Frequently, a diagnosis is not made until it is quite obvious that the child has serious language delays, most often between ages 3 and 4. Mars, and others in the field, believe that early diagnosis and early intervention—before the age of 3, and optimally by age 2-often make a significant difference in the child’s social and language development.

These early birthday movies also show that some children with autism appear to be developing normally on their first birthdays, but regress by age 18 months. Investigators—among them Lambert’s team at RWJMS—are looking for triggers in the environment that may set off a cascade of damaging events.

Mars also participated in the Coriell Institute Study of families having two or more children with autism, or one with autism and another with a related disorder. The ultimate goal was to develop a DNA bank for researchers worldwide to use in their search for the gene or genes that cause susceptibility to this disorder. Mars—who provided the confirming diagnoses and looked at family functioning and coping styles—often spent many hours in the children’s homes, arriving early in the day and sitting down with the family to lunch and dinner. She says she was overwhelmed with the day-to-day difficulties encountered by both parents and siblings, and also the enormous patience and energy they invest, especially families struck with this “double hardship.”

But what she finds particularly painful and haunting are memories of older parents caring for young adults with autism. “I am a pediatrician, and I usually see these children at about age 4, when the families are filled with hope and thoughts for the future,” she says. “But what about when these children reach their 20s and the choices narrow.”

Prevention and early diagnosis are crucial, she says, “but services for adults with autism are equally critical.“

In the current study looking at toxins in the home, the researchers will also turn to home movies and photos, trying to document if and when regression has occurred. “The hypothesis is that if a child has a genetic propensity to the disorder, then something in the environment is the trigger. If we can identify the trigger, then either we can remove the toxin or perhaps give that vulnerable child a supplement to ward off its effects,” explains Mars.

In conclusion, Mars advocates early diagnosis as the best hope right now. “First Signs–Children and Autism”—a videotape for physicians she helped develop—has made a difference, she says. Vigilance may not stop the autism from occurring, but it can help minimize the deficits.

Physicians and others involved in the early diagnosis of autism can request these materials from the NJ Governor’s Council on Autism at 732-235-9524.

Clockwise from top: Drs. Charles Cartwright, George Lambert and Audrey Mars

A “broken brain”

The human brain and nervous system develop in a finely orchestrated sequence of steps, from proliferation of cells, to migration of these cells to specific destinations, to differentiation, when they “reach out to make a connection” by growing axons and dendrites. Unfortunately, even one misstep in the prescribed dance of cells can trip up the choreography in ruinous ways. “In autism, we think the process of brain development may be abnormal,” says Manny DiCicco-Bloom, MD, a pediatric neurologist in the departments of Neuroscience and Cell Biology, and Pediatrics, at RWJMS. “This is distinctly different from disorders such as cerebral palsy, where we believe there is damage to part of a normally formed brain from physical or vascular injury.” Brain imaging of people with autism as well as pathology studies of autism brains indicate that several components of the sequence of development are abnormal, including the formation of the forebrain, especially cerebral cortex and hippocampus, as well as the hindbrain, particularly the cerebellum.

There are many theories about what goes wrong in the process of brain development, and each requires painstaking diligence to test in the lab. “Science is a supremely difficult and frustrating undertaking and the most beautiful and precise work can fail to bear fruit,” says the researcher.

DiCicco-Bloom is approaching the “broken brain” of autism using animal models of brain development. He is examining the production of new neurons, or neurogenesis, in the forebrain while the embryo is still in the uterus, and also in the hindbrain and hippocampus, processes occurring during the first few weeks in the newborn rodent. One theory is that in autism “the brain is abnormally built from the very beginning,” he explains. In humans, this means that in the first 20 to 25 days of gestation, something goes wrong that “controls the number of nerve cells that are produced, which ones live or die, and how they differentiate into specific kinds of neurons that do different tasks, such as moving and thinking. This may be due to abnormal levels of certain proteins that play important roles in these events.” Using animal models, the researcher is studying some of the proteins that play pivotal roles in this process. These proteins, or growth factors, determine whether to make more nerve cells through increased proliferation, or alternatively, to stop making cells and begin neuron differentiation. He explains that when a gene is faulty, it may alter the normal levels of a protein or the time of its appearance, or may produce a flawed version of a protein that cannot perform its proper function, or even produce no protein at all.

DiCicco-Bloom works with “still-developing as well as mature neurons in cell culture and in animal models” to research: a neuropeptide called Pituitary Adenylate Cyclase Activa-ting Peptide, PACAP; basic fibroblast growth factor (bFGF); and the neurotrophins. In one animal model, the investigator injects growth factors directly into the brains of developing embryos while still in the mother’s uterus, and then examines the consequences for neurogenesis, especially the types and numbers of neurons produced. In another model, factors are injected into newborn rats. Remarkably, just a single injection can cause a permanent enlargement of the hippocampus and cerebellum, which contain excess numbers of neurons.

These models may be relevant to the human condition, since recent imaging of developing autism in children suggests that their brains undergo excessive growth during the first years of life. By identifying which factors, genes and cellular processes are important for normal brain growth in animals, DiCicco-Bloom can consider them candidates for study in people with autism.

The scientist collaborates with another developmental neuroscientist, James Millonig, PhD, in the Department of Neuroscience & Cell Biology (RWJMS), who is using mouse genetic mutants to define genes responsible for normal development of the cerebellum. Importantly, as the investigators define genes and growth factors required for normal development, they pass on these candidates to human geneticist Linda Brzustowicz, MD, PhD, of the Gene-tics Department at Rutgers University. In turn, they can then test these genes for genetic association with the autism disorder, in patients in established DNA banks as well as persons newly identified with autism. The test of candidate developmental regulators in individuals with autism is the critically required step to establish its relevance to the human condition.

Although the complexity of this basic science means answers that lead to prevention or therapies are still probably years away, DiCicco-Bloom concludes: “By one count, as recently as seven to eight years ago, there was only a handful of scientists studying autism; today there are, in this country alone, as many as 200 to 250. We should be encouraged by the magnitude of the effort. Significantly, the autism advocacy groups, organizations of families with autistic individuals, have demanded and now receive attention and financial support for research from the NIH, which has encouraged more scientists to study this disorder.”

Medical issues

Xue Ming, MD, a pediatric neurologist at the Autism Center at NJMS, said she was taught that autism is a psychiatric disorder. But she says that more than half of the children with autism she has seen-and they now number more than 600-have debilitating medical disorders, including seizures; sleep disorders such as night terrors, an inability to fall asleep or stay asleep, disordered breathing and movement disorders; gastrointestinal problems, including chronic diarrhea, abdominal pain and reflux; allergies, asthma and other immune system disorders; and skin conditions, such as eczema. These medical problems beg attention, she says. Once recognized, many of them can be treated, sometimes with astounding results.

In treating these children, she also began noticing that many had symptoms-constipation, enlarged pupils, insensitivity to cold, abnormal facial flushing and sweating, unusual swings in blood pressure and heart rate-related to the dysfunction of the autonomic nervous system, which regulates involuntary bodily functions. Ming thinks these observations deserve further attention, and she has begun researching this connection.

In some children, successful treatment of associated medical conditions has been so beneficial that the child no longer fits the criteria used for a diagnosis of “autism spectrum disorder.” Ming does not know how the medical symptoms and brain dysfunction are related, but she firmly believes they are.

“Working with these children and their families is very labor intensive, but dedicating the time is so necessary,” she says. “We need more staff at this medical center and more people to do research. It’s so important to look for the causes, but equally important to relieve the pain and discomfort these kids are feeling now.”

Clockwise from top: Drs. Xue Ming, Walter Zahorodny and Manny DeCicco-Bloom

Face to face

“The core deficit in autism is the inability to relate to others in a reciprocal fashion,” says Charles Cartwright, MD, assistant professor of psychiatry at NJMS. The autism researcher is most interested in faces, how we engage with each other, make eye-to-eye contact, and how we communicate warmth and welcoming feelings.

“In autism, the initial greeting is often impaired,” he explains. “You put your hand out to the child, but get little response. You look into the child’s face, try to make eye contact, but he doesn’t look into your eyes. The child with autism tends to show less interest in the faces of others.”

Cartwright and his team are using fMRI (functional magnetic resonance imaging) to study which areas of the brain are activated in young adults with high-functioning autism while they are looking at a range of facial expressions.

“Specific regions of the fusiform gyrus, referred to as the ‘fusiform face area,’ are generally not activated in those with autism, but light up like a lightbulb in those with no autism. This has been shown in a number of prior studies,” he says.

“We are trying to replicate those studies and add to what’s known about the fusiform gyrus and other parts of the temporal cortex, as well as looking at the amygdala, a part of the limbic system that plays a critical role in processing the emotional meaning of facial expressions. We are also using the scans to correlate what’s happening in the brain with the degree of social difficulty experienced by the individual,” he continues.

The psychiatrist says that early diagnosis and intervention help a child with autism achieve optimal development and functioning. One avenue that has been shown to be effective is applied behavioral analysis, or ABA, which involves giving the child small tasks in a highly structured way and immediately rewarding the desired behavior. “For instance, you engage the young child’s attention with ‘look at me,’ and when he does that, immediately reward him. And you do that over and over and over again,” says Cartwright.

Another avenue is a “relational intervention,” where a therapist talks and plays with the child in an intense interaction for long periods of “floor time.”

“You engage with the child for hours and hours and hours,” he says. “You get the attention of the child, you facilitate the processing of facial expressions and other social cues in the hope that this has a positive impact on the developing neural circuits in the child’s brain.”

These early intervention programs can take up to 40 hours each week, and this places a huge financial burden on the family as the state only funds a portion of the costs of these therapies, the researcher explains. “But if you don’t invest this time and money early on, the financial and emotional burden later is enormous,” he comments.

Cartwright is part of a team of autism specialists who have formed the Autism Center at New Jersey Medical School. He has recently been appointed the Interim Director of the Center. “I want to build on the Center’s achievements of the past two years,” he says. He has a vision for the program. It will:
• identify children with autism spectrum disorders at a very young age;
• educate physicians, particularly pediatricians, in early detection;
• reach out to, and service, urban communities where the disorder is not diagnosed and treated at an early age;
• provide adequate medical work-ups and treat the underlying and associated medical problems that plague many of the children;
• offer psychiatric care and medication to those whose behavior problems are not responding to behavioral and educational interventions;
• provide families with more support;
• offer specialized evaluations that would help the families advocate for individually-tailored educational interventions for their children;
• provide services and support through the life span. “There is tremendous anxiety for parents who are growing older and want to ensure that their children are adequately cared for and can function as independently as possible within the community,” Cartwright says.

The Autism Center’s mission is to work toward eliminating the disorder in current and future generations, and improving the quality of life of the growing number of people affected with autism. Their goal—which is shared by parents, clinicians and researchers–is that no child will go through life in a “faceless” and isolated world.