Does the Brain Become Unglued in Autism?

A new study published in Biological Psychiatry suggests that autism is associated with reductions in the level of cellular adhesion molecules in the blood, where they play a role in immune function.

Cell adhesion molecules are the glue that binds cells together in the body. Deficits in adhesion molecules would be expected to compromise processes at the interfaces between cells, influencing tissue integrity and cell-to-cell signaling. In the brain, deficits in adhesion molecules could compromise brain development and communication between nerve cells.

Over the years, deficits in neural cell adhesion molecules have been implicated in schizophrenia and other psychiatric disorders. One adhesion molecule, neurexin, is strongly implicated in the heritable risk for autism.

Cell adhesion molecules also play a crucial role in regulating immune cell access to the central nervous system. Prior research provided evidence of immune system dysfunction in individuals diagnosed with autism spectrum disorder (ASD). This led scientists from the University of California, Davis to examine whether adhesion molecules are altered in children with ASD.

"For the first time, we show that levels of soluble sPECAM-1 and sP-selectin, two molecules that mediate leukocyte migration, are significantly decreased in young children with ASD compared with typically developing controls of the same age," explained the authors. "This finding is consistent with previous reports of decreased levels of both sPECAM-1 and sP-selectin in adults with high-functioning autism."

They also found that repetitive behavior scores and sPECAM-1 levels were associated in children with ASD. Repetitive, stereotyped behaviors are a typical feature of ASD and these data suggest a potential relationship between molecule levels and the severity of repetitive behaviors.

Finally, they also discovered that head circumference was associated with increased sPECAM-1 levels in the typically developing children, but not in the children with ASD. This indicates that perhaps sPECAM-1 plays a role in normal brain growth, as larger head circumference is a known feature of individuals with autism.

Diuretic Drug Offers Latest Hope for Autism Treatment

A drug used for decades to treat high blood pressure and other conditions has shown promise in a small clinical trial for autism. The drug, bumetanide, reduced the overall severity of behavioral symptoms after 3 months of daily treatment. The researchers say that many parents of children who received the drug reported that their children were more “present” and engaged in social interactions after taking it. The new findings are among several recent signs that treatments to address the social deficits at the core of autism may be on the horizon.

Several lines of evidence suggest that autism interferes with the neurotransmitter GABA, which typically puts a damper on neural activity. Bumetanide may enhance the inhibitory effects of GABA, and the drug has been used safely as a diuretic to treat a wide range of heart, lung, and kidney conditions. In the new study, researchers led by Yehezkel Ben-Ari at the Mediterranean Institute of Neurobiology in Marseille, France, recruited 60 autistic children between the ages of 3 and 11 and randomly assigned them to receive either a daily pill of bumetanide or a placebo. (Neither the children’s parents nor the researchers who assessed the children knew who received the actual drug).

As a group, those who got bumetanide improved by 5.6 points on a 60-point scale that’s often used to assess behaviors related to autism, the researchers report today in Translational Psychiatry. That was enough to nudge the group average just under the cutoff for severe autism and into the mild to medium category. The study did not look directly at whether the drug improved all symptoms equally or some more than others. “We have some indications that the symptoms particularly ameliorated with bumetanide are the genuine core symptoms of autism, namely communication and social interactions,” Ben-Ari says. More work will be needed to verify that impression. Ben-Ari says his team is now preparing for a larger, multicenter trial in Europe.

Autism Blood Test Shows Promise

Diagnosing autism could soon be much simpler, with researchers saying this week that they’ve developed a blood test that appears to identify those with the disorder even before symptoms are apparent.

The early-stage test developed at Boston Children’s Hospital may be able to flag about two-thirds of those with autism, researchers reported in the journal PLOS ONE.

Currently, clinicians rely on observation to screen children for autism. Most kids are not diagnosed until after age 4, according to the U.S. Centers for Disease Control and Prevention.

But a blood test offers the promise of flagging kids and potentially enrolling them in early intervention programs even before symptoms appear.

In order to develop the test, researchers analyzed blood samples from 66 boys with autism and 33 without the developmental disorder in an effort to establish patterns. Ultimately, the scientists were able to focus on a group of 55 genes that they used to successfully identify autism with 68 percent accuracy in a second test group made up of 104 people with autism and 82 controls.

“It’s clear that no single mutation or even a single pathway is responsible for all cases,” said Isaac Kohane of Boston Children’s Hospital who worked on the research. “By looking at this 55-gene signature, which can capture disruptions in multiple pathways at once, we can say with about 70 percent accuracy, ‘this child does not have autism,’ or ‘this child could be at risk,’ putting him at the head of the queue for early intervention and evaluation. And we can do it relatively inexpensively and quickly.”

The blood test is not yet ready for prime time, researchers said, but it has been licensed to the company SynapDx for further exploration and potential commercialization.

Combining two genome analysis approaches supports immune system contribution to autism

Researchers using novel approaches and methodologies of identifying genes that contribute to the development of autism have found evidence that disturbances in several immune-system-related pathways contribute to development of autism spectrum disorders. The report published December 4 in the open-access journal PLOS ONE powerfully supports a role for the immune function in autism by integrating analysis of autism-associated DNA sequence variations with that of markers identified in studies of families affected by autism.

"Others have talked about immune function contributions to autism, but in our study immune involvement has been identified through a completely nonbiased approach," says Vishal Saxena, PhD, of the Massachusetts General Hospital (MGH) Department of Neurology, first, corresponding and co-senior author of the PLOS ONE paper. “We let the data tell us what was most important; and most tellingly, viral infection pathways were most important in this immune-related mechanism behind autism.”

Genetic studies of families including individuals with autism have indentified linkages with different locations in the genome. Since traditional interpretation methods implicate the gene closest to a marker site as the cause of a condition, those studies appeared to point to different genes affecting different families. However, Saxena’s team realized that, since autism has typical symptoms and affects the same biological processes, a common molecular physiology must be affecting the different families studied. To search for genetic pathways incorporating these autism-associated sites, they developed a methodology called Linkage-ordered Gene Sets (LoGS) that analyzes all of the genes within a particular distance from marker sites and ranks them according to their distance from the marker.

Autism severity may stem from fear

Most people know when to be afraid and when it’s ok to calm down.

But new research on autism shows that children with the diagnosis struggle to let go of old, outdated fears. Even more significantly, the Brigham Young University study found that this rigid fearfulness is linked to the severity of classic symptoms of autism, such as repeated movements and resistance to change.

For parents and others who work with children diagnosed with autism, the new research highlights the need to help children make emotional transitions – particularly when dealing with their fears.

“People with autism likely don’t experience or understand their world in the same way we do,” said Mikle South, a psychology professor at BYU and lead author of the study. “Since they can’t change the rules in their brain, and often don’t know what to expect from their environment, we need to help them plan ahead for what to expect.”

The complete study appears in the journal Autism Research.

Trichuris suis ova (porcine whipworm eggs) as treatment for autism

Autism spectrum disorders are characterized by impairments in three core domains: social interaction, communication and restricted or repetitive behaviors. These impairments are frequently accompanied by disruptive behaviors, such as marked irritability, aggression, self-injury, impulsivity and temper tantrums. There is no treatment for the core symptoms, and only one class of medication — atypical antipsychotics — is approved by the U.S. Food and Drug Administration for treating these disruptive behaviors.

There is evidence for activation of pro-inflammatory processes and a positive family history of autoimmune illness in people with autism spectrum disorders. Therefore, a hygiene hypothesis has emerged for both autoimmune illness and autism, suggesting that in urban hygienic environments where there is a paucity of certain parasites that dampen immune activation, there is an increase in autoimmune processes.

People with autism have also been reported to improve when they have fevers. Given that fever is an immune-inflammatory response, Eric Hollander and his colleagues are investigating the use of immunomodulatory treatments such as Trichuris suis ova (TSO), or porcine whipworm eggs, for treating symptoms of autism. TSO has been shown to be effective in autoimmune disorders such as Crohn’s disease, ulcerative colitis and allergic rhinitis. A case series has also shown it to be effective in reducing symptoms of autism.

The researchers plan to complete a 28-week randomized crossover trial of TSO, including 12 weeks of TSO treatment, 12 weeks of placebo and a 4-week washout period. The investigators plan to compare the effects of TSO versus placebo on repetitive behaviors, aggression and irritability, and global functioning. They also plan to explore the relationship among clinical features, immune mechanisms and treatment response.

Work with immunomodulatory treatments such as TSO may be one way to test both the hygiene hypothesis as well as the fever hypothesis, and to develop alternative treatments for core and associated symptoms of autism spectrum disorders.

(Image credit: Wikimedia Commons)

Researchers Study Cry Acoustics of Infants to Determine Risk for Autism

Autism is a poorly understood family of related conditions. People with autism generally lack normal social interaction skills and engage in a variety of unusual and often characteristic behaviors, such as repetitive movements. While there is no specific medical treatment for autism, some success has been shown with early behavioral intervention.

Understanding the importance of early diagnosis, researchers at Women & Infants’Brown Center for the Study of Children at Riskin collaboration with researchers at University of Pittsburgh have been studying the cry acoustics of six-month-old infants. Their research has recently been published in Autism Research.

“Because we can measure various aspects of babies’ cries from the earliest days of life, it may be possible to use this technique to identify risk for neurological problems such as autism long before we can detect behavioral differences,” said Stephen J. Sheinkopf, PhD, lead researcher, psychologist at the Brown Center for the Study of Children at Risk, and assistant professor (research) in the Department of Psychiatry and Human Behavior at The Warren Alpert Medical School of Brown University.

The study examined ways in which infants at risk for autism produced cries as compared to the cries of low-risk infants. Recordings of babies’ cries were excerpted from vocal and video recordings of six-month-old infants at risk for autism spectrum disorder (ASD) and those with low risk. Infants were considered to be at risk if they had an older sibling with a confirmed ASD diagnosis.

Cries were categorized as either pain related or non-pain related based on observations of the videotapes. At-risk infants produced pain related cries with higher and more variable fundamental frequency (commonly referred to as “pitch”) as compared to low-risk infants. A small number of the at-risk infants were later diagnosed with an ASD at 36 months of age. The cries for these babies had among the highest fundamental frequency values and also differed in other acoustic characteristics.

“These findings demonstrate the potential of this approach for babies as young as six months of age,” said Dr. Sheinkopf.

(Photo: Thinkstock Source: Getty Images)

Schizophrenia Genetic Networks Identified; Connection to Autism Found

Although schizophrenia is highly genetic in origin, the genes involved in the disorder have been difficult to identify. In the past few years, researchers have implicated several genes, but it is unclear how they act to produce the disorder. A new study by researchers at Columbia University Medical Center identifies affected gene networks and provides insight into the molecular causes of the disease.

The paper was published in the online edition of the journal Nature Neuroscience.

Using an unbiased collection of hundreds of mutations associated with schizophrenia, the Columbia researchers applied a sophisticated computational approach to uncover hidden relationships among seemingly unrelated genes. The analysis revealed that many of the genes mutated in schizophrenia are organized into two main networks, which take part in a few key processes, including axon guidance, synapse function, neuron mobility, and chromosomal modification.

The study also uncovered an intriguing connection between schizophrenia and autism. “If we hadn’t known that these were two different diseases, and had put all the mutations into a single analysis, it would have come up with very similar networks,” said the study’s senior author, Dennis Vitkup, PhD, associate professor in the Department of Biomedical Informatics, the Center for Computational Biology and Bioinformatics, and the Columbia Initiative in Systems Biology at Columbia University Medical Center. “It shows how closely the autism and schizophrenia genetic networks are intertwined,” he added.