Posts Tagged ‘autism’

by MIKE MCRAE

Transforming the microbial environment in the guts of children diagnosed with autism could significantly ease the severity of their condition’s signature traits, according to newly published research.

A study on the effects of a form of faecal transplant therapy in children on the autism spectrum found participants not only experienced fewer gut problems, but continued to show ongoing improvements in autism symptoms two years after the procedure.

Arizona State University researchers had already discovered a dose of healthy gut microflora caused characteristics associated with autism spectrum disorder (ASD) to ease or vanish for at least a couple of months after treatment ended.

But to be taken seriously as a potential therapy, there needed to be long term improvements. So a return to the original group of volunteers for another check-up was in order.

It turned out those new microbes were settling in nicely.

“In our original paper in 2017, we reported an increase in gut diversity together with beneficial bacteria after microbiota transfer therapy (MTT), and after two years, we observed diversity was even higher and the presence of beneficial microbes remained,” says biotechnologist Dae-Wook Kang.

The gut might seem like an odd place to start in developing therapies that assist individuals with a neurological condition such as autism.

But in addition to its defining characteristics of impaired social and communication skills, sensory challenges, and reduced core strength and motor control, for up to half of those with ASD the condition can come with a bunch of gut problems.

“Many kids with autism have gastrointestinal problems, and some studies, including ours, have found that those children also have worse autism-related symptoms,” says environmental engineer Rosa Krajmalnik-Brown.

Previous studies have repeatedly pointed to the potential benefits of swapping out a ‘bad’ microbial communities for a better one, either through using probiotics or courses of antibiotics.

Most showed promising short-term effects, suggesting there was more to be explored when it comes to gut-based therapies.

“In many cases, when you are able to treat those gastrointestinal problems, their behaviour improves,” says Krajmalnik-Brown.

In an attempt to elicit a more long-term result, the researchers pulled out the big guns. Forget dropping in a few microbial tourists or killing off a handful of trouble-makers – they went for a whole mass migration.

Using a customised process of gut microflora transplantation called microbiota transfer therapy, the researchers gave 18 kids aged between 7 and 16 a belly full of new microorganisms.

All of the volunteers had both an autism diagnosis and moderate to severe gastrointestinal problems. This group was compared with 20 equivalent control subjects who had neither gut problems nor an ASD diagnosis.

Both were treated for 10 weeks and then had follow-up test sessions for a further 8 weeks.

Admittedly, the experiment wasn’t blinded, so we do need to be cautious in how we read into the results. Placebo effects can’t be ruled out in cases like this.

But saying they were ‘promising’ isn’t too strong a claim to make. The children not only experienced an 80 percent reduction in gastrointestinal symptoms, they showed significant improvements when tested with common ASD diagnostic tools.

Two years later, those same tests indicate the conditions have only improved.

“The team’s new publication reports that the study demonstrated that two years after treatment stopped the participants still had an average of a 58 percent reduction in GI symptoms compared to baseline,” says Krajmalnik-Brown.

“In addition, the parents of most participants reported a slow but steady improvement in core ASD symptoms.”

An external evaluation using a standard ASD diagnostic tool concluded 83 percent of the initial test group could be considered as severe on the autistic spectrum. Two years later, this dropped to just 17 percent.

Amazingly, 44 percent no longer made the cut-off for being on the mild end of the spectrum at all.

Overall, the evaluator determined the severity of ASD traits was reduced by 47 percent compared with their baseline.

For a therapy that has barely any side-effects, and such remarkable improvements in challenges many with ASD struggle with, it’s surely a treatment that will continue to attract attention for further research.

Faecal transplants might sound a little gross, but you might as well get used to them. We’re bound to be seeing them used for a variety of things in the future, from treating superbugs to winning sports.

Now that we’re learning our neurological health is intimately connected with our digestive system, transplanting microbial communities from a healthy gut is seen as the next big thing in treating brain disorders.

This isn’t to say microflora cause autism. It’s a complex condition that has its roots in a diverse range of genes and environmental influences that nudge the brain’s development early in life.

But if we can swap out even a few of those influences, we just might be able to make life a little easier for those who need it.

This research was published in Scientific Reports.

https://www.sciencealert.com/autism-severity-cut-in-half-in-kids-who-underwent-radical-faecal-transplant-therapy

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A new study shows the death of newborn brain cells may be linked to a genetic risk factor for five major psychiatric diseases, and at the same time shows a compound currently being developed for use in humans may have therapeutic value for these diseases by preventing the cells from dying.

In 2013, the largest genetic study of psychiatric illness to date implicated mutations in the gene called CACNA1C as a risk factor in five major forms of neuropsychiatric disease — schizophrenia, major depression, bipolar disorder, autism, and attention deficit hyperactivity disorder (ADHD). All the conditions also share the common clinical feature of high anxiety. By recognizing an overlap between several lines of research, scientists at the University of Iowa and Weill Cornell Medicine of Cornell University have now discovered a new and unexpected role for CACNA1C that may explain its association with these neuropsychiatric diseases and provide a new therapeutic target.

The new study, recently published in eNeuro, shows that loss of the CACNA1C gene from the forebrain of mice results in decreased survival of newborn neurons in the hippocampus, one of only two regions in the adult brain where new neurons are continually produced – a process known as neurogenesis. Death of these hippocampal neurons has been linked to a number of psychiatric conditions, including schizophrenia, depression, and anxiety.

“We have identified a new function for one of the most important genes in psychiatric illness,” says Andrew Pieper, MD, PhD, co-senior author of the study, professor of psychiatry at the UI Carver College of Medicine and a member of the Pappajohn Biomedical Institute at the UI. “It mediates survival of newborn neurons in the hippocampus, part of the brain that is important in learning and memory, mood and anxiety.”

Moreover, the scientists were able to restore normal neurogenesis in mice lacking the CACNA1C gene using a neuroprotective compound called P7C3-A20, which Pieper’s group discovered and which is currently under development as a potential therapy for neurodegenerative diseases. The finding suggests that the P7C3 compounds may also be of interest as potential therapies for these neuropsychiatric conditions, which affect millions of people worldwide and which often are difficult to treat.

Pieper’s co-lead author, Anjali Rajadhyaksha, associate professor of neuroscience in Pediatrics and the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine and director of the Weill Cornell Autism Research Program, studies the role of the Cav1.2 calcium channel encoded by the CACNA1C gene in reward pathways affected in various neuropsychiatric disorders.

“Genetic risk factors that can disrupt the development and function of brain circuits are believed to contribute to multiple neuropsychiatric disorders. Adult newborn neurons may serve a role in fine-tuning rewarding and environmental experiences, including social cognition, which are disrupted in disorders such as schizophrenia and autism spectrum disorders,” Rajadhyaksha says. “The findings of this study provide a direct link between the CACNA1C risk gene and a key cellular deficit, providing a clue into the potential neurobiological basis of CACNA1C-linked disease symptoms.”

Several years ago, Rajadhyaksha and Pieper created genetically altered mice that are missing the CACNA1C gene in the forebrain. The team discovered that the animals have very high anxiety.

“That was an exciting finding, because all of the neuropsychiatric diseases in which this gene is implicated are associated with symptoms of anxiety,” says Pieper who also holds appointments in the UI Departments of Neurology, Radiation Oncology, Molecular Physiology and Biophysics, the Holden Comprehensive Cancer Center, and the Iowa City VA Health Care System.

By studying neurogenesis in the mice, the research team has now shown that loss of the CACNA1C gene from the forebrain decreases the survival of newborn neurons in the hippocampus – only about half as many hippocampal neurons survive in mice without the gene compared to normal mice. Loss of CACNA1C also reduces production of BDNF, an important brain growth factor that supports neurogenesis.

The findings suggest that loss of the CACNA1C gene disrupts neurogenesis in the hippocampus by lowering the production of BDNF.

Pieper had previously shown that the “P7C3-class” of neuroprotective compounds bolsters neurogenesis in the hippocampus by protecting newborn neurons from cell death. When the team gave the P7C3-A20 compound to mice lacking the CACNA1C gene, neurogenesis was restored back to normal levels. Notably, the cells were protected despite the fact that BDNF levels remained abnormally low, demonstrating that P7C3-A20 bypasses the BDNF deficit and independently rescues hippocampal neurogenesis.

Pieper indicated the next step would be to determine if the P7C3-A20 compound could also ameliorate the anxiety symptoms in the mice. If that proves to be true, it would strengthen the idea that drugs based on this compound might be helpful in treating patients with major forms of psychiatric disease.

“CACNA1C is probably the most important genetic finding in psychiatry. It probably influences a number of psychiatric disorders, most convincingly, bipolar disorder and schizophrenia,” says Jimmy Potash, MD, professor and DEO of psychiatry at the UI who was not involved in the study. “Understanding how these genetic effects are manifested in the brain is among the most exciting challenges in psychiatric neuroscience right now.”

http://www.news-medical.net/news/20160427/Study-reveals-new-function-for-CACNA1C-gene-in-psychiatric-diseases.aspx

by BEC CREW

Evidence of autism can be identified in the composition of blood vessels in the brain, and certain defects or malfunctions in these vessels could serve as a new basis for detection, scientists have found.

While previous research has focussed on the neurological structure and function in a patient’s brain, a team from New York University (NYU) has found evidence of the disorder in the vascular system, suggesting that this could be a new target for medical treatments.

“Our findings show that those afflicted with autism have unstable blood vessels, disrupting proper delivery of blood to the brain,” says lead researcher, Efrain Azmitia.

“In a typical brain, blood vessels are stable, thereby ensuring a stable distribution of blood,” she adds. “Whereas in the autism brain, the cellular structure of blood vessels continually fluctuates, which results in circulation that is fluctuating and, ultimately, neurologically limiting.”

Azmita and her colleagues figured this out by examining the auditory cortex region in human postmortem brain tissue from people with diagnosed autism spectrum disorder (ADS) and an age-matched control group. To mitigate bias, they stripped the samples of all identifiers so they couldn’t tell which was which when examining them at a cellular level.

They found significant increases of two types of protein, called nestin and CD34, in the autistic brain vessels, but not in the control brains, which indicated that the vessels of the autistic patients had a higher level of plasticity. This protein surge was identified in several sections of the autistic brains, including the superior temporal cortex, the fusiform cortex (or face recognition centre), the pons/midbrain, and cerebellum.

This kind of plasticity is characteristic of a process known as angiogenesis, which controls the the production of new blood vessels. Publishing in the Journal of Autism and Developmental Disorders, the researchers suggest that evidence of angiogenesis in autistic brain tissue indicates that these vessels are being formed over and over and are in a state of constant flux. This could mean that inside the brains of people with autism, there’s a significant level of instability in the blood’s delivery mechanism.

“We found that angiogenesis is correlated with more neurogenesis in other brain diseases, therefore there is the possibility that a change in brain vasculature in autism means a change in cell proliferation or maturation, or survival, and brain plasticity in general,” said one of the team, psychiatrist Maura Boldrini. “These changes could potentially affect brain networks.”

So what now? The researchers hope to continue their investigation into how blood vessels in the brain differ in people with and without ADS, and if they can confirm angiogenesis markers as a reliable indication of the disorder, they could have a new detection method on their hands, and perhaps even a new avenue of research for future treatments.

“It’s clear that there are changes in brain vascularisation in autistic individuals from two to 20 years that are not seen in normally developing individuals past the age of two years,” says Azmitia. “Now that we know this, we have new ways of looking at this disorder and, hopefully with this new knowledge, novel and more effective ways to address it.”

http://www.sciencealert.com/evidence-of-autism-can-be-found-in-the-brain-s-blood-vessels-study-finds


An image depicting the measurement of nasal airflow while a child is presented with pleasant and unpleasant odors. Throughout the 10-minute study the children were seated comfortably in front of a computer monitor while viewing a cartoon. The nasal airflow measurement and the presentation of odorants were done using a modified pediatric nasal cannula and a custom built olfactometer.

Imagine the way you might smell a rose. You’d take a nice big sniff to breathe in the sweet but subtle floral scent. Upon walking into a public restroom, you’d likely do just the opposite–abruptly limiting the flow of air through your nose. Now, researchers reporting in the Cell Press journal Current Biology on July 2 have found that people with autism spectrum disorder (ASD) don’t make this natural adjustment like other people do. Autistic children go right on sniffing in the same way, no matter how pleasant or awful the scent.

The findings suggest that non-verbal tests related to smell might serve as useful early indicators of ASD, the researchers say.

“The difference in sniffing pattern between the typically developing children and children with autism was simply overwhelming,” says Noam Sobel of the Weizmann Institute of Science in Israel.

Earlier evidence had indicated that people with autism have impairments in “internal action models,” the brain templates we rely on to seamlessly coordinate our senses and actions. It wasn’t clear if this impairment would show up in a test of the sniff response, however.

To find out, Sobel, along with Liron Rozenkrantz and their colleagues, presented 18 children with ASD and 18 normally developing children (17 boys and 1 girl in each group) with pleasant and unpleasant odors and measured their sniff responses. The average age of children in the study was 7. While typical children adjusted their sniffing within 305 milliseconds of smelling an odor, the researchers report, children on the autism spectrum showed no such response.

That difference in sniff response between the two groups of kids was enough to correctly classify them as children with or without a diagnosis of ASD 81% of the time. Moreover, the researchers report that increasingly aberrant sniffing was associated with increasingly severe autism symptoms, based on social but not motor impairments.

The findings suggest that a sniff test could be quite useful in the clinic, although the researchers emphasize that their test is in no way ready for that yet.

“We can identify autism and its severity with meaningful accuracy within less than 10 minutes using a test that is completely non-verbal and entails no task to follow,” Sobel says. “This raises the hope that these findings could form the base for development of a diagnostic tool that can be applied very early on, such as in toddlers only a few months old. Such early diagnosis would allow for more effective intervention.”

The researchers now plan to test whether the sniff-response pattern they’ve observed is specific to autism or whether it might show up also in people with other neurodevelopmental conditions. They also want to find out how early in life such a test might be used. But the most immediate question for Sobel is “whether an olfactory impairment is at the heart of the social impairment in autism.”

Current Biology, Rozenkrantz et al.: “A Mechanistic Link between Olfaction and Autism Spectrum Disorder” http://dx.​doi.​org/​10.​1016/​j.​cub.​2015.​05.​048

By Elizabeth Norton

A single dose of a century-old drug has eliminated autism symptoms in adult mice with an experimental form of the disorder. Originally developed to treat African sleeping sickness, the compound, called suramin, quells a heightened stress response in neurons that researchers believe may underlie some traits of autism. The finding raises the hope that some hallmarks of the disorder may not be permanent, but could be correctable even in adulthood.

That hope is bolstered by reports from parents who describe their autistic children as being caught behind a veil. “Sometimes the veil parts, and the children are able to speak and play more normally and use words that didn’t seem to be there before, if only for a short time during a fever or other stress” says Robert Naviaux, a geneticist at the University of California, San Diego, who specializes in metabolic disorders.

Research also shows that the veil can be parted. In 2007, scientists found that 83% of children with autism disorders showed temporary improvement during a high fever. The timing of a fever is crucial, however: A fever in the mother can confer a higher risk for the disorder in the unborn child.

As a specialist in the cell’s life-sustaining metabolic processes, Naviaux was intrigued. Autism is generally thought to result from scrambled signals at synapses, the points of contact between nerve cells. But given the specific effects of something as general as a fever, Naviaux wondered if the problem lay “higher up” in the cell’s metabolism.

To test the idea, he and colleagues focused on a process called the cell danger response, by which the cell protects itself from threats like infection, temperature changes, and toxins. As part of this strategy, Naviaux explains, “the cells behave like countries at war. They harden their borders. They don’t trust their neighbors.” If the cells in question are neurons, he says, disrupted communication could result—perhaps underlying the social difficulties; heightened sensitivity to sights, sounds, and sensations; and intolerance for anything new that often afflict patients with autism.

The key player may be ATP, the chief carrier of energy within a cell, which can also relay messages to other nearby cells. When too much ATP is released for too long, it can induce a hair-trigger cell danger response in neighboring neurons. In 2013, Naviaux spelled out his hypothesis that autism involves a prolonged, heightened cell danger response, disrupting pathways within and between neurons and contributing to the symptoms of the disorder.

The same year, he and his colleagues homed in on the drug suramin as a way to call off the response. The medication has been in use since the early 20th century to kill the organisms that cause African sleeping sickness. In 1988, it was found to block the so-called purinergic receptors, which bind to compounds called purines and pyrimidines—including ATP. These receptors are found on every cell in the body; on neurons, they help orchestrate many of the processes impaired in autism—such as brain development, the production of new synapses, inflammation, and motor coordination.

To determine if suramin could protect these receptors from overstimulation by ATP, Naviaux’s team worked with mice that developed an autism-like disorder after their mothers had been exposed to a simulated viral infection (and heightened cell danger responses) during pregnancy. Like children with autism, the mice born after these pregnancies were less social and did not seek novelty; they avoided unfamiliar mice and passed up the chance to explore new runs of a maze. In the 2013 paper, the researchers reported that these traits vanished after weekly injections of suramin begun when the mice were 6 weeks old (equivalent to 15-year-old humans). Many consequences of altered metabolism—including the structure of synapses, body temperature, the production of key receptors, and energy transport within neurons—were either corrected or improved.

In the new study, published online today in Translational Psychiatry, the researchers found equally compelling results after a single injection of suramin given to 6-month-old mice (equivalent to 30-year-old humans) with the same autism-like condition. Once again, previously reclusive animals approached unknown mice and investigated unfamiliar parts of a maze, suggesting that the animals had overcome the aversion to novelty that’s a hallmark of autism in children. After the single injection, the team lowered the levels of suramin by half each week. Within 5 weeks most, but not all, of the benefits of treatment had been lost. The drug also corrected 17 of 18 metabolic pathways that are disrupted in mice with autism-like symptoms.

Naviaux cautions that mice aren’t people, and therapies that are promising in rodents have a track record of not panning out in humans. He also says that prolonged treatment with suramin is not an option for children, because it can have side effects such as anemia with long-term use. He notes that there are 19 different kinds of purinergic receptors; if suramin does prove to be helpful in humans, newer drugs could be developed that would target only one or a few key receptors. The researchers are beginning a small clinical trial in humans of a single dose of suramin that they hope will be completed by the end of the year.

The study is exciting, says Bruce Cohen, a pediatric neurologist at Akron Children’s Hospital in Ohio. “The authors have come up with a novel idea, tested it thoroughly, and got a very positive response after one dose.” He notes, however, that the mice with a few characteristics of autism don’t necessarily reflect the entire condition in humans. “Autism isn’t a disease. It’s a set of behaviors contributing to hundreds of conditions and resulting from multiple genes and environmental effects. Great work starts with a single study like this one, but there’s more work to be done.”

http://news.sciencemag.org/biology/2014/06/century-old-drug-reverses-signs-autism-mice