Chanaka N. Kahathuduwa, M.D., Ph.D., (center) led a collaborative team from TTUHSC and TTU who investigated potential links between autism spectrum disorder, cardiometabolic disorders and obesity. CREDIT TTUHSC

A study conducted by the Centers for Disease Control and Prevention (CDC) from 2009 to 2017 determined that approximately 1 in 44 children ages 3-17 are diagnosed with some form of autism). Research also has established that children with autism have an increased risk of obesity, and obesity has been linked to increased risks for cardiometabolic disorders such as diabetes and dyslipidemia (high level of cholesterol or fat in the blood). However, the question of whether or not there is an association between autism, cardiometabolic disorders and obesity remains largely unanswered.

To help provide an insight into the possible autism-cardiometabolic diseases link, Chanaka N. Kahathuduwa, M.D., Ph.D., and acollaborative team from Texas Tech University Health Sciences Center (TTUHSC) and Texas Tech University (TTU) conducted a systematic review and meta-analysis using the PubMed, Scopus, Web of Science, ProQuest, Embase and Ovid databases.

For Kahathuduwa, the seeds for the study were planted shortly after he received his Ph.D. in nutritional sciences with a focus on the neuroscience of obesity. Working as a research assistant professor under Mastergeorge, a nationally renowned autsm expert, he was invited by Naima Moustaid-Moussa, Ph.D., director of TTU’s Obesity Research Cluster (now the Obesity Research Institute),to present a seminar discussing the neuroscience of obesity and autism.

“When I searched the literature to prepare my presentation, I realized that the evidence on the association between obesity and autism was quite ambiguous,” Kahathuduwa recalled. “A solid meta-analysis was needed to address this gap.”

That initial meta-analysis led Kahathuduwa to investigate further. He explored how neuroimaging may provide insight into relationships between autism and obesity, the association between autism and under-weight patients, and the just-published study on autism and cardiometabolic risks. The studies accelerated after Dhanasekara, who focused on  obesity and metabolic health to earn her Ph.D. in nutritional sciences, joined the collaboration.

In their latest meta-analysis, Kahathuduwa, Dhanasekara and their collaborators evaluated 34 studies that included 276,173 participants who were diagnosed with ASD and 7,733,306 who were not. The results indicated that autism was associated with greater risks of developing diabetes overall, including both type 1 and type 2 diabetes.

The meta-analysis also determined that autism is associated with increased risks of dyslipidemia and heart disease, though there was no significant increased risk of hypertension and stroke associated with autism. However, meta-regression analyses revealed that children with autism were at a greater associated risk of developing diabetes and hypertension when compared with adults.

Kahathuduwa said the overall results demonstrate the associated increased risk of cardiometabolic diseases in As, which should prompt clinicians to more closely monitor these patients for potential contributors, including signs of cardiometabolic disease and their complications.

“We have established the associations between autism and obesity, as well as autism and cardiometabolic disease, including diabetes and dyslipidemia,” Kahathuduwa said. “We don’t have data to support a conclusion that autism is causing these metabolic derangements, but since we know that a child with autism is more likely to develop these metabolic complications and derangements down the road, I believe physicians should evaluate children with autism more vigilantly and maybe start screening them earlier than the usual.”

Kahathuduwa also believes the study shows that physicians should think twice before prescribing medications such as olanzapine that are well known to have metabolic adverse effects to children with autism.

“Our findings should also be an eye opener for patients with autism and parents of kids with autism to simply be mindful about the higher risk of developing obesity and metabolic complications,”  Kahathuduwa added. “Then they can talk with their physicians about strategies to prevent obesity and metabolic disease.”

Kahathuduwa said the next logical step for the collaborative team would be to generate evidence that either supports or rejects causality with regard to the observed associations.

“We have done some work with the ABIDE (Autism Brain Imaging Data Exchange) dataset regarding how neuroimaging shows the correlation between autism and obesity, but there is more work to be done,” Kahathuduwa said. “None of these studies would have been possible without the help of the wonderful mentors, collaborators and students at both TTUHSC and TTU who contributed in numerous ways, and who will continue their important efforts to move these studies forward.”

Rutgers research that may eventually enable far earlier autism diagnoses shows that typically developing infants perceive audio-video synchrony better than high-risk for autism infants.

Suppose follow-up research demonstrates that most infants who miss unmatched audio and video develop autism ). In that case, physicians may be able to diagnose the condition years earlier — a potentially important step as early treatment strongly predicts better outcomes.

“We’re a long way from validating this as a diagnostic tool, but the results definitely suggest it could be a diagnostic tool,” said Michael Lewis, University Distinguished Professor of Pediatrics and Psychiatry and director of the Institute for the Study of Child Development at Rutgers Robert Wood Johnson Medical School.

Lewis, the senior author of the study, and other researchers have long known children with autism struggle to perceive audio-visual speech as a unified event, and they’ve hypothesized that this difficulty may contribute to social impairments and language deficits in such children.

To study whether these difficulties arise before it’s currently possible to diagnose autism ,  generally around age 3, the researchers assembled two groups of infants ages 4 to 24 months, one comprised of children whose developmental delays indicate an elevated risk of autism and the other comprised typically developing children.

The researchers, whose work was published in the European Journal of Pediatrics, showed participants from both groups two types of videos with progressively longer time separation between image and sound. The first videos featured a ball making noises as it bounced against a wall. The second showed a woman talking.

When watching videos of the ball, the two groups performed similarly. When watching videos of the woman, however, the differences were stark. Typically, developing children perceive audio-visual gaps that are, on average, a tenth of a second smaller than those perceived by kids with developmental delays.

Although this result confirmed the researchers’ initial hypothesis, some findings were surprising. The ability to perceive audio-visual mismatch wasn’t associated with vocabulary size in children old enough to have a vocabulary.

If a high percentage of the children who were slowest to identify mismatched audio and video go on to be diagnosed with autism — and the findings are repeated with far more children than the 88 who participated in this study — audio-visual tests might prove a revolutionary diagnostic tool for a condition that’s becoming far more common, Lewis said.

GABA cells in fuchsia, and vGLUT cells in red and yellow CREDITUC Regents

Genes involved in inflammation, immune response and neural connectivity behave differently in brains of autistic folks

A new study led by UC Davis MIND Institute researchers confirms that brain development in people with autism differs from those with typical neurodevelopment. According to the study published in PNAS, these differences are linked to genes involved in inflammation, immunity response and neural transmissions. They begin in childhood and evolve across the lifespan.

About one in 44 children in the U.S. has autism. Autistic individuals may behave, communicate and learn in ways that are different from neurotypical people. As they age, they often have challenges with social communication and interaction.

The researchers aimed to understand how neurons in the brain communicate and the interaction between age and autism. They studied the genetic differences in brain neurons in people with autism at different ages and compared them to those with neurotypical development.

Earlier studies have shown that certain brain regions mark early excess, followed by reductions in volume, connectivity, and cell densities of neurons as autistic folks age through adulthood.

“Initial excess and overconnectivity of neurons may make the brain more vulnerable to early aging and inflammation, which may lead to further changes in the brain structure and function,” said co-senior author Cynthia Schumann. Schumann is a professor of neuroscience in the Department of Psychiatry and Behavioral Sciences. She is affiliated with the UC Davis MIND Institute. “Understanding how the brain in a person with autism changes throughout life will provide opportunities for early intervention.”

Method

The researchers analyzed brain tissues from 27 deceased autistic individuals and 32 without autism. The age of these individuals ranged between 2 and 73 years.

The tissues were taken from the superior temporal gyrus (STG) region — an area in the brain responsible for sound and language processing and social perception.

“The STG plays a critical role in integrating information. It helps provide meaning about our surroundings. Despite its importance, it remains relatively unexplored,” Schumann commented. “We wanted to understand how the molecular changes in this critical part of the brain are happening in autism.”

The team analyzed brain tissues as well as isolated neurons using laser capture microdissection techniques. They studied mRNA expression on a molecular level in the STG tissue and the isolated neurons. The mRNA translates the DNA code into instructions the cell machinery can recognize and use to make proteins for different body functions.

Main findings

Professor Cynthia Schumann in her laboratory with post-doctoral student Kari Hanson CREDIT UC Regents

The study identified 194 significantly different genes in the brains of people with autism. Of those genes, 143 produced more mRNA (upregulated) and 51 produced less (downregulated) in autistic brains than in typical ones.

The downregulated genes were mainly linked to brain connectivity. This may indicate that the neurons may not communicate as efficiently. Too much activity in the neurons may cause the brain to age faster in autistic individuals.

The study also found more mRNA for heat-shock proteins in autistic brains. These proteins respond to stress and activate immune response and inflammation.

Age-related brain differences between neurotypical and autistic people

The study identified 14 genes in bulk STG tissue that showed age-dependent differences between autistic and neurotypical individuals and three genes in isolated neurons. These genes were connected to synaptic as well as immunity and inflammation pathways.

For example, in typical brains, the expression of the HTRA2 gene is much higher before age 30 and decreases with age. In the STG neurons of people with autism, the expression levels of this gene begin lower and increase with age.

“Changes in HTRA2 have been implicated in neuronal cell loss and cell functions – such as proper protein folding, and reusing and recycling cell components,” explained co-senior author Boryana Stamova, associate professor in the Department of Neurology. She is also affiliated with the MIND Institute. “HTRA2’s role is vital for normal brain function.”

Boryana Stamova is an associate professor at the Department of Neurology CREDIT UC Regents

The researchers also uncovered different inflammation patterns in autistic brain tissues. Several immune and inflammation-related genes were strongly upregulated, indicating immune dysfunction that may get worse with age.

The study pointed to an age-related decrease in the gene expression involved in Gamma-aminobutyric acid (GABA) synthesis. GABA is a chemical messenger that helps slow down the brain. It works as an inhibitory neurotransmitter.

“GABA is known for producing a dampening effect in controlling neuronal hyperactivity in anxiety and stress. Our study showed age-dependent alterations in genes involved in GABA signaling in brains of people with autism,” Stamova said.

The study found direct molecular-level evidence that insulin signaling was altered in the neurons of people with autism. It also noted significant similarities of mRNA expressions in the STG region between people with autism and those with Alzheimer’s disease. These expressions may be linked to increased likelihood of neurodegenerative and cognitive decline.

“The findings from our study are really important in understanding what is happening in the brains of people with autism. Identifying these changes over time gives us an opportunity to think about some interventions that might be more useful in certain periods,” Schumann said.

Credits

The study’s co-authors are Bradley Ander of the UC Davis MIND Institute and the Department of Neurology; Alicja Omanska of the UC Davis MIND Institute and the Department of Psychiatry and Behavioral Sciences; and Michael Gandal and Pan Zhang of UCLA.

There is this picture – you may have seen it. It is black and white and has two silhouettes facing one another. Or maybe you see the black vase with a white background. But now, you likely see both.

It is an example of a visual illusion that reminds us to consider what we did not see at first glance, what we may not be able to see, or what our experience has taught us to know – there is always more to the picture or maybe even a different image to consider altogether. Researchers are finding the process in our brain that allows us to see these visual distinctions may not be happening the same way in the brains of children with autism spectrum disorder. They may be seeing these illusions differently.

“How our brain puts together pieces of an object or visual scene is important in helping us interact with our environments,” said Emily Knight, MD, PhD, assistant professor of Neuroscience and Pediatrics at the University of Rochester Medical Center, and first author on a study out today in the Journal of Neuroscience. “When we view an object or picture, our brains use processes that consider our experience and contextual information to help anticipate sensory inputs, address ambiguity, and fill in the missing information.”

Watching the brain ‘see’

Knight and fellow neuroscience researchers in the Frederick J. and Marion A. Schindler Cognitive Neurophysiology Laboratory at the Del Monte Institute for Neuroscience used visual illusions – groups of Pac-Man-shaped images that create the illusion of a shape in the empty space. They worked with 60 children ages seven to 17 with and without autism. Using electroencephalography (EEG) – a non-invasive neuroimaging technique that allows researchers to record the response of neurons in the brain – researchers revealed that children with autism did not automatically process the illusory shapes as well as children without autism. It suggests that something is going awry in the feedback processing pathways in their brain. 

“This tells us that these children may not be able to do the same predicting and filling in of missing visual information as their peers,” Knight said. “We now need to understand how this may relate to the atypical visual sensory behaviors we see in some children on the autism spectrum.”

Knight’s past research, published in Molecular Autism, found that children with autism may not be able to see or process body language like their peers, especially when distracted by something else. The kids in this study watched videos of dots that moved to represent a person. As part of the experiment, the dots changed color. Unlike in typical development, the brains of children with autism did not appear to notice the human movement when told to focus on the color. They had to pay specific attention to the human movement for their brains to process it well.

“We also need to continue this work with people on the autism spectrum who have a wider range of verbal and cognitive abilities and with other diagnoses such as ADHD,” Knight said. “Continuing to use these neuroscientific tools, we hope to understand better how people with autism see the world so that we can find new ways to support children and adults on the autism spectrum.”

Collaboration aims to reveal more about neurodevelopmental diseases

Tackling complex neurodevelopmental diseases, such as autism, requires collaboration. The University of Rochester is one of about a dozen Intellectual and Developmental Disabilities Research Centers (IDDRC) designated by the National Institute of Child Health and Human Development (NICHD) as a national leader in research for conditions such as autism, Batten disease, and Rett syndrome. Knight and fellow researchers in both studies collaborated with fellow IDD researchers at the Rose F. Kennedy Intellectual and Developmental Disabilities Research Center (RFK-IDDRC) at Albert Einstein College of Medicine.

“As scientists, we always need to pace ourselves. Research is a marathon – not a sprint. But being able to collaborate affords us time, space, and materials we may not otherwise have access to,” said John Foxe, PhD, senior author on both studies and co-director of the UR-IDDRC. “This recent work is a wonderful example of this. We can increase our pace in the marathon by collaborating with others on the IDDRC team.”

Northwestern Medicine scientists have identified the cause of a genetic subtype of autism and schizophrenia that results in social deficits and seizures and humans.

Scientists have discovered a key feature of this subtype is a duplicated gene that results in overactive or overexcited brain circuits. The subtype is called 16p11.2 duplication syndrome. 

“We found that genetic changes found in humans are more likely to have seizures and social deficits,” said lead author Marc Forrest, research assistant professor of neuroscience at Northwestern University Feinberg School of Medicine.

Peter Penzes, senior author of the study, and his team also showed when they reduced the levels of a gene — PRRT2 — in the duplicated region, brain activity in mice returned to normal, normal social behaviour was restored, and seizures decreased.

“Our data, therefore, demonstrates that brain over-activation could be causing both seizures and social deficits in this syndrome and that too much PRRT2 is responsible for this,” Forrest said.

The study was recently published in Nature Communications and was conducted in the laboratory of Penzes, director of the Center for Autism and Neurodevelopment and the Ruth and Evelyn Dunbar Professor of psychiatry and behavioural sciences at Northwestern.

Because the gene PRRT2 regulates how neurons talk to each other, inhibiting synapses or connection points between neurons could help treat both seizures and autism symptoms in this syndrome, Forrest said. This approach could also be used more broadly in other neurodevelopmental disorders with brain over-activation, which has been shown in other subtypes.

“Our work now shows that we can focus our efforts on targeting the PRRT2 pathway for novel therapies, and these could potentially cure core symptoms of 16p11.2 duplication syndrome,” Forrest said. “If we learn how the 16p11.2 duplication causes illness, maybe we can also learn more about what causes autism and schizophrenia, in general, and create better treatments.”

Neurodevelopmental disorders affect 10 million in U.S.

Neurodevelopmental disorders such as intellectual disability, autism and schizophrenia are common and affect approximately 3%, or about 10 million people in the U.S., but no effective treatments are available. The 16p11.2 duplication syndrome affects about 0.3% of these individuals or about 30,000 people in U.S.

“We lack a clear understanding of what causes neurodevelopmental disorders. Therefore, it is difficult to design good treatments,” Forrest said.

Different changes in DNA sequence can cause neurodevelopmental disorders

Genetic studies in the past decade have taught scientists that many different changes in the DNA sequence can cause neurodevelopmental disorders. One example is copy number variants (CNVs).

CNVs are deletions or duplications of chromosomal DNA. Unlike Trisomy 21 (Down syndrome), where an entire chromosome is copied, in CNVs just a small amount of genetic material is affected. In the CNV, Penzes and his team studied (the 16p11.2 duplication), about 30 genes on chromosome 16 are duplicated. 

The scientists are the first to look at protein changes that occur in a mouse model’s presence of the 16p11.2 duplication.

“This is important because proteins are the actual building blocks of the brain and neuronal circuits and offer unique insights compared to mRNA expression, which researchers have looked at previously,” Forrest said.