Autism Awareness

MRI Helps Researchers Link Enlarged Spaces in Infant Brains to Higher Risk of Autism, Sleep Disorders

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Researchers Dea Garic, PhD, and Mark Shen, PhD, both at the UNC School of Medicine’s Department of Psychiatry, discovered that infants with abnormally enlarged perivascular spaces have a 2.2 times greater chance of developing autism compared to infants with the same genetic risk. Their research also indicated that enlarged perivascular spaces in infancy are associated with sleep problems seven to 10 years after diagnosis.

“These results suggest that perivascular spaces could serve as an early marker for autism,” said Garic, assistant professor of psychiatry and a member of the Carolina Institute for Developmental Disabilities (CIDD).

The researchers studied infants at increased likelihood for developing autism, because they had an older sibling with autism. They followed these infants from 6-24 months of age, before the age of autism diagnosis. Their study, published in JAMA Network Open, found that thirty% of infants who later developed autism had enlarged perivascular spaces by 12 months. By 24 months of age, nearly half of the infants diagnosed with autism had enlarged perivascular spaces.

Starting 10 years ago, there has been a resurgence of research on the important functions of CSF in regulating brain health and development. Shen’s lab was the first to report that excessive volume of CSF was evident at 6 months of age in infants who would later develop autism. The current study showed that excessive CSF volume at 6 months was linked to enlarged perivascular spaces at 24 months.

Every six hours, the brain expels a wave of CSF that flows through perivascular spaces to remove potentially harmful neuroinflammatory proteins, such as amyloid beta, from building up in the brain. The CSF cleansing process is especially efficient when we are asleep, as the majority of CSF circulation and clearance occurs during sleep.

Disrupted sleep, however, can reduce CSF clearance from perivascular spaces, leading to dilation or enlargement, but this has previously only been studied in animal studies or in human studies of adults. This is the first study of its kind in children.

Shen, senior author of the JAMA Network Open paper, and Garic hypothesized that CSF abnormalities in infancy would be related to later sleep problems, based on  Shen’s earlier research. The current sleep analysis revealed children who had enlarged perivascular spaces at two years of age had higher rates of sleep disturbances at school age.

“Since autism is so highly linked with sleep problems, we were in this unique position to examine CSF dynamics and sleep,” said Garic, who is first author of the paper. “It was really striking to observe such a strong association separated by such a long period of time over childhood. But it really shows how perivascular spaces not only have an effect early in life, but they can have long term effects, too.”

The research was done in conjunction with the Infant Brain Imaging Study (IBIS), a nationwide network of researchers investigating brain development, autism, and related developmental disabilities. The network consists of five universities, of which the University of North Carolina-Chapel Hill is the lead site.

For their study, Garic and Shen analyzed 870 MRIs from IBIS to measure excessive CSF volume and enlarged perivascular spaces. MRIs were obtained from babies during natural sleep at six, 12, and 24 months of age to observe changes over time.

The infant brain undergoes rapid development over this period. Previously, measurement of perivascular spaces was only thought to be clinically relevant for disorders of aging in older adults, such as in dementia. These findings suggest that younger populations may need to be considered and monitored for these types of brain abnormalities.

“Our findings were striking, given that neuroradiologists typically view enlarged perivascular spaces as a sign of neurodegeneration in adults, but this study reported it in toddlers,” said Garic. “This is an important aspect of brain development in the first years of life that should be monitored.”

Garic and Shen hypothesize that excess CSF volume is stagnant, or clogged, and not circulating through the brain as efficiently as it should. For their next research endeavor, the researchers are planning to once again use MRIs to measure CSF in a sleeping infant’s brain, but this time focusing on the physiology and speed of CSF flow throughout the brain.

The research team is also working with other collaborators to quantify the size of perivascular spaces and the severity of behavioral outcomes. The team also plans to extend their research to neurogenetic syndromes associated with autism, such as Fragile X syndrome and Down syndrome.

“Collectively our research has shown that CSF abnormalities in the first year of life could have downstream effects on a variety of outcomes, including later autism diagnosis, sleep problems, neuroinflammation, and possibly, other developmental disabilities,” said Shen.

Autism Awareness: Disorder Begins Before Brain Is Fully Developed, Making Risks From Vaccinations Impossible.

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Scientists from the University of California, San Diego, have published a study that gives definitive proof that autism begins during pregnancy, while the brain is still forming, and not as the result of social or environmental factors post-childbirth.

Researchers from the University’s School of Medicine and the Seattle-based Allen Institute for Brain Science argue their findings erase all doubt that autism is somehow influenced by factors after a mother gives birth. While influencing factors may contribute to the disorder’s development in utero — such was the case of a 2013 Harvard School of Public Health study that found air pollution may raise a child’s risk — the UCSD team state the evidence is crystal clear.

“Building a baby’s brain during pregnancy involves creating a cortex that contains six layers,” said Eric Courchesne, neurosciences professor and director of the Autism Center of Excellence at UCSD, in a statement. “We discovered focal patches of disrupted development of these cortical layers in the majority of children with autism.”

Courchesne and his colleagues analyzed 25 genes from 22 children, post-mortem. Knowing that certain genes develop at different points in time, reflected in their place within the six cortical layers, similar to the rings on a tree, the team searched for specific genes that act as markers. These included genes marking certain cell types in each cortex layer, genes implicated with autism, and control genes.

When the researchers looked for each gene marker, what they found was a startling difference in the half of children who had autism and the half that didn’t. “The most surprising finding was the similar early developmental pathology across nearly all of the autistic brains,” explained Dr. Ed Lein, co-researcher from the Allen Institute. This was especially true given the diverse mix of symptoms in the 11 autistic children “as well as the extremely complex genetics behind the disorder,” he added.

As one of the great medical mysteries of our time, autism has been growing steadily in prevalence over the last decade. According to the Centers for Disease Control and Prevention (CDC), autism spectrum disorders — the umbrella term that includes low-functioning autism to high-functioning Asperger’s — have risen from one in 150 children in the year 2000 to one in 88 by 2008. Autism disorders are nearly five times more common in boys (one in 54) than in girls (one in 252).

But these trends aren’t reflected in other parts of the world. Asia, Europe, and other parts of North America display far lower prevalence rates, sometimes as low as one percent, which presents U.S. researchers with a curious challenge. There are no blood tests to diagnose autism, and behavioral observation is by nature imperfect. Some say we over-diagnose, especially on the higher-functioning end. Some say America’s obsession with vaccinations is to blame. So the question remains: How do stop something if we don’t fully know what it is?

The present research may not offer any insights into that question, but it can help explain its opposite, specifically, what autism isn’t. Given the development of gene markers in still-developing cortical layers, autism is not a product of a child’s exposure to the environment after birth.

This doesn’t rule out maternal exposure during gestation or earlier, but it does go a long way toward quieting many of today’s critics. The team found many of the defected patches were in regions commonly associated with autism, such as the frontal and temporal cortex, which underlie a person’s speech and language abilities.

“The finding that these defects occur in patches rather than across the entirety of cortex gives hope as well as insight about the nature of autism,” Courchesne said. If children with focal patch defects can work around their impairments and form new wiring systems while the brain is still malleable enough, doctors may be able to override the default settings made during pregnancy and, ultimately, restore the child’s brain to normal levels of functioning.

 

Source: Stoner R, Chow M, Boyle M, et al. Patches of Disorganization in the Neocortex of Children with Autism. NEJM. 2014.