An international team of scientists, led by researchers from the University of Cyprus and the San Diego School of Medicine at the University of California, identified a previously unknown large-scale association between the activity of molecular gene expression in blood leukocyte cells and altered neuronal responses to speech in young children with autism measured with functional magnetic resonance imaging (fMRI).
The findings were published online on November 26 in the journal. Nature neuroscience.
The large-scale gene-brain association occurs differently in young children diagnosed with autism spectrum disorder (ASD) and who have poor language development compared to young children with ASD and good language development or young children with a typical development. This large-scale association involved a large number of genes, many of which are commonly expressed in many tissues, including the brain and leukocytes, a type of blood cell.
"Many of the genes involved are known by other works that are involved in prenatal brain development and are specific to humans, are linked to vocal learning and, more importantly, have been directly implicated in ASD by other genetic studies. and postmortem, "said first author Michael Lombardo, Ph.D., assistant professor of psychology at the University of Cyprus. "The findings show that different molecular biological mechanisms support functional brain development in a subtype of young children with ASD with poor linguistic results, and this biology is present before these results are known."
Consequently, the authors say, the work suggests that functional measurements of neuroimaging and gene expression levels in blood leukocyte cells may offer a novelty Live Way to identify molecular mechanisms relevant to the brain in ASD.
"They also show how the use of peripheral blood samples could help better understand how brain development changes dynamically throughout life," said co-principal Eric Courchesne, Ph.D., professor of neurosciences at the School of Medicine. Medicine at UC San Diego. "For example, the methodology behind this work can be used in the future to monitor how a patient's biology, at the levels of the molecular and neural systems, responds to treatment or changes throughout life through different results. "
The early development of language in autism is highly variable, the authors noted. "Some young children with autism are minimally verbal, while at the other extreme, many people develop a language like that of young children in development," said Lombardo. "An important and long-standing question has been whether these language profiles so different in autism are subtype distinctions that point to different biological foundations."
"We need to better understand the biological foundations of the different early language developments in autism because early language ability is one of the most important predictors of early intervention response and later life outcomes," said Courchesne. "If we can understand that biology, this can have a high impact on future work by examining how to facilitate the change to biology that can substantially improve long-term outcomes for patients."
At the UC San Diego School of Medicine, a research team led by Courchesne and co-author Karen Pierce, Ph.D., professor of neuroscience and co-director with Courchesne of the Autism Center of Autism at UC San Diego, took samples of blood of 118 small children, with an average age of 29 months or just under 2 and a half years, and measured the transcriptional activity of all genes coding for proteins in the genome.
The UC San Diego team also collected fMRI data during the natural sleep of young children while they were passively exposed to speech stimuli. Using data from the clinical assessment of behavior collected each year between one and four years of age, Pierce divided young children with autism into subtypes that showed poor or good language results between three and four years of age.
Lombardo then used advanced biostatistical analysis to group the genes into highly correlated "genetic modules", evaluating how the activity in the modules is related to the neuronal response of the entire brain to speech. The researchers found that module activity linked to neuronal speech responses was widespread throughout the genome, spanning several thousand genes that work in a coordinated fashion.
The finding, the authors said, was highly linked to Live FMRI responds to living patients and is a methodological advance that could help improve the way physicians evaluate which individuals will respond to different types of treatment.
"One of the greatest challenges in advancing the understanding of ASD has been the lack of a method to identify which genetic activity differences underlie the initial brain differences and clinical symptoms in young children with ASD who live," Courchesne said. "This is because the brain of the living child is inaccessible to the direct measurement of genetic activity." As such, the differences in genetic activity that underlie emerging brain dysfunction and clinical symptoms have remained completely unknown until now.
"Our method takes advantage of the fact that a large number of genes and gene networks relevant to the brain and prenatals with ASD are widely expressed in easily accessible non-brain tissues, such as leukocytes and in the brain, carefully analyzing that early age. Genetic activity, it is possible to advance the understanding of this key biology in young children with ASD This unique method can not only have a great impact on the understanding of the molecular basis of ASD, but also on how to monitor changes in biology as a function of the principles.We think that this method to link molecular mechanisms in available peripheral samples, such as blood, with Live The measurements of the brain using neuroimaging help us substantially. "
Courchesne said the researchers plan to extend their work in clinically relevant directions, such as monitoring the response to treatment in ASD subtypes and potentially taking advantage of information derived from gene expression, FMR and clinical measures to develop tools that can better predict Language results for young children with ASD at a very early age centuries.
Brain images explain the reason for good and poor language outcomes in young children with ASD
Michael V. Lombardo et al. The large-scale associations between the transcriptome of leukocytes and the BOLD responses to speech differ in the subtypes of early language results in autism, Nature neuroscience (2018). DOI: 10.1038 / s41593-018-0281-3