Blood levels of a hormone linked to social behavior appear to predict the ability of children with autism to understand how their mental state may differ from others', new research suggests.
Investigators found that blood levels of arginine vasopressin (AVP) were significantly and positively correlated with scores on the Developmental Neuropsychological Assessment (NEPSY)–II Theory of Mind subscale among children with autism spectrum disorder (ASD) but not in neurotypical children.
Crucially, they also demonstrated that blood AVP levels were significantly correlated with brain AVP levels. Taken together, the findings raise the possibility that vasopressin treatment may reduce social problems in autistic children with low levels of the hormone.
"Our collective findings demonstrate that blood AVP concentrations can be used: 1) as a surrogate for brain AVP activity in humans; and 2) as a biomarker of Theory of Mind ability in children with ASD," the investigators write.
"The discovery of a robust blood-based biomarker of social functioning in ASD is particularly important given that invasive measures of brain activity are unlikely to be used in routine clinical settings. These findings also suggest that AVP signaling impairments might be a promising target for drug development," they add.
The research was published online July 22 in PLOS ONE.
Autism Only?
"There has been a bunch of work in animals showing that oxytocin and vasopressin, which are two structurally and functionally related neuropeptides, were critically involved in social functioning," said study investigator Karen Parker, PhD, associate professor of psychiatry and behavioral sciences, Stanford University School of Medicine, in California.
"So when neuroscientists were moving into the field of autism, which has historically been populated more by clinical researchers, the first questions we started asking were whether maybe the best candidates for biomarkers of impaired social functioning are the neurobiological systems that are critical for social functioning in animals," she added.
Dr Parker noted that although vasopressin has not been studied as much as oxytocin, it has been implicated in male social functioning in animals.
"Because autism is male-biased in prevalence, we were interested in asking the question of [whether] maybe vasopressin is a really good candidate biomarker," she said.
To those ends, the researchers conducted two separate experiments. In the first, they examined whether blood measures of AVP were related to brain AVP activity by concomitantly collecting blood and cerebrospinal fluid (CSF) samples from 28 children and adults undergoing clinical procedures.
This showed that blood AVP concentrations were significantly and positively predictive of CSF AVP levels (P = .0127). Importantly, the relationship held after controlling for age, sex, ethnicity, sample collection time, and type of anesthetic and when restricting the analysis to the 20 participants younger than 18 years.
In the second study, the researchers determined whether blood AVP levels differed between 57 children with ASD, 47 of their ASD-discordant siblings, and 55 neurotypical individuals who acted as controls. They then assessed whether blood AVP levels could predict social functioning on the NEPSY-II Theory of Mind and Affect Recognition tasks and the Social Responsiveness Scale.
After taking into account age, ethnicity, blood sample collection time, and full-scale IQ, the results indicated that there were no significant differences in blood AVP levels between the three groups of participants or by sex, and there was no interaction effect between group and sex.
However, there was a significant difference between children with and those without ASD in terms of the relationship between blood AVP concentrations and Theory of Mind scores (P = .017).
Post hoc analysis revealed that there was no relationship between blood AVP levels and Theory of Mind scores in children without ASD (P = .723), but that blood AVP levels significantly and positively predicted Theory of Mind scores in ASD children (P = .0118).
Blood AVP levels did not predict Affect Recognition or Social Responsiveness Scale total scores in either ASD or non-ASD children, the team notes.
Discussing the disparity in the relationship between blood AVP levels and Theory of Mind scores between ASD and non-ASD children, Dr Parker commented: "The difference between kids with autism and those without autism is that kids that are typically developing have an intact theory of mind."
"What we actually saw in this instrument was that there wasn't a lot of spread, that there was a, if you will, ceiling effect in their performance. It was really more sensitive to differences in kids who had the impaired theory of mind."
"I think the question would really be: Is this specific to autism, or if we look in these neurotypical kids, would we also see this similar relationship?"
"I think that that really remains to be determined," she added.
Building on their findings, the researchers are now conducting a clinical trial to determine whether vasopressin treatment improves social ability in children with autism.
If vasopressin does have an effect, it offers the enticing prospect of more tailored treatments for children with ASD.
"I think one the issues with autism is that it's a very wide spectrum, and so one of the things that neuroscientists wanted to do as we moved into the field was ask: Can we identify meaningful subtypes where these kids have very unique biological signatures?" said Dr Parker.
"It may be that kids in those subtypes respond differently to different drugs, and so different drugs would benefit them," she added.
Potential Limitations
Commenting on the findings for Medscape Medical News, Eric Hollander, MD, director, Autism and Obsessive Compulsive Spectrum Program and Anxiety and Depression Program, Albert Einstein College of Medicine, New York City, said that studies of potential biomarkers in individuals are important and helpful and that the findings were "interesting."
Nevertheless, he told Medscape Medical News there were a number of issues with the two experiments. For the first investigation, the population was very heterogeneous and the participants had a range of medical problems, for which they received a number of medications.
"It's possible that these could have been factors that influenced either the peripheral or central measures," said Dr Hollander.
"The other thing was that they only did a single sample, and if you're going to say that something's a biomarker, then you’d want to say that that biomarker is reliable, valid, and constant over time, particularly if they're going to say that it relates to a measure of social function."
He also observed that both central and peripheral measures of oxytocin and vasopressin are highly influenced by the environment, "so that these measures can very greatly respond to what's happening in the environment, and they can change over time; there could be diurnal rhythms."
Dr Hollander believes the findings of the second investigation were "a little unusual," inasmuch as previous studies have demonstrated that individuals in the general population can differ in terms of social functioning and that they seem to correlate with, for example, oxytocin levels.
"Here, there are not finding any relationship between theory of mind in the overall population and the blood-based vasopressin measure; they're only finding that in the ASD children."
Dr Hollander also pointed out that his team has conducted studies indicating that vasopressin 1A selective antagonists, which block central vasopressin receptors, can lead to improvements in certain features of autism in high-functioning adults, which would suggest the opposite effect of vasopressin than that implied by the current study findings.
Finally, he noted that detailed results of the correlations between blood AVP levels and measures of social functioning other than Theory of Mind scores were not included in the article.
"I don't think that the studies definitively suggest that arginine vasopressin in the blood is an effective or useful biomarker."
"It's nice that it seems to correlate in terms of a single measure with spinal fluid, so that suggests there may be a relationship between the peripheral measure and the central measures, and it's nice that, at least in the children with ASD who have low vasopressin, their theory of mind is low."
"But we'd to know a lot more in terms of how it relates to other social cognition or social communication measures, and it would be good to look at this in different treatment studies that affect oxytocin or vasopressin and see if it really is useful as a biomarker or not."
"That remains to be seen," he concluded.
The research was funded by a Simons Foundation Autism Research Initiative Pilot Award, the Katherine D. McCormick Fund, the Mosbacher Family Fund for Autism Research, Stanford's Bio-X NeuroVentures Program, the Weston Havens Foundation, Stanford's Child Health Research Institute, an Autism Speaks Meixner Fellowship in Translational Research, a Stanford School of Medicine Dean's Postdoctoral Fellowship, and the National Institutes of Health. The authors and Dr Hollander have disclosed no relevant financial relationships.
PLoS One. Published online July 22, 2015.
