Low levels of a hormone in cerebrospinal fluid (CSF) may be a biomarker for autism, new research suggests.
Investigators found that low levels of arginine vasopressin (AVP) in CSF was related to lower sociability in primates and humans.
Male rhesus monkeys with naturally occurring low sociality had less CSF AVP than their socially competent primate counterparts.
Furthermore, CSF AVP concentrations were lower in male children with autism spectrum disorder (ASD) than in age-matched male children without ASD, to the extent that it was possible to accurately distinguish ASD patients from control persons.
“Our study provides some evidence that CNS [central nervous system] concentrations of vasopressin may be a biomarker for the social deficit that is seen in ASD,” senior author John P. Capitanio, PhD, research psychologist, Department of Psychology, and core scientist, California National Primate Research Center, University of California, Davis, told Medscape Medical News.
Lead author Karen Parker, PhD, associate professor of psychiatry and behavioral sciences at Stanford University School of Medicine, California, added, “Currently, there are no laboratory-based diagnostic tests for autism.
“If these findings hold up after further research, they could represent a promising avenue not only for diagnosis but also for therapeutics,” she told Medscape Medical News.
The study was published online May 2 in Science Translational Medicine.
Ideal Model
Previous studies of disease biology in animal models have focused on mice, a species that lacks the “clinically relevant social cognitive abilities most relevant to understanding ASD,” the authors write. It was therefore necessary to develop an “animal model of social impairments with more behavioral and biological homologies to the human disease.”
Rhesus monkeys are an “ideal model organism” because “they are a highly social species capable of complex social cognition,” they add.
Monkeys with low sociality “initiate fewer affiliative interactions, spend less time in physical contact and grooming with conspecifics, and display more inappropriate social behaviors compared to monkeys with high sociality…suggesting lower social motivation and impaired social skills,” they write.
These traits are similar to endophenotypic autistic traits, so the naturally occurring variations in monkey behavior make monkeys a “useful model of the complex environmental and polygenic risk factors contributing to idiopathic ASD in human patients,” they state.
“Previous human and monkey studies have pointed to oxytocin [OCT] and vasopressin as two closely related peptides that may influence social behavior,” Capitanio noted.
The researchers’ goal was to test signaling molecules and pathways of AVP and OXT, as well as RAS-MAPK (mitogen-activated protein kinase) and P13K (phosphatidylinositol 3-kinase)–AKT and then test the “translational utility” of their preclinical findings in a small cohort of pediatric patients with ASD.
“We set out to ask if possible reductions or potential deficits in these pathways could be related to less sociality in rhesus monkeys and people,” Parker reported.
The study had three components, two utilizing a monkey model, and one with humans.
Robust Replication
From a pool of 222 male monkeys that were expected to show extremes in social functioning, the researchers identified 42. They then conducted ethologic observations in of the monkeys in their familial social groups.
They identified a subset of 15 monkeys with low social traits (low-social) and 15 monkeys with high social traits (high-social), as determined on the basis of the monkeys’ social interactions with other in their troop. The validity of the sociability scores in predicting these ethologic classifications was confirmed.
The researches tested whether the low-social vs the high-social monkeys exhibited differences in signaling molecules and pathways by measuring CSF and blood plasma concentrations of AVP and OXT.
They also measured gene expression of oxytocin receptor (OXTR) and arginine vasopressin receptor V1a (AVPRV1a) in peripheral blood mononuclear cells (PBMCs), as well as the ratios of phosphorylated/total extracellular signal–regulated kinase, PTEN, and AKT (components of the RAS-MAPK and PI3K-AKT signaling pathways) in PBMCs.
To avoid false discovery, they adopted a statistical winnowing strategy, through which nonpredictive and collinear biological measures were excluded.
Discriminant analysis showed a 93% correct classification of the monkeys into social groups (LR χ2 = 26.36; P < .0001), and logistical regression identified which biological measures were significantly predictive.
Ultimately, the stable logistical model ended up including only CSF concentrations of AVP and OXT, as well as the ratios of phosphorylated PTEN/total PTEN and phosphorylated AKT/total AKT.
When combined, these biological measures predicted social group classification.
Analysis of the significance of each biological measure revealed that CSF AVP concentration, the ratios of phosphorylated PTEN/total PTEN, and phosphorylated AKT/total AKT in blood predicted social group classification, whereas CSF OXT concentration did not.
When the researchers used a linear model to test whether social group predicted differences in the significant biological measures, they found that only CSF AVP concentrations were significantly lower in low-social vs high-social monkeys.
“Thus, only CSF AVP concentration survived the full winnowing strategy,” they report.
Additionally, CSF AVP was found to be a stable traitlike measure, as evaluated through analysis of banked CSF samples from a separate cohort of 10 adult male monkeys, evaluated across multiple time points.
The intraclass correlation coefficient was “significant” (F9,25 = 12.88; P < .0001) and was considered to be a large effect size.
Post hoc quality control checks confirmed these findings.
The findings were replicated in a separate test of 15 low-social and 15 high-social monkeys that were drawn from a cohort of 164 adult male monkeys. That test utilized a higher-throughput scan sampling-based method to identify the cohort.
In this analysis, CSF AVP concentration classified monkeys by social group. Low-social monkeys demonstrated lower CSF AVP concentrations in comparision with their high-social counterparts.
“What was cool about our study was that we used a naturally occurring model in assessing low- vs high-sociability status, instead of inducing low sociability through deprivation, and focused on extremes along that naturally occurring spectrum,” said Capitanio.
“Also noteworthy was the robust replication of our study, since the second cohort utilized a different procedure but found the same results. We were a little surprised to find that it was vasopressin associated with social behavior rather than oxytocin, since oxytocin is sometimes called the ‘love hormone’ and is generally considered to be associated with social cognition,” he added.
Potential Treatment?
The researchers tested the translational utility of the monkey model by quantifying CSF AVP concentrations in CSF samples previously collected as part of routine medical care from seven male children with ASD and from seven age-matched children who did not have ASD but who had other unrelated medical conditions (medical control persons).
Logistical regression analysis found that CSF AVP concentration was “sufficient to distinguish ASD cases from controls,” the investigators write.
Children with lower CSF AVP concentrations were more likely to have been previously diagnosed with ASD (LR χ2= 9.233; P = .0024), and ASD patients showed significantly lower CSF AVP concentrations compared to the medical control children (F1,10 = 11.02; P = .0078).
Parker noted “an important caveat” in both the monkey and human studies.
“We have not yet looked at females,” although “we do know that vasopressin is involved in male behavior.”
She noted that “autism is a somewhat more male-biased disorder, so it is interesting that we saw it implicated in male monkeys and male human patients with autism.”
She added that the group intends to conduct further research with females.
Capitanio cautioned that, although their study “provides some evidence that CNS concentrations of vasopressin may be a biomarker for the social deficit seen in autism, a biomarker is simply a correlate, and we don’t know if the deficit is causal.”
The group intends to administer vasopressin to low-social monkeys “to see if it improves their social abilities.”
The “overall goal of autism research is to see if there’s some way for folks diagnosed with ASD to regain social functioning through treatment, and our data suggest that people should be looking at vasopressin as a way of potentially doing this,” he concluded.
The research was funded by grants from the National Institutes of Health, the Simons Foundation, the Mosbacher Family Fund for Autism Research, Stanford Bio-X, the Weston Havens Foundation, Stanford ‘ s Child Health Research Institute, the Katherine D. McCormick Fund, and the Yani Calmidis Memorial Fund for Autism Research. Stanford University’s Department of Psychiatry and Behavioral Sciences also supported the work. Dr Parker and Dr Capitanio have disclosed no relevant financial relationships. The other authors ‘ relationships with industry are listed on the original article.
Sci Transl Med. Published online May 2, 2018. Abstract
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