A small study by researchers at Stanford University School of Medicine has identified a biological marker in the cerebrospinal fluid (CSF) of human infants that may predict the future development of autism spectrum disorder (ASD). The study, which exploited a “one-of-a-kind” archive of biomaterials, showed that the hormone vasopressin was present at much lower levels in the CSF of 0–3-month-old babies who were later diagnosed with ASD than it was in CSF samples from infants who weren’t subsequently diagnosed with ASD.
The researchers suggest that if their findings can be replicated in a much larger, prospective study, measurement of the neurochemical marker could “transform how ASD is detected, both in behaviorally symptomatic children, and in infants at risk for developing it.” The investigators reported on their results in the Proceedings of the National Academy of Sciences (PNAS), in a paper titled, “Neonatal CSF vasopressin concentration predicts later medical record diagnosis of autism spectrum disorder.” The study’s first author is Ozge Oztan, PhD, a research scientist in psychiatry and behavioral sciences at Stanford. The co-senior authors are Karen Parker, PhD, associate professor of psychiatry and behavioral sciences at Stanford University’s department of psychiatry and behavioral sciences, and John Constantino, MD, professor of psychiatry and pediatrics at Washington University in St. Louis.
ASD is a brain disorder characterized by social interaction impairments and restricted, repetitive behaviors. The condition is currently diagnosed on the basis of behavioral criteria, the authors explained, because disease biology remains poorly understood, and no robust biomarkers have yet been identified. “Consequently, there are no laboratory-based diagnostic tests to detect, or medications to treat, ASD’s core features.”
Even without effective medications, early ASD diagnosis provides the opportunity for intensive behavioral therapy, which leads to better developmental outcomes. “When young children aren’t appropriately processing basic social stimuli early in life, it puts their brains on a different developmental trajectory,” said Parker. And while autism can be diagnosed from behavioral symptoms at around two years of age, long appointment wait times and shortages of autism specialists often delay diagnosis until four years of age—which is the typical age for diagnosis in the United States—or even later, causing children to miss the benefits of early treatment. If we could identify these children earlier, we could intervene earlier, Parker added.
“By the time a child is showing behavioral abnormalities and has received a formal ASD diagnosis, cumulative delays in the early processing of basic social stimuli have contributed to an atypical trajectory of poor social learning and abnormal social skill acquisition that is immensely difficult to overcome,” the authors stated. “The capability of rapidly detecting ASD based on a patient’s biological markers, when a child’s symptoms emerge—or even more optimistically, before the disorder manifests behaviorally—would revolutionize ASD detection and enable timely intervention.”
The Stanford researchers have been pioneering efforts to find ASD biomarkers in CSF. Most prior biomarker research has focused on blood, but while blood sampling is much simpler than CSF sampling, blood is also less representative of brain biochemistry than CSF, the team pointed out.
Vasopressin (arginine vasopressin; AVP) is a protein hormone of nine amino acids in length. The hormone affects social behaviors such as pair-bonding and fathering in male mammals. Vasopressin differs by only two amino acids from oxytocin (OXT), another, more well-known protein hormone with social roles. “Preclinical research has shown that AVP plays a critical role in regulating prosocial behavior, particularly in male mammals,” the authors wrote. Studies have shown that experimentally disrupting the brain AVP signaling pathway produces social deficits in mice and voles, while silencing AVP gene activity from birth results in social developmental deficits in other rodent models, “suggesting that early impairment in brain AVP signaling may similarly contribute to the pathogenesis of social deficits in young humans.”
Prior work by Parker’s team has indicated that vasopressin may play an important role in autism in humans. Their previous studies found that CSF vasopressin levels are lower in children and teens with autism than in those without the disorder, and that individuals with the lowest CSF vasopressin levels had the most severe autism symptoms. In contrast, oxytocin levels in CSF were not associated with autism. Parker’s team also previously demonstrated that administering vasopressin to children with autism improves their social ability, whereas trials of oxytocin for autism have had inconsistent results. But despite this prior evidence, “AVP itself has yet to be implicated as high confidence ASD risk gene,” the investigators pointed out.
The new study was conducted using a rare archive of CSF samples collected from infants during routine medical care. If an infant younger than three months of age develops a fever, doctors typically collect CSF via a spinal tap to rule out brain infections. The reported study by Parker’s team used CSF that was left over from such procedures and had been frozen for subsequent research purposes. After matching 913 archived CSF samples to medical records, the researchers identified 11 infants who were later diagnosed with autism in childhood. The CSF samples from nine of them were large enough for testing. Each of these samples was compared with two control samples obtained from children whose medical records did not show an autism diagnosis by age 12.
The researchers found that CSF vasopressin levels were significantly lower in infants who were later diagnosed with autism than in those who were not. Individual vasopressin levels correctly predicted which children would develop autism in seven of the nine autism cases. The two samples that did not correctly predict autism were from infants who also later were diagnosed with attention deficit hyperactivity disorder. In contrast, oxytocin levels were no different in the CSF samples of children with and without autism. “The associations were specific to AVP, as ASD cases and controls did not differ in neonatal CSF concentrations of the structurally related neuropeptide, OXT,” they wrote.
The investigators say the results expand on their previous studies in behaviorally symptomatic children, to suggest that vasopressin may represent an ASD biomarker that is present very early in life, before symptoms develop. “If replicated, assessment of CSF AVP concentration in infants may be useful for identifying those at risk for developing ASD, prioritizing patients for early clinical monitoring, specifying biologically tractable subgroups, and facilitating intervention in high-risk individuals,” they noted.
The team acknowledged that the reported findings will need verifying through a much larger, prospective study, but say their preliminary results are scientifically important. “We note that the decision to disseminate these preliminary results issues from a number of critical scientific considerations,” they commented. “That a previously identified neurochemical marker of ASD may be present very early in life, before behavioral symptoms emerge, is of high scientific significance, particularly given no reliable biomarker of ASD yet exists.” And if the results can be confirmed in larger studies, they added “… neonatal assessment of CSF AVP concentration in high-risk individuals may stand to revolutionize how ASD is evaluated and treated, enabling earlier detection, improved diagnostic yield, and reduced time to treatment.”
Prior studies of infants at high risk for autism, such as those with an autistic sibling, have demonstrated that babies who later develop autism do not show behavioral symptoms very early in life. This indicates that there is likely a window of time before symptoms first appear when behavioral therapies to maintain social responsiveness could be maximally effective, Parker said. “If we could intervene when kids still look at faces, smile, and respond to their names, that could potentially change the trajectory of the disorder.”
The team would also like to study CSF samples from children with other disorders—such as neuromuscular diseases that have a neurologic component but do not impair social skills— to determine whether the finding of low CSF vasopressin is specific to autism. They also hope to study whether a blood biomarker exists for autism in infants.
