Potential Early Biomarkers for Autism Identified

Megan Brooks

July 10, 2013

Excessive cerebral spinal fluid and enlarged brain size in infancy may signal increased risk for autism, paving the way for early intervention.

Researchers at the MIND Institute at University of California, Davis, found that children who were later diagnosed with autism spectrum disorder (ASD) had elevated extra-axial fluid and enlarged brains at 6 to 9 months of age.

"This is the first report of an infant brain anomaly associated with autism that is detectable by using conventional structural MRI [magnetic resonance imaging]," David Amaral, PhD, MIND Institute director of research, who co-led the study, said in a statement.

The study raises the possibility of detecting ASD before symptoms appear.

"Early detection is critical, because early intervention can decrease the cognitive and behavioral impairments associated with autism and may result in more positive long-term outcomes for the child," Dr. Amaral said.

The findings were published online July 10 in Brain.

Clinical Utility

The study involved 55 infants between 6 and 36 months of age, including 33 high-risk infants with an older sibling with ASD and 22 low-risk infants with no family history of ASD.

All 55 infants underwent structural MRI (while naturally asleep) at 6 to 9 months of age. Forty-three of the infants (26 high-risk and 16 low-risk) underwent imaging again at 12 to 15 months of age, and 42 (26 high-risk and 16 low-risk) at 18 to 24 months of age.

At 24 months or later, 10 infants, all in the high-risk group, met criteria for ASD; 8 high-risk infants and 3 low-risk infants had other developmental delays, and the remaining 15 high-risk infants and 19 low-risk infants were developing typically.

On average, infants diagnosed with ASD had 20% greater extra-axial fluid than low-risk typically developing infants at age 6 to 9 months (P < .01), 33% greater extra-axial fluid at 12 to 15 months of age (P < .005), and 22% greater fluid at 18 to 24 months (P < .005), the researchers say.

The investigators note that extra-axial fluid is characterized by excessive cerebrospinal fluid in the subarchnoid space, particularly over the frontal lobes. In this study, the amount of extra-axial fluid detected as early as 6 months was predictive of more severe ASD symptoms.

"If our findings are replicated in a larger cohort, we believe that the presence of increased extra-axial fluid at 6 to 9 months of age in siblings of children with ASD, particularly if it persists at 12 to 24 months, may be a useful biomarker for early detection of ASD risk," the researchers write.

On average, infants diagnosed with ASD also had 7% larger brain volume at 12 months, compared with the typically developing infants. The researchers say that this is the first MRI evidence of brain enlargement in autism in infants younger than 24 months.

As previously reported by Medscape Medical News, the same research group at the MIND Institute found in an earlier study that preschool-age boys with regressive autism had larger brains than typically developing boys of the same age.

And a longitudinal MRI study by researchers from University of North Carolina at Chapel Hill recently found evidence that brains grow faster in children with autism.

Routine MRI Warranted?

In their latest study, Dr. Amaral and colleagues note that excessive extra-axial fluid and enlarged brain volume were detected by brain imaging before behavioral signs of autism were evident. They think their findings "increase justification for renewed discussions as to whether monitoring structural MRIs should become standard of practice for children at high risk for ASD."

The researchers at the MIND Institute are currently collaborating with other research centers to replicate their findings and to further evaluate how well these potential biomarkers can accurately predict a later diagnosis of ASD.

"It is critical to understand how often this brain finding is present in children who do not develop autism, as well," Sally Ozonoff, PhD, from the MIND Institute, who worked on the study, said in a statement. "For a biomarker to be useful in predicting autism outcomes, we want to be sure it does not produce an unacceptable level of false positives," she added.

Commenting on the study for Medscape Medical News, Alycia Halladay, PhD, senior director of clinical and environmental sciences at Autism Speaks, noted that studying high-risk infant siblings "offers the opportunity to study the earliest signs of autism, including behavioral symptoms and physical features."

"In this study," she observed, "the researchers found an excess of fluid in the brain as young as 6 months. This is much earlier than autism is diagnosed, or even when symptoms are normally seen. The presence of this excess fluid was associated with a more severe outcome at age of diagnosis and more challenging behavioral symptoms."

"These findings," Dr. Halladay said, "along with other recent studies looking at brain development before symptoms of autism are present, further the evidence that biological features are sometimes present prior to when behavioral symptoms emerge."

"The study described what standards should be applied if radiologists were to consider use of this as a risk factor for ASD, but more studies need to be conducted before clinical practice is changed," Dr. Halladay added.

The study was funded by the National Institutes of Health and the UC Davis MIND Institute. The authors and Dr. Halladay report no relevant financial relationships.

Brain. Published online July 10, 2013. Full article


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