Elsevier

Biological Psychiatry

Volume 82, Issue 3, 1 August 2017, Pages 186-193
Biological Psychiatry

Archival Report
Increased Extra-axial Cerebrospinal Fluid in High-Risk Infants Who Later Develop Autism

https://doi.org/10.1016/j.biopsych.2017.02.1095Get rights and content

Abstract

Background

We previously reported that infants who developed autism spectrum disorder (ASD) had increased cerebrospinal fluid (CSF) in the subarachnoid space (i.e., extra-axial CSF) from 6 to 24 months of age. We attempted to confirm and extend this finding in a larger independent sample.

Methods

A longitudinal magnetic resonance imaging study of infants at risk for ASD was carried out on 343 infants, who underwent neuroimaging at 6, 12, and 24 months. Of these infants, 221 were at high risk for ASD because of an older sibling with ASD, and 122 were at low risk with no family history of ASD. A total of 47 infants were diagnosed with ASD at 24 months and were compared with 174 high-risk and 122 low-risk infants without ASD.

Results

Infants who developed ASD had significantly greater extra-axial CSF volume at 6 months compared with both comparison groups without ASD (18% greater than high-risk infants without ASD; Cohen’s d = 0.54). Extra-axial CSF volume remained elevated through 24 months (d = 0.46). Infants with more severe autism symptoms had an even greater volume of extra-axial CSF from 6 to 24 months (24% greater at 6 months, d = 0.70; 15% greater at 24 months, d = 0.70). Extra-axial CSF volume at 6 months predicted which high-risk infants would be diagnosed with ASD at 24 months with an overall accuracy of 69% and corresponding 66% sensitivity and 68% specificity, which was fully cross-validated in a separate sample.

Conclusions

This study confirms and extends previous findings that increased extra-axial CSF is detectable at 6 months in high-risk infants who develop ASD. Future studies will address whether this anomaly is a contributing factor to the etiology of ASD or an early risk marker for ASD.

Section snippets

Participants

Infants at high and low familial risk for ASD were enrolled at four clinical sites (University of North Carolina, University of Washington, Washington University, and Children’s Hospital of Philadelphia) (22). HR infants had an older sibling with a clinical diagnosis of ASD, corroborated by the Autism Diagnostic Interview–Revised (24). LR infants had a typically developing older sibling and no first- or second-degree relatives with intellectual/psychiatric disorders (8). See Supplement for full

Results

There were no significant group differences in demographic variables (race/ethnicity, maternal education level, and family income) (22). There were no significant group differences in age at each MRI time point (Table 1). As expected, at 24 months the HR-ASD group had significantly lower cognitive ability on the Mullen Early Learning Composite and had higher ASD symptom scores on the ADOS (total scores for Social Affect + Repetitive Restricted Behaviors) compared with the two comparison groups (

Discussion

In this study, high-risk infants diagnosed with ASD at 24 months had significantly increased EA-CSF volume from 6 to 24 months of age. Differences in EA-CSF volume were not accounted for by brain size and were observed in the absence of enlarged ventricles. Because of the relatively large sample of infants at risk, it was possible to assess whether EA-CSF volume differed among subgroups defined by autism symptom severity. Increased EA-CSF volume was more pronounced from 6 to 24 months in the

Acknowledgments and Disclosures

This study was supported by grants from the National Institutes of Health (Grant Nos. R01-HD055741 [to JP], R01-HD05571-S1 [to JP], R01-HD059854 [to HCH], T32-HD040127 [to MDS], and U54HD086984 [to Childrenʼs Hospital of Philadelphia]), Autism Speaks [to JP], and the Simons Foundation (Grant No. 140209 [to JP]). The funders had no role in study design, data collection, analysis, data interpretation, or writing of the report.

Author contributions were as follows—study concept and design: all

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    DGA and JP are joint senior authors.

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