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Multicenter Study
. 2017 Aug 1;82(3):186-193.
doi: 10.1016/j.biopsych.2017.02.1095. Epub 2017 Mar 6.

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

Mark D Shen  1 , Sun Hyung Kim  2 , Robert C McKinstry  3 , Hongbin Gu  4 , Heather C Hazlett  2 , Christine W Nordahl  5 , Robert W Emerson  2 , Dennis Shaw  6 , Jed T Elison  7 , Meghan R Swanson  2 , Vladimir S Fonov  8 , Guido Gerig  9 , Stephen R Dager  6 , Kelly N Botteron  3 , Sarah Paterson  10 , Robert T Schultz  11 , Alan C Evans  8 , Annette M Estes  12 , Lonnie Zwaigenbaum  13 , Martin A Styner  2 , David G Amaral  5 , J Piven  14 , H C Hazlett  14 , C Chappell  14 , S Dager  15 , A Estes  15 , D Shaw  15 , K Botteron  16 , R McKinstry  16 , J Constantino  16 , J Pruett  16 , R Schultz  17 , L Zwaigenbaum  18 , J Elison  19 , A C Evans  20 , D L Collins  20 , G B Pike  20 , V Fonov  20 , P Kostopoulos  20 , S Das  20 , G Gerig  21 , M Styner  22 , H Gu  23 , Joseph Piven  2 ; Infant Brain Imaging Study Network
Affiliations
Multicenter Study

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

Mark D Shen et al. Biol Psychiatry. .

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.

Keywords: Autism; Brain development; CSF; Extra-axial fluid; Infancy; MRI.

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Conflict of interest statement

Financial Disclosures

All co-authors report no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1
Figure 1. Automated quantification of extra-axial CSF
T1- and T2-weighted images were acquired from each participant and used to segment the cerebrospinal fluid in the subarachnoid space between the dura and cortical surface, dorsal to the horizontal plane of the anterior-posterior commissure.
Figure 2
Figure 2. Example brain images indicating the presence of increased extra-axial CSF
(A) T1-weighted coronal images of a low-risk infant with normal MRI at 6, 12, and 24 months. (B) T1-weighted coronal images of a high-risk infant with increased extra-axial CSF at 6, 12, and 24 months. This child was diagnosed with ASD at 24 months.
Figure 3
Figure 3. Infants later diagnosed with ASD had increased extra-axial CSF by 6 months, which remained significantly elevated through 24 months
Note: LS means are adjusted for covariates in model [age, sex, total cerebral volume, scan site]. Error bars = ±1 SEM. *p<0.005 vs. HR-negative and vs. LR-negative. Percent differences are in relation to the HR-negative group (Cohen���s d).
Figure 4
Figure 4. ASD subgroup with more severe autism symptoms had a greater increase of extra-axial CSF throughout 6-24 months compared to all other groups
The ASD group was stratified into subgroups according to empirically derived categories on the ADOS. The ASD subgroup with more severe autism symptoms (HR-ASD-High) had a more pronounced increase in extra-axial CSF. Note: LS means are adjusted for covariates in model [age, sex, total cerebral volume, scan site]. Error bars = ±1 SEM. **p<0.0005 vs. HR-negative and vs. LR-negative, p<0.05 vs. HR-ASD-Moderate. Percent differences are in relation to the HR-negative group (Cohen’s d).
Figure 5
Figure 5. Extra-axial CSF is significantly correlated with poorer motor skills in the ASD group
Across the entire HR-ASD group, extra-axial CSF volume at 6 months of age was negatively correlated with motor scores at 6 months on the (A) direct examination Mullen gross motor subscale (standardized norm of M[SD] = 50[10]); and (B) parent-report Vineland motor subscale (standardized norm of M[SD] = 100[15]).
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Comment in

  • Charting a Course for Autism Biomarkers.
    Pelphrey K. Pelphrey K. Biol Psychiatry. 2017 Aug 1;82(3):155-156. doi: 10.1016/j.biopsych.2017.06.002. Biol Psychiatry. 2017. PMID: 28693737 Free PMC article. No abstract available.

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