title: Increased Extra-axial Cerebrospinal Fluid in High-Risk Infants Who Later Develop Autism.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Carolina Institute for Developmental Disabilities and Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina; MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California, Davis, School of Medicine, Sacramento, California. Electronic address: mark_shen@med.unc.edu.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Shen
authors.affiliation: Carolina Institute for Developmental Disabilities and Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
authors.forename: Sun Hyung
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missourt.
authors.forename: Robert C
authors.initials: RC
authors.lastname: McKinstry
authors.affiliation: Carolina Institute for Developmental Disabilities and Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina; Department of Biostatistics, School of Global Public Health, University of North Carolina at Chapel Hill School of Global Public Health, Chapel Hill, North Carolina.
authors.forename: Hongbin
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authors.affiliation: Carolina Institute for Developmental Disabilities and Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Hazlett
authors.affiliation: MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California, Davis, School of Medicine, Sacramento, California.
authors.forename: Christine W
authors.initials: CW
authors.lastname: Nordahl
authors.affiliation: Carolina Institute for Developmental Disabilities and Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Emerson
authors.affiliation: Department of Radiology, University of Washington Medical Center, Seattle, Washington.
authors.forename: Dennis
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authors.affiliation: Institute of Child Development, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jed T
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authors.lastname: Elison
authors.affiliation: Carolina Institute for Developmental Disabilities and Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
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authors.initials: MR
authors.lastname: Swanson
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, Quebec.
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authors.affiliation: Computer Science & Engineering, New York University Tandon School of Engineering, New York, New York.
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authors.lastname: Gerig
authors.affiliation: Department of Radiology, University of Washington Medical Center, Seattle, Washington.
authors.forename: Stephen R
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authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missourt.
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authors.affiliation: Department of Psychology, Temple University, Philadelphia, Pennsylvania.
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authors.affiliation: Center for Autism Research, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
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authors.affiliation: Department of Speech and Hearing Science, University of Washington, Seattle, Washington.
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authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
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authors.affiliation: Carolina Institute for Developmental Disabilities and Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
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authors.lastname: Styner
authors.affiliation: MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California, Davis, School of Medicine, Sacramento, California.
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authors.affiliation: Clinical sites-University of North Carolina.
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authors.affiliation: University of Washington.
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authors.lastname: Shaw
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authors.lastname: Botteron
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authors.forename: R
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authors.lastname: McKinstry
authors.affiliation: Washington University.
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authors.lastname: Constantino
authors.affiliation: Washington University.
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authors.initials: J
authors.lastname: Pruett
authors.affiliation: Children's Hospital of Philadelphia.
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authors.affiliation: Data Coordinating Center-Montreal Neurological Institute.
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authors.affiliation: Data Coordinating Center-Montreal Neurological Institute.
authors.forename: D L
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authors.affiliation: Data Coordinating Center-Montreal Neurological Institute.
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authors.affiliation: Data Coordinating Center-Montreal Neurological Institute.
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authors.affiliation: Data Coordinating Center-Montreal Neurological Institute.
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authors.affiliation: Image Processing Core-New York University.
authors.forename: G
authors.initials: G
authors.lastname: Gerig
authors.affiliation: University of North Carolina.
authors.forename: M
authors.initials: M
authors.lastname: Styner
authors.affiliation: Statistical Analysis Core-University of North Carolina.
authors.forename: H
authors.initials: H
authors.lastname: Gu
authors.affiliation: Carolina Institute for Developmental Disabilities and Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
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authors.lastname: Piven
mesh_terms: D000067877:Autism Spectrum Disorder / Q000134:cerebrospinal fluid* / Q000000981:diagnostic imaging* / Q000235:genetics; D001368:Axis, Cervical Vertebra; D002552:Cerebral Ventricles / Q000000981:diagnostic imaging; D002555:Cerebrospinal Fluid / Q000000981:diagnostic imaging*; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007223:Infant; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D009048:Motor Skills; D009929:Organ Size; D010363:Pattern Recognition, Automated; D062706:Prodromal Symptoms; D011379:Prognosis; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D035781:Siblings; D013346:Subarachnoid Space
keywords: Autism; Brain development; CSF; Extra-axial fluid; Infancy; MRI