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

Mark D. Shen, Sun Hyung Kim, Robert C. McKinstry, Hongbin Gu, Heather C. Hazlett, Christine W Nordahl, Robert W. Emerson, Dennis Shaw, Jed T. Elison, Meghan R. Swanson, Vladimir S. Fonov, Guido Gerig, Stephen R. Dager, Kelly N. Botteron, Sarah Paterson, Robert T. Schultz, Alan C. Evans, Annette M. Estes, Lonnie Zwaigenbaum, Martin A. Styner & 24 others David G Amaral, Joseph Piven, J. Piven, H. C. Hazlett, C. Chappell, S. Dager, A. Estes, D. Shaw, K. Botteron, R. McKinstry, J. Constantino, J. Pruett, R. Schultz, L. Zwaigenbaum, J. Elison, A. C. Evans, D. L. Collins, G. B. Pike, V. Fonov, P. Kostopoulos, S. Das, G. Gerig, M. Styner, H. Gu

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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.

Original languageEnglish (US)
JournalBiological Psychiatry
DOIs
StateAccepted/In press - Aug 5 2016

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Autistic Disorder
Cerebrospinal Fluid
Autism Spectrum Disorder
Subarachnoid Space
Neuroimaging
Siblings
Magnetic Resonance Imaging

Keywords

  • Autism
  • Brain development
  • CSF
  • Extra-axial fluid
  • Infancy
  • MRI

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Increased Extra-axial Cerebrospinal Fluid in High-Risk Infants Who Later Develop Autism. / Shen, Mark D.; Kim, Sun Hyung; McKinstry, Robert C.; Gu, Hongbin; Hazlett, Heather C.; Nordahl, Christine W; Emerson, Robert W.; Shaw, Dennis; Elison, Jed T.; Swanson, Meghan R.; Fonov, Vladimir S.; Gerig, Guido; Dager, Stephen R.; Botteron, Kelly N.; Paterson, Sarah; Schultz, Robert T.; Evans, Alan C.; Estes, Annette M.; Zwaigenbaum, Lonnie; Styner, Martin A.; Amaral, David G; Piven, Joseph; Piven, J.; Hazlett, H. C.; Chappell, C.; Dager, S.; Estes, A.; Shaw, D.; Botteron, K.; McKinstry, R.; Constantino, J.; Pruett, J.; Schultz, R.; Zwaigenbaum, L.; Elison, J.; Evans, A. C.; Collins, D. L.; Pike, G. B.; Fonov, V.; Kostopoulos, P.; Das, S.; Gerig, G.; Styner, M.; Gu, H.

In: Biological Psychiatry, 05.08.2016.

Research output: Contribution to journalArticle

Shen, MD, Kim, SH, McKinstry, RC, Gu, H, Hazlett, HC, Nordahl, CW, Emerson, RW, Shaw, D, Elison, JT, Swanson, MR, Fonov, VS, Gerig, G, Dager, SR, Botteron, KN, Paterson, S, Schultz, RT, Evans, AC, Estes, AM, Zwaigenbaum, L, Styner, MA, Amaral, DG, Piven, J, Piven, J, Hazlett, HC, Chappell, C, Dager, S, Estes, A, Shaw, D, Botteron, K, McKinstry, R, Constantino, J, Pruett, J, Schultz, R, Zwaigenbaum, L, Elison, J, Evans, AC, Collins, DL, Pike, GB, Fonov, V, Kostopoulos, P, Das, S, Gerig, G, Styner, M & Gu, H 2016, 'Increased Extra-axial Cerebrospinal Fluid in High-Risk Infants Who Later Develop Autism', Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2017.02.1095
Shen, Mark D. ; Kim, Sun Hyung ; McKinstry, Robert C. ; Gu, Hongbin ; Hazlett, Heather C. ; Nordahl, Christine W ; Emerson, Robert W. ; Shaw, Dennis ; Elison, Jed T. ; Swanson, Meghan R. ; Fonov, Vladimir S. ; Gerig, Guido ; Dager, Stephen R. ; Botteron, Kelly N. ; Paterson, Sarah ; Schultz, Robert T. ; Evans, Alan C. ; Estes, Annette M. ; Zwaigenbaum, Lonnie ; Styner, Martin A. ; Amaral, David G ; Piven, Joseph ; Piven, J. ; Hazlett, H. C. ; Chappell, C. ; Dager, S. ; Estes, A. ; Shaw, D. ; Botteron, K. ; McKinstry, R. ; Constantino, J. ; Pruett, J. ; Schultz, R. ; Zwaigenbaum, L. ; Elison, J. ; Evans, A. C. ; Collins, D. L. ; Pike, G. B. ; Fonov, V. ; Kostopoulos, P. ; Das, S. ; Gerig, G. ; Styner, M. ; Gu, H. / Increased Extra-axial Cerebrospinal Fluid in High-Risk Infants Who Later Develop Autism. In: Biological Psychiatry. 2016.
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title = "Increased Extra-axial Cerebrospinal Fluid in High-Risk Infants Who Later Develop Autism",
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.",
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author = "Shen, {Mark D.} and Kim, {Sun Hyung} and McKinstry, {Robert C.} and Hongbin Gu and Hazlett, {Heather C.} and Nordahl, {Christine W} and Emerson, {Robert W.} and Dennis Shaw and Elison, {Jed T.} and Swanson, {Meghan R.} and Fonov, {Vladimir S.} and Guido Gerig and Dager, {Stephen R.} and Botteron, {Kelly N.} and Sarah Paterson and Schultz, {Robert T.} and Evans, {Alan C.} and Estes, {Annette M.} and Lonnie Zwaigenbaum and Styner, {Martin A.} and Amaral, {David G} and Joseph Piven and J. Piven and Hazlett, {H. C.} and C. Chappell and S. Dager and A. Estes and D. Shaw and K. Botteron and R. McKinstry and J. Constantino and J. Pruett and R. Schultz and L. Zwaigenbaum and J. Elison and Evans, {A. C.} and Collins, {D. L.} and Pike, {G. B.} and V. Fonov and P. Kostopoulos and S. Das and G. Gerig and M. Styner and H. Gu",
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TY - JOUR

T1 - Increased Extra-axial Cerebrospinal Fluid in High-Risk Infants Who Later Develop Autism

AU - Shen, Mark D.

AU - Kim, Sun Hyung

AU - McKinstry, Robert C.

AU - Gu, Hongbin

AU - Hazlett, Heather C.

AU - Nordahl, Christine W

AU - Emerson, Robert W.

AU - Shaw, Dennis

AU - Elison, Jed T.

AU - Swanson, Meghan R.

AU - Fonov, Vladimir S.

AU - Gerig, Guido

AU - Dager, Stephen R.

AU - Botteron, Kelly N.

AU - Paterson, Sarah

AU - Schultz, Robert T.

AU - Evans, Alan C.

AU - Estes, Annette M.

AU - Zwaigenbaum, Lonnie

AU - Styner, Martin A.

AU - Amaral, David G

AU - Piven, Joseph

AU - Piven, J.

AU - Hazlett, H. C.

AU - Chappell, C.

AU - Dager, S.

AU - Estes, A.

AU - Shaw, D.

AU - Botteron, K.

AU - McKinstry, R.

AU - Constantino, J.

AU - Pruett, J.

AU - Schultz, R.

AU - Zwaigenbaum, L.

AU - Elison, J.

AU - Evans, A. C.

AU - Collins, D. L.

AU - Pike, G. B.

AU - Fonov, V.

AU - Kostopoulos, P.

AU - Das, S.

AU - Gerig, G.

AU - Styner, M.

AU - Gu, H.

PY - 2016/8/5

Y1 - 2016/8/5

N2 - 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.

AB - 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.

KW - Autism

KW - Brain development

KW - CSF

KW - Extra-axial fluid

KW - Infancy

KW - MRI

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U2 - 10.1016/j.biopsych.2017.02.1095

DO - 10.1016/j.biopsych.2017.02.1095

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JF - Biological Psychiatry

SN - 0006-3223

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