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Original Investigation |

Atypical Developmental Patterns of Brain Chemistry in Children With Autism Spectrum Disorder

Neva M. Corrigan, PhD1; Dennis W. W. Shaw, MD1,6; Annette M. Estes, PhD2; Todd L. Richards, PhD1; Jeff Munson, PhD3; Seth D. Friedman, PhD6; Geraldine Dawson, PhD7,8; Alan A. Artru, MD4; Stephen R. Dager, MD1,5
[+] Author Affiliations
1Department of Radiology, University of Washington, Seattle
2Department of Speech and Hearing Sciences, University of Washington, Seattle
3Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle
4Department of Anesthesiology, University of Washington, Seattle
5Department of Bioengineering, University of Washington, Seattle
6Department of Radiology, Seattle Children’s Hospital, Washington
7Autism Speaks, New York, New York
8Department of Psychiatry, University of North Carolina, Chapel Hill
JAMA Psychiatry. 2013;70(9):964-974. doi:10.1001/jamapsychiatry.2013.1388.
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Importance  Autism spectrum disorder (ASD) is a neurodevelopmental disorder with symptoms emerging during early childhood. The pathophysiology underlying the disorder remains incompletely understood.

Objective  To examine cross-sectional and longitudinal patterns of brain chemical concentrations in children with ASD or idiopathic developmental delay (DD) from 3 different age points, beginning early in the clinical course.

Design  Proton magnetic resonance spectroscopic imaging data were acquired longitudinally for children with ASD or DD, and primarily cross-sectionally for children with typical development (TD), at 3 to 4, 6 to 7, and 9 to 10 years of age.

Setting  Recruitment, diagnostic assessments, and magnetic resonance imaging were performed at the University of Washington in Seattle.

Participants  Seventy-three children (45 with ASD, 14 with DD, and 14 with TD) at 3 to 4 years of age; 69 children (35 with ASD, 14 with DD, and 20 with TD) at 6 to 7 years of age; and 77 children (29 with ASD, 15 with DD, and 33 with TD) at 9 to 10 years of age.

Main Outcomes and Measures  Concentrations of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), myo-inositol (mI), and glutamine plus glutamate (Glx) in cerebral gray matter (GM) and white matter (WM) at 3 to 4, 6 to 7, and 9 to 10 years of age, and calculation of rates of change of these chemicals between 3 and 10 years of age.

Results  At 3 to 4 years of age, the ASD group exhibited lower NAA, Cho, and Cr concentrations than did the TD group in both GM and WM, alterations that largely were not observed at 9 to 10 years of age. The DD group exhibited reduced GM and WM NAA concentrations at 3 to 4 years of age; GM NAA concentrations remained reduced at 9 to 10 years of age compared with the TD group. There were distinct differences between the ASD and DD groups in the rates of GM NAA, Cho, and Cr changes between 3 and 10 years of age.

Conclusions and Relevance  The GM chemical changes between 3 and 10 years of age differentiated the children with ASD from those with DD. Most notably, a dynamic reversal of GM NAA reductions was observed in the children with ASD. By contrast, persistent GM NAA reductions in the children with DD suggest a different, more static, underlying developmental process.

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Figure 1.
Example of Gray Matter Spectra for a Child With Autism Spectrum Disorder at 3, 6, and 9 Years of Age

The black lines are the combined spectra, and the gray lines represent the LCModel fit for N-acetylaspartate (NAA), choline (Cho), creatine (Cr), myo-inositol (mI), and the combined signal from glutamine and glutamate (Glx). All spectra are referenced to a corresponding unsuppressed water scan and scaled to the same absolute maximum y-axis value.

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Figure 2.
Gray Matter Chemical Concentrations

Gray matter chemical concentrations by diagnostic group plotted vs age. Individual data points represent measurements of chemical concentrations for individual participants. The yellow and blue lines represent the linear mixed-effects model results for the autism spectrum disorder (ASD) and developmental delay (DD) groups, respectively. The dashed gray line, which represents a simple linear fit of the cross-sectional data points for the typical development (TD) group, is shown as a point of reference but is not directly comparable to the longitudinal findings of the other 2 groups. Cho indicates choline; Cr, creatine; Glx, glutamine plus glutamate; mI, myo-inositol; and NAA, N-acetylaspartate.

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Place holder to copy figure label and caption
Figure 3.
White Matter Chemical Concentrations

White matter chemical concentrations by diagnostic group plotted vs age. Individual data points represent measurements of chemical concentrations for individual participants. The yellow and blue lines represent the linear mixed-effects model results for the autism spectrum disorder (ASD) and developmental delay (DD) groups, respectively. The dashed gray line, which represents a simple linear fit of the cross-sectional data points for the typical development (TD) group, is shown as a point of reference but is not directly comparable to the longitudinal findings of the other 2 groups. Cho indicates choline; Cr, creatine; Glx, glutamine plus glutamate; mI, myo-inositol; and NAA, N-acetylaspartate.

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