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, 136 (Pt 9), 2825-35

Early Brain Enlargement and Elevated Extra-Axial Fluid in Infants Who Develop Autism Spectrum Disorder

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Early Brain Enlargement and Elevated Extra-Axial Fluid in Infants Who Develop Autism Spectrum Disorder

Mark D Shen et al. Brain.

Abstract

Prospective studies of infants at risk for autism spectrum disorder have provided important clues about the early behavioural symptoms of autism spectrum disorder. Diagnosis of autism spectrum disorder, however, is not currently made until at least 18 months of age. There is substantially less research on potential brain-based differences in the period between 6 and 12 months of age. Our objective in the current study was to use magnetic resonance imaging to identify any consistently observable brain anomalies in 6-9 month old infants who would later develop autism spectrum disorder. We conducted a prospective infant sibling study with longitudinal magnetic resonance imaging scans at three time points (6-9, 12-15, and 18-24 months of age), in conjunction with intensive behavioural assessments. Fifty-five infants (33 'high-risk' infants having an older sibling with autism spectrum disorder and 22 'low-risk' infants having no relatives with autism spectrum disorder) were imaged at 6-9 months; 43 of these (27 high-risk and 16 low-risk) were imaged at 12-15 months; and 42 (26 high-risk and 16 low-risk) were imaged again at 18-24 months. Infants were classified as meeting criteria for autism spectrum disorder, other developmental delays, or typical development at 24 months or later (mean age at outcome: 32.5 months). Compared with the other two groups, infants who developed autism spectrum disorder (n = 10) had significantly greater extra-axial fluid at 6-9 months, which persisted and remained elevated at 12-15 and 18-24 months. Extra-axial fluid is characterized by excessive cerebrospinal fluid in the subarachnoid space, particularly over the frontal lobes. The amount of extra-axial fluid detected as early as 6 months was predictive of more severe autism spectrum disorder symptoms at the time of outcome. Infants who developed autism spectrum disorder also had significantly larger total cerebral volumes at both 12-15 and 18-24 months of age. This is the first magnetic resonance imaging study to prospectively evaluate brain growth trajectories from infancy in children who develop autism spectrum disorder. The presence of excessive extra-axial fluid detected as early as 6 months and the lack of resolution by 24 months is a hitherto unreported brain anomaly in infants who later develop autism spectrum disorder. This is also the first magnetic resonance imaging evidence of brain enlargement in autism before age 2. These findings raise the potential for the use of structural magnetic resonance imaging to aid in the early detection of children at risk for autism spectrum disorder or other neurodevelopmental disorders.

Keywords: autism; cerebrospinal fluid; external hydrocephalus; infant brain development; magnetic resonance imaging.

Figures

Figure 1
Figure 1
(A) Low-risk infant with normal MRI at 9 months, confirmed as having typical development at 36 months. (B) High-risk infant with excessive extra-axial fluid at 9 months. (C) The same high-risk infant with excessive extra-axial fluid still present at 15 months, and (D) at 21 months; infant was diagnosed with ASD at 36 months.
Figure 2
Figure 2
(A) T2-weighted image of a low-risk infant with normal MRI at 9 months, confirmed as having typical development at 36 months. CSF is indicated as brighter regions in these images. Images are of a horizontal section (left) coronal section (middle) and sagittal section (right) through the brain. (B) Similar T2-weighted images of a high-risk infant with excessive extra-axial fluid at 9 months, diagnosed with ASD at 36 months.
Figure 3
Figure 3
Quantification of extra-axial fluid. (A) Manual tracing of dura on successive coronal slices are summed to yield intracranial volume; (B) semi-automated tissue segmentation with manual intervention yields total cerebral volume; (C) resulting space between dura and cerebral surface yields extra-axial fluid volume.
Figure 4
Figure 4
Mean total cerebral volume by outcome group at each MRI time point.
Figure 5
Figure 5
Mean extra-axial fluid volume by outcome group at each MRI time point.
Figure 6
Figure 6
Predicting ASD cases using an extra-axial fluid threshold. The dotted line represents a level of fluid-to-brain volume that yields 78% sensitivity (percentage of ASD cases above the threshold) and 79% specificity (percentage of non-ASD cases below the threshold) in predicting ASD cases at 12–15 months (i.e. ratio of extra-axial fluid to total cerebral volume = 0.14).

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