Format

Send to

Choose Destination
J Neurodev Disord. 2019 Dec 16;11(1):36. doi: 10.1186/s11689-019-9293-x.

Early white matter development is abnormal in tuberous sclerosis complex patients who develop autism spectrum disorder.

Author information

1
Computational Radiology Laboratory, Department of Radiology, Boston Children's Hospital, Harvard Medical School, Harvard University, Boston, Massachusetts, USA.
2
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Harvard University, Boston, Massachusetts, USA.
3
Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
4
Department of Neurology and Rehabilitation Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
5
Department of Pediatrics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.
6
Division of Pediatric Neurology, University of California at Los Angeles Mattel Children's Hospital, David Geffen School of Medicine, University of California, California, Los Angeles, USA.
7
F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Harvard University, Boston, Massachusetts, USA.
8
Computational Radiology Laboratory, Department of Radiology, Boston Children's Hospital, Harvard Medical School, Harvard University, Boston, Massachusetts, USA. simon.warfield@childrens.harvard.edu.

Abstract

BACKGROUND:

Autism spectrum disorder (ASD) is prevalent in tuberous sclerosis complex (TSC), occurring in approximately 50% of patients, and is hypothesized to be caused by disruption of neural circuits early in life. Tubers, or benign hamartomas distributed stochastically throughout the brain, are the most conspicuous of TSC neuropathology, but have not been consistently associated with ASD. Widespread neuropathology of the white matter, including deficits in myelination, neuronal migration, and axon formation, exist and may underlie ASD in TSC. We sought to identify the neural circuits associated with ASD in TSC by identifying white matter microstructural deficits in a prospectively recruited, longitudinally studied cohort of TSC infants.

METHODS:

TSC infants were recruited within their first year of life and longitudinally imaged at time of recruitment, 12 months of age, and at 24 months of age. Autism was diagnosed at 24 months of age with the ADOS-2. There were 108 subjects (62 TSC-ASD, 55% male; 46 TSC+ASD, 52% male) with at least one MRI and a 24-month ADOS, for a total of 187 MRI scans analyzed (109 TSC-ASD; 78 TSC+ASD). Diffusion tensor imaging properties of multiple white matter fiber bundles were sampled using a region of interest approach. Linear mixed effects modeling was performed to test the hypothesis that infants who develop ASD exhibit poor white matter microstructural integrity over the first 2 years of life compared to those who do not develop ASD.

RESULTS:

Subjects with TSC and ASD exhibited reduced fractional anisotropy in 9 of 17 white matter regions, sampled from the arcuate fasciculus, cingulum, corpus callosum, anterior limbs of the internal capsule, and the sagittal stratum, over the first 2 years of life compared to TSC subjects without ASD. Mean diffusivity trajectories did not differ between groups.

CONCLUSIONS:

Underconnectivity across multiple white matter fiber bundles develops over the first 2 years of life in subjects with TSC and ASD. Future studies examining brain-behavior relationships are needed to determine how variation in the brain structure is associated with ASD symptoms.

KEYWORDS:

Autism spectrum disorder; Diffusion tensor imaging; Infant brain development; Tuberous sclerosis complex; White matter

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center