Journal Article

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

Krueger, Darcy A., Prabhu, Sanjay P., Scherrer, Benoit, Wu, Joyce Y., Filip-Dhima, Rajna, Sahin, Mustafa, Davis, Peter E., Northrup, Hope, Tomas-Fernandez, Xavier, Peters, Jurriaan M., Warfield, Simon K., Prohl, Anna K., Bebin, E. Martina

2019

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Age / Anisotropy / Autism / Autism spectrum disorder / Autism Spectrum Disorder - complications / Autism Spectrum Disorder - pathology / Behavior / Biomedical and Life Sciences / Biomedicine / Brain - growth & development / Brain - pathology / Brain research / Cell migration / Child, Preschool / Cingulum / Circuits / Complex patients / Corpus callosum / Diagnostic imaging / Diffusion Tensor Imaging / Electric equipment industry / Enrollments / Female / Future predictions / Human Genetics / Humans / IDDRC 2019 / Image processing / Infant / Infant brain development / Infants / Intellectual disabilities / Longitudinal Studies / Magnetic resonance imaging / Male / Myelination / Neural circuitry / Neural networks / Neuroimaging / Neurology / Neurons / Neuropathology / Neuropsychology / Neurosciences / Patients / Pediatrics / Prospective Studies / Psychiatry / Scanners / Substantia alba / Teenagers / Tuberous sclerosis / Tuberous Sclerosis - complications / Tuberous Sclerosis - pathology / Tuberous sclerosis complex / White matter / White Matter - growth & development / White Matter - pathology