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

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 bra...

Full description

Bibliographic Details
Main Authors: Anna K. Prohl, Benoit Scherrer, Xavier Tomas-Fernandez, Peter E. Davis, Rajna Filip-Dhima, Sanjay P. Prabhu, Jurriaan M. Peters, E. Martina Bebin, Darcy A. Krueger, Hope Northrup, Joyce Y. Wu, Mustafa Sahin, Simon K. Warfield, on behalf of the TACERN Study Group
Format: Article
Language:English
Published: BMC 2019-12-01
Series:Journal of Neurodevelopmental Disorders
Subjects:
Online Access:https://doi.org/10.1186/s11689-019-9293-x
id doaj-6eb2a9d3dc9d402682caa0776bb9eb4a
record_format Article
collection DOAJ
language English
format Article
sources DOAJ
author Anna K. Prohl
Benoit Scherrer
Xavier Tomas-Fernandez
Peter E. Davis
Rajna Filip-Dhima
Sanjay P. Prabhu
Jurriaan M. Peters
E. Martina Bebin
Darcy A. Krueger
Hope Northrup
Joyce Y. Wu
Mustafa Sahin
Simon K. Warfield
on behalf of the TACERN Study Group
spellingShingle Anna K. Prohl
Benoit Scherrer
Xavier Tomas-Fernandez
Peter E. Davis
Rajna Filip-Dhima
Sanjay P. Prabhu
Jurriaan M. Peters
E. Martina Bebin
Darcy A. Krueger
Hope Northrup
Joyce Y. Wu
Mustafa Sahin
Simon K. Warfield
on behalf of the TACERN Study Group
Early white matter development is abnormal in tuberous sclerosis complex patients who develop autism spectrum disorder
Journal of Neurodevelopmental Disorders
Autism spectrum disorder
Tuberous sclerosis complex
Infant brain development
Diffusion tensor imaging
White matter
author_facet Anna K. Prohl
Benoit Scherrer
Xavier Tomas-Fernandez
Peter E. Davis
Rajna Filip-Dhima
Sanjay P. Prabhu
Jurriaan M. Peters
E. Martina Bebin
Darcy A. Krueger
Hope Northrup
Joyce Y. Wu
Mustafa Sahin
Simon K. Warfield
on behalf of the TACERN Study Group
author_sort Anna K. Prohl
title Early white matter development is abnormal in tuberous sclerosis complex patients who develop autism spectrum disorder
title_short Early white matter development is abnormal in tuberous sclerosis complex patients who develop autism spectrum disorder
title_full Early white matter development is abnormal in tuberous sclerosis complex patients who develop autism spectrum disorder
title_fullStr Early white matter development is abnormal in tuberous sclerosis complex patients who develop autism spectrum disorder
title_full_unstemmed Early white matter development is abnormal in tuberous sclerosis complex patients who develop autism spectrum disorder
title_sort early white matter development is abnormal in tuberous sclerosis complex patients who develop autism spectrum disorder
publisher BMC
series Journal of Neurodevelopmental Disorders
issn 1866-1947
1866-1955
publishDate 2019-12-01
description 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.
topic Autism spectrum disorder
Tuberous sclerosis complex
Infant brain development
Diffusion tensor imaging
White matter
url https://doi.org/10.1186/s11689-019-9293-x
work_keys_str_mv AT annakprohl earlywhitematterdevelopmentisabnormalintuberoussclerosiscomplexpatientswhodevelopautismspectrumdisorder
AT benoitscherrer earlywhitematterdevelopmentisabnormalintuberoussclerosiscomplexpatientswhodevelopautismspectrumdisorder
AT xaviertomasfernandez earlywhitematterdevelopmentisabnormalintuberoussclerosiscomplexpatientswhodevelopautismspectrumdisorder
AT peteredavis earlywhitematterdevelopmentisabnormalintuberoussclerosiscomplexpatientswhodevelopautismspectrumdisorder
AT rajnafilipdhima earlywhitematterdevelopmentisabnormalintuberoussclerosiscomplexpatientswhodevelopautismspectrumdisorder
AT sanjaypprabhu earlywhitematterdevelopmentisabnormalintuberoussclerosiscomplexpatientswhodevelopautismspectrumdisorder
AT jurriaanmpeters earlywhitematterdevelopmentisabnormalintuberoussclerosiscomplexpatientswhodevelopautismspectrumdisorder
AT emartinabebin earlywhitematterdevelopmentisabnormalintuberoussclerosiscomplexpatientswhodevelopautismspectrumdisorder
AT darcyakrueger earlywhitematterdevelopmentisabnormalintuberoussclerosiscomplexpatientswhodevelopautismspectrumdisorder
AT hopenorthrup earlywhitematterdevelopmentisabnormalintuberoussclerosiscomplexpatientswhodevelopautismspectrumdisorder
AT joyceywu earlywhitematterdevelopmentisabnormalintuberoussclerosiscomplexpatientswhodevelopautismspectrumdisorder
AT mustafasahin earlywhitematterdevelopmentisabnormalintuberoussclerosiscomplexpatientswhodevelopautismspectrumdisorder
AT simonkwarfield earlywhitematterdevelopmentisabnormalintuberoussclerosiscomplexpatientswhodevelopautismspectrumdisorder
AT onbehalfofthetacernstudygroup earlywhitematterdevelopmentisabnormalintuberoussclerosiscomplexpatientswhodevelopautismspectrumdisorder
_version_ 1724376259970990080
spelling doaj-6eb2a9d3dc9d402682caa0776bb9eb4a2020-12-20T12:38:43ZengBMCJournal of Neurodevelopmental Disorders1866-19471866-19552019-12-0111111610.1186/s11689-019-9293-xEarly white matter development is abnormal in tuberous sclerosis complex patients who develop autism spectrum disorderAnna K. Prohl0Benoit Scherrer1Xavier Tomas-Fernandez2Peter E. Davis3Rajna Filip-Dhima4Sanjay P. Prabhu5Jurriaan M. Peters6E. Martina Bebin7Darcy A. Krueger8Hope Northrup9Joyce Y. Wu10Mustafa Sahin11Simon K. Warfield12on behalf of the TACERN Study GroupComputational Radiology Laboratory, Department of Radiology, Boston Children’s Hospital, Harvard Medical School, Harvard UniversityComputational Radiology Laboratory, Department of Radiology, Boston Children’s Hospital, Harvard Medical School, Harvard UniversityComputational Radiology Laboratory, Department of Radiology, Boston Children’s Hospital, Harvard Medical School, Harvard UniversityDepartment of Neurology, Boston Children’s Hospital, Harvard Medical School, Harvard UniversityDepartment of Neurology, Boston Children’s Hospital, Harvard Medical School, Harvard UniversityComputational Radiology Laboratory, Department of Radiology, Boston Children’s Hospital, Harvard Medical School, Harvard UniversityComputational Radiology Laboratory, Department of Radiology, Boston Children’s Hospital, Harvard Medical School, Harvard UniversityDepartment of Neurology, University of Alabama at BirminghamDepartment of Neurology and Rehabilitation Medicine, Cincinnati Children’s Hospital Medical CenterDepartment of Pediatrics, McGovern Medical School, University of Texas Health Science Center at HoustonDivision of Pediatric Neurology, University of California at Los Angeles Mattel Children’s Hospital, David Geffen School of Medicine, University of CaliforniaDepartment of Neurology, Boston Children’s Hospital, Harvard Medical School, Harvard UniversityComputational Radiology Laboratory, Department of Radiology, Boston Children’s Hospital, Harvard Medical School, Harvard UniversityAbstract 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.https://doi.org/10.1186/s11689-019-9293-xAutism spectrum disorderTuberous sclerosis complexInfant brain developmentDiffusion tensor imagingWhite matter