scholarly journals Cortical Overgrowth in a Preclinical Forebrain Organoid Model of CNTNAP2-Associated Autism Spectrum Disorder

2019 ◽  
Author(s):  
Job O. de Jong ◽  
Ceyda Llapashtica ◽  
Kevin Strauss ◽  
Frank Provenzano ◽  
Yan Sun ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Gray Matter Volume ◽  
Brain Mri ◽  
Neuronal Cell ◽  
Cell Types ◽  
Pathogenic Mutation ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Differentially Expressed ◽  
Public Health Burden

ABSTRACTAutism spectrum disorder (ASD) represents a major public health burden but translating promising treatment findings from preclinical non-human models of ASD to the clinic has remained challenging. The recent development of forebrain organoids generated from human induced pluripotent stem cells (hiPSCs) derived from subjects with brain disorders is a promising method to study human-specific neurobiology, and may facilitate the development of novel therapeutics.In this study, we utilized forebrain organoids generated from hiPSCs derived from patients from the Old Order Amish community with a rare syndromic form of ASD, carrying a homozygous c.3709DelG mutation in CNTNAP2 and healthy controls to investigate the effects of this mutation on cortical embryonic development.Patients carrying the c.3709DelG mutation in CNTNAP2 present with an increased head circumference and brain MRI reveals an increase in gray matter volume. Patient-derived organoids displayed an increase in total volume that was driven by an increased proliferation in neural progenitor cells, leading to an increase in the generation of cortical neuronal and non-neuronal cell types. The observed phenotypes were rescued after correction of the pathogenic mutation using CRISPR-Cas9. RNA sequencing revealed 339 genes differentially expressed between patient- and control-derived organoids of which a subset are implicated in cell proliferation and neurogenesis. Notably, these differentially expressed genes included previously identified ASD-associated genes and are enriched for genes in ASD-associated weighted gene co-expression networks.This work provides a critical step towards understanding the role of CNTNAP2 in human cortical development and has important mechanistic implications for ASD associated with brain overgrowth. This CNTNAP2 organoid model provides opportunity for further mechanistic inquiry and development of new therapeutic strategies for ASD.

The Implications of Brain MRI in Autism Spectrum Disorder

2016 ◽  
Vol 31 (14) ◽  
pp. 1611-1616 ◽  
Author(s):  
Alison S. Cooper ◽  
Eron Friedlaender ◽  
Susan E. Levy ◽  
Karuna V. Shekdar ◽  
Andrea Bennett Bradford ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Brain Mri ◽  
Brain Magnetic Resonance Imaging ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Neurologic Examination ◽  
Resonance Imaging ◽  
Magnetic Resonance Imaging Mri ◽  
Low Prevalence

Our objective was to describe the types of providers who refer children with autism spectrum disorder (ASD) for brain magnetic resonance imaging (MRI), the referral reason, and MRI results. The most common referral reasons were autism spectrum disorder with seizures (33.7%), autism spectrum disorder alone (26.3%), and autism spectrum disorder with abnormal neurologic examination or preexisting finding (24%). Neurology (62.5%), general pediatric (22.3%), and developmental/behavioral practitioners (8.9%) referred the most patients. The prevalence of definite pathology was highest in children referred for autism spectrum disorder with abnormal neurologic examination/preexisting finding (26.2%, 95% CI: 16.8%-36%), headaches (25.7%, 95% CI: 11.2%-40.2%), or seizures (22%, 95% CI: 14.6%-29.5%), and was lowest in children referred for autism spectrum disorder alone (6.5%, 95% CI: 1.5%-11.6%). We concluded that there is a low prevalence of definite pathology in children with autism spectrum disorder undergoing brain MRI. In children with abnormal neurologic examination or preexisting finding, seizures, or headaches, one may consider performing brain MRI given the higher prevalence of pathology.

scholarly journals Comparative meta-analyses of brain structural and functional abnormalities during cognitive control in attention-deficit/hyperactivity disorder and autism spectrum disorder

2020 ◽  
Vol 50 (6) ◽  
pp. 894-919 ◽  
Author(s):  
Steve Lukito ◽  
Luke Norman ◽  
Christina Carlisi ◽  
Joaquim Radua ◽  
Heledd Hart ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Attention Deficit Hyperactivity Disorder ◽  
Cognitive Control ◽  
Attention Deficit ◽  
Meta Analysis ◽  
Gray Matter Volume ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Hyperactivity Disorder ◽  
Meta Analyses

AbstractBackgroundPeople with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) have abnormalities in frontal, temporal, parietal and striato-thalamic networks. It is unclear to what extent these abnormalities are distinctive or shared. This comparative meta-analysis aimed to identify the most consistent disorder-differentiating and shared structural and functional abnormalities.MethodsSystematic literature search was conducted for whole-brain voxel-based morphometry (VBM) and functional magnetic resonance imaging (fMRI) studies of cognitive control comparing people with ASD or ADHD with typically developing controls. Regional gray matter volume (GMV) and fMRI abnormalities during cognitive control were compared in the overall sample and in age-, sex- and IQ-matched subgroups with seed-based d mapping meta-analytic methods.ResultsEighty-six independent VBM (1533 ADHD and 1295 controls; 1445 ASD and 1477 controls) and 60 fMRI datasets (1001 ADHD and 1004 controls; 335 ASD and 353 controls) were identified. The VBM meta-analyses revealed ADHD-differentiating decreased ventromedial orbitofrontal (z = 2.22, p < 0.0001) but ASD-differentiating increased bilateral temporal and right dorsolateral prefrontal GMV (zs ⩾ 1.64, ps ⩽ 0.002). The fMRI meta-analyses of cognitive control revealed ASD-differentiating medial prefrontal underactivation but overactivation in bilateral ventrolateral prefrontal cortices and precuneus (zs ⩾ 1.04, ps ⩽ 0.003). During motor response inhibition specifically, ADHD relative to ASD showed right inferior fronto-striatal underactivation (zs ⩾ 1.14, ps ⩽ 0.003) but shared right anterior insula underactivation.ConclusionsPeople with ADHD and ASD have mostly distinct structural abnormalities, with enlarged fronto-temporal GMV in ASD and reduced orbitofrontal GMV in ADHD; and mostly distinct functional abnormalities, which were more pronounced in ASD.

A systematic review of brain MRI findings in monogenic disorders strongly associated with autism spectrum disorder

2021 ◽  
Author(s):  
Veronica Frewer ◽  
Courtney P. Gilchrist ◽  
Simonne E. Collins ◽  
Katrina Williams ◽  
Marc L. Seal ◽  
...  
Keyword(s):  
Systematic Review ◽  
Autism Spectrum Disorder ◽  
Brain Mri ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Mri Findings ◽  
Monogenic Disorders

scholarly journals Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

2019 ◽  
Author(s):  
Charles E. Mordaunt ◽  
Julia M. Jianu ◽  
Ben Laufer ◽  
Yihui Zhu ◽  
Keith W. Dunaway ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Cord Blood ◽  
Neurodevelopmental Disorder ◽  
Familial Risk ◽  
Fetal Brain ◽  
Cell Types ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Blood Samples ◽  
Genome Bisulfite Sequencing

AbstractBackgroundAutism spectrum disorder (ASD) is a neurodevelopmental disorder with complex heritability and higher prevalence in males. Since the neonatal epigenome has the potential to reflect past interactions between genetic and environmental factors during early development, we performed whole-genome bisulfite sequencing of 152 umbilical cord blood samples from the MARBLES and EARLI high-familial risk prospective cohorts to identify an epigenomic signature of ASD at birth.ResultsWe identified differentially-methylated regions (DMRs) stratified by sex that discriminated ASD from control cord blood samples in discovery and replication sets. At a region level, 7 DMRs in males and 31 DMRs in females replicated across two independent groups of subjects, while 537 DMR genes in males and 1762 DMR genes in females replicated by gene association. These DMR genes were significantly enriched for brain and embryonic expression, X chromosome location, and identification in prior epigenetic studies of ASD in post-mortem brain. In males and females, autosomal ASD DMRs were significantly enriched for promoter and bivalent chromatin states across most cell types, while sex differences were observed for X-linked ASD DMRs. Lastly, these DMRs identified in cord blood were significantly enriched for binding sites of methyl-sensitive transcription factors relevant to fetal brain development.ConclusionsAt birth, prior to the diagnosis of ASD, a distinct DNA methylation signature was detected in cord blood over regulatory regions and genes relevant to early fetal neurodevelopment. Differential cord methylation in ASD supports the developmental and sex-biased etiology of ASD, and provides novel insights for early diagnosis and therapy.

scholarly journals Convergent Canonical Pathways in Autism Spectrum Disorder from Proteomic, Transcriptomic and DNA Methylation Data

2021 ◽  
Author(s):  
Caitlyn Mahony ◽  
Colleen O'Ryan
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Molecular Mechanisms ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Differentially Expressed ◽  
Methylation Data ◽  
Differentially Expressed Proteins ◽  
Canonical Pathways

Abstract: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with extensive genetic and aetiological heterogeneity. While the underlying molecular mechanisms involved remain unclear, significant progress has been facilitated by recent advances in high-throughput transcriptomic, epigenomic and proteomic technologies. Here, we review recently published ASD proteomic data and compare proteomic func-tional enrichment signatures to those of transcriptomic and epigenomic data. We iden-tify canonical pathways that are consistently implicated in ASD molecular data and find an enrichment of pathways involved in mitochondrial metabolism and neurogenesis. We identify a subset of differentially expressed proteins that are supported by ASD tran-scriptomic and DNA methylation data. Furthermore, these differentially expressed proteins are enriched for disease phenotype pathways associated with ASD aetiology. These proteins converge on protein-protein interaction networks that regulate cell pro-liferation and differentiation, metabolism and inflammation which demonstrates a link between canonical pathways, biological processes and the ASD phenotype. This review highlights how proteomics can uncover potential molecular mechanisms to explain a link between mitochondrial dysfunction and neurodevelopmental pathology.

Shared atypical brain anatomy and intrinsic functional architecture in male youth with autism spectrum disorder and their unaffected brothers

2016 ◽  
Vol 47 (4) ◽  
pp. 639-654 ◽  
Author(s):  
H.-Y. Lin ◽  
W.-Y. I. Tseng ◽  
M.-C. Lai ◽  
Y.-T. Chang ◽  
S. S.-F. Gau
Keyword(s):  
Autism Spectrum Disorder ◽  
Statistical Power ◽  
Inferior Frontal Gyrus ◽  
Neurodevelopmental Disorder ◽  
Gray Matter Volume ◽  
Cingulate Cortex ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Brain Anatomy ◽  
Male Youth

BackgroundAutism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder, yet the search for definite genetic etiologies remains elusive. Delineating ASD endophenotypes can boost the statistical power to identify the genetic etiologies and pathophysiology of ASD. We aimed to test for endophenotypes of neuroanatomy and associated intrinsic functional connectivity (iFC) via contrasting male youth with ASD, their unaffected brothers and typically developing (TD) males.MethodThe 94 participants (aged 9–19 years) – 20 male youth with ASD, 20 unaffected brothers and 54 TD males – received clinical assessments, and undertook structural and resting-state functional magnetic resonance imaging scans. Voxel-based morphometry was performed to obtain regional gray and white matter volumes. A seed-based approach, with seeds defined by the regions demonstrating atypical neuroanatomy shared by youth with ASD and unaffected brothers, was implemented to derive iFC. General linear models were used to compare brain structures and iFC among the three groups. Assessment of familiality was investigated by permutation tests for variance of the within-family pair difference.ResultsWe found that atypical gray matter volume in the mid-cingulate cortex was shared between male youth with ASD and their unaffected brothers as compared with TD males. Moreover, reduced iFC between the mid-cingulate cortex and the right inferior frontal gyrus, and increased iFC between the mid-cingulate cortex and bilateral middle occipital gyrus were the shared features of male ASD youth and unaffected brothers.ConclusionsAtypical neuroanatomy and iFC surrounding the mid-cingulate cortex may be a potential endophenotypic marker for ASD in males.

scholarly journals Brain Magnetic Resonance Findings in 117 Children with Autism Spectrum Disorder under 5 Years Old

2020 ◽  
Vol 10 (10) ◽  
pp. 741
Author(s):  
Magali Jane Rochat ◽  
Giacomo Distefano ◽  
Monica Maffei ◽  
Francesco Toni ◽  
Annio Posar ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Magnetic Resonance ◽  
Brain Mri ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Mri Findings ◽  
Children With Asd ◽  
Routine Magnetic Resonance Imaging ◽  
Eeg Abnormalities ◽  
Mri Scans

We examined the potential benefits of neuroimaging measurements across the first 5 years of life in detecting early comorbid or etiological signs of autism spectrum disorder (ASD). In particular, we analyzed the prevalence of neuroradiologic findings in routine magnetic resonance imaging (MRI) scans of a group of 117 ASD children younger than 5 years old. These data were compared to those reported in typically developing (TD) children. MRI findings in children with ASD were analyzed in relation to their cognitive level, severity of autistic symptoms, and the presence of electroencephalogram (EEG) abnormalities. The MRI was rated abnormal in 55% of children with ASD with a significant prevalence in the high-functioning subgroup compared to TD children. We report significant incidental findings of mega cisterna magna, ventricular anomalies and abnormal white matter signal intensity in ASD without significant associations between these MRI findings and EEG features. Based on these results we discuss the role that brain MRI may play in the diagnostic procedure of ASD.

scholarly journals Cortical overgrowth in a preclinical forebrain organoid model of CNTNAP2-associated autism spectrum disorder

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Job O. de Jong ◽  
Ceyda Llapashtica ◽  
Matthieu Genestine ◽  
Kevin Strauss ◽  
Frank Provenzano ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Cellular Proliferation ◽  
Cell Types ◽  
Cell Number ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Signature Genes ◽  
Truncating Mutation ◽  
Cell Type Specific ◽  
Induced Pluripotent

AbstractWe utilized forebrain organoids generated from induced pluripotent stem cells of patients with a syndromic form of Autism Spectrum Disorder (ASD) with a homozygous protein-truncating mutation in CNTNAP2, to study its effects on embryonic cortical development. Patients with this mutation present with clinical characteristics of brain overgrowth. Patient-derived forebrain organoids displayed an increase in volume and total cell number that is driven by increased neural progenitor proliferation. Single-cell RNA sequencing revealed PFC-excitatory neurons to be the key cell types expressing CNTNAP2. Gene ontology analysis of differentially expressed genes (DEgenes) corroborates aberrant cellular proliferation. Moreover, the DEgenes are enriched for ASD-associated genes. The cell-type-specific signature genes of the CNTNAP2-expressing neurons are associated with clinical phenotypes previously described in patients. The organoid overgrowth phenotypes were largely rescued after correction of the mutation using CRISPR-Cas9. This CNTNAP2-organoid model provides opportunity for further mechanistic inquiry and development of new therapeutic strategies for ASD.

scholarly journals Reduced Gray Matter Volume in the Social Brain Network in Adults with Autism Spectrum Disorder

2017 ◽  
Vol 11 ◽  
Author(s):  
Wataru Sato ◽  
Takanori Kochiyama ◽  
Shota Uono ◽  
Sayaka Yoshimura ◽  
Yasutaka Kubota ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Gray Matter ◽  
Gray Matter Volume ◽  
Autism Spectrum ◽  
Brain Network ◽  
Spectrum Disorder ◽  
Social Brain ◽  
Adults With Autism ◽  
Matter Volume ◽  
The Social
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