Synaptic and transcriptionally downregulated genes are associated with cortical thickness differences in autism.
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ABSTRACT:
SUBMITTER: Romero-Garcia R
PROVIDER: S-EPMC6755982 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mild cognitive impairment (MCI) is a transition between normal cognition (NC) and Alzheimer's disease (AD). Differences in cortical thickness (ΔCT) have been reported in cases that degenerate from MCI to AD. The aspects of genetic and transcriptional variation related to ΔCT are vague. In this study, using an 8-year longitudinal follow-up outcome, we investigated the genetic correlates of ΔCT in MCI subjects with degeneration from MCI to AD (MCI_AD). We employed partial least squares regression (PLSR) on brain T1-weighted magnetic resonance imaging (MRI) images of 180 participants [143 stable MCI (MCI_S) participants and 37 MCI_AD participants] and brain gene expression data from the Allen Institute for Brain Science (AIBS) database to investigate genes associated with ΔCT. We found that upregulated PLS component 1 ΔCT-related genes were enriched in chemical synaptic transmission. To verify the robustness and specificity of the results, we conducted PLSR analysis invalidation and specificity datasets and performed weighted gene co-expression network analysis instead of PLSR for the above three datasets. We also used gene expression data in the brain prefrontal cortex from the Gene Expression Omnibus (GEO) database to indirectly validate the robustness and specificity of our results. We conclude that transcriptionally upregulated genes involved in chemical synaptic transmission are strongly related to global ΔCT in MCI patients who experience degeneration from MCI to AD.
| S-EPMC8585991 | biostudies-literature
Project description:BackgroundOver the course of the last 30 years, autism spectrum disorder (ASD) diagnoses have increased, thus identifying a large group of aging individuals with ASD. Currently, little is known regarding how aging will affect these individual's neuroanatomy, compared to the neurotypical (NT) population. Because of the anatomical overlap of ASD-related cortical pathology and age-related cortical thinning, both following an anterior-to-posterior severity gradient, we hypothesize adults with ASD will show larger age-related cortical thinning than NT adults.MethodsWe analyzed cortical measurements using available data from the multi-site Autism Brain Imaging Data Exchange I (ABIDE I; n=282) and our own cohort of middle-age to older adults with and without ASD (n=47) mostly available in ABIDE II (n=35). We compared correlations between cortical measures and age in right-handed adults with ASD (n=157) and similar NT adults (n = 172), controlling for IQ and site. Participants were 18 to 64 years of age (mean=29.8 years; median=26 years).ResultsWe found significant differences between diagnosis groups in the relationship between age and cortical thickness for areas of left frontal lobe (pars opercularis), temporal lobe (inferior gyrus, middle gyrus, banks of the superior temporal sulcus, and entorhinal cortex), parietal lobe (inferior gyrus), and lateral occipital lobe. For all areas, adults with ASD showed a greater negative correlation between age and cortical thickness than NT adults.ConclusionAs hypothesized, adults with ASD demonstrated exacerbated age-related cortical thinning, compared to NT adults. These differences were the largest and most extensive in the left temporal lobe. Future longitudinal work is warranted to investigate whether differences in brain age trajectories will translate to unique behavioral needs in older adults with ASD.
| S-EPMC7304569 | biostudies-literature
Project description:Several studies have examined how individual differences in sustained attention relate to functional brain measures (e.g., functional connectivity), but far fewer studies relate sustained attention ability, or cognition in general, to individual differences in cortical structure. Functional magnetic resonance imaging meta-analyses and patient work have highlighted that frontoparietal regions, lateralized to the right hemisphere, are critical for sustained attention, though recent work implicates a broader expanse of brain regions. The current study sought to determine if and where variation in cortical thickness is significantly associated with sustained attention performance. Sustained attention was measured using the gradual onset continuous performance task and the Test of Variables of Attention in 125 adult Veteran participants after acquiring two high-resolution structural MRI scans. Whole-brain vertex-wise analyses of the cortex demonstrated that better sustained attention was associated with increased thickness in visual, somatomotor, frontal, and parietal cortices, especially in the right hemisphere. Network-based analyses revealed relationships between sustained attention and cortical thickness in the dorsal attention, ventral attention, somatomotor, and visual networks. These results indicate cortical thickness in multiple regions and networks is associated with sustained attention, and add to the growing knowledge of how structural MRI can help explain individual differences in cognition.
| S-EPMC6865816 | biostudies-literature
Project description:Autism (AUT), schizophrenia (SCZ) and bipolar disorder (BPD) are three highly heritable neuropsychiatric conditions. Clinical similarities and genetic overlap between the three disorders have been reported; however, the causes and the downstream effects of this overlap remain elusive. By analyzing transcriptomic RNA-sequencing data generated from post-mortem cortical brain tissues from AUT, SCZ, BPD and control subjects, we have begun to characterize the extent of gene expression overlap between these disorders. We report that the AUT and SCZ transcriptomes are significantly correlated (P<0.001), whereas the other two cross-disorder comparisons (AUT-BPD and SCZ-BPD) are not. Among AUT and SCZ, we find that the genes differentially expressed across disorders are involved in neurotransmission and synapse regulation. Despite the lack of global transcriptomic overlap across all three disorders, we highlight two genes, IQSEC3 and COPS7A, which are significantly downregulated compared with controls across all three disorders, suggesting either shared etiology or compensatory changes across these neuropsychiatric conditions. Finally, we tested for enrichment of genes differentially expressed across disorders in genetic association signals in AUT, SCZ or BPD, reporting lack of signal in any of the previously published genome-wide association study (GWAS). Together, these studies highlight the importance of examining gene expression from the primary tissue involved in neuropsychiatric conditions-the cortical brain. We identify a shared role for altered neurotransmission and synapse regulation in AUT and SCZ, in addition to two genes that may more generally contribute to neurodevelopmental and neuropsychiatric conditions.
| S-EPMC5070061 | biostudies-literature
Project description:BACKGROUND:Genetic studies in autism have pinpointed a heterogeneous group of loci and genes. Further, environment may be an additional factor conferring susceptibility to autism. Transcriptome studies investigate quantitative differences in gene expression between patient-derived tissues and control. These studies may pinpoint genes relevant to pathophysiology yet circumvent the need to understand genetic architecture or gene-by-environment interactions leading to disease. METHODS:We conducted alternate gene set enrichment analyses using differentially expressed genes from a previously published RNA-seq study of post-mortem autism cerebral cortex. We used three previously published microarray datasets for validation and one of the microarray datasets for additional differential expression analysis. The RNA-seq study used 26 autism and 33 control brains in differential gene expression analysis, and the largest microarray dataset contained 15 autism and 16 control post-mortem brains. RESULTS:While performing a gene set enrichment analysis of genes differentially expressed in the RNA-seq study, we discovered that genes associated with mitochondrial function were downregulated in autism cerebral cortex, as compared to control. These genes were correlated with genes related to synaptic function. We validated these findings across the multiple microarray datasets. We also did separate differential expression and gene set enrichment analyses to confirm the importance of the mitochondrial pathway among downregulated genes in post-mortem autism cerebral cortex. CONCLUSIONS:We found that genes related to mitochondrial function were differentially expressed in autism cerebral cortex and correlated with genes related to synaptic transmission. Our principal findings replicate across all datasets investigated. Further, these findings may potentially replicate in other diseases, such as in schizophrenia.
| S-EPMC5984825 | biostudies-literature
Project description:Structural magnetic resonance imaging (MRI) scans at high spatial resolution can detect potential foci of early brain dysmaturation in children with autism spectrum disorders (ASD). In addition, comparison between MRI and behavior measures over time can identify patterns of brain change accompanying specific outcomes. We report structural MRI data from two time points for a total of 84 scans in children with ASD and 30 scans in typical controls (mean age time one = 4.1 years, mean age at time two = 6.6 years). Surface-based cortical morphometry and linear mixed effects models were used to link changes in cortical anatomy to both diagnostic status and individual differences in changes in language and autism severity. Compared with controls, children with ASD showed accelerated gray matter volume gain with age, which was driven by a lack of typical age-related cortical thickness (CT) decrease within 10 cortical regions involved in language, social cognition, and behavioral control. Greater expressive communication gains with age in children with ASD were associated with greater CT gains in a set of right hemisphere homologues to dominant language cortices, potentially identifying a compensatory system for closer translational study. Hum Brain Mapp 37:2616-2629, 2016. © 2016 Wiley Periodicals, Inc.
| S-EPMC4905793 | biostudies-literature
Project description:Genes involved in synaptic function are enriched among those with autism spectrum disorder (ASD)-associated rare genetic variants. Dysregulated cortical neurogenesis has been implicated as a convergent mechanism in ASD pathophysiology, yet it remains unknown how 'synaptic' ASD risk genes contribute to these phenotypes, which arise before synaptogenesis. Here, we show that the synaptic Ras GTPase-activating (RASGAP) protein 1 (SYNGAP1, a top ASD risk gene) is expressed within the apical domain of human radial glia cells (hRGCs). In a human cortical organoid model of SYNGAP1 haploinsufficiency, we find dysregulated cytoskeletal dynamics that impair the scaffolding and division plane of hRGCs, resulting in disrupted lamination and accelerated maturation of cortical projection neurons. Additionally, we confirmed an imbalance in the ratio of progenitors to neurons in a mouse model of Syngap1 haploinsufficiency. Thus, SYNGAP1-related brain disorders may arise through non-synaptic mechanisms, highlighting the need to study genes associated with neurodevelopmental disorders (NDDs) in diverse human cell types and developmental stages.
| S-EPMC11349286 | biostudies-literature
Project description:Certain cognitive functions differ in men and women, although the anatomical and functional substrates underlying these differences remain unknown. Because neocortical activity is directly related with higher brain function, numerous studies have focused on the cerebral cortex when searching for possible structural correlates of cognitive gender differences. However, there are no studies on possible gender differences at the synaptic level. In the present work we have used stereological and correlative light and electron microscopy to show that men have a significantly higher synaptic density than women in all cortical layers of the temporal neocortex. These differences may represent a microanatomical substrate contributing to the functional gender differences in brain activity.
| S-EPMC2567215 | biostudies-other
Project description:The natural history of brain growth in autism spectrum disorders remains unclear. Cross-sectional studies have identified regional abnormalities in brain volume and cortical thickness in autism, although substantial discrepancies have been reported. Preliminary longitudinal studies using two time points and small samples have identified specific regional differences in cortical thickness in the disorder. To clarify age-related trajectories of cortical development, we examined longitudinal changes in cortical thickness within a large mixed cross-sectional and longitudinal sample of autistic subjects and age- and gender-matched typically developing controls. Three hundred and forty-five magnetic resonance imaging scans were examined from 97 males with autism (mean age = 16.8 years; range 3-36 years) and 60 males with typical development (mean age = 18 years; range 4-39 years), with an average interscan interval of 2.6 years. FreeSurfer image analysis software was used to parcellate the cortex into 34 regions of interest per hemisphere and to calculate mean cortical thickness for each region. Longitudinal linear mixed effects models were used to further characterize these findings and identify regions with between-group differences in longitudinal age-related trajectories. Using mean age at time of first scan as a reference (15 years), differences were observed in bilateral inferior frontal gyrus, pars opercularis and pars triangularis, right caudal middle frontal and left rostral middle frontal regions, and left frontal pole. However, group differences in cortical thickness varied by developmental stage, and were influenced by IQ. Differences in age-related trajectories emerged in bilateral parietal and occipital regions (postcentral gyrus, cuneus, lingual gyrus, pericalcarine cortex), left frontal regions (pars opercularis, rostral middle frontal and frontal pole), left supramarginal gyrus, and right transverse temporal gyrus, superior parietal lobule, and paracentral, lateral orbitofrontal, and lateral occipital regions. We suggest that abnormal cortical development in autism spectrum disorders undergoes three distinct phases: accelerated expansion in early childhood, accelerated thinning in later childhood and adolescence, and decelerated thinning in early adulthood. Moreover, cortical thickness abnormalities in autism spectrum disorders are region-specific, vary with age, and may remain dynamic well into adulthood.
| S-EPMC4032101 | biostudies-literature
Project description:Recent longitudinal neuroimaging and neurophysiological studies have shown that tracking relative age-related changes in neural signals, rather than a static snapshot of a neural measure, could offer higher sensitivity for discriminating typically developing (TD) individuals from those with autism spectrum disorder (ASD). It is not clear, however, which aspects of age-related changes (trajectories) would be optimal for identifying atypical brain development in ASD. Using a large cross-sectional data set (Autism Brain Imaging Data Exchange [ABIDE] repository; releases I and II), we aimed to explore age-related changes in cortical thickness (CT) in TD and ASD populations (age range 6-30 years old). Cortical thickness was estimated from T1-weighted MRI images at three scales of spatial coarseness (three parcellations with different numbers of regions of interest). For each parcellation, three polynomial models of age-related changes in CT were tested. Specifically, to characterize alterations in CT trajectories, we compared the linear slope, curvature, and aberrancy of CT trajectories across experimental groups, which was estimated using linear, quadratic, and cubic polynomial models, respectively. Also, we explored associations between age-related changes with ASD symptomatology quantified as the Autism Diagnostic Observation Schedule (ADOS) scores. While no overall group differences in cortical thickness were observed across the entire age range, ASD and TD populations were different in terms of age-related changes, which were located primarily in frontal and tempo-parietal areas. These atypical age-related changes were also associated with ADOS scores in the ASD group and used to predict ASD from TD development. These results indicate that the curvature is the most reliable feature for localizing brain areas developmentally atypical in ASD with a more pronounced effect with symptomatology and is the most sensitive in predicting ASD development.
| S-EPMC7338512 | biostudies-literature