1. Ahmad SF, Ansari MA, Nadeem A, Bakheet SA, Alzahrani MZ, Alshammari MA, Alanazi WA, Alasmari AF, Attia SM. {{Resveratrol attenuates pro-inflammatory cytokines and activation of JAK1-STAT3 in BTBR T(+) Itpr3(tf)/J autistic mice}}. {Eur J Pharmacol};2018 (Apr 11);829:70-78.
Autism is a neurodevelopmental disorder characterized by qualitative impairment in communication, social interaction, and repetitive stereotypic behavior. Resveratrol plays a role in several disorders such as neuroimmune, autoimmune, and allergic disorders. BTBR T(+) Itpr3(tf)/J (BTBR) mice, a model for autism, show several behavioral deficits that are physiological characteristics similar to those observed in patients with autism. Previous studies have shown that JAK-STAT signaling pathway is associated with many neurodevelopmental disorders. We investigated the possible role of resveratrol on IL-6(+), TNF-alpha(+), IFN-gamma(+), and STAT3(+) in CD4(+) T spleen cells in BTBR mice as compared to C57BL/6J mice. We also assessed the effect of resveratrol treatment on IL-6, TNF-alpha, IFN-gamma, JAK1, and STAT3 mRNA expression levels in the brain tissue. We further assessed IL-6, IFN-gamma, TNF-alpha, phosphorylated (p) JAK1, and pSTAT3 (Tyr705) protein expression levels in the brain tissue. Resveratrol (20 and 40mg/kg)-treated mice had significantly decreased in IL-6(+), TNF-alpha(+), IFN-gamma(+), and STAT3(+) in CD4(+) spleen cells as compared with BTBR control mice. Resveratrol treatment also decreased IL-6, TNF-alpha, IFN-gamma, JAK1, and STAT3 mRNA expression levels as compared with BTBR control mice in the brain tissue. Moreover, resveratrol treatment resulted in decreased protein expression levels of IL-6, IFN-gamma, TNF-alpha, pJAK1, and pSTAT3 (Tyr705) as compared with BTBR control mice in the brain tissues. Taken together, these results indicate the efficacy of resveratrol in reducing cytokines and JAK-1/STAT3 signaling in BTBR mice, which is a novel and important finding and might be important for future therapies in neuroimmune dysfunction.
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2. Balsters JH, Mantini D, Wenderoth N. {{Connectivity-based parcellation reveals distinct cortico-striatal connectivity fingerprints in Autism Spectrum Disorder}}. {Neuroimage};2018 (Apr 15);170:412-423.
Autism Spectrum Disorder (ASD) has been associated with abnormal synaptic development causing a breakdown in functional connectivity. However, when measured at the macro scale using resting state fMRI, these alterations are subtle and often difficult to detect due to the large heterogeneity of the pathology. Recently, we outlined a novel approach for generating robust biomarkers of resting state functional magnetic resonance imaging (RS-fMRI) using connectivity based parcellation of gross morphological structures to improve single-subject reproducibility and generate more robust connectivity fingerprints. Here we apply this novel approach to investigating the organization and connectivity strength of the cortico-striatal system in a large sample of ASD individuals and typically developed (TD) controls (N=130 per group). Our results showed differences in the parcellation of the striatum in ASD. Specifically, the putamen was found to be one single structure in ASD, whereas this was split into anterior and posterior segments in an age, IQ, and head movement matched TD group. An analysis of the connectivity fingerprints revealed that the group differences in clustering were driven by differential connectivity between striatum and the supplementary motor area, posterior cingulate cortex, and posterior insula. Our approach for analysing RS-fMRI in clinical populations has provided clear evidence that cortico-striatal circuits are organized differently in ASD. Based on previous task-based segmentations of the striatum, we believe that the anterior putamen cluster present in TD, but not in ASD, likely contributes to social and language processes.
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3. Bitar T, Mavel S, Emond P, Nadal-Desbarats L, Lefevre A, Mattar H, Soufia M, Blasco H, Vourc’h P, Hleihel W, Andres CR. {{Identification of metabolic pathway disturbances using multimodal metabolomics in autistic disorders in a Middle Eastern population}}. {J Pharm Biomed Anal};2018 (Apr 15);152:57-65.
We analyzed for the first time the metabolic profile of Lebanese children affected by autistic disorders to compare this profile to other metabolomics studies and to identify the associated metabolic disturbances. Urine samples of 40 patients with Autism spectrum disorder (ASD) and 40 healthy matched controls were analyzed using nuclear magnetic resonance (NMR) and liquid chromatography coupled to high-resolution mass spectrometry (LC-MS). Multivariate analysis on analytical data fusion was conducted on the training set of 50 urine samples, and then validated with a test set of 30 samples, this repeated 10 times. The model was also evaluated using a receiver operating characteristic curve showing a specificity and a sensitivity of 86% and 80%, respectively. Among the most significant metabolites that contributed to the discrimination between ASD and controls, we confirmed the perturbations of tyrosine, 2-hydroxybutyrate, creatine and glutamate. We found new metabolites such as trigonelline, cysteic acid and guanine. We found metabolic perturbations including amino acids, carbohydrates and oxidative stress pathways which added value for the contribution of known metabolic disturbances in ASD observed in populations of other ethnic and geographic origins.
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4. Hirofuji S, Hirofuji Y, Kato H, Masuda K, Yamaza H, Sato H, Takayama F, Torio M, Sakai Y, Ohga S, Taguchi T, Nonaka K. {{Mitochondrial dysfunction in dopaminergic neurons differentiated from exfoliated deciduous tooth-derived pulp stem cells of a child with Rett syndrome}}. {Biochem Biophys Res Commun};2018 (Apr 15);498(4):898-904.
Rett syndrome is an X-linked neurodevelopmental disorder associated with psychomotor impairments, autonomic dysfunctions and autism. Patients with Rett syndrome have loss-of-function mutations in MECP2, the gene encoding methyl-CpG-binding protein 2 (MeCP2). Abnormal biogenic amine signaling and mitochondrial function have been found in patients with Rett syndrome; however, few studies have analyzed the association between these factors. This study investigated the functional relationships between mitochondria and the neuronal differentiation of the MeCP2-deficient stem cells from the exfoliated deciduous teeth of a child with Rett syndrome. An enrolled subject in this study was a 5-year-old girl carrying a large deletion that included the methyl-CpG-binding domain, transcriptional repression domain, and nuclear localization signal of MECP2. Using the single-cell isolation technique, we found that the two populations of MeCP2-expressing and MeCP2-deficient stem cells kept their MECP2 expression profiles throughout the stages of cell proliferation and neuronal differentiation in vitro. Neurite outgrowth and branching were attenuated in MeCP2-deficient dopaminergic neurons. MeCP2-deficient cells showed reduced mitochondrial membrane potential, ATP production, restricted mitochondrial distribution in neurites, and lower expression of a central mitochondrial fission factor, dynamin-related protein 1 than MeCP2-expressing cells. These data indicated that MeCP2-deficiency dysregulates the expression of mitochondrial factors required for the maturation of dopaminergic neurons. This study also provides insight into the pathogenic mechanism underlying dysfunction of the intracerebral dopaminergic signaling pathway in Rett syndrome.
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5. Nobili A, Glazebrook C, Bouman WP, Glidden D, Baron-Cohen S, Allison C, Smith P, Arcelus J. {{Autistic Traits in Treatment-Seeking Transgender Adults}}. {J Autism Dev Disord};2018 (Apr 13)
The present study aimed to compare prevalence of autistic traits measured by the self-reported autism spectrum quotient-short (AQ-short) in a transgender clinical population (n = 656) matched by age and sex assigned at birth to a cisgender community sample. Results showed that transgender and cisgender people reported similar levels of possible autistic caseness. Transgender people assigned female were more likely to have clinically significant autistic traits compared to any other group. No difference was found between those assigned male. High AQ scores may not be indicative of the presence of an autism spectrum condition as the difference between groups mainly related to social behaviours; such scores may be a reflection of transgender people’s high social anxiety levels due to negative past experiences.
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6. Sapey-Triomphe LA, Sonie S, Henaff MA, Mattout J, Schmitz C. {{Adults with Autism Tend to Undermine the Hidden Environmental Structure: Evidence from a Visual Associative Learning Task}}. {J Autism Dev Disord};2018 (Apr 13)
The learning-style theory of Autism Spectrum Disorders (ASD) (Qian, Lipkin, Frontiers in Human Neuroscience 5:77, 2011) states that ASD individuals differ from neurotypics in the way they learn and store information about the environment and its structure. ASD would rather adopt a lookup-table strategy (LUT: memorizing each experience), while neurotypics would favor an interpolation style (INT: extracting regularities to generalize). In a series of visual behavioral tasks, we tested this hypothesis in 20 neurotypical and 20 ASD adults. ASD participants had difficulties using the INT style when instructions were hidden but not when instructions were revealed. Rather than an inability to use rules, ASD would be characterized by a disinclination to generalize and infer such rules.
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7. Sheldrick RC, Carter AS. {{State-Level Trends in the Prevalence of Autism Spectrum Disorder (ASD) from 2000 to 2012: A Reanalysis of Findings from the Autism and Developmental Disabilities Network}}. {J Autism Dev Disord};2018 (Apr 13)
Since 2000, the Autism and Developmental Disabilities Network (ADDM) has published detailed prevalence estimates for autism spectrum disorder (ASD) among 8 year-olds, which are widely interpreted as the U.S. national prevalence of ASD. Although differences in state-level ASD prevalence has been reported, state-level heterogeneity has not been explored systematically. We analyzed state-level estimates and trends in ASD prevalence from 2000 to 2012 using secondary data from bi-annual ADDM reports. Heterogeneity among state-level ASD prevalence estimates were apparent in 2000 and grew between 2000 and 2012. Findings highlight the need for greater understanding of how children with ASD are identified by the medical and educational systems, which has significant implications for the state-level resources required to effectively manage ASD.
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8. Traynor JM, Doyle-Thomas KAR, Hanford LC, Foster NE, Tryfon A, Hyde KL, Anagnostou E, Evans AC, Zwaigenbaum L, Hall GBC. {{Indices of repetitive behaviour are correlated with patterns of intrinsic functional connectivity in youth with autism spectrum disorder}}. {Brain Res};2018 (Apr 15);1685:79-90.
The purpose of the current study was to examine how repetitive behaviour in Autism Spectrum Disorder (ASD) is related to intrinsic functional connectivity patterns in a number of large-scale, neural networks. Resting-state fMRI scans from thirty subjects with ASD and thirty-two age-matched, typically developing control subjects were analysed. Seed-to-voxel and ROI-to-ROI functional connectivity analyses were used to examine resting-state connectivity in a number of cortical and subcortical neural networks. Bivariate correlation analysis was performed to examine the relationship between repetitive behaviour scores from the Repetitive Behaviour Scale – Revised and intrinsic functional connectivity in ASD subjects. Compared to control subjects, ASD subjects displayed marked over-connectivity of the thalamus with several cortical sensory processing areas, as well as over-connectivity of the basal ganglia with somatosensory and motor cortices. Within the ASD group, significant correlations were found between functional connectivity patterns and total RBS-R scores as well as one principal component analysis-derived score from the RBS-R. These results suggest that thalamocortical resting-state connectivity is altered in individuals with ASD, and that resting-state functional connectivity is associated with ASD symptomatology.
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9. Tse ACY, Lee PH, Zhang J, Lai EWH. {{Study protocol for a randomised controlled trial examining the association between physical activity and sleep quality in children with autism spectrum disorder based on the melatonin-mediated mechanism model}}. {BMJ Open};2018 (Apr 13);8(4):e020944.
INTRODUCTION: Sleep disturbance is commonly observed in children with autism spectrum disorders (ASD). Disturbed sleep may exacerbate the core symptoms of ASD. Behavioural interventions and supplemental melatonin medication are traditionally used to improve sleep quality, but poor sustainability of behavioural intervention effects and use of other medications that metabolise melatonin may degrade the effectiveness of these interventions. However, several studies have suggested that physical activity may provide an effective intervention for treating sleep disturbance in typically developing children. Thus, we designed a study to examine whether such an intervention is also effective in children with ASD. We present a protocol (4 December 2017) for a jogging intervention with a parallel and two-group randomised controlled trial design using objective actigraphic assessment and 6-sulfatoxymelatonin measurement to determine whether a 12-week physical activity intervention elicits changes in sleep quality or melatonin levels. METHODS AND ANALYSIS: All eligible participants will be randomly allocated to either a jogging intervention group or a control group receiving standard care. Changes in sleep quality will be monitored through actigraphic assessment and parental sleep logs. All participants will also be instructed to collect a 24-hour urine sample. 6-sulfatoxymelatonin, a creatinine-adjusted morning urinary melatonin representative of the participant’s melatonin levels, will be measured from the sample. All assessments will be carried out before the intervention (T1), immediately after the 12-week intervention or regular treatment (T2), 6 weeks after the intervention (T3) and 12 weeks after the intervention (T4) to examine the sustainability of the intervention effects. The first enrolment began in February 2018. ETHICS AND DISSEMINATION: Ethical approval was obtained through the Human Research Ethics Committee, Education University of Hong Kong. The results of this trial will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03348982.
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10. Yuan H, Li X, Wang Q, Yang W, Song J, Hu X, Shen Y. {{A de novo 921Kb microdeletion at 11q13.1 including neurexin 2 in a boy with developmental delay, deficits in speech and language without autistic behaviors}}. {Eur J Med Genet};2018 (Apr 11)
Microdeletions at 11q13.1 are very rare. At present only two patients with 11q13.1 deletion involving neurexin 2 (NRXN2) have been reported. Both patients exhibited autistic features, which supported the role of NRXN2 in autism pathogenicity. It is currently unknown whether heterozygous deletion of NRXN2 is of high penetrance or if it is sufficient to result in autism behaviors. Here we reported a 2-year-9-month old boy with developmental delay, short stature, significant language delay and other congenital anomalies. In contrast to previously reported cases, the boy did not present with autistic behaviors and did not meet the clinical diagnosis of autism. A de novo 921kb microdeletion at 11q13.1 was detected by chromosomal microarray analysis (CMA). Whole Exome Sequencing (WES) was also employed for our patient. The deletion was confirmed and no additional pathogenic variants were detected. We compared our patient’s genomic information and clinical features with those of two previously reported individuals. Three patients shared similar deleted intervals and had similar clinical features except for autistic behaviors. This study suggested that NRXN2 gene had incomplete penetrance for autistic behavioral phenotype. The finding is of interest for genetic counseling and clinical management to patients with NRXN2 defects.
