1. Akhtar N, Jaswal VK, Dinishak J, Stephan C. {{On Social Feedback Loops and Cascading Effects in Autism: A Commentary on Warlaumont, Richards, Gilkerson, and Oller (2014)}}. {Psychol Sci};2016 (Sep 23)
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2. Chen J, Xin K, Wei J, Zhang K, Xiao H. {{Lower maternal serum 25(OH) D in first trimester associated with higher autism risk in Chinese offspring}}. {J Psychosom Res};2016 (Oct);89:98-101.
OBJECTIVE: The aim of this study was to examine the association between maternal serum vitamin D status in first trimester and risk of ASD at age 3-7years in the offspring. METHODS: Using a case-control design, 68 children diagnosed with ASD and 68 sex and age matched typically-developing children were included. Archived maternal blood samples from the first trimester of pregnancy (11-13weeks gestational age) were identified for those participants. Maternal serum levels of 25 hydroxyvitamin D3 [25(OH) D], unmetabolized folic acid (FA), vitamin B12, homocysteine (HCY) and High Sensitivity C Reactive protein (CRP) were measured from those samples. We examined the associations between those factors in pregnancy and diagnosis of ASD with logistic regression using SPSS. RESULTS: Mothers in autistic group had significantly lower maternal serum levels of 25(OH) D than in typically-developing group [19.2(IQR: 15.8-22.9)ng/ml vs. 24.3(19.3-27.3)ng/ml, P<0.001], with 55.9% and 29.4% being vitamin D deficient, respectively (P<0.001). Levels of 25(OH) D increased with decreasing severity of ASD as defined by the CARS score (r=-0.302, P<0.001). Maternal first trimester serum levels of 25(OH) D in the lower 3 quartiles (quartile 1, 2, 3) (compared to the highest quartile) was associated with increased odds of ASD diagnosis in offspring [OR (95% CI) Q1: 1.36(0.84-2.58, P=0.25); Q2: 2.68(1.44-4.29, P=0.006); Q3:3.99(2.58-7.12, P<0.001)]. CONCLUSIONS: Lower first trimester maternal serum levels of 25(OH) D were associated with increased risk of developing autism in offspring. If these findings are confirmed, this may present an opportunity for prenatal intervention to reduce the risk for ASD. Lien vers le texte intégral (Open Access ou abonnement)
3. Geoffray MM, Thevenet M, Georgieff N. {{News in early intervention in autism}}. {Psychiatr Danub};2016 (Sep);28(Suppl-1):66-70.
BACKGROUND: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental trouble which prevents the child from socio-communicative interaction, and learning from his environment. Non-medical early intervention attempts to improve prognosis. We will review the main current hypothesis, intervention models and scientific supports about early intervention. METHODS: We conducted a search of the literature published on Medline between 2010 and 2015 related to intervention models provided to children with ASD aged less than 3 years. Data were extracted from systematic reviews and recent randomized controlled trials with moderate to high GRADE quality of evidence. RESULTS: Early intervention refers to brain plasticity theory. With the epidemiological studies of infant « at risk » there is an attempt to intervene earlier before full syndrome is present. Interventions tend to follow more on a developmental hierarchy of socio-communicative skills and to focus on the dyadic relation between the child and the caregivers to improve the core autistic symptoms. Over the last 6 years, there’s been news and fine-tuned ways about early intervention, and more and more systematic evaluation. CONCLUSION: However, there are only few interventions which were evaluated in trial with a strong GRADE recommendation and all of them have methodological concerns. It is important to be cautious in recommendations for mental health politic, even if it is important to improve access to services for all children and their families, hence finance and design rigorous project in research.
4. Khalfallah O, Jarjat M, Davidovic L, Nottet N, Cestele S, Mantegazza M, Bardoni B. {{Depletion of the fragile X mental retardation protein in embryonic stem cells alters the kinetics of neurogenesis}}. {Stem Cells};2016 (Sep 24)
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID) and a leading cause of autism. FXS is due to the silencing of the Fragile X Mental Retardation Protein (FMRP), an RNA binding protein mainly involved in translational control, dendritic spine morphology and synaptic plasticity. Despite extensive studies, there is currently no cure for FXS. With the purpose to decipher the initial molecular events leading to this pathology, we developed a stem-cell-based disease model by knocking-down the expression of Fmr1 in mouse embryonic stem cells (ESCs). Repressing FMRP in ESCs increased the expression of amyloid precursor protein (APP) and Ascl1. When inducing neuronal differentiation, betaIII-tubulin, p27kip1 , NeuN and NeuroD1 were up-regulated, leading to an accelerated neuronal differentiation, that was partially compensated at later stages. Interestingly, we observed that neurogenesis is also accelerated in the embryonic brain of Fmr1-knockout (KO) mice, indicating that our cellular model recapitulates the molecular alterations present in vivo. Importantly, we rescued the main phenotype of the Fmr1 knockdown cell line, not only by reintroducing FMRP but also by pharmacologically targeting APP processing, showing the role of this protein in the pathophysiology of FXS during the earliest steps of neurogenesis. Our work allows to define an early therapeutic window but also to identify more effective molecules for treating this disorder. This article is protected by copyright. All rights reserved.
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5. Moradi E, Khundrakpam B, Lewis JD, Evans AC, Tohka J. {{Predicting symptom severity in autism spectrum disorder based on cortical thickness measures in agglomerative data}}. {Neuroimage};2016 (Sep 21)
Machine learning approaches have been widely used for the identification of neuropathology from neuroimaging data. However, these approaches require large samples and suffer from the challenges associated with multi-site, multi-protocol data. We propose a novel approach to address these challenges, and demonstrate its usefulness with the Autism Brain Imaging Data Exchange (ABIDE) database. We predict symptom severity based on cortical thickness measurements from 156 individuals with autism spectrum disorder (ASD) from four different sites. The proposed approach consists of two main stages: a domain adaptation stage using partial least squares regression to maximize the consistency of imaging data across sites; and a learning stage combining support vector regression for regional prediction of severity with elastic-net penalized linear regression for integrating regional predictions into a whole-brain severity prediction. The proposed method performed markedly better than simpler alternatives, better with multi-site than single-site data, and resulted in a considerably higher cross-validated correlation score than has previously been reported in the literature for multi-site data. This demonstration of the utility of the proposed approach for detecting structural brain abnormalities in ASD from the multi-site, multi-protocol ABIDE dataset indicates the potential of designing machine learning methods to meet the challenges of agglomerative data.
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6. Patel AB, Tsilioni I, Leeman SE, Theoharides TC. {{Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism}}. {Proc Natl Acad Sci U S A};2016 (Sep 23)
We had reported elevated serum levels of the peptide neurotensin (NT) in children with autism spectrum disorders (ASD). Here, we show that NT stimulates primary human microglia, the resident immune cells of the brain, and the immortalized cell line of human microglia-SV40. NT (10 nM) increases the gene expression and release (P < 0.001) of the proinflammatory cytokine IL-1beta and chemokine (C-X-C motif) ligand 8 (CXCL8), chemokine (C-C motif) ligand 2 (CCL2), and CCL5 from human microglia. NT also stimulates proliferation (P < 0.05) of microglia-SV40. Microglia express only the receptor 3 (NTR3)/sortilin and not the NTR1 or NTR2. The use of siRNA to target sortilin reduces (P < 0.001) the NT-stimulated cytokine and chemokine gene expression and release from human microglia. Stimulation with NT (10 nM) increases the gene expression of sortilin (P < 0.0001) and causes the receptor to be translocated from the cytoplasm to the cell surface, and to be secreted extracellularly. Our findings also show increased levels of sortilin (P < 0.0001) in the serum from children with ASD (n = 36), compared with healthy controls (n = 20). NT stimulation of microglia-SV40 causes activation of the mammalian target of rapamycin (mTOR) signaling kinase, as shown by phosphorylation of its substrates and inhibition of these responses by drugs that prevent mTOR activation. NT-stimulated responses are inhibited by the flavonoid methoxyluteolin (0.1-1 muM). The data provide a link between sortilin and the pathological findings of microglia and inflammation of the brain in ASD. Thus, inhibition of this pathway using methoxyluteolin could provide an effective treatment of ASD. Lien vers le texte intégral (Open Access ou abonnement)
7. Raymaker DM, McDonald KE, Ashkenazy E, Gerrity M, Baggs AM, Kripke C, Hourston S, Nicolaidis C. {{Barriers to healthcare: Instrument development and comparison between autistic adults and adults with and without other disabilities}}. {Autism};2016 (Sep 22)
Our objective was to use a community-based participatory research approach to identify and compare barriers to healthcare experienced by autistic adults and adults with and without other disabilities. To do so, we developed a Long- and Short-Form instrument to assess barriers in clinical and research settings. Using the Barriers to Healthcare Checklist-Long Form, we surveyed 437 participants (209 autistic, 55 non-autistic with disabilities, and 173 non-autistic without disabilities). Autistic participants selected different and greater barriers to healthcare, particularly in areas related to emotional regulation, patient-provider communication, sensory sensitivity, and healthcare navigation. Top barriers were fear or anxiety (35% (n = 74)), not being able to process information fast enough to participate in real-time discussions about healthcare (32% (n = 67)), concern about cost (30% (n = 62)), facilities causing sensory issues 30% ((n = 62)), and difficulty communicating with providers (29% (n = 61)). The Long Form instrument exhibited good content and construct validity. The items combined to create the Short Form had predominantly high levels of correlation (range 0.2-0.8, p < 0.001) and showed responsiveness to change. We recommend healthcare providers, clinics, and others working in healthcare settings to be aware of these barriers, and urge more intervention research to explore means for removing them. Lien vers le texte intégral (Open Access ou abonnement)
8. Sawicka K, Pyronneau A, Chao M, Bennett MV, Zukin RS. {{Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice}}. {Proc Natl Acad Sci U S A};2016 (Sep 23)
Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and a leading genetic form of autism. The Fmr1 KO mouse, a model of FXS, exhibits elevated translation in the hippocampus and the cortex. ERK (extracellular signal-regulated kinase) and mTOR (mechanistic target of rapamycin) signaling regulate protein synthesis by activating downstream targets critical to translation initiation and elongation and are known to contribute to hippocampal defects in fragile X. Here we show that the effect of loss of fragile X mental retardation protein (FMRP) on these pathways is brain region specific. In contrast to the hippocampus, ERK (but not mTOR) signaling is elevated in the neocortex of fragile X mice. Phosphorylation of ribosomal protein S6, typically a downstream target of mTOR, is elevated in the neocortex, despite normal mTOR activity. This is significant in that S6 phosphorylation facilitates translation, correlates with neuronal activation, and is altered in neurodevelopmental disorders. We show that in fragile X mice, S6 is regulated by ERK via the « alternative » S6 kinase p90-ribosomal S6 kinase (RSK), as evidenced by the site of elevated phosphorylation and the finding that ERK inhibition corrects elevated RSK and S6 activity. These findings indicate that signaling networks are altered in the neocortex of fragile X mice such that S6 phosphorylation receives aberrant input from ERK/RSK. Importantly, an RSK inhibitor reduces susceptibility to audiogenic seizures in fragile X mice. Our findings identify RSK as a therapeutic target for fragile X and suggest the therapeutic potential of drugs for the treatment of FXS may vary in a brain-region-specific manner.
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9. Smith T, Aman MG, Arnold LE, Silverman LB, Lecavalier L, Hollway J, Tumuluru R, Hyman SL, Buchan-Page KA, Hellings J, Rice RR, Jr., Brown NV, Pan X, Handen BL. {{Atomoxetine and Parent Training for Children With Autism and Attention-Deficit/Hyperactivity Disorder: A 24-Week Extension Study}}. {J Am Acad Child Adolesc Psychiatry};2016 (Oct);55(10):868-876 e862.
OBJECTIVE: The authors previously reported on a 2-by-2 randomized clinical trial of individual and combined treatment with atomoxetine (ATX) and parent training (PT) for attention-deficit/hyperactivity disorder (ADHD) symptoms and behavioral noncompliance in 128 5- to 14-year-old children with autism spectrum disorder. In the present report, they describe a 24-week extension of treatment responders and nonresponders. METHOD: One-hundred seventeen participants from the acute trial (91%) entered the extension; 84 of these were in 2 subgroups: « treatment responders » (n = 43) from all 4 groups in the acute trial, seen monthly for 24 weeks, and « placebo nonresponders » (n = 41), treated with open-label ATX for 10 weeks. Participants originally assigned to PT continued PT during the extension; the remainder served as controls. Primary outcome measurements were the parent-rated Swanson, Nolan and Pelham ADHD scale and the Home Situations Questionnaire. RESULTS: Sixty percent (26 of 43) of treatment responders in the acute trial, including 68% of responders originally assigned to ATX, still met the response criteria at the end of the extension. The response rate of placebo nonresponders treated with 10-week open-label ATX was 37% (15 of 41), similar to the acute trial. Children receiving open-label ATX + PT were significantly more likely to be ADHD responders (53% versus 23%) and noncompliance responders (58% versus 14%) than those receiving open-label ATX alone. CONCLUSION: Most ATX responders maintained their responses during the extension. PT combined with ATX in the open-label trial appeared to improve ADHD and noncompliance outcomes more than ATX alone. Clinical trial registration information-Atomoxetine, Placebo and Parent Management Training in Autism (Strattera); http://clinicaltrials.gov; NCT00844753.
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10. Tsang SY, Ahmad T, Mat FW, Zhao C, Xiao S, Xia K, Xue H. {{Variation of global DNA methylation levels with age and in autistic children}}. {Hum Genomics};2016;10(1):31.
BACKGROUND: The change in epigenetic signatures, in particular DNA methylation, has been proposed as risk markers for various age-related diseases. However, the course of variation in methylation levels with age, the difference in methylation between genders, and methylation-disease association at the whole genome level is unclear. In the present study, genome-wide methylation levels in DNA extracted from peripheral blood for 2116 healthy Chinese in the 2-97 age range and 280 autistic trios were examined using the fluorescence polarization-based genome-wide DNA methylation quantification method developed by us. RESULTS: Genome-wide or global DNA methylation levels proceeded through multiple phases of variation with age, consisting of a steady increase from age 2 to 25 (r = 0.382) and another rise from age 41 to 55 to reach a peak level of ~80 % (r = 0.265), followed by a sharp decrease to ~40 % in the mid-1970s (age 56 to 75; r = -0.395) and leveling off thereafter. Significant gender effect in methylation levels was observed only for the 41-55 age group in which methylation in females was significantly higher than in males (p = 0.010). In addition, global methylation level was significantly higher in autistic children than in age-matched healthy children (p < 0.001). CONCLUSIONS: The multiphasic nature of changes in global methylation levels with age was delineated, and investigation into the factors underlying this profile will be essential to a proper understanding of the aging process. Furthermore, this first report of global hypermethylation in autistic children also illustrates the importance of age-matched controls in characterization of disease-associated variations in DNA methylation. Lien vers le texte intégral (Open Access ou abonnement)
11. Warlaumont AS, Richards JA, Gilkerson J, Messinger DS, Oller DK. {{The Social Feedback Hypothesis and Communicative Development in Autism Spectrum Disorder: A Response to Akhtar, Jaswal, Dinishak, and Stephan (2016)}}. {Psychol Sci};2016 (Sep 23)
