Pubmed du 12/08/19

lundi 12 août 2019

1. Arroyo-Araujo M, Graf R, Maco M, van Dam E, Schenker E, Drinkenburg W, Koopmans B, de Boer SF, Cullum-Doyle M, Noldus L, Loos M, van Dommelen W, Spooren W, Biemans B, Buhl DL, Kas MJ. Reproducibility via coordinated standardization : a multi-center study in a Shank2 genetic rat model for Autism Spectrum Disorders. Sci Rep ;2019 (Aug 12) ;9(1):11602.

Inconsistent findings between laboratories are hampering scientific progress and are of increasing public concern. Differences in laboratory environment is a known factor contributing to poor reproducibility of findings between research sites, and well-controlled multisite efforts are an important next step to identify the relevant factors needed to reduce variation in study outcome between laboratories. Through harmonization of apparatus, test protocol, and aligned and non-aligned environmental variables, the present study shows that behavioral pharmacological responses in Shank2 knockout (KO) rats, a model of synaptic dysfunction relevant to autism spectrum disorders, were highly replicable across three research centers. All three sites reliably observed a hyperactive and repetitive behavioral phenotype in KO rats compared to their wild-type littermates as well as a dose-dependent phenotype attenuation following acute injections of a selective mGluR1 antagonist. These results show that reproducibility in preclinical studies can be obtained and emphasizes the need for high quality and rigorous methodologies in scientific research. Considering the observed external validity, the present study also suggests mGluR1 as potential target for the treatment of autism spectrum disorders.

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2. Bruyneel E, Demurie E, Warreyn P, Beyers W, Boterberg S, Bontinck C, Dewaele N, Roeyers H. Language growth in very young siblings at risk for autism spectrum disorder. Int J Lang Commun Disord ;2019 (Aug 12)

BACKGROUND : Children with autism spectrum disorder (ASD) show substantial variability in their language development. Language problems are highly prevalent in these children. In addition, the quality of early language abilities contributes to the overall development of these children and is highly predictive of their adult outcome. Yet, little is known about language development in children at risk of ASD during the first years of life. AIMS : To compare early receptive language (RL) and expressive language (EL) development in children at risk of ASD and determine predictors of language development. METHODS & PROCEDURES : Developmental trajectories of RL and EL were investigated from 10 to 36 months of age in younger siblings of typically developing children (LR-sibs, N = 30) and in younger siblings of children with ASD (HR-sibs, N = 31) using the Mullen Scales of Early Learning. Furthermore, both child and demographic characteristics were examined as possible predictors of language development. OUTCOMES & RESULTS : Both groups showed similar growth curves for RL and EL and the majority of the children showed average (within +/-1.5 SD of the mean) or above-average language abilities. Nevertheless, the mean growth of EL was lower and the variation in growth of both RL and EL was higher in HR-sibs than in LR-sibs. Furthermore, early child characteristics were predictive of language development in both groups. Yet, some child characteristics seemed to be of more importance in HR-sibs than in LR-sibs. Consequently, lower non-verbal abilities at 10 months in both groups and a higher degree of ASD characteristics at 14 months in HR-sibs may be indicative of difficulties in language development. CONCLUSIONS & IMPLICATIONS : HR-sibs show more variation in their language development than LR-sibs during the first 3 years of life. The majority of HR-sibs, however, did not present with below-average language abilities. Yet, early characteristics of ASD may be a red flag for difficulties in the language development of HR-sibs.

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3. Hong MP, Erickson CA. Investigational drugs in early-stage clinical trials for autism spectrum disorder. Expert Opin Investig Drugs ;2019 (Aug) ;28(8):709-718.

Introduction : Pharmacologic interventions in Autism Spectrum Disorder (ASD) have historically focused on symptom-based approaches. However, a treatment for the core social deficits has remained unidentified. While a definitive theory for the cause of ASD is not yet known, recent advances in our understanding of ASD pathophysiology have opened the door for research on new pharmaceutical methods to target core symptomology. Areas covered : Herein, we review the novel pharmacologic therapies undergoing early-stage clinical trials for the treatment of the social symptoms associated with ASD. Specifically, these strategies center on altering neurologic excitatory and inhibitory imbalance, neuropeptide abnormalities, immunologic dysfunction, and biochemical deficiencies in ASD. Expert opinion : Utilizing the growing field of knowledge regarding the pathological mechanisms and altered neurobiology of individuals with ASD has led to the development of many innovative pharmaceutical interventions. Clinical trials for neurobiologic and immunologic targets show promise in impacting the social behavior and processing deficits in ASD but need evaluation in larger clinical trials and continued biomarker development to more effectively and consistently assess pharmacologic effects. Additionally, evaluating patient-specific drug responsivity and integrating behavioral intervention in conjunction with pharmacologic treatment is crucial to developing a successful approach to ASD treatment.

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4. Rabany L, Brocke S, Calhoun VD, Pittman B, Corbera S, Wexler BE, Bell MD, Pelphrey K, Pearlson GD, Assaf M. Dynamic functional connectivity in schizophrenia and autism spectrum disorder : Convergence, divergence and classification. Neuroimage Clin ;2019 (Aug 1) ;24:101966.

BACKGROUND : Over the recent years there has been a growing debate regarding the extent and nature of the overlap in neuropathology between schizophrenia (SZ) and autism spectrum disorder (ASD). Dynamic functional network connectivity (dFNC) is a recent analysis method that explores temporal patterns of functional connectivity (FC). We compared resting-state dFNC in SZ, ASD and healthy controls (HC), characterized the associations between temporal patterns and symptoms, and performed a three-way classification analysis based on dFNC indices. METHODS : Resting-state fMRI was collected from 100 young adults : 33 SZ, 33 ASD, 34 HC. Independent component analysis (ICA) was performed, followed by dFNC analysis (window=33s, step=1TR, k-means clustering). Temporal patterns were compared between groups, correlated with symptoms, and classified via cross-validated three-way discriminant analysis. RESULTS : Both clinical groups displayed an increased fraction of time (FT) spent in a state of weak, intra-network connectivity [p<.001] and decreased FT in a highly-connected state [p<.001]. SZ further showed decreased number of transitions between states [p<.001], decreased FT in a widely-connected state [p<.001], increased dwell time (DT) in the weakly-connected state [p<.001], and decreased DT in the highly-connected state [p=.001]. Social behavior scores correlated with DT in the widely-connected state in SZ [r=0.416, p=.043], but not ASD. Classification correctly identified SZ at high rates (81.8%), while ASD and HC at lower rates. CONCLUSIONS : Results indicate a severe and pervasive pattern of temporal aberrations in SZ (specifically, being "stuck" in a state of weak connectivity), that distinguishes SZ participants from both ASD and HC, and is associated with clinical symptoms.

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5. Vidal S, Xiol C, Pascual-Alonso A, O’Callaghan M, Pineda M, Armstrong J. Genetic Landscape of Rett Syndrome Spectrum : Improvements and Challenges. Int J Mol Sci ;2019 (Aug 12) ;20(16)

Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that primarily affects females, resulting in severe cognitive and physical disabilities, and is one of the most prevalent causes of intellectual disability in females. More than fifty years after the first publication on Rett syndrome, and almost two decades since the first report linking RTT to the MECP2 gene, the research community’s effort is focused on obtaining a better understanding of the genetics and the complex biology of RTT and Rett-like phenotypes without MECP2 mutations. Herein, we review the current molecular genetic studies, which investigate the genetic causes of RTT or Rett-like phenotypes which overlap with other genetic disorders and document the swift evolution of the techniques and methodologies employed. This review also underlines the clinical and genetic heterogeneity of the Rett syndrome spectrum and provides an overview of the RTT-related genes described to date, many of which are involved in epigenetic gene regulation, neurotransmitter action or RNA transcription/translation. Finally, it discusses the importance of including both phenotypic and genetic diagnosis to provide proper genetic counselling from a patient’s perspective and the appropriate treatment.

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