Pubmed du 30/05/18

mercredi 30 mai 2018

1. Bent S, Lawton B, Warren T, Widjaja F, Dang K, Fahey JW, Cornblatt B, Kinchen JM, Delucchi K, Hendren RL. Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli. Mol Autism. 2018 ; 9 : 35.

Background : Children with autism spectrum disorder (ASD) have urinary metabolites suggesting impairments in several pathways, including oxidative stress, inflammation, mitochondrial dysfunction, and gut microbiome alterations. Sulforaphane, a supplement with indirect antioxidant effects that are derived from broccoli sprouts and seeds, was recently shown to lead to improvements in behavior and social responsiveness in children with ASD. We conducted the current open-label study to determine if we could identify changes in urinary metabolites that were associated with clinical improvements with the goal of identifying a potential mechanism of action. Methods : Children and young adults enrolled in a school for children with ASD and related neurodevelopmental disorders were recruited to participate in a 12-week, open-label study of sulforaphane. Fasting urinary metabolites and measures of behavior (Aberrant Behavior Checklist-ABC) and social responsiveness (Social Responsiveness Scale-SRS) were measured at baseline and at the end of the study. Pearson’s correlation coefficient was calculated for the pre- to post-intervention change in each of the two clinical scales (ABS and SRS) versus the change in each metabolite. Results : Fifteen children completed the 12-week study. Mean scores on both symptom measures showed improvements (decreases) over the study period, but only the change in the SRS was significant. The ABC improved - 7.1 points (95% CI - 17.4 to 3.2), and the SRS improved - 9.7 points (95% CI - 18.7 to - 0.8). We identified 77 urinary metabolites that were correlated with changes in symptoms, and they clustered into pathways of oxidative stress, amino acid/gut microbiome, neurotransmitters, hormones, and sphingomyelin metabolism. Conclusions : Urinary metabolomics analysis is a useful tool to identify pathways that may be involved in the mechanism of action of treatments targeting abnormal physiology in ASD. Trial registration : This study was prospectively registered at clinicaltrials.gov (NCT02654743) on January 11, 2016.

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2. Besseling R, Lamerichs R, Michels B, Heunis S, de Louw A, Tijhuis A, Bergmans J, Aldenkamp B. Functional network abnormalities consistent with behavioral profile in Autism Spectrum Disorder. Psychiatry research Neuroimaging. 2018 ; 275 : 43-8.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder in which the severity of symptoms varies over subjects. The iCAPs model (innovation-driven co-activation patterns) is a recently developed spatio-temporal model to describe fMRI data. In this study, the iCAPs model was employed to find functional imaging biomarkers for ASD in resting-state fMRI data. MRI data from 125 ASD patients and 243 healthy controls was selected from the online ABIDE data repository. Following standard fMRI preprocessing steps, the iCAP patterns were fitted to the data to obtain network time series. Furthermore, specific combinations of iCAPs were mapped to behavioral domain time series. To quantify to which extent the time series contribute to the fMRI dynamics, their (temporal) standard deviation was calculated and compared between patients and controls. Abnormalities were found in networks involving subcortical and limbic areas and default mode network regions. When mapping the network dynamics to behavioral domain time series, abnormalities were found in emotional and visual behavioral subdomains, and within the ASD spectrum were more pronounced in subjects with autism compared to Asperger’s syndrome. Also a trend towards impairment in networks facilitating social cognition was found. The functional imaging abnormalities are consistent with the behavioral impairments typical for ASD.

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3. Curtin P, Austin C, Curtin A, Gennings C, Arora M, Tammimies K, Willfors C, Berggren S, Siper P, Rai D, Meyering K, Kolevzon A, Mollon J, David AS, Lewis G, Zammit S, Heilbrun L, Palmer RF, Wright RO, Bolte S, Reichenberg A. Dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder. Science advances. 2018 ; 4(5) : eaat1293.

Metals are critical to neurodevelopment, and dysregulation in early life has been documented in autism spectrum disorder (ASD). However, underlying mechanisms and biochemical assays to distinguish ASD cases from controls remain elusive. In a nationwide study of twins in Sweden, we tested whether zinc-copper cycles, which regulate metal metabolism, are disrupted in ASD. Using novel tooth-matrix biomarkers that provide direct measures of fetal elemental uptake, we developed a predictive model to distinguish participants who would be diagnosed with ASD in childhood from those who did not develop the disorder. We replicated our findings in three independent studies in the United States and the UK. We show that three quantifiable characteristics of fetal and postnatal zinc-copper rhythmicity are altered in ASD : the average duration of zinc-copper cycles, regularity with which the cycles recur, and the number of complex features within a cycle. In all independent study sets and in the pooled analysis, zinc-copper rhythmicity was disrupted in ASD cases. In contrast to controls, in ASD cases, the cycle duration was shorter (F = 52.25, P < 0.001), regularity was reduced (F = 47.99, P < 0.001), and complexity diminished (F = 57.30, P < 0.001). With two distinct classification models that used metal rhythmicity data, we achieved 90% accuracy in classifying cases and controls, with sensitivity to ASD diagnosis ranging from 85 to 100% and specificity ranging from 90 to 100%. These findings suggest that altered zinc-copper rhythmicity precedes the emergence of ASD, and quantitative biochemical measures of metal rhythmicity distinguish ASD cases from controls.

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4. DeRosa BA, El Hokayem J, Artimovich E, Garcia-Serje C, Phillips AW, Van Booven D, Nestor JE, Wang L, Cuccaro ML, Vance JM, Pericak-Vance MA, Cukier HN, Nestor MW, Dykxhoorn DM. Convergent Pathways in Idiopathic Autism Revealed by Time Course Transcriptomic Analysis of Patient-Derived Neurons. Sci Rep. 2018 ; 8(1) : 8423.

Potentially pathogenic alterations have been identified in individuals with autism spectrum disorders (ASDs) within a variety of key neurodevelopment genes. While this hints at a common ASD molecular etiology, gaps persist in our understanding of the neurodevelopmental mechanisms impacted by genetic variants enriched in ASD patients. Induced pluripotent stem cells (iPSCs) can model neurodevelopment in vitro, permitting the characterization of pathogenic mechanisms that manifest during corticogenesis. Taking this approach, we examined the transcriptional differences between iPSC-derived cortical neurons from patients with idiopathic ASD and unaffected controls over a 135-day course of neuronal differentiation. Our data show ASD-specific misregulation of genes involved in neuronal differentiation, axon guidance, cell migration, DNA and RNA metabolism, and neural region patterning. Furthermore, functional analysis revealed defects in neuronal migration and electrophysiological activity, providing compelling support for the transcriptome analysis data. This study reveals important and functionally validated insights into common processes altered in early neuronal development and corticogenesis and may contribute to ASD pathogenesis.

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5. Elmorsy SA, Soliman GF, Rashed LA, Elgendy H. Dexmedetomidine and propofol sedation requirements in an autistic rat model. Korean journal of anesthesiology. 2018.

Background : Autism is a challenging neurodevelopmental disorder. Previous clinical observations suggest altered sedation requirements for autistic children. Our study aimed to test this observation experimentally with an animal model and, to explore its possible mechanisms. Methods : Eight adult pregnant female Sprague Dawley rats were randomly selected into two groups. Four were injected with intraperitoneal sodium valproate on the gestational day 12 and four were injected with normal saline. On post-natal day 28 the newborn male rats were subjected to an open field test to confirm autistic features. Each rat was injected intraperitoneally with a single dose of propofol (50 mg/kg) or dexmedetomidine (0.2 mg/kg). Times to Loss of Righting Reflex (LORR) and to Return of Righting Reflex (RORR) were recorded. On the next day, all rats were re-sedated and their EEGs were recorded. The rats were sacrificed and hippocampal GABAA and glutamate NMDA receptor gene expression were assessed. Results : Autistic rats showed significantly longer time to LORR and a shorter time to RORR compared to controls (Median time to LORR : 12.0 versus 5.0 for dexmedetomidine and 22.0 and 8.0 for propofol ; p < 0.05). EEG showed a low frequency, high amplitude wave pattern two minutes after LORR in control rats. Autistic rats showed a high frequency, low amplitude awake pattern. Hippocampal GABAA receptor gene expression was significantly less in autistic rats and NMDA gene expression was greater. Conclusions : This study in rat supports the clinical observations of increased anesthetic sedative requirements in autistic children and proposes a mechanism for it.

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6. Gogou M, Kolios G. Are therapeutic diets an emerging additional choice in autism spectrum disorder management ?. World journal of pediatrics : WJP. 2018.

BACKGROUND : A nutritional background has been recognized in the pathophysiology of autism and a series of nutritional interventions have been considered as complementary therapeutic options. As available treatments and interventions are not effective in all individuals, new therapies could broaden management options for these patients. Our aim is to provide current literature data about the effect of therapeutic diets on autism spectrum disorder. DATA SOURCE : A systematic review was conducted by two reviewers independently. Prospective clinical and preclinical studies were considered. RESULT : Therapeutic diets that have been used in children with autism include ketogenic and gluten/casein-free diet. We were able to identify 8 studies conducted in animal models of autism demonstrating a beneficial effect on neurophysiological and clinical parameters. Only 1 clinical study was found showing improvement in childhood autism rating scale after implementation of ketogenic diet. With regard to gluten/casein-free diet, 4 clinical studies were totally found with 2 of them showing a favorable outcome in children with autism. Furthermore, a combination of gluten-free and modified ketogenic diet in a study had a positive effect on social affect scores. No serious adverse events have been reported. CONCLUSION : Despite encouraging laboratory data, there is controversy about the real clinical effect of therapeutic diets in patients with autism. More research is needed to provide sounder scientific evidence.

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7. Gosling CJ, Moutier S. Brief Report : Risk-Aversion and Rationality in Autism Spectrum Disorders. J Autism Dev Disord. 2018.

Risk-aversion and rationality have both been highlighted as core features of decision making in individuals with Autism Spectrum Disorders (ASD). This study tested whether risk-aversion is related to rational decision-making in ASD individuals. ASD and matched control adults completed a decision-making task that discriminated between the use of risk-averse and rational strategies. Results showed that overall, ASD participants were more risk-averse than control participants. Specifically, both groups made similar choices when risk-aversion was the less rational strategy but ASD participants chose more rational options than control participants when risk-aversion was the most rational strategy. This study confirmed that risk-aversion is a core feature of ASD and revealed that ASD individuals can switch their decision-making strategy adaptively to avoid negative consequences.

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8. Hwang-Gu SL, Lin HY, Chen YC, Tseng YH, Hsu WY, Chou MC, Chou WJ, Wu YY, Gau SS. Symptoms of ADHD Affect Intrasubject Variability in Youths with Autism Spectrum Disorder : An Ex-Gaussian Analysis. J Clin Child Adolesc Psychol. 2018 : 1-14.

Increased intrasubject variability in reaction times (RT-ISV) is frequently found in individuals with autism spectrum disorder (ASD). However, how dimensional attention deficit/hyperactivity disorder (ADHD) symptoms impact RT-ISV in individuals with ASD remains elusive. We assessed 97 high-functioning youths with co-occurring ASD and ADHD (ASD+ADHD), 124 high-functioning youths with ASD only, 98 youths with ADHD only, and 249 typically developing youths, 8-18 years of age, using the Conners Continuous Performance Test (CCPT). We compared the conventional CCPT parameters (omission errors, commission errors, mean RT and RT standard error (RTSE) as well as the ex-Gaussian parameters of RT (mu, sigma, and tau) across the four groups. We also conducted regression analyses to assess the relationships between RT indices and symptoms of ADHD and ASD in the ASD group (i.e., the ASD+ADHD and ASD-only groups). The ASD+ADHD and ADHD-only groups had higher RT-ISV than the other two groups. RT-ISV, specifically RTSE and tau, was significantly associated with ADHD symptoms rather than autistic traits in the ASD group. Regression models also revealed that sex partly accounted for RT-ISV variance in the ASD group. A post hoc analysis showed girls with ASD had higher tau and RTSE values than their male counterparts. Our results suggest that RT-ISV is primarily associated with co-occurring ADHD symptoms/diagnosis in children and adolescents with ASD. These results do not support the hypothesis of response variability as a transdiagnostic phenotype for ASD and ADHD and warrant further validation at a neural level.

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9. Libero LE, Schaer M, Li DD, Amaral DG, Nordahl CW. A Longitudinal Study of Local Gyrification Index in Young Boys With Autism Spectrum Disorder. Cereb Cortex. 2018.

Local gyrification index (LGI), a metric quantifying cortical folding, was evaluated in 105 boys with autism spectrum disorder (ASD) and 49 typically developing (TD) boys at 3 and 5 years-of-age. At 3 years-of-age, boys with ASD had reduced gyrification in the fusiform gyrus compared with TD boys. A longitudinal evaluation from 3 to 5 years revealed that while TD boys had stable/decreasing LGI, boys with ASD had increasing LGI in right inferior temporal gyrus, right inferior frontal gyrus, right inferior parietal lobule, and stable LGI in left lingual gyrus. LGI was also examined in a previously defined neurophenotype of boys with ASD and disproportionate megalencephaly. At 3 years-of-age, this subgroup exhibited increased LGI in right dorsomedial prefrontal cortex, cingulate cortex, and paracentral cortex, and left cingulate cortex and superior frontal gyrus relative to TD boys and increased LGI in right paracentral lobule and parahippocampal gyrus, and left precentral gyrus compared with boys with ASD and normal brain size. In summary, this study identified alterations in the pattern and development of LGI during early childhood in ASD. Distinct patterns of alterations in subgroups of boys with ASD suggests that multiple neurophenotypes exist and boys with ASD and disproportionate megalencephaly should be evaluated separately.

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10. Schiariti V, Mahdi S, Bolte S. International Classification of Functioning, Disability and Health Core Sets for cerebral palsy, autism spectrum disorder, and attention-deficit-hyperactivity disorder. Dev Med Child Neurol. 2018.

AIM : Capturing functional information is crucial in childhood disability. The International Classification of Functioning, Disability and Health (ICF) Core Sets promote assessments of functional abilities and disabilities in clinical practice regarding circumscribed diagnoses. However, the specificity of ICF Core Sets for childhood-onset disabilities has been doubted. This study aimed to identify content commonalities and differences among the ICF Core Sets for cerebral palsy (CP), and the newly developed Core Sets for autism spectrum disorder (ASD) and attention-deficit-hyperactivity disorder (ADHD). METHOD : The categories within each Core Set were aggregated at the ICF component and chapter levels. Content comparison was conducted using descriptive analyses. RESULTS : The activities and participation component of the ICF was the most covered across all Core Sets. Main differences included representation of ICF components and coverage of ICF chapters within each component. CP included all ICF components, while ADHD and ASD predominantly focused on activities and participation. Environmental factors were highly represented in the ADHD Core Sets (40.5%) compared to the ASD (28%) and CP (27%) Core Sets. INTERPRETATION : International Classification of Functioning, Disability and Health Core Sets for CP, ASD, and ADHD capture both common but also unique functional information, showing the importance of creating condition-specific, ICF-based tools to build functional profiles of individuals with childhood-onset disabilities. WHAT THIS PAPER ADDS : The International Classification of Functioning, Disability and Health (ICF) Core Sets for cerebral palsy (CP), autism spectrum disorder (ASD), and attention-deficit-hyperactivity disorder (ADHD) include unique functional information. The ICF-based tools for CP, ASD, and ADHD differ in terms of representation and coverage of ICF components and ICF chapters. Representation of environmental factors uniquely influences functioning and disability across ICF Core Sets for CP, ASD and ADHD.

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11. Zhao YT, Kwon DY, Johnson BS, Fasolino M, Lamonica JM, Kim YJ, Zhao BS, He C, Vahedi G, Kim TH, Zhou Z. Long genes linked to autism spectrum disorders harbor broad enhancer-like chromatin domains. Genome research. 2018.

Genetic variants associated with autism spectrum disorders (ASDs) are enriched in genes encoding synaptic proteins and chromatin regulators. Although the role of synaptic proteins in ASDs is widely studied, the mechanism by which chromatin regulators contribute to ASD risk remains poorly understood. Upon profiling and analyzing the transcriptional and epigenomic features of genes expressed in the cortex, we uncovered a unique set of long genes that contain broad enhancer-like chromatin domains (BELD) spanning across their entire gene bodies. Analyses of these BELD genes show that they are highly transcribed with frequent RNA polymerase II (Pol II) initiation, low Pol II pausing, and exhibit frequent chromatin-chromatin interactions within their gene bodies. These BELD features are conserved from rodents to humans, enriched in genes involved in synaptic function, and appear postnatally concomitant with synapse development. Importantly, we find that BELD genes are highly implicated in neurodevelopmental disorders, particularly ASDs, and that their expression is preferentially downregulated in individuals with idiopathic autism. Finally, we find that the transcription of BELD genes is particularly sensitive to alternations in ASD-associated chromatin regulators. These findings suggest that the epigenomic regulation of BELD genes is important for postnatal cortical development and lends support to a model by which mutations in chromatin regulators causally contribute to ASDs by preferentially impairing BELD gene transcription.

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