1. Anderson GM, Montazeri F, de Bildt A. {{Network Approach to Autistic Traits: Group and Subgroup Analyses of ADOS Item Scores}}. {J Autism Dev Disord};2015 (Jul 24)
A network conceptualization might contribute to understanding the occurrence and interacting nature of behavioral traits in the autism realm. Networks were constructed based on correlations of item scores of the Autism Diagnostic Observation Schedule for Modules 1, 2 and 3 obtained for a group of 477 Dutch individuals with developmental disorders. After combining Modules, networks were obtained and compared for male versus female, high- versus low-functioning, seizure versus non-seizure, autism spectrum disorder versus intellectual disability, and younger versus older subjects. The network visualizations and calculated network parameters provide new perspectives that generate new hypothesis and suggest follow-up studies. The approach should be useful in characterizing individuals and groups, in elucidating mechanisms of trait generation and routes to outcome phenotypes, and in suggesting points of intervention.
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2. Auzias G, Takerkart S, Deruelle C. {{On the Influence of Confounding Factors in Multi-site Brain Morphometry Studies of Developmental Pathologies: Application to Autism Spectrum Disorder}}. {IEEE J Biomed Health Inform};2015 (Jul 22)
Pooling data acquired on different MR scanners is a commonly used practice to increase the statistical power of studies based on MRI-derived measurements. Such studies are very appealing since they should make it possible to detect more subtle effects related to pathologies. However, the influence of confounds introduced by scanner-related variations remains unclear. When studying brain morphometry descriptors, it is crucial to investigate whether scanner-induced errors can exceed the effect of the disease itself. More specifically, in the context of developmental pathologies such as Autism Spectrum Disorders (ASD), it is essential to evaluate the influence of the scanner on age-related effects. In this paper, we studied a dataset composed of 159 anatomical MR images pooled from three different scanners, including 75 ASD patients and 84 healthy controls. We quantitatively assessed the effects of the age, pathology and scanner factors on cortical thickness measurements. Our results indicate that scan pooling from different sites would be less fruitful in some cortical regions than in others. Although the effect of age is consistent across scanners, the interaction between the age and scanner factors is important and significant in some specific cortical areas.
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3. Carmo JC, Duarte E, Pinho S, Marques JF, Filipe CN. {{Verbal fluency as a function of time in autism spectrum disorder: An impairment of initiation processes?}}. {J Clin Exp Neuropsychol};2015 (Jul 24):1-12.
In the present study, we aimed to evaluate the hypothesis that the reported discrepancy in the performance of verbal fluency in individuals with autism spectrum disorder (ASD), characterized by an overall word productivity impairment with normal clustering and switching abilities, may be due to an initiation deficit. In the present study, we evaluated the temporal dynamics of both letter and semantic verbal fluency tasks in a sample of 20 young adults with high-functioning ASD compared with a sample of 20 gender-, age-, education-, and verbal-IQ-matched participants. We first compared both the word productivity and the qualitative analysis of clustering and switching abilities during the entire task to replicate the discrepancy reported in the literature. Importantly, we next analyzed both word productivity and clustering and switching abilities in two time intervals (0-30 s and 31-60 s), as it was our primary interest to evaluate the functioning of the initial component of word retrieval. Directly supporting the idea that the discrepancy found between an impairment in global word productivity combined with normal clustering and switching strategies is due to an activation and initiation deficit, we observed an abnormal performance for the ASD group in the first time period only. We interpreted these results to be preliminary findings of deficits in initiation processes in ASD.
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4. Chapman NH, Nato AQ, Jr., Bernier R, Ankenman K, Sohi H, Munson J, Patowary A, Archer M, Blue EM, Webb SJ, Coon H, Raskind WH, Brkanac Z, Wijsman EM. {{Whole exome sequencing in extended families with autism spectrum disorder implicates four candidate genes}}. {Hum Genet};2015 (Jul 24)
Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders, characterized by impairment in communication and social interactions, and by repetitive behaviors. ASDs are highly heritable, and estimates of the number of risk loci range from hundreds to >1000. We considered 7 extended families (size 12-47 individuals), each with >/=3 individuals affected by ASD. All individuals were genotyped with dense SNP panels. A small subset of each family was typed with whole exome sequence (WES). We used a 3-step approach for variant identification. First, we used family-specific parametric linkage analysis of the SNP data to identify regions of interest. Second, we filtered variants in these regions based on frequency and function, obtaining exactly 200 candidates. Third, we compared two approaches to narrowing this list further. We used information from the SNP data to impute exome variant dosages into those without WES. We regressed affected status on variant allele dosage, using pedigree-based kinship matrices to account for relationships. The p value for the test of the null hypothesis that variant allele dosage is unrelated to phenotype was used to indicate strength of evidence supporting the variant. A cutoff of p = 0.05 gave 28 variants. As an alternative third filter, we required Mendelian inheritance in those with WES, resulting in 70 variants. The imputation- and association-based approach was effective. We identified four strong candidate genes for ASD (SEZ6L, HISPPD1, FEZF1, SAMD11), all of which have been previously implicated in other studies, or have a strong biological argument for their relevance.
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5. Delepine C, Nectoux J, Letourneur F, Baud V, Chelly J, Billuart P, Bienvenu T. {{Astrocyte Transcriptome from the Mecp2-Truncated Mouse Model of Rett Syndrome}}. {Neuromolecular Med};2015 (Jul 25)
Mutations in the gene encoding the transcriptional modulator methyl-CpG binding protein 2 (MeCP2) are responsible for the neurodevelopmental disorder Rett syndrome which is one of the most frequent sources of intellectual disability in women. Recent studies showed that loss of Mecp2 in astrocytes contributes to Rett-like symptoms and restoration of Mecp2 can rescue some of these defects. The goal of this work is to compare gene expression profiles of wild-type and mutant astrocytes from Mecp2308/y mice (B6.129S-MeCP2<tm1Heto>/J) by using Affymetrix mouse 2.0 microarrays. Results were confirmed by quantitative real-time RT-PCR and by Western blot analysis. Gene set enrichment analysis utilizing Ingenuity Pathways was employed to identify pathways disrupted by Mecp2 deficiency. A total of 2152 genes were statistically differentially expressed between wild-type and mutated samples, including 1784 coding transcripts. However, only 257 showed fold changes >1.2. We confirmed our data by replicative studies in independent primary cultures of cortical astrocytes from Mecp2-deficient mice. Interestingly, two genes known to encode secreted proteins, chromogranin B and lipocalin-2, showed significant dysregulation. These proteins secreted from Mecp2-deficient glia may exert negative non-cell autonomous effects on neuronal properties, including dendritic morphology. Moreover, transcriptional profiling revealed altered Nr2f2 expression which may explain down- and upregulation of several target genes in astrocytes such as Ccl2, Lcn2 and Chgb. Unraveling Nr2f2 involvement in Mecp2-deficient astrocytes could pave the way for a better understanding of Rett syndrome pathophysiology and offers new therapeutic perspectives.
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6. Dickerson AS, Rahbar MH, Han I, Bakian AV, Bilder DA, Harrington RA, Pettygrove S, Durkin M, Kirby RS, Wingate MS, Tian LH, Zahorodny WM, Pearson DA, Moye LA, 3rd, Baio J. {{Autism spectrum disorder prevalence and proximity to industrial facilities releasing arsenic, lead or mercury}}. {Sci Total Environ};2015 (Jul 25);536:245-251.
Prenatal and perinatal exposures to air pollutants have been shown to adversely affect birth outcomes in offspring and may contribute to prevalence of autism spectrum disorder (ASD). For this ecologic study, we evaluated the association between ASD prevalence, at the census tract level, and proximity of tract centroids to the closest industrial facilities releasing arsenic, lead or mercury during the 1990s. We used 2000 to 2008 surveillance data from five sites of the Autism and Developmental Disabilities Monitoring (ADDM) network and 2000 census data to estimate prevalence. Multi-level negative binomial regression models were used to test associations between ASD prevalence and proximity to industrial facilities in existence from 1991 to 1999 according to the US Environmental Protection Agency Toxics Release Inventory (USEPA-TRI). Data for 2489 census tracts showed that after adjustment for demographic and socio-economic area-based characteristics, ASD prevalence was higher in census tracts located in the closest 10th percentile compared of distance to those in the furthest 50th percentile (adjusted RR=1.27, 95% CI: (1.00, 1.61), P=0.049). The findings observed in this study are suggestive of the association between urban residential proximity to industrial facilities emitting air pollutants and higher ASD prevalence.
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7. Doshi-Velez F, Avillach P, Palmer N, Bousvaros A, Ge Y, Fox K, Steinberg G, Spettell C, Juster I, Kohane I. {{Prevalence of Inflammatory Bowel Disease Among Patients with Autism Spectrum Disorders}}. {Inflamm Bowel Dis};2015 (Jul 25)
BACKGROUND: The objective of this study was to measure the prevalence of inflammatory bowel disease (IBD) among patients with autism spectrum disorders (ASD), which has not been well described previously. METHODS: The rates of IBD among patients with and without ASD were measured in 4 study populations with distinct modes of ascertainment: a health care benefits company, 2 pediatric tertiary care centers, and a national ASD repository. The rates of IBD (established through International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes) were compared with respective controls and combined using a Stouffer meta-analysis. Clinical charts were also reviewed for IBD among patients with ICD-9-CM codes for both IBD and ASD at one of the pediatric tertiary care centers. This expert-verified rate was compared with the rate in the repository study population (where IBD diagnoses were established by expert review) and in nationally reported rates for pediatric IBD. RESULTS: In all of case-control study populations, the rates of IBD-related ICD-9-CM codes for patients with ASD were significantly higher than that of their respective controls (Stouffer meta-analysis, P < 0.001). Expert-verified rates of IBD among patients with ASD were 7 of 2728 patients in one study population and 16 of 7201 in a second study population. The age-adjusted prevalence of IBD among patients with ASD was higher than their respective controls and nationally reported rates of pediatric IBD. CONCLUSIONS: Across each population with different kinds of ascertainment, there was a consistent and statistically significant increased prevalance of IBD in patients with ASD than their respective controls and nationally reported rates for pediatric IBD.
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8. Hall D, Todorova-Koteva K, Pandya S, Bernard B, Ouyang B, Walsh M, Pounardjian T, Deburghraeve C, Zhou L, Losh M, Leehey M, Berry-Kravis E. {{Neurological and Endocrine Phenotypes of Fragile X Carrier Women}}. {Clin Genet};2015 (Jul 25)
INTRODUCTION: Women who carry fragile X mental retardation 1 (FMR1)gene premutation expansions frequently report neurological or endocrine symptoms and prior studies have predominantly focused on questionnaire report of medical issues. METHODS: Premutation carrier women (n = 33) and non-carrier controls (n = 13) were recruited and evaluated by a neurologist, neuropsychologist, and endocrinologist. Blood and skin biopsies were collected for molecular measures. Scales for movement disorders, neuropathy, cognitive function, psychiatric symptoms, sleep, and quality of life were completed. RESULTS: The average age of the women was 51 years (n = 46) and average CGG repeat size was 91 +/- 24.9 in the FMR1 premutation carrier women. Seventy-percent of the premutation carrier women had an abnormal neurological examination. Premutation carrier women had significantly higher scores on the FXTAS Rating Scale, more neuropathy, and difficulty with tandem gait compared to controls. Central sensitivity syndromes, a neuroticism profile on the NEO Personality Profile, and sleep disorders were also prevalent. Discrepancies between subject report and examination findings were also seen. CONCLUSIONS: This pilot study suggests that women with the FMR1 premutation may have a phenotype that overlaps with that seen in FXTAS. Additional research with larger sample sizes is warranted to better delineate the clinical features.
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9. Lough E, Hanley M, Rodgers J, South M, Kirk H, Kennedy DP, Riby DM. {{Violations of Personal Space in Young People with Autism Spectrum Disorders and Williams Syndrome: Insights from the Social Responsiveness Scale}}. {J Autism Dev Disord};2015 (Jul 24)
Interpersonal distance regulation is crucial for successful social interactions. We investigated personal space awareness in Williams syndrome (WS) and autism spectrum disorder (ASD) compared to typical development. Parents reported that individuals with WS and ASD were significantly more likely than those developing typically to invade the personal space of others. WS individuals were reported to have the least awareness of the personal space boundaries of others. Despite the suggested opposing social profiles of WS and ASD, some similarities are present in the ability, or indeed inability, to regulate interpersonal distance during social interactions. Findings are discussed in relation to implications of atypical amygdala function, inhibitory control and anxiety on real-world behaviour for such socially vulnerable groups.
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10. Melchior M, Pryor L, van der Waerden J. {{Commonalities and specificities between attention deficit/hyperactivity disorder and autism-spectrum disorders: can epidemiology contribute?}}. {Eur Child Adolesc Psychiatry};2015 (Jul 24)
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11. Pasciuto E, Borrie SC, Kanellopoulos AK, Santos AR, Cappuyns E, D’Andrea L, Pacini L, Bagni C. {{Autism Spectrum Disorders: translating human deficits into mouse behavior}}. {Neurobiol Learn Mem};2015 (Jul 25)
Autism spectrum disorders are a heterogeneous group of neurodevelopmental disorders, with rising incidence but little effective therapeutic intervention available. Currently two main clinical features are described to diagnose ASDs: impaired social interaction and communication, and repetitive behaviors. Much work has focused on understanding underlying causes of ASD by generating animal models of the disease, in the hope of discovering signaling pathways and cellular targets for drug intervention. Here we review how ASD behavioral phenotypes can be modeled in the mouse, the most common animal model currently in use in this field, and discuss examples of genetic mouse models of ASD with behavioral features that recapitulate various symptoms of ASD.
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12. Sharpley CF, Bitsika V, Agnew LL, Andronicos NM. {{Eight-month test-retest agreement in morning salivary cortisol, self- and parent-rated anxiety in boys with an Autism Spectrum Disorder}}. {Physiol Behav};2015 (Jul 25)
The agreement over time in morning salivary cortisol concentrations and also self- and parent-rated anxiety was investigated in a sample of 16 boys with an ASD. Cortisol and anxiety data were collected eight months apart. Results indicated that there were significant correlations between each pair of measures from the two occasions, suggesting that cortisol concentrations and anxiety did not vary much at all over that time, challenging the assumption that cortisol needs to be measured over multiple days to obtain reliable data from children with an ASD. Implications for research into the ways these children respond to chronic stressors are discussed.
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13. Shin S, Yu N, Choi JR, Jeong S, Lee KA. {{Routine Chromosomal Microarray Analysis is Necessary in Korean Patients With Unexplained Developmental Delay/Mental Retardation/Autism Spectrum Disorder}}. {Ann Lab Med};2015 (Sep);35(5):510-518.
BACKGROUND: All over the world, chromosomal microarray (CMA) is now the first tier diagnostic assay for genetic testing to evaluate developmental delay (DD), mental retardation (MR), and autism spectrum disorder (ASD) with unknown etiology. The average diagnostic yield of the CMA test is known to be about 12.2%, while that of conventional G-banding karyotype is below 3%. This study aimed to assess the usefulness of CMA for the purpose of clinical diagnostic testing in the Korean population. METHODS: We performed CMA and multiplex ligation-dependent probe amplification (MLPA) tests in 96 patients with normal karyotype and unexplained DD, MR, or ASD. The CMA was conducted with CytoScan 750K array (Affymetrix, USA) with an average resolution of 100 kb. RESULTS: Pathogenic copy number variations (CNVs) were detected in 15 patients by CMA and in two patients by MLPA for four known microdeletion syndromes (Prader-Willi/Angelman syndrome, DiGeorge syndrome, Miller-Dieker syndrome and Williams syndrome) designated by National Health Insurance system in Korea. The diagnostic yield was 15.6% and 2.1%, respectively. Thirteen (13.5%) patients (excluding cases with pathogenic CNVs) had variants of uncertain clinical significance. There was one patient with a 17.1-megabase (Mb) region of homozygosity on chromosome 4q. CONCLUSIONS: Our findings suggest the necessity of CMA as a routine diagnostic test for unexplained DD, MR, and ASD in Korea.
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14. Tessier S, Lambert A, Scherzer P, Jemel B, Godbout R. {{REM Sleep and Emotional Face Memory in Typically-developing Children and Children with Autism}}. {Biol Psychol};2015 (Jul 25)
Relationship between REM sleep and memory was assessed in 13 neurotypical and 13 children with Autistic Spectrum Disorder (ASD). A neutral/positive/negative face recognition task was administered the evening before (learning and immediate recognition) and the morning after (delayed recognition) sleep. The number of rapid eye movements (REMs), beta and theta EEG activity over the visual areas were measured during REM sleep. Compared to neurotypical children, children with ASD showed more theta activity and longer reaction time (RT) for correct responses in delayed recognition of neutral faces. Both groups showed a positive correlation between sleep and performance but different patterns emerged: in neurotypical children, accuracy for recalling neutral faces and overall RT improvement overnight was correlated with EEG activity and REMs; in children with ASD, overnight RT improvement for positive and negative faces correlated with theta and beta activity, respectively. These results suggest that neurotypical and children with ASD use different sleep-related brain networks to process faces.
