1. Addis L, Ahn JW, Dobson R, Dixit A, Ogilvie CM, Pinto D, Vaags AK, Coon H, Chaste P, Wilson S, Parr JR, Andrieux J, Lenne B, Tumer Z, Leuzzi V, Aubell K, Koillinen H, Curran S, Marshall CR, Scherer SW, Strug LJ, Collier DA, Pal DK. {{Microdeletions of ELP4 are Associated with Language Impairment, Autism Spectrum Disorder and Mental Retardation}}. {Hum Mutat};2015 (May 23)
Copy number variations (CNV) are important in the aetiology of neurodevelopmental disorders and show broad phenotypic manifestations. We compared the presence of small CNVs disrupting the ELP4-PAX6 locus in 4092 U.K. individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridisation (aCGH), with WTCCC controls (n = 4783). The phenotypic analysis was then extended using the DECIPHER database. We followed up association using an autism patient cohort (n = 3143) compared with six additional control groups (n = 6469). In the clinical discovery series we identified eight cases with ELP4 deletions, and one with a partial duplication of ELP4 and PAX6. These cases were referred for neurological phenotypes including language impairment, developmental delay, autism and epilepsy. Six further cases with a primary diagnosis of ASD and similar secondary phenotypes were identified with ELP4 deletions, as well as another six (out of 9) with neurodevelopmental phenotypes from DECIPHER. CNVs at ELP4 were only present in 1/11252 controls. We found a significant excess of CNVs in discovery cases compared with controls, p = 7.5×10-3 ; as well as for autism, p = 2.7×10-3 . Our results suggest ELP4 deletions are highly likely to be pathogenic, predisposing to a range of neurodevelopmental phenotypes from ASD to language impairment and epilepsy. This article is protected by copyright. All rights reserved.
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2. Banire B, Jomhari N, Ahmad R. {{Visual Hybrid Development Learning System (VHDLS) Framework for Children with Autism}}. {J Autism Dev Disord};2015 (May 22)
The effect of education on children with autism serves as a relative cure for their deficits. As a result of this, they require special techniques to gain their attention and interest in learning as compared to typical children. Several studies have shown that these children are visual learners. In this study, we proposed a Visual Hybrid Development Learning System (VHDLS) framework that is based on an instructional design model, multimedia cognitive learning theory, and learning style in order to guide software developers in developing learning systems for children with autism. The results from this study showed that the attention of children with autism increased more with the proposed VHDLS framework.
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3. Chandley MJ, Crawford JD, Szebeni A, Szebeni K, Ordway GA. {{NTRK2 expression levels are reduced in laser captured pyramidal neurons from the anterior cingulate cortex in males with autism spectrum disorder}}. {Mol Autism};2015;6:28.
BACKGROUND: The anterior cingulate cortex (ACC) is a brain area involved in modulating behavior associated with social interaction, disruption of which is a core feature of autism spectrum disorder (ASD). Functional brain imaging studies demonstrate abnormalities of the ACC in ASD as compared to typically developing control patients. However, little is known regarding the cellular basis of these functional deficits in ASD. Pyramidal neurons in the ACC are excitatory glutamatergic neurons and key cellular mediators of the neural output of the ACC. This study was designed to investigate the potential role of ACC pyramidal neurons in ASD brain pathology. METHODS: Postmortem ACC tissue from carefully matched ASD and typically developing control donors was obtained from two national brain collections. Pyramidal neurons and surrounding astrocytes were separately collected from layer III of the ACC by laser capture microdissection. Isolated RNA was subjected to reverse transcription and endpoint PCR to determine gene expression levels for 16 synaptic genes relevant to glutamatergic neurotransmission. Cells were also collected from the prefrontal cortex (Brodmann area 10) to examine those genes demonstrating differences in expression in the ACC comparing typically developing and ASD donors. RESULTS: The level of NTRK2 expression was robustly and significantly lower in pyramidal neurons from ASD donors as compared to typically developing donors. Levels of expression of GRIN1, GRM8, SLC1A1, and GRIP1 were modestly lower in pyramidal neurons from ASD donors, but statistical significance for these latter genes did not survive correction for multiple comparisons. No significant expression differences of any genes were found in astrocytes laser captured from the same neocortical area. In addition, expression levels of NTRK2 and other synaptic genes were normal in pyramidal neurons laser captured from the prefrontal cortex. CONCLUSIONS: These studies demonstrate a unique pathology of neocortical pyramidal neurons of the ACC in ASD. NTRK2 encodes the tropomyosin receptor kinase B (TrkB), transmission through which neurotrophic factors modify differentiation, plasticity, and synaptic transmission. Reduced pyramidal neuron NTRK2 expression in the ACC could thereby contribute to abnormal neuronal activity and disrupt social behavior mediated by this brain region.
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4. Gadke DL, McKinney C, Oliveros A. {{Autism Spectrum Disorder Symptoms and Comorbidity in Emerging Adults}}. {Child Psychiatry Hum Dev};2015 (May 21)
Autism spectrum disorder (ASD) continues to grow in prevalence each passing year. As more children are diagnosed, it makes sense that the emerging adult and adult population with ASD also will continue to grow. Although the body of research is quite large for children with ASD, the literature for emerging adults with ASD is sparse in comparison. The current study aimed to extend existing literature further by beginning to explore the realm of emerging adulthood. Specifically, the study investigated the presence of comorbid psychiatric symptoms in emerging adults who also presented with ASD symptoms as measured by the Adult Self-Report (Rescorla and Achenbach in The Achenbach System of Empirically Based Assessment (ASEBA) for ages 18 to 90 years. The use of psychological testing for treatment planning and outcomes assessment: volume 3: instruments for adults, 3rd edn. Lawrence Erlbaum Associates, Mahwah, pp 115-152, 2004). Emerging adults were categorized as having normal, mild, moderate, or severe levels of ASD symptoms and were compared for the presence of comorbid psychiatric symptoms. Overall, results suggested that emerging adults who presented with greater ASD symptom severity were more likely to experience the presence of additional comorbid symptoms.
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5. Ganz JB. {{AAC Interventions for Individuals with Autism Spectrum Disorders: State of the Science and Future Research Directions}}. {Augment Altern Commun};2015 (May 21):1-12.
Augmentative and alternative communication (AAC) provides a means of effective communication to individuals with autism spectrum disorder (ASD), many of whom are unable to use conventional speech effectively. The purposes of this article are (a) to summarize and synthesize the last few decades of research on the use of AAC with people with ASD; (b) to indicate implications of this research for stakeholders such as people with ASD, their family members, and educators with whom they work; and (c) to outline priorities for future research to improve communication and other outcomes for individuals with ASD and their loved ones. People with ASD stand to greatly benefit from AAC, particularly with current AAC technologies, as described in this article.
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6. Gu X, Eilam-Stock T, Zhou T, Anagnostou E, Kolevzon A, Soorya L, Hof PR, Friston KJ, Fan J. {{Autonomic and brain responses associated with empathy deficits in autism spectrum disorder}}. {Hum Brain Mapp};2015 (May 21)
Accumulating evidence suggests that autonomic signals and their cortical representations are closely linked to emotional processes, and that related abnormalities could lead to social deficits. Although socio-emotional impairments are a defining feature of autism spectrum disorder (ASD), empirical evidence directly supporting the link between autonomic, cortical, and socio-emotional abnormalities in ASD is still lacking. In this study, we examined autonomic arousal indexed by skin conductance responses (SCR), concurrent cortical responses measured by functional magnetic resonance imaging, and effective brain connectivity estimated by dynamic causal modeling in seventeen unmedicated high-functioning adults with ASD and seventeen matched controls while they performed an empathy-for-pain task. Compared to controls, adults with ASD showed enhanced SCR related to empathetic pain, along with increased neural activity in the anterior insular cortex, although their behavioral empathetic pain discriminability was reduced and overall SCR was decreased. ASD individuals also showed enhanced correlation between SCR and neural activities in the anterior insular cortex. Importantly, significant group differences in effective brain connectivity were limited to greater reduction in the negative intrinsic connectivity of the anterior insular cortex in the ASD group, indicating a failure in attenuating anterior insular responses to empathetic pain. These results suggest that aberrant interoceptive precision, as indexed by abnormalities in autonomic activity and its central representations, may underlie empathy deficits in ASD. Hum Brain Mapp, 2015. (c) 2015 Wiley Periodicals, Inc.
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7. Herguner A, Herguner S. {{Association between age at menarche and autistic traits in Turkish university students}}. {Am J Hum Biol};2015 (May 20)
OBJECTIVES: The androgen theory of autism suggests that masculinizing effect of fetal androgens may play a role in the expression of autism. Recent evidence showed that excessive prenatal androgen exposure might delay age at menarche (AAM). The aim of this study was to investigate the relation between autistic traits and AAM in a sample of nonclinical female university students. METHODS: Autistic traits were measured using the Autism Spectrum Quotient (AQ), and AAM was questioned by retrospective self-reports. The AQ was completed by 436 female university students. RESULTS: There were significant positive correlations between AAM and AQ total and subscales measuring Social Skills, Communication, and Imagination. Subjects with above average autistic traits reported later AAM than subjects with below average autistic traits. CONCLUSION: These findings suggest that there may be a common developmental mechanism between delayed menarche and autistic traits, possibly through elevated levels of prenatal androgens. Am. J. Hum. Biol., 2015. (c) 2015 Wiley Periodicals, Inc.
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8. Jac Fredo AR, Kavitha G, Ramakrishnan S. {{Subcortical Region Segmentation using Fuzzy Based Augmented Lagrangian Multiphase Level Sets Method in Autistic MR Brain Images}}. {Biomed Sci Instrum};2015 (Apr 10);51:323-331.
Observing and classifying the indirect immunofluorescence patterns on HEp-2 cells can help in detecting Anti-Nuclear-Antibodies. A computer algorithm to perform this function can lead to a more standardized, faster and accurate diagnosis of auto-immune diseases such as systemic lupus erythematosus, sjogrens syndrome, and rheumatoid arthritis. In this paper, HEp-2 staining patterns are classified using segmentation based fractal texture features. The images used for this experimentation are obtained from a publicly available database. The features extracted from a cell image is used to classify it into homogenous, fine speckled, coarse speckled, centromere and nucleolus. The cell images are segmented using the ground truth mask provided in the database. Adaptive histogram equalization is applied to the segmented images for contrast enhancement. Three features namely mean intensity, area and Hausdorff fractal dimension of the border are extracted for 8 different Otsu threshold levels. Finally, the 24 features thus extracted are fed to a support vector machine with Gaussian radial basis function kernel. It is observed that the overall accuracy of classification is 65.17%. The accuracy is greatly dependent on scaling and distribution of the features given to SVM. It appears that the segmentation based fractal texture features and SVM could help to build a robust automated diagnosis tool for auto-immune diseases.
9. Kelly MP, Leader G, Reed P. {{Stimulus Over-Selectivity and Extinction-Induced Recovery of Performance as a Product of Intellectual Impairment and Autism Severity}}. {J Autism Dev Disord};2015 (May 22)
The current experiment investigated the extent to which three variables (autism severity, nonverbal intellectual functioning, and verbal intellectual functioning) are associated with over-selective responding in a group of children with Autism Spectrum Disorder. This paper also analyzed the association of these three variables with the recovery of responding to a previously under-selected stimulus following extinction of the previously over-selected stimulus. The results demonstrated that participants showed over-selectivity, and demonstrated that extinction of the over-selected stimulus led to recovery of responding to the previously under-selected stimulus. For both over-selectivity, and recovery from over-selectivity, verbal functioning appeared to predict the effects most strongly, with greater over-selectivity in the lower functioning individuals, and greater recovery in the higher functioning individuals.
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10. Kumari D, Swaroop M, Southall N, Huang W, Zheng W, Usdin K. {{High-Throughput Screening to Identify Compounds That Increase Fragile X Mental Retardation Protein Expression in Neural Stem Cells Differentiated From Fragile X Syndrome Patient-Derived Induced Pluripotent Stem Cells}}. {Stem Cells Transl Med};2015 (May 21)
Fragile X syndrome (FXS), the most common form of inherited cognitive disability, is caused by a deficiency of the fragile X mental retardation protein (FMRP). In most patients, the absence of FMRP is due to an aberrant transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene. FXS has no cure, and the available treatments only provide symptomatic relief. Given that FMR1 gene silencing in FXS patient cells can be partially reversed by treatment with compounds that target repressive epigenetic marks, restoring FMRP expression could be one approach for the treatment of FXS. We describe a homogeneous and highly sensitive time-resolved fluorescence resonance energy transfer assay for FMRP detection in a 1,536-well plate format. Using neural stem cells differentiated from an FXS patient-derived induced pluripotent stem cell (iPSC) line that does not express any FMRP, we screened a collection of approximately 5,000 known tool compounds and approved drugs using this FMRP assay and identified 6 compounds that modestly increase FMR1 gene expression in FXS patient cells. Although none of these compounds resulted in clinically relevant levels of FMR1 mRNA, our data provide proof of principle that this assay combined with FXS patient-derived neural stem cells can be used in a high-throughput format to identify better lead compounds for FXS drug development.
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11. Lauer E, McCallion P. {{Mortality of People with Intellectual and Developmental Disabilities from Select US State Disability Service Systems and Medical Claims Data}}. {J Appl Res Intellect Disabil};2015 (May 21)
BACKGROUND: Monitoring population trends including mortality within subgroups such as people with intellectual and developmental disabilities and between countries provides crucial information about the population’s health and insights into underlying health concerns and the need for and effectiveness of public health efforts. METHODS: Data from both US state intellectual and developmental disabilities service system administrative data sets and de-identified state Medicaid claims were used to calculate average age at death and crude mortality rates. RESULTS: Average age at death for people in state intellectual and developmental disabilities systems was 50.4-58.7 years and 61.2-63.0 years in Medicaid data, with a crude adult mortality rate of 15.2 per thousand. CONCLUSIONS: Age at death remains lower and mortality rates higher for people with intellectual and developmental disabilities. Improved case finding (e.g. medical claims) could provide more complete mortality patterns for the population with intellectual and developmental disabilities to inform the range of access and receipt of supportive and health-related interventions and preventive care.
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12. Lin IF, Yamada T, Komine Y, Kato N, Kashino M. {{Enhanced segregation of concurrent sounds with similar spectral uncertainties in individuals with autism spectrum disorder}}. {Sci Rep};2015;5:10524.
When acoustic signals from different sound sources are mixed upon arrival at the ears, the auditory system organizes these acoustic elements by their features. This study shows that individuals with autism spectrum disorder (ASD) performed better in terms of hearing a target sequence among distractors that had similar spectral uncertainties. Their superior performance in this task indicates an enhanced discrimination between auditory streams with the same spectral uncertainties but different spectro-temporal details. The enhanced discrimination of acoustic components may be related to the absence of the automatic grouping of acoustic components with the same features, which results in difficulties in speech perception in a noisy environment. On the other hand, the ASD group and the control group had similar performance in hearing a target sequence among distractors that had different spatial cues defined by interaural intensity differences.
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13. Postorino V, Sanges V, Giovagnoli G, Fatta LM, De Peppo L, Armando M, Vicari S, Mazzone L. {{Clinical differences in children with autism spectrum disorder with and without food selectivity}}. {Appetite};2015 (May 18)
Several studies have described the atypical eating behaviors frequently occurring in children with autism spectrum disorder (ASD), and food selectivity is the most frequent of these problems. The everyday management of mealtime behaviors among children with ASD can have a negative impact on family routines and become a significant stressor for families. However, much remains unknown about why food selectivity is so prevalent among individuals with ASD. The objective of this study was to investigate clinical and behavioral features in individuals with ASD with the aim of identifying distinctive clinical profiles in children with and without food selectivity. A total of 158 children with ASD were enrolled in this study: 79 participants with food selectivity (FS) were age and sex matched with 79 participants without food selectivity (No FS). All participants and their parents completed a battery of psychological tests for a comprehensive evaluation of ASD symptoms, cognitive abilities, adaptive skills, behavioral problems and parental stress level. No statistically significant difference on gastrointestinal symptoms and growth adequacy was found between the FS group and the No FS group. Overall, the FS group showed significantly higher rates of ASD symptoms as compared to the No FS group in the questionnaires completed by parents. Furthermore, parents of the FS group reported significantly higher levels of parental stress and a larger degree of their children’s behavioral problems as compared to the No FS group. Finally, there were no differences between the FS and the No FS group on any adaptive skill domain. Our findings suggest that the identification of distinctive clinical and behavioral patterns in children with ASD and food selectivity is a crucial issue for parents and therapists in the daily management.
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14. Schieve LA, Fountain C, Boulet SL, Yeargin-Allsopp M, Kissin DM, Jamieson DJ, Rice C, Bearman P. {{Does Autism Diagnosis Age or Symptom Severity Differ Among Children According to Whether Assisted Reproductive Technology was Used to Achieve Pregnancy?}}. {J Autism Dev Disord};2015 (May 22)
Previous studies report associations between conception with assisted reproductive technology (ART) and autism. Whether these associations reflect an ascertainment or biologic effect is undetermined. We assessed diagnosis age and initial autism symptom severity among >30,000 children with autism from a linkage study of California Department of Developmental Services records, birth records, and the National ART Surveillance System. Median diagnosis age and symptom severity levels were significantly lower for ART-conceived than non-ART-conceived children. After adjustment for differences in the socio-demographic profiles of the two groups, the diagnosis age differentials were greatly attenuated and there were no differences in autism symptomatology. Thus, ascertainment issues related to SES, not ART per se, are likely the driving influence of the differences we initially observed.
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15. Takano T. {{Role of Microglia in Autism: Recent Advances}}. {Dev Neurosci};2015 (May 21)
The neurobiological basis for autism remains poorly understood. However, the neuroinflammation processes play an important role in the induction of autistic behavioral changes. Microglial cells can exhibit widely differing functions during brain development, including synaptogenesis and stem cell proliferation, in addition to playing a role in the innate immunity. Mounting evidence indicates that microglial activation or dysfunction can profoundly affect neural development, resulting in neurodevelopmental disorders, including autism. These mechanisms in autism have been investigated using neuropathological studies of human autopsy brains, a large number of murine experimental models and in vivo neuroimaging studies of the human brain. The purpose of this review is to discuss microglial activation or dysfunction and to highlight the detrimental role that microglia play in the development of autism. The recent advances presented in this review support that further elucidation of the mechanisms and kinetics of microglial responses will help to establish a window for therapeutic intervention in individuals with autism. (c) 2015 S. Karger AG, Basel.
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16. Travers BG, Bigler ED, Tromp DP, Adluru N, Destiche D, Samsin D, Froehlich A, Prigge MD, Duffield TC, Lange N, Alexander AL, Lainhart JE. {{Brainstem White Matter Predicts Individual Differences in Manual Motor Difficulties and Symptom Severity in Autism}}. {J Autism Dev Disord};2015 (May 23)
Mounting evidence suggests that poorer motor skills may be related to more severe autism symptoms. This study investigated if atypical white matter microstructure in the brain mediated the relationship between motor skills and ASD symptom severity. Sixty-seven males with ASD and 42 males with typical development (5-33 years old) completed a diffusion tensor imaging scan and measures of grip strength, finger tapping, and autism symptom severity. Within the ASD group, weaker grip strength predicted more severe autism symptoms. Fractional anisotropy of the brainstem’s corticospinal tract predicted both grip strength and autism symptom severity and mediated the relationship between the two. These findings suggest that brainstem white matter may contribute to autism symptoms and grip strength in ASD.
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17. Wang J, Wegener JE, Huang TW, Sripathy S, De Jesus-Cortes H, Xu P, Tran S, Knobbe W, Leko V, Britt J, Starwalt R, McDaniel L, Ward CS, Parra D, Newcomb B, Lao U, Nourigat C, Flowers DA, Cullen S, Jorstad NL, Yang Y, Glaskova L, Vigneau S, Kozlitina J, Yetman MJ, Jankowsky JL, Reichardt SD, Reichardt HM, Gartner J, Bartolomei MS, Fang M, Loeb K, Keene CD, Bernstein I, Goodell M, Brat DJ, Huppke P, Neul JL, Bedalov A, Pieper AA. {{Wild-type microglia do not reverse pathology in mouse models of Rett syndrome}}. {Nature};2015 (May 21);521(7552):E1-4.
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18. Yufune S, Satoh Y, Takamatsu I, Ohta H, Kobayashi Y, Takaenoki Y, Pages G, Pouyssegur J, Endo S, Kazama T. {{Transient Blockade of ERK Phosphorylation in the Critical Period Causes Autistic Phenotypes as an Adult in Mice}}. {Sci Rep};2015;5:10252.
The critical period is a distinct time-window during the neonatal stage when animals display elevated sensitivity to certain environmental stimuli, and particular experiences can have profound and long-lasting effects on behaviors. Increasing evidence suggests that disruption of neuronal activity during the critical period contributes to autistic phenotype, although the pathogenic mechanism is largely unknown. Herein we show that extracellular signal-regulated protein kinases (ERKs) play important roles in proper formation of neural circuits during the critical period. Transient blockade of ERKs phosphorylation at postnatal day 6 (P6) by intraperitoneal injection of blood-brain barrier-penetrating MEK inhibitor, alpha-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitril e (SL327) caused significant increase of apoptosis in the forebrain. Furthermore, this induced long-term deleterious effects on brain functioning later in adulthood, resulting in social deficits, impaired memory and reduced long-term potentiation (LTP). Conversely, blockade of ERK phosphorylation at P14 no longer induced apoptosis, nor behavioral deficits, nor the reduced LTP. Thus, surprisingly, these effects of ERKs are strongly age-dependent, indicating that phosphorylation of ERKs during the critical period is absolutely required for proper development of brain functioning. This study provides novel insight into the mechanistic basis for neurodevelopment disorders: various neurodevelopment disorders might be generally linked to defects in ERKs signaling during the critical period.
