1. Alokam R, Singhal S, Srivathsav GS, Garigipati S, Puppala S, Sriram D, Perumal Y. {{Design of dual inhibitors of ROCK-I and NOX2 as potential leads for the treatment of neuroinflammation associated with various neurological diseases including autism spectrum disorder}}. {Mol Biosyst}. 2014.
Inhibition of both Rho kinase (ROCK-I) and NADPH oxidase (NOX2) to treat neuroinflammation could be very effective in the treatment of progressive neurological diseases like Alzheimer’s disease, autism spectral disorder, and fragile X syndrome. NOX2 being a multi-enzyme component is activated during host defense in phagocytes such as microglia, to catalyze the production of superoxide from oxygen, while ROCK is an important mediator of fundamental cell processes like adhesion, proliferation and migration. Phosphorylated ROCK was found to activate NOX2 assembly via Ras related C3 botulinum toxin substrate (Rac) in disease conditions. Overexpression of ROCK-I and NOX2 in innate immune cells like microglial cells contribute to progressive neuronal damage early in neurological disease development. In the present study we employed a computer-aided methodology combining pharmacophores and molecular docking to identify new chemical entities that could inhibit ROCK-I as well as NOX2 (p47 phox). Among the huge dataset of a commercial database, top 18 molecules with crucial binding interactions were selected for biological evaluation. Seven among the lead molecules exhibited inhibitory potential against ROCK-I and NOX2 with IC50s ranging from 1.588 to 856.2 nM and 0.8942 to 10.24 muM, respectively, and emerged as potential hits as dual inhibitors with adequate selectivity index (SI = CC50/GIC50) in cell-based assays. The most active compound was further found to show reduction of the pro-inflammatory mediators such as TNFalpha, interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) mRNA expression levels in activated (MeHg treated) human neuroblastoma (IMR32) cell lines. Hence the present work documented the utility of these dual inhibitors as prototypical leads to be useful for the treatment of neurological disorders including autism spectrum disorder and Alzheimer’s disease.
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2. Ashwood KL, Buitelaar J, Murphy D, Spooren W, Charman T. {{European clinical network: autism spectrum disorder assessments and patient characterisation}}. {Eur Child Adolesc Psychiatry}. 2014.
The United Nations and World Health Organisation have identified autism spectrum disorder (ASD) as an important public health issue across global mental health services. Although a range of tools exist to identify and quantify ASD symptoms, there is a lack of information about which ASD measures are used in different services worldwide. This paper presents data from a large survey of measures used for patient characterisation in major ASD research and clinical centres across Europe collected between June 2013 and January 2014. The objective was to map the use of different instruments used to characterise ASD, comorbid psychopathology and cognitive and adaptive ability for patient diagnostic and characterisation purposes across Europe. Sixty-six clinical research sites diagnosing 14,844 patients per year contributed data. The majority of sites use the well-established Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview (ADI) instruments, though the proportion of sites in Western Europe using the ADI was almost double the rate in Eastern Europe. Approximately half the sites also used the Social Communication Questionnaire (SCQ) and Social Responsiveness Scale (SRS), although use of the SRS was over three times higher in Western Europe compared with Eastern Europe. The use of free/open access measures was lower than commercially available tools across all regions. There are clinical and scientific benefits in encouraging further convergence of clinical characterisation measures across ASD research and clinical centres in Europe to facilitate large-scale data sharing and collaboration, including clinical trials of novel medications and psychological interventions.
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3. Azouz HG, Kozou H, Khalil M, Abdou RM, Sakr M. {{The correlation between central auditory processing in autistic children and their language processing abilities}}. {Int J Pediatr Otorhinolaryngol}. 2014; 78(12): 2297-300.
AIM: To study the auditory profile at different levels of the auditory system in children with ASD and to verify the role of (Central) auditory processing disorder as an essential pathology of the autistic disorder or as an associated co-morbidity, and to establish the correlation between CAP findings and the language delay in these cases. PATIENTS: The study included 30 children with definite autistic disorder according to DSM-IV-TR criteria and ADI-R among those attending the outpatient neuropsychiatry clinic of Alexandria University Children Hospital at El Shatby. An informed consent was taken from all patients in this part of the study. Confidentiality of the records was maintained. METHODS: All cases were subjected to complete history taking and examination; special assessment to language skills and evoked potentials were done. RESULTS: The results concluded that (central) auditory processing disorder is an essential pathology of the autistic disorder. Autistic children possess a dysfunctioning or an immature central auditory nervous system at both the brainstem and cortical levels.
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4. Coulter RA, Bade A, Tea Y, Fecho G, Amster D, Jenewein E, Rodena J, Lyons KK, Mitchell GL, Quint N, Dunbar S, Ricamato M, Trocchio J, Kabat B, Garcia C, Radik I. {{Eye Examination Testability in Children with Autism and in Typical Peers}}. {Optom Vis Sci}. 2014.
PURPOSE: To compare testability of vision and eye tests in an examination protocol of 9- to 17-year-old patients with autism spectrum disorder (ASD) to typically developing (TD) peers. METHODS: In a prospective pilot study, 61 children and adolescents (34 with ASD and 27 who were TD) aged 9 to 17 years completed an eye examination protocol including tests of visual acuity, refraction, convergence (eye teaming), stereoacuity (depth perception), ocular motility, and ocular health. Patients who required new refractive correction were retested after wearing their updated spectacle prescription for 1 month. The specialized protocol incorporated visual, sensory, and communication supports. A psychologist determined group status/eligibility using DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) criteria by review of previous evaluations and parent responses on the Social Communication Questionnaire. Before the examination, parents provided information regarding patients’ sex, race, ethnicity, and, for ASD patients, verbal communication level (nonverbal, uses short words, verbal). Parents indicated whether the patient wore a refractive correction, whether the patient had ever had an eye examination, and the age at the last examination. Chi-square tests compared testability results for TD and ASD groups. RESULTS: Typically developing and ASD groups did not differ by age (p = 0.54), sex (p = 0.53), or ethnicity (p = 0.22). Testability was high on most tests (TD, 100%; ASD, 88 to 100%), except for intraocular pressure (IOP), which was reduced for both the ASD (71%) and the TD (89%) patients. Among ASD patients, IOP testability varied greatly with verbal communication level (p < 0.001). Although IOP measurements were completed on all verbal patients, only 37.5% of nonverbal and 44.4% of ASD patients who used short words were successful. CONCLUSIONS: Patients with ASD can complete most vision and eye tests within an examination protocol. Testability of IOPs is reduced, particularly for nonverbal patients and patients who use short words to communicate.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.
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5. De Pablo-Fernandez E, Doherty KM, Holton JL, Revesz T, Djamshidian A, Limousin P, Bhatia KP, Warner TT, Lees AJ, Ling H. {{Concomitant fragile X-associated tremor ataxia syndrome and Parkinson’s disease: a clinicopathological report of two cases}}. {J Neurol Neurosurg Psychiatry}. 2014.
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6. Fang WQ, Chen WW, Jiang L, Liu K, Yung WH, Fu AK, Ip NY. {{Overproduction of Upper-Layer Neurons in the Neocortex Leads to Autism-like Features in Mice}}. {Cell Rep}. 2014.
The functional integrity of the neocortex depends upon proper numbers of excitatory and inhibitory neurons; however, the consequences of dysregulated neuronal production during the development of the neocortex are unclear. As excess cortical neurons are linked to the neurodevelopmental disorder autism, we investigated whether the overproduction of neurons leads to neocortical malformation and malfunction in mice. We experimentally increased the number of pyramidal neurons in the upper neocortical layers by using the small molecule XAV939 to expand the intermediate progenitor population. The resultant overpopulation of neurons perturbs development of dendrites and spines of excitatory neurons and alters the laminar distribution of interneurons. Furthermore, these phenotypic changes are accompanied by dysregulated excitatory and inhibitory synaptic connection and balance. Importantly, these mice exhibit behavioral abnormalities resembling those of human autism. Thus, our findings collectively suggest a causal relationship between neuronal overproduction and autism-like features, providing developmental insights into the etiology of autism.
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7. Gkogkas CG, Khoutorsky A, Cao R, Jafarnejad SM, Prager-Khoutorsky M, Giannakas N, Kaminari A, Fragkouli A, Nader K, Price TJ, Konicek BW, Graff JR, Tzinia AK, Lacaille JC, Sonenberg N. {{Pharmacogenetic Inhibition of eIF4E-Dependent Mmp9 mRNA Translation Reverses Fragile X Syndrome-like Phenotypes}}. {Cell Rep}. 2014.
Fragile X syndrome (FXS) is the leading genetic cause of autism. Mutations in Fmr1 (fragile X mental retardation 1 gene) engender exaggerated translation resulting in dendritic spine dysmorphogenesis, synaptic plasticity alterations, and behavioral deficits in mice, which are reminiscent of FXS phenotypes. Using postmortem brains from FXS patients and Fmr1 knockout mice (Fmr1-/y), we show that phosphorylation of the mRNA 5′ cap binding protein, eukaryotic initiation factor 4E (eIF4E), is elevated concomitant with increased expression of matrix metalloproteinase 9 (MMP-9) protein. Genetic or pharmacological reduction of eIF4E phosphorylation rescued core behavioral deficits, synaptic plasticity alterations, and dendritic spine morphology defects via reducing exaggerated translation of Mmp9 mRNA in Fmr1-/y mice, whereas MMP-9 overexpression produced several FXS-like phenotypes. These results uncover a mechanism of regulation of synaptic function by translational control of Mmp-9 in FXS, which opens the possibility of new treatment avenues for the diverse neurological and psychiatric aspects of FXS.
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8. Kushki A, Khan A, Brian J, Anagnostou E. {{A Kalman Filtering Framework for Physiological Detection of Anxiety-Related Arousal in Children with Autism Spectrum Disorder}}. {IEEE Trans Biomed Eng}. 2014.
Objective: Anxiety is associated with physiological changes that can be non-invasively measured using inexpensive and wearable sensors. These changes provide an objective and language-free measure of arousal associated with anxiety, which can complement treatment programs for clinical populations who have difficulty with introspection, communication, and emotion recognition. This motivates the development of automatic methods for detection of anxiety-related arousal using physiology signals. While several supervised learning methods have been proposed for this purpose, these methods require regular collection and updating of training data and are therefore not suitable for clinical populations where obtaining labelled data may be challenging due to impairments in communication and introspection. In this context, the objective of this paper is to develop an unsupervised and realtime arousal detection algorithm. Methods: We propose a learning framework based on Kalman filtering theory for detection of physiological arousal based on cardiac activity. The performance of the system was evaluated on data obtained from a sample of children with autism spectrum disorder. Results: The results indicate that the system can detect anxietyrelated arousal in these children with sensitivity and specificity of 99% and 92%, respectively. Conclusion and significance: Our results show that the proposed method can detect physiological arousal associated with anxiety with high accuracy, providing support for technical feasibility of augmenting anxiety treatments with automatic detection techniques. This approach can ultimately lead to more effective anxiety treatment for a larger and more diverse population.
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9. London EB. {{Categorical diagnosis: a fatal flaw for autism research?}}. {Trends Neurosci}. 2014; 37(12): 683-6.
The use of autism as a diagnostic category guiding translational research is fraught with so many problems that the validity of research conclusions is suspect. Neuroscientists would benefit from attending to nosological difficulties to formulate meaningful research bridging basic biological systems and human disease. I propose a diagnostic schema that could translate more efficiently between the clinical and the neuroscience perspective as a step to improve the effectiveness of this type of research.
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10. Lukose R, Beebe K, Kulesza RJ. {{Organization of the human superior olivary complex in 15q duplication syndromes and autism spectrum disorders}}. {Neuroscience}. 2014.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by a number of behavioral and social features. Although the etiology of most cases of ASD is idiopathic, a significant number of cases can be attributed to genetic causes, such as chromosome 15q duplications [dup(15q)]. Recent neuropathological investigations have provided evidence for distinct patterns of heterotopias and dysplasias in ASD and subjects with both ASD and dup(15q). Individuals with ASD characteristically have hearing difficulties and we have previously demonstrated significant and consistent hypoplasia in a number of auditory brainstem nuclei in subjects with ASD. Herein, we compare results from a morphometric investigation of auditory brainstem nuclei in subjects with ASD, dup(15q) and controls. Our observations in subjects with ASD support our previous reports. However, in subjects with dup(15q), we find significantly fewer neurons and in many nuclei, neurons were significantly smaller than in ASD subjects. Finally, we find a notably higher incidence of ectopic neurons in dup(15q). These results suggest that in the brainstem, these neuropathological conditions may evolve from some of the same developmental errors but are distinguished on microscopic features.
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11. Miller J. {{DSM-5 and autism spectrum disorders: the changes you haven’t heard about yet}}. {J Clin Psychiatry}. 2014; 75(11): e1326-7.
To the Editor: Much attention has been drawn to the changes within autism spectrum disorder (ASD) criteria in DSM-5. However, in considering the ASD revisions, the changes to diagnoses throughout DSM-5 also warrant discussion, because they give clinicians new tools for diagnosing the co-occurring conditions often seen in ASD. These revisions may fundamentally change how we conceptualize ASD, because we will be better able to identify co-occurring conditions for research, clinical care, and even insurance coverage.
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12. Nelson TM, Sheller B, Friedman CS, Bernier R. {{Educational and therapeutic behavioral approaches to providing dental care for patients with Autism Spectrum Disorder}}. {Spec Care Dentist}. 2014.
PURPOSE: Autism Spectrum Disorder (ASD) is a condition which most dentists will encounter in their practices. Contemporary educational and behavioral approaches may facilitate successful dental care. METHODS: A literature review was conducted for relevant information on dental care for children with ASD. RESULTS: Educational principles used for children with ASD can be applied in the dental setting. Examples include: parent involvement in identifying strengths, sensitivities, and goal setting; using stories or video modeling in advance of the appointment; dividing dental treatment into sequential components; and modification of the environment to minimize sensory triggers. Patients with ASD are more capable of tolerating procedures that they are familiar with, and therefore should be exposed to new environments and stimuli in small incremental steps. CONCLUSIONS: By taking time to understand children with ASD as individuals and employing principles of learning, clinicians can provide high quality dental care for the majority of patients with ASD.
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13. Odom SL, Thompson JL, Hedges S, Boyd BA, Dykstra JR, Duda MA, Szidon KL, Smith LE, Bord A. {{Technology-Aided Interventions and Instruction for Adolescents with Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2014.
The use of technology in intervention and instruction for adolescents with autism spectrum disorder (ASD) is increasing at a striking rate. The purpose of this paper is to examine the research literature underlying the use of technology in interventions and instruction for high school students with ASD. In this paper, authors propose a theoretical and conceptual framework for examining the use of technology by and for adolescents with ASD in school, home, and community settings. This framework is then used to describe the research literature on efficacy of intervention and instruction that utilizes technology. A review of the literature from 1990 to the end of 2013 identified 30 studies that documented efficacy of different forms of technology and their impact on academics, adaptive behavior, challenging behavior, communication, independence, social competence, and vocational skills.
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14. Shen C, Huo LR, Zhao XL, Wang PR, Zhong N. {{Novel Interactive Partners of Neuroligin 3: New Aspects for Pathogenesis of Autism}}. {J Mol Neurosci}. 2014.
Autism is a neurodevelopmental disorder with a strong genetic predisposition. Neurolign 3 (NLGN3) as a postsynaptic transmembrane protein, functions in both neuron synaptogenesis and glia-neuron communications. Previously, a gain of function mutation (R451C) in NLGN3 was identified in autistic patients, which illustrates the involvement of NLGN3 in autism pathogenesis. As proper synaptic targeting and functioning are controlled by intracellular protein interactions, in the current study, we tried to discover the intracellular regulation network in which NLGN3 might be involved by a yeast two-hybrid-based interactor identification. Fifty-one protein candidate partners were identified after screening a human fetal complementary DNA (cDNA) library with an intracellular fragment of NLGN3. The interactions of NLGN3 with a subset of candidates, including EEF1A1, FLNA, ITPRIP, CYP11A1, MT-CO2, GPR175, ACOT2, and QPRT, were further validated in human neuroblastoma cells or brain tissues. Furthermore, our study suggested that NLGN3 was functioning in cytosolic calcium balance and participating in calcium-regulated cellular processes. Our findings of novel NLGN3 binding partners provide evidences of involvement of NLGN3 in multiple biological pathways, especially calcium regulating and mitochondrial function, thus suggesting further significance. This new data not only leads to a better understanding of the physiological functions of NLGN3, but also provide new aspects for pathogenesis of autism.
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15. Souza VA, Abreu MH, Resende VL, Castilho LS. {{Factors associated with bruxism in children with developmental disabilities}}. {Braz Oral Res}. 2015; 29(1): 1-5.
The aim of the present study was to investigate factors associated with bruxism in children aged from 1 to 13 years with developmental disabilities. A total of 389 dental records were examined. The bruxism analyzed was determined based on parental reports. The following variables were also analyzed: gender, age, International Code of Diseases (ICD), mouth breathing, history of gastroesophageal reflux, use of psychotropic drugs, gingival status, reports of xerostomia, hyperkinesis, pacifier use, thumb sucking and involuntary movements. For the purposes of analysis, the individuals were categorized as being with and without bruxism. Variables with a p-value < 0.25 in the bivariate analysis were incorporated into the logistic regression models. Females had a 0.44-fold (95%CI: 0.25 to 0.78) greater chance of exhibiting bruxism than males. Individuals with gastroesophageal reflux had a 2.28-fold (95%CI: 1.03 to 5.02) greater chance of exhibiting bruxism. Individuals with reported involuntary movements had a 2.24-fold (95%CI: 1.19 to 4.24) greater chance of exhibiting bruxism than those without such movements. Exhibiting involuntary movements, the male gender and gastroesophageal reflux are factors associated with bruxism in children with developmental disabilities.
16. Worsham W, Gray WE, Larson MJ, South M. {{Conflict adaptation and congruency sequence effects to social-emotional stimuli in individuals with autism spectrum disorders}}. {Autism}. 2014.
BACKGROUND: The modification of performance following conflict can be measured using conflict adaptation tasks thought to measure the change in the allocation of cognitive resources in order to reduce conflict interference and improve performance. While previous studies have suggested atypical processing during nonsocial cognitive control tasks, conflict adaptation (i.e. congruency sequence effects) for social-emotional stimuli have not been previously studied in autism spectrum disorder. METHODS: A total of 32 participants diagnosed with autism spectrum disorder and 27 typically developing matched controls completed an emotional Stroop conflict task that required the classification of facial affect while simultaneously ignoring an overlaid affective word. RESULTS: Both groups showed behavioral evidence for emotional conflict adaptation based on response times and accuracy rates. However, the autism spectrum disorder group demonstrated a speed-accuracy trade-off manifested through significantly faster response times and decreased accuracy rates on trials containing conflict between the emotional face and the overlaid emotional word. CONCLUSION: Reduced selective attention toward socially relevant information may bias individuals with autism spectrum disorder toward more rapid processing and decision making even when conflict is present. Nonetheless, the loss of important information from the social stimuli reduces decision-making accuracy, negatively affecting the ability to adapt both cognitively and emotionally when conflict arises.
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17. Zalla T, Miele D, Leboyer M, Metcalfe J. {{Metacognition of agency and theory of mind in adults with high functioning autism}}. {Conscious Cogn}. 2014; 31C: 126-38.
We investigated metacognition of agency in adults with high functioning autism or Asperger Syndrome (HFA/AS) using a computer task in which participants moved the mouse to get the cursor to touch the downward moving X’s and avoid the O’s. They were then asked to make judgments of performance and judgments of agency. Objective control was either undistorted, or distorted by adding turbulence (i.e., random noise) or a time Lag between the mouse and cursor movements. Participants with HFA/AS used sensorimotor cues available in the turbulence and lag conditions to a lesser extent than control participants in making their judgments of agency. Furthermore, the failure to use these internal diagnostic cues to their own agency was correlated with decrements in a theory of mind task. These findings suggest that a reduced sensitivity to veridical internal cues about the sense of agency is related to mentalizing impairments in autism.
