1. Ariza J, Rogers H, Hartvigsen A, Snell M, Dill M, Judd D, Hagerman P, Martinez-Cerdeno V. {{Iron accumulation and dysregulation in the putamen in fragile X-associated tremor/ataxia syndrome}}. {Mov Disord}. 2017.
BACKGROUND: Fragile X-associated tremor/ataxia syndrome is an adult-onset disorder associated with premutation alleles of the FMR1 gene. This disorder is characterized by progressive action tremor, gait ataxia, and cognitive decline. Fragile X-associated tremor/ataxia syndrome pathology includes dystrophic white matter and intranuclear inclusions in neurons and astrocytes. We previously demonstrated that the transport of iron into the brain is altered in fragile X-associated tremor/ataxia syndrome; therefore, we also expect an alteration of iron metabolism in brain areas related to motor control. Iron is essential for cell metabolism, but uncomplexed iron leads to oxidative stress and contributes to the development of neurodegenerative diseases. We investigated a potential iron modification in the putamen – a structure that participates in motor learning and performance – in fragile X-associated tremor/ataxia syndrome. METHODS: We used samples of putamen obtained from 9 fragile X-associated tremor/ataxia syndrome and 9 control cases to study iron localization using Perl’s method, and iron-binding proteins using immunostaining. RESULTS: We found increased iron deposition in neuronal and glial cells in the putamen in fragile X-associated tremor/ataxia syndrome. We also found a generalized decrease in the amount of the iron-binding proteins transferrin and ceruloplasmin, and decreased number of neurons and glial cells that contained ceruloplasmin. However, we found increased levels of iron, transferrin, and ceruloplasmin in microglial cells, indicating an attempt by the immune system to remove the excess iron. CONCLUSIONS: Overall, found a deficit in proteins that eliminate extra iron from the cells with a concomitant increase in the deposit of cellular iron in the putamen in Fragile X-associated tremor/ataxia syndrome. (c) 2017 International Parkinson and Movement Disorder Society.
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2. Bauminger-Zviely N, Golan-Itshaky A, Tubul-Lavy G. {{Speech Acts During Friends’ and Non-friends’ Spontaneous Conversations in Preschool Dyads with High-Functioning Autism Spectrum Disorder versus Typical Development}}. {J Autism Dev Disord}. 2017.
In this study, we videotaped two 10-min. free-play interactions and coded speech acts (SAs) in peer talk of 51 preschoolers (21 ASD, 30 typical), interacting with friend versus non-friend partners. Groups were matched for maternal education, IQ (verbal/nonverbal), and CA. We compared SAs by group (ASD/typical), by partner’s friendship status (friend/non-friend), and by partner’s disability status. Main results yielded a higher amount and diversity of SAs in the typical than the ASD group (mainly in assertive acts, organizational devices, object-dubbing, and pretend-play); yet, those categories, among others, showed better performance with friends versus non-friends. Overall, a more nuanced perception of the pragmatic deficit in ASD should be adopted, highlighting friendship as an important context for children’s development of SAs.
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3. Huang TN, Hsueh YP. {{Calcium/calmodulin-dependent serine protein kinase (CASK), a protein implicated in mental retardation and autism-spectrum disorders, interacts with T-Brain-1 (TBR1) to control extinction of associative memory in male mice}}. {J Psychiatry Neurosci}. 2017; 42(1): 37-47.
BACKGROUND: Human genetic studies have indicated that mutations in calcium/calmodulin-dependent serine protein kinase (CASK) result in X-linked mental retardation and autism-spectrum disorders. We aimed to establish a mouse model to study how Cask regulates mental ability. METHODS: Because Cask encodes a multidomain scaffold protein, a possible strategy to dissect how CASK regulates mental ability and cognition is to disrupt specific protein-protein interactions of CASK in vivo and then investigate the impact of individual specific protein interactions. Previous in vitro analyses indicated that a rat CASK T724A mutation reduces the interaction between CASK and T-brain-1 (TBR1) in transfected COS cells. Because TBR1 is critical for glutamate receptor, ionotropic, N-methyl-D-aspartate receptor subunit 2B (Grin2b) expression and is a causative gene for autism and intellectual disability, we then generated CASK T740A (corresponding to rat CASK T724A) mutant mice using a gene-targeting approach. Immunoblotting, coimmunoprecipitation, histological methods and behavioural assays (including home cage, open field, auditory and contextual fear conditioning and conditioned taste aversion) were applied to investigate expression of CASK and its related proteins, the protein-protein interactions of CASK, and anatomic and behavioural features of CASK T740A mice. RESULTS: The CASK T740A mutation attenuated the interaction between CASK and TBR1 in the brain. However, CASK T740A mice were generally healthy, without obvious defects in brain morphology. The most dramatic defect among the mutant mice was in extinction of associative memory, though acquisition was normal. LIMITATIONS: The functions of other CASK protein interactions cannot be addressed using CASK T740A mice. CONCLUSION: Disruption of the CASK and TBR1 interaction impairs extinction, suggesting the involvement of CASK in cognitive flexibility.
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4. Johnson MH. {{Autism as an adaptive common variant pathway for human brain development}}. {Dev Cogn Neurosci}. 2017.
While research on focal perinatal lesions has provided evidence for recovery of function, much less is known about processes of brain adaptation resulting from mild but widespread disturbances to neural processing over the early years (such as alterations in synaptic efficiency). Rather than being viewed as a direct behavioral consequence of life-long neural dysfunction, I propose that autism is best viewed as the end result of engaging adaptive processes during a sensitive period. From this perspective, autism is not appropriately described as a disorder of neurodevelopment, but rather as an adaptive common variant pathway of human functional brain development.
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5. Joyce C, Honey E, Leekam SR, Barrett SL, Rodgers J. {{Anxiety, Intolerance of Uncertainty and Restricted and Repetitive Behaviour: Insights Directly from Young People with ASD}}. {J Autism Dev Disord}. 2017.
In order to investigate the experience of anxiety and restricted and repetitive behaviours (RRB) in young people with ASD, 19 families with young people with ASD aged between 13 and 20 years completed questionnaire measures of RRB, anxiety, and intolerance of uncertainty. Ten young people also completed a novel semi-structured interview exploring an individualised example of an RRB. Findings demonstrated that young people with ASD can self-report and show insight in to their RRB, and replicated previous findings based on parent report showing a significant positive relationship between RRB and anxiety. This is the first evidence of young person self-report using both quantitative and qualitative data and indicates a range of reasons why young people may engage in RRB.
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6. Liu J, Yao L, Zhang W, Xiao Y, Liu L, Gao X, Shah C, Li S, Tao B, Gong Q, Lui S. {{Gray matter abnormalities in pediatric autism spectrum disorder: a meta-analysis with signed differential mapping}}. {Eur Child Adolesc Psychiatry}. 2017.
The gray matter abnormalities revealed by magnetic resonance imaging are inconsistent, especially in pediatric individuals with autism spectrum disorder (ASD) (age < 18 years old), a phenomenon possibly related to the core pathophysiology of ASD. The purpose of our meta-analysis was to identify and map the specific gray matter abnormalities in pediatric ASD individuals thereby exploring the potential effects of clinical and demographic characteristics of these gray matter changes. A systematic search was conducted to identify voxel-based morphometry studies in pediatric individuals with ASD. The effect-size signed differential mapping method was used to quantitatively estimate the regional gray matter abnormalities in pediatric ASD individuals. Meta-regression was used to examine the associations among age, gender, intelligence quotient, symptom severity and gray matter changes. Fifteen studies including 364 pediatric individuals with ASD (male = 282, age = 10.3 +/- 4.4 years) and 377 healthy controls (male = 289, age = 10.5 +/- 4.2 years) were included. Pediatric ASD individuals showed significant gray matter increases in the right angular gyrus, left superior and middle frontal gyrus, left precuneus, left inferior occipital gyrus and right inferior temporal gyrus, most of which involving the default mode network, and decreases in the left cerebellum and left postcentral gyrus. The meta-regression analysis showed that the repetitive behavior scores of the Autism Diagnostic Interview-Revised were positively associated with increased gray matter volumes in the right angular gyrus. Increased rather than decreased gray matter volume, especially involving the angular gyrus and prefrontal cortex may be the core pathophysiology in the early course of ASD. Lien vers le texte intégral (Open Access ou abonnement)
7. Masi A, Glozier N, Dale R, Guastella AJ. {{The Immune System, Cytokines, and Biomarkers in Autism Spectrum Disorder}}. {Neurosci Bull}. 2017.
Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental condition characterized by variable impairments in communication and social interaction as well as restricted interests and repetitive behaviors. Heterogeneity of presentation is a hallmark. Investigations of immune system problems in ASD, including aberrations in cytokine profiles and signaling, have been increasing in recent times and are the subject of ongoing interest. With the aim of establishing whether cytokines have utility as potential biomarkers that may define a subgroup of ASD, or function as an objective measure of response to treatment, this review summarizes the role of the immune system, discusses the relationship between the immune system, the brain, and behavior, and presents previously-identified immune system abnormalities in ASD, specifically addressing the role of cytokines in these aberrations. The roles and identification of biomarkers are also addressed, particularly with respect to cytokine profiles in ASD.
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8. Taylor LJ, Eapen V, Maybery M, Midford S, Paynter J, Quarmby L, Smith T, Williams K, Whitehouse AJ. {{Brief Report: An Exploratory Study of the Diagnostic Reliability for Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2017.
Previous research shows inconsistency in clinician-assigned diagnoses of Autism Spectrum Disorder (ASD). We conducted an exploratory study that examined the concordance of diagnoses between a multidisciplinary assessment team and a range of independent clinicians throughout Australia. Nine video-taped Autism Diagnostic Observation Schedule (ADOS) assessments were collected from two Australian sites. Twenty-seven Australian health professionals each observed two video-recordings and rated the degree to which the individual met the DSM-5 criteria for ASD. There was 100% agreement on the diagnostic classification for only 3 of the 9 video clips (33%), with the remaining 6 clips (66%) reaching poor reliability. In addition, only 24% of the participating clinicians achieved ‘good’ or ‘excellent’ levels of agreement (Cohen’s kappa > 0.6) with the original ASD assessment. These findings have implications for clinical guidelines for ASD assessments.
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9. Wang S, Deng H, You C, Chen K, Li J, Tang C, Ceng C, Zou Y, Zou X. {{Sex Differences in Diagnosis and Clinical Phenotypes of Chinese Children with Autism Spectrum Disorder}}. {Neurosci Bull}. 2017.
The aim of this study was to explore the differences between boys and girls in the diagnosis and clinical phenotypes of autism spectrum disorder (ASD) in China’s mainland. Children diagnosed with ASD (n = 1064, 228 females) were retrospectively included in the analysis. All children were assessed using the Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS). The results showed that girls scored significantly higher in ADI-R socio-emotional reciprocity than boys, and also scored lower in ADI-R and ADOS restricted and repetitive behaviors (RRBs). Meanwhile, the proportions of girls who satisfied the diagnostic cut-off scores in the ADI-R RRBs domain were lower than in boys (P < 0.05). Our results indicated that girls with ASD show greater socio-emotional reciprocity than boys. Girls also tended to show fewer RRBs than boys, and the type of RRBs in girls differ from those in boys. The ADI-R was found to be less sensitive in girls, particularly for assessment in the RRBs domain. Lien vers le texte intégral (Open Access ou abonnement)
10. Yrigollen CM, Pacini L, Nobile V, Lozano R, Hagerman RJ, Bagni C, Tassone F. {{Clinical and Molecular Assessment in a Female with Fragile X Syndrome and Tuberous Sclerosis}}. {J Genet Disord Genet Rep}. 2016; 5(3).
OBJECTIVE: Fragile X syndrome (FXS) and tuberous sclerosis (TSC) are genetic disorders that result in intellectual disability and an increased prevalence of autism spectrum disorders (ASD). While the clinical presentation of each disorder is distinct, the molecular causes are linked to a disruption in the mTORC1 (mammalian Target of Rapamycin Complex 1) and ERK1/2 (Extracellular signal-Regulated Kinase) signaling pathways. METHODS: We assessed the clinical and molecular characteristics of an individual seen at the UC Davis MIND Institute with a diagnosis of FXS and TSC. Clinical evaluation of physical, behavioral, and cognitive impairments were performed. Additionally, total and phosphorylated proteins along the mTORC1 and ERK1/2 pathways were measured in primary fibroblast cell lines from the proband. RESULTS: In this case the phenotypic effects that result in a human with both FXS and TSC are shown to be severe. Changes in mTORC1 and ERK1/2 signaling proteins and global protein synthesis were not found to be noticeably different between four cohorts (typically developing, FMR1 full mutation, FMR1 full mutation and TSC1 loss of function mutation, and TSC1 loss of function mutation); however cohort sizes prevented stringent comparisons. CONCLUSION: It has previously been suggested that disruption of the mTORC1 pathway was reciprocal in TSC and FXS double knock-out mouse models so that the regulation of these pathways were more similar to wild-type mice compared to mice harboring a Fmr1-/y or Tsc2-/+ mutation alone. However, in this first reported case of a human with a diagnosis of both FXS and TSC, substantial clinical impairments, as a result of these two disorders were observed. Differences in the mTORC and ERK1/2 pathways were not clearly established when compared between individuals with either disorder, or both.
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11. Zhou H, Zhang L, Luo X, Wu L, Zou X, Xia K, Wang Y, Xu X, Ge X, Jiang YH, Fombonne E, Yan W. {{Modifying the Autism Spectrum Rating Scale (6-18 years) to a Chinese Context: An Exploratory Factor Analysis}}. {Neurosci Bull}. 2017.
The purpose of this study was to explore the psychometric properties of the Chinese version of the autism spectrum rating scale (ASRS). We recruited 1,625 community-based children and 211 autism spectrum disorder (ASD) cases from 4 sites, and the parents of all participants completed the Chinese version of the ASRS. A robust weighted least squares means and variance adjusted estimator was used for exploratory factor analysis. The 3-factor structure included 59 items suitable for the current sample. The item reliability for the modified Chinese version of the ASRS (MC-ASRS) was excellent. Moreover, with 60 as the cut-off point, receiver operating characteristic analysis showed that the MC-ASRS had excellent discriminate validity, comparable to that of the unmodified Chinese version (UC-ASRS), with area under the curve values of 0.952 (95% CI: 0.936-0.967) and 0.948 (95% CI: 0.930-0.965), respectively. Meanwhile, the confirm factor analysis revealed that MC-ASRS had a better construct validity than UC-ASRS based on the above factor solution in another children sample. In conclusion, the MC-ASRS shows better efficacy in epidemiological screening for ASD in Chinese children.
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12. Zhou H, Zhang L, Zou X, Luo X, Xia K, Wu L, Wang Y, Xu X, Ge X, Jiang YH, Fombonne E, Yan W. {{Chinese Norms for the Autism Spectrum Rating Scale}}. {Neurosci Bull}. 2017.
This study aimed to establish norms for the modified Chinese version of the Autism Spectrum Rating Scale (ASRS). Participants were recruited from Shanghai, Harbin, Guangzhou, and Changsha, China, and their parents and teachers were invited to complete the Chinese Parent version and the Teacher version of the ASRS. In both versions, boys had significantly higher sub-scale scores and total score (T-score) by 1-3 and 4-5 points respectively, than girls (both P < 0.001). Age had weak correlations with some sub-scores and the T-score (r ranged from -0.1859 to 0.0738), and some reached significance (P < 0.03). The correlations appeared stronger and were more common in females. The T-score based on Chinese norms ideally correlated with the score based on the United States norms in boys and girls for both versions. Norms for the Chinese version of the ASRS for children aged 6-12 years are proposed and may be helpful for screening individuals with autism spectrum disorders from the general population of children. Lien vers le texte intégral (Open Access ou abonnement)
