Prevalence of Autism Spectrum Disorder in the Centro region of Portugal: a population based study of school age children within the ASDEU project.

Introduction: Accurate prevalence estimates for Autism Spectrum Disorder (ASD) are fundamental to adequately program medical and educational resources for children. However, estimates vary globally and across Europe, and it is therefore wise to conduct epidemiological studies in defined geo-cultural contexts. Methods: We used a population screening approach to estimate the prevalence of ASD in the Centro region of Portugal, using a harmonized protocol as part of the Autism Spectrum Disorders in the European Union (ASDEU) project. Results: The overall prevalence was estimated at 0.5% (95% CI 0.3-0.7), higher in schools with Autism Units (3.3%, 95%CI 2.7-3.9) than in regular schools (0.3%, 95% CI 0.1-0.5) or schools with Multiple Disability Units (0.3%, 95% CI 0.04-0.6). Discussion: The results indicate that the diagnosis of ASD is followed by the most effective educational policies in Centro Region. The variability in prevalence estimates across the different regions from the ASDEU project, and globally, is discussed.

Evidence for an association of prenatal exposure to particulate matter with clinical severity of Autism Spectrum Disorder.

Early-life exposure to air pollutants, including ozone (O3), particulate matter (PM2.5 or PM10, depending on diameter of particles), nitrogen dioxide (NO2) and sulfur dioxide (SO2) has been suggested to contribute to the etiology of Autism Spectrum Disorder (ASD). In this study, we used air quality monitoring data to examine whether mothers of children with ASD were exposed to high levels of air pollutants during critical periods of pregnancy, and if higher exposure levels may lead to a higher clinical severity in their offspring. We used public data from the Portuguese Environment Agency to estimate exposure to these pollutants during the first, second and third trimesters of pregnancy, full pregnancy and first year of life of the child, for 217 subjects with ASD born between 2003 and 2016. These subjects were stratified in two subgroups according to clinical severity, as defined by the Autism Diagnostic Observational Schedule (ADOS). For all time periods, the average levels of PM2.5, PM10 and NO2 to which the subjects were exposed were within the admissible levels defined by the European Union. However, a fraction of these subjects showed exposure to levels of PM2.5 and PM10 above the admissible threshold. A higher clinical severity was associated with higher exposure to PM2.5 (p = 0.001), NO2 (p = 0.011) and PM10 (p = 0.041) during the first trimester of pregnancy, when compared with milder clinical severity. After logistic regression, associations with higher clinical severity were identified for PM2.5 exposure during the first trimester (p = 0.002; OR = 1.14, 95%CI: 1.05-1.23) and full pregnancy (p = 0.04; OR = 1.07, 95%CI: 1.00-1.15) and for PM10 (p = 0.02; OR = 1.07, 95%CI: 1.01-1.14) exposure during the third trimester. Exposure to PM is known to elicit neuropathological mechanisms associated with ASD, including neuroinflammation, mitochondrial disruptions, oxidative stress and epigenetic changes. These results offer new insights on the impact of early-life exposure to PM in ASD clinical severity.

Parahippocampal deactivation and hyperactivation of central executive, saliency and social cognition networks in autism spectrum disorder.

BACKGROUND: The concomitant role of the Central Executive, the Saliency and the Social Cognition networks in autism spectrum disorder (ASD) in demanding ecological tasks remains unanswered. We addressed this question using a novel task-based fMRI virtual-reality task mimicking a challenging daily-life chore that may present some difficulties to individuals with ASD: the EcoSupermarketX. METHODS: Participants included 29 adolescents: 15 with ASD and 15 with typical neurodevelopment (TD). They performed the EcoSupermarketX (a shopping simulation with three goal-oriented sub-tasks including "no cue", "non-social" or "social" cues), during neuroimaging and eye-tracking. RESULTS: ASD differed from TD only in total time and distance to complete the "social cue" sub-task with matched eye-tracking measures. Neuroimaging revealed simultaneous hyperactivation across social, executive, and saliency circuits in ASD. In contrast, ASD showed reduced activation in the parahippocampal gyrus, involved in scene recognition. CONCLUSIONS: When performing a virtual shopping task matching the performance of controls, ASD adolescents hyperactivate three core networks: executive, saliency and social cognition. Parahippocampal hypoactivation is consistent with effortless eidetic scene processing, in line with the notion of peaks and valleys of neural recruitment in individuals with ASD. These hyperactivation/hypoactivation patterns in daily life tasks provide a circuit-level signature of neural diversity in ASD, a possible intervention target.

Attentional Cueing and Executive Deficits Revealed by a Virtual Supermarket Task Coupled With Eye-Tracking in Autism Spectrum Disorder.

Executive functioning (EF) impairments in Autism Spectrum Disorder (ASD) impact on complex functions, such as social cognition. We assessed this link between EF, attentional cueing, and social cognition with a novel ecological task, "EcoSupermarketX." Our task had three blocks of increasing executive load and incorporated social and non-social cues, with different degrees of saliency. Performance of ASD and typical neurodevelopment was compared. The ASD showed a significant performance dependence on the presence of contextual cues. Difficulties increased as a function of cognitive load. Between-group differences were found both for social and non-social salient cues. Eye-tracking measures showed significantly larger fixation time of more salient social cues in ASD. In sum, EcoSupermarketX is sensitive to detect EF and attentional cueing deficits in ASD.

Social Attention Deficits in Children With Autism Spectrum Disorder: Task Dependence of Objects vs. Faces Observation Bias.

Social attention deficits represent a central impairment of patients suffering from autism spectrum disorder (ASD), but the nature of such deficits remains controversial. We compared visual attention regarding social (faces) vs. non-social stimuli (objects), in an ecological diagnostic context, in 46 children and adolescents divided in two groups: ASD (N = 23) and typical neurodevelopment (TD) (N = 23), matched for chronological age and intellectual performance. Eye-tracking measures of visual scanning, while exploring and describing scenes from three different tasks from the Autism Diagnostic Observation Schedule (ADOS), were analyzed: "Description of a Picture," "Cartoons," and "Telling a Story from a Book." Our analyses revealed a three-way interaction between Group, Task, and Social vs. Object Stimuli. We found a striking main effect of group and a task dependence of attentional allocation: while the TD attended first and longer to faces, ASD participants became similar to TD when they were asked to look at pictures while telling a story. Our results suggest that social attention allocation is task dependent, raising the question whether spontaneous attention deficits can be rescued by guiding goal-directed actions.

Language Predictors in Autism Spectrum Disorder: Insights from Neurodevelopmental Profile in a Longitudinal Perspective.

Language outcome in individuals with autism spectrum disorder (ASD) is predicted by early developmental milestones and cognitive abilities. The development and acquisition of expressive language (particularly the onset of first phrases) is a relevant clinical milestone by school age, since its early presentation is associated to better long-term life outcomes and to lower core clinical severity of ASD. Focusing on predictors of language in ASD children, a number of outstanding questions remain to be answered, namely, whether there are differences in the early key neurodevelopmental abilities and whether those differences in a specific period of time might predict verbal development and acquisition of expressive language. We aim to understand how the neurodevelopmental profile of ASD children evolves from the preschool to the school age and if and which subarea can better predict acquisition of expressive language. Children with ASD (N = 205) were evaluated with a structured assessment of neurodevelopment in two different age periods: 1) preschool period (mean age four years) and 2) reassessment in the school period (mean age seven years). Our findings demonstrate that in nonverbal preschool children with ASD normal or near normal Performance Developmental Quotient (superior to 73.5) evaluated at preschool age is a good predictor of later language development in ASD, which has important implications for intervention programs targeting this population and family information.

Definition of a putative pathological region in PARK2 associated with autism spectrum disorder through in silico analysis of its functional structure.

OBJECTIVE: The PARK2 gene encodes Parkin, a component of a multiprotein E3 ubiquitin ligase complex that targets substrate proteins for proteasomal degradation. PARK2 mutations are frequently associated with Parkinson's disease, but structural alterations have also been described in patients with neurodevelopmental disorders (NDD), suggesting a pathological effect ubiquitous to neurodevelopmental and neurodegenerative brain processes. The present study aimed to define the critical regions for NDD within PARK2. MATERIALS AND METHODS: To clarify PARK2 involvement in NDDs, we examined the frequency and location of copy number variants (CNVs) identified in patients from our sample and reported in the literature and relevant databases, and compared with control populations. RESULTS: Overall, the frequency of PARK2 CNVs was higher in controls than in NDD cases. However, closer inspection of the CNV location in PARK2 showed that the frequency of CNVs targeting the Parkin C-terminal, corresponding to the ring-between-ring (RBR) domain responsible for Parkin activity, is significantly higher in NDD cases than in controls. In contrast, CNVs targeting the N-terminal of Parkin, including domains that regulate ubiquitination activity, are very common both in cases and in controls. CONCLUSION: Although PARK2 may be a pathological factor for NDDs, likely not all variants are pathogenic, and a conclusive assessment of PARK2 variant pathogenicity requires an accurate analysis of their location within the coding region and encoded functional domains.

Intellectual Profiles in the Autism Spectrum and Other Neurodevelopmental Disorders.

The influence of specific autism spectrum disorder (ASD) deficits in Intelligence Quotients (IQ), Indexes and subtests from the Wechsler Intelligence Scale for Children-III was investigated in 445 school-aged children: ASD (N = 224) and other neurodevelopmental disorders (N = 221), matched by Full-Scale IQ and chronological age. ASD have lower scores in the VIQ than PIQ. The core distinctive scores between groups are Processing Speed Index and "Comprehension" and "Coding" subtests with lower results in ASD. ASD group with normal/high IQ showed highest score on "Similarities" subtest whereas the lower IQ group performed better on "Object Assembly". The results replicated our previous work on adaptive behaviour, showing that adaptive functioning is positively correlated with intellectual profile, especially with the Communication domain in ASD.

Adaptive profiles in autism and other neurodevelopmental disorders.

We investigated the influence of specific autism spectrum disorder (ASD) deficits in learning adaptive behaviour, besides intelligence quotient (IQ). Participated 217 school-aged: ASD (N = 115), and other neurodevelopmental disorders (OND) groups (N = 102) matched by Full-Scale IQ. We compared standard scores of Vineland Adaptive Behaviour Scale (VABS) in communication, daily living skills, socialization and adaptive behaviour composite. Pearson-correlation analysis was performed between each domain of VABS and Full-Scale, Verbal and Performance IQ, and chronological age (CA). Results indicated that impairment in adaptive behaviour within the domain of socialization skills remains a distinctive factor of ASD versus OND, independently of intellectual disability (ID). Co-occurring ID result in further debilitating effects on overall functioning, especially in ASD. CA is negatively associated with VABS scores.

Recurrent duplications of the annexin A1 gene (ANXA1) in autism spectrum disorders.

BACKGROUND: Validating the potential pathogenicity of copy number variants (CNVs) identified in genome-wide studies of autism spectrum disorders (ASD) requires detailed assessment of case/control frequencies, inheritance patterns, clinical correlations, and functional impact. Here, we characterize a small recurrent duplication in the annexin A1 (ANXA1) gene, identified by the Autism Genome Project (AGP) study. METHODS: From the AGP CNV genomic screen in 2,147 ASD individuals, we selected for characterization an ANXA1 gene duplication that was absent in 4,964 population-based controls. We further screened the duplication in a follow-up sample including 1,496 patients and 410 controls, and evaluated clinical correlations and family segregation. Sequencing of exonic/downstream ANXA1 regions was performed in 490 ASD patients for identification of additional variants. RESULTS: The ANXA1 duplication, overlapping the last four exons and 3'UTR region, had an overall prevalence of 11/3,643 (0.30%) in unrelated ASD patients but was not identified in 5,374 controls. Duplication carriers presented no distinctive clinical phenotype. Family analysis showed neuropsychiatric deficits and ASD traits in multiple relatives carrying the duplication, suggestive of a complex genetic inheritance. Sequencing of exonic regions and the 3'UTR identified 11 novel changes, but no obvious variants with clinical significance. CONCLUSIONS: We provide multilevel evidence for a role of ANXA1 in ASD etiology. Given its important role as mediator of glucocorticoid function in a wide variety of brain processes, including neuroprotection, apoptosis, and control of the neuroendocrine system, the results add ANXA1 to the growing list of rare candidate genetic etiological factors for ASD.