1. Bahri J, Abbes ZS, Ben Yahia H, Halayem S, Jelili S, Hajri M, Amado I, Medalia A, Bouden A. Toward an integrative socio-cognitive approach in autism spectrum disorder: NEAR method adaptation-study protocol. Front Psychiatry;2023;14:940066.

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2. Bao XH, Chen BF, Liu J, Tan YH, Chen S, Zhang F, Lu HS, Li JC. Olink proteomics profiling platform reveals non-invasive inflammatory related protein biomarkers in autism spectrum disorder. Front Mol Neurosci;2023;16:1185021.

BACKGROUND: Owing to the lack of valid biomarkers, the diagnosis of autism spectrum disorder (ASD) diagnosis relies solely on the behavioral phenotypes of children. Several researchers have suggested an association between ASD and inflammation; however, the complex relationship between the two is unelucidated to date. Therefore, the current study aims to comprehensively identify novel circulating ASD inflammatory biomarkers. METHODS: Olink proteomics was applied to compare the plasma inflammation-related protein changes in a group of the healthy children (HC, n = 33) and another with ASD (n = 31). The areas under the receiver operating characteristic curves (AUCs) of the differentially expressed proteins (DEPs) were calculated. The functional analysis of the DEPs was performed using Gene Ontology and Kyoto Encyclopedia Genes and Genomes. Pearson correlation tests were used employed to analyze the correlation between the DEPs and clinical features. RESULTS: A total of 13 DEPs were significantly up-regulated in the ASD group compared with the HC group. The four proteins, namely, STAMBP, ST1A1, SIRT2, and MMP-10 demonstrated good diagnostic accuracy with the corresponding AUCs (95% confidence interval, CI) of 0.7218 (0.5946-0.8489), 0.7107 (0.5827-0.8387), 0.7016 (0.5713-0.8319), and 0.7006 (0.568-0.8332). Each panel of STAMBP and any other differential protein demonstrated a better classification performance [AUC values from 0.7147 (0.5858-0.8436, STAMBP/AXIN1) to 0.7681 (0.6496-0.8867, STAMBP/MMP-10)]. These DEP profiles were enriched in immune and inflammatory response pathways, including TNF and NOD-like receptor signaling pathways. The interaction between STAMBP and SIRT2 (R = 0.97, p = 8.52 × 10(-39)) was found to be the most significant. In addition, several DEPs related to clinical features in patients with ASD, particularly AXIN1 (R = 0.36, p = 0.006), SIRT2 (R = 0.34, p = 0.010) and STAMBP (R = 0.34, p = 0.010), were positively correlated with age and parity, indicating that older age and higher parity may be the inflammation-related clinical factors in ASD. CONCLUSION: Inflammation plays a crucial role in ASD, and the up-regulated inflammatory proteins may serve as potential early diagnostic biomarkers for ASD.

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3. Bojanek EK, Kelly SE, Schmitt LM, White SP, Sweeney JA, Sprenger A, Unruh KE, Mosconi MW. Sensorimotor Behavior in Individuals with Autism Spectrum Disorder and Their Unaffected Biological Parents. Res Sq;2023 (May 25)

Background: Sensorimotor impairments are common in autism spectrum disorder (ASD) and evident in unaffected first-degree relatives, suggesting that they may serve as important endophenotypes associated with inherited risk. We tested the familiality of sensorimotor impairments in ASD across multiple motor behaviors and effector systems and in relation to parental broader autism phenotypic (BAP) characteristics. Methods: Fifty-eight autistic individuals (probands), 109 parents, and 89 control participants completed tests of manual motor and oculomotor control. Sensorimotor tests varied in their involvement of rapid , feedforward control and sustained , sensory feedback control processes. Subgroup analyses compared families with at least one parent showing BAP traits (BAP+) and those in which neither parent showed BAP traits (BAP-). Results: Probands with BAP- parents (BAP- probands) showed rapid manual motor and oculomotor deficits, while BAP+ probands showed sustained motor impairments compared to controls. BAP- parents showed impaired rapid oculomotor and sustained manual motor abilities relative to BAP+ parents and controls. Atypical rapid oculomotor impairments also were familial. Limitations: Larger samples of ASD families including greater samples of probands with BAP+ parents are needed. Genetic studies also are needed to link sensorimotor endophenotype findings directly to genes. Conclusions: Results indicate rapid sensorimotor behaviors are selectively impacted in BAP- probands and their parents and may reflect familial liabilities for ASD that are independent of familial autistic traits. Sustained sensorimotor behaviors were affected in BAP+ probands and BAP- parents reflecting familial traits that may only confer risk when combined with parental autistic trait liabilities. These findings provide new evidence that rapid and sustained sensorimotor alterations represent strong but separate familial pathways of ASD risk that demonstrate unique interactions with mechanisms related to parental autistic traits.

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4. Celora L, Jaudon F, Vitale C, Cingolani LA. Regulation of dendritic spine length in corticopontine layer V pyramidal neurons by autism risk gene β3 integrin. Mol Brain;2023 (Jun 9);16(1):49.

The relationship between autism spectrum disorder (ASD) and dendritic spine abnormalities is well known, but it is unclear whether the deficits relate to specific neuron types and brain regions most relevant to ASD. Recent genetic studies have identified a convergence of ASD risk genes in deep layer pyramidal neurons of the prefrontal cortex. Here, we use retrograde recombinant adeno-associated viruses to label specifically two major layer V pyramidal neuron types of the medial prefrontal cortex: the commissural neurons, which put the two cerebral hemispheres in direct communication, and the corticopontine neurons, which transmit information outside the cortex. We compare the basal dendritic spines on commissural and corticopontine neurons in WT and KO mice for the ASD risk gene Itgb3, which encodes for the cell adhesion molecule β3 integrin selectively enriched in layer V pyramidal neurons. Regardless of the genotype, corticopontine neurons had a higher ratio of stubby to mushroom spines than commissural neurons. β3 integrin affected selectively spine length in corticopontine neurons. Ablation of β3 integrin resulted in corticopontine neurons lacking long (> 2 μm) thin dendritic spines. These findings suggest that a deficiency in β3 integrin expression compromises specifically immature spines on corticopontine neurons, thereby reducing the cortical territory they can sample. Because corticopontine neurons receive extensive local and long-range excitatory inputs before relaying information outside the cortex, specific alterations in dendritic spines of corticopontine neurons may compromise the computational output of the full cortex, thereby contributing to ASD pathophysiology.

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5. Chalkiadaki K, Statoulla E, Zafeiri M, Haji N, Lacaille JC, Powell CM, Jafarnejad SM, Khoutorsky A, Gkogkas CG. Reversal of memory and autism-related phenotypes in Tsc2(+/-) mice via inhibition of Nlgn1. Front Cell Dev Biol;2023;11:1205112.

Tuberous sclerosis complex (TSC) is a rare monogenic disorder co-diagnosed with high rates of autism and is caused by loss of function mutations in the TSC1 or TSC2 genes. A key pathway hyperactivated in TSC is the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which regulates cap-dependent mRNA translation. We previously demonstrated that exaggerated cap-dependent translation leads to autism-related phenotypes and increased mRNA translation and protein expression of Neuroligin 1 (Nlgn1) in mice. Inhibition of Nlgn1 expression reversed social behavior deficits in mice with increased cap-dependent translation. Herein, we report elevated translation of Nlgn1 mRNA and an increase in its protein expression. Genetic or pharmacological inhibition of Nlgn1 expression in Tsc2 (+/-) mice rescued impaired hippocampal mGluR-LTD, contextual discrimination and social behavior deficits in Tsc2 (+/-) mice, without correcting mTORC1 hyperactivation. Thus, we demonstrate that reduction of Nlgn1 expression in Tsc2 (+/-) mice is a new therapeutic strategy for TSC and potentially other neurodevelopmental disorders.

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6. Cook NE, Iverson IA, Maxwell B, Zafonte R, Berkner PD, Iverson GL. Neurocognitive Test Performance and Concussion-Like Symptom Reporting Among Adolescent Athletes With Self-Reported Autism on Preseason Assessments. Arch Clin Neuropsychol;2023 (Jun 8)

OBJECTIVE: To examine baseline neurocognitive functioning and symptom reporting among adolescents with self-reported autism. METHOD: Participants in this cross-sectional, observational study were 60,751 adolescents who completed preseason testing. There were 425 students (0.7%) who self-reported an autism spectrum disorder (ASD) diagnosis. Cognitive functioning was measured by Immediate Post-Concussion Assessment and Cognitive Testing and symptom ratings were obtained from the Post-Concussion Symptom Scale. RESULTS: Groups differed significantly across all neurocognitive composites (p values <.002); effect size magnitudes for most differences were small, though among boys a noteworthy difference on visual memory and among girls differences on verbal memory and visual motor speed composites were noted. Among boys, the ASD group endorsed 21 of the 22 symptoms at a greater rate. Among girls, the ASD group endorsed 11 of the 22 symptoms at a greater rate. Some examples of symptoms that were endorsed at a higher rate among adolescents with self-reported autism were sensitivity to noise (girls: odds ratio, OR = 4.38; boys: OR = 4.99), numbness or tingling (girls: OR = 3.67; boys: OR = 3.25), difficulty remembering (girls: OR = 2.01; boys: OR = 2.49), difficulty concentrating (girls: OR = 1.82; boys: OR = 2.40), sensitivity to light (girls: OR = 1.82; boys: OR = 1.76), sadness (girls: OR = 1.72; boys: OR = 2.56), nervousness (girls: OR = 1.80; boys: OR = 2.27), and feeling more emotional (girls: OR = 1.79; boys: OR = 2.84). CONCLUSION: Students with self-reported autism participating in organized sports likely experience a low degree of functional impairment, on average. If they sustain a concussion, their clinical management should be more intensive to maximize the likelihood of swift and favorable recovery.

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7. Doghadze I, Gagoshidze T. Language phenotypes in children with autism spectrum disorder, expressive language disorder, and typical language development. Appl Neuropsychol Child;2023 (Jun 9):1-11.

The aim of this study was to compare language abilities in 4-6-year-old Georgian-speaking children with typical language development (TLD), expressive language disorder (ELD), and autism spectrum disorder (ASD). Language linguistic components, such as phonology, semantics, syntax, morphology, and pragmatics, were examined along with verbal behavior types like « mand, » « tact, » « echoic, » and « intraverbal. » Our sample comprised 148 children, with a gender distribution of 50 girls and 98 boys. Significant differences were observed in the application of various parts of speech across the three groups. Children with ELD were found to use pronouns more frequently compared to TLD and ASD groups. Conversely, children exhibiting typical language development displayed a greater usage of conjunctions and particles than the other groups. Notably, linguistic error patterns varied across groups: children with ELD predominantly committed errors in phonetics and morphosyntax, while children with ASD had more pragmatic errors and also struggled with morphosyntax. Moreover, the ASD group was found to use « mands » and « echoics » more frequently than both the TLD and ELD groups.

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8. Ghanouni P, Seaker L. What does receiving autism diagnosis in adulthood look like? Stakeholders’ experiences and inputs. Int J Ment Health Syst;2023 (Jun 8);17(1):16.

INTRODUCTION: The age of diagnosis is crucial for optimal health outcomes; however, some individuals with Autism Spectrum Disorder (ASD) may not be diagnosed until adulthood. Limited information is available about the lived experience of receiving a diagnosis during adulthood. Thus, we aimed to investigate stakeholders’ experiences about the ASD diagnosis during adulthood. METHOD: We interviewed 18 individuals including 13 adults with ASD who had received a late diagnosis during adulthood and 5 parents of individuals with ASD from various Canadian provinces. RESULTS: Using a thematic analysis, three main themes emerged: (a) noticing differences and similarities, (b) hindering elements to diagnosis, and (c) emotional response to diagnostic odyssey. CONCLUSION: This study adds to the literature about experiences of receiving ASD diagnosis in adulthood. Given the impact of diagnosis on individuals, it is important to minimize the barriers to ensure individuals who require ASD-related supports can access them in a timely and effective manner. This study highlights the importance of receiving an ASD diagnosis and facilitates positive health outcomes. The findings from the current study can be used to guide adult diagnostic processes and practices to help make ASD diagnosis more accessible.

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9. Gonzales S, Zhao JZ, Choi NY, Acharya P, Jeong S, Lee MY. SOX7: Novel Autistic Gene Identified by Analysis of Multi-Omics Data. bioRxiv;2023 (May 28)

BACKGROUND: Genome-wide association studies and next generation sequencing data analyses based on DNA information have identified thousands of mutations associated with autism spectrum disorder (ASD). However, more than 99% of identified mutations are non-coding. Thus, it is unclear which of these mutations might be functional and thus potentially causal variants. Transcriptomic profiling using total RNA-sequencing has been one of the most utilized approaches to link protein levels to genetic information at the molecular level. The transcriptome captures molecular genomic complexity that the DNA sequence solely does not. Some mutations alter a gene’s DNA sequence but do not necessarily change expression and/or protein function. To date, few common variants reliably associated with the diagnosis status of ASD despite consistently high estimates of heritability. In addition, reliable biomarkers used to diagnose ASD or molecular mechanisms to define the severity of ASD do not exist. OBJECTIVES: It is necessary to integrate DNA and RNA testing together to identify true causal genes and propose useful biomarkers for ASD. METHODS: We performed gene-based association studies with adaptive test using genome-wide association studies (GWAS) summary statistics with two large GWAS datasets (ASD 2019 data: 18,382 ASD cases and 27,969 controls [discovery data]; ASD 2017 data: 6,197 ASD cases and 7,377 controls [replication data]) which were obtained from the Psychiatric Genomics Consortium (PGC). In addition, we investigated differential expression for genes identified in gene-based GWAS with a RNA-seq dataset (GSE30573: 3 cases and 3 controls) using the DESeq2 package. RESULTS: We identified 5 genes significantly associated with ASD in ASD 2019 data (KIZ-AS1, p=8.67×10 (-10) ; KIZ, p=1.16×10 (-9) ; XRN2, p=7.73×10 (-9) ; SOX7, p=2.22×10 (-7) ; PINX1-DT, p=2.14×10 (-6) ). Among these 5 genes, gene SOX7 (p=0.00087), LOC101929229 (p=0.009), and KIZ-AS1 (p=0.059) were replicated in ASD 2017 data. KIZ (p=0.06) was close to the boundary of replication in ASD 2017 data. Genes SOX7 (p=0.0017, adjusted p=0.0085), LOC101929229 (also known as PINX1-DT, p=5.83×10 (-7) , adjusted p=1.18×10 (-5) ), and KIZ (p=0.00099, adjusted p=0.0055) indicated significant expression differences between cases and controls in the RNA-seq data. SOX7 encodes a member of the SOX (SRY-related HMG-box) family of transcription factors pivotally contributing to determining of the cell fate and identity in many lineages. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins leading to autism. CONCLUSION: Gene SOX7 in the transcription factor family could be associated with ASD. This finding may provide new diagnostic and therapeutic strategies for ASD.

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10. Itahashi T, Yamashita A, Takahara Y, Yahata N, Nakamura M, Aoki Y, Aoki R, Fujino J, Ohta H, Yoshihara Y, Sakai Y, Takamura M, Ichikawa N, Okada G, Okada N, Kasai K, Tanaka S, Imamizu H, Kato N, Okamoto Y, Takahashi H, Kawato M, Yamashita O, Hashimoto R. Generalizable neuromarker for autism spectrum disorder across imaging sites and developmental stages: A multi-site study. Res Sq;2023 (May 15)

Autism spectrum disorder (ASD) is a lifelong condition, and its underlying biological mechanisms remain elusive. The complexity of various factors, including inter-site and development-related differences, makes it challenging to develop generalizable neuroimaging-based biomarkers for ASD. This study used a large-scale, multi-site dataset of 730 Japanese adults to develop a generalizable neuromarker for ASD across independent sites and different developmental stages. Our adult ASD neuromarker achieved successful generalization for the US and Belgium adults and Japanese adults. The neuromarker demonstrated significant generalization for children and adolescents. We identified 141 functional connections (FCs) important for discriminating individuals with ASD from TDCs. Finally, we mapped schizophrenia (SCZ) and major depressive disorder (MDD) onto the biological axis defined by the neuromarker and explored the biological continuity of ASD with SCZ and MDD. We observed that SCZ, but not MDD, was located proximate to ASD on the biological dimension defined by the ASD neuromarker. The successful generalization in multifarious datasets and the observed relations of ASD with SCZ on the biological dimensions provide new insights for a deeper understanding of ASD.

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11. Laxton P, Healy S, Brewer B, Patterson F. Prevalence of current smoking and association with meeting 24-h movement guidelines: Results from a national convenience sample of autistic adults. Autism;2023 (Jun 8):13623613231178571.

Cigarette smoking is a leading risk behavior for cardiovascular disease; yet its prevalence and determinants are not clear in autistic adults. We examined the prevalence of current smoking and its association between meeting 24-h movement (i.e. sleep, physical activity, and sedentary behavior) guidelines in a self-selecting convenience sample of 259 autistic adults in the United States. We found that current smokers met fewer 24-h movement guidelines. Most significant, those who had insufficient sleep and those with high levels of sedentary behavior were more likely to be current smokers. Therefore, targeting these movement behaviors may be potential intervention targets for smoking cessation.

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12. Li L, Møller Christensen B, Falkmer M, Zhao Y, Huus K. Content validity of the instrument ‘Picture My Participation’ for measuring participation of children with and without autism spectrum disorder in mainland China. Scand J Occup Ther;2023 (Jun 9):1-11.

BACKGROUND: Picture My Participation (PMP) is a valid instrument for measuring participation of children with disabilities, but it has not yet been evaluated for its content validity for children with autism spectrum disorders (ASD) in mainland China. AIM: To explore the content validity of the simplified Chinese version of PMP (PMP-C; Simplified) for children with ASD and typically developing (TD) children in mainland China. METHODS: A sample of children with ASD (n = 63) and TD children (n = 63) recruited through purposive sampling were interviewed using the PMP-C (Simplified), which contains 20 items of everyday activities. Children rated attendance and involvement on all activities and selected three most important activities. RESULTS: Children with ASD selected 19 of 20 activities as the most important activity while TD children selected 17 activities. Children with ASD used all scale points for rating attendance and involvement on all activities. TD children used all scale points for rating attendance and involvement in 10 and 12 of 20 activities, respectively. CONCLUSION: The contents of 20 activities of PMP-C (Simplified) were relevant for all children and especially for children with ASD for assessing participation in community, school and home activities.

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13. Liu X, Liu H, Gu N, Pei J, Lin X, Zhao W. Preeclampsia promotes autism in offspring via maternal inflammation and fetal NFκB signaling. Life Sci Alliance;2023 (Aug);6(8)

Preeclampsia (PE) is a risk factor for autism spectrum disorder (ASD) in offspring. However, the exact mechanisms underlying the impact of PE on progeny ASD are not fully understood, which hinders the development of effective therapeutic approaches. This study shows the offspring born to a PE mouse model treated by N(ω)-nitro-L-arginine methyl ester (L-NAME) exhibit ASD-like phenotypes, including neurodevelopment deficiency and behavioral abnormalities. Transcriptomic analysis of the embryonic cortex and adult offspring hippocampus suggested the expression of ASD-related genes was dramatically changed. Furthermore, the level of inflammatory cytokines TNFα in maternal serum and nuclear factor kappa B (NFκB) signaling in the fetal cortex were elevated. Importantly, TNFα neutralization during pregnancy enabled to ameliorate ASD-like phenotypes and restore the NFκB activation level in the offspring exposed to PE. Furthermore, TNFα/NFκB signaling axis, but not L-NAME, caused deficits in neuroprogenitor cell proliferation and synaptic development. These experiments demonstrate that offspring exposed to PE phenocopies ASD signatures reported in humans and indicate therapeutic targeting of TNFα decreases the likelihood of bearing children with ASD phenotypes from PE mothers.

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14. Naralan YS, Gül AH, Altunkaynak K. Is autism spectrum disorder an inflammation?. Ideggyogy Sz;2023 (May 30);76(5-6):212-216.

BACKGROUND AND PURPOSE:

In our study, we aimed to evaluate inflammation by measuring serum Adenosine deaminase and dipeptidyl peptidase IV levels of individuals diagnosed with autism spectrum disorder and to determine its relationship with the Childhood Autism Rating Scale.

. METHODS:

37 children aged 2-12 years with a diagnosis of autism spectrum disorder and 27 children aged 2-12 years without any psychiatric disease were included in the study. Psychiatric examination and clinical evaluation according to DSM-5 diagnostic criteria for the diagnosis of autism spectrum disorder were performed on the children included in the study. The Childhood Autism Rating Scale was filled in by the researcher by interviewing the parents of the children diagnosed with autism spectrum disorder. 5 ml of venous blood samples were taken from the children in both groups in the morning on a full stomach.

. RESULTS:

There was no statistically significant difference between the groups in terms of age, gender, and sociodemographic data. While serum adenosine deaminase levels were found to be statistically significantly higher in the group with autism spectrum disorder, serum dipeptidyl peptidase IV levels were found to be significantly lower. A positive correlation was found between dipeptidyl peptidase IV and Childhood Autism Rating Scale.

. CONCLUSION:

We think that inflammation may play a role in the etiology of autism spectrum disorder due to altered adenosine deaminase and dipeptidyl peptidase IV levels in children with autism spectrum disorder.

.

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15. Neul JL, Percy AK, Benke TA, Berry-Kravis EM, Glaze DG, Marsh ED, Lin T, Stankovic S, Bishop KM, Youakim JM. Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study. Nat Med;2023 (Jun 8)

Rett syndrome is a rare, genetic neurodevelopmental disorder. Trofinetide is a synthetic analog of glycine-proline-glutamate, the N-terminal tripeptide of the insulin-like growth factor 1 protein, and has demonstrated clinical benefit in phase 2 studies in Rett syndrome. In this phase 3 study ( https://clinicaltrials.gov identifier NCT04181723 ), females with Rett syndrome received twice-daily oral trofinetide (n = 93) or placebo (n = 94) for 12 weeks. For the coprimary efficacy endpoints, least squares mean (LSM) change from baseline to week 12 in the Rett Syndrome Behaviour Questionnaire for trofinetide versus placebo was -4.9 versus -1.7 (P = 0.0175; Cohen’s d effect size, 0.37), and LSM Clinical Global Impression-Improvement at week 12 was 3.5 versus 3.8 (P = 0.0030; effect size, 0.47). For the key secondary efficacy endpoint, LSM change from baseline to week 12 in the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist Social Composite score was -0.1 versus -1.1 (P = 0.0064; effect size, 0.43). Common treatment-emergent adverse events included diarrhea (80.6% for trofinetide versus 19.1% for placebo), which was mostly mild to moderate in severity. Significant improvement for trofinetide compared with placebo was observed for the coprimary efficacy endpoints, suggesting that trofinetide provides benefit in treating the core symptoms of Rett syndrome.

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16. O’Reilly C, Huberty S, Noordt S, Desjardins J, Wright N, Scorah J, Webb SJ, Team B, Elsabbagh M. EEG functional connectivity in infants at elevated familial risk for autism spectrum disorder. Res Sq;2023 (May 15)

BACKGROUND: Many studies have reported that autism spectrum disorder (ASD) is associated with atypical structural and functional connectivity. However, relatively little is known about the development of these differences in infancy and on how trajectories may vary between sexes. METHODS: We used the International Infant EEG Platform (EEG-IP), a high-density electroencephalogram (EEG) dataset pooled from two independent infant sibling cohorts, to characterize such neurodevelopmental deviations during the first years of life. EEG was recorded at 6, 12, and 18 months of age at typical (N=97) or high familial risk for ASD (N=98), determined by the presence of an older sibling with a confirmed ASD diagnosis. We computed the functional connectivity between cortical EEG sources during video watching using the corrected imaginary part of phase-locking values. RESULTS: Our findings showed low regional specificity for group differences in functional connectivity but revealed different sex-specific trajectories between females and males in the group of high-risk infants. Specifically, functional connectivity was negatively correlated with ADOS calibrated severity scores, particularly at 12 months for the social affect score for females and for the restrictive and repetitive behaviors for males. LIMITATIONS: This study has been limited mostly due to issues related to the relatively small effective sample size inherent in sibling studies, particularly for diagnostic group comparisons. CONCLUSIONS: These results are consistent with sex differences in ASD observed in previous research and provide further insights into the role of functional connectivity in these differences.

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17. Sandhu A, Rawat K, Gautam V, Sharma A, Kumar A, Saha L. Phosphodiesterase inhibitor, Ibudilast alleviates core behavioral and biochemical deficits in the prenatal valproic acid exposure model of autism spectrum disorder. Brain Res;2023 (Jun 6):148443.

BACKGROUND: Autism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder, presenting with a variety of aetiological and phenotypical features. Ibudilast is known to produce beneficial effects in several neurological disorders including neuropathic pain, multiple sclerosis, etc. by displaying its neuroprotective and anti-inflammatory properties. Here, in our study, the pharmacological outcome of ibudilast administration was investigated in the prenatal valproic acid (VPA)-model of ASD in Wistar rats. METHODS: Autistic-like symptoms were induced in Wistar male pups of dams administered with Valproic acid (VPA) on embryonic day 12.5. VPA-exposed male pups were administered with two doses of ibudilast (5 and10 mg/kg) and all the groups were evaluated for behavioral parameters like social interaction, spatial memory/learning, anxiety, locomotor activity, and nociceptive threshold. Further, the possible neuroprotective effect of ibudilast was evaluated by assessing oxidative stress, neuroinflammation (IL-1β, TNF-α, IL-6, IL-10) in the hippocampus, % area of Glial fibrillary acidic protein (GFAP)-positive cells and neuronal damage in the cerebellum. KEY FINDINGS: Treatment with ibudilast significantly attenuated prenatal VPA exposure associated social interaction and spatial learning/memory deficits, anxiety, hyperactivity, and increased nociceptive threshold, and it decreased oxidative stress markers, pro-inflammatory markers (IL-1β, TNF-α, IL-6), and % area of GFAP-positive cells and restored neuronal damage. CONCLUSIONS: Ibudilast treatment has restored crucial ASD-related behavioural abnormalities, potentially through neuroprotection. Therefore, benefits of ibudilast administration in animal models of ASD suggest that ibudilast may have therapeutic potential in the treatment of ASD.

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18. Todorova GK, Hatton REM, Sadique S, Pollick FE. The world is nuanced but pixelated: Autistic individuals’ perspective on HIPPEA. Autism;2023 (Jun 9):13623613231176714.

Autism is a condition comprised of difficulties in social and communication contexts, sensory sensitivities as well as restrictive and repetitive behaviours. Many theories have tried to explain all the symptoms and behaviours associated with autism. We focus on one recent theory – High, Inflexible Precision of Prediction Errors in Autism (HIPPEA). We aim to understand how much this theory fits the experiences of autistic individuals. We collected data through 21 online questionnaires and 8 follow-up interviews. One of our participants was a parent of an autistic child, and the remaining were adults who reported a diagnosis of autism. We analysed the data by thinking about how it fitted with what we already knew and by looking for new insights which came up. Our results suggest that autistic individuals can make generalisations but that this happens more slowly across both social and non-social areas. These generalisations are very reliant on detail – in computer terms, they are ‘pixelated’. This is in line with what HIPPEA suggests. We also showed that autistic individuals can be motivated to explore and engage socially, something that needs more consideration within HIPPEA. Overall, this study shows that HIPPEA can explain many autistic experiences, but that further refinement is needed.

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19. Tong X, Xie H, Fonzo GA, Zhao K, Satterthwaite TD, Carlisle N, Zhang Y. Dissecting Symptom-linked Dimensions of Resting-State Electroencephalographic Functional Connectivity in Autism with Contrastive Learning. bioRxiv;2023 (May 24)

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder characterized by social interaction deficits, communication difficulties , and restricted/repetitive behaviors or fixated interests . Despite its high prevalence, development of effective therapy for ASD is hindered by its symptomatic and neurophysiological heterogeneities. To collectively dissect the ASD heterogeneity in neurophysiology and symptoms, we develop a new analytical framework combining contrastive learning and sparse canonical correlation analysis to identify resting-state EEG connectivity dimensions linked to ASD behavioral symptoms within 392 ASD samples. Two dimensions are successfully identified, showing significant correlations with social/communication deficits (r = 0.70) and restricted/repetitive behaviors (r = 0.45), respectively. We confirm the robustness of these dimensions through cross-validation and further demonstrate their generalizability using an independent dataset of 223 ASD samples. Our results reveal that the right inferior parietal lobe is the core region displaying EEG activity associated with restricted/repetitive behaviors, and functional connectivity between the left angular gyrus and the right middle temporal gyrus is a promising biomarker of social/communication deficits. Overall, these findings provide a promising avenue to parse ASD heterogeneity with high clinical translatability, paving the way for treatment development and precision medicine for ASD.

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20. Zhu J, Meng H, Zhang L, Li Y. Exploring the molecular mechanism of comorbidity of autism spectrum disorder and inflammatory bowel disease by combining multiple data sets. J Transl Med;2023 (Jun 8);21(1):372.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is difficult to diagnose. Inflammatory bowel disease (IBD) is a common chronic digestive disease. Previous studies have shown a potential correlation between ASD and IBD, but the pathophysiological mechanism remains unclear. The purpose of this research was to examine the biological mechanisms underlying the differentially expressed genes (DEGs) of ASD and IBD using bioinformatics tools. METHODS: Limma software was used to evaluate the DEGs between ASD and IBD. The GSE3365, GSE18123, and GSE150115 microarray data sets were acquired from the Gene Expression Omnibus (GEO) database. We then performed 6 analyses, namely, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional annotation; weighted gene coexpression network analysis; correlation analysis of hub genes with autophagy, ferroptosis and immunity; transcriptional regulation analysis of hub genes; single-cell sequencing analysis; and potential therapeutic drug prediction. RESULTS: A total of 505 DEGs associated with ASD and 616 DEGs associated with IBD were identified, and 7 genes overlapped between these sets. GO and KEGG analyses revealed several pathways enriched in both diseases. A total of 98 common genes related to ASD and IBD were identified by weighted gene coexpression network analysis (WGCNA), and 4 hub genes were obtained by intersection with the 7 intersecting DEGs, which were PDGFC, CA2, GUCY1B3 and SDPR. We also found that 4 hub genes in the two diseases were related to autophagy, ferroptosis or immune factors. In addition, motif-TF annotation analysis showed that cisbp__M0080 was the most relevant motif. We also used the Connectivity Map (CMap) database to identify 4 potential therapeutic agents. CONCLUSION: This research reveals the shared pathogenesis of ASD and IBD. In the future, these common hub genes may provide new targets for further mechanistic research as well as new therapies for patients with ASD and IBD.

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