1. Autism spectrum disorder and GABA levels in children with succinic semialdehyde dehydrogenase deficiency. Dev Med Child Neurol. 2024.

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2. Aghajani M, Aghajani M, Moghaddam EK, Faghihi M, Imani A. Acute sleep deprivation (ASD) and cardioprotection: Impact of ASD on oxytocin-mediated sympathetic nervous activation preceding myocardial infarction. Neuropeptides. 2024; 107: 102453.

INTRODUCTION: This study explored how acute sleep deprivation (ASD) before myocardial ischemia influences oxytocin release from paraventricular (PVN) neurons and its correlation with sympathetic nervous system (SNS) activity post-acute sleep loss, impacting subsequent left ventricular (LV) remodeling following myocardial infarction (MI). METHODS: The study was conducted in two phases: induction of ASD, inducing MI, blood sampling, euthanizing animals and collecting their heart and brain for histological and gene expression evaluations. The animals in first and second phase were euthanized 24 h and 14 days after MI, respectively. RESULTS: Pre-MI ASD, accompanied by increased serum epinephrine levels within 24 h of MI, upregulated oxytocin and cFos expression in the PVN. Also, pre-MI ASD resulted in decreased serum PAB levels 14 days post-MI (P < 0.001). While notable echocardiographic changes were seen in MI versus sham groups, ASD demonstrated protective effects. This was evidenced by reduced infarct size, elevated TIMP1, MMP2, and MMP9 in the LV of SD + MI animals versus MI alone (P < 0.05). Additionally, histological analysis showed reduced LV fibrosis in pre-MI ASD subjects (P < 0.05). CONCLUSION: Our study supports the notion that activation of oxytocin neurons within the PVN subsequent to ASD interacts with autonomic centers in the central nervous system. This enhanced sympathetic outflow to the heart prior to MI triggers a preconditioning response, thereby mediating cardioprotection through decreased oxidative stress biomarkers and regulated extracellular matrix (ECM) turnover.

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3. Berger TD, Fogel Berger C, Gara S, Ben-Zeev B, Weiss B. Nutritional and gastrointestinal manifestations in Rett syndrome: long-term follow-up. Eur J Pediatr. 2024.

PURPOSE: Rett syndrome is a rare neurodevelopmental disorder associated with methyl CpG binding protein 2 (MECP2) gene mutations. We aimed to characterize the long-term nutritional and gastrointestinal course of Rett syndrome in a large national patient population. METHODS: We conducted a retrospective cohort study of patients followed during 1991-2021 at a national center for Rett syndrome. The data retrieved included clinical features, laboratory and genetic analyses. Continuous anthropometric measurements were calculated for the closest visit to the median ages: 2.5, 7.5, 12.5 and 17.5 years. Kaplan Meier curves were used to describe the appearance of clinical manifestations during the follow up period. Generalized estimating equation models were used to compare repeated measurements. RESULTS: Included were 141 patients (139 females), the median age at the first visit was 3.2 years (interquartile range [IQR] 2.3-5.7), and the median length of follow-up was 94.5 months (IQR 28.6-153.3). Mean weight, height and BMI Z-scores were -1.09, -1.03 and -0.56, respectively, at median age 2.5 years; and deteriorated to -3.95, -3.01 and -1.19, respectively, at median age 17.5 years (P < 0.001). Gastrointestinal features included constipation (47.5%, 67/141) and chewing/feeding difficulties (20%, 28/141) at presentation; and an additional 47 (33.3%) and 24 (17.0%), respectively, during follow up. Twenty-eight patients (20%) developed aerophagia and 44 (31.2%) gastroesophageal reflux. No relation was found between genetic mutation types and clinical manifestations. GI manifestations were more prevalent in patients with typical form of Rett syndrome. CONCLUSIONS: Anthropometric parameters were shown to deteriorate with age, regardless of the specific genetic mutation. Chewing/feeding difficulties, constipation and gastroesophageal reflux are common in Rett patients.

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4. Billey T, Kushman E, Meese J, Martin L, Jim L, Austin-Garrison MA, Allison-Burbank JD. Development of a culturally enhanced caregiver-facilitated language nutrition intervention « +Language is Medicine » to address developmental delay in Diné (Navajo) toddlers. Front Public Health. 2024; 12: 1376742.

INTRODUCTION: Developmental Delay (DD) is highly common in American Indian and Alaska Native (AI/AN; Indigenous) toddlers and leads to high numbers of AI/AN children who eventually need special education services. AI/AN children are 2.89 times more likely to receive special education compared to other children in the U.S., yet developmental disorders are more frequently under diagnosed and untreated in AI/AN infants and toddlers. DD, which can be identified as early as toddlerhood, can lead to negative impacts on developmental trajectories, school readiness, and long-term health. Signs of DD can be identified early with proper developmental screening and remediated with high quality early intervention that includes effective parent training. There are many evidence-based language facilitation interventions often used in Early Intervention programs. However, in communities in rural parts of the Navajo Nation where there are limited services and resources, infants and toddlers with early signs of DD are often missed and do not get the culturally responsive support and evidence-based intervention they deserve. METHODS: The community-based +Language is Medicine (+LiM) study team partnered with tribal home visitors, community members, and a Diné linguist/elder using a collaborative virtual workgroup approach in 2021 and 2022 to present the +LiM pilot study aims and to discuss strategies for enhancing a language intervention for toddlers experiencing DD in their tribal community. This paper will detail the stages of community engagement, intervention enhancement and preparation for field testing of the +LiM intervention to address elevated rates of DD in toddlers in the Northern Agency of the Navajo Nation. RESULTS: Two major outcomes from this collaborative workgroup included: (1) a team-initiated redefining of language nutrition to align with Indigenous values that center cultural connectedness and native language use and (2) a five-lesson caregiver-facilitated curriculum titled +Language is Medicine which includes caregiver lessons on language nutrition, language facilitation, shared book reading, pretend play, and incorporation of native language into home routines. These two workgroup outcomes were leveraged to develop a pilot pre-/post-intervention study to test the effectiveness of the +LiM intervention with caregiver-toddler dyads living on the Navajo Nation. DISCUSSION: Delivering tailored child interventions through tribal home visiting are cost-effective and innovative methods for reaching reservation-based families who benefit from culturally responsive parent coaching and instruction. The +LiM team has applied a precision tribal home visiting approach to enhance methods of early intervention for children with DD. Our enhancement process was grounded in Indigenous community-based participatory research that centered culture and language.

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5. De Giacomo A, Craig F, Medicamento S, Gradia F, Sardella D, Costabile A, Matera E, Turi M. Identifying Autistic-Like Symptoms in Children with ADHD: A Comparative Study Using ADOS-2. Neuropsychiatr Dis Treat. 2024; 20: 1367-76.

PURPOSE: Recent literature has focused attention on the presence of autistic-like symptoms in children with Attention Deficit/Hyperactivity Disorder (ADHD), who often exhibit social difficulties, posing challenges for a distinct clinical diagnosis. The current study aimed to identify the specific pattern of autistic symptoms in subjects with ADHD or Autistic Spectrum Disorder (ASD), examining similarities or differences at both the domain and individual item levels. PATIENTS AND METHODS: In this study, we enrolled 43 school-age children divided into the following: the ADHD group (n=25) consisted of children initially referred for ASD symptoms but subsequently clinically diagnosed with ADHD, and the ASD group consisted of 18 children with ASD. We used the Autism Diagnostic Observation Schedule, 2nd edition (ADOS-2), to examine relative differences in the presence of symptoms such as deficits in communication and social interaction, and restricted and repetitive behaviors in these two groups. Comparison between groups was conducted to explore differences in IQ, age, ADOS-2 domains, and externalizing and internalizing problems among the groups. RESULTS: We found significant differences between the groups when comparing summary scores of ADOS-2 domains (Social Affect, Restricted and Repetitive Behavior, and Total Score). Interestingly, at the individual item level, the ADHD group exhibited a similar level of atypical behaviors compared to the ASD group in two items related to the social-communication area: « Pointing » and « Gestures ». Additionally, the frequencies of « Stereotyped/idiosyncratic words or phrases », « Mannerisms », and « Repetitive interests and behaviors » also showed similarities between groups. CONCLUSION: These findings indicate the importance of exploring and developing potential transdiagnostic domains that could be targeted for treatments specifically designed for children with ADHD.

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6. Dudoignon B, Maruani A, Delorme R, Patout M, Fefeu M, Ellul P, Bokov P, Delclaux C. Autism spectrum disorder in young patients with congenital central hypoventilation syndrome: role of the autonomic nervous system dysfunction. Orphanet J Rare Dis. 2024; 19(1): 249.

BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is a rare condition characterized by alveolar hypoventilation and autonomic nervous system (ANS) dysfunction requiring long-term ventilation. CCHS could constitute a risk factor of autism spectrum disorder (ASD) due to birth injury related to respiratory failure, which remains to be determined. ANS dysfunction has also been described in ASD and there are indications for altered contribution of ANS-central nervous system interaction in processing of social information; thus, CCHS could be a risk factor for ASD based on pathophysiological background also. Our study aimed to determine the prevalence of ASD among CCHS patients, identify risk factors, and explore the relationship between the ANS, evaluated by heart rate variability indices, and adaptative functioning. RESULTS: Our retrospective study, based on the analysis of records of a French national center of patients with CCHS under 20 years of age, determined that the prevalence of ASD (diagnosed by a psychiatrist, following the criteria of DSM-4 or DSM-5) was 6/69 patients, 8.7% (95% confidence interval: 3.3-18.0%). In a case (CCHS with ASD, n = 6) – control (CCHS without ASD, n = 12) study with matching on sex, longer neonatal hospitalization stay and glycemic dysfunction were associated with ASD. Adaptative functioning was assessed using Vineland Adaptative behavioral scales (VABS) and heart rate variability indices (including daytime RMSSD as an index of parasympathetic modulation) were obtained from ECG Holter performed the same day. In 19 young subjects with CCHS who had both ECG Holter and VABS, significant positive correlations were observed between RMSSD and three of four sub-domains of the VABS (communication: R = 0.50, p = 0.028; daily living skills: R = 0.60, p = 0.006; socialization: R = 0.52, p = 0.021). CONCLUSION: Our study suggests a high prevalence of ASD in patients with CCHS. Glycemic dysfunction and longer initial hospitalization stays were associated with ASD development. A defect in parasympathetic modulation was associated with worse adaptative functioning.

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7. Faker K, de Paula VAC, Tostes MA. Psychometric Properties of the Portuguese Version of the Quality of Life in Autism Questionnaire (QoLA). J Autism Dev Disord. 2024.

The aim of this study was to cross-culturally adapt and validate of the Brazilian Portuguese version of the Quality of Life in Autism Questionnaire (QoLA) among parents of children ASD. The translated version was administered to 91 parents (Male: 4, Female: 85, other: 2) of individuals diagnosed with ASD. Among these, 22 completed the questionnaire twice, providing data for the assessment of test-retest reliability (ICC). The B-QoLA score ranged from 41 to 122, with a mean (SD) of 74.3 ± 18.5 in Part A and ranged from 22 to 94, with a mean (SD) of 61.6 ± 16.4, in Part B. Cronbach’s alpha coefficient was 0.94 for Part A, 0.92 for Part B and 0.94 for total B-QoLA, indicating excellent internal consistency. Test-retest reliability was assessed using the intraclass correlation coefficient, which was 0.96 for the total scale, 0.94 for Part A, and 0.95 for Part B. Part A-X2 (df) = 297, (167), X2/2 = 1.7, CFI = 0.85, TLI = 0.84, GFI = 0.78, AGFI = 0.75, and RMSEA (95%CI) = 0.09 (0.07-0.11); Part B-X2 (df) = 297, (167), X2/2 = 1.7, CFI = 0.85, TLI = 0.84, GFI = 0.78, AGFI = 0.75, and RMSEA (95%CI) = 0.09 (0.07-0.11), thus indicating moderate fit of the model. The Brazilian version of the QoLA shows encouraging psychometric properties on each of the two subscales, showing strong internal consistency and good construct validity.

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8. Farzanegan F, Shadmehri SA, Shooshtari Z, Hamidi AR, Shahri A. Evaluating malocclusion patterns in children with autism spectrum disorder using the index of complexity, outcome and need: a cross-sectional study. BMC Oral Health. 2024; 24(1): 759.

BACKGROUND: The purpose of this study was to evaluate the complexity of malocclusion and existing patterns in children with autism spectrum disorders (ASD) using the index of complexity, outcome and need (ICON). METHODS: This cross-sectional study included children diagnosed with ASD, aged 9-15 years. A group of healthy children with the same demographic characteristics was randomly selected as the control group. Malocclusion was assessed according to ICON scoring protocol. The following parameters were recorded: dental aesthetics, upper arch crowding/spacing, presence of crossbite, anterior-vertical relationship (open and deep bite) and buccal segment anterior-posterior relationship. Finally, an overall ICON score was derived and reported for each patient. Descriptive analysis was performed for all investigated variables. Significance level was set at p < 0.05. RESULTS: A total of 324 children, divided into ASD (162) and control (162) groups, comprised the study population. Our results demonstrated that the average overall ICON score was significantly higher in the ASD group compared to the control group (38.77 vs. 27.43, p < 0.001). ASD children also obtained significantly higher scores regarding the dental aesthetics component (3.84 vs 2.78, p < 0.001). Study groups were significantly different in terms of the prevalence of incisor overbite and open bite (p = 0.002 and p < 0.001, respectively). Patients in the ASD group showed a higher prevalence of Class II and Class III malocclusions (p < 0.001). CONCLUSION: ASD children obtained significantly higher overall ICON scores, indicating more complex and severe malocclusions. These children also exhibited a greater tendency towards Class II and III malocclusions.

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9. Ferguson EF, Barnett ML, Goodwin JW, Vernon TW. « There is No Help: » Caregiver Perspectives on Service Needs for Adolescents and Adults with Profound Autism. J Autism Dev Disord. 2024.

The underrepresentation of individuals with profound autism (who require 24/7 access to care) in autism research has resulted in limited knowledge about their service needs and a lack of evidence-based practices tailored to those needs. This study explored caregiver perspectives on service needs, barriers to accessing care, and treatment priorities to guide treatment development and improvement of service delivery. A sequential mixed-methods design integrated quantitative survey data (n = 423; Mage = 18.89 years; 26.7% female) with qualitative interviews (n = 20) with caregivers of adolescents and adults with profound autism. Quantitative findings indicated regular socialization opportunities were the most frequently endorsed unmet service need (60.3% of caregivers), followed by primary health care with autism-trained staff (59.3%), social skills instruction (55.8%), life skills instruction (51.3%), and behavioral support (47.3%). Higher likelihood of needing social activity groups was associated with elevated emotional reactivity, higher language level, minoritized ethnicity, and lower household income. Greater need for specialized primary health care was associated with lower income, while the need for social and life skills instruction was associated with increased age and elevated dysphoria. Qualitative analysis identified 10 themes that converged and expanded quantitative findings by highlighting a pervasive shortage of individualized, goal-oriented services, common barriers to care, and the priority of developing centralized treatment settings that coordinate care throughout adulthood. This study identified pressing service needs for adolescents and adults with profound autism in the United States. These insights are crucial for improving the accessibility and quality of clinical care.

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10. Hewett K, Hawkins E. The Use of Multiple Exemplar Instruction to Induce Emergent Listener Discriminations and Emergent Intraverbal Vocal Responses in Autistic Children. Anal Verbal Behav. 2024; 40(1): 63-75.

This study tested for the emergence of listener discriminations and intraverbal vocal responses following tact training with four autistic children. All participants were trained to tact the name and the favorite food of two contrived cartoon monsters in the presence of a picture of the monster (e.g., « What is the name of this monster? » – « Max » and « What food does the monster eat? » – « Sweets ») to evaluate the effects of emergent listener discriminations and emergent intraverbal vocal responses. Once criterion was met on the tact training, participants were tested for emergent listener discriminations (e.g., « Who eats sweets? » And « Who is Max? ») and emergent intraverbal vocal responses (e.g., « What food does Max eat? » – « Sweets » and « Who eats sweets? » – « Max » in the absence of the picture). After training, all four participants engaged in emergent listener responding but only one participant engaged in emergent intraverbal responding. Multiple exemplar instruction (MEI) was used to teach those who could not engage in emergent intraverbal responding, and it was demonstrated to be effective. These findings are educationally significant because efficiency of instruction is important to maximize instructional impact, and to reduce the time and resource-intensive nature of behavior-analytic programming.

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11. Hussein Z, Alzamily A. MITOCHONDRIAL VITIATION CONGRUENTLY APTLY WITH AUTISM SPECTRUM DISORDER. Georgian Med News. 2024; (349): 154-60.

Mitochondrial dysfunction in autism leads to impair the mitochondria’s ability to synthesis adenosine triphosphate (ATP) by impairment citric acid cycle as well as increase anaerobic glycolysis. Aim – measuring and evaluating the levels of mitochondrial markers; including glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), malate dehydrogenase, and pyruvate kinase) in the autistic group and knowing the possibility of using these markers to diagnose children with autism spectrum disorder. A case-control study was done in the Al-Zahraa Teaching Hospital (Kut City, Iraq) on 100 Iraqi children (male and female), between (April 2023 and January 2024). Their ages ranged between 3 and 9 years. Among them were 50 patients enrolled as autistic group and 50 healthy enrolled as control group. Blood samples were collected and bioassays for GOT, GPT, pyruvate kinase, and malate dehydrogenase were measured by ELISA technique. The autistic group showed that the urine GOT, urine GPT, serum malate, and serum pyruvate levels in the ASD group was significantly higher (P<0.001) than the control group. The ROC analysis showed that urine GOT, urine GOT, serum malate and serum pyruvate had an accuracy level of (81%,71%,77%, and 80 %) and the area under the curve (AUC) was > 0.7 (0.8),0.7, 0.7(0.76), and 0.7(0.8) thus urine GOT, urine GPT, serum, malate, and serum pyruvate are a valid diagnostic marker. There was a significant difference in the mean urine and serum concentrations of mitochondrial markers (GOT, GPT, malate dehydrogenase, and pyruvate kinase) between autistic children and the control group due to mitochondrial dysfunction.

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12. Jan TY, Wong LC, Hsu CJ, Huang CJ, Peng SS, Tseng WI, Lee WT. Developmental change of brain volume in Rett syndrome in Taiwan. J Neurodev Disord. 2024; 16(1): 36.

OBJECTIVE: Rett syndrome (RTT) is characterized by neurological regression. This pioneering study investigated the effect of age on brain volume reduction by analyzing magnetic resonance imaging findings in participants with RTT, ranging from toddlers to adults. METHODS: Functional evaluation and neuroimaging were performed. All scans were acquired using a Siemens Tim Trio 3 T scanner with a 32-channel head coil. RESULTS: The total intracranial volume and cerebral white matter volume significantly increased with age in the control group compared with that in the RTT group (p < 0.05). Cortical gray matter volume reduction in the RTT group continued to increase in bilateral parietal lobes and left occipital lobes (p < 0.05). The differences in cortical gray matter volume between typically developing brain and RTT-affected brain may tend to continuously increase until adulthood in both temporal lobes although not significant after correction for multiple comparison. CONCLUSIONS: A significant reduction in brain volume was observed in the RTT group. Cortical gray matter volume in the RTT group continued to reduce in bilateral parietal lobes and left occipital lobes. These results provide a baseline for future studies on the effect of RTT treatment and related neuroscience research.

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13. Journal F, Franchini M, Godel M, Kojovic N, Latrèche K, Solazzo S, Schneider M, Schaer M. Phenotyping variability in early socio-communicative skills in young children with autism and its influence on later development. Autism Res. 2024.

Children with autism spectrum disorder (ASD) often face challenges in early social communication skills, prompting the need for a detailed exploration of specific behaviors and their impact on cognitive and adaptive functioning. This study aims to address this gap by examining the developmental trajectories of early social communication skills in preschoolers with ASD aged 18-60 months, comparing them to age-matched typically developing (TD) children. Utilizing the early social communication scales (ESCS), the research employs a longitudinal design to capture changes over time. We apply a principal component analysis (PCA) to ESCS variables to identify underlying components, and cluster analysis to identify subgroups based on preverbal communication profiles. The results reveal consistent differences in early social communication skills between ASD and TD children, with ASD children exhibiting reduced skills. PCA identifies two components, distinguishing objects-directed behaviors and social interaction-directed behaviors. Cluster analysis identifies three subgroups of autistic children, each displaying specific communication profiles associated with distinct cognitive and adaptive functioning trajectories. In conclusion, this study provides a nuanced understanding of early social communication development in ASD, emphasizing the importance of low-level behaviors. The identification of subgroups and their unique trajectories contributes to a more comprehensive understanding of ASD heterogeneity. These findings underscore the significance of early diagnosis, focusing on specific behaviors predicting cognitive and adaptive functioning outcomes. The study encourages further research to explore the sequential development of these skills, offering valuable insights for interventions and support strategies.

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14. Jutla A, Shuffrey LC, Guter SJ, O’Reilly KC, Anderson GM, Sutcliffe JS, Cook EH, Veenstra-VanderWeele J. Relationship between maternal serotonin levels and autism-associated genetic variants. J Clin Invest. 2024.

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15. Karimi Z, Zarifkar A, Mirzaei E, Dianatpour M, Dara M, Aligholi H. Therapeutic effects of nanosilibinin in valproic acid-zebrafish model of autism spectrum disorder: Focusing on Wnt signaling pathway and autism spectrum disorder-related cytokines. Int J Dev Neurosci. 2024.

In this study, we delved into the intricate world of autism spectrum disorder (ASD) and its connection to the disturbance in the Wnt signaling pathway and immunological abnormalities. Our aim was to evaluate the impact of silibinin, a remarkable modulator of both the Wnt signaling pathway and the immune system, on the neurobehavioral and molecular patterns observed in a zebrafish model of ASD induced by valproic acid (VPA). Because silibinin is a hydrophobic molecule and highly insoluble in water, it was used in the form of silibinin nanoparticles (nanosilibinin, NS). After assessing survival, hatching rate, and morphology of zebrafish larvae exposed to different concentrations of NS, the appropriate concentrations were chosen. Then, zebrafish embryos were exposed to VPA (1 μM) and NS (100 and 200 μM) at the same time for 120 h. Next, anxiety and inattentive behaviors and the expression of CHD8, CTNNB, GSK3beta, LRP6, TNFalpha, IL1beta, and BDNF genes were assessed 7 days post fertilization. The results indicated that higher concentrations of NS had adverse effects on survival, hatching, and morphological development. The concentrations of 100 and 200 μM of NS could ameliorate the anxiety-like behavior and learning deficit and decrease ASD-related cytokines (IL1beta and TNFalpha) in VPA-treated larvae. In addition, only 100 μM of NS prevented raising the gene expression of Wnt signaling-related factors (CHD8, CTNNB, GSK3beta, and LRP6). In conclusion, NS treatment for the first 120 h showed therapeutic effect on an autism-like phenotype probably via reducing the expression of pro-inflammatory cytokines genes and changing the expression of Wnt signaling components genes.

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16. Liloia D, Zamfira DA, Tanaka M, Manuello J, Crocetta A, Keller R, Cozzolino M, Duca S, Cauda F, Costa T. Disentangling the role of gray matter volume and concentration in autism spectrum disorder: A meta-analytic investigation of 25 years of voxel-based morphometry research. Neurosci Biobehav Rev. 2024; 164: 105791.

Despite over two decades of neuroimaging research, a unanimous definition of the pattern of structural variation associated with autism spectrum disorder (ASD) has yet to be found. One potential impeding issue could be the sometimes ambiguous use of measurements of variations in gray matter volume (GMV) or gray matter concentration (GMC). In fact, while both can be calculated using voxel-based morphometry analysis, these may reflect different underlying pathological mechanisms. We conducted a coordinate-based meta-analysis, keeping apart GMV and GMC studies of subjects with ASD. Results showed distinct and non-overlapping patterns for the two measures. GMV decreases were evident in the cerebellum, while GMC decreases were mainly found in the temporal and frontal regions. GMV increases were found in the parietal, temporal, and frontal brain regions, while GMC increases were observed in the anterior cingulate cortex and middle frontal gyrus. Age-stratified analyses suggested that such variations are dynamic across the ASD lifespan. The present findings emphasize the importance of considering GMV and GMC as distinct yet synergistic indices in autism research.

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17. Lyall K, Westlake M, Musci R, Gachigi K, Barrett ES, Bastain TM, Bush NR, Buss C, Camargo CA, Jr., Croen LA, Dabelea D, Dunlop AL, Elliott AJ, Ferrara A, Ghassabian A, Gern JE, Hare ME, Hertz-Picciotto I, Hipwell AE, Hockett CW, Karagas MR, Lugo-Candelas C, O’Connor TG, Schmidt RJ, Stanford JB, Straughen JK, Shuster CL, Wright RO, Wright RJ, Zhao Q, Oken E. Association of Maternal Fish Consumption and Omega-3 Supplement Use During Pregnancy With Child Autism-Related Outcomes: Results from a Cohort Consortium Analysis. Am J Clin Nutr. 2024.

BACKGROUND: Prenatal fish intake is a key source of omega-3 polyunsaturated fatty acids needed for brain development, yet intake is generally low, and studies addressing associations with autism spectrum disorder (ASD) and related traits are lacking. OBJECTIVE: To examine associations of prenatal fish intake and omega-3 supplement use with both autism diagnosis and broader autism-related traits. METHODS: Participants were drawn from 32 cohorts in the Environmental influences on Child Health Outcomes (ECHO) Cohort Consortium. Children were born between 1999 and 2019 and part of ongoing follow-up with data available for analysis by August 2022. Exposures included self-reported maternal fish intake and omega-3/fish oil supplement use during pregnancy. Outcome measures included parent report of clinician-diagnosed ASD and parent-reported autism-related traits measured by the Social Responsiveness Scale (SRS)-Second Edition (n=3939 and n=3609 for fish intake analyses, respectively; n=4537 and n=3925 for supplement intake analyses, respectively). RESULTS: In adjusted regression models, relative to no fish intake, fish intake during pregnancy was associated with reduced odds of autism diagnosis (OR=0.84, 95% CI 0.77 to 0.92), and a modest reduction in raw total SRS scores (b=-1.69, 95% CI -3.3 to -0.08). Estimates were similar across categories of fish consumption from « any » or « less than once per week » to « more than twice per week. » For omega-3 supplement use, relative to no use, no significant associations with autism diagnosis were identified, whereas a modest relation with SRS score was suggested (β=1.98, 95% CI 0.33-3.64). CONCLUSIONS: These results extend prior work by suggesting that prenatal fish intake, but not omega-3 supplement use, may be associated with lower likelihood of both autism diagnosis and related traits. Given the low fish intake in the U.S. general population and the rising autism prevalence, these findings suggest the need for better public health messaging regarding guidelines on fish intake for pregnant individuals.

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18. Otgonbayar G, Lo T, Hayashi Y, Furuta S, Aleksic B, Nawa Y, Kushima I, Kato H, Kimura H, Ozaki N. Study of the genetic association between selected 3q29 region genes and schizophrenia and autism spectrum disorder in the Japanese population. Nagoya J Med Sci. 2024; 86(2): 216-22.

Psychiatric disorders are highly inheritable, and most psychiatric disorders exhibit genetic overlap. Recent studies associated the 3q29 recurrent deletion with schizophrenia (SCZ) and autism spectrum disorder (ASD). In this study, we investigated the association of genes in the 3q29 region with SCZ and ASD. TM4SF19 and PAK2 were chosen as candidate genes for this study based on evidence from previous research. We sequenced TM4SF19 and PAK2 in 437 SCZ cases, 187 ASD cases and 524 controls in the Japanese population. Through targeted sequencing, we identified 6 missense variants among the cases (ASD & SCZ), 3 missense variants among controls, and 1 variant common to both cases and controls; however, no loss-of-function variants were identified. Fisher’s exact test showed a significant association of variants in TM4SF19 among cases (p=0.0160). These results suggest TM4SF19 variants affect the etiology of SCZ and ASD in the Japanese population. Further research examining 3q29 region genes and their association with SCZ and ASD is thus needed.

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19. Rafi’i MR, Ja’afar MH, Abd Wahil MS, Md Hanif SA. Urine manganese, cadmium, lead, arsenic, and selenium among autism spectrum disorder children in Kuala Lumpur. PeerJ. 2024; 12: e17660.

BACKGROUND: The development of autism spectrum disorder (ASD) may stem from exposure to environmental pollutants such as heavy metals. The primary objective of this study is to determine the role of heavy metals of concern such as manganese (Mn), cadmium (Cd), lead (Pb), arsenic (As), and essential trace element selenium (Se) among ASD children in Kuala Lumpur, Malaysia. METHOD: A total of 155 preschoolers in Kuala Lumpur between the ages 3 to 6 participated in an unmatched case-control study, comprising ASD children (n = 81) recruited from an early intervention program for autism, and 74 children without autism who were recruited from public preschools. Urine samples were collected at home, delivered to the study site, and transported to the environmental lab within 24 hours. Inductively coupled plasma mass spectrometry (ICP-MS) was applied to measure the concentration of heavy metals in the samples. Data were analysed using bivariate statistical tests (Chi-square and T-test) and logistic regression models. RESULT: This study demonstrated that Cd, Pb, and As urine levels were significantly greater in children without autism relative to those affected with ASD (p < 0.05). No significant difference was in the levels of Se (p = 0.659) and Mn (p = 0.875) between children with ASD and the control group. The majority of children in both groups have urine As, Pb, and Cd values lower than 15.1 µg/dL, 1.0 µg/dL, and 1.0 µg/dL, respectively which are the minimal risk values for noncarcinogenic detrimental human health effect due to the heavy metal's exposure . Factors associated with having an ASD child included being a firstborn, male, and higher parental education levels (adjusted odds ratios (aOR) > 1, p < 0.05). CONCLUSION: Preschoolers in this study demonstrated low levels of heavy metals in their urine samples, which was relatively lower in ASD children compared to the healthy matched controls. These findings may arise from the diminished capacity to excrete heavy metals, especially among ASD children, thereby causing further accumulation of heavy metals in the body. These findings, including the factors associated with having an ASD child, may be considered by healthcare professionals involved in child development care, for early ASD detection. Further assessment of heavy metals among ASD children in the country and interventional studies to develop effective methods of addressing exposure to heavy metals will be beneficial for future reference.

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20. Reisinger DL, Goodwin MS, Horn PS, Schmitt LM, Coffman MC, Shaffer RC. Examining the feasibility and utility of heart rate variability on intervention outcomes targeting emotion regulation in autism: a brief report. Sci Rep. 2024; 14(1): 15409.

Autistic youth experience several behavioral and emotional characteristics that can predispose them to emotion dysregulation (ED). Current literature examining ED in autism spectrum disorder (ASD) is limited to parent- and self-reported measures, indicating a need for biological or physiological methods to better assess emotion regulation in ASD. Utilizing the autonomic nervous system, specifically heart rate variability (HRV), may be a promising method to objectively measure ED in ASD, given it is one of the body’s primary means of regulating physiological arousal. Our pilot study is one of the first to examine the feasibility, utility, and construct validity of HRV along with clinical measures within an intervention targeting ED-specific symptoms in ASD. Participants included 30 autistic youth ages 8-17 years who participated in the pilot study of Regulating Together, a group-based intervention targeting emotion regulation. We demonstrate HRV is feasible, demonstrates adequate test-retest reliability, and is complimentary to clinician- and parent-reported measures. Our preliminary findings also point to certain HRV profiles being indicative of long-term outcomes after receiving treatment. HRV may be a useful, objective tool in determining differential needs of long-term follow-up care for treatment maintenance at screening or baseline stages.

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21. Salomonsen R, Eldevik S. Effects of Serial Multiple Exemplar Training on Bidirectional Naming in Children with Autism. Anal Verbal Behav. 2024; 40(1): 28-52.

This study examined the effect of a serial multiple exemplar training (S-MET) procedure on bidirectional naming (BiN) in four preschool children diagnosed with autism spectrum disorder (ASD). A non-concurrent multiple baseline design was used to evaluate the effects of training listener and speaker behavior for one stimulus at a time until BiN occurred. When BiN occurred, probes were conducted to measure whether generalization occurred across settings and people. Three out of four participants’ responding met the mastery criterion for BiN, while the fourth participant improved her performance. The results of this study suggest that S-MET may be a promising intervention and contribute to our knowledge about learning histories required for BiN.

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22. Scarpitti MR, Pastore B, Tang W, Kearse MG. Characterization of ribosome stalling and no-go mRNA decay stimulated by the Fragile X protein, FMRP. J Biol Chem. 2024: 107540.

Loss of functional fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS) and is the leading monogenic cause of autism spectrum disorders and intellectual disability. FMRP is most notably a translational repressor and is thought to inhibit translation elongation by stalling ribosomes as FMRP-bound polyribosomes from brain tissue are resistant to puromycin and nuclease treatment. Here, we present data showing that the C-terminal non-canonical RNA-binding domain of FMRP is essential and sufficient to induce puromycin-resistant mRNA•ribosome complexes. Given that stalled ribosomes can stimulate ribosome collisions and no-go mRNA decay (NGD), we tested the ability of FMRP to drive NGD of its target transcripts in neuroblastoma cells. Indeed, FMRP and ribosomal proteins, but not poly(A)-binding protein, were enriched in isolated nuclease-resistant disomes compared to controls. Using siRNA knockdown and RNA-seq, we identified 16 putative FMRP-mediated NGD substrates, many of which encode proteins involved in neuronal development and function. Increased mRNA stability of 4 putative substrates was also observed when either FMRP was depleted or NGD was prevented via RNAi. Taken together, these data support that FMRP stalls ribosomes but only stimulates NGD of a small select set of transcripts, revealing a minor role of FMRP that would be misregulated in FXS.

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23. Sivayokan B, King C, Mali I, Payne M, Strating H, Warnes E, Bossmann SH, Plakke B. Aerobic Exercise Improves Cognitive Flexibility and Modulates Regional Volume Changes in a Rat Model of Autism. Behav Brain Res. 2024: 115136.

Gestational exposure to valproic acid (VPA) is a risk factor for autism spectrum disorder (ASD). Rodents exposed to VPA in utero display common features of ASD, including volumetric dysregulation in higher-order cognitive regions like the medial prefrontal cortex (mPFC), the anterior cingulate cortex (ACC), and the hippocampus. Exercise has been shown in elderly populations to boost cognition and to buffer against brain volume losses with age. This study employed an adolescent treadmill exercise intervention to facilitate cognitive flexibility and regional brain volume regulation in rats exposed to VPA during gestation. It was found that exercise improved performance on extra-dimensional shifts of attention on a set-shifting task, which is indicative of improved cognitive flexibility. Exercise decreased frontal cortex volume in females, whereas in males exercise increased the ventral hippocampus. These findings suggest that aerobic exercise may be an effective intervention to counteract the altered development of prefrontal and hippocampal regions often observed in ASD.

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24. Yuan YX, Liu Y, Zhang J, Bing YH, Chen CY, Li GG, Chu CP, Yin MJ, Qiu DL. Gestational valproic acid exposure enhances facial stimulation-evoked cerebellar mossy fiber-granule cell transmission via GluN2A subunit-containing NMDA receptor in offspring mice. Transl Psychiatry. 2024; 14(1): 272.

Valproic acid (VPA) is one of the most effective antiepileptic drugs, and exposing animals to VPA during gestation has been used as a model for autism spectrum disorder (ASD). Numerous studies have shown that impaired synaptic transmission in the cerebellar cortical circuits is one of the reasons for the social deficits and repetitive behavior seen in ASD. In this study, we investigated the effect of VPA exposure during pregnancy on tactile stimulation-evoked cerebellar mossy fiber-granule cell (MF-GC) synaptic transmission in mice anesthetized with urethane. Three-chamber testing showed that mice exposed to VPA mice exhibited a significant reduction in social interaction compared with the control group. In vivo electrophysiological recordings revealed that a pair of air-puff stimulation on ipsilateral whisker pad evoked MF-GC synaptic transmission, N1, and N2. The evoked MF-GC synaptic responses in VPA-exposed mice exhibited a significant increase in the area under the curve (AUC) of N1 and the amplitude and AUC of N2 compared with untreated mice. Cerebellar surface application of the selective N-methyl-D-aspartate (NMDA) receptor blocker D-APV significantly inhibited facial stimulation-evoked MF-GC synaptic transmission. In the presence of D-APV, there were no significant differences between the AUC of N1 and the amplitude and AUC of N2 in the VPA-exposed mice and those of the untreated mice. Notably, blockade of the GluN2A subunit-containing, but not the GluN2B subunit-containing, NMDA receptor, significantly inhibited MF-GC synaptic transmission and decreased the AUC of N1 and the amplitude and AUC of N2 in VPA-exposed mice to levels similar to those seen in untreated mice. In addition, the GluN2A subunit-containing NMDA receptor was expressed at higher levels in the GC layer of VPA-treated mice than in control mice. These results indicate that gestational VPA exposure in mice produces ASD-like behaviors, accompanied by increased cerebellar MF-GC synaptic transmission and an increase in GluN2A subunit-containing NMDA receptor expression in the offspring.

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25. Zaki M, Youness ER, Orban HA, Ahmed HM, Moustafa RSI, Alzaree FA, Ashaat EA, El-Bassyouni HT. Potential biomarkers of ASD a target for future treatments: oxidative stress, chemokines, apoptotic, and methylation capacity. J Complement Integr Med. 2024.

OBJECTIVES: The study aimed to assess the effect of these biomarkers on a sample of children with autism spectrum disorder (ASD) to help in early diagnosis and intervention. METHODS: A total of 71 autistic patients and 65 normal controls were enrolled in this study. Their ages ranged from 5 to 11 years (mean ± SD 7.47 ± 3.81). Childhood Autism Rating Scale (CARS) was assessed for all patients and controls. Assessment of oxidative stress, monocyte chemoattractant protein-1, B-cell lymphoma 2, S-adenosylhomocysteine (SAH), and apelin was performed. RESULTS: Oxidative stress (oxidized low-density lipoprotein and malonaldehyde) increased while antioxidant paraoxonase (PON) decreased. Monocyte chemoattractant protein-1, B-cell lymphoma 2, and S-adenosylhomocysteine (SAH) were all elevated whereas, apelin was downregulated. CONCLUSIONS: It is important to note that many factors that may contribute to ASD including genetic factors. To open the door for novel treatment strategies, it is still necessary to precisely understand how oxidative stress, chemokines, apoptosis, and methylation capability affect the metabolism of people with ASD.

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