Samia M. Ltaief, Wared Nour-Eldine, Nimshitha Pavathuparambil Abdul Manaph, Ti-Myen Tan, Nur Diana Anuar, Ilham Bensmail, Jilbin George, Houari B. Abdesselem, Abeer R. Al-Shammari
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction and communication, as well as the occurrence of stereotyped and repetitive behaviors. Previous studies have provided solid evidence of dysregulated immune system in ASD; however, limited studies have investigated autoantibody profiles in individuals with ASD. This study aims to screen plasma autoantibodies in a well-defined cohort of young children with ASD (n = 100) and their matched controls (n = 60) utilizing a high-throughput KoRectly Expressed (KREX) i-Ome protein-array technology. We identified differential protein expression of 16 autoantibodies in ASD, which were correlated with differential gene expression of these markers in independent ASD cohorts. Meanwhile, we identified a distinct list of 33 autoantibodies associated with ASD severity; several of which were correlated with maternal age and birth weight in ASD. In addition, we found dysregulated numbers of circulating B cells and activated HLADR+ B cells in ASD, which were correlated with altered levels of several autoantibodies. Further in-depth analysis of B cell subpopulations revealed an increased frequency of activated naïve B cells in ASD, as well as an association of resting naïve B cells and transitional B cells with ASD severity. Pathway enrichment analysis revealed disrupted MAPK signaling in ASD, suggesting a potential relevance of this pathway to altered autoantibodies and B cell dysfunction in ASD. Finally, we found that a combination of eight autoantibodies associated with ASD severity showed an area under the curve (ROC-AUC) of 0.937 (95% CI = 0.890, 0.983; p < 0.001), which demonstrated the diagnostic accuracy of the eight-marker signature in the severity classification of ASD cases. Overall, this study determined dysregulated autoantibody profiles and B cell dysfunction in children with ASD and identified an eight-autoantibody panel for ASD severity classification.
自闭症谱系障碍(ASD)是一种神经发育障碍,其特点是社会交往和沟通能力受损,以及出现刻板和重复行为。以往的研究已提供了 ASD 免疫系统失调的确凿证据;然而,对 ASD 患者自身抗体谱的研究却很有限。本研究旨在利用高通量的KoRectly Expressed(KREX)i-Ome蛋白芯片技术,筛查一组明确定义的ASD幼儿(100人)及其匹配对照组(60人)的血浆自身抗体。我们发现了16种自身抗体在ASD中的差异蛋白表达,这些差异蛋白表达与独立ASD队列中这些标记物的差异基因表达相关。同时,我们还发现了33种与ASD严重程度相关的自身抗体,其中有几种与ASD患者的母体年龄和出生体重相关。此外,我们还发现 ASD 中循环 B 细胞和活化的 HLADR+ B 细胞数量失调,这与几种自身抗体水平的改变有关。对B细胞亚群的进一步深入分析显示,ASD患者中活化的幼稚B细胞频率增加,静息的幼稚B细胞和过渡性B细胞也与ASD的严重程度有关。通路富集分析显示,MAPK 信号在 ASD 中被破坏,这表明该通路可能与 ASD 中自身抗体的改变和 B 细胞功能障碍有关。最后,我们发现,与ASD严重程度相关的八种自身抗体的组合显示曲线下面积(ROC-AUC)为0.937(95% CI = 0.890, 0.983; p
{"title":"Dysregulated plasma autoantibodies are associated with B cell dysfunction in young Arab children with autism spectrum disorder in Qatar","authors":"Samia M. Ltaief, Wared Nour-Eldine, Nimshitha Pavathuparambil Abdul Manaph, Ti-Myen Tan, Nur Diana Anuar, Ilham Bensmail, Jilbin George, Houari B. Abdesselem, Abeer R. Al-Shammari","doi":"10.1002/aur.3235","DOIUrl":"10.1002/aur.3235","url":null,"abstract":"<p>Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction and communication, as well as the occurrence of stereotyped and repetitive behaviors. Previous studies have provided solid evidence of dysregulated immune system in ASD; however, limited studies have investigated autoantibody profiles in individuals with ASD. This study aims to screen plasma autoantibodies in a well-defined cohort of young children with ASD (<i>n</i> = 100) and their matched controls (<i>n</i> = 60) utilizing a high-throughput KoRectly Expressed (KREX) i-Ome protein-array technology. We identified differential protein expression of 16 autoantibodies in ASD, which were correlated with differential gene expression of these markers in independent ASD cohorts. Meanwhile, we identified a distinct list of 33 autoantibodies associated with ASD severity; several of which were correlated with maternal age and birth weight in ASD. In addition, we found dysregulated numbers of circulating B cells and activated HLADR+ B cells in ASD, which were correlated with altered levels of several autoantibodies. Further in-depth analysis of B cell subpopulations revealed an increased frequency of activated naïve B cells in ASD, as well as an association of resting naïve B cells and transitional B cells with ASD severity. Pathway enrichment analysis revealed disrupted MAPK signaling in ASD, suggesting a potential relevance of this pathway to altered autoantibodies and B cell dysfunction in ASD. Finally, we found that a combination of eight autoantibodies associated with ASD severity showed an area under the curve (ROC-AUC) of 0.937 (95% CI = 0.890, 0.983; <i>p</i> < 0.001), which demonstrated the diagnostic accuracy of the eight-marker signature in the severity classification of ASD cases. Overall, this study determined dysregulated autoantibody profiles and B cell dysfunction in children with ASD and identified an eight-autoantibody panel for ASD severity classification.</p>","PeriodicalId":131,"journal":{"name":"Autism Research","volume":"17 10","pages":"1974-1993"},"PeriodicalIF":5.3,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/aur.3235","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142309234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amanda L. Richdale, Amy M. Shui, Linnea A. Lampinen, Terry Katz
Autistic children frequently have one or more co-occurring psychological, behavioral, or medical conditions. We examined relationships between child behaviors, sleep, adaptive behavior, autistic traits, mental health conditions, and health in autistic children using network analysis. Network analysis is hypothesis generating and can inform our understanding of relationships between multiple conditions and behaviors, directing the development of transdiagnostic treatments for co-occurring conditions. Participants were two child cohorts from the Autism Treatment Network registry: ages 2–5 years (n = 2372) and 6–17 years (n = 1553). Least absolute-shrinkage and selection operator (LASSO) regularized partial correlation network analysis was performed in the 2–5 years cohort (35 items) and the 6–17 years cohort (36 items). The Spinglass algorithm determined communities within each network. Two-step expected influence (EI2) determined the importance of network variables. The most influential network items were sleep difficulties (2 items) and aggressive behaviors for young children and aggressive behaviors, social problems, and anxious/depressed behavior for older children. Five communities were found for younger children and seven for older children. Of the top three most important bridge variables, night-waking/parasomnias and anxious/depressed behavior were in both age-groups, and somatic complaints and sleep initiation/duration were in younger and older cohorts respectively. Despite cohort differences, sleep disturbances were prominent in all networks, indicating they are a transdiagnostic feature across many clinical conditions, and thus a target for intervention and monitoring. Aggressive behavior was influential in the partial correlation networks, indicating a potential red flag for clinical monitoring. Other items of strong network importance may also be intervention targets or screening flags.
{"title":"Sleep disturbance and other co-occurring conditions in autistic children: A network approach to understanding their inter-relationships","authors":"Amanda L. Richdale, Amy M. Shui, Linnea A. Lampinen, Terry Katz","doi":"10.1002/aur.3233","DOIUrl":"10.1002/aur.3233","url":null,"abstract":"<p>Autistic children frequently have one or more co-occurring psychological, behavioral, or medical conditions. We examined relationships between child behaviors, sleep, adaptive behavior, autistic traits, mental health conditions, and health in autistic children using network analysis. Network analysis is hypothesis generating and can inform our understanding of relationships between multiple conditions and behaviors, directing the development of transdiagnostic treatments for co-occurring conditions. Participants were two child cohorts from the Autism Treatment Network registry: ages 2–5 years (<i>n</i> = 2372) and 6–17 years (<i>n</i> = 1553). Least absolute-shrinkage and selection operator (LASSO) regularized partial correlation network analysis was performed in the 2–5 years cohort (35 items) and the 6–17 years cohort (36 items). The Spinglass algorithm determined communities within each network. Two-step expected influence (EI2) determined the importance of network variables. The most influential network items were sleep difficulties (2 items) and aggressive behaviors for young children and aggressive behaviors, social problems, and anxious/depressed behavior for older children. Five communities were found for younger children and seven for older children. Of the top three most important bridge variables, night-waking/parasomnias and anxious/depressed behavior were in both age-groups, and somatic complaints and sleep initiation/duration were in younger and older cohorts respectively. Despite cohort differences, sleep disturbances were prominent in all networks, indicating they are a transdiagnostic feature across many clinical conditions, and thus a target for intervention and monitoring. Aggressive behavior was influential in the partial correlation networks, indicating a potential red flag for clinical monitoring. Other items of strong network importance may also be intervention targets or screening flags.</p>","PeriodicalId":131,"journal":{"name":"Autism Research","volume":"17 11","pages":"2386-2404"},"PeriodicalIF":5.3,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/aur.3233","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142302311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Diana Schendel, Linda Ejlskov, Morten Overgaard, Zeal Jinwala, Viktor Kim, Erik Parner, Amy E. Kalkbrenner, Christine Ladd Acosta, M. Danielle Fallin, Sherlly Xie, Preben Bo Mortensen, Brian K. Lee
The relatively few conditions and family member types (e.g., sibling, parent) considered in investigations of family health history in autism spectrum disorder (ASD, or autism) limits understanding of the role of family history in autism etiology. For more comprehensive understanding and hypothesis-generation, we produced an open-source catalog of autism associations with family histories of mental, neurologic, cardiometabolic, birth defect, asthma, allergy, and autoimmune conditions. All live births in Denmark, 1980–2012, of Denmark-born parents (1,697,231 births), and their 3-generation family members were followed through April 10, 2017 for each of 90 diagnoses (including autism), emigration or death. Adjusted hazard ratios (aHR) were estimated via Cox regression for each diagnosis-family member type combination, adjusting for birth year, sex, birth weight, gestational age, parental ages at birth, and number of family member types of index person; aHRs also calculated for sex-specific co-occurrence of each disorder. We obtained 6462 individual family history aHRS across autism overall (26,840 autistic persons; 1.6% of births), by sex, and considering intellectual disability (ID); and 350 individual co-occurrence aHRS. Results are cataloged in interactive heat maps and down-loadable data files: https://ncrr-au.shinyapps.io/asd-riskatlas/ and interactive graphic summaries: https://public.tableau.com/app/profile/diana.schendel/viz/ASDPlots_16918786403110/e-Figure5.
While primarily for reference material or use in other studies (e.g., meta-analyses), results revealed considerable breadth and variation in magnitude of familial health history associations with autism by type of condition, family member type, sex of the family member, side of the family, sex of the index person, and ID status, indicative of diverse genetic, familial, and nongenetic autism etiologic pathways. Careful attention to sources of autism likelihood in family health history, aided by our open data resource, may accelerate understanding of factors underlying neurodiversity.
{"title":"3-generation family histories of mental, neurologic, cardiometabolic, birth defect, asthma, allergy, and autoimmune conditions associated with autism: An open-source catalog of findings","authors":"Diana Schendel, Linda Ejlskov, Morten Overgaard, Zeal Jinwala, Viktor Kim, Erik Parner, Amy E. Kalkbrenner, Christine Ladd Acosta, M. Danielle Fallin, Sherlly Xie, Preben Bo Mortensen, Brian K. Lee","doi":"10.1002/aur.3232","DOIUrl":"10.1002/aur.3232","url":null,"abstract":"<p>The relatively few conditions and family member types (e.g., sibling, parent) considered in investigations of family health history in autism spectrum disorder (ASD, or autism) limits understanding of the role of family history in autism etiology. For more comprehensive understanding and hypothesis-generation, we produced an open-source catalog of autism associations with family histories of mental, neurologic, cardiometabolic, birth defect, asthma, allergy, and autoimmune conditions. All live births in Denmark, 1980–2012, of Denmark-born parents (1,697,231 births), and their 3-generation family members were followed through April 10, 2017 for each of 90 diagnoses (including autism), emigration or death. Adjusted hazard ratios (aHR) were estimated via Cox regression for each diagnosis-family member type combination, adjusting for birth year, sex, birth weight, gestational age, parental ages at birth, and number of family member types of index person; aHRs also calculated for sex-specific co-occurrence of each disorder. We obtained 6462 individual family history aHRS across autism overall (26,840 autistic persons; 1.6% of births), by sex, and considering intellectual disability (ID); and 350 individual co-occurrence aHRS. Results are cataloged in interactive heat maps and down-loadable data files: https://ncrr-au.shinyapps.io/asd-riskatlas/ and interactive graphic summaries: https://public.tableau.com/app/profile/diana.schendel/viz/ASDPlots_16918786403110/e-Figure5.</p><p>While primarily for reference material or use in other studies (e.g., meta-analyses), results revealed considerable breadth and variation in magnitude of familial health history associations with autism by type of condition, family member type, sex of the family member, side of the family, sex of the index person, and ID status, indicative of diverse genetic, familial, and nongenetic autism etiologic pathways. Careful attention to sources of autism likelihood in family health history, aided by our open data resource, may accelerate understanding of factors underlying neurodiversity.</p>","PeriodicalId":131,"journal":{"name":"Autism Research","volume":"17 10","pages":"2144-2155"},"PeriodicalIF":5.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/aur.3232","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142302310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Leah R. Ketcheson, Franziska Loetzner, Chandler F. Wentz, Samantha Miller, E. Andrew Pitchford
Autistic children, as well as their primary caregivers (e.g., parents), experience greater health disparities when compared with the general population. Despite this reality, there has been relatively little priority placed on promoting positive trajectories of health in either of these underserved populations. The primary purpose of this study was to examine the impact of participation in a 12-month, longitudinal health promotion program designed for both autistic children and their parent. A total of 27 families participated in the intervention, including 29 autistic children (83% male, M = 8.28 ± 3.60 years) and 27 parents (93% female, M = 40.04 ± 7.95). Families attended in-person health promotion programming for 90 min per week. Children and parents were evaluated at four time points across the program, including baseline (0-months), 4-months, 8-months, and 12-months. Children were measured on fundamental motor competence, physical fitness, body composition, and proxy-reported physical activity. Parents were measured on body composition, physical fitness, and self-reported physical activity. Significant improvements were observed for autistic children in motor competence (p < 0.001) and grip strength (p = 0.006), and for parents in body mass index (p = 0.004) and aerobic capacity (p = 0.003) across the 12-month intervention. Differing trajectories of improvement were noted between urban- and suburban-dwelling families on multiple outcomes. The knowledge acquired from this research may offer initial support for the need to bolster opportunities for accessible and ongoing health promotion programs for both autistic children and their parents.
{"title":"A longitudinal health promotion program for autistic children and their caregivers: Impact of an urban community-based program","authors":"Leah R. Ketcheson, Franziska Loetzner, Chandler F. Wentz, Samantha Miller, E. Andrew Pitchford","doi":"10.1002/aur.3231","DOIUrl":"10.1002/aur.3231","url":null,"abstract":"<p>Autistic children, as well as their primary caregivers (e.g., parents), experience greater health disparities when compared with the general population. Despite this reality, there has been relatively little priority placed on promoting positive trajectories of health in either of these underserved populations. The primary purpose of this study was to examine the impact of participation in a 12-month, longitudinal health promotion program designed for both autistic children and their parent. A total of 27 families participated in the intervention, including 29 autistic children (83% male, <i>M</i> = 8.28 ± 3.60 years) and 27 parents (93% female, <i>M</i> = 40.04 ± 7.95). Families attended in-person health promotion programming for 90 min per week. Children and parents were evaluated at four time points across the program, including baseline (0-months), 4-months, 8-months, and 12-months. Children were measured on fundamental motor competence, physical fitness, body composition, and proxy-reported physical activity. Parents were measured on body composition, physical fitness, and self-reported physical activity. Significant improvements were observed for autistic children in motor competence (<i>p</i> < 0.001) and grip strength (<i>p</i> = 0.006), and for parents in body mass index (<i>p</i> = 0.004) and aerobic capacity <i>(p</i> = 0.003) across the 12-month intervention. Differing trajectories of improvement were noted between urban- and suburban-dwelling families on multiple outcomes. The knowledge acquired from this research may offer initial support for the need to bolster opportunities for accessible and ongoing health promotion programs for both autistic children and their parents.</p>","PeriodicalId":131,"journal":{"name":"Autism Research","volume":"17 10","pages":"2156-2176"},"PeriodicalIF":5.3,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lisa R. Hamrick, Rosmary Ros-Demarize, Stephen Kanne, Laura Arnstein Carpenter
Autistic individuals exhibit differences in their use and understanding of nonverbal communication; however, individual patterns of nonverbal strengths and challenges vary significantly. This heterogeneity can complicate the diagnostic and screening processes and can result in delayed or missed diagnoses. In this study, we characterize various profiles of nonverbal communication skills among 215 pre-verbal children with autism (Mage = 36.27 months, range = 18–70) and explore how these profiles are related to screening outcomes, diagnostic certainty, and developmental and behavioral features. We conducted a latent class analysis of nine items assessing nonverbal communication skills from the Toddler Module and Module 1 of the Autism Diagnostic Observation Schedule, 2nd Edition. Five nonverbal profiles were identified that differentiated children based on the form, function, and frequency of their nonverbal communication skills. Furthermore, screening outcomes and clinician certainty in autism diagnosis varied by nonverbal profile. False negative screening outcomes based on parent report were highest for children who used a range of nonverbal skills but with limited frequency or consistency. Clinicians, on the other hand, tended to have high certainty in an autism diagnosis for children with this profile, and instead rated their lowest certainty in diagnosing children who demonstrated consistent integration of eye contact with their nonverbal communication. The profiles identified in this study could be clinically useful in helping to identify children at highest likelihood of being overlooked during the screening or diagnostic processes, providing an opportunity to improve early identification and intervention for autism.
{"title":"Profiles of nonverbal skills used by young pre-verbal children with autism on the ADOS-2: Relation to screening disposition and outcomes","authors":"Lisa R. Hamrick, Rosmary Ros-Demarize, Stephen Kanne, Laura Arnstein Carpenter","doi":"10.1002/aur.3229","DOIUrl":"10.1002/aur.3229","url":null,"abstract":"<p>Autistic individuals exhibit differences in their use and understanding of nonverbal communication; however, individual patterns of nonverbal strengths and challenges vary significantly. This heterogeneity can complicate the diagnostic and screening processes and can result in delayed or missed diagnoses. In this study, we characterize various profiles of nonverbal communication skills among 215 pre-verbal children with autism (<i>M</i><sub>age</sub> = 36.27 months, range = 18–70) and explore how these profiles are related to screening outcomes, diagnostic certainty, and developmental and behavioral features. We conducted a latent class analysis of nine items assessing nonverbal communication skills from the Toddler Module and Module 1 of the Autism Diagnostic Observation Schedule, 2nd Edition. Five nonverbal profiles were identified that differentiated children based on the form, function, and frequency of their nonverbal communication skills. Furthermore, screening outcomes and clinician certainty in autism diagnosis varied by nonverbal profile. False negative screening outcomes based on parent report were highest for children who used a range of nonverbal skills but with limited frequency or consistency. Clinicians, on the other hand, tended to have high certainty in an autism diagnosis for children with this profile, and instead rated their lowest certainty in diagnosing children who demonstrated consistent integration of eye contact with their nonverbal communication. The profiles identified in this study could be clinically useful in helping to identify children at highest likelihood of being overlooked during the screening or diagnostic processes, providing an opportunity to improve early identification and intervention for autism.</p>","PeriodicalId":131,"journal":{"name":"Autism Research","volume":"17 11","pages":"2370-2385"},"PeriodicalIF":5.3,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142156805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fragile X syndrome (FXS) is the primary hereditary cause of intellectual disability and autism spectrum disorder. It is characterized by exacerbated neuronal excitability, and its correction is considered an objective measure of treatment response in animal models, a marker albeit rarely used in clinical trials. Here, we used an extensive transcranial magnetic stimulation (TMS) battery to assess the neurophysiological effects of a therapy combining two disease-modifying drugs, lovastatin (40 mg) and minocycline (100 mg), administered alone for 8 weeks and in combination for 12 weeks, in 19 patients (mean age of 23.58 ± 1.51) with FXS taking part in the LOVAmix trial. The TMS battery, which included the resting motor threshold, short-interval intracortical inhibition, long-interval intracortical inhibition, corticospinal silent period, and intracortical facilitation, was completed at baseline after 8 weeks of monotherapy (visit 2 of the clinical trial) and after 12 weeks of dual therapy (visit 4 of the clinical trial). Repeated measure ANOVAs were performed between baseline and visit 2 (monotherapy) and visit 3 (dual therapy) with interactions for which monotherapy the participants received when they began the clinical trial. Results showed that dual therapy was associated with reduced cortical excitability after 20 weeks. This was reflected by a significant increase in the resting-motor threshold after dual therapy compared to baseline. There was a tendency for enhanced short-intracortical inhibition, a marker of GABAa-mediated inhibition after 8 weeks of monotherapy compared to baseline. Together, these results suggest that a combined therapy of minocycline and lovastatin might act on the core neurophysiopathology of FXS. This trial was registered at clinicaltrials.gov (NCT02680379).
{"title":"Neurophysiological effects of a combined treatment of lovastatin and minocycline in patients with fragile X syndrome: Ancillary results of the LOVAMIX randomized clinical trial","authors":"Florence Morin-Parent, Camille Champigny, Samantha Côté, Teddy Mohamad, Seyede Anis Hasani, Artuela Çaku, François Corbin, Jean-François Lepage","doi":"10.1002/aur.3222","DOIUrl":"10.1002/aur.3222","url":null,"abstract":"<p>Fragile X syndrome (FXS) is the primary hereditary cause of intellectual disability and autism spectrum disorder. It is characterized by exacerbated neuronal excitability, and its correction is considered an objective measure of treatment response in animal models, a marker albeit rarely used in clinical trials. Here, we used an extensive transcranial magnetic stimulation (TMS) battery to assess the neurophysiological effects of a therapy combining two disease-modifying drugs, lovastatin (40 mg) and minocycline (100 mg), administered alone for 8 weeks and in combination for 12 weeks, in 19 patients (mean age of 23.58 ± 1.51) with FXS taking part in the LOVAmix trial. The TMS battery, which included the resting motor threshold, short-interval intracortical inhibition, long-interval intracortical inhibition, corticospinal silent period, and intracortical facilitation, was completed at baseline after 8 weeks of monotherapy (visit 2 of the clinical trial) and after 12 weeks of dual therapy (visit 4 of the clinical trial). Repeated measure ANOVAs were performed between baseline and visit 2 (monotherapy) and visit 3 (dual therapy) with interactions for which monotherapy the participants received when they began the clinical trial. Results showed that dual therapy was associated with reduced cortical excitability after 20 weeks. This was reflected by a significant increase in the resting-motor threshold after dual therapy compared to baseline. There was a tendency for enhanced short-intracortical inhibition, a marker of GABAa-mediated inhibition after 8 weeks of monotherapy compared to baseline. Together, these results suggest that a combined therapy of minocycline and lovastatin might act on the core neurophysiopathology of FXS. This trial was registered at clinicaltrials.gov (NCT02680379).</p>","PeriodicalId":131,"journal":{"name":"Autism Research","volume":"17 9","pages":"1944-1956"},"PeriodicalIF":5.3,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/aur.3222","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142156804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sex heterogeneity has been frequently reported in autism spectrum disorders (ASD) and has been linked to static differences in brain function. However, given the complexity of ASD and diagnosis-by-sex interactions, dynamic characteristics of brain activity and functional connectivity may provide important information for distinguishing ASD phenotypes between females and males. The aim of this study was to explore sex heterogeneity of functional networks in the ASD brain from a dynamic perspective. Resting-state functional magnetic resonance imaging data from the Autism Brain Imaging Data Exchange database were analyzed in 128 ASD subjects (64 males/64 females) and 128 typically developing control (TC) subjects (64 males/64 females). A sliding-window approach was adopted for the estimation of dynamic amplitude of low-frequency fluctuation (dALFF) and dynamic functional connectivity (dFC) to characterize time-varying brain activity and functional connectivity respectively. We then examined the sex-related changes in ASD using two-way analysis of variance. Significant diagnosis-by-sex interaction effects were identified in the left anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) and left precuneus in the dALFF analysis. Furthermore, there were significant diagnosis-by-sex interaction effects of dFC variance between the left ACC/mPFC and right ACC, left postcentral gyrus, left precuneus, right middle temporal gyrus and left inferior frontal gyrus, triangular part. These findings reveal the sex heterogeneity in brain activity and functional connectivity in ASD from a dynamic perspective, and provide new evidence for further exploring sex heterogeneity in ASD.
自闭症谱系障碍(ASD)的性别异质性已被频繁报道,并与大脑功能的静态差异有关。然而,鉴于自闭症的复杂性和诊断与性别之间的相互作用,大脑活动和功能连接的动态特征可能会为区分女性和男性的自闭症表型提供重要信息。本研究旨在从动态角度探讨ASD大脑功能网络的性别异质性。研究人员分析了自闭症脑成像数据交换数据库(Autism Brain Imaging Data Exchange)中128名ASD受试者(64名男性/64名女性)和128名发育典型对照组(TC)受试者(64名男性/64名女性)的静息态功能磁共振成像数据。我们采用滑动窗口法估算了低频波动的动态振幅(dALFF)和动态功能连通性(dFC),以分别描述时变大脑活动和功能连通性的特征。然后,我们利用双向方差分析研究了 ASD 患者与性别相关的变化。在dALFF分析中,左侧前扣带回皮层/内侧前额叶皮层(ACC/MPFC)和左侧楔前皮层出现了显著的诊断与性别交互效应。此外,在左侧扣带回/前额皮质与右侧扣带回、左侧中央后回、左侧楔前回、右侧颞中回和左侧额叶下回三角部分之间,dFC方差存在明显的诊断性别交互效应。这些发现从动态的角度揭示了ASD患者大脑活动和功能连接的性别异质性,为进一步探讨ASD的性别异质性提供了新的证据。
{"title":"Sex heterogeneity of dynamic brain activity and functional connectivity in autism spectrum disorder","authors":"Huibin Lu, Qi Dong, Le Gao, Zaifa Xue, Xiaoxia Niu, Rongjuan Zhou, Xiaonan Guo","doi":"10.1002/aur.3227","DOIUrl":"10.1002/aur.3227","url":null,"abstract":"<p>Sex heterogeneity has been frequently reported in autism spectrum disorders (ASD) and has been linked to static differences in brain function. However, given the complexity of ASD and diagnosis-by-sex interactions, dynamic characteristics of brain activity and functional connectivity may provide important information for distinguishing ASD phenotypes between females and males. The aim of this study was to explore sex heterogeneity of functional networks in the ASD brain from a dynamic perspective. Resting-state functional magnetic resonance imaging data from the Autism Brain Imaging Data Exchange database were analyzed in 128 ASD subjects (64 males/64 females) and 128 typically developing control (TC) subjects (64 males/64 females). A sliding-window approach was adopted for the estimation of dynamic amplitude of low-frequency fluctuation (dALFF) and dynamic functional connectivity (dFC) to characterize time-varying brain activity and functional connectivity respectively. We then examined the sex-related changes in ASD using two-way analysis of variance. Significant diagnosis-by-sex interaction effects were identified in the left anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) and left precuneus in the dALFF analysis. Furthermore, there were significant diagnosis-by-sex interaction effects of dFC variance between the left ACC/mPFC and right ACC, left postcentral gyrus, left precuneus, right middle temporal gyrus and left inferior frontal gyrus, triangular part. These findings reveal the sex heterogeneity in brain activity and functional connectivity in ASD from a dynamic perspective, and provide new evidence for further exploring sex heterogeneity in ASD.</p>","PeriodicalId":131,"journal":{"name":"Autism Research","volume":"17 9","pages":"1796-1809"},"PeriodicalIF":5.3,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142147024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a neurodevelopmental disease caused by mutations in the X-linked CDKL5 gene and characterized by early-onset epilepsy, intellectual disability, and autistic features. To date, the etiological mechanisms underlying CDD are largely unknown and no effective therapies are available. The Cdkl5 knock-out (KO) mouse has been broadly employed in preclinical studies on CDD; Cdkl5-KO mice display neurobehavioral abnormalities recapitulating most CDD symptoms, including alterations in motor, sensory, cognitive, and social abilities. However, most available preclinical studies have been carried out on adult Cdkl5-KO mice, so little is known about the phenotypic characteristics of this model earlier during development. Furthermore, major autistic-relevant phenotypes, for example, social and communication deficits, have been poorly investigated and mostly in male mutants. Here, we assessed the autistic-relevant behavioral phenotypes of Cdkl5-KO mice during the first three post-natal weeks and in adulthood. Males and females were tested, the latter including both heterozygous and homozygous mutants. Cdkl5 mutant pups showed qualitative and quantitative alterations in ultrasonic communication, detected first at 2 weeks of age and confirmed later in adulthood. Increased levels of anxiety-like behaviors were observed in mutants at 3 weeks and in adulthood, when stereotypies, reduced social interaction and memory deficits were also observed. These behavioral effects of the mutation were evident in both sexes, being more marked and varied in homozygous than heterozygous females. These findings provide novel evidence for the autistic-relevant behavioral profile of the Cdkl5 mouse model, thus supporting its use in future preclinical studies investigating CDD pathology and autism spectrum disorders.
{"title":"Autistic-relevant behavioral phenotypes of a mouse model of cyclin-dependent kinase-like 5 deficiency disorder","authors":"Nicola Mottolese, Oceane Coiffard, Celeste Ferraguto, Athanasios Manolis, Elisabetta Ciani, Susanna Pietropaolo","doi":"10.1002/aur.3226","DOIUrl":"10.1002/aur.3226","url":null,"abstract":"<p>Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a neurodevelopmental disease caused by mutations in the X-linked CDKL5 gene and characterized by early-onset epilepsy, intellectual disability, and autistic features. To date, the etiological mechanisms underlying CDD are largely unknown and no effective therapies are available. The <i>Cdkl5</i> knock-out (KO) mouse has been broadly employed in preclinical studies on CDD; <i>Cdkl5</i>-KO mice display neurobehavioral abnormalities recapitulating most CDD symptoms, including alterations in motor, sensory, cognitive, and social abilities. However, most available preclinical studies have been carried out on adult <i>Cdkl5</i>-KO mice, so little is known about the phenotypic characteristics of this model earlier during development. Furthermore, major autistic-relevant phenotypes, for example, social and communication deficits, have been poorly investigated and mostly in male mutants. Here, we assessed the autistic-relevant behavioral phenotypes of <i>Cdkl5</i>-KO mice during the first three post-natal weeks and in adulthood. Males and females were tested, the latter including both heterozygous and homozygous mutants. <i>Cdkl5</i> mutant pups showed qualitative and quantitative alterations in ultrasonic communication, detected first at 2 weeks of age and confirmed later in adulthood. Increased levels of anxiety-like behaviors were observed in mutants at 3 weeks and in adulthood, when stereotypies, reduced social interaction and memory deficits were also observed. These behavioral effects of the mutation were evident in both sexes, being more marked and varied in homozygous than heterozygous females. These findings provide novel evidence for the autistic-relevant behavioral profile of the <i>Cdkl5</i> mouse model, thus supporting its use in future preclinical studies investigating CDD pathology and autism spectrum disorders.</p>","PeriodicalId":131,"journal":{"name":"Autism Research","volume":"17 9","pages":"1742-1759"},"PeriodicalIF":5.3,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/aur.3226","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Parent-mediated, naturalistic developmental behavioral interventions (NDBIs) are a promising approach for supporting social communication development in young autistic children. This study examined the effect of telehealth delivery of a parent-mediated NDBI, Project ImPACT, on children's expressive language ability using a randomized control trial with intent-to-treat analysis. Sixty-four young autistic children and their primary caregiver were matched on age and developmental quotient and randomly assigned to receive 6 months of therapist-assisted Project ImPACT (i.e., telehealth coaching), self-directed Project ImPACT, or an active control. Parent–child interactions were recorded at intake and immediately post-treatment, and the children's expressive language skills were assessed at intake and a 9-month follow-up using standardized measures. Although there was no total effect of treatment group assignment on child outcomes, a serial mediation analysis revealed that therapist-assisted ImPACT had an indirect effect on children's expressive language ability at follow-up through their parents' use of the intervention strategies and their intentional communication immediately post-treatment. Findings support Project ImPACT's program theory and highlight the importance of coaching in achieving positive outcomes when delivered via telehealth.
{"title":"Telehealth coaching in Project ImPACT indirectly affects children's expressive language ability through parent intervention strategy use and child intentional communication: An RCT","authors":"Brooke Ingersoll, Kyle M. Frost, Diondra Straiton, Anamiguel Pomales Ramos, Karis Casagrande","doi":"10.1002/aur.3230","DOIUrl":"10.1002/aur.3230","url":null,"abstract":"<p>Parent-mediated, naturalistic developmental behavioral interventions (NDBIs) are a promising approach for supporting social communication development in young autistic children. This study examined the effect of telehealth delivery of a parent-mediated NDBI, Project ImPACT, on children's expressive language ability using a randomized control trial with intent-to-treat analysis. Sixty-four young autistic children and their primary caregiver were matched on age and developmental quotient and randomly assigned to receive 6 months of therapist-assisted Project ImPACT (i.e., telehealth coaching), self-directed Project ImPACT, or an active control. Parent–child interactions were recorded at intake and immediately post-treatment, and the children's expressive language skills were assessed at intake and a 9-month follow-up using standardized measures. Although there was no total effect of treatment group assignment on child outcomes, a serial mediation analysis revealed that therapist-assisted ImPACT had an indirect effect on children's expressive language ability at follow-up through their parents' use of the intervention strategies and their intentional communication immediately post-treatment. Findings support Project ImPACT's program theory and highlight the importance of coaching in achieving positive outcomes when delivered via telehealth.</p>","PeriodicalId":131,"journal":{"name":"Autism Research","volume":"17 10","pages":"2177-2187"},"PeriodicalIF":5.3,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/aur.3230","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study aims to assess the prevalence of Autism Spectrum Disorder (ASD) and its treatment. The study population was children aged 3–17 years with information on current ASD from National Survey of Children's Health, 2016–2022. Analysis of treatment was also conducted within the population of children with a current ASD diagnosis. A multivariate log-binomial regression model was used to assess the change of current ASD prevalence and ASD treatment by two study period (prior to COVID-19 pandemic: 2016–2019; during COVID-19 pandemic: 2020–22) and sociodemographic information. Compared to the current ASD at 2.5% in 2016, it increased to 3.6% in 2022. The treatment has decreased from 70.5% in 2016 to 61.6% in 2022 for any treatment and from 27.2% in 2016 to 20.4% in 2022 for medication treatment. Compared to children from 2016–2019, children from the following group were more likely to have ASD diagnosis during the pandemic (2020–2022), including those aged 3–5 years (aPR = 1.66, 95%CI 1.29–2.13), non-Hispanic white children, children from family with above national family income, and those with private insurance. However, medication treatment almost halved during the pandemic for non-Hispanic black children (aPR = 0.49, 95%CI 0.26–0.93) and children born overseas. In conclusion, higher prevalence of ASD might indicate a better awareness of ASD. The reduction in treatment correlates to the health service disruption caused by the pandemic, highlighting the needs of policy efforts to improve treatment for ASD.
{"title":"Prevalence and treatment of autism spectrum disorder in the United States, 2016–2022","authors":"Chenxi Li, Wen-Qiang He","doi":"10.1002/aur.3228","DOIUrl":"10.1002/aur.3228","url":null,"abstract":"<p>This study aims to assess the prevalence of Autism Spectrum Disorder (ASD) and its treatment. The study population was children aged 3–17 years with information on current ASD from National Survey of Children's Health, 2016–2022. Analysis of treatment was also conducted within the population of children with a current ASD diagnosis. A multivariate log-binomial regression model was used to assess the change of current ASD prevalence and ASD treatment by two study period (prior to COVID-19 pandemic: 2016–2019; during COVID-19 pandemic: 2020–22) and sociodemographic information. Compared to the current ASD at 2.5% in 2016, it increased to 3.6% in 2022. The treatment has decreased from 70.5% in 2016 to 61.6% in 2022 for any treatment and from 27.2% in 2016 to 20.4% in 2022 for medication treatment. Compared to children from 2016–2019, children from the following group were more likely to have ASD diagnosis during the pandemic (2020–2022), including those aged 3–5 years (aPR = 1.66, 95%CI 1.29–2.13), non-Hispanic white children, children from family with above national family income, and those with private insurance. However, medication treatment almost halved during the pandemic for non-Hispanic black children (aPR = 0.49, 95%CI 0.26–0.93) and children born overseas. In conclusion, higher prevalence of ASD might indicate a better awareness of ASD. The reduction in treatment correlates to the health service disruption caused by the pandemic, highlighting the needs of policy efforts to improve treatment for ASD.</p>","PeriodicalId":131,"journal":{"name":"Autism Research","volume":"17 9","pages":"1916-1927"},"PeriodicalIF":5.3,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/aur.3228","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}