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Dysregulated plasma autoantibodies are associated with B cell dysfunction in young Arab children with autism spectrum disorder in Qatar 卡塔尔患有自闭症谱系障碍的阿拉伯幼儿血浆自身抗体失调与 B 细胞功能障碍有关。
IF 5.3 2区 医学 Q1 BEHAVIORAL SCIENCES Pub Date : 2024-09-24 DOI: 10.1002/aur.3235
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
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引用次数: 0
Sleep disturbance and other co-occurring conditions in autistic children: A network approach to understanding their inter-relationships 自闭症儿童的睡眠障碍和其他并发症:通过网络了解它们之间的相互关系。
IF 5.3 2区 医学 Q1 BEHAVIORAL SCIENCES Pub Date : 2024-09-20 DOI: 10.1002/aur.3233
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.

自闭症儿童经常同时患有一种或多种心理、行为或医疗疾病。我们利用网络分析法研究了自闭症儿童的儿童行为、睡眠、适应行为、自闭症特征、心理健康状况和健康之间的关系。网络分析是一种假设生成方法,可以帮助我们了解多种病症和行为之间的关系,指导开发针对共存病症的跨诊断治疗方法。研究对象是自闭症治疗网络登记处的两组儿童:2-5 岁(n = 2372)和 6-17 岁(n = 1553)。对 2-5 岁队列(35 个项目)和 6-17 岁队列(36 个项目)进行了最小绝对收缩和选择算子(LASSO)正则化偏相关网络分析。Spinglass 算法确定了每个网络中的群落。两步预期影响(EI2)确定了网络变量的重要性。对幼儿影响最大的网络项目是睡眠困难(2 个项目)和攻击行为,对年长儿童影响最大的网络项目是攻击行为、社交问题和焦虑/抑郁行为。年幼儿童有五个社区,年长儿童有七个社区。在前三个最重要的桥梁变量中,夜醒/parasomnias 和焦虑/抑郁行为在两个年龄组中都存在,而躯体不适和睡眠开始/持续时间则分别在年幼组和年长组中存在。尽管各年龄组之间存在差异,但睡眠障碍在所有网络中都很突出,这表明睡眠障碍是许多临床疾病的一个跨诊断特征,因此也是干预和监测的目标。攻击性行为在部分相关网络中很有影响力,表明这是临床监测的一个潜在信号。其他具有较强网络重要性的项目也可能是干预目标或筛查标志。
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引用次数: 0
3-generation family histories of mental, neurologic, cardiometabolic, birth defect, asthma, allergy, and autoimmune conditions associated with autism: An open-source catalog of findings 与自闭症相关的精神、神经、心脏代谢、先天缺陷、哮喘、过敏和自身免疫疾病的三代家族史:研究结果的开源目录。
IF 5.3 2区 医学 Q1 BEHAVIORAL SCIENCES Pub Date : 2024-09-16 DOI: 10.1002/aur.3232
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.

自闭症谱系障碍(ASD,或自闭症)家族健康史调查中考虑的疾病和家庭成员类型(如兄弟姐妹、父母)相对较少,这限制了人们对家族史在自闭症病因学中作用的理解。为了更全面地理解和提出假设,我们制作了一份自闭症与精神、神经、心脏代谢、出生缺陷、哮喘、过敏和自身免疫性疾病家族史相关性的开源目录。对 1980-2012 年丹麦所有活产婴儿(1,697,231 名出生婴儿)及其三代家庭成员的 90 种诊断(包括自闭症)、移民或死亡病史进行了跟踪调查,直至 2017 年 4 月 10 日。我们通过 Cox 回归估算了每种诊断-家庭成员类型组合的调整危险比(aHR),并对出生年份、性别、出生体重、胎龄、父母出生时的年龄以及指标人物的家庭成员类型数量进行了调整;还计算了每种疾病的性别特异性共存危险比。我们获得了 6462 个自闭症患者(26840 名自闭症患者,占出生人口的 1.6%)的个体家族史 aHRS,按性别分列,并考虑了智力残疾(ID);还获得了 350 个共患病 aHRS。研究结果以交互式热图和可下载的数据文件形式编目:https://ncrr-au.shinyapps.io/asd-riskatlas/,交互式图表摘要:https://public.tableau.com/app/profile/diana.schendel/viz/ASDPlots_16918786403110/e-Figure5。虽然这些结果主要用于参考资料或其他研究(如荟萃分析),但结果显示,按疾病类型、家庭成员类型、家庭成员性别、家族旁系亲属、发病者性别和 ID 状态划分,家族健康史与自闭症相关性的广度和差异相当大,表明自闭症的遗传、家族和非遗传致病途径多种多样。在我们开放数据资源的帮助下,仔细关注家族健康史中自闭症可能性的来源,可能会加快对神经多样性潜在因素的理解。
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引用次数: 0
A longitudinal health promotion program for autistic children and their caregivers: Impact of an urban community-based program 针对自闭症儿童及其照顾者的纵向健康促进计划:城市社区计划的影响
IF 5.3 2区 医学 Q1 BEHAVIORAL SCIENCES Pub Date : 2024-09-14 DOI: 10.1002/aur.3231
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.

与普通人群相比,自闭症儿童及其主要照顾者(如父母)在健康方面的差距更大。尽管存在这种现实情况,但促进这些未得到充分服务的人群健康的积极轨迹却相对较少受到重视。本研究的主要目的是考察参与一项为期 12 个月的纵向健康促进计划对自闭症儿童及其父母的影响。共有 27 个家庭参加了干预活动,其中包括 29 名自闭症儿童(83% 为男性,平均年龄为 8.28 ± 3.60 岁)和 27 名家长(93% 为女性,平均年龄为 40.04 ± 7.95 岁)。这些家庭每周参加 90 分钟的面对面健康促进课程。儿童和家长在整个计划的四个时间点接受评估,包括基线(0 个月)、4 个月、8 个月和 12 个月。对儿童进行了基本运动能力、体能、身体成分和代理报告的体育活动等方面的测量。对家长的身体成分、体能和自我报告的体育锻炼情况进行了测量。在为期 12 个月的干预中,自闭症儿童的运动能力(p < 0.001)和握力(p = 0.006)以及家长的体重指数(p = 0.004)和有氧运动能力(p = 0.003)均有显著改善。城市家庭和郊区家庭在多项结果上的改善轨迹有所不同。从这项研究中获得的知识可以初步证明,有必要为自闭症儿童及其父母提供更多机会,开展可获得的、持续的健康促进计划。
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引用次数: 0
Profiles of nonverbal skills used by young pre-verbal children with autism on the ADOS-2: Relation to screening disposition and outcomes 自闭症儿童在 ADOS-2 中使用的非语言技能概况:与筛查倾向和结果的关系。
IF 5.3 2区 医学 Q1 BEHAVIORAL SCIENCES Pub Date : 2024-09-09 DOI: 10.1002/aur.3229
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.

自闭症患者在使用和理解非语言交流方面表现出差异;然而,个体在非语言交流方面的优势和挑战也大相径庭。这种异质性会使诊断和筛查过程复杂化,并可能导致诊断延迟或漏诊。在本研究中,我们描述了 215 名患有自闭症的前语言沟通能力儿童(年龄 = 36.27 个月,范围 = 18-70)的各种非语言沟通能力特征,并探讨了这些特征与筛查结果、诊断确定性以及发育和行为特征之间的关系。我们对自闭症诊断观察表(第二版)幼儿模块和模块 1 中评估非语言沟通技能的九个项目进行了潜类分析。根据儿童非语言沟通技能的形式、功能和频率,确定了五种非语言特征。此外,筛查结果和临床医生对自闭症诊断的确定性也因非语言特征而异。根据家长报告,使用一系列非语言技能但频率或一致性有限的儿童的假阴性筛查结果最高。另一方面,临床医生往往对具有这种特征的儿童的自闭症诊断具有较高的确定性,而对那些在非言语交流中持续融入眼神交流的儿童的诊断确定性最低。本研究发现的特征可能对临床有用,有助于识别在筛查或诊断过程中最有可能被忽视的儿童,为改善自闭症的早期识别和干预提供了机会。
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引用次数: 0
Neurophysiological effects of a combined treatment of lovastatin and minocycline in patients with fragile X syndrome: Ancillary results of the LOVAMIX randomized clinical trial 洛伐他汀和米诺环素联合疗法对脆性X综合征患者神经生理学的影响:LOVAMIX随机临床试验的辅助结果。
IF 5.3 2区 医学 Q1 BEHAVIORAL SCIENCES Pub Date : 2024-09-09 DOI: 10.1002/aur.3222
Florence Morin-Parent, Camille Champigny, Samantha Côté, Teddy Mohamad, Seyede Anis Hasani, Artuela Çaku, François Corbin, Jean-François Lepage

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).

脆性 X 综合征(FXS)是导致智力障碍和自闭症谱系障碍的主要遗传原因。它的特征是神经元兴奋性加剧,其校正被认为是动物模型治疗反应的客观衡量标准,但在临床试验中却很少使用。在此,我们使用了一种广泛的经颅磁刺激(TMS)疗法来评估两种疾病调节药物(洛伐他汀(40 毫克)和米诺环素(100 毫克))联合疗法的神经生理学效果,这两种药物分别单独使用 8 周和联合使用 12 周。TMS 测试包括静息运动阈值、短时段皮层内抑制、长时段皮层内抑制、皮质脊髓沉默期和皮层内促进,分别在单药治疗 8 周后(临床试验第 2 次)和双药治疗 12 周后(临床试验第 4 次)完成。在基线与第 2 次就诊(单一疗法)和第 3 次就诊(双重疗法)之间进行了重复测量方差分析,并对参与者开始临床试验时接受的单一疗法进行了交互作用。结果显示,双重疗法与 20 周后大脑皮层兴奋性降低有关。与基线相比,双重疗法后的静息运动阈值明显提高,这反映了这一点。与基线相比,单药治疗8周后皮质短抑制(GABAa介导的抑制标记)有增强的趋势。这些结果表明,米诺环素和洛伐他汀联合疗法可能会对 FXS 的核心神经生理病理学产生作用。该试验已在 clinicaltrials.gov (NCT02680379) 上注册。
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引用次数: 0
Sex heterogeneity of dynamic brain activity and functional connectivity in autism spectrum disorder 自闭症谱系障碍患者大脑动态活动和功能连接的性别异质性。
IF 5.3 2区 医学 Q1 BEHAVIORAL SCIENCES Pub Date : 2024-09-07 DOI: 10.1002/aur.3227
Huibin Lu, Qi Dong, Le Gao, Zaifa Xue, Xiaoxia Niu, Rongjuan Zhou, Xiaonan Guo

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。
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引用次数: 0
Autistic-relevant behavioral phenotypes of a mouse model of cyclin-dependent kinase-like 5 deficiency disorder 细胞周期蛋白依赖性激酶样 5 缺乏症小鼠模型的自闭症相关行为表型。
IF 5.3 2区 医学 Q1 BEHAVIORAL SCIENCES Pub Date : 2024-09-05 DOI: 10.1002/aur.3226
Nicola Mottolese, Oceane Coiffard, Celeste Ferraguto, Athanasios Manolis, Elisabetta Ciani, Susanna Pietropaolo

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.

细胞周期蛋白依赖性激酶样 5(CDKL5)缺乏症(CDD)是一种由 X 连锁 CDKL5 基因突变引起的神经发育疾病,以早发癫痫、智力障碍和自闭症为特征。迄今为止,CDD 的病因机制尚不清楚,也没有有效的治疗方法。Cdkl5基因敲除(KO)小鼠已被广泛用于CDD的临床前研究;Cdkl5-KO小鼠表现出的神经行为异常再现了大多数CDD症状,包括运动、感觉、认知和社交能力的改变。然而,现有的临床前研究大多是在成年 Cdkl5-KO 小鼠身上进行的,因此对这一模型在发育早期的表型特征知之甚少。此外,与自闭症相关的主要表型,例如社交和沟通障碍,也很少得到研究,而且大多是在雄性突变体中发现的。在这里,我们评估了 Cdkl5-KO 小鼠在出生后前三周和成年期的自闭症相关行为表型。我们测试了雄性和雌性小鼠,后者包括杂合子和同合子突变体。Cdkl5突变幼鼠在超声波交流方面表现出定性和定量的改变,这种改变首先在2周大时被检测到,并在成年后得到证实。在突变体3周大时和成年后,观察到焦虑样行为水平升高,同时还观察到刻板行为、社会交往减少和记忆缺陷。突变的这些行为影响在雌雄个体中都很明显,但在同卵雌性个体中比杂合子雌性个体更明显,差异也更大。这些发现为Cdkl5小鼠模型与自闭症相关的行为特征提供了新的证据,从而支持将其用于未来研究CDD病理和自闭症谱系障碍的临床前研究。
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引用次数: 0
Telehealth coaching in Project ImPACT indirectly affects children's expressive language ability through parent intervention strategy use and child intentional communication: An RCT ImPACT 项目中的远程医疗辅导通过家长干预策略的使用和儿童有意交流间接影响儿童的语言表达能力:一项 RCT 研究。
IF 5.3 2区 医学 Q1 BEHAVIORAL SCIENCES Pub Date : 2024-09-04 DOI: 10.1002/aur.3230
Brooke Ingersoll, Kyle M. Frost, Diondra Straiton, Anamiguel Pomales Ramos, Karis Casagrande

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.

以家长为中介的自然发展行为干预(NDBIs)是支持自闭症幼儿社会交流发展的一种很有前景的方法。本研究采用随机对照试验和意向治疗分析法,考察了远程医疗提供以家长为中介的 NDBI 项目 ImPACT 对儿童语言表达能力的影响。64 名患有自闭症的幼儿和他们的主要照顾者在年龄和发育商数上相匹配,并被随机分配到接受为期 6 个月的治疗师辅助型 Project ImPACT(即远程医疗辅导)、自我指导型 Project ImPACT 或积极对照组。亲子互动在接受治疗时和治疗后立即进行记录,儿童的语言表达能力则在接受治疗时和 9 个月的随访中使用标准化方法进行评估。虽然治疗组的分配对儿童的结果没有总体影响,但序列中介分析显示,治疗师辅助的 ImPACT 对儿童的语言表达能力有间接影响,这种间接影响是通过父母使用干预策略和他们在治疗后立即进行有意交流来实现的。研究结果支持 ImPACT 项目的计划理论,并强调了通过远程医疗取得积极成果时辅导的重要性。
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引用次数: 0
Prevalence and treatment of autism spectrum disorder in the United States, 2016–2022 2016-2022 年美国自闭症谱系障碍的患病率和治疗情况。
IF 5.3 2区 医学 Q1 BEHAVIORAL SCIENCES Pub Date : 2024-09-02 DOI: 10.1002/aur.3228
Chenxi Li, Wen-Qiang He

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.

本研究旨在评估自闭症谱系障碍(ASD)的患病率及其治疗情况。研究对象为 3-17 岁的儿童,其当前 ASD 的信息来自 2016-2022 年全国儿童健康调查。此外,还在当前确诊为 ASD 的儿童人群中进行了治疗分析。采用多变量对数二叉回归模型,按两个研究时段(COVID-19 流行前:2016-2019 年;COVID-19 流行期间:2020-22 年)和社会人口学信息评估当前 ASD 患病率和 ASD 治疗的变化。与目前相比,2016 年 ASD 的发病率为 2.5%,2022 年则增至 3.6%。任何治疗的比例从 2016 年的 70.5%下降到 2022 年的 61.6%,药物治疗的比例从 2016 年的 27.2%下降到 2022 年的 20.4%。与2016-2019年的儿童相比,以下群体的儿童在大流行期间(2020-2022年)更有可能被诊断为ASD,包括3-5岁的儿童(aPR = 1.66,95%CI 1.29-2.13)、非西班牙裔白人儿童、家庭收入高于全国平均水平的儿童以及有私人保险的儿童。然而,在大流行期间,非西班牙裔黑人儿童(aPR = 0.49,95%CI 0.26-0.93)和海外出生儿童的药物治疗几乎减少了一半。总之,自闭症发病率较高可能表明人们对自闭症的认识有所提高。治疗的减少与大流行病造成的医疗服务中断有关,凸显了改善 ASD 治疗的政策需求。
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引用次数: 0
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Autism Research
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