1. de Carvalho LM, Carvalho VMA, Camargo AP, Papes F. Gene network analysis identifies dysregulated pathways in an autism spectrum disorder caused by mutations in Transcription Factor 4. Sci Rep;2025 (Feb 10);15(1):4993.

Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental monogenic disorder in the autistic spectrum caused by mutations in the Transcription Factor 4 gene. Even though the genetic etiology is known, the molecular mechanisms underlying PTHS remain poorly understood. To gain insight into the disease’s pathophysiology, we set out to identify genes and pathways putatively involved in the pathology through co-expression and gene hub analyses using transcriptomic data from neural progenitor cells, neurons, and brain organoids derived from PTHS patients. Our results revealed several groups of co-expressed genes that are differentially regulated in PTHS neural cells compared to controls. These groups were enriched for genes involved in neural development and function, including synaptic transmission, membrane excitability, and cell adhesion. We identified several hub genes (highly connected nodes within gene networks that are central in these modules), including some that encode proteins involved in histone modification, synaptic vesicle trafficking, and cell signaling. Furthermore, we found that the differential expression of hub genes in PTHS neural cells was associated with altered cellular processes linked to neurodevelopment, such as cell-cell communication and irregular synaptic networks. Notably, we identified a set of hub genes related to the histone gene family, which is associated with neuronal differentiation and may contribute to PTHS pathogenesis and potentially serve as a biomarker for disease prognosis. Our results support the notion that PTHS involves alterations in neural development and function, particularly in excitatory neurons. The groups of co-expressed genes and hub genes we identified provide new insights into the molecular mechanisms underlying PTHS pathogenesis and could potentially be targeted for therapeutic intervention.

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2. Du Y, Wang C, Zou B, Xia Y. Personalizing AI tools for second language speaking: the role of gender and autistic traits. Front Psychiatry;2024;15:1464575.

INTRODUCTION: It is important to consider individual differences in research on educational technology. This study investigates the interplay between autistic traits, gender, and the perception of artificial intelligence (AI) tools designed for second language (L2) speaking practice, contributing to a deeper understanding of inclusive educational technology. METHODS: A sample of 111 university students completed the Broad Autism Phenotype Questionnaire (BAPQ) to measure autistic traits (AU) and their sub-traits Aloof (AF), Rigid (RD), and Pragmatic Language (PL). Perceptions of AI tools were assessed across five dimensions: Perceived Usefulness (PU), Perceived Ease of Use (PEOU), Attitude (AT), Behavioral Intention (BI), and Usage Behavior (UB). The study utilized correlation and regression analyses to examine relationships between these variables, while exploring gender-specific moderating effects. RESULTS: Key findings revealed no significant gender differences in autistic traits or overall perceptions of AI tools. Contrary to expectations, autistic traits were negatively correlated with perceptions of AI tools, suggesting that current AI designs may not adequately support individuals with pronounced autistic traits. Additionally, gender moderated some relationships, with males displaying stronger associations between autistic traits and both PEOU and UB. DISCUSSION: This research bridges critical gaps by linking neurodiversity and gender to technology acceptance, advancing the field’s understanding of individual differences in AI-based language learning. It underscores the importance of designing personalized and adaptive educational tools that address diverse learner needs, promoting inclusivity and effectiveness in L2 practice.

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3. Hao Y, Banker S, Trayvick J, Barkley S, Peters AW, Thinakaran A, McLaughlin C, Gu X, Schiller D, Foss-Feig J. Understanding depression in autism: the role of subjective perception and anterior cingulate cortex volume. Mol Autism;2025 (Feb 10);16(1):9.

BACKGROUND: The prevalence of depression is elevated in individuals with autism spectrum disorder (ASD) compared to the general population, yet the reasons for this disparity remain unclear. While social deficits central to ASD may contribute to depression, it is uncertain whether social interaction behavior themselves or individuals’ introspection about their social behaviors are more impactful. Although the anterior cingulate cortex (ACC) is frequently implicated in ASD, depression, and social functioning, it is unknown if it explains differences between ASD adults with and without co-occurring depression. METHODS: The present study contrasted observed vs. subjective perception of autism symptoms and social interaction assessed with both standardized measures and a lab task, in 65 sex-balanced (52.24% male) autistic young adults. We also quantified ACC and amygdala volume with 7-Tesla structural neuroimaging to examine correlations with self-reported depression and social functioning. RESULTS: We found that ASD individuals with self-reported depression exhibited differences in subjective evaluations including heightened self-awareness of ASD symptoms, lower subjective satisfaction with social relations, and less perceived affiliation during the social interaction task, yet no differences in corresponding observed measures, compared to those without depression. Larger ACC volume was related to depression, greater self-awareness of ASD symptoms, and worse subjective satisfaction with social relations. In contrast, amygdala volume, despite its association with clinician-rated ASD symptoms, was not related to depression. LIMITATIONS: Due to the cross-sectional nature of our study, we cannot determine the directionality of the observed relationships. Additionally, we included only individuals with an IQ over 60 to ensure participants could complete the social task. We also utilized self-reported depression indices instead of clinically diagnosed depression, which may limit the comprehensiveness of the findings. CONCLUSIONS: Our approach highlights the unique role of subjective perception of autism symptoms and social interactions, beyond the observable manifestation of social impairment in ASD, in contributing to self-reported depression, with the ACC playing a crucial role. These findings imply possible heterogeneity of ASD concerning co-occurring depression. Using neuroimaging, we were able to demarcate depressive phenotypes co-occurring alongside autistic phenotypes.

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4. Hayward BE, Kim GY, Miller CJ, McCann C, Lowery MG, Wood RD, Usdin K. Repeat expansion in a fragile X model is independent of double strand break repair mediated by Pol θ, RAD52, RAD54 or RAD54B. Sci Rep;2025 (Feb 11);15(1):5033.

Microsatellite instability is responsible for the human repeat expansion diseases (REDs). The mutagenic process differs from classical cancer-associated microsatellite instability (MSI) in that it requires the mismatch repair proteins that normally protect against MSI. LIG4, an enzyme essential for non-homologous end-joining (NHEJ), the major pathway for double-strand break repair (DSBR) in mammalian cells, protects against expansion in mouse models. Thus, NHEJ may compete with the expansion pathway for access to a common intermediate. This raises the possibility that expansion involves an NHEJ-independent form of DSBR. Pol θ, a polymerase involved in the theta-mediated end joining (TMEJ) DSBR pathway, has been proposed to play a role in repeat expansion. Here we examine the effect of the loss of Pol θ on expansion in FXD mouse embryonic stem cells (mESCs), along with the effects of mutations in Rad52, Rad54l and Rad54b, genes important for multiple DSBR pathways. None of these mutations significantly affected repeat expansion. These observations put major constraints on what pathways are likely to drive expansion. Together with our previous demonstration of the protective effect of nucleases like EXO1 and FAN1, and the importance of Pol β, they suggest a plausible model for late steps in the expansion process.

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5. Hendry A, Bedford R, Agyapong M, Begum Ali J, Bazelmans T, Ersoy M, Goodwin A, Mason L, Narvekar N, Pasco G, Johnson MH, Jones EJH, Charman T. Simple Executive Function as an endophenotype of autism-ADHD, and differing associations between simple versus complex Executive Functions and autism/ADHD traits. Sci Rep;2025 (Feb 10);15(1):4925.

Autism and ADHD are associated with difficulties with Executive Functions (EFs), but the prevalence and nature of these difficulties in early development is not well understood. In this longitudinal study, 107 children with a family history of autism and/or ADHD (FH-autism/ADHD), and 24 children with No-FH-autism/ADHD completed multiple EF tasks (5 at age 2 years, 7 at age 3 years). Parents reported on their child’s autism- (Q-CHAT at age 2, SRS-2 at age 3), and ADHD-related traits (CBCL DSM-ADHD scale, both ages). Compared to the No-FH-autism/ADHD group, the FH-autism/ADHD group showed lower scores on simple EFs (involving response inhibition, and holding in mind) at ages 2 and 3. Exploratory analysis linked FH-autism specifically with lower Executive Attention (top-down attentional control) at age 2, and the combination of FH-autism and FH-ADHD with lower Complex EF (involving selectively deploying responses, or updating information) at age 3. Three-year-olds’ Simple EF scores were negatively associated with ADHD-related traits. Complex EF scores were negatively associated with autism traits (before correcting for multiple comparisons). Toddlers with a family history of autism and/or ADHD may benefit from interventions to support simple EF development, whilst those already showing autistic traits may benefit from support with more-complex EF skills.

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6. Ibrahim AT, Lee V, Vashi N, Roudbarani F, Tablon Modica P, Pouyandeh A, Sellitto T, Ameis SH, Elkader A, Gray KM, Kerns CM, Lai MC, Lake J, Thomson K, Weiss JA. Parent Outcomes Following Participation in Cognitive Behavior Therapy for Autistic Children in a Community Setting: Parent Mental Health, Mindful Parenting, and Parenting Practices. Autism Res;2025 (Feb 11)

Parents of autistic children are at a higher risk for mental health problems, including anxiety, depression, and stress. Cognitive behavior therapy (CBT) that targets children’s emotion regulation may have an indirect influence on parent outcomes, especially if they play a supporting role in their child’s intervention. However, most CBT interventions have been carried out in highly controlled research settings and there are a few studies that examined parental outcomes after participating in autistic child-focused CBT within a community setting. The current study examined parent outcomes (i.e., mental health problems, mindful parenting, and parenting practices) following a community-based CBT program with concurrent parent involvement for autistic children, as well as associations between changes in parent and child outcomes (i.e., autism symptoms and emotion dysregulation). Participants included 77 parent-child dyads across seven community organizations in Ontario, Canada. Parents reported improved mindful parenting and positive parenting practices post-intervention, and no significant changes in their mental health. Multiple mediation analyses revealed that positive changes in parent outcomes (i.e., mindful parenting and parenting practices) were associated with positive changes in child emotion regulation. These positive changes in parenting practices mediated the relationship between mindful parenting and child emotion regulation. Results suggest that participating in community-based CBT is mutually beneficial for autistic children and their parents, particularly in improving parenting behaviors.

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7. Matsuda S, Hattori Y, Kimura H. Drug discovery strategy for TAK-418, a specific inhibitor of LSD1 enzyme activity, as a novel therapy for autism. Adv Pharmacol;2025;102:267-300.

The pathophysiology of neurodevelopmental disorders is associated with multiple genetic and environmental risk factors. Epigenetics, owing to its potential to recover global gene expression changes associated with disease conditions, is a crucial target to address neurodevelopmental disorders influenced by genetic and environmental factors. Here, we discuss the discovery of selective inhibitors of lysine-specific demethylase 1 (LSD1) enzyme activity and their therapeutic potential for neurodevelopmental disorders through epigenetic regulation in the brain. Conventional LSD1 inhibitors not only inhibit LSD1 enzymatic activity but also interfere with LSD1-cofactor complex formation, thus leading to hematological side effects. Notably, investigations on the structure-activity relationship have revealed (aminocyclopropyl)benzamide and (aminocyclopropyl)thiophene carboxamide derivatives as novel series of LSD1 inhibitors with fewer hematological side effects. Subsequently, we discovered T-448 and TAK-418 (clinical candidate) that selectively and potently inhibit LSD1 enzymatic activity without disrupting the LSD1-cofactor complex, resulting in potent epigenetic modulation without significant hematological toxicity risks in rodents. T-448 and TAK-418, at doses that achieved almost complete LSD1 occupancy in the brain, improved behavioral abnormalities in multiple rodent models of neurodevelopmental disorders. Furthermore, comprehensive RNA expression analyses revealed that, although gene expression abnormalities exhibited limited commonality across disease models, TAK-418 normalized each aberrant gene expression pattern in these rodent models. A positron emission tomography tracer was discovered to potentially measure the occupancy of TAK-418 at the LSD1 active site in the brain to improve the translatability of its preclinical efficacy to therapeutic effects in humans. TAK-418-type LSD1 inhibitors may offer novel treatment options for neurodevelopmental disorders.

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8. McLellan J, Iosif AM, Cichewicz K, Canales C, Rahbarian D, Corea M, Bauman M, Nord AS, Van de Water J. Gestational autoantibody exposure impacts early brain development in a rat model of MAR autism. Mol Psychiatry;2025 (Feb 10)

Maternal autoantibody-related autism (MARA) is a subtype of autism characterized by the maternal production of specific patterns of autoantibodies during pregnancy, which significantly increases the likelihood of an autism diagnosis in their children. Multiple patterns of MARA autoantibodies (MARA-ABS) have been identified, and differences in the severity of the autism phenotype associated with each autoantibody pattern have been described. In this study, we utilized preclinical rat models to further elucidate the differential effects of MARA-AB exposure based on the known clinical patterns, including the originally reported pattern of lactate dehydrogenase A and B (LDHA/B) + collapsin response mediator protein 1 (CRMP1) + stress-induced phosphoprotein 1 (STIP1), as well as the more recently described patterns of CRMP1+CRMP2, CRMP1 + guanine deaminase (GDA), and STIP1+ neuron-specific enolase (NSE). We induced endogenous MARA-AB production in rat dams before pregnancy to expose offspring to the ABs throughout gestation. We found that in postnatal day 2 offspring exposed to MARA-ABS, the levels of brain and serum cytokines/chemokines/growth factors were altered based on the pattern of MARA-AB exposure. Further, bulk transcriptomic profiles of coronal sections containing hippocampal formation and the adjacent cortical and subcortical structures suggested changes in cellular proliferation and differentiation following MARA exposure. These combined observations demonstrate that gestational exposure to MARA-ABS alters early gene expression and immune signaling molecules, both of which may contribute to the altered neurodevelopment and behaviors associated with MARA.

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9. Miao H, Zhang C, Qian J, Jing H, Nan H, Li S, Shen X, Zhao J. Association between maternal smoking during pregnancy and developmental disabilities in US children and adolescents: A cross-sectional study from NHANES. Tob Induc Dis;2025;23

INTRODUCTION: Maternal smoking during pregnancy is associated with placental DNA methylation and RNA expression, offspring DNA methylation, and affects the decline of mature neurons and the prenatal human brain development trajectory. METHODS: This study is a secondary analysis of data from the National Health and Nutrition Examination Survey (NHANES) spanning 2003 to 2008, comprising 10111 children and adolescents. Inclusion criteria required participants to have complete questionnaire responses regarding maternal smoking during pregnancy and receipt of special education or early intervention services. The risk of developmental disabilities was assessed using a multifactor logistic regression model. RESULTS: In the cohort of 10111 children and adolescents, 727 (7.2%) received special education or early intervention services. Of these participants, 1504 (14.9%) were exposed to maternal smoking during pregnancy. The prevalence of maternal smoking was higher (12.3%) in the group receiving special education or early intervention compared to those who did not (6.3%). After adjusting for other relevant factors in a multifactorial logistic regression model, maternal smoking during pregnancy was significantly associated with an increased likelihood of requiring special education or early intervention services (adjusted odds ratio, AOR=1.51; 95% CI: 1.24-1.83, p<0.001). CONCLUSIONS: This cross-sectional analysis found an association between maternal smoking during pregnancy and the need for special education or early intervention services among US children and adolescents, after adjusting for confounding variables. Our findings suggest that maternal smoking during pregnancy may increase the odds of developmental disabilities.

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10. Mirzaei V, Wolstencroft J, Lockwood Estrin G, Buckley E, Sayani S, Katakis P, Anand R, Squire T, Short E, Frankson P, Skuse D, Heys M. Novel Procedures for Evaluating Autism Online in a Culturally Diverse Population of Children: Protocol for a Mixed Methods Pathway Development Study. JMIR Res Protoc;2025 (Feb 11);14:e55741.

BACKGROUND: Current autism assessment procedures are costly and resource-intensive. The COVID-19 pandemic accelerated the adoption of telemedicine, highlighting the benefits of innovative diagnostic tools. Telemedicine-based pathways could enhance accessibility and equity in autism diagnostics. OBJECTIVE: The Children with Autism Technology Enabled Assessment (CHATA) project aims to develop and pilot an open-source autism diagnostic pathway for children up to 5 years old, delivered through telemedicine. The pathway is designed to be culturally and linguistically adaptable, increasing its applicability to diverse populations and integrating with existing National Health Service digital systems. METHODS: Initial pathway development was informed by systematic evidence reviews, coproduction, and mixed methods usability. CHATA comprises 2 key elements: online self-completed standardized autism questionnaires and a structured online interview and observation by a trained clinician. Out of 60 families near the top of the local waiting list will be invited to participate in the pilot evaluation, assessed using both the CHATA and usual assessment pathways. Sensitivity and specificity will be calculated by comparing the diagnosis of autism through CHATA with usual care. Quantitative usability assessment will be gathered from all families using the System Usability Scale (where a mean above 68 indicates above-average usability). A subset of CHATA assessments will be reviewed for interrater reliability (measured by the Cohen κ for categorical data [diagnosis present or absent], with values indicating the level of agreement; eg, <0 indicating no agreement, 0.61-0.80 indicating substantial agreement). Qualitative data on acceptability, feasibility, and usability will be gathered from semistructured interviews with a subset of families and health care providers. We will recruit 60 families for the main pilot study (including the usability testing) and 10-15 participants for the qualitative substudy. Data will estimate CHATA's diagnostic accuracy, validity, reliability, usability, and acceptability. Patient and public involvement will be integral throughout. The study will take place in a socio-economically deprived, ethnically diverse inner-London Borough within a community-based child health National health service responsible for the Autism assessment of children and young people up to the age of 13 years. RESULTS: Ethics approval was received in June 2023 (Research Ethics Committee reference 22/LO/0751; IRAS project ID 320499). Data collection commenced in April 2023 and completed in October 2024. Project end date is March 2025. As of November 2024, we had enrolled 57 participants to the pilot study and 12 to the qualitative substudy. CONCLUSIONS: The CHATA project aims to establish a novel, culturally sensitive, equitable, and accurate online autism assessment pathway. By addressing geographical and linguistic barriers, this pathway seeks to reduce service costs, shorten waiting times, and promote equity in autism diagnosis. The procedures developed are expected to be generalized to other populations nationwide. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55741.

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11. Norris LA, Rabner JC, Marklin M, Crane ME, Renschler K, Jenkins E, Kemp J, Storch EA, Wood JJ, Kerns CM, Lewin AB, Small BJ, Kendall PC. Caregiver Satisfaction with Anxiety Treatment for Autistic Youth: A Mixed Methods Examination. J Autism Dev Disord;2025 (Feb 10)

For Cognitive Behavioral Therapy to best meet the specific needs of autistic youth with co-occurring anxiety and to continue to grow as a sustainable treatment option, it is important to incorporate caregiver perspectives and feedback. Data were drawn from a randomized controlled trial and included 148 caregivers of autistic youth (ages 7-13 years, M = 9.89, SD = 1.79; 23% female; 77.7% White) with co-occurring anxiety disorders randomized to one of two active treatment conditions (Coping Cat, n = 72, or Behavioral Interventions for Anxiety in Children with Autism [BIACA], n = 76). A systematic inductive thematic analysis was used to code open-ended parent responses on the Consumer Satisfaction Questionnaire to identify what caregivers of autistic children with co-occurring anxiety liked most and least about their child’s treatment. Satisfaction with treatment was high (M = 64.98, SD = 5.48). Caregivers’ most-liked treatment features across treatments included (a) tools and coping skills, (b) therapeutic alliance, (c) caregiver support and involvement, (d) personalized treatment, and (e) treatment efficacy. Least-liked features of treatment and family participation included (a) the commute to the clinic, (b) treatment length, (c) commitment required at home, (d) questionnaires, and (e) scheduling. Treatment responders endorsed therapeutic alliance more frequently. Caregivers in BIACA endorsed caregiver support and involvement at higher rates, in addition to commitment required at home. Caregiver responses indicated a preference for more sessions and highlighted the importance of balancing need for caregiver involvement in treatment while reducing caregiver burden.

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12. Oppenheim D, Dolev S, Hamburger L, Lottan R, Kunst S, Friedelman J, Mottes-Peleg M, Yirmiya N. The Association Between Classroom Quality and the Social Competence of Autistic Preschool-Age Boys. J Autism Dev Disord;2025 (Feb 11)

Research on the impact of the classroom environment on neurotypical children has demonstrated that higher classroom quality contributes to children’s development, but whether this is also true with regard to autistic preschoolers has not been examined. Therefore, the goal of this study was to address this gap hypothesizing that higher classroom quality would be associated with higher child social competence both in and outside the classroom. The quality of the classrooms of 43 autistic preschooler boys was assessed by observation, and children’s social competence in preschool was assessed by observation and teacher-report, and outside preschool by observing children’s interactions with an unfamiliar adult. Controlling for the severity of the boys’ symptoms, results revealed that higher classroom emotional support and organization was associated with higher child social competence as observed and reported by teachers in preschool, and with the boys’ involvement with of an unfamiliar adult during play. The quality of the classroom environment was associated with the social skills of autistic boys.

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13. Qing L, Qian X, Zhu H, Wang J, Sun J, Jin Z, Tang X, Zhao Y, Wang G, Zhao J, Chen W, Tian P. Maternal-infant probiotic transmission mitigates early-life stress-induced autism in mice. Gut Microbes;2025 (Dec);17(1):2456584.

Autism, a disorder influenced by both genetic and environmental factors, presents significant challenges for prevention and treatment. While maternal-infant gut microbiota has been a focus in autism research, preventive strategies targeting maternal gut microbiota remain underexplored. This study demonstrates that prenatal probiotic intake can effectively prevent maternal separation-induced autistic-like behaviors in offspring without altering the embryonic neurodevelopment in mice. Using specific PCR primers and cross-fostering experiments, we traced the vertical transmission of probiotics, primarily via fecal/vaginal contamination. Early probiotic colonization conferred resilience against stress-induced gut pathogenic microbes and Th17-mediated peripheral inflammation while significantly inhibiting hypermyelination and neuroinflammation linked to systemic inflammation. Microbial metabolites like tyrosol and xanthurenic acid alleviated neuroinflammation and hypermyelination in vitro, though the causal relationship among neuroinflammation, hypermyelination, and autism in vivo requires further validation. These findings underscore the importance of the maternal-infant microbiota transmission window in autism prevention and highlight the clinical potential of prenatal probiotic interventions.

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14. Wei X, Jiawei Z, Maoyuan N, Weiyong Y, Zhenbo C, Hongwei B, Jianjun L, Qi L, Xinyu D, Jiaerheng B, Qiang W, Hao Z. Efficacy and Safety of Propofol as a Sole Sedative for fMRI Sedation in Autism Spectrum Disorder Individuals with Low IQ. J Autism Dev Disord;2025 (Feb 11)

Autism spectrum disorder (ASD) is a group of complicated neurodevelopmental disorders. Functional magnetic resonance imaging (fMRI) can help to analyze the aberrant neurological functioning in ASD. However, due to their limited cognitive abilities, ASD individuals with low IQ may face challenges in cooperating during fMRI scanning. Consequently, sedation becomes necessary for them. To analyze and evaluate the sedative efficacy and safety of a single intravenous propofol sedation regimen for ASD individuals with low IQ undergoing fMRI examination. Seventy-seven ASD individuals with low IQ, aged 4 to 23 years, who underwent fMRI examination under propofol sedation, were included. Details of the sedation protocol, evaluation indices for effectiveness such as framewise displacement (FD) and temporal signal-to-noise ratio (tSNR), as well as safety assessment measures including pulse oxygen saturation (S(P)O2) and blood pressure were collected. Adverse events were also recorded. Data analysis was conducted upon completion of the study. Body movement was observed in 12 patients. The median and quartiles (25th percentile, 75th percentile) of FD was 0.065 (0.057, 0.086) mm, while the tSNR averaged at 89.6 ± 11.4. The image data from sixty-two cases (80.5%) were classified as high quality based on their tSNR surpassing 80. No serious adverse events, such as oxygen desaturation, hypotension, nausea, or vomiting, occurred that necessitated hospitalization. The exclusive propofol intravenous sedation protocol employed in this study demonstrates efficacy and safety for administering fMRI examinations to ASD individuals with low IQ, thereby warranting further investigation and validation towards its adoption in clinical practice.

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15. Yu X, Rahman MM, Lin JC, Chow T, Lurmann FW, Chen JC, Martinez MP, Schwartz J, Eckel SP, Chen Z, McConnell R, Hackman DA, Xiang AH, Garcia E. The potential effects of hypothetical PM2.5 interventions on childhood autism in different neighborhood socioeconomic contexts. Am J Epidemiol;2025 (Feb 11)

Particulate air pollution is associated with autism spectrum disorder (ASD), with disadvantaged neighborhoods potentially increasing vulnerability due to stress or other social determinants of health. Understanding the impact of air pollution interventions on ASD incidence across neighborhood disadvantage levels can guide policies to protect vulnerable populations. We examined two sets of hypothetical PM2.5 interventions: percentage reduction and regulatory standards as thresholds, to assess their potential effects on ASD cumulative incidence. Using G-computation under a counterfactual framework, we estimated changes in the cumulative incidence of ASD by age 5 under hypothetical interventions compared to observed exposures. Our study involved a birth cohort of 318,298 children born between 2001-2014 in Southern California, with 4,548 diagnosed with ASD by age 5. Pregnancy average PM2.5 and neighborhood disadvantage were assigned to residential addresses. Adjusted Cox regression models were applied to estimate ASD cumulative incidence. Reducing pregnancy average PM2.5 by 30% or below 9 μg/m3 would have prevented 10.6 (95% CI, 3.6-19.2) and 12.5 (2.7-23.6) ASD cases per 10,000 children, respectively. The decreases in ASD cumulative incidence under hypothetical interventions were similar across neighborhood disadvantage levels. These findings suggest that reducing ambient PM2.5 levels to meet or surpass current standards could help prevent ASD.

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16. Yurumez E, Cikili-Uytun M, Kaymak B, Dogan O, Ozturk HH, Baysar-Kanoglu BN, Oztop DB. Neurodegeneration in Autism: A Study of Clusterin, Very Long-Chain Fatty Acids, and Carnitine. J Mol Neurosci;2025 (Feb 11);75(1):18.

The clinical identification of regression phenomena in ASD lacks specific biological or laboratory criteria and is often based on family history and highly subjective observations by clinicians. The present study aimed to investigate the potential role of plasma clusterin (CLU), very long-chain fatty acids (VLCFA), and carnitine as biomarkers of neurodegeneration in children with autism spectrum disorder (ASD) with and without regression. By exploring these biomarkers, we sought to provide insights into mitochondrial dysfunction, glial activation, and lipid metabolism, which may contribute to the pathophysiology of ASD and aid in the early diagnosis and intervention of regression phenomena in ASD. Ninety children aged 2-6 years were included: 30 with autism spectrum disorder (ASD), 30 with regressive ASD, and 30 healthy controls. Psychiatric assessments were conducted using DSM-5 criteria, CARS, ABC, RBS-R, and ASSQ scales. Regression in ASD was evaluated retrospectively using a modified ADI-R questionnaire. Fasting blood samples were collected, and plasma clusterin (CLU), VLCFA, and carnitine levels were measured. Statistical analyses were performed using MANOVA to assess the effect of group differences on dependent biochemical variables. Serum clusterin and carnitine levels showed no significant differences between groups. However, C22 VLCFA levels were significantly higher in both autism groups compared to controls (p = 0.04), with post hoc analysis indicating the difference between the non-regressive and control groups (p = 0.02). Serum carnitine was positively correlated with stereotypic behaviors subscale scores (r = 0.37, p = 0.004) and total scores (r = 0.35, p = 0.006) of RBS-R. Our study provides insights into the complexities of biomarker research in autism spectrum disorder (ASD), highlighting the challenges in identifying consistent biological markers for regression and non-regression phenotypes. Although no significant findings were observed, further biomarker studies are essential to distinguish possible endophenotypes, improve early diagnosis, and uncover potential therapeutic targets in ASD.

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