1. Alberca CD, Papale LA, Madrid A, Alisch RS. Hippocampal and peripheral blood DNA methylation signatures correlate at the gene and pathway level in a mouse model of autism. Human molecular genetics. 2023.

Autism spectrum disorders (ASD) are polygenic multifactorial disorders influenced by environmental factors. ASD-related differential DNA methylation has been found in human peripheral tissues, such as placenta, paternal sperm, buccal epithelium, and blood. However, these data lack direct comparison of DNA methylation levels with brain tissue from the same individual to determine the extent that peripheral tissues are surrogates for behavior-related disorders. Here, whole genome methylation profiling at all the possible sites throughout the mouse genome (>25 million) from both brain and blood tissues revealed novel insights into the systemic contributions of DNA methylation to ASD. Sixty-six differentially methylated regions (DMRs) share the same genomic coordinates in these two tissues, many of which are linked to risk genes for neurodevelopmental disorders and intellectual disabilities (e.g. Prkch, Ptn, Hcfc1, Mid1, and Nfia). Gene ontological pathways revealed a significant number of common terms between brain and blood (n = 65 terms), and nearly half (30/65) were associated with brain/neuronal development. Furthermore, seven DMR-associated genes among these terms contain methyl-sensitive transcription factor sequence motifs within the DMRs of both tissues; four of them (Cux2, Kcnip2, Fgf13, and Mrtfa) contain the same methyl-sensitive transcription factor binding sequence motifs (HES1/2/5, TBX2 and TFAP2C), suggesting DNA methylation influences the binding of common transcription factors required for gene expression. Together, these findings suggest that peripheral blood is a good surrogate tissue for brain and support that DNA methylation contributes to altered gene regulation in the pathogenesis of ASD.

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2. Bhandari R, Varma M, Rana P, Dhingra N, Kuhad A. Taurine as a potential therapeutic agent interacting with multiple signaling pathways implicated in autism spectrum disorder (ASD): An in-silico analysis. IBRO neuroscience reports. 2023; 15: 170-7.

Autism spectrum disorders (ASD) are a complex sequelae of neurodevelopmental disorders which manifest in the form of communication and social deficits. Currently, only two agents, namely risperidone and aripiprazole have been approved for the treatment of ASD, and there is a dearth of more drugs for the disorder. The exact pathophysiology of autism is not understood clearly, but research has implicated multiple pathways at different points in the neuronal circuitry, suggesting their role in ASD. Among these, the role played by neuroinflammatory cascades like the NF-KB and Nrf2 pathways, and the excitotoxic glutamatergic system, are said to have a bearing on the development of ASD. Similarly, the GPR40 receptor, present in both the gut and the blood brain barrier, has also been said to be involved in the disorder. Consequently, molecules which can act by interacting with one or multiple of these targets might have a potential in the therapy of the disorder, and for this reason, this study was designed to assess the binding affinity of taurine, a naturally-occurring amino acid, with these target molecules. The same was scored against these targets using in-silico docking studies, with Risperidone and Aripiprazole being used as standard comparators. Encouraging docking scores were obtained for taurine across all the selected targets, indicating promising target interaction. But the affinity for targets actually varied in the order NRF-KEAP > NF-κB > NMDA > Calcium channel > GPR 40. Given the potential implication of these targets in the pathogenesis of ASD, the drug might show promising results in the therapy of the disorder if subjected to further evaluations.

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3. Boccaccio FM, Platania GA, Guerrera CS, Varrasi S, Privitera CR, Caponnetto P, Pirrone C, Castellano S. Autism Spectrum Disorder: recommended psychodiagnostic tools for early diagnosis. Health psychology research. 2023; 11: 77357.

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4. Fusaro M, Fanti V, Chakrabarti B. Greater interpersonal distance in adults with autism. Autism research : official journal of the International Society for Autism Research. 2023.

Social interactions are often shaped by the space we prefer to maintain between us and others, that is, interpersonal distance. Being too distant or too close to a stranger can often be perceived as odd, and lead to atypical social interactions. This calibration of appropriate interpersonal distance thus constitutes an important social skill. Individuals with autism spectrum disorder (ASD, hereafter autism) often experience difficulties with this skill, and anecdotal accounts suggest atypical interpersonal distances in their social interactions. In the current study, we systematically measured interpersonal distance in individuals with autism using immersive virtual reality (IVR) to recreate a naturalistic interaction with a full body avatar of a similar age. Participants observed their own virtual body in first-person perspective, and the other avatar in two tasks: in the first task, they approached the other avatar (active), in the second one they were approached by the other avatar (passive). Two groups of neurotypical and autistic adults, performed both tasks. Autistic adults showed greater interpersonal distance when compared to non-autistic adults. Additionally, the difference between the passive and active conditions was smaller for non-autistic compared to autistic adults. Across the full sample, greater interpersonal distance was associated with higher autism-related traits. This study provides systematic evidence for greater interpersonal distance in autistic adults using a paradigm with high ecological validity and can be useful in informing the design of appropriate environmental adjustments for shared spaces.

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5. Heraty S, Lautarescu A, Belton D, Boyle A, Cirrincione P, Doherty M, Douglas S, Plas JRD, Van Den Bosch K, Violland P, Tercon J, Ruigrok A, Murphy DGM, Bourgeron T, Chatham C, Loth E, Oakley B, McAlonan GM, Charman T, Puts N, Gallagher L, Jones EJH. Bridge-building between communities: Imagining the future of biomedical autism research. Cell. 2023; 186(18): 3747-52.

A paradigm shift in research culture is required to ease perceived tensions between autistic people and the biomedical research community. As a group of autistic and non-autistic scientists and stakeholders, we contend that through participatory research, we can reject a deficit-based conceptualization of autism while building a shared vision for a neurodiversity-affirmative biomedical research paradigm.

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6. Hessl D, Rojas KM, Ferrer E, Espinal G, Famula J, Schneider A, Hagerman R, Tassone F, Rivera SM. A Longitudinal Study of Executive Function in Daily Life in Male Fragile X Premutation Carriers and Association with FXTAS Conversion. medRxiv : the preprint server for health sciences. 2023.

BACKGROUND: Men with fragile X-associated tremor/ataxia syndrome (FXTAS) often develop executive dysfunction, characterized by disinhibition, frontal dyscontrol of movement, and working memory and attention changes. Although cross-sectional studies have suggested that earlier executive function changes may precede FXTAS, the lack of longitudinal studies have made it difficult to address this hypothesis. METHODS: This study included 66 FMR1 premutation carriers (PC) ranging from 40-78 years (Mean=59.5) and 31 well-matched healthy controls (HC) ages 40-75 (Mean 57.7) at baseline. Eighty-four participants returned for 2-5 follow up visits over a duration of 1 to 9 years (Mean=4.6); 28 of the PC developed FXTAS. The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) was completed by participants and their spouses/partners at each visit. RESULTS: Longitudinal mixed model regression analyses showed a greater decline with age in PC compared to HC on the Metacognition Index (MI; self-initiation, working memory, organization, task monitoring). Conversion to FXTAS was associated with worsening MI and Behavioral Regulation Index (BRI; inhibition, flexibility, emotion modulation). For spouse/partner report, FXTAS conversion was associated with worsening MI. Finally, BRIEF-A executive function problems at baseline significantly predicted later development of FXTAS. CONCLUSIONS: These findings suggest that executive function changes represent a prodrome of the later movement disorder.

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7. Jenabi E, Farashi S, Salehi AM, Parsapoor H. The association between post-term births and autism spectrum disorders: an updated systematic review and meta-analysis. European journal of medical research. 2023; 28(1): 316.

BACKGROUND: This study aimed to conduct a meta-analysis to determine whether post-term birth has an increased risk of ASD. MATERIALS AND METHODS: To retrieve eligible studies regarding the effect of post-term and ASD in children, major databases including PubMed, Scopus, and Web of Science were searched. A random effect model was used for meta-analysis. For assessing the quality of included studies, the GRADE checklist was used. RESULTS: In total, 18 records were included with 1,412,667 sample populations from 12 countries. The pooled estimates of RR and OR showed a significant association between post-term birth and ASD among children, respectively (RR = 1.34, 95% CI 1.10 to 1.58) and (OR = 1.47, 95% CI 1.03 to 1.91). There was no heterogeneity among the studies that reported the risk of ASD among children based on RR (I(2) = 6.6%, P = 0.301). There was high heterogeneity in the studies reported risk of ASD based on OR (I(2) = 94.1%, P = 0.000). CONCLUSION: Post-term births still occur relatively frequently (up to 5-10%) even in developed countries. Our results showed that post-term birth is an increased risk of ASD, although high heterogeneity was found among the studies reported based on adjusted and crude forms, however, after subgroup analysis by gender, this heterogeneity disappeared among males.

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8. Li Y, Zhu M, Chen WX, Luo J, Li X, Cao Y, Zheng M, Ma S, Xiao Z, Zhang Y, Jiang L, Wang X, Tan T, Li X, Gong Q, Xiong X, Wang J, Tang M, Li M, Tang YP. A novel mutation in intron 1 of Wnt1 causes developmental loss of dopaminergic neurons in midbrain and ASD-like behaviors in rats. Molecular psychiatry. 2023.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with a strong genetic liability. Despite extensive studies, however, the underlying pathogenic mechanism still remains elusive. In the present study, we identified a homozygous mutation in the intron 1 of Wnt1 via large-scale screening of ASD risk/causative genes and verified that this mutation created a new splicing donor site in the intron 1, and consequently, a decrease of WNT1 expression. Interestingly, humanized rat models harboring this mutation exhibited robust ASD-like behaviors including impaired ultrasonic vocalization (USV), decreased social interactions, and restricted and repetitive behaviors. Moreover, in the substantia nigra compacta (SNpc) and the ventral tegmental area (VTA) of mutant rats, dopaminergic (DAergic) neurons were dramatically lost, together with a comparable decrease in striatal DAergic fibers. Furthermore, using single-cell RNA sequencing, we demonstrated that the decreased DAergic neurons in these midbrain areas might attribute to a shift of the boundary of the local pool of progenitor cells from the hypothalamic floor plate to the midbrain floor plate during the early embryonic stage. Moreover, treatments of mutant rats with levodopa could attenuate the impaired USV and social interactions almost completely, but not the restricted and repetitive behaviors. Our results for the first time documented that the developmental loss of DAergic neurons in the midbrain underlies the pathogenesis of ASD, and that the abnormal progenitor cell patterning is a cellular underpinning for this developmental DAergic neuronal loss. Importantly, the effective dopamine therapy suggests a translational significance in the treatment of ASD.

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9. Tveten KM, Strand LI, Riiser K, Nilsen RM, Dragesund T. The ability of the Ages and Stages Questionnaire (ASQ) to indicate motor difficulties in infants in primary care. Physiotherapy theory and practice. 2023; 39(9): 1974-80.

INTRODUCTION: Delayed achievement of motor milestones may be an early indicator of motor difficulties. Parent-reported questionnaires may serve as an efficient, low-cost screening to identify infants in need of further clinical assessment, and thus be a helpful tool in busy health care centers. PURPOSE: To examine the ability of the Ages and Stages Questionnaire, second edition (ASQ-2) to indicate motor difficulties in infants using the Infant Motor Profile (IMP) as the reference standard. METHODS: A cross-sectional design was applied to examine the correlation between parent-reported data of the ASQ-2 and data from physiotherapist assessment using IMP. Included were 432 mainly low-risk infants aged 3-12 months from primary care. RESULTS: Overall, ASQ-2 gross and fine motor scores did not correlate well with the IMP total or domain scores. The ASQ-2 gross motor cut point (> 2SD below the mean), showed 34.3% sensitivity and 96.7% specificity using the 15(th) percentile from IMP performance domain as reference standard. The positive predictive value to indicate motor difficulties was 48%. CONCLUSION: The motor domains of ASQ-2 have poor ability to identify infants with motor difficulties as indicated by their IMP scores in low-risk infants.

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10. Zhao Y, Zhong Y, Chen W, Chang S, Cao Q, Wang Y, Yang L. Ocular and neural genes jointly regulate the visuospatial working memory in ADHD children. Behavioral and brain functions : BBF. 2023; 19(1): 14.

OBJECTIVE: Working memory (WM) deficits have frequently been linked to attention deficit hyperactivity disorder (ADHD). Despite previous studies suggested its high heritability, its genetic basis, especially in ADHD, remains unclear. The current study aimed to comprehensively explore the genetic basis of visual-spatial working memory (VSWM) in ADHD using wide-ranging genetic analyses. METHODS: The current study recruited a cohort consisted of 802 ADHD individuals, all met DSM-IV ADHD diagnostic criteria. VSWM was assessed by Rey-Osterrieth complex figure test (RCFT), which is a widely used psychological test include four memory indexes: detail delayed (DD), structure delayed (SD), structure immediate (SI), detail immediate (DI). Genetic analyses were conducted at the single nucleotide polymorphism (SNP), gene, pathway, polygenic and protein network levels. Polygenic Risk Scores (PRS) were based on summary statistics of various psychiatric disorders, including ADHD, autism spectrum disorder (ASD), major depressive disorder (MDD), schizophrenia (SCZ), obsessive compulsive disorders (OCD), and substance use disorder (SUD). RESULTS: Analyses at the single-marker level did not yield significant results (5E-08). However, the potential signals with P values less than E-05 and their mapped genes suggested the regulation of VSWM involved both ocular and neural system related genes, moreover, ADHD-related genes were also involved. The gene-based analysis found RAB11FIP1, whose encoded protein modulates several neurodevelopment processes and visual system, as significantly associated with DD scores (P = 1.96E-06, P(adj) = 0.036). Candidate pathway enrichment analyses (N = 53) found that forebrain neuron fate commitment significantly enriched in DD (P = 4.78E-04, Padj = 0.025), and dopamine transport enriched in SD (P = 5.90E-04, Padj = 0.031). We also observed a significant negative relationship between DD scores and ADHD PRS scores (P = 0.0025, Empirical P = 0.048). CONCLUSIONS: Our results emphasized the joint contribution of ocular and neural genes in regulating VSWM. The study reveals a shared genetic basis between ADHD and VSWM, with GWAS indicating the involvement of ADHD-related genes in VSWM. Additionally, the PRS analysis identifies a significant relationship between ADHD-PRS and DD scores. Overall, our findings shed light on the genetic basis of VSWM deficits in ADHD, and may have important implications for future research and clinical practice.

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