1. Avolio E, Olivito I, Leo A, De Matteo C, Guarnieri L, Bosco F, Mahata SK, Minervini D, Alò R, De Sarro G, Citraro R, Facciolo RM. Vasostatin-1 restores autistic disorders in an idiopathic autism model (BTBR T+ Itpr3(tf)/J mice) by decreasing hippocampal neuroinflammation. Prog Neuropsychopharmacol Biol Psychiatry;2024 (Aug 30);135:111131.

Chromogranin A (CgA), a ∼ 49 kDa acidic secretory protein, is ubiquitously distributed in endocrine and neuroendocrine cells and neurons. As a propeptide, CgA is proteolytically cleaved to generate several peptides of biological importance, including pancreastatin (PST: hCgA(250)(-)(301)), Vasostatin 1 (VS1: hCgA(1-76)), and catestatin (CST: CgA (352)(-)(372)). VS1 represents the most conserved fragment of CgA. A 20 amino acid domain within VS1 (CgA 47-66) exhibits potent antimicrobial and anti-inflammatory activities. Autism is known to be associated with inflammation. Therefore, we seek to test the hypothesis that VS1 modulates autism behaviors by reducing inflammation in the hippocampus. Treatment of C57BL/6 (B6) and BTBR (a mouse model of idiopathic autism) mice with VS1 revealed the following: BTBR mice showed a significant decrease in chamber time in the presence of a stranger or a novel object. Treatment with VS1 significantly increased chamber time in both cases, underscoring a crucial role for VS1 in improving behavioral deficits in BTBR mice. In contrast to chamber time, sniffing time in BTBR mice in the presence of a stranger was less compared to B6 control mice. VS1 did not improve this latter parameter. Surprisingly, sniffing time in BTBR mice in the presence of a novel object was comparable with B6 mice. Proinflammatory cytokines such as IL-6 and IL-1b, as well as other inflammatory markers, were elevated in BTBR mice, which were dramatically reduced after supplementation with VS1. Interestingly, even Beclin-1/p62, pAKT/AKT, and p-p70-S6K/p70-S6K ratios were notably reduced by VS1. We conclude that VS1 plays a crucial role in restoring autistic spectrum disorders (ASD) plausibly by attenuating neuroinflammation.

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2. Carrazana R, Espinoza F, Ávila A. Mechanistic perspective on the actions of vitamin a in autism spectrum disorder etiology. Neuroscience;2024 (Aug 30);554:72-82.

Vitamin A (VA) has many functions in the body, some of which are key for the development and functioning of the nervous system, while some others might indirectly influence neural function. Both hypovitaminosis and hypervitaminosis A can lead to clinical manifestations of concern for individuals and for general global health. Scientific evidence on the link between VA and autism spectrum disorder (ASD) is growing, with some clinical studies and accumulating results obtained from basic research using cellular and animal models. Remarkably, it has been shown that VA deficiency can exacerbate autistic symptomatology. In turn, VA supplementation has been shown to be able to improve autistic symptomatology in selected groups of individuals with ASD. However, it is important to recognize that ASD is a highly heterogeneous condition. Therefore, it is important to clarify how and when VA supplementation can be of benefit for affected individuals. Here we delve into the relationship between VA and ASD, discussing clinical observations and mechanistic insights obtained from research on selected autistic syndromes and laboratory models to advance in defining how the VA signaling pathway can be exploited for treatment of ASD.

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3. Castellanos FX. Back to the future: Some similarities and many differences between autism spectrum disorder and early onset schizophrenia. Clues to pathophysiology?. Sci Bull (Beijing);2024 (Aug 30);69(16):2476-2477.

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4. Chow BJ, Raharja A, Dahir R, Khaier A, Posner M. Understanding the diagnostic challenges of Miller Fisher syndrome in children: a case report from an ophthalmological perspective. Br J Hosp Med (Lond);2024 (Aug 30);85(8):1-5.

We report a case of a 6-year-old boy with autism spectrum disorder presenting with new-onset squint and ‘ptosis’ following a recent infection. Clinical examination revealed ataxia and areflexia alongside a dilated pupil poorly reactive to light. Subsequently, his eye movements deteriorated to near-complete ophthalmoplegia at 1-week review. Further investigations inclusive of a magnetic resonance imaging (MRI) brain scan, a computed tomography (CT) venogram and a lumbar puncture were conducted to consider and rule out differential diagnoses. Cerebrospinal fluid analysis revealed an albuminocytologic dissociation. The clinical triad of progressive ophthalmoplegia, areflexia and areflexia alongside albuminocytologic dissociation led to the diagnosis of Miller Fisher syndrome. The patient was commenced on intravenous immunoglobulin and his symptoms showed significant improvement. We use this interesting case to provide context for key learning points about diagnosing Miller Fisher syndrome in children.

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5. Erdogan MA, Nesil P, Altuntas I, Sirin C, Uyanikgil Y, Erbas O. Amelioration of propionic acid-induced autism spectrum disorder in rats through dapagliflozin: The role of IGF-1/IGFBP-3 and the Nrf2 antioxidant pathway. Neuroscience;2024 (Aug 30);554:16-25.

The biological effects of dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, reveal its antioxidant and anti-inflammatory properties, suggesting therapeutic benefits beyond glycemic control. This study explores the neuroprotective effects of dapagliflozin in a rat model of autism spectrum disorder (ASD) induced by propionic acid (PPA), characterized by social interaction deficits, communication challenges, repetitive behaviors, cognitive impairments, and oxidative stress. Our research aims to find effective treatments for ASD, a condition with limited therapeutic options and significant impacts on individuals and families. PPA induces ASD-like symptoms in rodents, mimicking biochemical and behavioral features of human ASD. This study explores dapagliflozin’s potential to mitigate these symptoms, providing insights into novel therapeutic avenues. The findings demonstrate that dapagliflozin enhances the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant pathway and increases levels of neurotrophic and growth factors such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor-binding protein-3 (IGFBP-3). Additionally, dapagliflozin reduces pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-17 (IL-17), and decreases the oxidative stress marker malondialdehyde (MDA). Dapagliflozin’s antioxidant properties support cognitive functions by modulating apoptotic mechanisms and enhancing antioxidant capacity. These combined effects contribute to reducing learning and memory impairments in PPA-induced ASD, highlighting dapagliflozin’s potential as an adjunctive therapy for oxidative stress and inflammation-related cognitive decline in ASD. This study underscores the importance of exploring new therapeutic strategies targeting molecular pathways involved in the pathophysiology of ASD, potentially improving the quality of life for individuals affected by this disorder.

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6. Gao L, Cao Y, Zhang Y, Liu J, Zhang T, Zhou R, Guo X. Sex differences in the flexibility of dynamic network reconfiguration of autism spectrum disorder based on multilayer network. Brain Imaging Behav;2024 (Aug 30)

Dynamic network reconfiguration alterations in the autism spectrum disorder (ASD) brain have been frequently reported. However, since the prevalence of ASD in males is approximately 3.8 times higher than that in females, and previous studies of dynamic network reconfiguration of ASD have predominantly used male samples, it is unclear whether sex differences exist in dynamic network reconfiguration in ASD. This study used resting-state functional magnetic resonance imaging data from the Autism Brain Imaging Data Exchange database, which included balanced samples of 64 males and 64 females with ASD, along with 64 demographically-matched typically developing control (TC) males and 64 TC females. The multilayer network analysis was used to explore the flexibility of dynamic network reconfiguration. The two-way analysis of variance was further performed to examine the sex-related changes in ASD in flexibility of dynamic network reconfiguration. A diagnosis-by-sex interaction effect was identified in the cingulo-opercular network (CON), central executive network (CEN), salience network (SN), and subcortical network (SUB). Compared with TC females, females with ASD showed lower flexibility in CON, CEN, SN, and SUB. The flexibility of CEN and SUB in males with ASD was higher than that in females with ASD. In addition, the flexibility of CON, CEN, SN, and SUB predicted the severity of social communication impairments and stereotyped behaviors and restricted interests only in females with ASD. These findings highlight significant sex differences in the flexibility of dynamic network reconfiguration in ASD and emphasize the importance of further study of sex differences in future ASD research.

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7. Huang WA, Engelhard M, Coffman M, Hill ED, Weng Q, Scheer A, Maslow G, Henao R, Dawson G, Goldstein BA. A conditional multi-label model to improve prediction of a rare outcome: An illustration predicting autism diagnosis. J Biomed Inform;2024 (Aug 30);157:104711.

OBJECTIVE: This study aimed to develop a novel approach using routinely collected electronic health records (EHRs) data to improve the prediction of a rare event. We illustrated this using an example of improving early prediction of an autism diagnosis, given its low prevalence, by leveraging correlations between autism and other neurodevelopmental conditions (NDCs). METHODS: To achieve this, we introduced a conditional multi-label model by merging conditional learning and multi-label methodologies. The conditional learning approach breaks a hard task into more manageable pieces in each stage, and the multi-label approach utilizes information from related neurodevelopmental conditions to learn predictive latent features. The study involved forecasting autism diagnosis by age 5.5 years, utilizing data from the first 18 months of life, and the analysis of feature importance correlations to explore the alignment within the feature space across different conditions. RESULTS: Upon analysis of health records from 18,156 children, we are able to generate a model that predicts a future autism diagnosis with moderate performance (AUROC=0.76). The proposed conditional multi-label method significantly improves predictive performance with an AUROC of 0.80 (p < 0.001). Further examination shows that both the conditional and multi-label approach alone provided marginal lift to the model performance compared to a one-stage one-label approach. We also demonstrated the generalizability and applicability of this method using simulated data with high correlation between feature vectors for different labels. CONCLUSION: Our findings underscore the effectiveness of the developed conditional multi-label model for early prediction of an autism diagnosis. The study introduces a versatile strategy applicable to prediction tasks involving limited target populations but sharing underlying features or etiology among related groups.

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8. Ludyga S, Bruggisser F, Leuenberger R, Ishihara T, Kamijo K, Brotzmann M, Trescher S, Förster M, Gerber M. Acute effects of exercise on gaze fixation and affective response inhibition in children with autism spectrum disorder: A randomized cross-over study. Autism Res;2024 (Aug 30)

Children with autism spectrum disorder (ASD) show impairments in response inhibition, especially in socio-emotional contexts. A single aerobic exercise session has the potential to temporarily reduce such impairments as findings from neurotypical children support acute benefits of this exercise type for inhibitory control and emotion recognition. In children with ASD, we therefore aimed to investigate the effects of an aerobic exercise bout on response inhibition in an emotional Go/NoGo task and gaze fixation as possible mechanism underlying changes in performance. Using a cross-over design, 29 patients completed a 20-min aerobic exercise bout at moderate intensity on a cycling ergometer and a control condition in a randomized order. An emotional Go/NoGo task was administered before and after both experimental conditions. Eye-tracking was performed during the cognitive task to assess the duration of gaze fixation of eyes and mouth parts of faces expressing happy or sad emotions. The results support no beneficial effect of exercise on performance on the emotional Go/NoGo task. Instead, patients showed a greater decrease in accuracy on Go trials displaying happy faces in the exercise compared to the control condition. This change was associated with a more pronounced decrease in the fixation duration of the eyes for faces expressing either happy or sad emotions. In conclusion, while a single session of moderately intense aerobic exercise does not affect response inhibition, it temporarily aggravates ASD-specific deficits in the processing of and response to facial emotions.

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9. Lundy KM, Fischer AJ, Illapperuma-Wood CR, Schultz B. Understanding autistic youths’ menstrual product preferences and caregivers’ product choices. Autism;2024 (Aug 30):13623613241275280.

There is little research exploring the menstrual product preferences of autistic youth, especially those who recently started their period. Study authors surveyed caregivers’ choice of menstrual products for their autistic children. They provided popular menstrual materials to autistic youth to try, then asked them which product(s) they preferred, did not try, and why they did not try it. Caregivers selected sensory impact as the most important feature they consider when choosing a menstrual product for their child, and youth participants preferred to use period underwear. Therefore, autistic youth may benefit from purchasing and using period underwear, and caregivers, clinicians, and companies should consider the impact of menstrual product features, like sensory sensitivities, on young autistic menstruators and how best to support them.

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10. Martins PLB, Torquato GCP, Dias G, Leite IB, Gaspar TM, Pinto JP, Macedo DS. Effectiveness of pharmacological interventions for managing ADHD symptoms in individuals with autism spectrum disorder: A systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry;2024 (Aug 30);134:111089.

OBJECTIVES: This systematic review sought to provide evidence for the effectiveness of common pharmacological interventions used for treating attention deficit hyperactivity disorder (ADHD) symptoms in the autism spectrum disorder (ASD) population, considering studies attempting to find safe and effective drugs. METHODS: We searched for randomized controlled trials describing the effectiveness and/or safety profile of pharmacological interventions for treating ASD and ADHD or ASD with ADHD symptoms using three bibliographic databases: PubMed, Cochrane Library, and Embase. We have chosen ADHD symptoms measured by any clinical scale as the primary outcome. As additional outcomes, we have used other symptoms of aberrant behavior measured by the aberrant behavior checklist, satisfaction with treatment, and peer satisfaction. RESULTS: Twenty-two publications met the inclusion criteria for the systematic review and eight for the meta-analysis. In our investigation, we found a few articles using clonidine, modafinil, and bupropion as interventions when compared to methylphenidate (MPH). Our meta-analysis showed that MPH had positive changes compared to placebo in symptoms such as hyperactivity, irritability, or inattention. However, no effect was found in stereotyped symptoms, and our data’s quantitative analysis revealed a large effect of MPH-induced adverse effects on the dropout rate. On the other hand, atomoxetine initiation had positive effects when compared to placebo on symptoms of hyperactivity and inattention. We have found no effect of atomoxetine on stereotypes or irritability. Furthermore, atomoxetine did not influence side effects that caused dropouts from studies. CONCLUSION: Our results indicated that atomoxetine has a modest effect on hyperactivity and inattention symptoms, with a relatively benign profile of side effects. MPH appears to be effective in handling hyperactivity, inattention, and irritability symptoms. However, our results on atomoxetine revealed increased dropouts due to adverse effects when compared to MPH or placebo. Evidence for other substances such as guanfacine, clonidine, bupropion, or modafinil is either preliminary or nonexistent.

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11. Zhang B, Zhang J, Chen H, Qiao D, Guo F, Hu X, Qin C, Jin X, Zhang K, Wang C, Cui H, Li S. Role of FMRP in AKT/mTOR pathway-mediated hippocampal autophagy in fragile X syndrome. Prog Neuropsychopharmacol Biol Psychiatry;2024 (Aug 30);134:111036.

Fragile X syndrome (FXS) is caused by epigenetic silencing of the Fmr1 gene, leading to the deletion of the coding protein FMRP. FXS induces abnormal hippocampal autophagy and mTOR overactivation. However, it remains unclear whether FMRP regulates hippocampal autophagy through the AKT/mTOR pathway, which influences the neural behavior of FXS. Our study revealed that FMRP deficiency increased the protein levels of p-ULK-1 and p62 and decreased LC3II/LC3I level in Fmr1 knockout (KO) mice. The mouse hippocampal neuronal cell line HT22 with knockdown of Fmr1 by lentivirus showed that the protein levels of p-ULK-1 and p62 were increased, whereas LC3II/LC3I was unchanged. Further observations revealed that FMRP deficiency obstructed autophagic flow in HT22 cells. Therefore, FMRP deficiency inhibited autophagy in the mouse hippocampus and HT22 cells. Moreover, FMRP deficiency increased reactive oxygen species (ROS) level, decreased the co-localization between the mitochondrial outer membrane proteins TOM20 and LC3 in HT22 cells, and caused a decrease in the mitochondrial autophagy protein PINK1 in HT22 cells and Fmr1 KO mice, indicating that FMRP deficiency caused mitochondrial autophagy disorder in HT22 cells and Fmr1 KO mice. To explore the mechanism by which FMRP deficiency inhibits autophagy, we examined the AKT/mTOR signaling pathway in the hippocampus of Fmr1 KO mice, found that FMRP deficiency caused overactivation of the AKT/mTOR pathway. Rapamycin-mediated mTOR inhibition activated and enhanced mitochondrial autophagy. Finally, we examined whether rapamycin affected the neurobehavior of Fmr1 KO mice. The Fmr1 KO mice exhibited stereotypical behavior, impaired social ability, and learning and memory impairment, while rapamycin treatment improved behavioral disorders in Fmr1 KO mice. Thus, our study revealed the molecular mechanism by which FMRP regulates autophagy function, clarifying the role of hippocampal neuron mitochondrial autophagy in the pathogenesis of FXS, and providing novel insights into potential therapeutic targets of FXS.

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12. Zhang S, Jiang L, Hu Z, Liu W, Yu H, Chu Y, Wang J, Chen Y. T1w/T2w ratio maps identify children with autism spectrum disorder and the relationships between myelin-related changes and symptoms. Prog Neuropsychopharmacol Biol Psychiatry;2024 (Aug 30);134:111040.

BACKGROUND: Modern neuroimaging methods have revealed that autistic symptoms are associated with abnormalities in brain morphology, connectivity, and activity patterns. However, the changes in brain microstructure underlying the neurobiological and behavioral deficits of autism remain largely unknown. METHODS: we characterized the associated abnormalities in intracortical myelination pattern by constructing cortical T1-weighted/T2-weighted ratio maps. Voxel-wise comparisons of cortical myelination were conducted between 150 children with autism spectrum disorder (ASD) and 139 typically developing (TD) children. Group differences in cortical T1-weighted/T2-weighted ratio and gray matter volume were then examined for associations with autistic symptoms. A convolutional neural network (CNN) model was also constructed to examine the utility of these regional abnormalities in cortical myelination for ASD diagnosis. RESULTS: Compared to TD children, the ASD group exhibited widespread reductions in cortical myelination within regions related to default mode, salience, and executive control networks such as the inferior frontal gyrus, bilateral insula, left fusiform gyrus, bilateral hippocampus, right calcarine sulcus, bilateral precentral, and left posterior cingulate gyrus. Moreover, greater myelination deficits in most of these regions were associated with more severe autistic symptoms. In addition, children with ASD exhibited reduced myelination in regions with greater gray matter volume, including left insula, left cerebellum_4_5, left posterior cingulate gyrus, and right calcarine sulcus. Notably, the CNN model based on brain regions with abnormal myelination demonstrated high diagnostic efficacy for ASD. CONCLUSIONS: Our findings suggest that microstructural abnormalities in myelination contribute to autistic symptoms and so are potentially promising therapeutic targets as well as biomarkers for ASD diagnosis.

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