Pathophysiology Of Autism Spectrum Disorder Research Articles

Quantitative Relaxometry Assessment of Brain Microstructural Abnormality of Preschool Children With Autism Spectrum Disorder With Synthetic Magnetic Resonance Imaging.

This study aimed to perform an assessment of brain microstructure in children with autism aged 2 to 5 years using relaxation times acquired by synthetic magnetic resonance imaging. Thirty-four children with autism spectrum disorder (ASD) (ASD group) and 17 children with global developmental delay (GDD) (GDD group) were enrolled, and synthetic magnetic resonance imaging was performed to obtain T1 and T2 relaxation times. The differences in brain relaxation times between the 2 groups of children were compared, and the correlation between significantly changed T1/T2 and clinical neuropsychological scores in the ASD group was analyzed. Compared with the GDD group, shortened T1 relaxation times in the ASD group were distributed in the genu of corpus callosum (GCC) ( P = 0.003), splenium of corpus callosum ( P = 0.002), and right thalamus (TH) ( P = 0.014), whereas shortened T2 relaxation times in the ASD group were distributed in GCC ( P = 0.011), left parietal white matter ( P = 0.035), and bilateral TH (right, P = 0.014; left, P = 0.016). In the ASD group, the T2 of the left parietal white matter is positively correlated with gross motor (developmental quotient [DQ] 2) and personal-social behavior (DQ5), respectively ( r = 0.377, P = 0.028; r = 0.392, P = 0.022); the T2 of the GCC was positively correlated with DQ5 ( r = 0.404, P = 0.018); and the T2 of the left TH is positively correlated with DQ2 and DQ5, respectively ( r = 0.433, P = 0.009; r = 0.377, P = 0.028). All significantly changed relaxation values were not significantly correlated with Childhood Autism Rating Scale scores. The shortened relaxometry times in the brain of children with ASD may be associated with the increased myelin content and decreased water content in the brain of children with ASD in comparison with GDD, contributing the understanding of the pathophysiology of ASD. Therefore, the T1 and T2 relaxometry may be used as promising imaging markers for ASD diagnosis.

Sex Differences in Mouse Models of Autism Spectrum Disorders: Their Potential to Uncover the Impact of Brain Sexual Differentiation on Gender Bias

Autism spectrum disorder (ASD) is a neurodevelopmental condition with a prevalence rate of 2.78%, and it is characterized by deficits in sociability and communication and restricted patterns of interests and activities. Remarkably, this psychiatric disorder exhibits a pronounced gender bias, with 80% of children diagnosed with ASD being boys. In this review, we will present advancements in mouse models of ASD and their potential contributions to our understanding of the disorder. We will highlight how initial pre-clinical investigations focused solely on male mice due to the gender bias in ASD and explain why we believe that this approach might have had detrimental consequences regarding our understanding of ASD etiology and pathophysiology. We will highlight the evidence of two sensitive periods during brain development when differential exposure to gonadal hormones may result in sex differences in brain function and behavior: the perinatal period and the pre-pubertal period. Finally, we will suggest neuroinflammation as a feasible biological mechanism that may converge different ASD etiological factors and cellular mechanisms into a brain sexual differentiation context, thus accounting for the gender disparities observed in the disorder.

Chronic inhibition of astrocytic aquaporin-4 induces autistic-like behavior in control rat offspring similar to maternal exposure to valproic acid

Social communication and interaction deficits, memory impairment, and anxiety-like behavior are characterized in many people identified with autism spectrum disorder (ASD). A thorough understanding of the specific aspects that contribute to the deficiencies associated with ASD can aid research into the etiology of the disorder while also providing targets for more effective intervention. As part of the ASD pathophysiology, alterations in synaptogenesis and abnormal network connections were seen in high-order brain areas, which control social behavior and communication. The early emergence of microglia during nervous system development may contribute to synaptic dysfunction and the pathobiology of ASD. Since aquaporin-4 (AQP4) appears to be required for the basic procedures of synapse activation, certain behavioral and cognitive impairments as well as disturbance in water homeostasis might likely arise from AQP4 deficiency. Here, through the measurement of the water content of the hippocampus and behavioral experiments we aim to explore the contribution of astrocytic AQP4 to the autism-like behavior induced by prenatal valproic acid (VPA) exposure and whether inhibition of AQP4 per se can induce autistic-like behavior in control rats.Microinjection of TGN-020 (10 µM, i.c.v), a specific AQP4 inhibitor, for 7 successive days before behavioral tasks from postnatal day 28 to 35 revealed that inhibition of AQP4 in the control offspring caused lower social interaction and locomotor activity, higher anxiety, and decreased ability to recognize novel objects, very similar to the behavioral changes observed in offspring prenatally exposed to VPA. However, VPA-exposed offspring treated with TGN-020, showed no further remarkable behavioral impairments than those detected in the autistic-like rats. Furthermore, both control offspring treated with TGN-020 and offspring exposed to VPA had a considerable accumulation of water in their hippocampi. But AQP4 inhibition did not affect the water status of the autistic-like rats.The findings of this study revealed that control offspring exhibited similar hippocampal water retention and behavioral impairments that were observed in maternal VPA-exposed offspring following inhibition of astrocytic AQP4, whereas, in autistic-like rats, it did not produce any significant change in water content and behaviors. Findings suggest that AQP4 deficiency could be associated with autistic disorder and may be a potential pharmaceutical target for treating autism in the future.

Endogenous oxytocin levels in children with autism: Associations with cortisol levels and oxytocin receptor gene methylation

Alterations in the brain’s oxytocinergic system have been suggested to play an important role in the pathophysiology of autism spectrum disorder (ASD), but insights from pediatric populations are sparse. Here, salivary oxytocin was examined in the morning (AM) and afternoon (PM) in school-aged children with (n = 80) and without (n = 40) ASD (boys/girls 4/1), and also characterizations of DNA methylation (DNAm) of the oxytocin receptor gene (OXTR) were obtained. Further, cortisol levels were assessed to examine links between the oxytocinergic system and hypothalamic-pituitary-adrenal (HPA) axis signaling. Children with ASD displayed altered (diminished) oxytocin levels in the morning, but not in the afternoon, after a mildly stress-inducing social interaction session. Notably, in the control group, higher oxytocin levels at AM were associated with lower stress-induced cortisol at PM, likely reflective of a protective stress-regulatory mechanism for buffering HPA stress activity. In children with ASD, on the other hand, a significant rise in oxytocin levels from the morning to the afternoon was associated with a higher stress-induced cortisol release in the afternoon, likely reflective of a more reactive stress regulatory release of oxytocin for reactively coping with heightened HPA activity. Regarding epigenetic modifications, no overall pattern of OXTR hypo- or hypermethylation was evident in ASD. In control children, a notable association between OXTR methylation and levels of cortisol at PM was evident, likely indicative of a compensatory downregulation of OXTR methylation (higher oxytocin receptor expression) in children with heightened HPA axis activity. Together, these observations bear important insights into altered oxytocinergic signaling in ASD, which may aid in establishing relevant biomarkers for diagnostic and/or treatment evaluation purposes targeting the oxytocinergic system in ASD.

Glutaminase 1 deficiency confined in forebrain neurons causes autism spectrum disorder-like behaviors

An abnormal glutamate signaling pathway has been proposed in the mechanisms of autism spectrum disorder (ASD). However, less is known about the involvement of alterations of glutaminase 1 (GLS1) in the pathophysiology of ASD. We show that the transcript level of GLS1 is significantly decreased in the postmortem frontal cortex and peripheral blood of ASD subjects. Mice lacking Gls1 in CamKIIα-positive neurons display a series of ASD-like behaviors, synaptic excitatory and inhibitory (E/I) imbalance, higher spine density, and glutamate receptor expression in the prefrontal cortex, as well as a compromised expression pattern of genes involved in synapse pruning and less engulfed synaptic puncta in microglia. A low dose of lipopolysaccharide treatment restores microglial synapse pruning, corrects synaptic neurotransmission, and rescues behavioral deficits in these mice. In summary, these findings provide mechanistic insights into Gls1 loss in ASD symptoms and identify Gls1 as a target for the treatment of ASD.

Therapeutic Profile of Cannabidiol in the Broad Symptomatology of Autism Spectrum Disorder: Evidence From Basic Science to Clinical Approaches

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders whose symptoms include impaired communication and social interaction, stereotypies, and varying levels of intellectual disability. Together with these symptoms are co-occurring psychiatric or neurological conditions, often with hyperactivity and attention disorders, anxiety, depression, and epilepsy. So far, no effective treatment for ASD is available, possibly because its neurobiological basis and heterogeneous nature are not clearly understood. Clinical and preclinical trials support the involvement of the endocannabinoid system in the patho-physiology of ASD. Cannabidiol (CBD), the main nonpsychotomimetic compound of the cannabis plant, interacts with the endocannabinoid system and has significant therapeutic potential in treating several psychiatric disorders and manifestations of ASD. After this article, readers are expected to have a broad understanding of current scientific evidence and perspectives on the use of CBD in cases of ASD. [ Psychiatr Ann . 2023;53(6):247–251.]

Reduced levels of plasma strong antioxidant uric acid in children with Autism Spectrum Disorder and Attention deficit-hyperactivity disorder

Objective: Uric acid (UA) is one of the most powerful antioxidants in human body fluids, as well as being the end product of purine metabolism. UA alone constitutes half of the scavenging effect of oxidant substances in the plasma.It has proinflammatory and metal chelation effects. In this study, UA levels and UA situation according to the normal range were investigated in patients with Autism Spectrum Disorder (ASD), and Attention deficit-hyperactivity disorder (ADHD). Methods: Eighty-two ASD, 28 ADHD patients and 66 healthy control subjects were compared and serum UA levels were measured. ASD and ADHD severity were determined by CARS and Atilla Turgay ADHD scale. K-SADS-PL was administered to all subjects over the age of 6 years. Results: UA levels were found to be significantly lower in the ASD and ADHD groups. UA levels were found to be lower than the normal range in nearly half of the ASD and ADHD groups. This rate was found to be 18.2% in the control group. Conclusion: it was determined that UA levels were low in ASD and ADHD patients. It can be suggested that it may play a role in the pathophysiology of ASD and ADHD. UA may be a potential treatment target.

0789 Sleep Spindle Density is Associated with Core Symptom Severity in Autism Spectrum Disorder

Abstract Introduction Converging evidence suggests that dysregulation of thalamocortical interactions, mediated by the thalamic reticular nucleus (TRN), contributes to the expression of autism spectrum disorder (ASD). Risk genes for ASD have been found to affect the TRN early in development. Two hallmarks of NREM sleep –slow oscillations (SO) and sleep spindles– reflect TRN function and distinct thalamic/thalamocortical circuits. While studies demonstrate disrupted sleep quality that correlates with symptoms in children with ASD, studies of spindles in ASD have produced inconsistent findings. It is yet unclear if and how spindle properties are associated with ASD symptoms. Herein, based on studies implicating TRN-mediated thalamocortical dysregulation in ASD, we hypothesized that 1) sleep spindles are reduced in ASD; 2) spindle abnormalities correlate with worse clinical symptoms and cognition. Methods Forty participants with ASD (32 males, age: 11.8 ± 3.2; range 6-15) and 46 typically developing (TD) controls (32 males, age: 11.2 ± 2.3; range 6-15) participated in the study. All participants underwent ambulatory overnight polysomnography (PSG) for sleep assessment after systematic desensitization. The Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview-Revised (ADI-R) were used to assess core behavioral symptoms. Results Spindle density was significantly lower in ASD compared to TD participants (ASD: 2.5 ± 2.0; TD: 3.0 ± 2.1; d= 0.45, p=0.01). In the ASD group, less spindle density was associated with more severe behavioral symptoms, as measured by the total ADOS score (R2=0.15, p=0.01) and the three main subscales of the ADI-R (reciprocal social interaction: R2=0.22, p=0.002; communication and language: R2=0.19, p=0.003; and restricted and repetitive, stereotyped interests and behaviors: R2=0.14, p=0.01). Conclusion Alterations in the maturational trajectory of spindles are related to the core symptoms of ASD individuals. The results have the potential to identify novel biomarkers that index distinct aspects of ASD pathophysiology and point to multiple neural mechanisms underlying disease heterogeneity. The study may contribute to producing novel evidence to elucidate the bidirectional relationship between sleep and ASD. Support (if any) Simons Foundation Autism Research Initiative grant (177986).

Autism spectrum disorder and GABA levels in children with succinic semialdehyde dehydrogenase deficiency.

To elucidate the etiological aspects of autism spectrum disorder (ASD) in succinic semialdehyde dehydrogenase deficiency (SSADHD), related to dysregulation of γ-aminobutyric acid (GABA) and the imbalance of excitatory and inhibitory neurotransmission. In this prospective, international study, individuals with SSADHD underwent neuropsychological assessments, as well as biochemical, neurophysiological, and neuroimaging evaluations. Of the 29 individuals (17 females) enrolled (median age [IQR] 10 years 5 months [5 years 11 months-18 years 1 month]), 16 were diagnosed with ASD. ASD severity significantly increased with age (r = 0.67, p < 0.001) but was inversely correlated with plasma GABA (r = -0.67, p < 0.001) and γ-hydroxybutyrate levels (r = -0.538, p = 0.004), and resting motor threshold as measured by transcranial magnetic stimulation (r = -0.44, p = 0.03). A discriminative analysis indicated that an age older than 7 years 2 months (p = 0.004) and plasma GABA levels less than 2.47 μM (p = 0.01) are the threshold values beyond which the likelihood of ASD presenting in individuals with SSADHD is increased. ASD is prevalent but not universal in SSADHD, and it can be predicted by lower levels of plasma GABA and GABA-related metabolites. ASD severity in SSADHD increases with age and the loss of cortical inhibition. These findings add insight into the pathophysiology of ASD and may facilitate its early diagnosis and intervention in individuals with SSADHD.

The Environment Affects Autism Spectrum Disorder by Moderating Gene Expression and Mutation

Autism spectrum disorder (ASD) is a kind of developmental condition that is brought on by flaws in the brain. The "exclusive environment" approach of the Bettelheim period has given way to the "exclusive genetic" approach, and a significant amount of study has been concentrated on the causes of ASD, especially variables related to genetics. The question of whether or not ASD is influenced by one's surroundings is still being discussed. The purpose of this paper is to explore how the environment affects ASD and to argue, based on the publications that were evaluated, that genes are important variables that directly impact ASD, especially gene mutation, and that the environment factors are an influence that affects ASD indirectly. Through its regulation of gene expression and gene mutations, the environment factors have an indirect impact on the pathophysiology of ASD. It is more advantageous for the prevention and treatment of ASD to study the environmental and genetic variables that contribute to autism, which needs to be further explored and verified by future research.

The importance of comprehensive support based on the three pillars of exercise, nutrition, and sleep for improving core symptoms of autism spectrum disorders.

Autism spectrum disorder (ASD) is classified as a neurodevelopmental disorder. The Diagnostic and Statistical Manual of Mental Disorders (DSM)-V, which first described ASD, lists persistent deficits in social communication and interrelationships, as well as limited and recurrent modes of behavior, interests, and activities as diagnostic items. Until recently, understanding the pathophysiology of ASD has been mostly from a neurophysiological perspective, and interventions have been mostly behavioral and psychological. In recent years, however, it has become clear that ASD also affects many bodily systems, including the immune system, the sensorimotor system, and the gut-brain axis, and that these factors simultaneously influence it. In light of this background, a new "connectivome theory" has been proposed as a hypothesis for understanding ASD. "Exercise," "nutrition," and "sleep," which are discussed in this mini-review, have a particularly strong relationship with the immune, musculoskeletal, and gut systems among the pathologies mentioned in the "connectivome theory," furthermore, many reports suggest improvements in stereo-responsive behavior and social and communication skills, which are the core symptoms of ASD. In addition, these interventions are characterized by being less subject to location and cost limitations and excel in the continuity of therapeutic intervention, and the three interventions may have a reciprocal positive impact and may function as three pillars to support ASD.

Valproate-induced murine autism spectrum disorder is associated with dysfunction of amygdala parvalbumin interneurons and downregulation of AMPK/SIRT1/PGC1α signaling.

Autism spectrum disorder (ASD) is a neurodevelopmental condition that is characterized by difficulty in social behavior and restricted behaviors. Also, in ASD, several accompanying disorders such as anxiety are observed. Considering the important role of amygdala in the pathophysiology of ASD, the present study focused on the neuronal changes and it possible signaling pathway in amygdala. After prenatal exposure to valproate (VPA; 600mg/kg, i.p, on embryonic day 12.5), amount of ROS, MMP, caspase-3 activity, AMPK, SIRT1 and PGC1α proteins, and parvalbumin interneurons in the amygdala were assessed following evaluation of ASD and anxiety-like behaviors. Amygdala analysis revealed ROS accumulation and decreased MMP in autistic rats. In addition, caspase-3 activation elevated and immunoreactivity for parvalbumin interneurons decreased. These were accompanied by anxiety and autistic-like behaviors in open field test, elevated zero maze and U-Shaped 2 Choice Field maze. Also, our data showed that in the valproate group, protein levels of AMPK, SIRT1 and PGC1α reduced. Collectively, our results indicate that prenatal exposure to valproate leads to anxiety and autistic-like behaviors, partly through its targeting amygdala parvalbumin interneurons dysfunction and this might be affected by disturbed AMPK/SIRT1/PGC1α signaling pathway.

Neurometabolite levels in the brains of patients with autism spectrum disorders: A meta-analysis of proton magnetic resonance spectroscopy studies (N = 1501).

Evidence suggests that neurometabolite alterations may be involved in the pathophysiology of autism spectrum disorders (ASDs). We performed a meta-analysis of proton magnetic resonance spectroscopy (1H-MRS) studies to examine the neurometabolite levels in the brains of patients with ASD. A systematic search of PubMed and Web of Science identified 54 studies for the meta-analysis. A random-effects meta-analysis demonstrated that compared with the healthy controls, patients with ASD had lower N-acetyl-aspartate-containing compound (NAA) and choline-containing compound (Cho) levels and NAA/(creatine-containing compound) Cr ratios in the gray matter and lower NAA and glutamate + glutamine (Glx) levels in the white matter. Furthermore, NAA and gamma-aminobutyric acid (GABA) levels, NAA/Cr ratios, and GABA/Cr ratios were significantly decreased in the frontal cortex of patients with ASD, whereas glutamate (Glu) levels were increased in the prefrontal cortex. Additionally, low NAA levels and GABA/Cr ratios in the temporal cortex, low NAA levels and NAA/Cr ratios in the parietal and dorsolateral prefrontal cortices, and low NAA levels in the cerebellum and occipital cortex were observed in patients with ASD. Meta-regression analysis revealed that age was positively associated with effect size in studies analyzing the levels of gray matter NAA and white matter Glx. Taken together, these results provide strong clinical evidence that neurometabolite alterations in specific brain regions are associated with ASD and age is a confounding factor for certain neurometabolite levels in patients with ASD.

Cross-disease Transcriptomic Analysis Elucidating the Roles of Astrocytic Signaling Pathways Regulating Neuroinflammation in Autism Spectrum Disorder (S2.003)

<h3>Objective:</h3> This research aims to elucidate the roles of astrocytic signaling pathways regulating neuroinflammation in autism spectrum disorder. <h3>Background:</h3> While neuroinflammation has been implicated as a major component in autism spectrum disorder (ASD) and its etiology, the molecular mechanism in the disease is not well understood. Advances in single-cell genomics and transcriptomics have fueled the identification of novel pathways that control astrocyte functions associated with chronic neuroinflammatory disorders such as multiple sclerosis (MS). These advances present an opportunity to study the common molecular mechanisms involved in both ASD and MS, and ultimately elucidate ASD etiology. <h3>Design/Methods:</h3> In this paper, we analyze and characterize the common astrocytes subpopulations shared in both ASD and MS using the large-scale single-cell RNA-seq expression data collected from postmortem brain samples of subjects diagnosed with ASD (PRJNA434002) and MS (PRJNA544731). Batch correction was implemented using Harmony to strengthen the unbiased analysis. Seurat and SC3 were used for the identification of common astrocyte clusters and their marker genes; DESeq2 for disease-specific differential expressed gene (DEG) analysis; Monocle and Enrichr for trajectory and ingenuity pathway analysis (IPA) of DEGs. Finally, GSEA was performed on IPSC bulk-RNA sequencing data to further characterize the common pro-inflammatory astrocytes subpopulations using secondary progressive stage transcriptional signatures of MS. <h3>Results:</h3> This research identified two astrocyte subpopulations common to ASD and MS. Our analysis revealed that oxidative stress-mediated ferroptosis plays a pronounced role in the pathological astrocyte subpopulations. This discovery enables us to hypothesize that FTH1, SLC7A11, SAT1, CP, FTL and MAPK signaling are potentially involved in ASD pathophysiology, which could be further explored as novel targets for intervention. <h3>Conclusions:</h3> Linking transcriptionally-defined astrocyte subpopulations cross diseases could yield better understanding of their roles in each disease-specific context. Inflammation-promoting oxidative stress-mediated ferroptosis should be further studied for its roles in the pathological astrocyte subpopulations in ASD. <b>Disclosure:</b> Miss Zhang has nothing to disclose.

The Neurogenetics of Functional Connectivity Alterations in Autism: Insights From Subtyping in 657 Individuals

BackgroundThere is little consensus and controversial evidence on anatomical alterations in the brains of people with autism spectrum disorder (ASD), due in part to the large heterogeneity present in ASD, which in turn is a major drawback for developing therapies. One strategy to characterize this heterogeneity in ASD is to cluster large-scale functional brain connectivity profiles. MethodsA subtyping approach based on consensus clustering of functional brain connectivity patterns was applied to a population of 657 autistic individuals with quality-assured neuroimaging data. We then used high-resolution gene transcriptomic data to characterize the molecular mechanism behind each subtype by performing enrichment analysis of the set of genes showing a high spatial similarity with the profiles of functional connectivity alterations between each subtype and a group of typically developing control participants. ResultsTwo major stable subtypes were found: subtype 1 exhibited hypoconnectivity (less average connectivity than typically developing control participants) and subtype 2, hyperconnectivity. The 2 subtypes did not differ in structural imaging metrics in any of the analyzed regions (68 cortical and 14 subcortical) or in any of the behavioral scores (including IQ, Autism Diagnostic Interview, and Autism Diagnostic Observation Schedule). Finally, only subtype 2, comprising about 43% of ASD participants, led to significant enrichments after multiple testing corrections. Notably, the dominant enrichment corresponded to excitation/inhibition imbalance, a leading well-known primary mechanism in the pathophysiology of ASD. ConclusionsOur results support a link between excitation/inhibition imbalance and functional connectivity alterations, but only in one ASD subtype, overall characterized by brain hyperconnectivity and major alterations in somatomotor and default mode networks.

Candidate biomarkers from the integration of methylation and gene expression in discordant autistic sibling pairs

While the genetics of autism spectrum disorders (ASD) has been intensively studied, resulting in the identification of over 100 putative risk genes, the epigenetics of ASD has received less attention, and results have been inconsistent across studies. We aimed to investigate the contribution of DNA methylation (DNAm) to the risk of ASD and identify candidate biomarkers arising from the interaction of epigenetic mechanisms with genotype, gene expression, and cellular proportions. We performed DNAm differential analysis using whole blood samples from 75 discordant sibling pairs of the Italian Autism Network collection and estimated their cellular composition. We studied the correlation between DNAm and gene expression accounting for the potential effects of different genotypes on DNAm. We showed that the proportion of NK cells was significantly reduced in ASD siblings suggesting an imbalance in their immune system. We identified differentially methylated regions (DMRs) involved in neurogenesis and synaptic organization. Among candidate loci for ASD, we detected a DMR mapping to CLEC11A (neighboring SHANK1) where DNAm and gene expression were significantly and negatively correlated, independently from genotype effects. As reported in previous studies, we confirmed the involvement of immune functions in the pathophysiology of ASD. Notwithstanding the complexity of the disorder, suitable biomarkers such as CLEC11A and its neighbor SHANK1 can be discovered using integrative analyses even with peripheral tissues.

Peripheral Expression of ADORA2A Is Increased and Is Correlated with Autism Spectrum Disorder Severity in a Sample of Turkish Children.

The aim of this study was to evaluate the peripheral expression of ADORA2A (Adenosine A2A receptor gene) in young subjects with autism spectrum disorder compared with healthy controls and its relationship with clinical characteristics. This study included 93 children and adolescents with a diagnosis of autism spectrum disorder as the study group and 105 healthy age- and gender-matched controls. Blood samples were obtained from all participants, and a real-time quantitative polymerase chain reaction was performed. Parent- and clinician-rated assessment instruments were used to assess and rate the severity of autism spectrum disorder and other emotional/behavioral problems. The mean age of the study group was 9.06 ± 3.57 and 86% were male (n = 83), whereas the mean age of the control group was 9.22 ± 3.86 and 86.7% were male (n = 91). We have found a higher level of peripheral expression of ADORA2A in children and adolescents with autism spectrum disorder compared with healthy controls (fold change = 1.33, P = .001). We also found a weak negative correlation with autism spectrum disorder severity (r = -0.216; P = .038) and stereotyped behaviors (r = -0.207, P = .046). ADORA2A genes may have a role in the pathophysiology of autism spectrum disorder. Further studies are needed to evaluate whether peripheral expression of ADORA2A genes may be among the biomarkers for diagnosing or measuring the severity of autism spectrum disorder.

Biochemical, Genetic and Clinical Diagnostic Approaches to Autism-Associated Inherited Metabolic Disorders

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders characterized by impaired social interaction, limited communication skills, and restrictive and repetitive behaviours. The pathophysiology of ASD is multifactorial and includes genetic, epigenetic, and environmental factors, whereas a causal relationship has been described between ASD and inherited metabolic disorders (IMDs). This review describes biochemical, genetic, and clinical approaches to investigating IMDs associated with ASD. The biochemical work-up includes body fluid analysis to confirm general metabolic and/or lysosomal storage diseases, while the advances and applications of genomic testing technology would assist with identifying molecular defects. An IMD is considered likely underlying pathophysiology in ASD patients with suggestive clinical symptoms and multiorgan involvement, of which early recognition and treatment increase their likelihood of achieving optimal care and a better quality of life.

Associations between dysbiosis gut microbiota and changes of neurotransmitters and short-chain fatty acids in valproic acid model rats.

Introduction: The microbiota-gut-brain axis plays an important role in the pathophysiology of autism spectrum disorder, but its specific mechanisms remain unclear. This study aimed to explore the associations of changes in neurotransmitters and short-chain fatty acids with alterations in gut microbiota in valproic acid model rats. Methods: The autism model rats were established by prenatal exposure to valproic acid (VPA). The Morris water maze test, open field test, and three-chamber test were conducted to assess the behaviors of rats. 16S rRNA gene sequences extracted from fecal samples were used to assess the gut microbial composition. Gas and liquid chromatography-mass spectroscopy was used to identify short-chain fatty acids in fecal samples and neurotransmitters in the prefrontal cortex (PFC). Results: The results showed that 28 bacterial taxa between valproic acid model rats and control rats were identified, and the most differential bacterial taxa in valproic acid model rats and control rats belonged to metagenomic species and Lactobacillus intestinalis. Acetic acid, butyric acid, valeric acid, isobutyric acid, and isovaleric acid were significantly decreased in the valproic acid model rats compared to those in control rats. Five neurotransmitters (threonine, kynurenine, tryptophan, 5-hydroxyindoleacetic acid, denoted as 5-HIAA, and betaine aldehyde chloride, denoted as BAC) were significantly decreased, whereas betaine was increased in the prefrontal cortex of valproic acid model rats compared to control rats. A variety of neurotransmitters (≥4) were correlated with Pseudomonas, Collisella, and Streptococcus at the genus level, and they were also related to the decrease of short-chain fatty acids. Discussion: According to this study, we can preliminarily infer that gut microbiota or their metabolic productions (such as SCFAs) may influence central neurotransmitter metabolism through related pathways of the gut-brain axis. These results provide microbial and short-chain fatty acid (SCFA) frameworks for understanding the role of the microbiota-gut-brain axis in autism spectrum disorder and shed new light on autism spectrum disorder treatment.

Self/other distinction in adolescents with autism spectrum disorder (ASD) assessed with a double mirror paradigm.

Self/other distinction (SOD), which refers to the ability to distinguish one's own body, actions, and mental representations from those of others, is an essential skill for effective social interaction. A large body of clinical evidence suggests that disruptions in SOD may be key to social communication deficits in individuals with autism spectrum disorders (ASD). In particular, egocentric biases have been found in cognitive, affective, behavioural, and motor domains. However, research in this area is scarce and consists of recognition paradigms that have used only static images; these methods may be insufficient for assessing SOD, given the increasing role of embodiment in our understanding of the pathophysiology of ASD. A single-centre, prospective pilot study was carried out to investigate, for the first time, self-recognition and SOD in seven adolescents with ASD compared with matched, typically developing controls (TDCs) using the "Alter Ego"TM double mirror paradigm. The participants viewed a double mirror in which their own face was gradually morphed into the face of an unfamiliar other (self-to-other sequence) or vice versa (other-to-self sequence); participants were instructed to indicate at which point the morph looked more like their own face than the other's face. Two judgement criteria were used: 1) M1: the threshold at which subjects started to recognize their own face during the other-to-self morphing sequence; 2) M2: the threshold at which subjects started to recognize the other's face during the self-to-other morphing sequence. Consistent with the predictions, the results showed that the participants with ASD exhibited earlier self-recognition in the other-to-self sequence and delayed other-recognition in the self-to-other sequence, suggesting an egocentric bias. SOD impairments were also marginally correlated with ASD severity, indicating earlier face recognition in more severely affected individuals. Furthermore, in contrast with that of TDCs, the critical threshold for switching between self and other varied with the direction of morphing in ASD participants. Finally, these differences in face recognition and SOD using mirrors, unlike previous research using static images, support the central place of bodily self-consciousness in SOD impairments. Although additional research is needed to replicate the results of this preliminary study, it revealed the first behavioural evidence of altered SOD in ASD individuals on an embodied, semiecological face-recognition paradigm. Implications for understanding ASD are discussed from a developmental perspective, and new research and therapeutic perspectives are presented.