Dysfunction In Autism Spectrum Disorder Research Articles

Mutation in the mitochondrial chaperone TRAP1 leads to autism with more severe symptoms in males.

There is increasing evidence of mitochondrial dysfunction in autism spectrum disorders (ASD), but the causal relationships are unclear. In an ASD patient whose identical twin was unaffected, we identified a postzygotic mosaic mutation p.Q639* in the TRAP1 gene, which encodes a mitochondrial chaperone of the HSP90 family. Additional screening of 176 unrelated ASD probands revealed an identical TRAP1 variant in a male patient who had inherited it from a healthy mother. Notably, newly generated knock-in Trap1 p.Q641* mice display ASD-related behavioral abnormalities that are more pronounced in males than in females. Accordingly, Trap1 p.Q641* mutation also resulted in sex-specific changes in synaptic plasticity, the number of presynaptic mitochondria, and mitochondrial respiration. Thus, the TRAP1 p.Q639* mutation is the first example of a monogenic ASD caused by impaired mitochondrial protein homeostasis.

Dysregulated plasma autoantibodies are associated with B cell dysfunction in young Arab children with autism spectrum disorder in Qatar.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction and communication, as well as the occurrence of stereotyped and repetitive behaviors. Previous studies have provided solid evidence of dysregulated immune system in ASD; however, limited studies have investigated autoantibody profiles in individuals with ASD. This study aims to screen plasma autoantibodies in a well-defined cohort of young children with ASD (n = 100) and their matched controls (n = 60) utilizing a high-throughput KoRectly Expressed (KREX) i-Ome protein-array technology. We identified differential protein expression of 16 autoantibodies in ASD, which were correlated with differential gene expression of these markers in independent ASD cohorts. Meanwhile, we identified a distinct list of 33 autoantibodies associated with ASD severity; several of which were correlated with maternal age and birth weight in ASD. In addition, we found dysregulated numbers of circulating B cells and activated HLADR+ B cells in ASD, which were correlated with altered levels of several autoantibodies. Further in-depth analysis of B cell subpopulations revealed an increased frequency of activated naïve B cells in ASD, as well as an association of resting naïve B cells and transitional B cells with ASD severity. Pathway enrichment analysis revealed disrupted MAPK signaling in ASD, suggesting a potential relevance of this pathway to altered autoantibodies and B cell dysfunction in ASD. Finally, we found that a combination of eight autoantibodies associated with ASD severity showed an area under the curve (ROC-AUC) of 0.937 (95% CI = 0.890, 0.983; p < 0.001), which demonstrated the diagnostic accuracy of the eight-marker signature in the severity classification of ASD cases. Overall, this study determined dysregulated autoantibody profiles and B cell dysfunction in children with ASD and identified an eight-autoantibody panel for ASD severity classification.

Harnessing the Gut Microbiome: To What Extent Can Pre-/Probiotics Alleviate Immune Activation in Autism Spectrum Disorder?

Children diagnosed with autism spectrum disorder (ASD) are at an increased risk of experiencing gastrointestinal (GI) discomfort, which has been linked to dysfunctions in the microbiome-gut-brain axis. The bidirectional communication between gut and brain plays a crucial role in the overall health of individuals, and alterations in the gut microbiome can contribute to immune activation and gut-brain dysfunction in ASD. Despite the limited and controversial results of pre-/probiotic applications in ASD, this review comprehensively maps the association between ASD clinical symptoms and specific bacterial taxa and evaluates the efficacy of pre-/probiotics in modulating microbiota composition, reducing inflammatory biomarkers, alleviating difficulties in GI distress, sleep problems, core and other ASD-associated symptoms, as well as relieving parental concerns, separately, in individuals with ASD. Beyond simply targeting core ASD symptoms, this review highlights the potential of pre-/probiotic supplementations as a strategy to modulate gut homeostasis and immune response, and to delineate the potential mechanisms by which its direct or mediating effects can alleviate gut-brain dysfunction and poor nutritional status in ASD management. Further well-designed randomized controlled trials are needed to strengthen the existing evidence and establish optimal protocols for the use of pre-/probiotics in the context of ASD.

Altered white matter connectivity of ventral language networks in autism spectrum disorder: An automated fiber quantification analysis with multi-site datasets

Comprehension and pragmatic deficits are prevalent in autism spectrum disorder (ASD) and are potentially linked to altered connectivity in the ventral language networks. However, previous magnetic resonance imaging studies have not sufficiently explored the microstructural abnormalities in the ventral fiber tracts underlying comprehension dysfunction in ASD. Additionally, the precise locations of white matter (WM) changes in the long tracts of patients with ASD remain poorly understood. In the current study, we applied the automated fiber-tract quantification (AFQ) method to investigate the fine-grained WM properties of the ventral language pathway and their relationships with comprehension and symptom manifestation in ASD. The analysis included diffusion/T1 weighted imaging data of 83 individuals with ASD and 83 age-matched typically developing (TD) controls. Case-control comparisons were performed on the diffusion metrics of the ventral tracts at both the global and point-wise levels. We also explored correlations between diffusion metrics, comprehension performance, and ASD traits, and conducted subgroup analyses based on age range to examine developmental moderating effects. Individuals with ASD exhibited remarkable hypoconnectivity in the ventral tracts, particularly in the temporal portions of the left inferior longitudinal fasciculus (ILF) and the inferior fronto-occipital fasciculus (IFOF). These WM abnormalities were associated with poor comprehension and more severe ASD symptoms. Furthermore, WM alterations in the ventral tract and their correlation with comprehension dysfunction were more prominent in younger children with ASD than in adolescents. These findings indicate that WM disruptions in the temporal portions of the left ILF/IFOF are most notable in ASD, potentially constituting the core neurological underpinnings of comprehension and communication deficits in autism. Moreover, impaired WM connectivity and comprehension ability in patients with ASD appear to improve with age.

Altered intra- and inter-network connectivity in autism spectrum disorder.

A neurodevelopmental illness termed as the autism spectrum disorder (ASD) is described by social interaction impairments. Previous studies employing resting-state functional imaging (rs-fMRI) identified both hyperconnectivity and hypoconnectivity patterns in ASD people. However, specific patterns of connectivity within and between networks linked to ASD remain largely unexplored. We utilized a meticulously selected subset of high-quality data, comprising 45 individuals diagnosed with ASD and 47 HCs, obtained from the ABIDE dataset. The pre-processed rs-fMRI time series signals were partitioned into ninety regions of interest. We focused on eight intrinsic connectivity networks and further performed intra- and inter-network analysis. Finally, support vector machine was used to discriminate ASD from HC. Through different sparsities, ASD exhibited significantly decreased intra-network connectivity within default mode network and dorsal attention network, increased connectivity between limbic network and subcortical network, and decreased connectivity between default mode network and limbic network. Using the classifier trained on altered intra- and inter-network connectivity, multivariate pattern analyses classified the ASD from HC with 71.74% accuracy, 70.21% specificity and 75.56% sensitivity in 10% sparsity of functional connectivity. ASD showed characteristic reorganization of the brain networks and this provided new insight into the underlying process of the functional connectome dysfunction in ASD.

Aflatoxin B1 exposure deteriorates immune abnormalities in a BTBR T+ Itpr3tf/J mouse model of autism by increasing inflammatory mediators' production in CD19-expressing cells

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficiencies in communication, repetitive and stereotyped behavioral patterns, and difficulties in reciprocal social engagement. The presence of immunological dysfunction in ASD has been well established. Aflatoxin B1 (AFB1) is a prevalent mycotoxin found in food and feed, causing immune toxicity and hepatotoxicity. AFB1 is significantly elevated in several regions around the globe. Existing research indicates that prolonged exposure to AFB1 results in neurological problems. The BTBR T+ Itpr3tf/J (BTBR) mice, which were used as an autism model, exhibit the primary behavioral traits that define ASD, such as repeated, stereotyped behaviors and impaired social interactions. The main objective of this work was to assess the toxic impact of AFB1 in BTBR mice. This work aimed to examine the effects of AFB1 on the expression of Notch-1, IL-6, MCP-1, iNOS, GM-CSF, and NF-κB p65 by CD19+ B cells in the spleen of the BTBR using flow cytometry. We also verified the impact of AFB1 exposure on the mRNA expression levels of Notch-1, IL-6, MCP-1, iNOS, GM-CSF, and NF-κB p65 in the brain of BTBR mice using real-time PCR. The findings of our study showed that the mice treated with AFB1 in the BTBR group exhibited a substantial increase in the presence of CD19+Notch-1+, CD19+IL-6+, CD19+MCP-1+, CD19+iNOS+, CD19+GM-CSF+, and CD19+NF-κB p65+ compared to the mice in the BTBR group that were treated with saline. Our findings also confirmed that administering AFB1 to BTBR mice leads to elevated mRNA expression levels of Notch-1, IL-6, MCP-1, iNOS, GM-CSF, and NF-κB p65 in the brain, in comparison to BTBR mice treated with saline. The data highlight that exposure to AFB1 worsens immunological abnormalities by increasing the expression of inflammatory mediators in BTBR mice.

Interactions between circulating inflammatory factors and autism spectrum disorder: a bidirectional Mendelian randomization study in European population.

Extensive observational studies have reported an association between inflammatory factors and autism spectrum disorder (ASD), but their causal relationships remain unclear. This study aims to offer deeper insight into causal relationships between circulating inflammatory factors and ASD. Two-sample bidirectional Mendelian randomization (MR) analysis method was used in this study. The genetic variation of 91 circulating inflammatory factors was obtained from the genome-wide association study (GWAS) database of European ancestry. The germline GWAS summary data for ASD were also obtained (18,381 ASD cases and 27,969 controls). Single nucleotide polymorphisms robustly associated with the 91 inflammatory factors were used as instrumental variables. The random-effects inverse-variance weighted method was used as the primary analysis, and the Bonferroni correction for multiple comparisons was applied. Sensitivity tests were carried out to assess the validity of the causal relationship. The forward MR analysis results suggest that levels of sulfotransferase 1A1, natural killer cell receptor 2B4, T-cell surface glycoprotein CD5, Fms-related tyrosine kinase 3 ligand, and tumor necrosis factor-related apoptosis-inducing ligand are positively associated with the occurrence of ASD, while levels of interleukin-7, interleukin-2 receptor subunit beta, and interleukin-2 are inversely associated with the occurrence of ASD. In addition, matrix metalloproteinase-10, caspase 8, tumor necrosis factor-related activation-induced cytokine, and C-C motif chemokine 19 were considered downstream consequences of ASD. This MR study identified additional inflammatory factors in patients with ASD relative to previous studies, and raised a possibility of ASD-caused immune abnormalities. These identified inflammatory factors may be potential biomarkers of immunologic dysfunction in ASD.

Innate Immune Dysfunction and Neuroinflammation in Autism Spectrum Disorder (ASD).

Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder characterized by communication and social behavior deficits. The presence of restricted and repetitive behaviors often accompanies these deficits, and these characteristics can range from mild to severe. The past several decades have seen a significant rise in the prevalence of ASD. The etiology of ASD remains unknown; however, genetic and environmental risk factors play a role. Multiple hypotheses converge to suggest that neuroinflammation, or at least the interaction between immune and neural systems, may be involved in the etiology of some ASD cases or groups. Repeated evidence of innate immune dysfunction has been seen in ASD, often associated with worsening behaviors. This evidence includes data from circulating myeloid cells and brain resident macrophages/microglia in both human and animal models. This comprehensive review presents recent findings of innate immune dysfunction in ASD, including aberrant innate cellular function, evidence of neuroinflammation, and microglia activation. Appeared originally in Brain Behav Immun 2023; 108:245-254.

Neural circuit disruptions of eye gaze processing in autism spectrum disorder and schizophrenia: An activation likelihood estimation meta-analysis

BackgroundImpairment in social cognition, particularly eye gaze processing, is a shared feature common to autism spectrum disorder (ASD) and schizophrenia. However, it is unclear if a convergent neural mechanism also underlies gaze dysfunction in these conditions. The present study examined whether this shared eye gaze phenotype is reflected in a profile of convergent neurobiological dysfunction in ASD and schizophrenia. MethodsActivation likelihood estimation (ALE) meta-analyses were conducted on peak voxel coordinates across the whole brain to identify spatial convergence. Functional coactivation with regions emerging as significant was assessed using meta-analytic connectivity modeling. Functional decoding was also conducted. ResultsFifty-six experiments (n = 30 with schizophrenia and n = 26 with ASD) from 36 articles met inclusion criteria, which comprised 354 participants with ASD, 275 with schizophrenia and 613 healthy controls (1242 participants in total). In ASD, aberrant activation was found in the left amygdala relative to unaffected controls during gaze processing. In schizophrenia, aberrant activation was found in the right inferior frontal gyrus and supplementary motor area. Across ASD and schizophrenia, aberrant activation was found in the right inferior frontal gyrus and right fusiform gyrus during gaze processing. Functional decoding mapped the left amygdala to domains related to emotion processing and cognition, the right inferior frontal gyrus to cognition and perception, and the right fusiform gyrus to visual perception, spatial cognition, and emotion perception. These regions also showed meta-analytic connectivity to frontoparietal and frontotemporal circuitry. ConclusionAlterations in frontoparietal and frontotemporal circuitry emerged as neural markers of gaze impairments in ASD and schizophrenia. These findings have implications for advancing transdiagnostic biomarkers to inform targeted treatments for ASD and schizophrenia.

A Vascular-Centric Approach to Autism Spectrum Disorders.

Brain development and function are highly reliant on adequate establishment and maintenance of vascular networks. Early impairments in vascular health can impact brain maturation and energy metabolism, which may lead to neurodevelopmental anomalies. Our recent work not only provides novel insights into the development of cerebrovascular networks but also emphasizes the importance of their well-being for proper brain maturation. In particular, we have demonstrated that endothelial dysfunction in autism spectrum disorders (ASD) mouse models is causally related to altered behavior and brain metabolism. In the prenatal human brain, vascular cells change metabolic states in the second trimester. Such findings highlight the need to identify new cellular and molecular players in neurodevelopmental disorders, raising awareness about the importance of a healthy vasculature for brain development. It is thus essential to shift the mostly neuronal point of view in research on ASD and other neurodevelopmental disorders to also include vascular and metabolic features.

Autism spectrum disorders and the gastrointestinal tract: insights into mechanisms and clinical relevance.

Autism spectrum disorders (ASDs) are recognized as central neurodevelopmental disorders diagnosed by impairments in social interactions, communication and repetitive behaviours. The recognition of ASD as a central nervous system (CNS)-mediated neurobehavioural disorder has led most of the research in ASD to be focused on the CNS. However, gastrointestinal function is also likely to be affected owing to the neural mechanistic nature of ASD and the nervous system in the gastrointestinal tract (enteric nervous system). Thus, it is unsurprising that gastrointestinal disorders, particularly constipation, diarrhoea and abdominal pain, are highly comorbid in individuals with ASD. Gastrointestinal problems have also been repeatedly associated with increased severity of the core symptoms diagnostic of ASD and other centrally mediated comorbid conditions, including psychiatric issues, irritability, rigid-compulsive behaviours and aggression. Despite the high prevalence of gastrointestinal dysfunction in ASD and its associated behavioural comorbidities, the specific links between these two conditions have not been clearly delineated, and current data linking ASD to gastrointestinal dysfunction have not been extensively reviewed. This Review outlines the established and emerging clinical and preclinical evidence that emphasizes the gut as a novel mechanistic and potential therapeutic target for individuals with ASD.

Link between the skin and autism spectrum disorder.

Autism spectrum disorder (ASD) is a common neurological disorder. Although the etiologies of ASD have been widely speculated, evidence also supports the pathogenic role of cutaneous inflammation in autism. The prevalence of ASD is higher in individuals with inflammatory dermatoses than in those without inflammatory diseases. Anti-inflammation therapy alleviates symptoms of ASD. Recent studies suggest a link between epidermal dysfunction and ASD. In the murine model, mice with ASD display epidermal dysfunction, accompanied by increased expression levels of proinflammatory cytokines in both the skin and the brain. Children with ASD, which develops in their early lifetime, also exhibit altered epidermal function. Interestingly, improvement in epidermal function alleviates some symptoms of ASD. This line of evidence suggests a pathogenic role of cutaneous dysfunction in ASD. Either an improvement in epidermal function or effective treatment of inflammatory dermatoses can be an alternative approach to the management of ASD. We summarize here the current evidence of the association between the skin and ASD.

Altered markers of mitochondrial function in adults with autism spectrum disorder.

Previous research suggests potential mitochondrial dysfunction and changes in fatty acid metabolism in a subgroup of individuals with autism spectrum disorder (ASD), indicated by higher lactate, pyruvate levels, and mitochondrial disorder prevalence. This study aimed to further investigate potential mitochondrial dysfunction in ASD by assessing blood metabolite levels linked to mitochondrial metabolism. Blood levels of creatine kinase (CK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate, pyruvate, free and total carnitine, as well as acylcarnitines were obtained in 73 adults with ASD (47 males, 26 females) and compared with those of 71 neurotypical controls (NTC) (44 males, 27 females). Correlations between blood parameters and psychometric ASD symptom scores were also explored. Lower CK (pcorr = 0.045) levels were found exclusively in males with ASD compared to NTC, with no such variation in females. ALT and AST levels did not differ significantly between both groups. After correction for antipsychotic and antidepressant medication, CK remained significant. ASD participants had lower serum lactate levels (pcorr = 0.036) compared to NTC, but pyruvate and carnitine concentrations showed no significant difference. ASD subjects had significantly increased levels of certain acylcarnitines, with a decrease in tetradecadienoyl-carnitine (C14:2), and certain acylcarnitines correlated significantly with autistic symptom scores. We found reduced serum lactate levels in ASD, in contrast to previous studies suggesting elevated lactate or pyruvate. This difference may reflect the focus of our study on high-functioning adults with ASD, who are likely to have fewer secondary genetic conditions associated with mitochondrial dysfunction. Our findings of significantly altered acylcarnitine levels in ASD support the hypothesis of altered fatty acid metabolism in a subset of ASD patients.

Neurobiological Factors of Executive Dysfunction in Autism Spectrum Disorders

Neurobiological Factors of Executive Dysfunction in Autism Spectrum Disorders

Social circuits and their dysfunction in autism spectrum disorder.

Social behaviors, how individuals act cooperatively and competitively with conspecifics, are widely seen across species. Rodents display various social behaviors, and many different behavioral paradigms have been used for investigating their neural circuit bases. Social behavior is highly vulnerable to brain network dysfunction caused by neurological and neuropsychiatric conditions such as autism spectrum disorders (ASDs). Studying mouse models of ASD provides a promising avenue toward elucidating mechanisms of abnormal social behavior and potential therapeutic targets for treatment. In this review, we outline recent progress and key findings on neural circuit mechanisms underlying social behavior, with particular emphasis on rodent studies that monitor and manipulate the activity of specific circuits using modern systems neuroscience approaches. Social behavior is mediated by a distributed brain-wide network among major cortical (e.g., medial prefrontal cortex (mPFC), anterior cingulate cortex, and insular cortex (IC)) and subcortical (e.g., nucleus accumbens, basolateral amygdala (BLA), and ventral tegmental area) structures, influenced by multiple neuromodulatory systems (e.g., oxytocin, dopamine, andserotonin). We particularly draw special attention to IC as a unique cortical area that mediates multisensory integration, encoding of ongoing social interaction, social decision-making, emotion, and empathy. Additionally, a synthesis of studies investigating ASD mouse models demonstrates that dysfunctions in mPFC-BLA circuitry and neuromodulation are prominent. Pharmacological rescues by local or systemic (e.g., oral) administration of various drugs have provided valuable clues for developing new therapeutic agents for ASD. Future efforts and technological advances will push forward the next frontiers in this field, such as the elucidation of brain-wide network activity and inter-brain neural dynamics during real and virtual social interactions, and the establishment of circuit-based therapy for disorders affecting social functions.

The Role of Circadian Rhythm in Autism Spectrum Disorder

With the development of technology and gradual enrichment in life, there is a significant increase in attention towards neurodevelopment and child health. Autism Spectrum Disorder (ASD) is defined as a neurological and developmental disorder that affects how people speak, behave, and interact with others. Communication and social interaction issues, sensory abnormalities, repetitive habits, and varying degrees of intellectual disability are some of the symptoms of autism. ASDs influences about 1 in 44 children in the USA, with the number of incidents sharply increasing over the years. Epigenetic neurobiology factors and environment related factors should both be considered when interpreting the pathophysiology that lies behind ASD. The 24-hour physiological cycle that displays an endogenous and entrainable oscillation is known as the circadian rhythm, which is generated by a molecular clock system. Mounting evidence are linking circadian rhythm disorder and autism. This includes sleep chaos as a common epiphenomenon of ASD, melatonin level disorder in ASD and circadian gene dysfunction in ASD. This article revolves around three perspectives: 1) Sleep Disorder in ASD 2) Role of Circadian Biomarkers in ASD 3) Variants and deficiency of circadian genes in ASD. In conclusion, the article reveals the important role circadian rhythm plays in neurodevelopmental processes. Through examining the circadian rhythm not only as an epiphenomenon but also as a possible indicator for ASD, the article anticipates the implication of circadian rhythm in novel treatments of ASD as a conclusion.

Quantitative Spatial Analysis of Neuroligin-3 mRNA Expression in the Enteric Nervous System Reveals a Potential Role in Neuronal-Glial Synapses and Reduced Expression in Nlgn3R451C Mice.

Mutations in the Neuroligin-3 (Nlgn3) gene are implicated in autism spectrum disorder (ASD) and gastrointestinal (GI) dysfunction, but cellular Nlgn3 expression in the enteric nervous system remains to be characterised. We combined RNAScope in situ hybridization and immunofluorescence to measure Nlgn3 mRNA expression in cholinergic and VIP-expressing submucosal neurons, nitrergic and calretinin-containing myenteric neurons and glial cells in both WT and Nlgn3R451C mutant mice. We measured Nlgn3 mRNA neuronal and glial expression via quantitative three-dimensional image analysis. To validate dual RNAScope/immunofluorescence data, we interrogated available single-cell RNA sequencing (scRNASeq) data to assess for Nlgn3, Nlgn1, Nlgn2 and their binding partners, Nrxn1-3, MGDA1 and MGDA2, in enteric neural subsets. Most submucosal and myenteric neurons expressed Nlgn3 mRNA. In contrast to other Nlgns and binding partners, Nlgn3 was strongly expressed in enteric glia, suggesting a role for neuroligin-3 in mediating enteric neuron-glia interactions. The autism-associated R451C mutation reduces Nlgn3 mRNA expression in cholinergic but not in VIPergic submucosal neurons. In the myenteric plexus, Nlgn3 mRNA levels are reduced in calretinin, nNOS-labelled neurons and S100 β -labelled glia. We provide a comprehensive cellular profile for neuroligin-3 expression in ileal neuronal subpopulations of mice expressing the R451C autism-associated mutation in Nlgn3, which may contribute to the understanding of the pathophysiology of GI dysfunction in ASD.

Replicable Patterns of Memory Impairments in Children With Autism and Their Links to Hyperconnected Brain Circuits

BackgroundMemory impairments have profound implications for social communication and educational outcomes in children with autism spectrum disorder (ASD). However, the precise nature of memory dysfunction in children with ASD and the underlying neural circuit mechanisms remain poorly understood. The default mode network (DMN) is a brain network that is associated with memory and cognitive function, and DMN dysfunction is among the most replicable and robust brain signatures of ASD. MethodsWe used a comprehensive battery of standardized episodic memory assessments and functional circuit analyses in 25 8- to 12-year-old children with ASD and 29 matched typically developing control children. ResultsMemory performance was reduced in children with ASD compared with control children. General and face memory emerged as distinct dimensions of memory difficulties in ASD. Importantly, findings of diminished episodic memory in children with ASD were replicated in 2 independent data sets. Analysis of intrinsic functional circuits associated with the DMN revealed that general and face memory deficits were associated with distinct, hyperconnected circuits: Aberrant hippocampal connectivity predicted diminished general memory while aberrant posterior cingulate cortex connectivity predicted diminished face memory. Notably, aberrant hippocampal-posterior cingulate cortex circuitry was a common feature of diminished general and face memory in ASD. ConclusionsOur results represent a comprehensive appraisal of episodic memory function in children with ASD and identify extensive and replicable patterns of memory reductions in children with ASD that are linked to dysfunction of distinct DMN-related circuits. These findings highlight a role for DMN dysfunction in ASD that extends beyond face memory to general memory function.

Altered rich-club organization of brain functional network in autism spectrum disorder.

Despite numerous research showing the association between brain network abnormalities and autism spectrum disorder (ASD), contrasting findings have been reported from broad functional underconnectivity to broad overconnectivity. Thus, the significance of rich-hub organizations in the brain functional connectome of individuals with ASD remains largely unknown. High-quality data subset of ASD (n= 45) and healthy controls (HC; n= 47) children (7-15 years old) were retrieved from the ABIDE data set, and rich-club organization and network-based statistic (NBS) were assessed from resting-state functional magnetic resonance imaging (rs-fMRI). The rich-club organization functional network (normalized rich-club coefficients >1) was observed in all subjects under a range of thresholds. Compared with HC, ASD patients had higher degree of feeder connections and lower degree of local connections (degree of feeder connections: ASD=259.20 ± 32.97, HC=244.98 ± 30.09, p= 0.041; degree of local connections: ASD=664.02 ± 39.19, HC=679.89 ± 34.05, p= 0.033) but had similar in rich-club connections. Further, nonparametric NBS analysis showed the presence of abnormal connectivity in the functional network of ASD individuals. Our findings indicated that local connection might be more vulnerable, and feeder connection may compensate for its disruption in ASD, enhancing our understanding on the mechanism of functional connectome dysfunction in ASD.

Purine signaling pathway dysfunction in autism spectrum disorders: Evidence from multiple omics data.

Previous studies have suggested that the dysregulation of purine metabolism may be associated with autism spectrum disorder (ASD). Here, we adopted metabolomics and transcriptomics to verify and explore the underlying molecular mechanism of purine metabolism dysfunction in ASD and identify potential biomarkers within the purine metabolism pathway. Ultra-high-performance liquid chromatography-mass spectrometry was used to obtain the plasma metabolic profiles of 12 patients with ASD and 12 typically developing (TD) children. RNA sequencing was used to screen differentially expressed genes related to the purine metabolic pathway and purine receptor-coding genes in 24 children with ASD and 21 healthy controls. Finally, serum uric acid levels were compared in 80 patients with ASD and 174 TD children to validate the omics results. A total of 66 identified metabolites showed significant between-group differences. Network analysis showed that purine metabolism was the most strongly enriched. Uric acid was one of the most highlighted nodes within the network. The transcriptomic study revealed significant differential expression of three purine metabolism-related genes (adenosine deaminase, adenylosuccinate lyase, and bifunctional enzyme neoformans 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/inosine monophosphate (IMP) cyclohydrolase) (p < 0.01) and five purinergic receptor genes (P2X7, P2Y2, P2Y6, P2Y8, and P2Y10) (p < 0.05). In the validation sample, there was a significant difference in serum uric acid levels between the two groups (p < 0.001), and the area under the curve for uric acid was 0.812 (sensitivity, 82.5%; specificity, 63.8%). Patients with ASD had dysfunctional purine metabolic pathways, and blood uric acid may be a potential biomarker for ASD.