Autistic Subjects Research Articles

Urinary opioid peptides in children with autism spectrum disorders. A Pilot Study

BACKGROUND: Circulating β-casomorphins (BCM) and gluten exorphins (GE), which are exogenous opioid peptides originating from bovine milk protein casein and cereal protein gluten, respectively, have been proposed as potential trigger factor to symptoms observed in children with autism. OBJECTIVE: Given the debate surrounding the detectability of these opioid peptides in body fluids, particularly using highly sensitive and specific mass spectrometry (HPLC-MS) techniques, we aimed to investigate their presence in urine samples of autistic subjects. METHODS: We employed an HPLC-MS method for peptide detection. RESULTS: The presence of several BCMs and GEs in the urine of both autistic children (ASD) and healthy controls (HC) was documented. The detection of dietary opioid peptides even at very low concentrations underscores the sensitivity of this novel HPLC-MS method. BCM-8 was more often detected in the ASD group compared to the HC group. A higher prevalence of gastrointestinal (GI) symptoms were also observed in the ASD group. CONCLUSIONS: This pilot study supports the presence of BCMs and GEs in urine samples in subjects with autism as well as healthy controls which was the main goal of this pilot study. Prolonged exposure to bovine BCMs and GEs may play a role in the manifestation of core and GI symptoms in subgroups of autism. Further research is warranted to investigate this phenomenon thoroughly.

Classification of autistic subjects employing modified volume local binary pattern (MVLBP) and stacked Autoencoder (SAE) on functional magnetic resonance imaging (fMRI)

Classification of autistic subjects employing modified volume local binary pattern (MVLBP) and stacked Autoencoder (SAE) on functional magnetic resonance imaging (fMRI)

Effects of Memantine on Cognitive Flexibility in a Valproic Acid Rat Model of Autism

Abstract Autistic children frequently struggle with cognitive flexibility. The potential molecular mechanism underlying cognitive inflexibility remains unclear. Decreased level of brain-derived neurotrophic factor (BDNF), which plays a vital role in neural development and synaptic plasticity may have a role. This study aimed to investigate the effects of memantine on (BDNF) expression in hippocampus of prenatal VPA exposed rats, and its consequent effects on cognitive flexibility. Pregnant female rats received a single intraperitoneal injection of VPA (600 mg/kg) on gestational day 12.5 to induce autistic-like behaviors in their offspring. Afterwards, the 23-day-old male Wistar rat pups received daily intraperitoneal injections of memantine (20 mg/kg) for 4 weeks. The prenatal VPA-exposed rats exhibited reduced cognitive flexibility in the attentional set- shifting task (ASST) reflecting ASD-associated cognitive flexibility deficits, a common ASD- associated problem with accompanied reduction in hippocampal BDNF. The defective performance in ASST was more prominent in the reversal stages. Memantine associated increased hippocampal BDNF could alleviate cognitive inflexibility in ASD. This study draws attention to the potential favorable effect of memantine on cognitive performance in autistic subjects.

Gut Microbiota in Autism Spectrum Disorder: A Systematic Review

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition with stereotyped behavior and deficits in communication and social interaction. There is increasing evidence of the implication of gut microbiota in ASD. We conducted a systematic review to summarize previously published data to compare the profile of gut microbiota between autistic and neurotypical subjects. The outcomes of interventions such as prebiotics, probiotics, and microbiota transplantation therapy to overcome the symptomatology of ASD were also discussed. The current review allows us to associate gut microbiota dysbiosis and ASD. To date, there is still little consensus on which bacterial species are consistently altered in individuals with autism. Further studies are required to obtain stronger evidence of the relationship between gut microbiota and the severity of ASD conjointly with the effectiveness of dietary/probiotic interventions in reducing autistic behaviors compared to their healthy siblings.

Increased gene dosage of RFWD2 causes autistic-like behaviors and aberrant synaptic formation and function in mice

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions, communication deficits and repetitive behaviors. A study of autistic human subjects has identified RFWD2 as a susceptibility gene for autism, and autistic patients have 3 copies of the RFWD2 gene. The role of RFWD2 as an E3 ligase in neuronal functions, and its contribution to the pathophysiology of ASD, remain unknown. We generated RFWD2 knockin mice to model the human autistic condition of high gene dosage of RFWD2. We found that heterozygous knockin (Rfwd2+/−) male mice exhibited the core symptoms of autism. Rfwd2+/− male mice showed deficits in social interaction and communication, increased repetitive and anxiety-like behavior, and spatial memory deficits, whereas Rfwd2+/− female mice showed subtle deficits in social communication and spatial memory but were normal in anxiety-like, repetitive, and social behaviors. These autistic-like behaviors in males were accompanied by a reduction in dendritic spine density and abnormal synaptic function on layer II/III pyramidal neurons in the prelimbic area of the medial prefrontal cortex (mPFC), as well as decreased expression of synaptic proteins. Impaired social behaviors in Rfwd2+/− male mice were rescued by the expression of ETV5, one of the major substrates of RFWD2, in the mPFC. These findings indicate an important role of RFWD2 in the pathogenesis of autism.

Identifying autism using EEG: unleashing the power of feature selection and machine learning

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that is characterized by communication barriers, societal disengagement, and monotonous actions. Currently, the diagnosis of ASD is made by experts through a subjective and time-consuming qualitative behavioural examination using internationally recognized descriptive standards. In this paper, we present an EEG-based three-phase novel approach comprising 29 autistic subjects and 30 neurotypical people. In the first phase, preprocessing of data is performed from which we derived one continuous dataset and four condition-based datasets to determine the role of each dataset in the identification of autism from neurotypical people. In the second phase, time-domain and morphological features were extracted and four different feature selection techniques were applied. In the last phase, five-fold cross-validation is used to evaluate six different machine learning models based on the performance metrics and computational efficiency. The neural network outperformed when trained with maximum relevance and minimum redundancy (MRMR) algorithm on the continuous dataset with 98.10% validation accuracy and 0.9994 area under the curve (AUC) value for model validation, and 98.43% testing accuracy and AUC test value of 0.9998. The decision tree overall performed the second best in terms of computational efficiency and performance accuracy. The results indicate that EEG-based machine learning models have the potential for ASD identification from neurotypical people with a more objective and reliable method.

Contribution of the serotonergic system to developmental brain abnormalities in autism spectrum disorder.

This review highlights a key role of the serotonergic system in brain development and in distortions of normal brain development in early stages of fetal life resulting in cascades of abnormalities, including defects of neurogenesis, neuronal migration, neuronal growth, differentiation, and arborization, as well as defective neuronal circuit formation in the cortex, subcortical structures, brainstem, and cerebellum of autistic subjects. In autism, defects in regulation of neuronal growth are the most frequent and ubiquitous developmental changes associated with impaired neuron differentiation, smaller size, distorted shape, loss of spatial orientation, and distortion of cortex organization. Common developmental defects of the brain in autism include multiregional focal dysplastic changes contributing to local neuronal circuit distortion, epileptogenic activity, and epilepsy. There is a discrepancy between more than 500 reports demonstrating the contribution of the serotonergic system to autism's behavioral anomalies, highlighted by lack of studies of autistic subjects' brainstem raphe nuclei, the center of brain serotonergic innervation, and of the contribution of the serotonergic system to the diagnostic features of autism spectrum disorder (ASD). Discovery of severe fetal brainstem auditory system neuronal deficits and other anomalies leading to a spectrum of hearing deficits contributing to a cascade of behavioral alterations, including deficits of social and verbal communication in individuals with autism, is another argument to intensify postmortem studies of the type and topography of, and the severity of developmental defects in raphe nuclei and their contribution to abnormal brain development and to the broad spectrum of functional deficits and comorbid conditions in ASD.

Introduction à une pulsion du mouvement à partir de « L’esquisse d’une Psychologie » de S. Freud. Le cas des mouvements autistiques

AimThe aim of this article is to identify the psychic function of those movements referred to as “wandering and roaming including the motor agitation that certain patients are presenting.” These considerations, which interested the first alienists, are still relevant in contemporary psychopathology, in particular regarding hyperactivity in autism, which will be our main focus. Based on the psychoanalytical concept of the drive, we propose an economic model leading from the body to the psyche, a model of the movement drive operating in clinical psychology. MethodFor this purpose, we will combine data from an epistemological study of the movement drive hypothesis with research on hyperactivity (Jean Bergès, Jean-Marie Forget) and autism (Marie Couvert or Marie Christine Laznik). An in-depth study of one of Freud's pre-psychoanalytical texts will enable us to identify Freud's special interest in the question of movement (Bewegung) rather than motor skills, and its effects on the psychic structuring of the new-born child at the dawn of its encounter with its environment. ResultsIt will then be possible to develop a model of a movement drive and its structuring effects: on the body, from motor agitation to the appropriate action, and on the psyche by the construction of the subject's own singular spaces. On the basis of this theoretical model, we will identify what we call “continuous walking” in autistic subjects. DiscussionWe will then discuss whether or not each individual/human subject is able to move within the space produced by the structure; in other words, the possibility of a differential diagnosis based on the question of movement and the appropriation of space. ConclusionThe movement drive finds coherence in psychoanalytical writings, and proves to be effective for thinking about the support of the suffering individual/human subject, taking into account the articulation between body, psyche, and space.

Attention Analysis in Robotic-Assistive Therapy for Children With Autism.

Children with Autism Spectrum Disorder (ASD) show severe attention deficits, hindering their capacity to acquire new skills. The automatic assessment of their attention response would provide the therapists with an important biomarker to better quantify their behaviour and monitor their progress during therapy. This work aims to develop a quantitative model, to evaluate the attention response of children with ASD, during robotic-assistive therapeutic sessions. Previous attempts to quantify the attention response of autistic subjects during human-robot interaction tasks were limited to restrained child movements. Instead, we developed an accurate quantitative system to assess the attention of ASD children in unconstrained scenarios. Our approach combines gaze extraction (Gaze360 model) with the definition of angular Areas-of-Interest, to characterise periods of attention towards elements of interest in the therapy environment during the session. The methodology was tested with 12 ASD children, achieving a mean test accuracy of 79.5 %. Finally, the proposed attention index was consistent with the therapists' evaluation of patients, allowing a meaningful interpretation of the automatic evaluation. This encourages the future clinical use of the proposed system.

Exploring the multidimensional nature of repetitive and restricted behaviors and interests (RRBI) in autism: neuroanatomical correlates and clinical implications

BackgroundRepetitive and restricted behaviors and interests (RRBI) are core symptoms of autism with a complex entity and are commonly categorized into ‘motor-driven’ and ‘cognitively driven’. RRBI symptomatology depends on the individual’s clinical environment limiting the understanding of RRBI physiology, particularly their associated neuroanatomical structures. The complex RRBI heterogeneity needs to explore the whole RRBI spectrum by integrating the clinical context [autistic individuals, their relatives and typical developing (TD) individuals]. We hypothesized that different RRBI dimensions would emerge by exploring the whole spectrum of RRBI and that these dimensions are associated with neuroanatomical signatures—involving cortical and subcortical areas.MethodA sample of 792 individuals composed of 267 autistic subjects, their 370 first-degree relatives and 155 TD individuals was enrolled in the study. We assessed the whole patterns of RRBI in each individual by using the Repetitive Behavior Scale-Revised and the Yale-Brown Obsessive Compulsive Scale. We estimated brain volumes using MRI scanner for a subsample of the subjects (n = 152, 42 ASD, 89 relatives and 13 TD). We first investigated the dimensionality of RRBI by performing a principal component analysis on all items of these scales and included all the sampling population. We then explored the relationship between RRBI-derived factors with brain volumes using linear regression models.ResultsWe identified 3 main factors (with 30.3% of the RRBI cumulative variance): Factor 1 (FA1, 12.7%) reflected mainly the ‘motor-driven’ RRBI symptoms; Factor 2 and 3 (respectively, 8.8% and 7.9%) gathered mainly Y-BOCS related items and represented the ‘cognitively driven’ RRBI symptoms. These three factors were significantly associated with the right/left putamen volumes but with opposite effects: FA1 was negatively associated with an increased volume of the right/left putamen conversely to FA2 and FA3 (all uncorrected p < 0.05). FA1 was negatively associated with the left amygdala (uncorrected p < 0.05), and FA2 was positively associated with the left parietal structure (uncorrected p = 0.001).ConclusionOur results suggested 3 coherent RRBI dimensions involving the putamen commonly and other structures according to the RRBI dimension. The exploration of the putamen’s integrative role in RSBI needs to be strengthened in further studies.

An individual-supported program to enhance placement in a sheltered work environment of autistic individuals mostly with intellectual disability: a prospective observational case series in an Italian community service.

Autism spectrum disorder is a lifelong neurodevelopmental disorder. The profile of functioning in autistic people is very heterogeneous, and it is necessary to take into account individual characteristics to better support integration in the workplace. However, unemployment rates are higher for autistic people than for other types of disabilities. We present a prospective case series to explore the feasibility and efficacy of an individual-supported program to enhance placement in a sheltered work environment delivered by an Italian community day care center. Autistic subjects, aged from 12 to 31 years, participated in an individual-supported program regarding employment in sheltered art workshops, integrated into the regular activity of a semi-residential center three times a week for 1 year. Their feasibility retention rate and time worked per session were registered; moreover, working methods efficacy and self-organization improvement were tracked by the Likert-based rating system. Secondary outcome measures span functional levels, challenge behaviors, and sensory problems. All the individuals presented a good adaptation to the environment, with a significant increase in time worked per session. After 1 year, the intervention allowed an increase in tasks completed in an assigned complex job and an improvement in self-organization within the work schedule in a group of subjects consisting mainly of severe-to-moderate levels of autism severity (86.6%). Finally, we observed a significant increase in independent functioning areas of the TEACCH transitional assessment profile. Challenge behaviors and sensory problems were also recorded. This case series supports the idea that individual-supported programs for placement in sheltered job environments delivered by community day care centers could be feasible and effective for ASD with higher levels of severity and co-occurring intellectual disability. Further targeted studies based on community models and accessible methods need to be planned to define the effectiveness of the intervention and promote improved practice at the community level with a better social impact.

Novel deep learning models with novel integrated activation functions for autism screening: AutiNet and MinAutiNet

Deep Learning (DL) particularly CNN has the potential to outplay conventional Machine Learning (ML) procedures in the realm of computer vision. With the advent of DL, profound research on autism utilizing fMRI data has declared advancements in autism screening. Yet, DL models are inadequate for heterogeneous datasets encompassing complex fMRI data. To resolve these problems, two cutting-edge AutiNet and MinAutiNet models are proposed with a minimum number of layers and neurons in classifying the autistic subjects. Both AutiNet and MinAutiNet models are the two refined forms of the traditional LeNet-5 model. AutiNet model includes two convolutional layers, two average pooling layers, a flatten layer, and one fully connected layer. One convolutional layer, one average pooling layer, one flatten layer, and one fully connected layer make up the MinAutiNet model. Pre-processing is a pre-requisite phase in the AutiNet and MinAutiNet models where denoising of raw fMRI data is done with slice time correction, realignment, min–max normalization and one hot encoding to obtain numerical values. As inspired by the promising results of non-handcrafted feature extraction, the proposed DL models have been used for feature extraction. Two novel integrated activation functions namely Li-ReLU and S-RReLU are developed and incorporated into the proposed DL models towards improving the performance of autism screening. Both AutiNet and MinAutiNet models surpass the standard accuracy in classifying autistic subjects with minimum number of layers and neurons. Experimental results reveal that the proposed AutiNet attains the maximum accuracy of 77.78% with Caltech and KKI datasets and the proposed MinAutiNet achieves the maximum accuracy of 88.89% with SBL dataset. The proposed models are compared with other state-of-the-art works to ensure its superiority.

Cytokine Dynamics in Autism: Analysis of BMAC Therapy Outcomes.

Autism spectrum disorder (ASD) has recently been linked to neuroinflammation and an aberrant immune response within the central nervous system. The intricate relationship between immune response and ASD remains elusive, with a gap in understanding the connection between specific immune mechanisms and neural manifestations in autism. In this study, we employed a comprehensive statistical approach, fusing both overarching and granular methods to examine the concentration of 16 cytokines in the cerebrospinal fluid (CSF) across each autologous bone marrow aspirate concentrate (BMAC) intrathecal administration in 63 male and 17 female autism patients. Following a six-month period post the third administration, patients were stratified into three categories based on clinical improvement: Group 1- no/mild (28 subjects), Group 2-moderate (16 subjects), and Group 3-major improvement (15 subjects). Our integrated analysis revealed pronounced disparities in CSF cytokine patterns and clinical outcomes in autism subjects pre- and post-BMAC transplantation. Crucially, our results suggest that these cytokine profiles hold promise as predictive markers, pinpointing ASD individuals who might not exhibit notable clinical amelioration post-BMAC therapy.

La perspective créatrice de l’autisme : le cas extraordinaire de l’autiste peintre Iris Grace

ObjectivesThe aim of this work is to examine the subjective relationship of autistic subjects to artistic creation, particularly graphic creation. More specifically, it examines the conditions under which graphic creativity can be an autistic subject's preferred means of directing the excess impulses that invade him or her into an out-of-body object, and thereby opening up the possibility of creating a multidimensional space for him- or herself. MethodCritical analysis of the main theories in the scientific literature on the graphic abilities of autistic subjects. Confrontation of the hypotheses of a cognitive deficit and those of a psychodynamic current. We propose our theoretical development based on a case study. Psychodynamic study of the functions of art and, more generally, of creativity and inventiveness in autistic subjects. ResultsPainting allowed Iris Grace to build her relationship to the world, to her body, to others, and to speech, that is to say, to build a real subjective dynamic. Iris Grace's graphic creativity testifies to one autistic subject's preference for directing an invasive instinctual excess onto paper, into an out-of-body object, thereby allowing her to create a multidimensional space where libido, body, and link to the other were unfolded and complexified. DiscussionThe use of drawings, and their infinite details, allows us to see that artistic creation raises the question of writing. We develop the link with the use of computerized devices and their 3D software: certain autistic subjects prefer this mode of writing because the computer allows them to isolate, in details, the dimensions of the language. Each form, each place, each color, each detail, all these “Ones” lead us to consider that the work of autistic subjects is more about making a consistent whole out of these “Ones”. What clinical work with autistic people teaches us is how effective it is to bet on the strengths of each individual, even if they are first and foremost fixation, obsession, or focus. In this way, they can have some chance of being invested as an out-of-body object, enabling the creation of a multidimensional space. This is not to suggest that painting and/or drawing can be a therapy for every autistic person, or a particularly suitable form of art mediation. ConclusionSupporting the creativity of each autistic person in this way helps them to deal with excess jouissance, and to locate it on an edge, thus facilitating the regulation of libido and drives, thanks to the creation of a link and an openness to the world and to learning. In institutional care, it's a question of welcoming the autistic subject as he or she presents him- or herself, welcoming the real the subject has to deal with, and ensuring that his or her creation and inventiveness, whatever it may be, is increasingly cobbled together as a Borromean knot; in short, guaranteeing the construction of a subjective dynamic, so that art, invention, or affinity can rise to the level of a sinthome.

Autism in Preschool-Aged Children: The Effects of COVID-19 Lockdown.

The COVID-19 lockdown affected children, especially those with autism spectrum disorder, due to the disruption in rehabilitation and educational activities. We conducted a cross-sectional study of 315 preschool-aged children, 35 of which had autism, to investigate this impact. A questionnaire was administered to explore socio-demographic status, familiar/home environment, and COVID-19 exposure. The clinical features of autistic subjects were also examined. Seven variables were considered to describe the effect of pandemic: Remote learning, Behavior changes, Home activities, Sleep habits, Night awakenings, Physical activity, Information about the virus. The lockdown had a significant impact on Remote learning, Behavior changes, and Information about the virus in participants with autism. Moreover, we found a worsening in repetitive movements, echolalia, restricted interests, and aggressive behaviors.

Salivary Oxytocin and Antioxidative Response to Robotic Touch in Adults with Autism Spectrum Disorder.

Individuals with ASD are known to have a tendency to have tactile sensory processing issues that could be associated with their impairment as regards social communication. The alterations in tactile processing in autistic subjects are usually accompanied by hypersensitivity and other unpleasant emotions induced by tactile contact. In our study, we investigated the impact of the velocity and the force of a tactile stroke received impersonally by a custom-built robotic device. A total of 21 adults with ASD and 22 adults from a control group participated in our study. The participants' responses were assessed according to subjective scales, EEG changes, and the dynamics of saliva antioxidants and oxytocin. It was found that the oxytocin level was significantly lower in subjects with ASD but increased after tactile stimulation. However, contrary to expectations, the increase in the oxytocin level in the target group negatively correlated with the subjective pleasantness of tactile stimulation and was probably associated with a stress-induced effect. The basic levels of antioxidants did not differ between the TD and ASD groups; however, these had significantly increased in individuals with ASD by the end of the study. The EEG findings, which revealed enhanced antioxidant levels, contributed to the relief of the cognitive control during the study.

The autistic pseudosignifier: Imaginary dialectization of signs in the clinic of autism

Specificities in language and speech development are a defining feature of autism. Several psychoanalysts have hypothesized that these specificities originate in a unique mode of access to language that exclusively relies on signs rather than signifiers. Compared to the flexibility and dynamism of a language made of signifiers, a language made of signs is rigid, cumbersome, and poor in its capacity to encode complex concepts. This article investigates the supplementary methods that autistic subjects adopt to compensate for these setbacks, methods that enable them to encode complex concepts into their vocabulary using iconic signs. These methods are then developed into a psychoanalytic theory on the use of iconic signs in the strengthening of autistic language in the context of art therapy. A variety of case studies are then used to illustrate how newly gained access to a level of conceptual complexity can also bring dramatic changes to their lives.

Efficacy of auditory integration therapy (AIT) on plasma syntaxin1A (STX1A) levels and amelioration of behavioral, social, and sensory symptoms in children with autism spectrum disorder (ASD)

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder. Previous research reported the beneficial effects of Auditory Integration Training (AIT) on a considerable range of behavior and learning problems. Limited studies examined the association between AIT and biological biomarkers in autistic subjects. Therefore, this study aims to examine the effect of auditory integrative training on the plasma syntaxin1A protein (STX1A) level and also to assess its impact on behavioral, social, and sensory symptoms in autistic children, using a sandwich enzyme-linked immunoassay (ELISA). Total scores of the Childhood Autism Rating Scale (CARS), Social Responsiveness Scale (SRS), and Short Sensory Profile (SSP) were calculated before one month and three months after AIT for all participants. Results show that the plasma level of STX1A was significantly increased immediately, one month, and three months after AIT (P&lt;0.05). Moreover, Pearson correlation (r) values between STX1A levels before and after AIT shows strong and positive significant correlations between STX1A levels before AIT and immediately after AIT (r=0.594, p=0.01) and one month after AIT (r=0.819, p=0.01). Additionally, our results revealed that behavioral, social, and sensory symptoms were significantly improved in terms of disease severity three months after AIT (p&lt;0.05). The study supports the usefulness of AIT as a therapeutic intervention to improve some measures of ASD such as symptoms. It may also induce the up-regulation of STX1A in plasma in ASD subjects. However, Additional research, on a larger size population, is necessary to evaluate the AIT effect on behavioral and social changes in ASD children, and the up-regulation of STX1A.

The use of data independent acquisition based proteomic analysis and machine learning to reveal potential biomarkers for autism spectrum disorder

Autism spectrum disorder (ASD) is a complex neurological developmental disorder in children, and is associated with social isolation and restricted interests. The etiology of this disorder is still unknown. There is neither any confirmed laboratory test nor any effective therapeutic strategy to diagnose or cure it. We performed data independent acquisition (DIA) and multiple reaction monitoring (MRM) analysis of plasma from children with ASD and controls. The result showed that 45 differentially expressed proteins (DEPs) were identified between autistic subjects and controls. Among these, only one DEP was down-regulated in ASD; other DEPs were up-regulated in ASD children's plasma. These proteins are found associated with complement and coagulation cascades, vitamin digestion and absorption, cholesterol metabolism, platelet degranulation, selenium micronutrient network, extracellular matrix organization and inflammatory pathway, which have been reported to be related to ASD. After MRM verification, five key proteins in complement pathway (PLG, SERPINC1, and A2M) and inflammatory pathway (CD5L, ATRN, SERPINC1, and A2M) were confirmed to be significantly up-regulated in ASD group. Through the screening of machine learning model and MRM verification, we found that two proteins (biotinidase and carbonic anhydrase 1) can be used as early diagnostic markers of ASD (AUC = 0.8, p = 0.0001). SignificanceASD is the fastest growing neurodevelopmental disorder in the world and has become a major public health problem worldwide. Its prevalence has been steadily increasing, with a global prevalence rate of 1%. Early diagnosis and intervention can achieve better prognosis. In this study, data independent acquisition (DIA) and multiple reaction monitoring (MRM) analysis was applied to analyze the plasma proteome of ASD patients (31 (±5) months old), and 378 proteins were quantified. 45 differentially expressed proteins (DEPs) were identified between the ASD group and the control group. They mainly were associated with platelet degranulation, ECM proteoglycar, complement and coagulation cascades, selenium micronutrient network, regulation of insulin-like growth factor (IGF) transport and uptake by insulin-like growth factor binding proteins (IGFBPs), cholesterol metabolism, vitamin metabolism, and inflammatory pathway. Through the integrated machine learning methods and the MRM verification of independent samples, it is considered that biotinidase and carbon anhydrase 1 have the potential to become biomarkers for the early diagnosis of ASD. These results complement proteomics database of the ASD patients, broaden our understanding of ASD, and provide a panel of biomarkers for the early diagnosis of ASD.

Memantine/Aripiprazole Combination Alleviates Cognitive Dysfunction in Valproic Acid Rat Model of Autism: Hippocampal CREB/BDNF Signaling and Glutamate Homeostasis

SummarySignificant efforts are increasingly directed towards identifying novel therapeutic targets for autism spectrum disorder (ASD) with a rising role of aberrant glutamatergic transmission in the pathogenesis of ASD-associated cellular and behavioral deficits. This study aimed at investigating the role of chronic memantine (20 mg/kg/day) and aripiprazole (3 mg/kg/day) combination therapy in the management of prenatal sodium valproate (VPA)-induced autistic-like/cognitive deficits in male Wistar rats. Pregnant female rats received a single intraperitoneal injection of VPA (600 mg/kg) to induce autistic-like behaviors in their offspring. Prenatal VPA induced autistic-like symptoms (decreased social interaction and the appearance of stereotyped behavior) with deficits in spatial learning (in Morris water maze) and cognitive flexibility (in the attentional set-shifting task) in addition to decreased hippocampal protein levels of phosphorylated cAMP response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and gene expression of glutamate transporter-1 (Glt-1) with a decline in GABA/glutamate ratio (both measured by HPLC). These were accompanied by the appearance of numerous neurofibrillary tangles (NFTs) with enhanced apoptosis in hippocampal sections. Memantine/aripiprazole combination increased the protein levels of p-CREB, BDNF, and Glt-1 gene expression with restoration of GABA/glutamate balance, attenuation of VPA-induced neurodegenerative changes and autistic-like symptoms, and improvement of cognitive performance. This study draws attention to the favorable cognitive effects of memantine/aripiprazole combination in autistic subjects which could be mediated via enhancing CREB/BDNF signaling with increased expression of astrocytic Glt-1 and restoration of GABA/glutamate balance, leading to inhibition of hippocampal NFTs formation and neuronal apoptosis.