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Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism / F. GEVI in Molecular Autism, 7 (2016)
[article]
Titre : Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism Type de document : Texte imprimé et/ou numérique Auteurs : F. GEVI, Auteur ; L. ZOLLA, Auteur ; S. GABRIELE, Auteur ; A. M. PERSICO, Auteur Article en page(s) : 47p. Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/complications/diagnosis/urine Biomarkers/urine Case-Control Studies Child Child, Preschool Chromatography, High Pressure Liquid Coenzyme A/urine Dysbiosis/complications/diagnosis/urine Female Humans Hydrophobic and Hydrophilic Interactions Indoleacetic Acids/urine Italy Kynurenic Acid/urine Male Melatonin/urine Metabolomics/methods Pantothenic Acid/urine Purines/urine Pyrimidines/urine Quinolinic Acid/urine Riboflavin/urine Tryptophan/urine Vitamin B 6/urine Xanthurenates/urine Autism Autism spectrum disorder Kynurenine Melatonin Metabolomics Purinergic signaling Quinolinic acid Serotonin Tryptophan Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is still diagnosed through behavioral observation, due to a lack of laboratory biomarkers, which could greatly aid clinicians in providing earlier and more reliable diagnoses. Metabolomics on human biofluids provides a sensitive tool to identify metabolite profiles potentially usable as biomarkers for ASD. Initial metabolomic studies, analyzing urines and plasma of ASD and control individuals, suggested that autistic patients may share some metabolic abnormalities, despite several inconsistencies stemming from differences in technology, ethnicity, age range, and definition of "control" status. METHODS: ASD-specific urinary metabolomic patterns were explored at an early age in 30 ASD children and 30 matched controls (age range 2-7, M:F = 22:8) using hydrophilic interaction chromatography (HILIC)-UHPLC and mass spectrometry, a highly sensitive, accurate, and unbiased approach. Metabolites were then subjected to multivariate statistical analysis and grouped by metabolic pathway. RESULTS: Urinary metabolites displaying the largest differences between young ASD and control children belonged to the tryptophan and purine metabolic pathways. Also, vitamin B6, riboflavin, phenylalanine-tyrosine-tryptophan biosynthesis, pantothenate and CoA, and pyrimidine metabolism differed significantly. ASD children preferentially transform tryptophan into xanthurenic acid and quinolinic acid (two catabolites of the kynurenine pathway), at the expense of kynurenic acid and especially of melatonin. Also, the gut microbiome contributes to altered tryptophan metabolism, yielding increased levels of indolyl 3-acetic acid and indolyl lactate. CONCLUSIONS: The metabolic pathways most distinctive of young Italian autistic children largely overlap with those found in rodent models of ASD following maternal immune activation or genetic manipulations. These results are consistent with the proposal of a purine-driven cell danger response, accompanied by overproduction of epileptogenic and excitotoxic quinolinic acid, large reductions in melatonin synthesis, and gut dysbiosis. These metabolic abnormalities could underlie several comorbidities frequently associated to ASD, such as seizures, sleep disorders, and gastrointestinal symptoms, and could contribute to autism severity. Their diagnostic sensitivity, disease-specificity, and interethnic variability will merit further investigation. En ligne : http://dx.doi.org/10.1186/s13229-016-0109-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328
in Molecular Autism > 7 (2016) . - 47p.[article] Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism [Texte imprimé et/ou numérique] / F. GEVI, Auteur ; L. ZOLLA, Auteur ; S. GABRIELE, Auteur ; A. M. PERSICO, Auteur . - 47p.
Langues : Anglais (eng)
in Molecular Autism > 7 (2016) . - 47p.
Mots-clés : Autism Spectrum Disorder/complications/diagnosis/urine Biomarkers/urine Case-Control Studies Child Child, Preschool Chromatography, High Pressure Liquid Coenzyme A/urine Dysbiosis/complications/diagnosis/urine Female Humans Hydrophobic and Hydrophilic Interactions Indoleacetic Acids/urine Italy Kynurenic Acid/urine Male Melatonin/urine Metabolomics/methods Pantothenic Acid/urine Purines/urine Pyrimidines/urine Quinolinic Acid/urine Riboflavin/urine Tryptophan/urine Vitamin B 6/urine Xanthurenates/urine Autism Autism spectrum disorder Kynurenine Melatonin Metabolomics Purinergic signaling Quinolinic acid Serotonin Tryptophan Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is still diagnosed through behavioral observation, due to a lack of laboratory biomarkers, which could greatly aid clinicians in providing earlier and more reliable diagnoses. Metabolomics on human biofluids provides a sensitive tool to identify metabolite profiles potentially usable as biomarkers for ASD. Initial metabolomic studies, analyzing urines and plasma of ASD and control individuals, suggested that autistic patients may share some metabolic abnormalities, despite several inconsistencies stemming from differences in technology, ethnicity, age range, and definition of "control" status. METHODS: ASD-specific urinary metabolomic patterns were explored at an early age in 30 ASD children and 30 matched controls (age range 2-7, M:F = 22:8) using hydrophilic interaction chromatography (HILIC)-UHPLC and mass spectrometry, a highly sensitive, accurate, and unbiased approach. Metabolites were then subjected to multivariate statistical analysis and grouped by metabolic pathway. RESULTS: Urinary metabolites displaying the largest differences between young ASD and control children belonged to the tryptophan and purine metabolic pathways. Also, vitamin B6, riboflavin, phenylalanine-tyrosine-tryptophan biosynthesis, pantothenate and CoA, and pyrimidine metabolism differed significantly. ASD children preferentially transform tryptophan into xanthurenic acid and quinolinic acid (two catabolites of the kynurenine pathway), at the expense of kynurenic acid and especially of melatonin. Also, the gut microbiome contributes to altered tryptophan metabolism, yielding increased levels of indolyl 3-acetic acid and indolyl lactate. CONCLUSIONS: The metabolic pathways most distinctive of young Italian autistic children largely overlap with those found in rodent models of ASD following maternal immune activation or genetic manipulations. These results are consistent with the proposal of a purine-driven cell danger response, accompanied by overproduction of epileptogenic and excitotoxic quinolinic acid, large reductions in melatonin synthesis, and gut dysbiosis. These metabolic abnormalities could underlie several comorbidities frequently associated to ASD, such as seizures, sleep disorders, and gastrointestinal symptoms, and could contribute to autism severity. Their diagnostic sensitivity, disease-specificity, and interethnic variability will merit further investigation. En ligne : http://dx.doi.org/10.1186/s13229-016-0109-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328 A Metabolomics Approach to Screening for Autism Risk in the Children's Autism Metabolome Project / Alan M. SMITH in Autism Research, 13-8 (August 2020)
[article]
Titre : A Metabolomics Approach to Screening for Autism Risk in the Children's Autism Metabolome Project Type de document : Texte imprimé et/ou numérique Auteurs : Alan M. SMITH, Auteur ; Marvin R. NATOWICZ, Auteur ; Daniel BRAAS, Auteur ; Michael A. LUDWIG, Auteur ; Denise M. NEY, Auteur ; Elizabeth L. R. DONLEY, Auteur ; Robert E. BURRIER, Auteur ; David G. AMARAL, Auteur Article en page(s) : p.1270-1285 Langues : Anglais (eng) Mots-clés : amino acids autism spectrum disorder biomarkers energy metabolism metabolomics mitochondria risk Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is biologically and behaviorally heterogeneous. Delayed diagnosis of ASD is common and problematic. The complexity of ASD and the low sensitivity of available screening tools are key factors in delayed diagnosis. Identification of biomarkers that reduce complexity through stratification into reliable subpopulations can assist in earlier diagnosis, provide insight into the biology of ASD, and potentially suggest targeted interventions. Quantitative metabolomic analysis was performed on plasma samples from 708 fasting children, aged 18 to 48?months, enrolled in the Children's Autism Metabolome Project (CAMP). The primary goal was to identify alterations in metabolism helpful in stratifying ASD subjects into subpopulations with shared metabolic phenotypes (i.e., metabotypes). Metabotypes associated with ASD were identified in a discovery set of 357 subjects. The reproducibility of the metabotypes was validated in an independent replication set of 351 CAMP subjects. Thirty-four candidate metabotypes that differentiated subsets of ASD from typically developing participants were identified with sensitivity of at least 5% and specificity greater than 95%. The 34 metabotypes formed six metabolic clusters based on ratios of either lactate or pyruvate, succinate, glycine, ornithine, 4-hydroxyproline, or ?-ketoglutarate with other metabolites. Optimization of a subset of new and previously defined metabotypes into a screening battery resulted in 53% sensitivity (95% confidence interval [CI], 48%-57%) and 91% specificity (95% CI, 86%-94%). Thus, our metabolomic screening tool detects more than 50% of the autistic participants in the CAMP study. Further development of this metabolomic screening approach may facilitate earlier referral and diagnosis of ASD and, ultimately, more targeted treatments. LAY SUMMARY: Analysis of a selected set of metabolites in blood samples from children with autism and typically developing children identified reproducible differences in the metabolism of about half of the children with autism. Testing for these differences in blood samples can be used to help screen children as young as 18?months for risk of autism that, in turn, can facilitate earlier diagnoses. In addition, differences may lead to biological insights that produce more precise treatment options. We are exploring other blood-based molecules to determine if still a higher percentage of children with autism can be detected using this strategy. Autism Res 2020, 13: 1270-1285. © 2020 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals LLC. En ligne : http://dx.doi.org/10.1002/aur.2330 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=430
in Autism Research > 13-8 (August 2020) . - p.1270-1285[article] A Metabolomics Approach to Screening for Autism Risk in the Children's Autism Metabolome Project [Texte imprimé et/ou numérique] / Alan M. SMITH, Auteur ; Marvin R. NATOWICZ, Auteur ; Daniel BRAAS, Auteur ; Michael A. LUDWIG, Auteur ; Denise M. NEY, Auteur ; Elizabeth L. R. DONLEY, Auteur ; Robert E. BURRIER, Auteur ; David G. AMARAL, Auteur . - p.1270-1285.
Langues : Anglais (eng)
in Autism Research > 13-8 (August 2020) . - p.1270-1285
Mots-clés : amino acids autism spectrum disorder biomarkers energy metabolism metabolomics mitochondria risk Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is biologically and behaviorally heterogeneous. Delayed diagnosis of ASD is common and problematic. The complexity of ASD and the low sensitivity of available screening tools are key factors in delayed diagnosis. Identification of biomarkers that reduce complexity through stratification into reliable subpopulations can assist in earlier diagnosis, provide insight into the biology of ASD, and potentially suggest targeted interventions. Quantitative metabolomic analysis was performed on plasma samples from 708 fasting children, aged 18 to 48?months, enrolled in the Children's Autism Metabolome Project (CAMP). The primary goal was to identify alterations in metabolism helpful in stratifying ASD subjects into subpopulations with shared metabolic phenotypes (i.e., metabotypes). Metabotypes associated with ASD were identified in a discovery set of 357 subjects. The reproducibility of the metabotypes was validated in an independent replication set of 351 CAMP subjects. Thirty-four candidate metabotypes that differentiated subsets of ASD from typically developing participants were identified with sensitivity of at least 5% and specificity greater than 95%. The 34 metabotypes formed six metabolic clusters based on ratios of either lactate or pyruvate, succinate, glycine, ornithine, 4-hydroxyproline, or ?-ketoglutarate with other metabolites. Optimization of a subset of new and previously defined metabotypes into a screening battery resulted in 53% sensitivity (95% confidence interval [CI], 48%-57%) and 91% specificity (95% CI, 86%-94%). Thus, our metabolomic screening tool detects more than 50% of the autistic participants in the CAMP study. Further development of this metabolomic screening approach may facilitate earlier referral and diagnosis of ASD and, ultimately, more targeted treatments. LAY SUMMARY: Analysis of a selected set of metabolites in blood samples from children with autism and typically developing children identified reproducible differences in the metabolism of about half of the children with autism. Testing for these differences in blood samples can be used to help screen children as young as 18?months for risk of autism that, in turn, can facilitate earlier diagnoses. In addition, differences may lead to biological insights that produce more precise treatment options. We are exploring other blood-based molecules to determine if still a higher percentage of children with autism can be detected using this strategy. Autism Res 2020, 13: 1270-1285. © 2020 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals LLC. En ligne : http://dx.doi.org/10.1002/aur.2330 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=430 The urinary 1H-NMR metabolomics profile of an italian autistic children population and their unaffected siblings / Milena LUSSU in Autism Research, 10-6 (June 2017)
[article]
Titre : The urinary 1H-NMR metabolomics profile of an italian autistic children population and their unaffected siblings Type de document : Texte imprimé et/ou numérique Auteurs : Milena LUSSU, Auteur ; Antonio NOTO, Auteur ; Alice MASILI, Auteur ; Andrea C. RINALDI, Auteur ; Angelica DESSÌ, Auteur ; Maria DE ANGELIS, Auteur ; Andrea DE GIACOMO, Auteur ; Vassilios FANOS, Auteur ; Luigi ATZORI, Auteur ; Ruggiero FRANCAVILLA, Auteur Article en page(s) : p.1058-1066 Langues : Anglais (eng) Mots-clés : metabolomics autistic children siblings biomarkers Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASD) make a dishomogeneous group of psychiatric diseases having either genetic and environmental components, including changes of the microbiota. The rate of diagnosis, based on a series of psychological tests and observed behavior, dramatically increased in the past few decades. Currently, no biological markers are available and the pathogenesis is not defined. The purpose of this study was to evaluate the potential use of 1H-NMR metabolomics to analyze the global biochemical signature of ASD patients (n?=?21) and controls (n?=?21), these being siblings of autistic patients. A multivariate model has been used to extrapolate the variables of importance. The discriminating urinary metabolites were identified; in particular, significantly increased levels of hippurate, glycine, creatine, tryptophan, and d-threitol and decreased concentrations of glutamate, creatinine, lactate, valine, betaine, and taurine were observed in ASD patients. Based on the identified discriminant metabolites, the attention was focused on two possible mechanisms that could be involved in ASD: oxidative stress conditions and gut microflora modifications. In conclusion, nuclear magnetic resonance-based metabolomics analysis of the urine seems to have the potential for the identification of a metabolic fingerprint of ASD phenotypes and appears to be suitable for further investigation of the disease mechanisms. En ligne : http://dx.doi.org/10.1002/aur.1748 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=309
in Autism Research > 10-6 (June 2017) . - p.1058-1066[article] The urinary 1H-NMR metabolomics profile of an italian autistic children population and their unaffected siblings [Texte imprimé et/ou numérique] / Milena LUSSU, Auteur ; Antonio NOTO, Auteur ; Alice MASILI, Auteur ; Andrea C. RINALDI, Auteur ; Angelica DESSÌ, Auteur ; Maria DE ANGELIS, Auteur ; Andrea DE GIACOMO, Auteur ; Vassilios FANOS, Auteur ; Luigi ATZORI, Auteur ; Ruggiero FRANCAVILLA, Auteur . - p.1058-1066.
Langues : Anglais (eng)
in Autism Research > 10-6 (June 2017) . - p.1058-1066
Mots-clés : metabolomics autistic children siblings biomarkers Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASD) make a dishomogeneous group of psychiatric diseases having either genetic and environmental components, including changes of the microbiota. The rate of diagnosis, based on a series of psychological tests and observed behavior, dramatically increased in the past few decades. Currently, no biological markers are available and the pathogenesis is not defined. The purpose of this study was to evaluate the potential use of 1H-NMR metabolomics to analyze the global biochemical signature of ASD patients (n?=?21) and controls (n?=?21), these being siblings of autistic patients. A multivariate model has been used to extrapolate the variables of importance. The discriminating urinary metabolites were identified; in particular, significantly increased levels of hippurate, glycine, creatine, tryptophan, and d-threitol and decreased concentrations of glutamate, creatinine, lactate, valine, betaine, and taurine were observed in ASD patients. Based on the identified discriminant metabolites, the attention was focused on two possible mechanisms that could be involved in ASD: oxidative stress conditions and gut microflora modifications. In conclusion, nuclear magnetic resonance-based metabolomics analysis of the urine seems to have the potential for the identification of a metabolic fingerprint of ASD phenotypes and appears to be suitable for further investigation of the disease mechanisms. En ligne : http://dx.doi.org/10.1002/aur.1748 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=309 Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli / Stephen BENT in Molecular Autism, 9 (2018)
[article]
Titre : Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli Type de document : Texte imprimé et/ou numérique Auteurs : Stephen BENT, Auteur ; B. LAWTON, Auteur ; T. WARREN, Auteur ; F. WIDJAJA, Auteur ; K. DANG, Auteur ; J. W. FAHEY, Auteur ; Brian CORNBLATT, Auteur ; J. M. KINCHEN, Auteur ; K. DELUCCHI, Auteur ; R. L. HENDREN, Auteur Article en page(s) : 35p. Langues : Anglais (eng) Mots-clés : Adolescent Antioxidants/administration & dosage/analysis/therapeutic use Autistic Disorder/drug therapy/urine Biomarkers/urine Brassica/chemistry Child Female Humans Isothiocyanates/administration & dosage/analysis/therapeutic use Male Metabolome Social Behavior Young Adult Antioxidant Autism Biomarker Metabolomics Index. décimale : PER Périodiques Résumé : Background: Children with autism spectrum disorder (ASD) have urinary metabolites suggesting impairments in several pathways, including oxidative stress, inflammation, mitochondrial dysfunction, and gut microbiome alterations. Sulforaphane, a supplement with indirect antioxidant effects that are derived from broccoli sprouts and seeds, was recently shown to lead to improvements in behavior and social responsiveness in children with ASD. We conducted the current open-label study to determine if we could identify changes in urinary metabolites that were associated with clinical improvements with the goal of identifying a potential mechanism of action. Methods: Children and young adults enrolled in a school for children with ASD and related neurodevelopmental disorders were recruited to participate in a 12-week, open-label study of sulforaphane. Fasting urinary metabolites and measures of behavior (Aberrant Behavior Checklist-ABC) and social responsiveness (Social Responsiveness Scale-SRS) were measured at baseline and at the end of the study. Pearson's correlation coefficient was calculated for the pre- to post-intervention change in each of the two clinical scales (ABS and SRS) versus the change in each metabolite. Results: Fifteen children completed the 12-week study. Mean scores on both symptom measures showed improvements (decreases) over the study period, but only the change in the SRS was significant. The ABC improved - 7.1 points (95% CI - 17.4 to 3.2), and the SRS improved - 9.7 points (95% CI - 18.7 to - 0.8). We identified 77 urinary metabolites that were correlated with changes in symptoms, and they clustered into pathways of oxidative stress, amino acid/gut microbiome, neurotransmitters, hormones, and sphingomyelin metabolism. Conclusions: Urinary metabolomics analysis is a useful tool to identify pathways that may be involved in the mechanism of action of treatments targeting abnormal physiology in ASD. Trial registration: This study was prospectively registered at clinicaltrials.gov (NCT02654743) on January 11, 2016. En ligne : https://dx.doi.org/10.1186/s13229-018-0218-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371
in Molecular Autism > 9 (2018) . - 35p.[article] Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli [Texte imprimé et/ou numérique] / Stephen BENT, Auteur ; B. LAWTON, Auteur ; T. WARREN, Auteur ; F. WIDJAJA, Auteur ; K. DANG, Auteur ; J. W. FAHEY, Auteur ; Brian CORNBLATT, Auteur ; J. M. KINCHEN, Auteur ; K. DELUCCHI, Auteur ; R. L. HENDREN, Auteur . - 35p.
Langues : Anglais (eng)
in Molecular Autism > 9 (2018) . - 35p.
Mots-clés : Adolescent Antioxidants/administration & dosage/analysis/therapeutic use Autistic Disorder/drug therapy/urine Biomarkers/urine Brassica/chemistry Child Female Humans Isothiocyanates/administration & dosage/analysis/therapeutic use Male Metabolome Social Behavior Young Adult Antioxidant Autism Biomarker Metabolomics Index. décimale : PER Périodiques Résumé : Background: Children with autism spectrum disorder (ASD) have urinary metabolites suggesting impairments in several pathways, including oxidative stress, inflammation, mitochondrial dysfunction, and gut microbiome alterations. Sulforaphane, a supplement with indirect antioxidant effects that are derived from broccoli sprouts and seeds, was recently shown to lead to improvements in behavior and social responsiveness in children with ASD. We conducted the current open-label study to determine if we could identify changes in urinary metabolites that were associated with clinical improvements with the goal of identifying a potential mechanism of action. Methods: Children and young adults enrolled in a school for children with ASD and related neurodevelopmental disorders were recruited to participate in a 12-week, open-label study of sulforaphane. Fasting urinary metabolites and measures of behavior (Aberrant Behavior Checklist-ABC) and social responsiveness (Social Responsiveness Scale-SRS) were measured at baseline and at the end of the study. Pearson's correlation coefficient was calculated for the pre- to post-intervention change in each of the two clinical scales (ABS and SRS) versus the change in each metabolite. Results: Fifteen children completed the 12-week study. Mean scores on both symptom measures showed improvements (decreases) over the study period, but only the change in the SRS was significant. The ABC improved - 7.1 points (95% CI - 17.4 to 3.2), and the SRS improved - 9.7 points (95% CI - 18.7 to - 0.8). We identified 77 urinary metabolites that were correlated with changes in symptoms, and they clustered into pathways of oxidative stress, amino acid/gut microbiome, neurotransmitters, hormones, and sphingomyelin metabolism. Conclusions: Urinary metabolomics analysis is a useful tool to identify pathways that may be involved in the mechanism of action of treatments targeting abnormal physiology in ASD. Trial registration: This study was prospectively registered at clinicaltrials.gov (NCT02654743) on January 11, 2016. En ligne : https://dx.doi.org/10.1186/s13229-018-0218-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 Oxytocin-induced increase in N,N-dimethylglycine and time course of changes in oxytocin efficacy for autism social core symptoms / Y. KATO in Molecular Autism, 12 (2021)
[article]
Titre : Oxytocin-induced increase in N,N-dimethylglycine and time course of changes in oxytocin efficacy for autism social core symptoms Type de document : Texte imprimé et/ou numérique Auteurs : Y. KATO, Auteur ; H. KUWABARA, Auteur ; T. OKADA, Auteur ; T. MUNESUE, Auteur ; S. BENNER, Auteur ; M. KURODA, Auteur ; M. KOJIMA, Auteur ; W. YASSIN, Auteur ; Y. ERIGUCHI, Auteur ; Y. KAMENO, Auteur ; C. MURAYAMA, Auteur ; T. NISHIMURA, Auteur ; K. TSUCHIYA, Auteur ; Kiyoto KASAI, Auteur ; N. OZAKI, Auteur ; H. KOSAKA, Auteur ; H. YAMASUE, Auteur Article en page(s) : 15 p. Langues : Anglais (eng) Mots-clés : Administration, Intranasal Adolescent Adult Autistic Disorder/blood/drug therapy/metabolism/psychology Double-Blind Method Facial Expression Humans Male Metabolomics Middle Aged Oxytocin/administration & dosage/blood/pharmacokinetics Sarcosine/analogs & derivatives/blood Social Behavior Treatment Outcome Young Adult Asperger Autism Clinical trial Developmental disorders Facial expression N,N-Dimethylglycine Neuropeptide Oxytocin Plasticity collection, management, analysis, and interpretation of the data preparation, review, or approval of the manuscript or decision to submit the manuscript for publication. There are no conflicts of interest. Index. décimale : PER Périodiques Résumé : BACKGROUND: Oxytocin is expected as a novel therapeutic agent for autism spectrum disorder (ASD) core symptoms. However, previous results on the efficacy of repeated administrations of oxytocin are controversial. Recently, we reported time-course changes in the efficacy of the neuropeptide underlying the controversial effects of repeated administration; however, the underlying mechanisms remained unknown. METHODS: The current study explored metabolites representing the molecular mechanisms of oxytocin's efficacy using high-throughput metabolomics analysis on plasma collected before and after 6-week repeated intranasal administration of oxytocin (48 IU/day) or placebo in adult males with ASD (N?=?106) who participated in a multi-center, parallel-group, double-blind, placebo-controlled, randomized controlled trial. RESULTS: Among the 35 metabolites measured, a significant increase in N,N-dimethylglycine was detected in the subjects administered oxytocin compared with those given placebo at a medium effect size (false discovery rate (FDR) corrected P?=?0.043, d?=?0.74, N?=?83). Furthermore, subgroup analyses of the participants displaying a prominent time-course change in oxytocin efficacy revealed a significant effect of oxytocin on N,N-dimethylglycine levels with a large effect size (P(FDR)?=?0.004, d?=?1.13, N?=?60). The increase in N,N-dimethylglycine was significantly correlated with oxytocin-induced clinical changes, assessed as changes in quantifiable characteristics of autistic facial expression, including both of improvements between baseline and 2 weeks (P(FDR)?=?0.006, r?=?-?0.485, N?=?43) and deteriorations between 2 and 4 weeks (P(FDR)?=?0.032, r?=?0.415, N?=?37). LIMITATIONS: The metabolites changes caused by oxytocin administration were quantified using peripheral blood and therefore may not directly reflect central nervous system changes. CONCLUSION: Our findings demonstrate an association of N,N-dimethylglycine upregulation with the time-course change in the efficacy of oxytocin on autistic social deficits. Furthermore, the current findings support the involvement of the N-methyl-D-aspartate receptor and neural plasticity to the time-course change in oxytocin's efficacy. TRIAL REGISTRATION: A multi-center, parallel-group, placebo-controlled, double-blind, confirmatory trial of intranasal oxytocin in participants with autism spectrum disorders (the date registered: 30 October 2014; UMIN Clinical Trials Registry: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017703 ) (UMIN000015264). En ligne : http://dx.doi.org/10.1186/s13229-021-00423-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459
in Molecular Autism > 12 (2021) . - 15 p.[article] Oxytocin-induced increase in N,N-dimethylglycine and time course of changes in oxytocin efficacy for autism social core symptoms [Texte imprimé et/ou numérique] / Y. KATO, Auteur ; H. KUWABARA, Auteur ; T. OKADA, Auteur ; T. MUNESUE, Auteur ; S. BENNER, Auteur ; M. KURODA, Auteur ; M. KOJIMA, Auteur ; W. YASSIN, Auteur ; Y. ERIGUCHI, Auteur ; Y. KAMENO, Auteur ; C. MURAYAMA, Auteur ; T. NISHIMURA, Auteur ; K. TSUCHIYA, Auteur ; Kiyoto KASAI, Auteur ; N. OZAKI, Auteur ; H. KOSAKA, Auteur ; H. YAMASUE, Auteur . - 15 p.
Langues : Anglais (eng)
in Molecular Autism > 12 (2021) . - 15 p.
Mots-clés : Administration, Intranasal Adolescent Adult Autistic Disorder/blood/drug therapy/metabolism/psychology Double-Blind Method Facial Expression Humans Male Metabolomics Middle Aged Oxytocin/administration & dosage/blood/pharmacokinetics Sarcosine/analogs & derivatives/blood Social Behavior Treatment Outcome Young Adult Asperger Autism Clinical trial Developmental disorders Facial expression N,N-Dimethylglycine Neuropeptide Oxytocin Plasticity collection, management, analysis, and interpretation of the data preparation, review, or approval of the manuscript or decision to submit the manuscript for publication. There are no conflicts of interest. Index. décimale : PER Périodiques Résumé : BACKGROUND: Oxytocin is expected as a novel therapeutic agent for autism spectrum disorder (ASD) core symptoms. However, previous results on the efficacy of repeated administrations of oxytocin are controversial. Recently, we reported time-course changes in the efficacy of the neuropeptide underlying the controversial effects of repeated administration; however, the underlying mechanisms remained unknown. METHODS: The current study explored metabolites representing the molecular mechanisms of oxytocin's efficacy using high-throughput metabolomics analysis on plasma collected before and after 6-week repeated intranasal administration of oxytocin (48 IU/day) or placebo in adult males with ASD (N?=?106) who participated in a multi-center, parallel-group, double-blind, placebo-controlled, randomized controlled trial. RESULTS: Among the 35 metabolites measured, a significant increase in N,N-dimethylglycine was detected in the subjects administered oxytocin compared with those given placebo at a medium effect size (false discovery rate (FDR) corrected P?=?0.043, d?=?0.74, N?=?83). Furthermore, subgroup analyses of the participants displaying a prominent time-course change in oxytocin efficacy revealed a significant effect of oxytocin on N,N-dimethylglycine levels with a large effect size (P(FDR)?=?0.004, d?=?1.13, N?=?60). The increase in N,N-dimethylglycine was significantly correlated with oxytocin-induced clinical changes, assessed as changes in quantifiable characteristics of autistic facial expression, including both of improvements between baseline and 2 weeks (P(FDR)?=?0.006, r?=?-?0.485, N?=?43) and deteriorations between 2 and 4 weeks (P(FDR)?=?0.032, r?=?0.415, N?=?37). LIMITATIONS: The metabolites changes caused by oxytocin administration were quantified using peripheral blood and therefore may not directly reflect central nervous system changes. CONCLUSION: Our findings demonstrate an association of N,N-dimethylglycine upregulation with the time-course change in the efficacy of oxytocin on autistic social deficits. Furthermore, the current findings support the involvement of the N-methyl-D-aspartate receptor and neural plasticity to the time-course change in oxytocin's efficacy. TRIAL REGISTRATION: A multi-center, parallel-group, placebo-controlled, double-blind, confirmatory trial of intranasal oxytocin in participants with autism spectrum disorders (the date registered: 30 October 2014; UMIN Clinical Trials Registry: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017703 ) (UMIN000015264). En ligne : http://dx.doi.org/10.1186/s13229-021-00423-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 Alterations in Gut Vitamin and Amino Acid Metabolism are Associated with Symptoms and Neurodevelopment in Children with Autism Spectrum Disorder / Jiang ZHU in Journal of Autism and Developmental Disorders, 52-7 (July 2022)
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