Modulation of striatal functional connectivity differences in adults with and without autism spectrum disorder in a single-dose randomized trial of cannabidivarin / C. M. PRETZSCH in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 49 p. Titre : Modulation of striatal functional connectivity differences in adults with and without autism spectrum disorder in a single-dose randomized trial of cannabidivarin Type de document : Texte imprimé et/ou numérique Auteurs : C. M. PRETZSCH, Auteur ; D. L. FLORIS, Auteur ; B. VOINESCU, Auteur ; M. ELSAHIB, Auteur ; M. A. MENDEZ, Auteur ; R. WICHERS, Auteur ; L. AJRAM, Auteur ; G. IVIN, Auteur ; M. HEASMAN, Auteur ; E. PRETZSCH, Auteur ; S. WILLIAMS, Auteur ; D. G. M. MURPHY, Auteur ; Eileen DALY, Auteur ; G. M. MCALONAN, Auteur Article en page(s) : 49 p. Langues : Anglais (eng) Mots-clés : Autism spectrum condition  Autism spectrum disorder  Cbdv  Cannabidivarin  Functional connectivity  Striatum Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) has a high cost to affected individuals and society, but treatments for core symptoms are lacking. To expand intervention options, it is crucial to gain a better understanding of potential treatment targets, and their engagement, in the brain. For instance, the striatum (caudate, putamen, and nucleus accumbens) plays a central role during development and its (atypical) functional connectivity (FC) may contribute to multiple ASD symptoms. We have previously shown, in the adult autistic and neurotypical brain, the non-intoxicating cannabinoid cannabidivarin (CBDV) alters the balance of striatal 'excitatory-inhibitory' metabolites, which help regulate FC, but the effects of CBDV on (atypical) striatal FC are unknown. METHODS: To examine this in a small pilot study, we acquired resting state functional magnetic resonance imaging data from 28 men (15 neurotypicals, 13 ASD) on two occasions in a repeated-measures, double-blind, placebo-controlled study. We then used a seed-based approach to (1) compare striatal FC between groups and (2) examine the effect of pharmacological probing (600 mg CBDV/matched placebo) on atypical striatal FC in ASD. Visits were separated by at least 13 days to allow for drug washout. RESULTS: Compared to the neurotypicals, ASD individuals had lower FC between the ventral striatum and frontal and pericentral regions (which have been associated with emotion, motor, and vision processing). Further, they had higher intra-striatal FC and higher putamenal FC with temporal regions involved in speech and language. In ASD, CBDV reduced hyperconnectivity to the neurotypical level. LIMITATIONS: Our findings should be considered in light of several methodological aspects, in particular our participant group (restricted to male adults), which limits the generalizability of our findings to the wider and heterogeneous ASD population. CONCLUSION: In conclusion, here we show atypical striatal FC with regions commonly associated with ASD symptoms. We further provide preliminary proof of concept that, in the adult autistic brain, acute CBDV administration can modulate atypical striatal circuitry towards neurotypical function. Future studies are required to determine whether modulation of striatal FC is associated with a change in ASD symptoms. TRIAL REGISTRATION: clinicaltrials.gov, Identifier: NCT03537950. Registered May 25th, 2018-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03537950?term=NCT03537950&draw=2&rank=1 . En ligne : http://dx.doi.org/10.1186/s13229-021-00454-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] Modulation of striatal functional connectivity differences in adults with and without autism spectrum disorder in a single-dose randomized trial of cannabidivarin [Texte imprimé et/ou numérique] / C. M. PRETZSCH, Auteur ; D. L. FLORIS, Auteur ; B. VOINESCU, Auteur ; M. ELSAHIB, Auteur ; M. A. MENDEZ, Auteur ; R. WICHERS, Auteur ; L. AJRAM, Auteur ; G. IVIN, Auteur ; M. HEASMAN, Auteur ; E. PRETZSCH, Auteur ; S. WILLIAMS, Auteur ; D. G. M. MURPHY, Auteur ; Eileen DALY, Auteur ; G. M. MCALONAN, Auteur . - 49 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 49 p. Mots-clés : Autism spectrum condition  Autism spectrum disorder  Cbdv  Cannabidivarin  Functional connectivity  Striatum Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) has a high cost to affected individuals and society, but treatments for core symptoms are lacking. To expand intervention options, it is crucial to gain a better understanding of potential treatment targets, and their engagement, in the brain. For instance, the striatum (caudate, putamen, and nucleus accumbens) plays a central role during development and its (atypical) functional connectivity (FC) may contribute to multiple ASD symptoms. We have previously shown, in the adult autistic and neurotypical brain, the non-intoxicating cannabinoid cannabidivarin (CBDV) alters the balance of striatal 'excitatory-inhibitory' metabolites, which help regulate FC, but the effects of CBDV on (atypical) striatal FC are unknown. METHODS: To examine this in a small pilot study, we acquired resting state functional magnetic resonance imaging data from 28 men (15 neurotypicals, 13 ASD) on two occasions in a repeated-measures, double-blind, placebo-controlled study. We then used a seed-based approach to (1) compare striatal FC between groups and (2) examine the effect of pharmacological probing (600 mg CBDV/matched placebo) on atypical striatal FC in ASD. Visits were separated by at least 13 days to allow for drug washout. RESULTS: Compared to the neurotypicals, ASD individuals had lower FC between the ventral striatum and frontal and pericentral regions (which have been associated with emotion, motor, and vision processing). Further, they had higher intra-striatal FC and higher putamenal FC with temporal regions involved in speech and language. In ASD, CBDV reduced hyperconnectivity to the neurotypical level. LIMITATIONS: Our findings should be considered in light of several methodological aspects, in particular our participant group (restricted to male adults), which limits the generalizability of our findings to the wider and heterogeneous ASD population. CONCLUSION: In conclusion, here we show atypical striatal FC with regions commonly associated with ASD symptoms. We further provide preliminary proof of concept that, in the adult autistic brain, acute CBDV administration can modulate atypical striatal circuitry towards neurotypical function. Future studies are required to determine whether modulation of striatal FC is associated with a change in ASD symptoms. TRIAL REGISTRATION: clinicaltrials.gov, Identifier: NCT03537950. Registered May 25th, 2018-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03537950?term=NCT03537950&draw=2&rank=1 . En ligne : http://dx.doi.org/10.1186/s13229-021-00454-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA) / S. STIVAROS in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 12p. Titre : Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA) Type de document : Texte imprimé et/ou numérique Auteurs : S. STIVAROS, Auteur ; S. GARG, Auteur ; M. TZIRAKI, Auteur ; Y. CAI, Auteur ; O. THOMAS, Auteur ; J. MELLOR, Auteur ; A. A. MORRIS, Auteur ; C. JIM, Auteur ; K. SZUMANSKA-RYT, Auteur ; L. M. PARKES, Auteur ; H. A. HAROON, Auteur ; D. MONTALDI, Auteur ; N. WEBB, Auteur ; J. KEANE, Auteur ; Francisco Xavier CASTELLANOS, Auteur ; A. J. SILVA, Auteur ; S. HUSON, Auteur ; S. WILLIAMS, Auteur ; D. GARETH EVANS, Auteur ; R. EMSLEY, Auteur ; J. GREEN, Auteur Article en page(s) : 12p. Langues : Anglais (eng) Mots-clés : Autism  Neurofibromatosis type 1  Neuroimaging  Randomised controlled trial  Simvastatin  Statin Index. décimale : PER Périodiques Résumé : Background: Neurofibromatosis 1 (NF1) is a monogenic model for syndromic autism. Statins rescue the social and cognitive phenotype in animal knockout models, but translational trials with subjects > 8 years using cognition/behaviour outcomes have shown mixed results. This trial breaks new ground by studying statin effects for the first time in younger children with NF1 and co-morbid autism and by using multiparametric imaging outcomes. Methods: A single-site triple-blind RCT of simvastatin vs. placebo was done. Assessment (baseline and 12-week endpoint) included peripheral MAPK assay, awake magnetic resonance imaging spectroscopy (MRS; GABA and glutamate+glutamine (Glx)), arterial spin labelling (ASL), apparent diffusion coefficient (ADC), resting state functional MRI, and autism behavioural outcomes (Aberrant Behaviour Checklist and Clinical Global Impression). Results: Thirty subjects had a mean age of 8.1 years (SD 1.8). Simvastatin was well tolerated. The amount of imaging data varied by test. Simvastatin treatment was associated with (i) increased frontal white matter MRS GABA (t(12) = - 2.12, p = .055), GABA/Glx ratio (t(12) = - 2.78, p = .016), and reduced grey nuclei Glx (ANCOVA p < 0.05, Mann-Whitney p < 0.01); (ii) increased ASL perfusion in ventral diencephalon (Mann-Whitney p < 0.01); and (iii) decreased ADC in cingulate gyrus (Mann-Whitney p < 0.01). Machine-learning classification of imaging outcomes achieved 79% (p < .05) accuracy differentiating groups at endpoint against chance level (64%, p = 0.25) at baseline. Three of 12 (25%) simvastatin cases compared to none in placebo met 'clinical responder' criteria for behavioural outcome. Conclusions: We show feasibility of peripheral MAPK assay and autism symptom measurement, but the study was not powered to test effectiveness. Multiparametric imaging suggests possible simvastatin effects in brain areas previously associated with NF1 pathophysiology and the social brain network. Trial registration: EU Clinical Trial Register (EudraCT) 2012-005742-38 (www.clinicaltrialsregister.eu). En ligne : http://dx.doi.org/10.1186/s13229-018-0190-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA) [Texte imprimé et/ou numérique] / S. STIVAROS, Auteur ; S. GARG, Auteur ; M. TZIRAKI, Auteur ; Y. CAI, Auteur ; O. THOMAS, Auteur ; J. MELLOR, Auteur ; A. A. MORRIS, Auteur ; C. JIM, Auteur ; K. SZUMANSKA-RYT, Auteur ; L. M. PARKES, Auteur ; H. A. HAROON, Auteur ; D. MONTALDI, Auteur ; N. WEBB, Auteur ; J. KEANE, Auteur ; Francisco Xavier CASTELLANOS, Auteur ; A. J. SILVA, Auteur ; S. HUSON, Auteur ; S. WILLIAMS, Auteur ; D. GARETH EVANS, Auteur ; R. EMSLEY, Auteur ; J. GREEN, Auteur . - 12p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 12p. Mots-clés : Autism  Neurofibromatosis type 1  Neuroimaging  Randomised controlled trial  Simvastatin  Statin Index. décimale : PER Périodiques Résumé : Background: Neurofibromatosis 1 (NF1) is a monogenic model for syndromic autism. Statins rescue the social and cognitive phenotype in animal knockout models, but translational trials with subjects > 8 years using cognition/behaviour outcomes have shown mixed results. This trial breaks new ground by studying statin effects for the first time in younger children with NF1 and co-morbid autism and by using multiparametric imaging outcomes. Methods: A single-site triple-blind RCT of simvastatin vs. placebo was done. Assessment (baseline and 12-week endpoint) included peripheral MAPK assay, awake magnetic resonance imaging spectroscopy (MRS; GABA and glutamate+glutamine (Glx)), arterial spin labelling (ASL), apparent diffusion coefficient (ADC), resting state functional MRI, and autism behavioural outcomes (Aberrant Behaviour Checklist and Clinical Global Impression). Results: Thirty subjects had a mean age of 8.1 years (SD 1.8). Simvastatin was well tolerated. The amount of imaging data varied by test. Simvastatin treatment was associated with (i) increased frontal white matter MRS GABA (t(12) = - 2.12, p = .055), GABA/Glx ratio (t(12) = - 2.78, p = .016), and reduced grey nuclei Glx (ANCOVA p < 0.05, Mann-Whitney p < 0.01); (ii) increased ASL perfusion in ventral diencephalon (Mann-Whitney p < 0.01); and (iii) decreased ADC in cingulate gyrus (Mann-Whitney p < 0.01). Machine-learning classification of imaging outcomes achieved 79% (p < .05) accuracy differentiating groups at endpoint against chance level (64%, p = 0.25) at baseline. Three of 12 (25%) simvastatin cases compared to none in placebo met 'clinical responder' criteria for behavioural outcome. Conclusions: We show feasibility of peripheral MAPK assay and autism symptom measurement, but the study was not powered to test effectiveness. Multiparametric imaging suggests possible simvastatin effects in brain areas previously associated with NF1 pathophysiology and the social brain network. Trial registration: EU Clinical Trial Register (EudraCT) 2012-005742-38 (www.clinicaltrialsregister.eu). En ligne : http://dx.doi.org/10.1186/s13229-018-0190-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

The association between socioeconomic status and autism diagnosis in the United Kingdom for children aged 5-8 years of age: Findings from the Born in Bradford cohort / B. KELLY in Autism, 23-1 (January 2019)  

Public ISBD [article]  inAutism > 23-1 (January 2019) . - p.131-140 Titre : The association between socioeconomic status and autism diagnosis in the United Kingdom for children aged 5-8 years of age: Findings from the Born in Bradford cohort Type de document : Texte imprimé et/ou numérique Auteurs : B. KELLY, Auteur ; S. WILLIAMS, Auteur ; S. COLLINS, Auteur ; F. MUSHTAQ, Auteur ; M. MON-WILLIAMS, Auteur ; B. WRIGHT, Auteur ; D. MASON, Auteur ; J. WRIGHT, Auteur Article en page(s) : p.131-140 Langues : Anglais (eng) Mots-clés : autism spectrum disorders  diagnosis  school-age children  spectrum disorders  risk-factors  prevalence  Psychology Index. décimale : PER Périodiques Résumé : There has been recent interest in the relationship between socioeconomic status and the diagnosis of autism in children. Studies in the United States have found lower rates of autism diagnosis associated with lower socioeconomic status, while studies in other countries report no association, or the opposite. This article aims to contribute to the understanding of this relationship in the United Kingdom. Using data from the Born in Bradford cohort, comprising 13,857 children born between 2007 and 2011, it was found that children of mothers educated to A-level or above had twice the rate of autism diagnosis, 1.5% of children (95% confidence interval: 1.1%, 1.9%) compared to children of mothers with lower levels of education status 0.7% (95% confidence interval: 0.5%, 0.9%). No statistically significant relationship between income status or neighbourhood material deprivation was found after controlling for mothers education status. The results suggest a substantial level of underdiagnosis for children of lower education status mothers, though further research is required to determine the extent to which this is replicated across the United Kingdom. Tackling inequalities in autism diagnosis will require action, which could include increased education, awareness, further exploration of the usefulness of screening programmes and the provision of more accessible support services. En ligne : http://dx.doi.org/10.1177/1362361317733182 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=379 [article] The association between socioeconomic status and autism diagnosis in the United Kingdom for children aged 5-8 years of age: Findings from the Born in Bradford cohort [Texte imprimé et/ou numérique] / B. KELLY, Auteur ; S. WILLIAMS, Auteur ; S. COLLINS, Auteur ; F. MUSHTAQ, Auteur ; M. MON-WILLIAMS, Auteur ; B. WRIGHT, Auteur ; D. MASON, Auteur ; J. WRIGHT, Auteur . - p.131-140. Langues : Anglais (eng) in Autism > 23-1 (January 2019) . - p.131-140 Mots-clés : autism spectrum disorders  diagnosis  school-age children  spectrum disorders  risk-factors  prevalence  Psychology Index. décimale : PER Périodiques Résumé : There has been recent interest in the relationship between socioeconomic status and the diagnosis of autism in children. Studies in the United States have found lower rates of autism diagnosis associated with lower socioeconomic status, while studies in other countries report no association, or the opposite. This article aims to contribute to the understanding of this relationship in the United Kingdom. Using data from the Born in Bradford cohort, comprising 13,857 children born between 2007 and 2011, it was found that children of mothers educated to A-level or above had twice the rate of autism diagnosis, 1.5% of children (95% confidence interval: 1.1%, 1.9%) compared to children of mothers with lower levels of education status 0.7% (95% confidence interval: 0.5%, 0.9%). No statistically significant relationship between income status or neighbourhood material deprivation was found after controlling for mothers education status. The results suggest a substantial level of underdiagnosis for children of lower education status mothers, though further research is required to determine the extent to which this is replicated across the United Kingdom. Tackling inequalities in autism diagnosis will require action, which could include increased education, awareness, further exploration of the usefulness of screening programmes and the provision of more accessible support services. En ligne : http://dx.doi.org/10.1177/1362361317733182 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=379

There is variability in the attainment of developmental milestones in the CDKL5 disorder / S. FEHR in Journal of Neurodevelopmental Disorders, 7-1 (December 2015)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 7-1 (December 2015) . - p.2 Titre : There is variability in the attainment of developmental milestones in the CDKL5 disorder Type de document : Texte imprimé et/ou numérique Auteurs : S. FEHR, Auteur ; H. LEONARD, Auteur ; G. HO, Auteur ; S. WILLIAMS, Auteur ; N. DE KLERK, Auteur ; D. FORBES, Auteur ; J. CHRISTODOULOU, Auteur ; J. DOWNS, Auteur Article en page(s) : p.2 Langues : Anglais (eng) Mots-clés : CDKL5 disorder  Developmental disabilities  Early infantile epileptic encephalopathy  Epileptic encephalopathy Index. décimale : PER Périodiques Résumé : BACKGROUND: Individuals with the CDKL5 disorder have been described as having severely impaired development. A few individuals have been reported having attained more milestones including walking and running. Our aim was to investigate variation in attainment of developmental milestones and associations with underlying genotype. METHODS: Data was sourced from the International CDKL5 Disorder Database, and individuals were included if they had a pathogenic or probably pathogenic CDKL5 mutation and information on early development. Kaplan-Meier time-to-event analyses investigated the occurrence of developmental milestones. Mutations were grouped by their structural/functional consequence, and Cox regression was used to investigate the relationship between genotype and milestone attainment. RESULTS: The study included 109 females and 18 males. By 5 years of age, only 75% of the females had attained independent sitting and 25% independent walking whilst a quarter of the males could sit independently by 1 year 3 months. Only one boy could walk independently. No clear relationship between mutation group and milestone attainment was present, although females with a late truncating mutation attained the most milestones. CONCLUSION: Attainment of developmental milestones is severely impaired in the CDKL5 disorder, with the majority who did attain skills attaining them at a late age. It appears as though males are more severely impaired than the females. Larger studies are needed to further investigate the role of genotype on clinical variability. En ligne : http://dx.doi.org/10.1186/1866-1955-7-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=347 [article] There is variability in the attainment of developmental milestones in the CDKL5 disorder [Texte imprimé et/ou numérique] / S. FEHR, Auteur ; H. LEONARD, Auteur ; G. HO, Auteur ; S. WILLIAMS, Auteur ; N. DE KLERK, Auteur ; D. FORBES, Auteur ; J. CHRISTODOULOU, Auteur ; J. DOWNS, Auteur . - p.2. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 7-1 (December 2015) . - p.2 Mots-clés : CDKL5 disorder  Developmental disabilities  Early infantile epileptic encephalopathy  Epileptic encephalopathy Index. décimale : PER Périodiques Résumé : BACKGROUND: Individuals with the CDKL5 disorder have been described as having severely impaired development. A few individuals have been reported having attained more milestones including walking and running. Our aim was to investigate variation in attainment of developmental milestones and associations with underlying genotype. METHODS: Data was sourced from the International CDKL5 Disorder Database, and individuals were included if they had a pathogenic or probably pathogenic CDKL5 mutation and information on early development. Kaplan-Meier time-to-event analyses investigated the occurrence of developmental milestones. Mutations were grouped by their structural/functional consequence, and Cox regression was used to investigate the relationship between genotype and milestone attainment. RESULTS: The study included 109 females and 18 males. By 5 years of age, only 75% of the females had attained independent sitting and 25% independent walking whilst a quarter of the males could sit independently by 1 year 3 months. Only one boy could walk independently. No clear relationship between mutation group and milestone attainment was present, although females with a late truncating mutation attained the most milestones. CONCLUSION: Attainment of developmental milestones is severely impaired in the CDKL5 disorder, with the majority who did attain skills attaining them at a late age. It appears as though males are more severely impaired than the females. Larger studies are needed to further investigate the role of genotype on clinical variability. En ligne : http://dx.doi.org/10.1186/1866-1955-7-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=347

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