Alteraciones a medio y largo plazo en el rendimiento cognitivo y potenciales evocados (P300) en policonsumidores recreativos de éxtasis

Consultable des del TDXDescripció del recurs: el 9 d'abril 2009Títol obtingut de la portada digitalitzadaEn la actualidad se desconocen con certeza los efectos derivados del uso prolongado del "éxtasis" (MDMA) con fines recreativos, aunque existen numerosos indicios de una clara asociación entre el uso habitual e intenso de esta sustancia y la aparición de alteraciones cognitivas y neurofisiológicas en seres humanos. Estos efectos se atribuyen a la neurodegeneración selectiva y persistente del sistema serotoninérgico cerebral observada en experimentación preclínica con animales. Estos indicios son motivo de preocupación ya que cabe la posibilidad que la persistencia de estas alteraciones a lo largo del tiempo pudieran contribuir a la aparición de deterioro cognitivo más allá del proceso de envejecimiento normal. El objetivo principal de este trabajo de investigación es aportar nuevas pruebas de la neurotoxicidad del éxtasis como factor de riesgo en la aparición de déficit cognitivos y cambios electrofisiológicos cerebrales (potencial evocado P300) a medio y largo plazo. Otros objetivos perseguidos fueron: estudiar el curso de dichas alteraciones a lo largo del tiempo, explorar las relaciones existentes entre los parámetros de latencia y amplitud de la onda P300, funciones cognitivas y consumo acumulado de éxtasis a lo largo de la vida (consumo-vida). Por último, se pretendió explorar la contribución del uso concomitante de cannabis sobre dichas alteraciones. Para ello se realizó el seguimiento de una muestra de policonsumidores habituales de éxtasis, consumidores habituales de cannabis y controles no consumidores de sustancias de abuso, durante un período natural de 3 años dividido en dos períodos diferenciados de 24 y 12 meses. Los resultados muestran que los consumidores de éxtasis obtienen rendimientos cognitivos significativamente más pobres en comparación al grupo control pero no respecto al grupo cannabis tanto a nivel basal como a medio y largo plazo. A largo plazo los consumidores de éxtasis presentan déficit persistentes de carácter subclínico en funciones ejecutivas, memoria episódica y velocidad de procesamiento mental. Se hallaron relaciones dosis-respuesta entre el consumo-vida de éxtasis y el rendimiento mnésico y velocidad de procesamiento mental. El consumo-vida de cannabis y una edad de inicio temprana en el uso de esta sustancia contribuyen a explicar los déficit observados en el grupo éxtasis. En cuanto a la respuesta del potencial evocado P300, no se observan diferencias significativas entre los tres grupos, mostrando valores de latencia y amplitud dentro de la normalidad y sin alteraciones clínicamente relevantes a medio plazo. Los análisis muestran correlaciones significativas entre la latencia del potencial y memoria de trabajo, fluencia verbal, atención dividida y reconocimiento verbal. Se observó una asociación significativa aunque paradójica entre el consumo-vida de cannabis y la latencia de este potencial. No se observaron correlaciones significativas con el uso de éxtasis. Los resultados de este trabajo aportan nuevas pruebas de que el consumo de éxtasis de forma habitual y prolongada en el tiempo, especialmente en cantidades elevadas, induce efectos negativos sobre la cognición en forma de alteraciones discretas de magnitud subclínica, las cuales persisten con un curso estable a medio y largo plazo. Estas manifestaciones cognitivas responden a los efectos neurotóxicos inducidos no sólo por el uso del éxtasis, sino por la interacción éxtasis/cannabis sobre el sustrato cerebral. Por el contrario, el consumo de éxtasis no afecta significativamente a la actividad eléctrica cerebral registrada mediante el potencial evocado P300. En cuanto a la contribución del cannabis, su uso concomitante ejerce efectos solapados sobre la cognición, pero tampoco induce cambios significativos sobre la actividad eléctrica cerebral. Independientemente de cual sea la naturaleza de la interacción entre ambas sustancias, la relevancia clínica de los efectos del éxtasis sobre la cognición es discreta pero no por ello despreciable, ya que los policonsumidores de éxtasis manifiestan alteraciones, aunque éstas son de carácter subclínico. PALABRAS CLAVE: Éxtasis, déficit cognitivos, potenciales evocadosUp to date there is no conclusive evidence on the effects induced by long-term recreational "ecstasy" (MDMA) consumption, although extensive research suggests a clear linkage between prolonged and intensive use of this substance and cognitive and neurophysiological changes in humans. Animal studies raise the possibility that these alterations could respond to selective and persistent neurodegenerative effects upon central serotonergic systems. There is concern that in humans the persistency of these alterations over long periods of time could contribute to developing cognitive impairment beyond normal aging processes. The main aim of this investigation was to provide new and additional evidence on the neurotoxic effects of ecstasy use as a risk factor associated with short and long-term changes in neurocognitive performance and neuroelectric brain activity (P300 event-related potentials). Other aims explored in the present study were: examine the course of neurocognitive and electrophysiological changes over time, explore the relationships between P300 main components: latency and amplitude with specific cognitive domains and lifetime MDMA cumulative use (lifetime consumption), as well as the relative contribution of cannabis on these alterations. In other to cover these goals, follow-up of a sample of current ecstasy polydrug users, current cannabis users and drug naïve controls was conducted over a natural period of 3 years, divided in two different periods of time: 24 and 12 months. The results of this study showed that at baseline, one year and two years follow-up assessments, ecstasy polydrug users presented significantly poorer cognitive performance than non-drug using controls. No significant differences were found between ecstasy and cannabis users on cognitive tests. In the long-term, ecstasy polydrug users showed consistently persistent subclinical deficits on executive functions, episodic memory and mental processing speed. Significant dose-response relations were found between ecstasy lifetime consumption and performance in memory and mental processing speed. Age at onset of cannabis use before 15 years predicted lower performance in memory and mental processing speed. Concerning P300 response, no group differences were shown on P300 event-related potentials. The analyses revealed significant correlations between P300 latency and specific cognitive domains of working memory, verbal fluency, divided attention and verbal recognition, although the direction of those associations regarding P300 latency, attention and recognition was counterintuitive. Moreover, a significant but paradoxical association emerged between cannabis lifetime use and P300 latency, but no association was found between ecstasy exposure and P300 main components. The results of this study provide new and additional evidence that regular and prolonged ecstasy consumption, especially an intensive pattern of use, induces negative effects on cognition in terms of mild sub-clinical cognitive deficits, which remain persistent and stable in the short and the long-term. Cognitive impairment observed in ecstasy polydrug users supports that not only ecstasy use but ecstasy/cannabis interaction account for the neurotoxic effects upon the brain substrate. On the contrary, ecstasy intake does not affect significantly brain electric activity (P300). Regarding the role of cannabis, co-use of this substance shows overlapping effects on cognition but does not induce significant changes on brain electric activity (P300). No matter the nature of the dynamic interaction between both drugs, the clinical relevance of their effects on cognition is subtle but not negligible, due to the fact that cognitive deficits are found in recreational ecstasy polydrug users, although these are of sub-clinical magnitude

Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down's syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial

Background Early cognitive intervention is the only routine therapeutic approach used for amelioration of intellectual deficits in individuals with Down's syndrome, but its effects are limited. We hypothesised that administration of a green tea extract containing epigallocatechin-3-gallate (EGCG) would improve the effects of non-pharmacological cognitive rehabilitation in young adults with Down's syndrome.; Methods We enrolled adults (aged 16-34 years) with Down's syndrome from outpatient settings in Catalonia, Spain, with any of the Down's syndrome genetic variations (trisomy 21, partial trisomy, mosaic, or translocation) in a double-blind, placebo-controlled, phase 2, single centre trial (TESDAD). Participants were randomly assigned at the IMIM-Hospital del Mar Medical Research Institute to receive EGCG (9 mg/kg per day) or placebo and cognitive training for 12 months. We followed up participants for 6 months after treatment discontinuation. We randomly assigned participants using random-number tables and balanced allocation by sex and intellectual quotient. Participants, families, and researchers assessing the participants were masked to treatment allocation. The primary endpoint was cognitive improvement assessed by neuropsychologists with a battery of cognitive tests for episodic memory, executive function, and functional measurements. Analysis was on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01699711.; Findings The study was done between June 5, 2012, and June 6, 2014. 84 of 87 participants with Down's syndrome were included in the intention-to-treat analysis at 12 months (43 in the EGCG and cognitive training group and 41 in the placebo and cognitive training group). Differences between the groups were not significant on 13 of 15 tests in the TESDAD battery and eight of nine adaptive skills in the Adaptive Behavior Assessment System II (ABAS-II). At 12 months, participants treated with EGCG and cognitive training had significantly higher scores in visual recognition memory (Pattern Recognition Memory test immediate recall, adjusted mean difference: 6.23 percentage points [95% CI 0.31 to 12.14], p=0.039; d 0.4 [0.05 to 0.84]), inhibitory control (Cats and Dogs total score, adjusted mean difference: 0.48 [0.02 to 0.93], p=0.041; d 0.28 [0.19 to 0.74]; Cats and Dogs total response time, adjusted mean difference: -4.58 s [-8.54 to -0.62], p=0.024; d -0.27 [-0.72 to -0.20]), and adaptive behaviour (ABAS-II functional academics score, adjusted mean difference: 5.49 [2.13 to 8.86], p=0.002; d 0.39 [-0.06 to 0.84]). No differences were noted in adverse effects between the two treatment groups.; Interpretation EGCG and cognitive training for 12 months was significantly more effective than placebo and cognitive training at improving visual recognition memory, inhibitory control, and adaptive behaviour. Phase 3 trials with a larger population of individuals with Down's syndrome will be needed to assess and confirm the long-term efficacy of EGCG and cognitive training.; Funding Jerome Lejeune Foundation, Instituto de Salud Carlos III FEDER, MINECO, Generalitat de Catalunya.Peer ReviewedPostprint (author's final draft

The Influence of Genetic and Environmental Factors among MDMA Users in Cognitive Performance

This study is aimed to clarify the association between MDMA cumulative use and cognitive dysfunction, and the potential role of candidate genetic polymorphisms in explaining individual differences in the cognitive effects of MDMA. Gene polymorphisms related to reduced serotonin function, poor competency of executive control and memory consolidation systems, and high enzymatic activity linked to bioactivation of MDMA to neurotoxic metabolites may contribute to explain variations in the cognitive impact of MDMA across regular users of this drug. Sixty ecstasy polydrug users, 110 cannabis users and 93 non-drug users were assessed using cognitive measures of Verbal Memory (California Verbal Learning Test, CVLT), Visual Memory (Rey-Osterrieth Complex Figure Test, ROCFT), Semantic Fluency, and Perceptual Attention (Symbol Digit Modalities Test, SDMT). Participants were also genotyped for polymorphisms within the 5HTT, 5HTR2A, COMT, CYP2D6, BDNF, and GRIN2B genes using polymerase chain reaction and TaqMan polymerase assays. Lifetime cumulative MDMA use was significantly associated with poorer performance on visuospatial memory and perceptual attention. Heavy MDMA users (>100 tablets lifetime use) interacted with candidate gene polymorphisms in explaining individual differences in cognitive performance between MDMA users and controls. MDMA users carrying COMT val/val and SERT s/s had poorer performance than paired controls on visuospatial attention and memory, and MDMA users with CYP2D6 ultra-rapid metabolizers performed worse than controls on semantic fluency. Both MDMA lifetime use and gene-related individual differences influence cognitive dysfunction in ecstasy users

VNTR-DAT1 and COMTVal158Met genotypes modulate mental flexibility and adaptive behavior skills in Down syndrome

Down syndrome (DS) is an aneuploidy syndrome that is caused by trisomy for human chromosome 21 resulting in a characteristic cognitive and behavioral phenotype, which includes executive functioning and adaptive behavior difficulties possibly due to prefrontal cortex (PFC) deficits. DS also present a high risk for early onset of Alzheimer Disease-like dementia. The dopamine (DA) system plays a neuromodulatory role in the activity of the PFC. Several studies have implicated trait differences in DA signaling on executive functioning based on genetic polymorphisms in the genes encoding for the catechol-O-methyltransferase (COMTVal158Met) and the dopamine transporter (VNTR-DAT1). Since it is known that the phenotypic consequences of genetic variants are modulated by the genetic background in which they occur, we here explore whether these polymorphisms variants interact with the trisomic genetic background to influence gene expression, and how this in turn mediates DS phenotype variability regarding PFC cognition. We genotyped 69 young adults of both genders with DS, and found that VNTR-DAT1 was in Hardy-Weinberg equilibrium but COMTVal158Met had a reduced frequency of Met allele homozygotes. In our population, genotypes conferring higher DA availability, such as Met allele carriers and VNTR-DAT1 10-repeat allele homozygotes, resulted in improved performance in executive function tasks that require mental flexibility. Met allele carriers showed worse adaptive social skills and self-direction, and increased scores in the social subscale of the Dementia Questionnaire for People with Intellectual Disabilities than Val allele homozygotes. The VNTR-DAT1 was not involved in adaptive behavior or early dementia symptoms. Our results suggest that genetic variants of COMTVal158Met and VNTR-DAT1 may contribute to PFC-dependent cognition, while only COMTVal158Met is involved in behavioral phenotypes of DS, similar to euploid population.Peer Reviewe

Semantic verbal fluency pattern, dementia rating scores and adaptive behavior correlate with plasma Aß42 concentrations in down syndrome young adults

© 2015 Del Hoyo, Xicota, Sánchez-Benavides, Cuenca-Royo, de Sola, Langohr, Fagundo, Farre, Dierssen and de La Torre. Down syndrome (DS) is an intellectual disability (ID) disorder in which language and specifically, verbal fluency are strongly impaired domains; nearly all adults show neuropathology of Alzheimer’s disease (AD), including amyloid deposition by their fifth decade of life. In the general population, verbal fluency deficits are considered a strong AD predictor being the semantic verbal fluency task (SVFT) a useful tool for enhancing early diagnostic. However, there is a lack of information about the association between the semantic verbal fluency pattern (SVFP) and the biological amyloidosis markers in DS. In the current study, we used the SVFT in young adults with DS to characterize their SVFP, assessing total generated words, clustering, and switching. We then explored its association with early indicators of dementia, adaptive behavior and amyloidosis biomarkers, using the Dementia Questionnaire for Persons with Intellectual Disability (DMR), the Adaptive Behavior Assessment System-Second Edition (ABAS-II), and plasma levels of Aß peptides (Aß40 and Aß42), as a potent biomarker of AD. In DS, worse performance in SVFT and poorer communication skills were associated with higher plasma Aß42 concentrations, a higher DMR score and impaired communication skills (ABAS–II). The total word production and switching ability in SVFT were good indicators of plasma Aß42 concentration. In conclusion, we propose the SVFT as a good screening test for early detection of dementia and amyloidosis in young adults with DS.Peer Reviewe

Assessment of cognitive Scales to examine memory, executive function and language in individuals with down syndrome: implications of a 6-month bservational study.

Down syndrome (DS) is the most commonly identifiable genetic form of intellectual disability. Individuals with DS have considerable deficits in intellectual functioning (i.e., low intellectual quotient, delayed learning and/or impaired language development) and adaptive behavior. Previous pharmacological studies in this population have been limited by a lack of appropriate endpoints that accurately measured change in cognitive and functional abilities. Therefore, the current longitudinal observational study assessed the suitability and reliability of existing cognitive scales to determine which tools would be the most effective in future interventional clinical studies. Subtests of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Cambridge Neuropsychological Test Automated Battery (CANTAB), and Clinical Evaluation of Language Fundamentals-Preschool-2 (CELF-P-2), and the Observer Memory Questionnaire-Parent Form (OMQ-PF), Behavior Rating Inventory of Executive Function®-Preschool Version (BRIEF-P) and Leiter International Performance Scale-Revised were assessed. The results reported here have contributed to the optimization of trial design and endpoint selection for the Phase 2 study of a new selective negative allosteric modulator of the GABAA receptor α5-subtype (Basmisanil), and can be applied to other studies in the DS population.Medical writing support was provided by Tara N. Miller, PhD, of Envision Scientific Solutions, funded by F. Hoffmann-La Roche

Effects of GLP-1 receptor agonists on mitochondrial function, inflammatory markers and leukocyte-endothelium interactions in type 2 diabetes

Objective: Type 2 diabetes (T2D) is linked to metabolic, mitochondrial and inflammatory alterations, atherosclerosis development and cardiovascular diseases (CVDs). The aim was to investigate the potential therapeutic benefits of GLP-1 receptor agonists (GLP-1 RA) on oxidative stress, mitochondrial respiration, leukocyte-endothelial interactions, inflammation and carotid intima–media thickness (CIMT) in T2D patients. Research design and methods: Type 2 diabetic patients (255) and control subjects (175) were recruited, paired by age and sex, and separated into two groups: without GLP-1 RA treatment (196) and treated with GLP-1 RA (59). Peripheral blood polymorphonuclear leukocytes (PMNs) were isolated to measure reactive oxygen species (ROS) production by flow cytometry and oxygen consumption with a Clark electrode. PMNs were also used to assess leukocyte-endothelial interactions. Circulating levels of adhesion molecules and inflammatory markers were quantified by Luminex's technology, and CIMT was measured as surrogate marker of atherosclerosis. Results: Treatment with GLP-1 RA reduced ROS production and recovered mitochondrial membrane potential, oxygen consumption and MPO levels. The velocity of leukocytes rolling over endothelial cells increased in PMNs from GLP-1 RA-treated patients, whereas rolling and adhesion were diminished. ICAM-1, VCAM-1, IL-6, TNFα and IL-12 protein levels also decreased in the GLP-1 RA-treated group, while IL-10 increased. CIMT was lower in GLP-1 RA-treated T2D patients than in T2D patients without GLP-1 RA treatment. Conclusions: GLP-1 RA treatment improves the redox state and mitochondrial respiration, and reduces leukocyte-endothelial interactions, inflammation and CIMT in T2D patients, thereby potentially diminishing the risk of atherosclerosis and CVDs

Semantic Verbal Fluency Pattern, Dementia Rating Scores and Adaptive Behavior Correlate With Plasma Aβ42 Concentrations in Down Syndrome Young Adults.

Down syndrome (DS) is an intellectual disability (ID) disorder in which language and specifically, verbal fluency are strongly impaired domains; nearly all adults show neuropathology of Alzheimer's disease (AD), including amyloid deposition by their fifth decade of life. In the general population, verbal fluency deficits are considered a strong AD predictor being the semantic verbal fluency task (SVFT) a useful tool for enhancing early diagnostic. However, there is a lack of information about the association between the semantic verbal fluency pattern (SVFP) and the biological amyloidosis markers in DS. In the current study, we used the SVFT in young adults with DS to characterize their SVFP, assessing total generated words, clustering, and switching. We then explored its association with early indicators of dementia, adaptive behavior and amyloidosis biomarkers, using the Dementia Questionnaire for Persons with Intellectual Disability (DMR), the Adaptive Behavior Assessment System-Second Edition (ABAS-II), and plasma levels of Aβ peptides (Aβ40 and Aβ42), as a potent biomarker of AD. In DS, worse performance in SVFT and poorer communication skills were associated with higher plasma Aβ42 concentrations, a higher DMR score and impaired communication skills (ABAS-II). The total word production and switching ability in SVFT were good indicators of plasma Aβ42 concentration. In conclusion, we propose the SVFT as a good screening test for early detection of dementia and amyloidosis in young adults with DS.This work was supported by grants, donations and agreements from Fondation Jérôme Lejeune (Paris, France), Instituto de Salud Carlos III FEDER, (PI11/00744), MINECO (SAF2010-19434 and SAF2013-49129-C2-1-R), EU (Era Net Neuron PCIN-2013-060), DIUE de la Generalitat de Catalunya (SGR 2009/1450 and SGR 2009/718)

The influence of genetic and environmental factors among MDMA users in cognitive performance

This study is aimed to clarify the association between MDMA cumulative use and cognitive dysfunction, and the potential role of candidate genetic polymorphisms in explaining individual differences in the cognitive effects of MDMA. Gene polymorphisms related to reduced serotonin function, poor competency of executive control and memory consolidation systems, and high enzymatic activity linked to bioactivation of MDMA to neurotoxic metabolites may contribute to explain variations in the cognitive impact of MDMA across regular users of this drug. Sixty ecstasy polydrug users, 110 cannabis users and 93 non-drug users were assessed using cognitive measures of Verbal Memory (California Verbal Learning Test, CVLT), Visual Memory (Rey-Osterrieth Complex Figure Test, ROCFT), Semantic Fluency, and Perceptual Attention (Symbol Digit Modalities Test, SDMT). Participants were also genotyped for polymorphisms within the 5HTT, 5HTR2A, COMT, CYP2D6, BDNF, and GRIN2B genes using polymerase chain reaction and TaqMan polymerase assays. Lifetime cumulative MDMA use was significantly associated with poorer performance on visuospatial memory and perceptual attention. Heavy MDMA users (>100 tablets lifetime use) interacted with candidate gene polymorphisms in explaining individual differences in cognitive performance between MDMA users and controls. MDMA users carrying COMT val/val and SERT s/s had poorer performance than paired controls on visuospatial attention and memory, and MDMA users with CYP2D6 ultra-rapid metabolizers performed worse than controls on semantic fluency. Both MDMA lifetime use and gene-related individual differences influence cognitive dysfunction in ecstasy users

The influence of genetic and environmental factors among MDMA users in cognitive performance

This study is aimed to clarify the association between MDMA cumulative use and cognitive dysfunction, and the potential role of candidate genetic polymorphisms in explaining individual differences in the cognitive effects of MDMA. Gene polymorphisms related to reduced serotonin function, poor competency of executive control and memory consolidation systems, and high enzymatic activity linked to bioactivation of MDMA to neurotoxic metabolites may contribute to explain variations in the cognitive impact of MDMA across regular users of this drug. Sixty ecstasy polydrug users, 110 cannabis users and 93 non-drug users were assessed using cognitive measures of Verbal Memory (California Verbal Learning Test, CVLT), Visual Memory (Rey-Osterrieth Complex Figure Test, ROCFT), Semantic Fluency, and Perceptual Attention (Symbol Digit Modalities Test, SDMT). Participants were also genotyped for polymorphisms within the 5HTT, 5HTR2A, COMT, CYP2D6, BDNF, and GRIN2B genes using polymerase chain reaction and TaqMan polymerase assays. Lifetime cumulative MDMA use was significantly associated with poorer performance on visuospatial memory and perceptual attention. Heavy MDMA users (>100 tablets lifetime use) interacted with candidate gene polymorphisms in explaining individual differences in cognitive performance between MDMA users and controls. MDMA users carrying COMT val/val and SERT s/s had poorer performance than paired controls on visuospatial attention and memory, and MDMA users with CYP2D6 ultra-rapid metabolizers performed worse than controls on semantic fluency. Both MDMA lifetime use and gene-related individual differences influence cognitive dysfunction in ecstasyThis study was supported by grants from the National Institutes of Health (NIH) grant no. 1 R01 DA017987, Grant 2005SGR00032, Fondo de Investigaciones Sanitarias (FIS-00/00777), Plan Nacional Sobre Drogas (INT/2012/2002) Spain, Plan Nacional Sobre Drogas: PNSD 2006/101(2007–2009) Spain. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscrip