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

Semantic Verbal Fluency Pattern, Dementia Rating Scores and Adaptive Behavior Correlate With Plasma Aβ 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 (Aβ and Aβ), as a potent biomarker of AD. In DS, worse performance in SVFT and poorer communication skills were associated with higher plasma Aβ 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 Aβ concentration. In conclusion, we propose the SVFT as a good screening test for early detection of dementia and amyloidosis in young adults with DS

Are Peripheral Biomarkers Determinants of Eating Styles in Childhood and Adolescence Obesity? A Cross-Sectional Study

Disturbances in eating behaviors have been widely related to obesity. However, little is known about the role of obesity-related biomarkers in shaping habitual patterns of eating be haviors (i.e., eating styles) in childhood. The objective of the present study was to explore the relationships between several biomarkers crucially involved in obesity (ghrelin, insulin resistance, and leptin/adiponectin ratio) and eating styles in children and adolescents with obesity. Seventy participants aged between 8 and 16 (56.2% men) fulfilled the Spanish version of the Dutch Eating Behavior Questionnaire for Children to measure external, emotional, and restrained eating styles. In addition, concentrations of ghrelin, leptin, adiponectin, insulin, and glucose were obtained through a blood test. Hierarchical multiple regression analyses controlling for age and sex were computed for each eating style. Results indicated that individuals with higher ghrelin concentration levels showed lower scores in restrained eating (β = −0.61, p < 0.001). The total model explained 32% of the variance of the restrained pattern. No other relationships between obesity-related biomarkers and eating behaviors were found. This study highlights that one of the obesity-risk factors, namely lower plasma ghrelin levels, is substantially involved in a well-known maladaptive eating style, restraint eating, in childhood obesity

Cannabis Use Induces Distinctive Proteomic Alterations in Olfactory Neuroepithelial Cells of Schizophrenia Patients.

A close epidemiological link has been reported between cannabis use and schizophrenia (SCZ). However, biochemical markers in living humans related to the impact of cannabis in this disease are still missing. Olfactory neuroepithelium (ON) cells express neural features and offer a unique advantage to study biomarkers of psychiatric diseases. The aim of our study was to find exclusively deregulated proteins in ON cells of SCZ patients with and without a history of cannabis use. Thus, we compared the proteomic profiles of SCZ non-cannabis users (SCZ/nc) and SCZ cannabis users (SCZ/c) with control subjects non-cannabis users (C/nc) and control cannabis users (C/c). The results revealed that the main cascades affected in SCZ/nc were cell cycle, DNA replication, signal transduction and protein localization. Conversely, cannabis use in SCZ patients induced specific alterations in metabolism of RNA and metabolism of proteins. The levels of targeted proteins in each population were then correlated with cognitive performance and clinical scores. In SCZ/c, the expression levels of 2 proteins involved in the metabolism of RNA (MTREX and ZNF326) correlated with several cognitive markers and clinical signs. Moreover, use duration of cannabis negatively correlated with ZNF326 expression. These findings indicate that RNA-related proteins might be relevant to understand the influence of cannabis use on SCZ

Impulsive Personality Traits Predicted Weight Loss in Individuals with Type 2 Diabetes after 3 Years of Lifestyle Interventions

Impulsivity has been associated with type 2 diabetes (T2D) and may negatively impact its management. This study aimed to investigate impulsive personality traits in an older adult population with T2D and their predicting role in long-term weight control and glycemic management, through glycated hemoglobin (HbA(1c)), following 3 years of intervention with a Mediterranean diet. The Impulsive Behavior Scale (UPPS-P) was administered as a measure of impulsive traits at baseline. Results showed higher total baseline scores of UPPS-P, and higher positive urgency in individuals with T2D, compared with those without T2D. The regression analysis in patients with T2D showed that sensation seeking and lack of perseverance predicted weight loss at follow-up. By contrast, impulsive traits did not predict follow-up levels of HbA(1c). In conclusion, the present findings suggest that higher impulsive traits in individuals with T2D seem to affect long-term weight control, but not glycemic control

Safety and preliminary efficacy on cognitive performance and adaptive functionality of epigallocatechin gallate (EGCG) in children with Down syndrome. A randomized phase Ib clinical trial (PERSEUS study)

Purpose: Although some caregivers are using epigallocatechin gallate (EGCG) off label in hopes of improving cognition in young adults with Down syndrome (DS), nothing is known about its safety, tolerability, and efficacy in the DS pediatric population. We aimed to evaluate safety and tolerability of a dietary supplement containing EGCG and if EGCG improves cognitive and functional performance. Methods: A total of 73 children with DS (aged 6-12 years) were randomized. Participants received 0.5% EGCG (10 mg/kg daily dose) or placebo for 6 months with 3 months follow up after treatment discontinuation. Results: In total, 72 children were treated and 66 completed the study. A total of 38 participants were included in the EGCG group and 35 in the placebo group. Of 72 treated participants, 62 (86%) had 229 treatment-emergent adverse events (AEs). Of 37 participants in the EGCG group, 13 (35%) had 18 drug-related treatment-emergent AEs and 12 of 35 (34%) from the placebo group had 22 events. In the EGCG group, neither severe AEs nor increase in the incidence of AEs related to safety biomarkers were observed. Cognition and functionality were not improved compared with placebo. Secondary efficacy outcomes in girls point to a need for future work. Conclusion: The use of EGCG is safe and well-tolerated in children with DS, but efficacy results do not support its use in this population. (C) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics

Cannabis en los jóvenes: patología psiquiátrica y escalas de consumo

El cannabis es la droga ilegal de uso más extendido en España siendo la prevalencia de su consumo elevada (17% en el último año-población de 15 a 34 años). Dado que diversos estudios muestran que sólo una pequeña proporción de personas con abuso o dependencia de cannabis buscan tratamiento, para detectar un consumo patológico se hace necesario disponer de instrumentos que se puedan utilizar tanto en atención primaria como en las encuestas a población general o escolar. Por otro lado, teniendo en cuenta la asociación entre problemas mentales y consumo de sustancias (comorbilidad psiquiátrica) y dado que en nuestro país no existen estudios de morbilidad psiquiátrica en población joven consumidora de cannabis fuera de tratamiento, es de interés estudiar la patología psiquiátrica asociada a dicho consumo en una muestra de sujetos jóvenes reclutados fuera del marco asistencial. Este estudio se diseñó para dar respuesta a estas deficiencias.El cànnabis és la droga d’ús il·legal més extensa a Espanya sent la prevalença del seu consum elevada (17% en l’últim any-població de 15 a 34 anys). Donat que diversos estudis mostren que només una petita proporció de persones amb abús o dependència de cànnabis busquen tractament, per a detectar un consum patològic és necessari disposar d’instruments que es puguin utilitzar tant en atenció primària como en las enquestes a població general o escolar. Per una altra banda, tenint en compte l’associació entre problemes mentals y consum de substàncies (comorbiditat psiquiàtrica) i donat que en el nostre país no existeixen estudis de morbiditat psiquiàtrica en població jove consumidora de cànnabis fora de tractament, és d’interès estudiar la patologia psiquiàtrica associada a aquest consum en una mostra de subjectes joves reclutats fora del marc assistencial. Aquest estudi va ser dissenyat per donar resposta a aquestes deficiències.Cannabis is the illicit drug most widely used in Spain being prevalence of consumption high (17% in the last year-population 15-34 years). Since studies show that only a small proportion of people with cannabis abuse or dependence seek treatment, to detect abnormal consumption is necessary to have instruments that can be used both in primary care and in general population surveys or school. On the other hand, given the association between mental health problems and substance use (psychiatric comorbidity) and given that in our country there are no studies of psychiatric morbidity in young people consuming cannabis off treatment, is of interest to study psychiatric disorders associated this consumption in a sample of young subjects recruited outside the care setting. This study was designed to address these shortcomings

Type 2 diabetes and cognitive impairment in an older population with overweight or obesity and metabolic syndrome: baseline cross-sectional analysis of the PREDIMED-plus study

This study cross-sectionally examines in the elderly population: (a) the association of type 2 diabetes with executive function (EF); (b) the effect of BMI on both type 2 diabetes and EF; (c) the association between glycaemia control and EF in type 2 diabetes. 6823 older individuals with overweight/obesity and metabolic syndrome participating in the PREDIMED-PLUS study, were assessed with a battery of cognitive tests and a medical interview. ANOVA showed a significantly worse performance on EF in type 2 diabetes vs. non-diabetic individuals. Two complementary models were displayed: (1) in the whole sample, the presence of type 2 diabetes, depressive symptoms and BMI had a direct negative effect on EF, while apnoea had an indirect negative effect; (2) in the diabetes subsample, higher illness duration was associated with worse performance in EF. Participants with type 2 diabetes and HbA1c<53 mmol/mol displayed better cognitive performance when compared to those with HbA1c≥53 mmol/mol. Our results provide a controlled comprehensive model that integrates relevant neuropsychological and physical variables in type 2 diabetes. The model suggests that, to improve treatment adherence and quality of life once diabetes has been diagnosed, cognitive decline prevention strategies need to be implemented while monitoring depressive symptoms, BMI and glycaemia control.This project is funded by Instituto de Salud Carlos III (ISCIII), the Spanish Government Official Agency for funding biomedical research - with competitive grants for the periods 2014–2016, 2015–2017, 2017–2019 and 2018–2020, through the Fondo de Investigación para la Salud (FIS), which is co-funded by the European Regional Development Fund [grants: PI13/00673, PI13/00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/00728 PI13/01090 PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/00696, PI14/01206, PI14/01919, PI14/00853, PI14/01374, PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183, PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441, PI17/00508, PI17/01732, PI17/00926] and the European Research Council [Advanced Research Grant 2014–2019; agreement #340918]. Additional grants: Acciones Especiales from ISCIIII, Consejería-Salud, Junta -Andalucía [PI0458/2013, PS0358/2016], Recercaixa-grant 2013 [2013ACUP00194], a SEMERGEN grant, International Nut & Dried Fruit Council – FESNAD No. 201302. Fundación Patrimonio Comunal Olivarero is providing the necessary amounts of olive oil. Nuts were initially and only partially provided by Pistachios Growers and Almond Board of California, for the pilot study. This research was also partially funded by EU-H2020 Grant (Eat2beNICE/H2020-SFS-2016–2; Ref 728018), PI14/00290 y PI17/1167(Co-funded by European Regional Development Fund, ERDF, a way to build Europe), PERIS (Generalitat de Catalunya, SLT006/17/00077), Grant PROMETEO/2017/017 (Generalitat Valenciana) and Grant FEA/SEA 2017 for Primary Care Research. We thank CERCA Programme/Generalitat de Catalunya for institutional support. ML-M is supported by a predoctoral Grant of the Ministerio de Educación, Cultura y Deporte (FPU15/02911). None of these funding sources plays any role in the design, collection, analysis, or interpretation of the data or in the decision to submit manuscripts for publication

Association between ankle-brachial index and cognitive function in participants in the PREDIMED-Plus study: cross-sectional assessment

Introducción y objetivos: El índice tobillo-brazo (ITB) es un indicador de enfermedad arterial periférica (EAP). El objetivo de este estudio es evaluar la asociación entre la EAP medida con el ITB y el rendimiento cognitivo de individuos con sobrepeso u obesidad y síndrome metabólico. Métodos: Estudio transversal realizado con los datos basales del estudio PREDIMED-Plus, en el que se incluyó a un total de 4.898 participantes (tras excluir a aquellos sin medición de ITB) de entre 55 y 75 años, con sobrepeso u obesidad y síndrome metabólico. En la visita basal se midió el ITB según un protocolo estandarizado, así como otros factores de riesgo cardiovascular (diabetes mellitus, dislipemia e hipertensión arterial, entre otros). Para la evaluación del rendimiento cognitivo, se aplicaron diferentes pruebas validadas en población española (Mini-mental Test, test de fluencia verbal semántica y fonológica, test de valoración de memoria de trabajo, test del trazo y test del reloj). Para evaluar la asociación entre el ITB y el rendimiento cognitivo, se utilizaron modelos lineales generalizados. Resultados: El 3,4% de los participantes tenían EAP, definida por un ITB ≤ 0,9, y un 3,3%, calcificación arterial definida por un ITB ≥ 1,4. La EAP se asoció con la edad, la presión arterial sistólica y los indicadores de obesidad, mientras que la calcificación arterial se asoció también con obesidad y diabetes. Entre el rendimiento cognitivo y el ITB o la EAP, no se observaron asociaciones significativas. Conclusiones: En nuestra muestra la EAP aumenta con la edad, la presión arterial y los indicadores de obesidad. No se observa una asociación significativa entre el ITB, la EAP y el rendimiento cognitivo.Introduction and objectives: The ankle-brachial index (ABI) is an indicator of peripheral artery disease (PAD). The aim of this study was to assess the association between PAD, measured with the ABI, and cognitive function in persons with overweight or obesity and metabolic syndrome. Methods: Cross-sectional study conducted with baseline data from the PREDIMED-Plus study, which included 4898 participants (after exclusion of those without ABI measurements) aged between 55 and 75 years, and with overweight or obesity and metabolic syndrome. At the baseline assessment, we measured the ABI with a standardized protocol and assessed the presence of other cardiovascular risk factors (eg, diabetes, dyslipidemia, hypertension). Cognitive function was evaluated using several tests validated for the Spanish population (mini-mental state examination [MMSE], phonological and semantic verbal fluency test, WAIS-III working memory index [WMI], parts A and B of the trail making test (TMT), and clock drawing test). Generalized linear models were used to assess the association between the ABI and cognitive function. Results: Among the participants, 3.4% had PAD defined as ABI ≤ 0.9, and 3.3% had arterial calcification defined as ABI ≥ 1.4. PAD was associated with age, systolic blood pressure and obesity indicators, while arterial calcification was also associated with obesity and diabetes. No significant associations were observed between cognitive function and ABI or PAD. Conclusions: In our sample, the presence of PAD increased with age, blood pressure, and obesity. No significant association was observed between ABI, PAD, or cognitive function

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