Klaus Langohr

Principal Component Analysis of the Effects of Environmental Enrichment and (-)-epigallocatechin-3-gallate on Age-Associated Learning Deficits in a Mouse Model of Down Syndrome.

Down syndrome (DS) individuals present increased risk for Alzheimers disease (AD) neuropathology and AD-type dementia. Here, we investigated the use of green tea extracts containing (-)-epigallocatechin-3-gallate (EGCG), as co-adjuvant to enhance the effects of environmental enrichment (EE) in Ts65Dn mice, a segmental trisomy model of DS that partially mimics DS/AD pathology, at the age of initiation of cognitive decline. Classical repeated measures ANOVA showed that combined EE-EGCG treatment was more efficient than EE or EGCG alone to improve specific spatial learning related variables. Using principal component analysis (PCA) we found that several spatial learning parameters contributed similarly to a first PC and explained a large proportion of the variance among groups, thus representing a composite learning measure. This PC1 revealed that EGCG or EE alone had no significant effect. However, combined EE-EGCG significantly ameliorated learning alterations of middle age Ts65Dn mice. Interestingly, PCA revealed an increased variability along learning sessions with good and poor learners in Ts65Dn, and this stratification did not disappear upon treatments. Our results suggest that combining EE and EGCG represents a viable therapeutic approach for amelioration of age-related cognitive decline in DS, although its efficacy may vary across individuals.

Interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis.

OBJECTIVE To carry out a systematic review of the risk factors for, and incidence of, major depressive episode (MDE) related to antiviral therapy for chronic hepatitis C. DATA SOURCES The MEDLINE, PsycINFO, and Cochrane databases were searched to locate articles published from the earliest available online year until June 2011 using the keywords hepatitis C, interferon-alpha, peginterferon, pegylated interferon, depression, and mood and Boolean operators. Articles written in English, Spanish, and French were included. STUDY SELECTION Prospective studies reporting incidence of interferon-alpha-induced MDE were included. At baseline, patients did not present a DSM-IV/ICD depressive episode, and evaluation was performed by a trained clinician. Twenty-six observational studies met the inclusion criteria. DATA EXTRACTION Extracted data included authors, year of publication, design, characteristics of the population, viral coinfection, adjunctive psychopharmacology, instruments to assess depression, dose and type of interferon-alpha, adjunctive ribavirin treatment, and follow-up time. Outcome of incidence of MDE (primary outcome measure) was abstracted, as were potential predictive variables. DATA SYNTHESIS A full review was performed. Meta-analysis of the cumulative incidence of induced MDE as a function of time was carried out. Odds ratios (ORs) and mean differences were used to estimate the strength of association of variables. RESULTS Overall cumulative incidence of depression was 0.25 (95% CI, 0.16 to 0.35) and 0.28 (95% CI, 0.17 to 0.42) at 24 and 48 weeks of treatment, respectively. According to our analysis, high baseline levels of interleukin 6 (mean difference = 1.81; 95% CI, 1.09 to 2.52), female gender (OR = 1.40; 95% CI, 1.02 to 1.91), history of MDE (OR = 3.96; 95% CI, 2.52 to 6.21), history of psychiatric disorder (OR = 3.18; 95% CI, 1.60 to 6.32), subthreshold depressive symptoms (mean difference = 0.96; 95% CI, 0.31 to 1.61), and low educational level (mean difference = -0.99; 95% CI, -1.59 to -0.39) were predictive variables of MDE during antiviral treatment. CONCLUSIONS One in 4 chronic hepatitis C patients who start interferon and ribavirin treatment will develop an induced major depressive episode. Clinicians should attempt a full evaluation of patients before starting antiviral treatment in order to identify those at risk of developing interferon-induced depression.

Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans

SCOPE Trisomy for human chromosome 21 results in Down syndrome (DS), which is among the most complex genetic perturbations leading to intellectual disability. Accumulating data suggest that overexpression of the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), is a critical pathogenic mechanisms in the intellectual deficit. METHODS AND RESULTS Here we show that the green tea flavonol epigallocatechin-gallate (EGCG), a DYRK1A inhibitor, rescues the cognitive deficits of both segmental trisomy 16 (Ts65Dn) and transgenic mice overexpressing Dyrk1A in a trisomic or disomic genetic background, respectively. It also significantly reverses cognitive deficits in a pilot study in DS individuals with effects on memory recognition, working memory and quality of life. We used the mouse models to ensure that EGCG was able to reduce DYRK1A kinase activity in the hippocampus and found that it also induced significant changes in plasma homocysteine levels, which were correlated with Dyrk1A expression levels. Thus, we could use plasma homocysteine levels as an efficacy biomarker in our human study. CONCLUSION We conclude that EGCG is a promising therapeutic tool for cognitive enhancement in DS, and its efficacy may depend of Dyrk1A inhibition.

γ‐Hydroxybutyrate (GHB) in Humans

Abstract:  Despite γ‐hydroxybutyrate (GHB) therapeutic uses and the increasing concern about its toxicity, few studies have addressed GHB dose‐related effects under controlled administration and their relationship with its pharmacokinetics. The study design was double‐blind, randomized, crossover, and controlled. As a pilot pharmacology phase I study, increasing doses of GHB were given. Single oral sodium GHB doses (40, 50, 60, and 72 mg/kg) were administered to eight volunteers. Plasma and urine were analyzed for GHB by gas chromatography–mass spectrometry. Physiological effects, psychomotor performance, and subjective effects were examined simultaneously. GHB produced dose‐related changes in subjective effects as measured by questionnaires and VAS. GHB showed a mixed stimulant‐sedative pattern, with initially increased scores in subjective feeling of euphoria, high, and liking followed by mild‐moderate symptoms of sedation with impairment of performance and balance. Mean peak GHB plasma concentrations were 79.1, 83.1, 113.5, and 130.1 μg/L for 40, 50, 60, and 72 mg/kg, respectively. GHB‐mediated physiological and subjective effects were dose dependent and related to GHB plasma concentrations. GHB urinary excretion was mainly related to administered doses. GHB‐mediated subjective and physiological effects seem dose dependent and related to GHB plasma concentrations. Results suggest a high abuse liability of GHB in the range of dose usually consumed.

Tutorial on methods for interval-censored data and their implementation in R

Interval censoring is encountered in many practical situations when the event of interest cannot be observed and it is only known to have occurred within a time window. The theory for the analysis of interval-censored data has been developed over the past three decades and several reviews have been written. However, it is still a common practice in medical and reliability studies to simplify the interval censoring structure of the data into a more standard right censoring situation by, for instance, imputing the midpoint of the censoring interval. The availability of software for right censoring might well be the main reason for this simplifying practice. In contrast, several methods have been developed to deal with interval-censored data and the corresponding algorithms to make the procedures feasible are scattered across the statistical software or remain behind the personal computers of many researchers. The purpose of this tutorial is to present, in a pedagogical and unified manner, the methodology and the available software for analyzing interval-censored data. The paper covers frequentist non-parametric, parametric and semiparametric estimating approaches, non-parametric tests for comparing survival curves and a section on simulation of interval-censored data. The methods and the software are described using the data from a dental study.

Relative abuse liability of gamma-hydroxybutyric acid, flunitrazepam, and ethanol in club drug users.

Objectives: Despite the increasing concern about γ-hydroxybutyric acid (GHB) toxicity, there are few studies examining the clinical pharmacology of GHB and its abuse potential. To evaluate GHB-induced subjective and physiological effects, its relative abuse liability and its impact on psychomotor performance in club drug users. Materials and Methods: Twelve healthy male recreational users of GHB participated in 5 experimental sessions in the framework of a clinical trial. The study was randomized, double-blind, double-dummy, and crossover. Drug conditions were a single oral dose of GHB (40 or 60 mg/kg), ethanol (0.7 g/kg), flunitrazepam (1.25 mg), and placebo. Study variables included vital signs (blood pressure, heart rate, oral temperature, pupil diameter), psychomotor performance (digit symbol substitution test, balance, Maddox-Wing), subjective effects (a set of 13 visual analogue scales, Addiction Research Center Inventory-49 items, and Evaluation of the Subjective Effects of Substances with Potential of Abuse questionnaires), and pharmacokinetics. Results: All active conditions induced positive effects related to their abuse potential. The administration of GHB produced euphoria and pleasurable effects with slightly higher ratings than those observed for flunitrazepam and ethanol. γ-Hydroxybutyric acid induced a biphasic time profile with an initial stimulantlike effect related to the simultaneous rise of plasma concentrations and a latter sedative effect not related to GHB kinetics. γ-Hydroxybutyric acid increased blood pressure and pupil diameter. Ethanol induced its prototypical effects, and flunitrazepam produced marked sedation. γ-Hydroxybutyric acid and flunitrazepam impaired psychomotor performance, digit symbol substitution test, and balance task, whereas ethanol, at the dose tested, induced only mild effects exclusively affecting the balance task. Conclusions: Our results suggest a high abuse liability of GHB and flunitrazepam in club drug users.

Cognitive performance in recreational ecstasy polydrug users: a two-year follow-up study

There is important preclinical evidence of long lasting neurotoxic and selective effects of ecstasy MDMA on serotonin systems in non-human primates. In humans long-term recreational use of ecstasy has been mainly associated with learning and memory impairments. The aim of the present study was to investigate the neuropsychological profile associated with ecstasy use within recreational polydrug users, and describe the cognitive changes related to maintained or variable ecstasy use along a two years period. We administered cognitive measures of attention, executive functions, memory and learning to three groups of participants: 37 current polydrug users with regular consumption of ecstasy and cannabis, 23 current cannabis users and 34 non-users free of illicit drugs. Four cognitive assessments were conducted during two years. At baseline, ecstasy polydrug users showed significantly poorer performance than cannabis users and non-drug using controls in a measure of semantic word fluency. When ecstasy users were classified according to lifetime use of ecstasy, the more severe users (more than 100 tablets) showed additional deficits on episodic memory. After two years ecstasy users showed persistent deficits on verbal fluency, working memory and processing speed. These findings should be interpreted with caution, since the possibility of premorbid group differences cannot be entirely excluded. Our findings support that ecstasy use, or ecstasy/cannabis synergic effects, are responsible for the sub-clinical deficits observed in ecstasy polydrug users, and provides additional evidence for long-term cognitive impairment owing to ecstasy consumption in the context of polydrug use.

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 Downs 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 Downs syndrome. METHODS We enrolled adults (aged 16-34 years) with Downs syndrome from outpatient settings in Catalonia, Spain, with any of the Downs 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 Downs 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 Downs syndrome will be needed to assess and confirm the long-term efficacy of EGCG and cognitive training. FUNDING Jérôme Lejeune Foundation, Instituto de Salud Carlos III FEDER, MINECO, Generalitat de Catalunya.

Glucocorticoid Receptors, Brain-Derived Neurotrophic Factor, Serotonin and Dopamine Neurotransmission are Associated with Interferon-Induced Depression.

Background: The role of inflammation in mood disorders has received increased attention. There is substantial evidence that cytokine therapies, such as interferon alpha (IFN-alpha), can induce depressive symptoms. Indeed, proinflammatory cytokines change brain function in several ways, such as altering neurotransmitters, the glucocorticoid axis, and apoptotic mechanisms. This study aimed to evaluate the impact on mood of initiating IFN-alpha and ribavirin treatment in a cohort of patients with chronic hepatitis C. We investigated clinical, personality, and functional genetic variants associated with cytokine-induced depression. Methods: We recruited 344 Caucasian outpatients with chronic hepatitis C, initiating IFN-alpha and ribavirin therapy. All patients were euthymic at baseline according to DSM-IV-R criteria. Patients were assessed at baseline and 4, 12, 24, and 48 weeks after treatment initiation using the Patient Health Questionnaire (PHQ), the Hospital Anxiety and Depression Scale (HADS), and the Temperament and Character Inventory (TCI). We genotyped several functional polymorphisms of interleukin-28 (IL28B), indoleamine 2,3-dioxygenase (IDO-1), serotonin receptor-1A (HTR1A), catechol-O-methyl transferase (COMT), glucocorticoid receptors (GCR1 and GCR2), brain-derived neurotrophic factor (BDNF), and FK506 binding protein 5 (FKBP5) genes. A survival analysis was performed, and the Cox proportional hazards model was used for the multivariate analysis. Results: The cumulative incidence of depression was 0.35 at week 24 and 0.46 at week 48. The genotypic distributions were in Hardy-Weinberg equilibrium. Older age (p = 0.018, hazard ratio [HR] per 5 years = 1.21), presence of depression history (p = 0.0001, HR = 2.38), and subthreshold depressive symptoms at baseline (p = 0.005, HR = 1.13) increased the risk of IFN-induced depression. So too did TCI personality traits, with high scores on fatigability (p = 0.0037, HR = 1.17), impulsiveness (p = 0.0200 HR = 1.14), disorderliness (p = 0.0339, HR = 1.11), and low scores on extravagance (p = 0.0040, HR = 0.85). An interaction between HTR1A and COMT genes was found. Patients carrying the G allele of HTR1A plus the Met substitution of the COMT polymorphism had a greater risk for depression during antiviral treatment (HR = 3.83) than patients with the CC (HTR1A) and Met allele (COMT) genotypes. Patients carrying the HTR1A CC genotype and the COMT Val/Val genotype (HR = 3.25) had a higher risk of depression than patients with the G allele (HTR1A) and the Val/Val genotype. Moreover, functional variants of the GCR1 (GG genotype: p = 0.0436, HR = 1.88) and BDNF genes (Val/Val genotype: p = 0.0453, HR = 0.55) were associated with depression. Conclusions: The results of the study support the theory that IFN-induced depression is associated with a complex pathophysiological background, including serotonergic and dopaminergic neurotransmission as well as glucocorticoid and neurotrophic factors. These findings may help to improve the management of patients on antiviral treatment and broaden our understanding of the pathogenesis of mood disorders.

Significant reductions of HIV prevalence but not of hepatitis C virus infections in injection drug users from metropolitan Barcelona: 1987–2001

OBJECTIVES To characterize trends from 1987 to 2001 in the prevalence of HIV and HCV infections among 2219 injection drug users (IDUs) starting treatment for substance abuse in two large hospitals in metropolitan Barcelona. METHODS The study population comprised IDUs with HIV tests completed from 1987 to 2001 and admitted for detoxification. Testing for HCV started in 1991 (n=1132). Characterization of temporal trends was carried out using logistic regression methods. Stratification was used to describe possible heterogeneities of the temporal trends. RESULTS The overall prevalence of HIV, HCV, and HBV (HBsAg+) was 55%, 88%, and 7%, respectively. Adjusted by duration of IDU, sex, and age at initiation, the prevalence of HIV infection declined significantly (p<0.001) from 1989 to 2004. The substantially higher prevalence of HCV showed a decline (p=0.065) of lesser magnitude. The decline of HIV infection was consistently observed among those with duration of IDU of less than 10 years. In turn, the decline of HCV was restricted to those with short duration of IDU (<4 years) because the prevalence of HCV infection was close to 100% for durations longer than 4 years in all calendar periods. CONCLUSIONS Preventive interventions and treatment for substance abuse might have contributed to the waning of the HIV epidemic in Spain. However, the extremely high levels of HCV infection and the underlying prevalence of HIV might lead to a large health burden of liver disease.