Elsevier

The Lancet Neurology

Volume 15, Issue 8, July 2016, Pages 801-810
The Lancet Neurology

Articles
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

https://doi.org/10.1016/S1474-4422(16)30034-5Get rights and content

Summary

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

Jérôme Lejeune Foundation, Instituto de Salud Carlos III FEDER, MINECO, Generalitat de Catalunya.

Introduction

Down's syndrome is the most common intellectual disability of genetic origin, affecting more than 5 million people worldwide. Medical interventions have substantially increased the life expectancy of individuals with Down's syndrome in high-income countries, but cognitive and behavioural features have a strong effect on functional ability. No approved intervention exists for the amelioration of cognitive deficits in individuals with Down's syndrome.1, 2 Only early intervention programmes have resulted in some improvement in intellectual disability.3 Also, memory-training programmes have been reported to improve memory in adults with Down's syndrome.4

Evidence suggests that flavonoid-rich foods (eg, green tea) can improve normal cognitive function and might have therapeutic effects in Alzheimer's disease because their biological actions include antioxidant effects; they also have the potential to protect susceptible neurons, enhance existing neuronal function, reduce toxic concentrations of amyloid (Aβ), and stimulate neuronal plasticity.1, 5 Bain and colleagues6 described the non-competitive inhibition properties of epigallocatechin-3-gallate (EGCG), the major catechin in green tea leaves (40–50% of total catechins) on the kinase activity of the dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (DYRK1A), a serine-threonine kinase encoded by the DYRK1A gene, located in the Down's syndrome critical region (ie, on the long arm of chromosome 21) and thought to be a major contributor to cognitive phenotypes of Down's syndrome. EGCG can cross the blood–brain barrier,7 and chronic administration of a green tea extract containing 45% EGCG promoted learning and memory in Down's syndrome mouse models8 and was safe in young individuals with Down's syndrome in our phase 1 trial.9 Housing conditions that facilitate enhanced sensory, cognitive, motor, and social stimulation normalises DYRK1A kinase activity in the hippocampus of Down's syndrome mouse models, suggesting that EGCG acts synergistically with cognitive stimulation.10 The long-term efficacy of cognitive training has not been conclusively shown in individuals with Down's syndrome. In this phase 2 trial, we compared the effectiveness of cognitive training plus placebo with cognitive training plus EGCG in adults with Down's syndrome.

Research in context

Evidence before this study

We searched PubMed for reports published from Jan 1, 1995, to Dec 31, 2015 in English, with the terms “Down syndrome”, “trisomy 21”, “supplements”, “drugs”, and “cognitive treatment” or “cognition therapy”. We included all randomised clinical trials of dietary supplements and drugs reporting any assessment of cognitive function in patients with Down's syndrome. Apart from the pilot clinical trial by our study group in 2010, we identified six additional clinical trials with four different interventions: three with donepezil, one with folinic acid, vitamins, and minerals, one with memantine, and one with L-acetyl carnitine.

Added value of this study

Cognitive impairments associated with intellectual disability syndromes were believed to be intractable, but recent progress in our understanding of the mechanisms underlying the impairments associated with genetic syndromes, such as fragile X syndrome and tuberous sclerosis, has resulted in identification of potential treatment targets, which are being tested in clinical trials. It is increasingly argued that even complex syndromes such as Down's syndrome are potentially treatable. Most therapies targeting cognition in Down's syndrome are neurotransmitter based, and are more often used in treating Alzheimer's disease, like acetylcholinesterase inhibitors (donezepil, rivastagmine, galantamine), GABAergic antagonists (eg, pentetrazol), and N-methyl-D-aspartate receptor antagonists (memantine). Additionally, other compounds such as vitamins, mineral supplements, piracetam, or growth hormone have been used with little or no success. None of the previous clinical trials had combined pharmacological treatment with cognitive training and none of them showed significant improvement in cognition, adaptive functionality, or language performance. This is the first randomised controlled clinical trial using a dietary supplement (green tea extracts containing epigallocatechin-3-gallate [EGCG], a green tea catechin), combined with cognitive training. Our study shows a significant improvement in memory, executive function, and facilitated adaptive behaviour. A major strength of the trial is the inclusion of secondary outcome measures, such as neuroimaging and neurophysiology complementary explorations. Our findings suggest that the treatment had a measurable effect on biomarkers such as cholesterol and homocysteine. Additionally, neuroimaging showed increased functional connectivity and normalised cortical excitability. Furthermore, the treatment resulted in few side-effects.

Implications of all the available evidence

Our findings suggest the possibility of improving long-term outcomes in individuals with Down's syndrome, and also open the way for clinical trials of other treatments in this population, such as more specific or more potent DYRK1A inhibitors (already in development), antioxidants, or lipid modulators. EGCG and cognitive training are easy-to-use, affordable, and widely accessable. This approach could lead to clinically validated interventions manageable at the primary care level. Effective treatments will have substantial implications for health services because even small clinical improvements in cognitive outcomes could lead to substantial reductions in lifetime care needs for individuals with intellectual disability syndromes.

Section snippets

Study design and participants

The TESDAD study was a randomised, double-blind, placebo-controlled, phase 2 trial in adults with Down's syndrome, and was done at the Hospital del Mar Medical Research Institute of Barcelona (Spain).

The trial was approved by the local ethics committee (CEIC Parc de Salut Mar, EGCG/DYRK1A/DS/IMIM/1), and done according to the Declaration of Helsinki and Spanish guidelines and regulations for data privacy.

Eligible participants, whose parent or carer agreed to ensure administration of the

Results

Between June 5, 2012, and June 6, 2014, we randomly assigned 87 patients (98% of 89 initially contacted). Three individuals withdrew before treatment initiation; 84 were included in the intention-to-treat analysis (41 in the placebo and cognitive training group and 43 in the EGCG and cognitive training group; figure 1). Demographic, genetic, and IQ characteristics were similarly distributed in both groups (table 1).

During the run-in period, patients were trained by neuropsychologists on how to

Discussion

Our study showed that patients in the EGCG plus cognitive training group performed better than those in the placebo plus cognitive training group in some cognitive tests and in adaptive behaviour after the 12 months of treatment (appendix p 13–15). The EGCG and cognitive training group had better preservation of recognition memory tasks and improvement in executive function than the placebo and cognitive training group. Improvements in memory and executive function were accompanied by improved

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