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.