Ellis JM, Tan HK, Gilbert RE, Muller DP, Henley W, Moy R, Pumphrey R, Ani C, Davies S, Edwards V, Green H, Salt A, Logan S. Supplementation with antioxidants and folinic acid for children with Down's syndrome: randomised controlled trial. BMJ. 2008 Mar 15;336(7644):594-7. PubMed.
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The Rockefeller University
This study presents results of a clinical trial involving dietary supplementation of several antioxidant vitamins and related compounds in 156 children with Down syndrome (DS) (Ellis et al. 2008). Supplementation consisted of daily, oral 10 μg selenium, 5 mg zinc, 0.9 mg vitamin A, 100 mg vitamin E, 50 mg vitamin C, and 0.1 mg folinic acid (alone or in combination with the other supplements to address a functional folate deficiency), as well as a placebo. This began at 4 months (mean age) and continued for 18 months, at which time mental development, including language and psychomotor skills, was assessed, as were biochemical markers of oxidative stress and antioxidant effects. There was no evidence of benefit in any of the behavioral endpoints, a finding consistent with previous studies (Salman, 2002). Remarkably, no changes in biochemical markers of oxidative stress were noted, either.
Oxidative stress is an established component of DS pathology (Nunomura et al., 2000) and triplication (trisomy 21) of SOD1 is thought to play a role (Bar-Peled et al., 1996; Odetti et al., 1998; Iannello et al., 1999). However, as in the case of Alzheimer disease (AD), evidence of an oxidative lesion contrasts with lack of strong evidence for clinical benefit of antioxidant supplements in established disease (Grundman et al., 2002; Kontush and Schekatolina, 2004; Fillenbaum et al., 2005). Ellis and colleagues looked for reduction in markers of oxidative stress (red blood cell superoxide dismutase and glutathione peroxidase activities, and urinary isoprostane as a measure of lipid peroxidation), but found no effect, though vitamin E levels in blood were consistently high in the vitamin-treated group. This does not weaken the conclusion that antioxidant supplementation, at least as described in the present study, failed to improve cognition in children with DS at the age tested here, but because there was no change in oxidative markers, the study does not inform as to whether behavior/cognition can be improved in these children by amelioration of OS. The authors point out that the dosage of vitamins, metals, and folinic acid were 100 to 200 percent of the recommended daily allowances, which may be considerably lower than doses provided by parents or touted by supplement makers (the authors did not want to risk the possibility of adverse effects that might result from higher dose supplementation).
Ellis and colleagues point out that this trial was unusual in that participants were very young children and that this has not generally been the case in other studies. This was a proposed strength of the current study; however, it might also be a shortcoming. The DS phenotype is complex; mental deficits may result from multiple inputs that are age-related. For example, developmental delay might contribute to deficits in children under the age of 2, whereas markers of OS appear to increase with age, especially from adolescence onward (Venkitaramani et al., 2007). Hence, antioxidant supplements in older children might have different outcomes, though this has not been the case with the rather limited trials that have been undertaken previously (Ellis et al., 2008).
Therapeutic intervention in DS has recently become a topic of considerable interest because of similarities to AD. An amyloid and neurodegenerative phenotype, including pronounced degeneration of cholinergic neurons pathologically indistinguishable from AD, develops in DS adults by the fourth decade of life. Many if not most go on to develop dementia. Much of this is thought to result from triplication of APP and other genes (such as ETS2) (Wolvetang et al., 2003; Rachidi and Lopes, 2007) that further upregulate APP expression or affect its metabolism, causing elevation in Aβ levels that persist throughout life. This begs the question: does Aβ contribute to mental retardation? Amyloid plaques generally do not appear in DS until adulthood but lifelong, high levels of soluble or intracellular Aβ might contribute to deficits in synaptic plasticity.
Aβ lowering or neutralizing therapies (when made available) might prove beneficial. We provided some preliminary evidence supporting this hypothesis at the SfN conference in San Diego, November 2007 (Netzer, Greengard, and colleagues mini-symposium, The Role of Beta-amyloid in Down Syndrome, Beta-amyloid Modulation of Synaptic Transmission and Plasticity; Venkitaramani et al., 2007).
The cholinergic deficit shared by DS and AD has piqued interest in the possibility of treating DS with cholinesterase inhibitors. Several small clinical trials have been reported involving donepezil and rivastigmine in children (8 years and older) and in adults with and without an Alzheimer-like progressive dementia. These trials report modest benefits in language, memory, and adaptive behavior (Spiridigliozzi et al., 2007; Heller et al., 2006). At least one small clinical trial (currently recruiting at Kings College, London) will be testing the tolerability and efficacy of memantine in DS adults age 40 and over, with and without dementia. Additionally, Costa and colleagues recently showed that acute administration of memantine rescues deficits in fear conditioning in the widely used Ts65Dn DS mouse model (Costa et al., 2007). Their recent report suggests that deficits in synaptic plasticity in Ts65Dn mice are influenced by reduced calcineurin activity, which can be at least partially corrected by memantine-induced normalization of NMDAR function.
In summary, the present study cautions against the use of antioxidant supplements in children with DS. Nevertheless, the possibilities for intervention in mental retardation and DS are likely to become more vivid as an understanding of DS and AD and their intersections continues to grow.
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