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van der Zwaluw NL, Dhonukshe-Rutten RA, van Wijngaarden JP, Brouwer-Brolsma EM, van de Rest O, In 't Veld PH, Enneman AW, van Dijk SC, Ham AC, Swart KM, van der Velde N, van Schoor NM, van der Cammen TJ, Uitterlinden AG, Lips P, Kessels RP, de Groot LC. Results of 2-year vitamin B treatment on cognitive performance: secondary data from an RCT. Neurology. 2014 Dec 2;83(23):2158-66. Epub 2014 Nov 12 PubMed.
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University of Oxford
In this paper by van der Zwaluw and colleagues, there are some points to consider. First, in eight out of 12 cognitive tests there was no cognitive decline in the placebo group over two years: There was either no change, or even an improvement, and so it is difficult to know what effect of B vitamins was expected. In four of the tests there was decline in the placebo group and in one test (MMSE) this was significantly reduced by B vitamin treatment. But the changes in the other tests were very small and the authors did not provide a power estimate of whether there were enough subjects to detect a significant effect of B vitamin treatment. It should be noted that the whole cohort was only used for MMSE and episodic memory tests. The other tests were done in a subgroup of between 721 and 759 subjects.
Given these caveats, the authors cannot claim that they have “provided Class I evidence that two-year supplementation with B vitamins … does not affect cognitive performance,” because there was either no cognitive decline in the placebo group, or when there was decline it was small and it is likely that the number of subjects and/or the duration of the trial would not have been sufficient to detect a treatment effect. In other words, the trial was probably underpowered. The authors themselves note other limitations of the study, in particular the lack of an intermediate testing session, which prevents any modelling of longitudinal change and also means that the fairly large number of drop-outs (422) cannot be included in the analysis.
The authors reported that in a post-hoc analysis the subjects with low baseline holotranscobalamin, a measure of vitamin B12 sufficiency, showed a beneficial effect of B vitamin treatment on episodic memory. This result is consistent with the view that this was on the whole a very healthy population mostly with a good B vitamin status and so one would not expect much effect of extra B vitamins, except in the subgroup with poorer status.
It would have been interesting to look at the subgroup in the cohort who did show cognitive decline and test by logistic regression to see if the relative risk of cognitive decline was influenced by B vitamin treatment.
The authors correctly pointed out in their last paragraph that “we cannot extrapolate this [result] to persons who already have cognitive problems.” So readers should not assume that the results are relevant to the possible treatment of cognitive impairment.
Previous studies on normal elderly, many of which were included in Clarke’s recent meta-analysis, were consistent about one thing: In the placebo groups there was little, if any, cognitive decline. This was mainly for two reasons: the groups studied were very healthy, with good nutrition and so good B vitamin status on the whole; secondly, the tests used (such as MMSE) were far too insensitive for longitudinal studies. For example, MMSE declines about 0.1 point per year so you need a very long trial to show an effect. The published trials were all too short and/or underpowered in terms of number of participants. However, in those subjects who either start with poor vitamin status or who are already cognitively impaired (as in mild cognitive impairment, MCI) the story is different. In Durga’s FACIT trial (see Durga et al., 2007) the subjects recruited on the basis of having high homocysteine and then folic acid did indeed slow cognitive decline. In the WAFACS trial (Kang et al., 2008), women with low B vitamin status at the start showed slowing of decline by B vitamin treatment. Even the Aisen trial (see Aisen et al., 2008) in people with AD was not as negative as people think: In a subgroup analysis they reported that those with mild AD did show slowing of cognitive decline over 15 months with B vitamins, whereas those with moderate AD did not show any effect.
So that could be indicative of a critical window: Those in whom the disease has progressed too far will not benefit, while those who have not started to decline cannot benefit because there is no decline to slow down. Only those in between, typified by people with MCI or mild AD, will show benefit. In these people, the high homocysteine is driving more rapid brain atrophy which, in turn, is driving cognitive decline. We recently showed this causal pathway by Bayesian network modelling (Douaud et al., 2013).
Whether or not normal people with high homocysteine who do not show any cognitive impairment will benefit from lowering homocysteine is unanswered: For that we need larger and much longer clinical trials. In the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort we observed that high homocysteine in controls increased the risk of progressing to MCI, but that took at least eight years (A. Oulhaj et al., unpublished). The famous Gothenburg women’s study by Skoog and colleagues (see Zylberstein et al., 2011) showed that raised homocysteine was a strong risk factor for dementia 35 years later. More trials are needed because, if it is really true, then a lot of people will benefit from increasing B vitamin intake, especially B12. The population-attributable risk of AD due to raised homocysteine is 22 percent and the prevalence of raised homocysteine is about 30 percent (see Beydoun et al., 2014). Fundamentally, there is a difference between the slow cognitive decline of normal aging and the more rapid decline due to a disease process: Homocysteine is one factor in the latter but we do not yet know if it is involved in the former.
References:
Durga J, van Boxtel MP, Schouten EG, Kok FJ, Jolles J, Katan MB, Verhoef P. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet. 2007 Jan 20;369(9557):208-16. PubMed.
Kang JH, Cook N, Manson J, Buring JE, Albert CM, Grodstein F. A trial of B vitamins and cognitive function among women at high risk of cardiovascular disease. Am J Clin Nutr. 2008 Dec;88(6):1602-10. PubMed.
Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF, Bottiglieri T, Jin S, Stokes KT, Thomas RG, Thal LJ, . High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008 Oct 15;300(15):1774-83. PubMed.
Douaud G, Refsum H, de Jager CA, Jacoby R, Nichols TE, Smith SM, Smith AD. Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9523-8. PubMed.
Zylberstein DE, Lissner L, Björkelund C, Mehlig K, Thelle DS, Gustafson D, Ostling S, Waern M, Guo X, Skoog I. Midlife homocysteine and late-life dementia in women. A prospective population study. Neurobiol Aging. 2011 Mar 1;32(3):380-6. PubMed.
Beydoun MA, Beydoun HA, Gamaldo AA, Teel A, Zonderman AB, Wang Y. Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC Public Health. 2014 Jun 24;14:643. PubMed.
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