Why Randomised Trials in Humans
should be the Gold Standard for Data
on Nutrients and Aging?
Dr Robert Clarke
on behalf of
B-Vitamin Treatment Trialists’ Collaboration (BVTT)
Clinical Trial Service Unit &
Epidemiological Studies Unit
University of Oxford
Organised by
The ILSI Europe Nutrition and Mental Performance Task Force
Do B-vitamins positively impact cognition?
The choices we make about the foods we eat (or
not eat) may alter our risks of dementia.
Observational studies have reported that people
with high blood concentrations of homocysteine (a
marker for B vitamin insufficiency) have elevated
risk for vascular disease1 & Alzheimer disease.2
These studies prompted randomised trials to
assess whether B-vitamins positively impacted
cognition, but their results have been mixed.
1.Clarke
2
et al, NEJM 1991;324:1149-55::
Clarke et al ,Arch Neurology 1998:55:1449-55
Conflicting results of trials of B-vitamins
FACIT trial (n=800) reported that folic acid had a
significant effect on memory of ~ 5 yr younger age.1
VITACOG trial (n=271) reported that B-vitamins
slowed the rate of brain atrophy by 30%.2
But small trials are highly susceptible to chance
and can yield spurious results. Reliable evidence
requires large trials, avoidance of bias and subgroup analysis and meta-analyses of such trials.
1Durga
2Smith
,Lancet 2007: 369: 208-16
, PLoS ONE 2010; 5: c12244
Meta-analysis of B-vitamin trials assessing
effects on cognitive function1
Meta-analysis of all trials of B-vitamins (with at
least 100 participants treated for 3+ months),
that measured relevant cognition outcomes.
It assessed the effects of B-vitamins on:
- individual domains of cognitive function,
- global cognitive function and
- cognitive aging.
1Clarke
, Am J Clin Nutr 2014:;100:657-66
Selected characteristics of the trials
(11 trials; n=22,000)
Cognitive domain trials (n=4)
Participants: 1340
Duration: 2.3 yrs
Homocysteine reduction: 28.4%
Global cognition trials (n=7)
Participants: 20,431
Duration: 5.0
Homocysteine reduction: 26.1%
Characteristics of cognitive domain and
Global cognition trials
Methods: Effects on individual domains and
on global cognitive function
Domain-based Z-scores (for memory, speed, executive
function and a domain-composite score for global
cognitive function) were available before and after
treatment in 4 cognitive-domain trials (1340 individuals)
Mini-Mental-State Examination-type (MMSE-type) tests
were available at end-treatment in the 7 global cognition
trials (20,431 individuals)
Methods: Effects on cognitive aging
Equivalent study years per 25% tHcy reduction were
estimated for each trial
The Z-scores per year per 25% tHcy reduction were
estimated by dividing the Z-scores for the effects of
treatment by duration at 25% lower tHcy
The Z-score differences per 25% tHcy reduction were
divided by the effect of age on cognitive function for all
trials to provide equivalent years of cognitive aging
Selected characteristics of included trials
Correlation and variance of cognitive scores
in placebo group with repeat assessments
Effects on specific domains of cognitive function
and on domain-composite score
Effects of B-vitamins on memory and
on executive function in all trials
Effects on MMSE-type global cognitive function score
Effects of B-vitamins on global cognitive score in sub-groups
Effects of B-vitamins on cognitive aging
Conclusions
Dietary supplementation with B-vitamins to lower tHcy
levels had no significant effect on individual domains or
global cognitive function or on cognitive aging.
This meta-analysis, involving 60,000 person years at
25% tHcy reduction, excluded reductions of more than
one month of cognitive aging per year of treatment.
Overall, B-vitamins have no beneficial effect on either
vascular disease1 or cognitive aging2, but also have no
adverse effect on overall or site-specific cancers3.
1Clarke
, Arch Int Med 2010;170;1622-31
Am J Clin Nutr 2014:100;657-66
3 Vollset, Clarke, Lancet 2013;381:1029-36
2 Clarke,
Acknowledgements
Secretariat D Bennett, S Parish, S Lewington, J Halsey, A Dangour,
R Collins
Collaborators in cognitive domain trials:
McMahon: M Skeaff, J McMahon, TJ Green, JI Mann, R Knight, S
Williams;
Lewerin: C Lewerin, H Nilsson Ehle;
Eussen: S Eussen, LC de Groot, W A van Staveren, WHL Hoefnagels,
LW Joosten;
Collaborators in Global cognition trials:
SEARCH: J Armitage, R Collins; VITATOPS G Hankey; VISP: J Toole, MR
Malinow, LE Chambless, JD Spence, LC Pettigrew, VJ Howard, EG
Sides, CH Wang, M Stampfer; WAFACS: JE Manson, W Christen, F
Grodstein;SU.FOL.OM3 P Galan, S Hercberg; HOPE-2: E Lonn, S
Yusuf; Stott: DJ Stott.
Supported by FSA, MRC and BHF. It is CTSU staff policy not to accept honoraria for
speaking at scientific meetings.
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