Low vitamin B-12 status and risk of cognitive decline in older adults

Clinical Trial Service Unit, University of Oxford,, University of Oxford, Oxford, United Kingdom.
American Journal of Clinical Nutrition (Impact Factor: 6.77). 11/2007; 86(5):1384-91.
Source: PubMed


Elevated total homocysteine (tHcy) concentrations have been associated with cognitive impairment, but it is unclear whether low vitamin B-12 or folate status is responsible for cognitive decline.
We examined the associations of cognitive decline with vitamin B-12 and folate status in a longitudinal cohort study performed from 1993 to 2003 in Oxford, United Kingdom.
Cognitive function was assessed with the Mini-Mental State Examination on >/=3 occasions during 10 y and related to serum concentrations of vitamin B-12, holotranscobalamin (holoTC), tHcy, methylmalonic acid (MMA), and folate with the use of linear mixed models in 1648 participants who provided blood in 1995.
Cognitive function declined abruptly at younger ages in some participants but remained intact in others until very old age. In multivariate regression analyses after adjustment for established risk factors, concentrations of holoTC (a marker of reduced vitamin B-12 status), tHcy, and MMA predicted cognitive decline, but folate did not. A doubling in holoTC concentrations (from 50 to 100 pmol/L) was associated with a 30% slower rate of cognitive decline (-0.137 to -0.083), whereas a doubling in tHcy (from 10 to 20 micromol/L) or MMA (from 0.25 to 0.50 micromol/L) was associated with >50% more rapid cognitive decline (-0.090 to -0.169) and (-0.104 to -0.169), respectively. After adjustment for all vitamin markers simultaneously, the associations of cognitive decline with holoTC and MMA remained significant.
Low vitamin B-12 status was associated with more rapid cognitive decline. Randomized trials are required to determine the relevance of vitamin B-12 supplementation for prevention of dementia.

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    • "One potentially important methodological confound between studies in this area is the method used to measure vitamin B status. This potential conflict is highlighted by the results of Clarke et al. [17] who investigated the associations between cognitive decline and levels of vitamins B12, B9, and Hcy (measuring holoTC, tHcy, MMA, and vitamins B12 and B9 levels). Cognitive function was assessed in 1648 participants at baseline (mean age 75 years; mean MMSE 26.2) and again at a minimum of 3 time points over a 10-year period. "
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    ABSTRACT: A copious amount of scientific scrutiny has been dedicated to documenting typical and atypical human ageing, with a substantial body of work focusing upon the impact of lifestyle choices. One such lifestyle choice is that of diet and, in particular, micronutrient ingestion. Epidemiological studies have reported positive associations between B vitamin status and cognitive function, including negative associations between biological markers (i.e., homocysteine) of dysregulated one-carbon metabolism and cognitive function. This has led to a surge of randomised control trials (RCTs) investigations into B vitamin therapy. However, results have continuingly failed to show beneficial behavioural effects. Despite this, results reliably show treatment-related increases in B vitamin level and decreases in homocysteine level—both of which have been identified as risk factors for atypical ageing. In this paper we argue that it would be premature to conclude that B vitamin therapy has no potential and that more research is needed to systematically investigate the optimal dose, the therapeutic “window,” and individual differences in therapy responders and nonresponders. We start with a brief look at one-carbon metabolism and then consider the evidence from epidemiological studies and RCTs in relation to three specific B vitamins: folic acid (B9), pyridoxine (B6), and cobamides (B12).
    03/2013; 2013. DOI:10.5402/2013/650983
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    • "Epidemiological studies have linked high circulating MMA with declined cognitive function [5,6]. Doubling serum MMA concentration from 0.25 to 0.50 μmol//L was associated with > 50% more rapid cognitive decline in a longitudinal study conducted in the UK [5]. In another longitudinal study in the US, serum MMA concentrations were predictive of rapid cognitive decline in older subjects [6]. "
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    ABSTRACT: Serum methylmalonic acid (MMA) is regarded as a sensitive marker of vitamin B-12 status. Elevated circulating MMA is linked to neurological abnormalities. Contribution of age, supplement use, kidney dysfunction, and vitamin B-12 deficiency to high serum MMA in post-folic acid fortification period is unknown. We investigated prevalence, population attributable risk (PAR), and PAR% for high MMA concentrations in the US. Data from 3 cross-sectional National Health and Nutrition Examination Surveys conducted in post-folic acid fortification period were used (n = 18569). Likelihood of having high serum MMA for white relative to black was 2.5 (P < 0.0001), ≥ 60 y old persons relative to < 60 y old persons was 4.0 (P < 0.0001), non-supplement users relative to supplement users was 1.8 (P < 0.0001), persons with serum creatinine ≥ 130 μmol/L relative to those with < 130 μmol/L was 12.6 (P < 0.0001), and persons with serum vitamin B-12 < 148 pmol/L relative to those with ≥ 148 pmol/L was 13.5 (P < 0.0001). PAR% for high MMA for old age, vitamin B-12 deficiency, kidney dysfunction, and non-supplement use were 40.5, 16.2, 13.3, and 11.8, respectively. By improving serum vitamin B-12 (≥ 148 pmol/L), prevalence of high MMA would be reduced by 16-18% regardless of kidney dysfunction. Old age is the strongest determinant of PAR for high MMA. About 5 cases of high serum MMA/1000 people would be reduced if vitamin B-12 deficiency (< 148 pmol/L) is eliminated. Large portion of high MMA cases are not attributable to serum vitamin B-12. Thus, caution should be used in attributing high serum MMA to vitamin B-12 deficiency.
    Nutrition & Metabolism 01/2012; 9(1):2. DOI:10.1186/1743-7075-9-2 · 3.26 Impact Factor
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    • "The roundtable generally agreed that, if NHANES reinstates 2 vitamin B-12–related biomarkers, serum vitamin B-12 and plasma MMA would provide continuity with past surveys and provide circulating and functional indicators of vitamin B-12 status. These variables have shown associations with anemia and cognitive decline in previous NHANES and in other studies (12–15, 59). Reliable measurement procedures are available, and the NIST is developing reference materials. "
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    ABSTRACT: A roundtable to discuss the measurement of vitamin B-12 (cobalamin) status biomarkers in NHANES took place in July 2010. NHANES stopped measuring vitamin B-12-related biomarkers after 2006. The roundtable reviewed 3 biomarkers of vitamin B-12 status used in past NHANES--serum vitamin B-12, methylmalonic acid (MMA), and total homocysteine (tHcy)--and discussed the potential utility of measuring holotranscobalamin (holoTC) for future NHANES. The roundtable focused on public health considerations and the quality of the measurement procedures and reference methods and materials that past NHANES used or that are available for future NHANES. Roundtable members supported reinstating vitamin B-12 status measures in NHANES. They noted evolving concerns and uncertainties regarding whether subclinical (mild, asymptomatic) vitamin B-12 deficiency is a public health concern. They identified the need for evidence from clinical trials to address causal relations between subclinical vitamin B-12 deficiency and adverse health outcomes as well as appropriate cutoffs for interpreting vitamin B-12-related biomarkers. They agreed that problems with sensitivity and specificity of individual biomarkers underscore the need for including at least one biomarker of circulating vitamin B-12 (serum vitamin B-12 or holoTC) and one functional biomarker (MMA or tHcy) in NHANES. The inclusion of both serum vitamin B-12 and plasma MMA, which have been associated with cognitive dysfunction and anemia in NHANES and in other population-based studies, was preferable to provide continuity with past NHANES. Reliable measurement procedures are available, and National Institute of Standards and Technology reference materials are available or in development for serum vitamin B-12 and MMA.
    American Journal of Clinical Nutrition 07/2011; 94(1):313S-321S. DOI:10.3945/ajcn.111.013243 · 6.77 Impact Factor
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