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

BACKGROUND: 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. OBJECTIVE: 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. DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.     

Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification

BACKGROUND: Historic reports on the treatment of pernicious anemia with folic acid suggest that high-level folic acid fortification delays the diagnosis of or exacerbates the effects of vitamin B-12 deficiency, which affects many seniors. This idea is controversial, however, because observational data are few and inconclusive. Furthermore, experimental investigation is unethical. OBJECTIVE: We examined the relations between serum folate and vitamin B-12 status relative to anemia, macrocytosis, and cognitive impairment (ie, Digit Symbol-Coding score < 34) in senior participants in the 1999-2002 US National Health and Nutrition Examination Survey. DESIGN: The subjects had normal serum creatinine concentrations and reported no history of stroke, alcoholism, recent anemia therapy, or diseases of the liver, thyroid, or coronary arteries (n = 1459). We defined low vitamin B-12 status as a serum vitamin B-12 concentration < 148 pmol/L or a serum methylmalonic acid concentration > 210 nmol/L-the maximum of the reference range for serum vitamin B-12-replete participants with normal creatinine. RESULTS: After control for demographic characteristics, cancer, smoking, alcohol intake, serum ferritin, and serum creatinine, low versus normal vitamin B-12 status was associated with anemia [odds ratio (OR): 2.7; 95% CI: 1.7, 4.2], macrocytosis (OR: 1.8; 95% CI: 1.01, 3.3), and cognitive impairment (OR: 2.5; 95% CI: 1.6, 3.8). In the group with a low vitamin B-12 status, serum folate > 59 nmol/L (80th percentile), as opposed to < or = 59 nmol/L, was associated with anemia (OR: 3.1; 95% CI: 1.5, 6.6) and cognitive impairment (OR: 2.6; 95% CI: 1.1, 6.1). In the normal vitamin B-12 group, ORs relating high versus normal serum folate to these outcomes were < 1.0 (P(interaction) < 0.05), but significantly < 1.0 only for cognitive impairment (0.4; 95% CI: 0.2, 0.9). CONCLUSION: In seniors with low vitamin B-12 status, high serum folate was associated with anemia and cognitive impairment. When vitamin B-12 status was normal, however, high serum folate was associated with protection against cognitive impairment.     

Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial

BACKGROUND: Vitamin B-12 deficiency is associated with cognitive impairment in older people. However, evidence from randomized trials of the effects of vitamin B-12 supplementation on cognitive function is limited and inconclusive. OBJECTIVE: The objective was to investigate whether daily supplementation with high doses of oral vitamin B-12 alone or in combination with folic acid has any beneficial effects on cognitive function in persons aged >/=70 y with mild vitamin B-12 deficiency. DESIGN: In a double-blind, placebo-controlled trial, 195 subjects were randomly assigned to receive 1000 microg vitamin B-12, 1000 microg vitamin B-12 + 400 microg folic acid, or placebo for 24 wk. Vitamin B-12 status was assessed on the basis of methylmalonic acid, total homocysteine (tHcy), and holotranscobalamin (holoTC) concentrations before and after 12 and 24 wk of treatment. Cognitive function was assessed before and after 24 wk of treatment with the use of an extensive neuropsychologic test battery that included the domains of attention, construction, sensomotor speed, memory, and executive function. RESULTS: Vitamin B-12 status did not change significantly after treatment in the placebo group; however, oral vitamin B-12 supplementation corrected mild vitamin B-12 deficiency. Vitamin B-12 + folic acid supplementation increased red blood cell folate concentrations and decreased tHcy concentrations by 36%. Improvement in memory function was greater in the placebo group than in the group who received vitamin B-12 alone (P = 0.0036). Neither supplementation with vitamin B-12 alone nor that in combination with folic acid was accompanied by any improvement in other cognitive domains. CONCLUSION: Oral supplementation with vitamin B-12 alone or in combination with folic acid for 24 wk does not improve cognitive function.     

Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer disease, and vascular dementia

BACKGROUND: Evidence supports an independent association between plasma total homocysteine concentrations and the risk of vascular disease. Recent epidemiologic studies reappraised the possibility that vascular risk factors might play a role in the pathogenesis not only of vascular dementia (VaD) but also of Alzheimer disease (AD). OBJECTIVE: The objective was to investigate the relations of mild cognitive impairment, AD, and VaD with blood homocysteine, folate, and vitamin B-12. DESIGN: The study population consisted of 314 consecutive subjects, 228 of whom were eligible for analyses. Plasma total homocysteine, serum folate, and serum vitamin B-12 concentrations were measured in 55 nondemented elderly control subjects, 81 mildly cognitively impaired subjects (Clinical Dementia Rating: 0.5), and 92 demented patients prevalently in a mild disease stage and with a clinical diagnosis of AD (n = 74) or VaD (n = 18). RESULTS: Subjects in the lowest folate tertile had significantly higher adjusted odds ratios (ORs) for mild cognitive impairment (OR: 3.1; 95% CI: 1.2, 8.1) and dementia (3.8; 1.3, 11.2). Hyperhomocysteinemia was significantly associated with dementia (adjusted OR: 4.3; 1.3, 14.7) and AD (adjusted OR: 3.7; 1.1, 13.1). In subjects with a Clinical Dementia Rating of 0.5, the mean (+/- SE) Mini-Mental State Examination score was significantly lower (P < 0.05) in the highest homocysteine tertile (24.5 +/- 0.5) than in the lowest tertile (26.6 +/- 0.5). No significant associations were found between minimum medial temporal lobe thickness or leukoaraiosis and any biochemical measure in the dementia and AD groups. CONCLUSIONS: These findings suggest that relative folate deficiency may precede AD and VaD onset. Hyperhomocysteinemia might also be an early risk factor for cognitive decline in the elderly, but its role in dementia development must be addressed in future longitudinal studies.     

Breakfast cereal fortified with folic acid, vitamin B-6, and vitamin B-12 increases vitamin concentrations and reduces homocysteine concentrations: a randomized trial

BACKGROUND: High homocysteine and low B vitamin concentrations have been linked to the risk of vascular disease, stroke, and dementia and are relatively common in older adults. OBJECTIVE: We assessed the effect of breakfast cereal fortified with folic acid, vitamin B-6, and vitamin B-12 on vitamin and homocysteine status. DESIGN: A randomized, double-blind trial was conducted in 189 volunteers aged 50-85 y. The subjects had no history of hypertension, anemia, asthma, cancer, or cardiovascular or digestive disease and did not regularly consume multiple or B vitamin supplements or highly fortified breakfast cereal. Subjects were randomly assigned to consume 1 cup (0.24 L) breakfast cereal fortified with 440 microg folic acid, 1.8 mg vitamin B-6, and 4.8 microg vitamin B-12 or placebo cereal for 12 wk. Blood was drawn at 0, 2, 12, and 14 wk. Methionine-loading tests were conducted at baseline and week 14. RESULTS: Final baseline-adjusted plasma homocysteine concentrations were significantly lower and B vitamin concentrations were significantly higher in the treatment group than in the placebo group (P < 0.001). The percentage of subjects with plasma folate concentrations < 11 nmol/L decreased from 2% to 0%, with vitamin B-12 concentrations < 185 pmol/L from 9% to 3%, with vitamin B-6 concentrations < 20 nmol/L from 6% to 2%, and with homocysteine concentrations > 10.4 micromol/L (women) or > 11.4 micromol/L (men) from 6.4% to 1.6%. The percentage of control subjects with values beyond these cutoff points remained nearly constant or increased. CONCLUSIONS: In this relatively healthy group of volunteers, consumption of 1 cup fortified breakfast cereal daily significantly increased B vitamin and decreased homocysteine concentrations, including post-methionine-load homocysteine concentrations.     

Bread cofortified with folic acid and vitamin B-12 improves the folate and vitamin B-12 status of healthy older people: a randomized controlled trial

BACKGROUND: Mandatory fortification of flour with folic acid has reduced the number of neural tube defects in North America. Concerns that high intakes of folic acid might mask vitamin B-12 deficiency in older persons have delayed the introduction of fortification in many European countries. Cofortification of flour with folic acid and vitamin B-12 could simultaneously improve folate and vitamin B-12 status. OBJECTIVE: The objective was to estimate the effect of the consumption of bread fortified with modest amounts of folic acid and vitamin B-12 on folate and vitamin B-12 status in healthy older persons living in the Netherlands, where folic acid fortification is not taking place. DESIGN: Men and women aged 50-75 y were randomly assigned in this 12-wk double-blind, placebo-controlled trial to consume bread fortified with 138 mug folic acid and 9.6 mug vitamin B-12 daily (n = 72) or unfortified bread (n = 70). RESULTS: The consumption of fortified bread increased serum folate concentrations by 45% (mean: 6.3 nmol/L; 95% CI: 4.5, 8.1 nmol/L) and serum vitamin B-12 concentrations by 49% (mean: 102 pmol/L; 95% CI: 82, 122 pmol/L) relative to the placebo group. Fortified bread increased erythrocyte folate concentrations by 22% and holotranscobalamin concentrations by 35%; it decreased homocysteine concentrations by 13% and methylmalonic acid concentrations by 10%. Consumption of fortified bread decreased the proportion of individuals with marginal serum vitamin B-12 concentrations (<133 pmol/L) from 8% at enrollment to 0% after 12 wk. CONCLUSION: Bread fortified with modest amounts of folic acid and vitamin B-12 will improve folate and vitamin B-12 status and a considerable proportion of vitamin B-12 deficiency in older people. This trial was registered at clinicaltrials.gov as NCT00353353.     

Homocysteine, folate, and vitamin B-12 and cognitive performance in older Chinese adults: findings from the Singapore Longitudinal Ageing Study

BACKGROUND: The relations of elevated homocysteine, low folate, and vitamin B-12 with cognitive performance in nondemented elderly are not well established. Limited research data suggest differential effects of homocysteine and folate on specific cognitive domains. OBJECTIVE: The aim was to examine the independent associations of homocysteine, folate, and vitamin B-12 with cognitive performance in high-functioning elderly Chinese. DESIGN: Homocysteine, folate, and vitamin B-12 concentrations were measured in fasting blood samples of 451 Chinese aged >or=55 y with Mini-Mental State Examination scores >or=24 and who were considered fully independent based on Activities of Daily Living score. Cognitive functions were assessed by a neuropsychological test battery. Independent associations (standardized beta) were determined in multiple linear regression models that simultaneously controlled for potential confounders. RESULTS: Log-transformed homocysteine was inversely associated with performance on Block Design (beta = -0.319, P = 0.006) and the written Symbol Digit Modality Test (beta = -0.129, P = 0.031). Log-transformed folate was significantly associated with Rey Auditory Verbal Learning Test delayed recall (beta = 0.139, P = 0.010), verbal learning (beta = 0.112, P = 0.038), percentage of forgetting (beta = -0.139, P = 0.013), and the Categorical Verbal Fluency test (beta = 0.104, P = 0.042). Vitamin B-12 was not significantly associated with any cognitive test score. CONCLUSIONS: In this high-functioning elderly Chinese population, elevated homocysteine is associated with deficits in constructional ability and processing speed and folate is associated with measures of episodic memory and language. Our results provide support for differential effects of homocysteine and folate on specific cognitive functions.     

Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain

BACKGROUND: In some patients with vitamin B-12 deficiency mistakenly treated with folic acid, anemia resolved but neurologic complications became worse (masking). Fortification of enriched cereal grains with folic acid has raised concerns that people who consume large quantities of cereal grains, particularly the elderly, may be at increased risk of masking. It is unclear, however, what proportion of people with low vitamin B-12 concentrations do not have anemia and whether the proportion is increasing. OBJECTIVE: We investigated whether fortification has increased the proportion of patients with low vitamin B-12 but without anemia. DESIGN: We reviewed the laboratory results of every patient for whom a vitamin B-12 concentration was measured at the Veterans Affairs Medical Center in Washington, DC, between 1992 and 2000. Those with a low vitamin B-12 concentration (< 258 pmol/L) had their hematocrits and mean cell volumes checked. The proportion without anemia was examined by year before, during, and after folic acid fortification began. RESULTS: There were 1573 subjects with a low vitamin B-12 concentration. The proportion without anemia did not increase significantly from the prefortification period (39.2%) to the period of optional fortification (45.5%) and the postfortification period (37.6%). These findings did not change when the analysis was limited to patients aged > 60 y or when a more conservative definition of low vitamin B-12 (< 150 pmol/L) was used. CONCLUSIONS: Despite evidence that folic acid exposure has increased dramatically since food fortification began, this population showed no evidence of an increase in low vitamin B-12 concentrations without anemia. If confirmed, these results would indicate that food fortification has not caused a major increase in masking of vitamin B-12 deficiency.     

Prospective study of plasma folate, vitamin B12, and cognitive function and decline

BACKGROUND: The relation between B vitamins and cognitive decline is controversial. In this study, we explored the association of plasma folate and vitamin B12 with cognitive function measured approximately 10 years later. METHODS: We determined plasma folate and vitamin B12 levels from blood samples collected in 1989 to 1990 and initially evaluated cognition in 1995 to 2001 among 635 women, age 70+ years, from the Nurses' Health Study. In a subset of 391, 3 repeated cognitive tests were completed for evaluation of cognitive decline over 4 years; repeated testing is ongoing for the remaining women. Our primary outcome was a global composite score of 6 neuropsychologic tests administered by telephone. We used linear regression models to estimate multivariable-adjusted mean cognitive performance across quartiles of the vitamins and longitudinal models for cognitive decline. RESULTS: Higher vitamin levels were not associated with either initial cognitive performance or subsequent cognitive decline. Mean difference in initial global score for top versus bottom quartiles was 0.06 standard units for folate (95% confidence interval [CI] = -0.10 to 0.22) and 0.15 units for vitamin B12 (0.00 to 0.31). There were no dose-response trends for either nutrient. Women with high levels of both nutrients initially performed better than women low in both nutrients (global score, mean difference = 0.34; 95% CI = 0.05 to 0.62); this association did not hold for subsequent cognitive decline. CONCLUSIONS: Combined B vitamin deficiency may be associated with impaired cognition, but in these healthy, well-nourished women, plasma folate and vitamin B12 were not related to cognitive function.     

Combined dietary folate, vitamin B-12, and vitamin B-6 intake influences plasma docosahexaenoic acid concentration in rats

Background

Folate, vitamin B-12, and vitamin B-6 are essential nutritional components in one-carbon metabolism and are required for methylation capacity. The availability of these vitamins may therefore modify methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) by PE-N-methyltransferase (PEMT) in the liver. It has been suggested that PC synthesis by PEMT plays an important role in the transport of polyunsaturated fatty acids (PUFAs) like docosahexaenoic acid (DHA) from the liver to plasma and possibly other tissues. We hypothesized that if B-vitamin supplementation enhances PEMT activity, then supplementation could also increase the concentration of plasma levels of PUFAs such as DHA. To test this hypothesis, we determined the effect of varying the combined dietary intake of these three B-vitamins on plasma DHA concentration in rats.

Methods

In a first experiment, plasma DHA and plasma homocysteine concentrations were measured in rats that had consumed a B-vitamin-poor diet for 4?weeks after which they were either continued on the B-vitamin-poor diet or switched to a B-vitamin-enriched diet for another 4?weeks. In a second experiment, plasma DHA and plasma homocysteine concentrations were measured in rats after feeding them one of four diets with varying levels of B-vitamins for 4?weeks. The diets provided 0% (poor), 100% (normal), 400% (enriched), and 1600% (high) of the laboratory rodent requirements for each of the three B-vitamins.

Results

Plasma DHA concentration was higher in rats fed the B-vitamin-enriched diet than in rats that were continued on the B-vitamin-poor diet (P?=?0.005; experiment A). Varying dietary B-vitamin intake from deficient to supra-physiologic resulted in a non-linear dose-dependent trend for increasing plasma DHA (P?=?0.027; experiment B). Plasma DHA was lowest in rats consuming the B-vitamin-poor diet (P?>?0.05 vs. normal, P?. enriched and high) and highest in rats consuming the B-vitamin-high diet (P?. poor and normal, P?>?0.05 vs. enriched). B-vitamin deficiency significantly increased plasma total homocysteine but increasing intake above normal did not significantly reduce it. Nevertheless, in both experiments plasma DHA was inversely correlated with plasma total homocysteine.

Conclusion

These data demonstrate that dietary folate, vitamin B-12, and vitamin B-6 intake can influence plasma concentration of DHA.     

Assessment of vitamin B-12, folate, and vitamin B-6 status and relation to sulfur amino acid metabolism in neonates

BACKGROUND: Total serum homocysteine (tHcy) has been used as an indicator of intracellular vitamin B-12, vitamin B-6, and folate status in adults, but data for neonates and infants are lacking. Vitamin B-12 deficiency may have fatal effects on neurologic development in infants; therefore, early diagnosis is crucial. OBJECTIVE: Our aim was to provide a reference range for tHcy in neonates and to explore the relation of tHcy to 1) serum vitamin concentrations, 2) the product of the transsulfuration pathway (cysteine), and 3) nutritional factors. DESIGN: tHcy, cysteine, folate, vitamin B-12, and vitamin B-6 were measured in 123 healthy, breast-fed neonates. The influence of nutrition (formula or human milk) on these variables was investigated in 60 infants. RESULTS: The mean (+/-SD) tHcy concentration was 7.8 +/- 3.1 micromol/L. tHcy showed a linear association with log vitamin B-12 (r = -0.64, P: < 0. 001), red blood cell folate (r = -0.33, P: < 0.001), and cysteine (r = 0.36, P: < 0.001). The strongest linear association was found between tHcy and the ratio of log cysteine to log vitamin B-12 (r = 0.71, P: < 0.0001). We found more neonates with probable tissue deficiencies of vitamin B-12 and folate on the basis of tHcy measurements than was expected from the analysis of serum vitamin concentrations alone (15.4% compared with 9.7%). Breast-fed infants had significantly lower vitamin B-12 concentrations and significantly higher serum tHcy and cysteine concentrations and ratios of log cysteine to log vitamin B-12 than did formula-fed infants (P: < 0.001). CONCLUSIONS: tHcy can be used as a functional indicator of vitamin B-12 and folate status in neonates. The ratio of cysteine to vitamin B-12 can be used as an additional index of impaired intracellular Hcy metabolism. tHcy and cysteine concentrations in infants are affected by nutritional factors.