Dietary counseling to increase natural folate intake: a ransomized placebo-controlled trial in free-living subjects to assess effects on serum folate and plasma total homocysteine.

BACKGROUND: The association between vascular disease and elevated plasma total homocysteine (tHcy) concentrations is caused, in part, by inadequate intakes of dietary folate. Increasing folate intake either through supplements or foods naturally rich in folates has been shown to decrease tHcy concentrations. OBJECTIVE: The aim of this study was to determine whether a similar reduction in tHcy was possible in free-living persons receiving dietary counseling. DESIGN: The study included a 4-wk placebo-controlled dietary intervention trial in which participants consumed either unfortified breakfast cereal (control group) or an extra 350 micro g folate derived from food/d (dietary group). Serum folate and tHcy concentrations in both groups were measured before and after the intervention period, and the concentrations in the dietary group were also measured 17 wk after the intervention period. RESULTS: During the 4-wk intervention, mean dietary folate intake in the dietary group increased from 263 (95% CI: 225, 307) to 618 micro g/d (535, 714), resulting in a mean increase in serum folate of 37% (15%, 63%) and a decrease in tHcy from 12.0 (10.9, 13.3) to 11.3 micro mol/L (10.2, 12.5). A further decrease in tHcy occurred in the dietary group during follow-up, with a final tHcy concentration of 9.7 micro mol/L (8.8, 10.8). CONCLUSIONS: Increasing natural folate intake improved folate status and decreased tHcy concentrations to an extent that may significantly reduce the risk of vascular disease. Dietary modification may have advantages over folic acid fortification because the altered food-consumption patterns lead to increased intakes of several vitamins and minerals and decreased intakes of saturated fatty acids.

Assessment of three levels of folic acid on serum folate and plasma homocysteine: a randomised placebo-controlled double-blind dietary intervention trial.

Objective: To determine the minimum effective dose of folic acid required to appreciably increase serum folate and to produce a significant reduction in plasma total homocysteine (tHcy).

Design: Double-blind, randomised placebo-controlled intervention trial.

Setting: Community-based project in a New Zealand city.

Subjects: Seventy free living men and women with tHcy10 µmol/l. Mean age (range) was 58 (29-90) y.

Interventions: Daily consumption over 4 weeks of 20 g breakfast cereal either unfortified (placebo) or fortified with 100, 200 or 300 µg folic acid. Dietary intake was determined by weighed diet records and consumption of commercially fortified products was avoided.

Main outcome measures: Plasma tHcy and serum folate concentrations.

Results: Average serum folate concentrations (95% CI) increased significantly in the treatment groups relative to the control group by 28(9-51)%, 60(37-87)% and 79(51-114)% for supplementation with 100, 200 and 300 µg folic acid, respectively. A reduction in tHcy was observed, being 16(8-22)%, 12(4-18)% and 17(9-24)% in the three treatment groups, respectively.

Conclusions: A regular intake of as little as 100 µg folic acid per day was sufficient to lower tHcy in persons at the upper end of the normal range for tHcy. Low-level fortification may also be appropriate for lowering the risk of neural tube defects given that, when aggregated from all sources, the total intake of folic acid may be sufficiently high to adequately improve the folate status of young women.

Homocysteine concentration, related B vitamins, and betaine in pregnant women recruited to the Seychelles Child Development Study

Background: Both folate and betaine are important predictors of total homocysteine (tHcy) during pregnancy. However, studies to date have only been undertaken in populations with Western dietary patterns.

Objective: We investigated the predictors of tHcy in pregnant women recruited in the Seychelles, a population where access to fortified foods is limited and where women habitually consume diets rich in fish, eggs, rice, and fruit.

Design: Pregnant women (n = 226) provided blood samples at enrollment, at week 28 of gestation, and at delivery. Cord blood was obtained from a subset of participants (n = 135).

Results: As in other studies, maternal tHcy was lower during pregnancy than at delivery, whereas folate and vitamin B-12 status declined significantly to delivery. Despite low maternal folate status at delivery (median: 9.0 nmol/L), with 35% of women in the deficient range (serum folate: <6.8 nmol/L), cord blood folate status (median: 40.2 nmol/L) was similar to concentrations reported in Western populations. Folate was a significant predictor of tHcy at all time points (P < 0.001). In contrast with previous studies, betaine was only a significant predictor of maternal tHcy (P < 0.001) when the essential amino acid methionine was low.

Conclusions: The current study reports 2 important findings. First, fetal requirements for folate are paramount, such that cord blood folate status is maintained, even when maternal status is low. Second, betaine is a significant predictor of tHcy in pregnant women with low serum folate and low serum methionine concentrations.

Homocysteine as a potential biomarker in bipolar disorders: a critical review and suggestions for improved studies

Introduction: Homocysteine levels have been associated with major depression, but associations with bipolar disorder remain less clear. Some data suggest homocysteine levels have potential as a biomarker of treatment response; however the literature is mixed.

Areas covered: Oxidized forms of homocysteine can be potentially neurotoxic leading to glutamate toxicity, apoptotic transformation and neurodegenerative processes. High homocysteine may be a risk biomarker for bipolar disorders, but the empirical base remains too weak for firm conclusions. This review discusses the current literature for homocysteine levels as a biomarker.

Expert opinion: It is premature to foreclose the utility of homocysteine levels as a biomarker for bipolar disorder due the methodological inadequacies in the existing literature. These methodological design issues include lack of control for the confounding variables of concurrent medication, phase of bipolar disorder, gender, age, nutritional status, thyroid, liver and renal function, smoking or lean body mass. Well-powered association studies with confounder control could help shed more light on the important clinical question of homocysteine's utility as a biomarker in bipolar disorder. Future experiments are needed to examine the outcome of interventions modulating homocysteine for treating bipolar disorder. Only prospective randomized control trials will provide definitive evidence of the utility of homocysteine as a biomarker or therapeutic target.

A combination of omega-3 fatty acids, folic acid and B-group vitamins is superior at lowering homocysteine than omega-3 alone: a meta-analysis

The aim of the study was to assess whether omega-3 polyunsaturated fatty acid supplementation alone or in combination with folic acid and B-group vitamins is effective in lowering homocysteine. The Medline Ovid, Embase and Cochrane databases were searched for randomized-controlled trial studies that intervened with omega-3 supplementation (with or without folic acid) and measured changes in homocysteine concentration. Studies were pooled using a random effects model for meta-analysis. Three different models were analyzed: all trials combined, omega-3 polyunsaturated fatty acid trials, and omega-3 polyunsaturated fatty acids with folic acid and B-group vitamin trials. Nineteen studies were included, consisting of 3267 participants completing 21 trials. Studies were heterogeneous; varying by dose, duration and participant health conditions. Across all trials, omega-3 supplementation was effective in lowering homocysteine by an average of 1.18μmol/L (95%CI: (-1.89, -0.48), P=.001). The average homocysteine-lowering effect was greater when omega-3 supplementation was combined with folic acid and B-group vitamins (-1.37μmol/L, 95%CI: (-2.38, -0.36), P<.01) compared to omega-3 supplementation alone (-1.09μmol/L 95%CI: (-2.04, -0.13), P=.03). Omega-3 polyunsaturated fatty acid supplementation was associated with a modest reduction in homocysteine. For the purposes of reducing homocysteine, a combination of omega-3s (0.2-6g/day), folic acid (150 - 2500μg/day) and vitamins B6 and B12 may be more effective than omega-3 supplementation alone.

The link between judgements of comparative risk and own risk: Further evidence

Individuals typically believe that they are less likely than the average person to experience negative events, a phenomenon termed “unrealistic optimism”. The direct method of assessing unrealistic optimism employs a question of the form, “Compared with the average person, what is the chance that X will occur to you?”. However, it has been proposed that responses to such a question (direct-estimates) are based essentially just on estimates that X will occur to the self (self-estimates). If this is so, any factors that affect one of these estimates should also affect the other. This prediction was tested in two experiments. In each, direct- and self-estimates for an unfamiliar health threat—homocysteine-related heart problems—were recorded. It was found that both types of estimate were affected in the same way by varying the stated probability of having unsafe levels of homocysteine (Study 1, N = 149) and varying the stated probability that unsafe levels of homocysteine will lead to heart problems (Study 2, N = 111). The results are consistent with the proposal that direct-estimates are constructed just from self-estimates.

Sustained weight loss in obese subjects has benefits that are independent of attained weight

Objective: To explore the hypothesis that sustained weight loss in severely obese patients may have benefits that are independent of their attained BMI. Research Methods and Procedures: We conducted a comparison of two weight-stable groups with BMI in the 30 to 35 kg/m2 range. Subjects (n = 79) were selected obese patients 3 years after laparoscopic adjustable gastric band surgery, and controls (n = 79) were obese patients seeking weight loss therapy. Subjects were selected in a de-identified manner from our database to best match the control group. A range of clinical, biochemical, and questionnaire measures were obtained to assess obesity-related health status Results: Subjects maintained a mean weight loss of 32.8 plusminus 18 kg after surgery. The weight loss subjects had significantly lower fasting plasma glucose, insulin, and triglyceride concentrations, along with higher high-density lipoprotein-cholesterol levels and better indirect measures of insulin sensitivity when compared with controls (p < 0.05 for all). In addition, aminotransferase levels, neutrophil counts, and globulin levels were also significantly lower in weight loss subjects. All differences in laboratory variables remained significant after controlling for BMI. The subjects also reported better health-related quality of life, fewer symptoms of depression, and greater satisfaction with their appearance than controls. Discussion: These findings suggest that the post-weight loss state conveys benefits that are greater than predicted by the attained BMI. These findings may have important implications regarding the expectations of weight loss therapy, and mechanisms for this effect should be carefully sought.

A significant inverse relationship between concentrations of plasma hoocysteine and phospholipid docosahexaenoic acid in healthy male subjects

The aim of this study was to investigate the possibility of a relationship between plasma homocysteine (Hcy) and phospholipid FA (PUFA) in healthy Australian males. One hundred thirty six healthy male subjects aged 20–55 yr were recruited from the Melbourne metropolitan area. Each volunteer completed a semiquantitative food frequency questionnaire and gave a blood sample. Plasma Hcy concentrations were determined by an established HPLC method; the plasma phospholipid FA were determined by standard methods. Plasma Hcy concentration was significantly negatively correlated with plasma phospholipid concentration of the PUFA 20∶5n−3 (r=−0.226, P=0.009), 22∶5n−3 (r=−0.182, P=0.036), 22∶6n−3 (r=−0.286, P=0.001), total n−3 (r=−0.270, P=0.002) and the ratio n−3/n−6 PUFA (r=−0.265, P=0.002), and significantly positively correlated with 20∶4n−6 (r=0.180, P=0.037). In the partial correlation analysis, after controlling for serum vitamin B12 and folate concentration, plasma Hcy was significantly negatively correlated with the plasma phospholipid concentration of 22∶6n−3 (r=−0.205, P=0.019), total n−3 (r=−0.182, P=0.038) and the ratio n−3/n−6 PUFA (r=−0.174, P=0.048). Evidence indicates that an increased concentration of n−3 PUFA in tissues has a beneficial effect on cardiovascular health. Our findings provide further evidence that increased consumption of dietary n−3 PUFA increases the concentration of n−3 PUFA in plasma phospholipid, which is associated with a protective effect on cardiovascular diseases and lower plasma Hcy levels. The mechanism that might explain the association between plasma 22∶6n−3 and Hcy levels is not clear.

Markers of inflammation in South Asian and European infants from birth to 2 years in Manchester, UK

Inflammatory markers, including serum C-reactive protein (CRP), are predictors of coronary heart disease (CHD) in adults. South Asians in the UK have higher rates of CHD in adulthood than national rates.We tested the hypotheses that South Asian infants would have higher serum concentrations of CRP and homocysteine than European infants up to 2 years of age and that higher infant weight is associated with elevation of inflammatory markers. Infants of South Asian and European origin were investigated in a mixed cross sectional-longitudinal cohort study. Mothers were recruited ante-natally from St Mary’s Hospital,Manchester by postal invitation and telephone call to non-responders. Infants with metabolic or congenital abnormalities, known syndromes or pre-maturity were excluded. Measurements were collected at birth and either 3, 6, 12 or 24 months. High sensitivity CRP and homocysteine were measured by an immulite immunoassay. We used mixed linear modelling to assess whether infant weight, ethnicity, length of follow-up or their interaction were associated with inflammatory makers in infants during follow-up. Data are presented on 306 infants (109 South Asian and 197 European). We found that European infants had higher serum CRP than South Asian infants during follow-up which was of borderline significance.There was no difference in serum homocysteine between ethnic groups during followup and no significant interaction between ethnicity and follow-up. Infant weight was significantly associated with CRP but not homocysteine. In this ongoing longitudinal study,we found little difference in inflammatory markers in infants from birth to 2 years despite markedly higher rates of CHD in South Asian than European adults. Life course exposure to risk factors may play a more dominant role in the development of CHD.

Epithelial cell folate is an accurate marker when compared with whole tissue biopsy folate for examining the role of folate status in colorectal cancer

Background – Epidemiological studies have shown low folate status is associated with colorectal cancer. Colonic tissue folate levels at different stages of cancer development should give important information, but different methodologies to extract the colonic tissue folates have been used. This has hampered progress in defining the relationship between systemic and tissue folate levels.
Objective – To evaluate two methods of colonic tissue preparation for estimation of total folate content.
Design – Whole tissue punch biopsy samples were obtained from the descending colon of 31individuals following a normal colonoscopy. Blood samples were obtained for the determination of plasma homocysteine (Hcy), red cell folate (RCF), methylenetetrahydrofolate reductase 677C>T genotype, and serum vitamin B12 and folate. Colonic tissue folate was measured both in washed whole tissue biopsies and in epithelial cells isolated from tissue biopsies.
Outcomes - Whole biopsy and epithelial cell folate concentrations were significantly correlated (R=.375; P=.038). Hcy was inversely correlated with both measures (R=-.365; P=.043 and R=-.364; P=.044 respectively). RCF was significantly correlated with isolated epithelial cell folate (R=.477; P=.007) but not with whole tissue biopsy folate (R=.264; P=.151). There were no significant associations between serum and colonic folate in this study.
Conclusion - Both methods are useful for comparing systemic and localised tissue folate status but epithelial cells may provide more reliable data.

Cognitive impairment and vitamin B12 : a review

Background: This review examines the associations between low vitamin B12 levels, neurodegenerative disease, and cognitive impairment. The potential impact of comorbidities and medications associated with vitamin B12 derangements were also investigated. In addition, we reviewed the evidence as to whether vitamin B12 therapy is efficacious for cognitive impairment and dementia.

Methods: A systematic literature search identified 43 studies investigating the association of vitamin B12 and cognitive impairment or dementia. Seventeen studies reported on the efficacy of vitamin B12 therapy for these conditions.

Results: Vitamin B12 levels in the subclinical low-normal range (<250 ρmol/L) are associated with Alzheimer's disease, vascular dementia, and Parkinson's disease. Vegetarianism and metformin use contribute to depressed vitamin B12 levels and may independently increase the risk for cognitive impairment. Vitamin B12 deficiency (<150 ρmol/L) is associated with cognitive impairment. Vitamin B12 supplements administered orally or parenterally at high dose (1 mg daily) were effective in correcting biochemical deficiency, but improved cognition only in patients with pre-existing vitamin B12 deficiency (serum vitamin B12 levels <150 ρmol/L or serum homocysteine levels >19.9 μmol/L).

Conclusion: Low serum vitamin B12 levels are associated with neurodegenerative disease and cognitive impairment. There is a small subset of dementias that are reversible with vitamin B12 therapy and this treatment is inexpensive and safe. Vitamin B12 therapy does not improve cognition in patients without pre-existing deficiency. There is a need for large, well-resourced clinical trials to close the gaps in our current understanding of the nature of the associations of vitamin B12 insufficiency and neurodegenerative disease.