Jane Durga

No effect of folic acid supplementation on global DNA methylation in men and women with moderately elevated homocysteine

A global loss of cytosine methylation in DNA has been implicated in a wide range of diseases. There is growing evidence that modifications in DNA methylation can be brought about by altering the intake of methyl donors such as folate. We examined whether long-term daily supplementation with 0.8 mg of folic acid would increase global DNA methylation compared with placebo in individuals with elevated plasma homocysteine. We also investigated if these effects were modified by MTHFR C677T genotype. Two hundred sixteen participants out of 818 subjects who had participated in a randomized double-blind placebo-controlled trial were selected, pre-stratified on MTHFR C677T genotype and matched on age and smoking status. They were allocated to receive either folic acid (0.8 mg/d; nu200a=u200a105) or placebo treatment (nu200a=u200a111) for three years. Peripheral blood leukocyte DNA methylation and serum and erythrocyte folate were assessed. Global DNA methylation was measured using liquid chromatography-tandem mass spectrometry and expressed as a percentage of 5-methylcytosines versus the total number of cytosine. There was no difference in global DNA methylation between those randomized to folic acid and those in the placebo group (differenceu200a=u200a0.008, 95%CIu200a=u200a−0.05,0.07, Pu200a=u200a0.79). There was also no difference between treatment groups when we stratified for MTHFR C677T genotype (CC, nu200a=u200a76; CT, nu200a=u200a70; TT, nu200a=u200a70), baseline erythrocyte folate status or baseline DNA methylation levels. In moderately hyperhomocysteinemic men and women, long-term folic acid supplementation does not increase global DNA methylation in peripheral blood leukocytes. ClinicalTrials.gov NCT00110604

Serum Iron Parameters, HFE C282Y Genotype, and Cognitive Performance in Older Adults: Results From the FACIT Study

Although iron homeostasis is essential for brain functioning, the effects of iron levels on cognitive performance in older individuals have scarcely been investigated. In the present study, serum iron parameters and hemochromatosis (HFE) C282Y genotype were determined in 818 older individuals who participated in a 3-year randomized, placebo-controlled double-blind trial examining the effects of folic acid on carotid intima-media thickness. All participants had slightly elevated homocysteine levels and were vitamin B12 replete. Cognitive functioning was assessed at baseline and after 3 years by means of a neuropsychological test battery. At baseline, increased serum ferritin was associated with decreased sensorimotor speed, complex speed, and information-processing speed and increased serum iron was associated with decreased sensorimotor speed. Cognitive performance over 3 years was not associated with HFE C282Y genotype or iron parameters. In conclusion, serum iron parameters do not show a straightforward relationship with cognitive functioning, although elevated iron levels may decrease cognitive speed in older individuals susceptible to cognitive impairment.

Genetic variation in folate metabolism is not associated with cognitive functioning or mood in healthy adults.

The present study examined the associations between genetic variation in folate metabolism on the one hand and cognitive functioning and mood on the other in healthy individuals. Two independent population-based samples were used, including 777 participants, aged 24-82 years, from the Maastricht Aging Study (MAAS); and 818 participants, aged 50-70 years, from the Folic Acid and Carotid Intima-Media Thickness (FACIT) study. Thymidylate synthase (TS) 2R→3R and serine hydroxymethyltransferase (SHMT1) 1420C→T polymorphisms were determined in both populations. In addition, the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T polymorphism was determined in the MAAS population. Cognitive performance was assessed in both populations using a neuropsychological test battery. In the MAAS population only, cognitive performance was retested after 12years of follow-up (n=612), and mood was measured at baseline (n=772) and 12-year follow-up (n=565) by means of the depression subscale of the Symptom Checklist 90. We found that in both study populations, cognitive performance was not associated with TS 2R→3R or SHMT1 1420C→T polymorphisms at baseline, after correction for age, sex, and level of education. The MTHFR 677C→T polymorphism was not associated with cognitive performance in the MAAS population. None of the polymorphisms in the MAAS population were related to mood at baseline or over 12 years. In conclusion, our findings do not support the involvement of genetic variation in folate metabolism in cognitive performance or mood in healthy individuals.

Folate nutrition and blood–brain barrier dysfunction

Mammals require essential nutrients from dietary sources to support normal metabolic, physiological and neuronal functions, to prevent diseases of nutritional deficiency as well as to prevent chronic disease. Disease and/or its treatment can modify fundamental biological processes including cellular nutrient accretion, stability and function in cells. These effects can be isolated to a specific diseased organ in the absence of whole-body alterations in nutrient status or biochemistry. Loss of blood-brain barrier function, which occurs in in-born errors of metabolism and in chronic disease, can cause brain-specific folate deficiency and contribute to disease co-morbidity. The role of brain folate deficiency in neuropsychiatric disorders is reviewed, as well as emerging diagnostic and nutritional strategies to identify and address brain folate deficiency in blood-brain barrier dysfunction.