Folic acid

Bibliography and References. Review.
List of selected scientific articles (abstracts). Experimental and clinical data.

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Folic acid, or folate, is one of the essential vitamins in the body, which is very hard to obtain through diet sources. The body has its own storage of the substance in the liver but supplementation is highly recommended. Folic acid is so important because it plays a central role in a number of metabolic reactions involving amino acids and nucleotides. During periods of high metabolic activity, such as pregnancy, the body’s need for folate increases and if it is not supplemented, a deficiency can arise. The symptoms of the deficiency are not so pronounced in the mother, but for the embryo they are very significant. Low birthweight, abruptio placenta and neural tube defects are common outcomes of folic acid deficiency. Pregnant and lactating women are the most vulnerable group for deficiency. It also leads to an increases risk of atherosclerosis in adults. Folate can be obtained by high consumption of citrus fruits, spinach and legumes or by supplementation.

J Am Coll Cardiol. 2005 May 17;45(10):1580-4. Epub 2005 Apr 26.
High-dose folic Acid acutely improves coronary vasodilator function in patients with coronary artery disease.
Tawakol A, Migrino RQ, Aziz KS, Waitkowska J, Holmvang G, Alpert NM, Muller JE, Fischman AJ, Gewirtz H.
Department of Medicine (Cardiac Unit), Massachusetts General Hospital, Boston, Massachusetts.

OBJECTIVES: We investigated the acute effect of orally administered high-dose folic acid on coronary dilator function in humans. BACKGROUND: Folic acid and its active metabolite, 5-methyltetrahydrofolate, increase endothelium-dependent vasodilation in human peripheral circulation. However, the acute effect on coronary circulation is not known. METHODS: Fourteen patients with ischemic heart disease, age 62 +/- 12 years (mean +/- SD), were enrolled in a double-blind, placebo-controlled crossover trial. Basal and adenosine-stimulated myocardial blood flow (MBF) were determined by positron emission tomography, and myocardial flow reserve was calculated. Each patient was studied after ingestion of placebo and after ingestion of 30 mg folic acid. Myocardial zones were prospectively defined physiologically as "normal" versus "abnormal" on the basis of MBF response to adenosine 140 mug/kg/min (normal = MBF >1.65 ml/min/g). Abnormal and normal zones were analyzed separately in a patient-based analysis. RESULTS: Folate was associated with a reduction in mean arterial pressure (100 +/- 12 mm Hg vs. 96 +/- 11 mm Hg, placebo vs. folate, p < 0.03). Despite the fall in mean arterial pressure, folic acid significantly increased the MBF dose response to adenosine (p < 0.001 using analysis of variance) in abnormal zones, whereas MBF in normal zones did not change. In abnormal segments, folic acid increased peak MBF by 49% (1.45 +/- 0.59 ml/min/g vs. 2.16 +/- 1.01 ml/min/g, p < 0.02). Furthermore, folate increased dilator reserve by 83% in abnormal segments (0.77 +/- 0.59 vs. ml/min/g 1.41 +/- 1.08 ml/min/g, placebo vs. folate, p < 0.05), whereas dilator reserve in normal segments remained unchanged (2.00 +/- 0.61 ml/min/g vs. 2.12 +/- 0.69 ml/min/g, placebo vs. folate, p = NS). CONCLUSIONS: The data demonstrate that high-dose oral folate acutely lowers blood pressure and enhances coronary dilation in patients with coronary artery disease.

Cancer Gene Ther. 2005 May 13;
Folate-linked nanoparticle-mediated suicide gene therapy in human prostate cancer and nasopharyngeal cancer with herpes simplex virus thymidine kinase.
Hattori Y, Maitani Y.
1Institute of Medicinal Chemistry, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 142-8501, Japan.

For targeted gene delivery to human prostate cancer LNCaP and PC-3 cells and nasopharyngeal cancer KB cells, we developed a folate-linked nanoparticle (NP-F), and evaluated the potential of NP-F-mediated suicide gene therapy in the cells and xenografts with herpes simplex virus thymidine kinase (HSV-tk) and connexin 43 (Cx43). An NP-F-plasmid DNA complex (NP-F nanoplex) showed high DNA transfection efficiency in KB, LNCaP and PC-3 cells. Cell growth inhibition in the presence of ganciclovir (GCV) was enhanced with HSV-tk and Cx43 genes in LNCaP cells. In suicide gene therapy, the tumor growths of KB and LNCaP xenografts were significantly inhibited when an NP-F nanoplex of the HSV-tk gene, and HSV-tk and Cx43 genes, respectively, was injected intratumorally and GCV was administered intraperitoneally. These findings suggested that the NP-F is a potential target vector in prostate and nasopharyngeal cancer for suicide gene therapy.Cancer Gene Therapy advance online publication, 13 May 2005; doi:10.1038/sj.cgt.7700844.

N Engl J Med. 2005 May 12;352(19):1985-91.
Autoantibodies to folate receptors in the cerebral folate deficiency syndrome.
Ramaekers VT, Rothenberg SP, Sequeira JM, Opladen T, Blau N, Quadros EV, Selhub J.
Division of Pediatric Neurology, Department of Pediatrics, University Hospital Aachen, Aachen, Germany. vramaekers@ukaachen.de

In infantile-onset cerebral folate deficiency, 5-methyltetrahydrofolate (5MTHF) levels in the cerebrospinal fluid are low, but folate levels in the serum and erythrocytes are normal. We examined serum specimens from 28 children with cerebral folate deficiency, 5 of their mothers, 28 age-matched control subjects, and 41 patients with an unrelated neurologic disorder. Serum from 25 of the 28 patients and 0 of 28 control subjects contained high-affinity blocking autoantibodies against membrane-bound folate receptors that are present on the choroid plexus. Oral folinic acid normalized 5MTHF levels in the cerebrospinal fluid and led to clinical improvement. Cerebral folate deficiency is a disorder in which autoantibodies can prevent the transfer of folate from the plasma to the cerebrospinal fluid. Copyright 2005 Massachusetts Medical Society.

JAMA. 2005 Mar 2;293(9):1082-8.
Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial.
Sato Y, Honda Y, Iwamoto J, Kanoko T, Satoh K.
Department of Neurology, Mitate Hospital, Tagawa, Japan. y-sato@ktarn.or.jp

CONTEXT: Stroke increases the risk of subsequent hip fracture by 2 to 4 times. Hyperhomocysteinemia is a risk factor for both ischemic stroke and osteoporotic fractures in elderly men and women. Treatment with folate and mecobalamin (vitamin B12) may improve hyperhomocysteinemia. OBJECTIVE: To investigate whether treatment with folate and vitamin B12 reduces the incidence of hip fractures in patients with hemiplegia following stroke. DESIGN, SETTING, AND PATIENTS: A double-blind, randomized controlled study of 628 consecutive patients aged 65 years or older with residual hemiplegia at least 1 year following first ischemic stroke, who were recruited from a single Japanese hospital from April 1, 2000, to May 31, 2001. Patients were assigned to daily oral treatment with 5 mg of folate and 1500 microg of mecobalamin, or double placebo; 559 completed the 2-year follow-up. MAIN OUTCOME MEASURE: Incidence of hip fractures in the 2 patient groups during the 2-year follow-up. RESULTS: At baseline, patients in both groups had high levels of plasma homocysteine and low levels of serum cobalamin and serum folate. After 2 years, plasma homocysteine levels decreased by 38% in the treatment group and increased by 31% in the placebo group (P<.001). The number of hip fractures per 1000 patient-years was 10 and 43 for the treatment and placebo groups, respectively (P<.001). The adjusted relative risk, absolute risk reduction, and the number needed to treat for hip fractures in the treatment vs placebo groups were 0.20 (95% confidence interval [CI], 0.08-0.50), 7.1% (95% CI, 3.6%-10.8%), and 14 (95% CI, 9-28), respectively. No significant adverse effects were reported. CONCLUSION: In this Japanese population with a high baseline fracture risk, combined treatment with folate and vitamin B12 is safe and effective in reducing the risk of a hip fracture in elderly patients following stroke.

Cancer Detect Prev. 2005;29(1):46-53. Epub 2004 Nov 11.
The role of folates in squamous cell carcinoma of the head and neck.
Kane MA.
Division of Medical Oncology, University of Colorado Health Sciences Center and the Denver Veterans Affairs Medical Center, Denver VA Medical Center (111F), 1055 Clermont Street, Denver, CO 80220, USA.

The primary objective of this review is to explore the hypothesis that folate insufficiency may be important in the pathogenesis of squamous cell carcinomas of the head and neck (SCCHN) and that folate repletion may be an effective component of chemoprevention. The main results are that folate insufficiency disrupts DNA global and specific gene methylation patterns such that the activity of certain tumor suppressor genes such as p16 and possibly p53 may be lost. Folate pool imbalance and impaired repair mechanisms may contribute to DNA instability and strand breaks. Sensitive methods exist for identification of individuals with folate insufficiency in contrast to the relatively insensitive conventional serum or red cell folate assays with broad "normal" ranges. The impact of folate supplementation can thus be quantified. Folate imbalance may result from alterations in folate cellular uptake by the reduced folate carrier (RFC) and/or the folate receptor (FR) and polymorphisms in enzymes important in folate retention such as folylpolyglutamate synthetase and in folate modification such as methylene tetrahydrofolate reductase (MTHFR). Known predisposing factors for SCCHN such as alcohol and tobacco carcinogens may influence folate balance. Folate supplementation may reduce primary or secondary risk of cancer. Formal studies of folate sufficiency in persons at risk for or diagnosed and treated for SCCHN are needed to define the role of folate supplementation in the prevention of these cancers.

Ann Hematol. 2003 Nov 26.
Case of complete recovery of pancytopenia after treatment of hypopituitarism.
Kim DY, Kim JH, Park YJ, Jung KH, Chung HS, Shin S, Yun SS, Park S, Kim BK.
Department of Internal Medicine, Seoul National University College of Medicine, Yongon-dong, Jongro-gu, 110-744, Seoul, Korea.

We describe a 55-year-old woman who presented with pancytopenia with a normocytic and normochromic anemia which was progressive despite conventional treatments such as folic acid, vitamin B6, and oxymetholone. Her physical findings and history of a previous massive postpartum hemorrhage suggested Sheehan's syndrome, and the pituitary hormonal studies revealed panhypopituitarism. After 4 months of thyroxine and glucocorticoid replacement therapy, her pancytopenia and bone marrow hypoplasia recovered completely. Pancytopenia is a rare manifestation of a hormonal abnormality, but hematologists need to be aware of panhypopituitarism as a differential diagnosis when women showing features of hypopituitarism present with pancytopenia because it can be reversed with adequate hormone replacement.

Biomaterials. 2005 Mar;26(9):1053-61.
Preparation and characterization of methoxy poly(ethylene glycol)/poly(-caprolactone) amphiphilic block copolymeric nanospheres for tumor-specific folate-mediated targeting of anticancer drugs.
Park EK, Lee SB, Lee YM.

College of Engineering, School of Chemical Engineering, Hanyang University, Haengdang-dong, Seungdong-ku, Seoul 133-791, South Korea.
Biodegradable methoxy poly(ethylene glycol)/poly(-caprolactone) (MPEG/PCL) amphiphilic block copolymer nanospheres coupled to folic acid have been designed to target a folate-binding protein that is overexpressed on the surface of many tumoral cells. For this purpose, hydroxy groups terminated on the MPEG/PCL copolymer were converted into primary amino groups, which were used to conjugate with the carboxylic group of folic acid. Nanospheres were prepared by the formation of micelles of the copolymer with or without the anticancer agent paclitaxel. Folate-mediated MPEG/PCL nanospheres were compared with hydroxyl- and amino-terminated nanospheres in terms of their size, surface characteristics, and drug-loading efficiency. Regardless of the type of terminal group, the MPEG/PCL nanospheres showed a narrow size distribution with an average diameter <80nm without paclitaxel, and an average diameter of 115nm when loaded with the drug. The results from zeta potential and X-ray photoelectron spectroscopy measurements revealed that the folate molecules were partially exposed, and were expressed on the surface of the nanospheres allowing folate receptor recognition. In in vitro, cytotoxicity tests, the nanospheres loaded with paclitaxel showed a higher cell viability than in cases where paclitaxel was absent. Thus, folate-mediated nanospheres composed of MPEG and PCL are potentially new drug carriers for tumor cell-selective targeting treatments.

Int J Oncol. 2004 Nov;25(5):1465-71.
Polymorphisms in the methylenetetrahydrofolate reductase gene and prostate cancer risk.
Singal R, Ferdinand L, Das PM, Reis IM, Schlesselman JJ.
Division of Hematology/Oncology, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA. rsingal@med.miami.edu.

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, which is involved in the methylation of homocysteine to methionine. Genetic polymorphisms that decrease MTHFR activity result in an altered cancer risk depending on folic acid intake. In this study we examined the C677T and A1298C polymorphisms of the MTHFR gene in specimens from 81 patients with prostate cancer and 42 controls selected from patients with benign prostatic hypertrophy (BPH). Genomic DNA was isolated from archived formaldehyde-fixed and paraffin-embedded tissue blocks. MTHFR genotypes were determined by restriction-fragment-length-polymorphism polymerase chain reaction. The MTHFR polymorphism frequencies in the prostate-cancer and BPH specimens were, respectively, 60% and 48% for 677CC, 31% and 48% for 677CT, 9% and 5% for 677TT, 36% and 43% for 1298AA, 53% and 40% for 1298AC, and 11% and 17% for 1298CC. Although such differences fall within the realm of chance variation (P>0.05), the data suggest that the 677CT genotype may be associated with a reduced risk of prostate cancer: the age-adjusted odds ratio (aOR) was 0.6 [95% confidence interval (CI): 0.3-1.4]; the odds-ratio reduction was similar in both blacks and whites (aOR=0.4 in blacks, and 0.6 in whites); and when polymorphisms at the 677 and 1298 loci were analyzed in conjunction, a lower frequency of the 677CT-1298AA genotype was observed in the patients with prostate cancer (aOR=0.3, 95% CI: 0.1-1.1). This particular genotype, moreover, was associated with lower Gleason score tumors (aOR=0.1 for Gleason-score 7 versus 6 tumors, 95% CI: 0.0-0.7) and earlier stage disease (aOR=0.3 for stage III versus II, 95% CI: 0.3-2.6). These findings suggest that polymorphisms of the MTHFR gene may alter the risk of developing prostate cancer.

J Clin Gastroenterol. 2004 Nov;38(10):844-854.
Vitamin Supplementation: What The Gastroenterologist Needs To Know.
Sharma N, Trope B, Lipman TO.
From the daggerDepartment of Veterans Affairs Medical Center, and *Georgetown University Medical Center, Washington, DC.

BACKGROUND:: The vitamin business is a multimillion dollar industry. Aggressive marketing strategies are used to make claims for the health benefits of these products. Observational studies suggest that people who consume vitamin supplements decrease their risks for cancer, cardiovascular disease, and gastrointestinal disease. What is the evidence for these claims, and as a prescribing gastroenterologist, is there a scientific basis for vitamin supplementation? METHODS:: A narrative review focusing on randomized controlled trials, where available, plus observational studies obtained from personal files, "on-line" searches, and references in reviewed articles. RESULTS:: From the perspective of a gastroenterologist, there is strong evidence to recommend B12 supplementation in gastric and intestinal disease, as well as pernicious anemia. There exists moderate evidence to support B12 supplements in pancreatic disease. Vitamin D and calcium supplementation are recommended for persons with disorders of malabsorption, cholestasis, and illnesses requiring chronic steroids. Only observational studies suggest a correlation between vitamin D/calcium and decreased colorectal adenoma recurrence. Although folic acid supplementation is beneficial in persons on medications such as methotrexate and sulfasalazine, studies are contradictory with regard to folic acid and colon cancer prevention. Overall, antioxidants have not been proven to decrease the risk for colorectal adenoma, gastric cancer, or esophageal cancer. CONCLUSIONS:: Observational studies do not correlate with randomized clinical trials; therefore, few definitive recommendations can be made. Vitamin supplements are appropriate for recognized deficiencies; however, there is a lack of evidence to support their effects in the prevention of chronic disease.

J Intern Med. 2004 Nov;256(5):446-452.
A population-based intervention study on elevated serum levels of methylmalonic acid and total homocysteine in elderly people: results after 36 months of follow-up.
Bjorkegren K, Svardsudd K.
Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology Section, University Hospital, Uppsala University, Uppsala, Sweden.

Abstract. Bjorkegren K, Svardsudd K (Uppsala University, Uppsala; and Skutskar Primary Health Care Centre, Skutskar, Sweden). A population-based intervention study on elevated serum levels of methylmalonic acid and total homocysteine in elderly people: results after 36 months of follow-up. J Intern Med 2004; 256: 446-452.Objectives. To study the effects of vitamin B12 and folic acid treatment on haematological measures, reported symptoms and clinical findings over a 3-year period. Design. A longitudinal two-cohort study. Setting. A mid-Swedish community. Subjects. A 20% random sample of persons 70 years or older in a defined geographical area were invited to a survey (n = 266). Sixty-nine persons who had serum cobalamin <300 pmol L(-1) and serum methylmalonic acid (MMA) >/=0.37 μmol L(-1) or serum total homocysteine (tHcy) >/=15 μmol L(-1) and who had no vitamin B12 or folic acid substitution were selected for treatment. Main outcome measures. Serum cobalamin, folate, MMA and tHcy. Presence of gastrointestinal, neurological, psychiatric and some other symptoms, obtained by questionnaire, and Mini Mental State Examination (MMSE) score, vibration sense measurement and findings at a physical examination. Results. After combined vitamin B12-folic acid treatment, all persons normalized their serum tHcy and MMA levels and the effect remained after 3 years. The study design allowed separation of pure vitamin B12 deficiencies from folate and combined deficiencies. There was a tendency towards improvement of vibration sense, especially in the long nerve paths, and improvement of neurological symptoms and oral mucosa findings. No improvement was seen for other symptoms, reflex activity or MMSE score. Conclusions. Vitamin treatment of elderly people in the early phase of the condition may reverse damage that otherwise would become irreversible. If initiated, the treatment should be combined with vitamin B12 and folic acid.

CMAJ. 2004 Oct 12;171(8):897-904.
Homocysteine and cognitive function in elderly people.
Garcia A, Zanibbi K.
Department of Medicine, Queen's University, Kingston, Ont.

DEMENTIA IS HIGHLY PREVALENT AMONG ELDERLY PEOPLE, and projections show that the number of people affected might triple over the next 50 years, mainly because of a large increase in the oldest-old segment of the population. Because of this and the disease's devastating effects, measures for the prevention and early detection of dementia are crucial. Age and years of education are among the most relevant risk factors for dementia, but in recent years the role of homocysteine has also been investigated. Homocysteine is an amino acid produced in the metabolism of methionine, a process dependent on the B vitamins cobalamin, vitamin B(6) and folic acid. There is evidence that increased serum homocysteine levels are associated with declining cognitive function and dementia. We review this evidence in addition to the potential mechanisms through which homocysteine acts on the brain to cause cognitive dysfunction, the metabolism of homocysteine and factors associated with alteration of the normal metabolism

J Agric Food Chem. 2004 Oct 6;52(20):6338-40.
Folate content in commercial white and whole wheat sandwich breads.
Johnston KE, Tamura T.
Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama 35294.

After the U.S. mandate of folic acid fortification of enriched grain products, a report indicated higher than expected fortification. Limited information is available on folic acid in enriched products. We measured the folate content in 92 sandwich breads (46 white breads and 46 whole wheat breads) in Birmingham, Alabama, during 2001-2003. The mean folate content in white bread declined significantly from 2001 to 2002 or 2003, whereas the decline in folate content in whole wheat bread containing enriched flour was not significant. White bread contained significantly more folate than whole wheat bread containing enriched flour in 2001 and 2003. In 2002 and 2003, >40% of breads made of enriched flour contained <115 microg of folate/100 g and >70% contained <160 microg/100 g. These percentages were markedly higher than those in 2001. Our data suggest that folic acid in breads containing enriched flour declined after 2001 and monitoring of fortification may be necessary.

Neuroreport. 2004 Oct 5;15(14):2241-2244.
Group B vitamins protect murine cerebellar granule cells from glutamate/NMDA toxicity.
Lin Y, Desbois A, Jiang S, Hou ST.
Department of Clinical Neurological Sciences, The No. 252 Hospital of P.L.A., No. 81, Huayuan Street, Baoding City, Hebei Province, China, 071000; Experimental Therapeutics Laboratory, NRC Institute for Biological Sciences, National Research Council of Canada, Building M54, 1500 Montreal Road, Ottawa, ON K1A OR6, Canada.

The role of B group vitamins in preventing neuronal death against excitotoxicity was investigated. Neuronal death of cultured mouse cerebellar granule neurons (CGNs) caused by glutamate (50 microM) or NMDA (200 microM) was delayed in CGNs that had been treated with riboflavin (B2), folic acid (B9) or cynocobalamin (B12) for 18 h. Such neuroprotection by B2, B9 and B12 was in a dose- and time-dependent manner. In contrast, application of thiamin (B1), nicotinamide (B3), d-pantothenic acid (B5), pyridoxine (B6) or carnitine (BT) did not ameliorate glutamate or NMDA-mediated excitotoxicity to CGCs. These results are the first indication that certain B group vitamins are not only required for the normal brain function, but can also play a protective role against excitotoxicity to the brain.

Am J Clin Nutr. 2004 Oct;80(4):1050-7.
Phenotypic expression of the methylenetetrahydrofolate reductase 677C-->T polymorphism and flavin cofactor availability in thyroid dysfunction.
Hustad S, Nedrebo BG, Ueland PM, Schneede J, Vollset SE, Ulvik A, Lien EA.
LOCUS for Homocysteine and Related Vitamins, University of Bergen, Bergen, Norway. steinar.hustad@farm.uib.no

BACKGROUND: The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) 677C-->T polymorphism modifies the risk of coronary artery disease and colon cancer and is related to plasma concentrations of total homocysteine (tHcy). Riboflavin status modifies the metabolic effect of the polymorphism, and thyroid hormones increase the synthesis of flavin cofactors. OBJECTIVE: The aim of the study was to investigate the phenotypic expression of the MTHFR 677C-->T polymorphism in terms of plasma tHcy concentrations in patients with thyroid dysfunction. DESIGN: The study population consisted of 182 patients with hyperthyroidism. We studied plasma tHcy in relation to MTHFR genotype, riboflavin, and folate before and during 6 mo of treatment with antithyroid drugs. RESULTS: Before treatment, tHcy was higher in patients with the mutant enzyme than in those with the wild-type enzyme. A genotype effect was observed only at low riboflavin or folate concentrations (P T polymorphism, possibly by modifying the availability of flavin cofactors.

Am J Clin Nutr. 2004 Oct;80(4):1024-8.
Plasma folate concentrations are associated with depressive symptoms in elderly Latina women despite folic acid fortification.
Ramos MI, Allen LH, Haan MN, Green R, Miller JW.
Department of Pathology and Laboratory Medicine, University of California, Davis School of Medicine, Davis, USA.

BACKGROUND: A relation between low folate status and depression has been recognized since the 1960s. Since 1998, flour in the United States has been fortified with folic acid, and the prevalence of folate deficiency has decreased dramatically. OBJECTIVE: We investigated whether, in this era of folic acid fortification, low folate status is a determinant of depressive symptoms in a cohort of elderly Latinos (aged >/=60 y) participating in the Sacramento Area Latino Study on Aging (SALSA). DESIGN: In a cross-sectional logistic regression analysis of data from SALSA (n = 627 M, 883 F), odds ratios (ORs) were ascertained for elevated depressive symptoms [Center for Epidemiologic Studies Depression Scale (CES-D) score >/=16] among tertiles of plasma folate. Depressive symptoms were assessed by using the CES-D. Plasma folate concentrations were determined by radioassay. RESULTS: The prevalence of folate deficiency (plasma folate

Am J Clin Nutr. 2004 Oct;80(4):911-8.
Determining bioavailability of food folates in a controlled intervention study.
Hannon-Fletcher MP, Armstrong NC, Scott JM, Pentieva K, Bradbury I, Ward M, Strain JJ, Dunn AA, Molloy AM, Kerr MA, McNulty H.
Northern Ireland Centre for Food and Health and the School of Hotel, Leisure, and Tourism, University of Ulster, Coleraine, United Kingdom. p.hannon@ulster.ac.uk

BACKGROUND: The concept of dietary folate equivalents (DFEs) in the United States recognizes the differences in bioavailability between natural food folates and the synthetic vitamin, folic acid. However, many published reports on folate bioavailability are problematic because of several confounding factors. OBJECTIVE: We compared the bioavailability of food folates with that of folic acid under controlled conditions. To broadly represent the extent to which natural folates are conjugated in foods, we used 2 natural sources of folate, spinach (50% polyglutamyl folate) and yeast (100% polyglutamyl folate). DESIGN: Ninety-six men were randomly assigned according to their screening plasma homocysteine (tHcy) concentration to 1 of 4 treatment groups for an intervention period of 30 d. Each subject received (daily under supervision) either a folate-depleted "carrier" meal or a drink plus 1) placebo tablet, 2) 200 microg folic acid in a tablet, 3) 200 microg natural folate provided as spinach, or 4) 200 microg natural folate provided as yeast. RESULTS: Among the subjects who completed the intervention, responses (increase in serum folate, lowering of tHcy) relative to those in the placebo group (n = 18) were significant in the folic acid group (n = 18) but not in the yeast folate (n = 19) or the spinach folate (n = 18) groups. Both natural sources of folate were significantly less bioavailable than was folic acid. Overall estimations of folate bioavailability relative to that of folic acid were found to be between 30% (spinach) and 59% (yeast). CONCLUSION: Relative bioavailability estimates were consistent with the estimates from the metabolic study that were used as a basis to derive the US DFE value.

Arch Microbiol. 2004 Oct;182(4):313-325. Epub 2004 Sep 3.
Tetrahydrofolate-specific enzymes in Methanosarcina barkeri and growth dependence of this methanogenic archaeon on folic acid or p-aminobenzoic acid.
Buchenau B, Thauer RK.
Max-Planck-Institut fur terrestrische Mikrobiologie and Laboratorium fur Mikrobiologie, Fachbereich Biologie, Philipps-Universitat, Karl-von-Frisch-Strasse, 35043, Marburg, Germany.

Methanogenic archaea are generally thought to use tetrahydromethanopterin or tetrahydrosarcinapterin (H(4)SPT) rather than tetrahydrofolate (H(4)F) as a pterin C(1) carrier. However, the genome sequence of Methanosarcina species recently revealed a cluster of genes, purN, folD, glyA and metF, that are predicted to encode for H(4)F-specific enzymes. We show here for folD and glyA from M. barkeri that this prediction is correct: FolD (bifunctional N(5), N(10)-methylene-H(4)F dehydrogenase/ N(5), N(10)-methenyl-H(4)F cyclohydrolase) and GlyA (serine:H(4)F hydroxymethyltransferase) were heterologously overproduced in Escherichia coli, purified and found to be specific for methylene-H(4)F and H(4)F, respectively (apparent K(m) below 5 μM). Western blot analyses and enzyme activity measurements revealed that both enzymes were synthesized in M. barkeri. The results thus indicate that M. barkeri should contain H(4)F, which was supported by the finding that growth of M. barkeri was dependent on folic acid and that the vitamin could be substituted by p-aminobenzoic acid, a biosynthetic precursor of H(4)F. From the p-aminobenzoic acid requirement, an intracellular H(4)F concentration of approximately 5 μM was estimated. Evidence is presented that the p-aminobenzoic acid taken up by the growing cells was not required for the biosynthesis of H(4)SPT, which was found to be present in the cells at a concentration above 3 mM. The presence of both H(4)SPT and H(4)F in M. barkeri is in agreement with earlier isotope labeling studies indicating that there are two separate C(1) pools in these methanogens.

Arthritis Rheum. 2004 Oct;50(10):3104-11.
The effect of folic acid and folinic acid supplements on purine metabolism in methotrexate-treated rheumatoid arthritis.
Morgan SL, Oster RA, Lee JY, Alarcon GS, Baggott JE.
University of Alabama at Birmingham.

OBJECTIVE: To determine if folinic acid supplementation during methotrexate (MTX) therapy for rheumatoid arthritis (RA) reduces both urinary 5-aminoimidazole-4-carboxamide (AICA) and urinary adenosine excretion more than does folic acid supplementation. AICA and adenosine are markers for MTX interference with purine metabolism. METHODS: Forty patients with RA who received MTX for 6 weeks were randomized to receive either daily folic acid or folinic acid supplements during an additional week of MTX therapy. Colorimetric and radioimmunocompetition assays were used to measure 24-hour urinary AICA and adenosine excretion levels, respectively. RESULTS: At the end of 6 weeks, 24-hour urinary levels of AICA, but not adenosine, were elevated as compared with baseline levels (i.e., prior to MTX therapy). Folinic acid, but not folic acid, supplementation normalized urinary AICA levels during MTX therapy. Relatively high urinary levels of AICA were correlated with reduced disease activity. No similar correlations were seen with urinary adenosine levels. CONCLUSION: The blockade of purine nucleotide biosynthesis by MTX at the AICA ribonucleotide transformylase-catalyzed step may be related to the efficacy of MTX, and this blockade is effectively relieved by folinic acid, but not by folic acid, supplementation.

Br J Haematol. 2004 Oct;127(2):204-8.
The effects of folic acid supplements on coagulation status in pregnancy.
Deol PS, Barnes TA, Dampier K, John Pasi K, Oppenheimer C, Pavord SR.
Department of Haematology, Leicester Royal Infirmary, Leicester, UK.

Summary Thromboembolic disease remains the leading cause of maternal death in the UK. Recent literature has proposed that folate status is a strong predictor for venous thrombosis. Using thrombelastography (TEG((R))), we tested the hypothesis that folic acid supplementation is associated with a reduction in whole blood coagulability. Blood samples and questionnaire data were obtained at a mean gestation of 13.6 weeks (SD: 3.8, range: 6-38 weeks) from unselected consecutive women attending for their antenatal booking scan. Of 588 patients, 439 (74.7%) took folic acid. All TEG((R)) parameters were less hypercoagulable in women that had taken folic acid compared with those that had not: mean maximum amplitude (MA) 60.3 versus 62.1; mean difference 1.8; 95% confidence interval 0.8, 2.8; P = 0.0001; mean coagulation index (CI) 0.54 versus 0.85; mean difference 0.31; 95% confidence interval 0.11, 0.5; P = 0.002. There was no difference in the incidence of the homozygous MTHFR mutation in patients taking folic acid (5.53%) compared with those that were not (4.08%). This study suggests that benefit may be derived from longer-term treatment, although large multicentre studies are required to determine whether the relative hypocoagulability is associated with a reduction in risk of venous thrombosis.

Chest. 2004 Oct;126(4):1318-29.
Malignant pleural mesothelioma: update, current management, and newer therapeutic strategies.
Pistolesi M, Rusthoven J.
Section of Respiratory Medicine, Department of Critical Care, University of Florence, Viale G.B. Morgagni 85, 50134 Firenze, Italy. massimo@unifi.it.

The diagnosis and management of malignant pleural mesothelioma are major challenges that often frustrate both patient and clinician alike. Occupational asbestos exposure to crocidolite or amosite forms of the fiber is the most important known risk factor in North America and Western Europe. Other mineral fibers such as erionite, a naturally occurring fibrous zeolite crystal, are associated with mesothelioma in volcanic tuffs of the Cappadocia region of central Anatolia in Turkey. In addition, other possible factors such as the presence of simian virus 40 and genetic susceptibility have been associated recently with the development of mesothelioma in animal models. These latter findings are increasing our understanding of this disease. In addition, the discovery of elevated levels of various markers such as folic acid receptor alpha, cyclooxygenase 2, and multidrug resistance proteins 1 and 2 in mesothelioma tissue have opened up new areas of potential diagnostic and therapeutic importance. However, traditional treatment modalities-surgery, radiotherapy, and chemotherapy-have evolved slowly, and few gains in therapeutic efficacy have occurred. Recently, however, continuing research efforts have led to novel treatment strategies that are changing the way clinicians view a disease that has traditionally been managed with almost universal therapeutic nihilism. This review explores our current knowledge of this disease and presents current and novel therapeutic strategies.

Clin Lab Haematol. 2004 Oct;26(5):323-5.
The relationship between serum cobalamin concentration and mean red cell volume at varying concentrations of serum folate.
Metz J, McNeil AR, Levin M.
Department of Haematology, Dorevitch Pathology, Melbourne, Australia.

Summary There is concern that exposure of patients to folic acid may prevent the development of the macrocytosis of cobalamin deficiency and thus delay the detection of the neurological complications. We examined the relationship between low cobalamin levels and mean cell volume (MCV) at different serum folate concentrations in 63 472 blood samples tested in a community pathology laboratory over 2 years. We found no evidence that high serum folate levels masked the macrocytosis of cobalamin deficiency in this population with similar increases in MCV regardless of whether the serum folate was low, normal or high. Macrocytosis appears to retain its value as a marker of cobalamin deficiency in people with serum folate concentrations above the population average.

Eur J Endocrinol. 2004 Oct;151(4):483-489.
Insulin resistance and endothelial function are improved after folate and vitamin B12 therapy in patients with metabolic syndrome: relationship between homocysteine levels and hyperinsulinemia.
Setola E, Monti LD, Galluccio E, Palloshi A, Fragasso G, Paroni R, Magni F, Sandoli EP, Lucotti P, Costa S, Fermo I, Galli-Kienle M, Origgi A, Margonato A, Piatti P.
Cardiovascular and Metabolic Rehabilitation Unit, Rehabilitation and Functional Reeducation Division, Scientific Institute H. San Raffaele, Italy.

OBJECTIVE: The purpose of this study was (a) to study whether a folate and vitamin B12 treatment, aimed at decreasing homocysteine levels, might ameliorate insulin resistance and endothelial dysfunction in patients with metabolic syndrome according to the National Cholesterol Education Program-Adult Treatment Panel-III criteria and (b) to evaluate whether, under these metabolic conditions, there is a relationship between hyperhomocysteinemia and insulin resistance. DESIGN AND METHODS: A double-blind, parallel, identical placebo-drug, randomized study was performed for 2 months in 50 patients. Patients were randomly allocated to two groups. In group 1, patients were treated with diet plus placebo for 2 months. In group 2, patients were treated with diet plus placebo for 1 month, followed by diet plus folic acid (5 mg/day) plus vitamin B12 (500 μg/day) for another month. RESULTS: In group 2, folate treatment significantly decreased homocysteine levels by 27.8% (12.2+/-1.2 vs 8.8+/-0.7 μmol/l; P<0.01). A significant decrement was observed for insulin levels (19.9+/-1.7 vs 14.8+/-1.6 μU/ml; P<0.01) accompanied by a 27% reduction in the homeostasis model assessment levels. A positive relationship was found between the decrement of homocysteine and insulin levels (r=0.60; P<0.002). In parallel, endothelial dysfunction significantly improved in the treated group, since post-ischemic maximal hyperemic vasodilation increased by 29.8% and cGMP by 13.6% while asymmetrical dimethylarginine levels decreased by 21.7%. On the contrary, in group 1 patients, treated with placebo, no changes were shown in any of the variables. CONCLUSIONS: Folate and vitamin B12 treatment improved insulin resistance and endothelial dysfunction, along with decreasing homocysteine levels, in patients with metabolic syndrome, suggesting that folic acid has several beneficial effects on cardiovascular disease risk factors.

Eur J Nutr. 2004 Oct;43(5):285-7. Epub 2004 Jan 06.
Abnormal folic acid-homocysteine metabolism as maternal risk factors for Down syndrome in Japan.
Takamura N, Kondoh T, Ohgi S, Arisawa K, Mine M, Yamashita S, Aoyagi K.
Dept. of Public Health, Nagasaki University, Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan, takamura@net.nagasaki-u.ac.jp.

BACKGROUND:. Japan has been considered as "a folate sufficient area", since traditional Japanese food contains an adequate amount of folic acid. However, the recent westernized food style of young Japanese mothers may affect the intake of folic acid among them. This food style may contribute to the occurrence of Down syndrome, which has proved to be linked to abnormal folate and homocysteine metabolisms. AIM OF THE STUDY:. To preliminarily evaluate the levels of folic acid,homocysteine and other relevant factors which are associated with folate metabolism, among Japanese women who had pregnancies affected by Down syndrome. METHODS:. Blood samples from 31 women who had pregnancies affected by Down syndrome (DS) were obtained. 60 age-matched control blood samples were also obtained from mothers who had not experienced miscarriages or abnormal pregnancies (CONT). Plasma homocysteine and serum folic acid, vitamin B12, and B6 were measured and compared between DS and CONT. Furthermore, the frequency of MTHFR polymorphism (C677T) was also investigated. RESULTS:. Plasma levels of homocysteine were significantly increased in DS mothers (p = 0.004). In contrast, serum levels of folic acid were significantly decreased in DS mothers (p = 0.0001). There were no significant differences in the vitamin B12 and B6 levels between DS and CONT. Also, the frequency of 5,10-methylenetetrahydrofolate reductase gene (MTHFR) homozygous polymorphism showed no differences between DS and CONT. CONCLUSION:. Different levels of serum folic acid and plasma homocysteine between both groups may contribute to the occurrence of Down syndrome even in Japan. Although there was no significant difference in the frequency of MTHFR polymorphism between the groups, probably because of an inadequate number of samples, further studies may contribute to the understanding of the occurrence of Down syndrome in Japan.

Hum Psychopharmacol. 2004 Oct;19(7):477.
Folic acid: neurochemistry, metabolism and relationship to depression.
Paul RT, McDonnell AP, Kelly CB.
Department of Mental Health, Queen's University Belfast, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland.

The associations of folic acid and its derivatives with depressive disorder are reviewed. Derivatives of folic acid such as biopterins and the synthesis of S-adenosyl methionine (SAM) are known either to be associated with improvement or to have a direct therapeutic effect in depressive disorder. Studies investigating plasma and red cell folic acid levels in depressed patients have used differing assay methodologies which make comparison difficult, although there is substantial evidence of the association between depressive disorder (particularly severe depression) and low folic acid levels. The few studies available suggest folic acid has either antidepressant properties or can act as an augmenting agent for standard antidepressant treatment. A recently discovered genetic variant (5,10 MTHFR) leading to altered folic acid metabolism may explain why some individuals are vulnerable to the effects of folic acid deficiency, despite adequate intake. The links of 5,10 MTHFR to the presence of depressive disorder in the community are being investigated. Copyright (c) 2004 John Wiley & Sons, Ltd.

Int J Biochem Cell Biol. 2004 Oct;36(10):1919-32.
Vitamin C or Vitamin B6 supplementation prevent the oxidative stress and decrease of prostacyclin generation in homocysteinemic rats.
Mahfouz MM, Kummerow FA.
The H.E. Moore Heart Research Foundation, Champaign, IL 61820, USA.

We hypothesize that homocysteinemia causes oxidative stress, decreases the aortic ability to generate prostacyclin and that antioxidants have a protective role. Four groups of eight rats each were fed for 8 weeks the control diet (group A), control diet with folic acid omitted and excess methionine (Me) added to drinking water (group B), diet B + 500 mg/kg of Vitamin C (group C) or diet B + 60 mg/kg Vitamin B6 (group D). The three groups of rats fed folic acid deficient (FD) diets (groups B, C and D) were homocysteinemic as indicated by the significant increase in their serum homocysteine (HC) concentration. Rats fed diet B had oxidative stress as indicated by an increase in serum thiobarbituric acid reactive substances (TBARS) and advanced oxidation protein products (AOPP) and urinary isoprostanes and had a decreased ability of their aortas to generate prostacyclin. Homocysteinemic rats fed a FD diet + Vitamin C (group C) or Vitamin B6 (group D) also had high levels of serum homocysteine but the oxidative stress markers and the ability of their aortas to generate prostacyclin returned to normal. This indicates that the homocysteinemic effect is through an oxidative mechanism and that Vitamin C as a free radical scavenger prevents these effects. Serum Vitamin C and liver glutathione concentrations significantly increased in rats fed excess Vitamin B6 compared to the control or FD rats. This may explain why Vitamin B6 has an antioxidative effect.

Rheumatology (Oxford). 2004 Jan 6 [Epub ahead of print].
Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review.
Whittle SL, Hughes RA.
Department of Rheumatology, Ashford & St Peters NHS Trust, Chertsey, UK.

OBJECTIVES: The folate antagonist methotrexate (MTX) has become established as the most commonly used disease-modifying anti-rheumatic drug (DMARD) in the treatment of rheumatoid arthritis (RA) but is commonly discontinued due to adverse effects. Adverse effects are thought to be mediated via folate antagonism. In this paper we summarize the current data on the use of folates as a supplement to MTX use in RA for the prevention of adverse effects and as a potential modulator of cardiovascular risk, and propose guidelines for standard practice. METHODS: A Medline search was performed using the search terms 'methotrexate', 'folic acid', 'folinic acid', 'folate' and 'homocysteine'. Literature relevant to the use of folates as a supplement to MTX in the treatment of RA was reviewed and other papers referred to as references were explored. RESULTS: The use of supplemental folates, including folic and folinic acid, in RA patients treated with MTX has been shown to improve continuation rates by reducing the incidence of liver function test abnormalities and gastrointestinal intolerance. Folate supplements do not appear to significantly reduce the effectiveness of MTX in the treatment of RA. Furthermore, supplemental folic acid offsets the elevation in plasma homocysteine associated with the use of MTX. This may in turn reduce the risk of cardiovascular disease, which is over-represented amongst patients with RA, and for which hyperhomocysteinaemia is now recognized as an independent risk factor. CONCLUSIONS: We propose that folic acid supplements be prescribed routinely to all patients receiving MTX for the treatment of RA. We recommend a pragmatic dosing schedule of 5 mg of oral folic acid given on the morning following the day of MTX administration.

Proc Nutr Soc. 2003 Aug;62(3):591-8.
Is there more to folates than neural-tube defects?
Finglas PM, Wright AJ, Wolfe CA, Hart DJ, Wright DM, Dainty JR.
Nutrition Department, Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, UK.

The purpose of the present paper is to review our current understanding of the chemistry and biochemistry of folic acid and related folates, and to discuss their impact on public health beyond that already established in relation to neural-tube defects. Our understanding of the fascinating world of folates and C1 metabolism, and their role in health and disease, has come a long way since the discovery of the B-vitamin folic acid by Wills (1931), and its first isolation by Mitchell et al. (1941). However, there is still much to do in perfecting methods for the measurement of folate bioavailability, and status, with a high extent of precision and accuracy. Currently, examination of the relationships between common gene polymorphisms involved in C1 metabolism and folate bioavailability and folate status, morbidity, mortality and longevity is evaluated as a series of individual associations. However, in the future, examination of the concurrent effects of such common gene polymorphisms may be more beneficial.

J Obstet Gynaecol Can. 2003 Nov;25(11):959-73.
Wilson RD, Davies G, Desilets V, Reid GJ, Summers A, Wyatt P, Young D.
The use of folic Acid for the prevention of neural tube defects and other congenital anomalies.
To provide information regarding the use of folic acid for the prevention of neural tube defects (NTDs) and other congenital anomalies, in order that physicians, midwives, nurses, and other health-care workers can assist in the education of women in the preconception phase of their health care. OPTION: Folic acid supplementation is problematic, since 50% of pregnancies are unplanned and the health status of women may not be optimal.: Folic acid supplementation has been proven to decrease or minimize specific birth defects. A systematic review of the literature, including review and peer-reviewed articles, government publications, the previous Society of Obstetricians and Gynaecologists of Canada (SOGC) Policy Statement of March 1993, and statements from the American College of Obstetrics and Gynecology, was used to develop a new clinical practice guideline for the SOGC. VALUES: Peer-review process within the committee structure. The benefit is reduced lethal and severe morbidity birth defects and the harm is minimal. The personal cost is of vitamin supplementation on a daily basis and eating a healthy diet. RECOMMENDATIONS:1. Women in the reproductive age group should be advised about the benefits of folic acid supplementation during wellness visits (birth control renewal, Pap testing, yearly examination), especially if pregnancy is contemplated. (III-A) 2. Women should be advised to maintain a healthy nutritional diet, as recommended in Canada's Food Guide to Healthy Eating (good or excellent sources of folic acid: broccoli, spinach, peas, Brussels sprouts, corn, beans, lentils, oranges). (III-A) 3. Women who could become pregnant should be advised to take a multivitamin containing 0.4 mg to 1.0 mg of folic acid daily. (II-1A) 4. Women taking a multivitamin with folic acid supplement should be advised not to take more than 1 daily dose of vitamin supplement, as indicated on the product label. (II-2A) 5. Women in intermediate- to high-risk categories for NTDs (NTD-affected previous pregnancy, family history, insulin-dependent diabetes, epilepsy treatment with valproic acid or carbamazepine) should be advised that high-dose folic acid (4.0 mg-5.0 mg daily) supplementation is recommended. This should be taken as folic acid alone, not in a multivitamin format, due to risk of excessive intake of other vitamins such as vitamin A. (I-A) 6. The choice of a 5 mg folic acid daily dose for women considering a pregnancy should be made under medical supervision after minimizing the risk of undiagnosed vitamin B12 deficiency (hypersegmentation of polymorphonuclear cells, macrocystic indices, large ovalocytes, leukopenia, thrombocytopenia, markedly elevated lactate dehydrogenase level, confirmed red blood cell folate level). (II-2A) 7. Signs or symptoms of vitamin B12 deficiency should be considered before initiating folic acid supplementation of doses greater than 1.0 mg. (III-A) 8. A three-generation pedigree on the families of both the pregnant woman and the biological father should be obtained to identify increased risk for congenital birth defects (i.e., NTD, cardiac, chromosomal, genetic). (III-A) 9. Women who become pregnant should be advised of the availability of noninvasive screening tests and invasive diagnostic tests for congenital birth defects (including NTDs): maternal serum "triple marker screen" at 15 to 20 weeks, ultrasound at 16 to 20 weeks, and amniocentesis after 15 weeks of pregnancy if a positive screening test is present. (I-A) This is a revision of a previous guideline and information from other consensus reviews from medical and government publications has been used.

J Nutr. 2003 Nov;133(11):3492-8.
Supplementation with micronutrients in addition to iron and folic acid does not further improve the hematologic status of pregnant women in rural Nepal.
Christian P, Shrestha J, LeClerq SC, Khatry SK, Jiang T, Wagner T, Katz J, West KP Jr.
Center for Human Nutrition, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Iron deficiency is one of the main causes of anemia during pregnancy, although other micronutrient deficiencies may play a role. We examined the effects of daily antenatal and postnatal supplementation with four combinations of micronutrients on maternal hematologic indicators in a double-masked randomized controlled community trial. Communities, called sectors, were randomly assigned to supplementation with folic acid (400 microg), folic acid plus iron (60 mg), folic acid plus iron and zinc (30 mg) and folic acid plus iron, zinc and 11 other micronutrients, each at the approximate recommended daily allowance for pregnancy all given with vitamin A as retinol acetate (1000 microg retinol equivalent), or vitamin A alone as the control group. Hemoglobin (Hb) and indicators of iron status were assessed at baseline and at 32 wk of gestation. At 6-wk postpartum, Hb assessment was repeated using a finger stick. Severely anemic women (Hb < 70 g/L) were treated according to WHO recommendations. Folic acid alone had no effect on maternal anemia or iron status. Hb concentrations were 14 g/L, [95% confidence limits (CL), 8.3-19.2], 10.0 g/L (CL, 5.2-14.8) and 9.4 g/L (CL, 4.7-14.1) higher in the groups receiving folic acid plus iron, folic acid plus iron and zinc and folic acid plus iron, zinc and multiple micronutrients, respectively, relative to the control. Anemia in the third trimester was reduced by 54% with folic acid plus iron, by 48% with folic acid plus iron and zinc and by 36% with folic acid plus iron, zinc and multiple micronutrients supplementation, relative to the control (P < 0.05). Thus, the combinations of folic acid plus iron and zinc and folic acid plus iron, zinc and multiple micronutrients provided no additional benefit in improving maternal hematologic status during pregnancy compared with folic acid plus iron. The level of compliance and baseline Hb concentrations modified the effect of iron.

Eur J Clin Nutr. 2003 Nov;57(11):1411-7.
Folic acid supplement decreases the homocysteine increasing effect of filtered coffee. A randomised placebo-controlled study.
Strandhagen E, Landaas S, Thelle DS.
Department of Medicine, Cardiovascular Institute, Sahlgrenska University Hospital/Ostra, Goteborg, Sweden.

OBJECTIVE: Elevated levels of plasma total homocysteine (tHcy) are identified as independent risk factors for coronary heart disease and for fetal neural tube defects. tHcy levels are negatively associated with folic acid, pyridoxine and cobalamine, and positively associated with coffee consumption and smoking. A total of 600 ml of filtered coffee results in a tHcy increase that 200 mug of folic acid or 40 mg of pyridoxine supplementation might eliminate. DESIGN: Randomised, blinded study with two consecutive trial periods. SETTING: Free living population. Volunteers. SUBJECTS: A total of 121 healthy, nonsmoking men and women (78%) aged 29-65 y. INTERVENTIONS: (1) A coffee-free period of 3 weeks, (2) 600 ml coffee/day and a supplement of 200 mug folic acid/day or placebo for 4 weeks, (3) 3-week coffee-free period, (4) 600 ml coffee/day and 40 mg pyridoxine/day or placebo for 4 weeks. MAIN OUTCOME MEASURES: The difference between the change in tHcy in the supplement group and the change in tHcy in the placebo group during the 4-week trial period. RESULTS: Coffee abstention resulted in a tHcy decrease of 1.04 mumol/l for the whole group. In the subsequent coffee period, a further decrease of 0.17 mumol/l was observed in the folic acid group whereas an increase of 1.26 mumol/l was observed in the placebo group, the difference was 1.43 mumol/l (95% CI: 0.80, 2.07). Pyridoxine supplement had no impact on tHcy levels. CONCLUSIONS: Supplementation of 200 mug folic acid/day eliminates the tHcy increasing effect of 600 ml filtered coffee in subjects not already on folic acid supplements. A supplement of 40 mg pyridoxine/day does not have the same effect.

Ageing Res Rev 2002 Feb;1(1):95-111
Folic acid and homocysteine in age-related disease
Mattson MP, Kruman II, Duan W
Laboratory of Neurosciences, Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. mattsonm@grc.nia.nih.gov

It has been known for decades that babies born to women that have a dietary deficiency in folic acid (folate) are at increased risk for birth defects, and that the nervous system is particularly susceptible to such defects. Folate deficiency in adults can increase risk of coronary artery disease, stroke, several types of cancer, and possibly Alzheimer's and Parkinson's diseases. Recent findings have begun to reveal the cellular and molecular mechanisms whereby folate counteracts age-related disease. An increase in homocysteine levels is a major consequence of folate deficiency that may have adverse effects on multiple organ systems during aging. Humans with inherited defects in enzymes involved in homocysteine metabolism, including cystathionine beta-synthase and 5,10-methylenetetrahydrofolate reductase, exhibit features of accelerated aging and a marked propensity for several age-related diseases. Homocysteine enhances accumulation of DNA damage by inducing a methyl donor deficiency state and impairing DNA repair. In mitotic cells such DNA damage can lead to cancer, while in postmitotic cells such as neurons it promotes cell death. The emerging data strongly suggest that elevated homocysteine levels increase the risk of multiple age-related diseases, and point to dietary supplementation with folate as a primary means of normalizing homocysteine levels and increasing healthspan.

Dement Geriatr Cogn Disord 2002;13(4):225-34
Serum folate levels and subsequent adverse cerebrovascular outcomes in elderly persons
Maxwell CJ, Hogan DB, Ebly EM
Department of Community Health Sciences, Medicine, University of Calgary, Alta, Canada

Recent epidemiologic studies have shown an association between low serum folate levels and risk of vascular disease, including stroke and various types of vascular cognitive impairment. We examined data from the Canadian Study of Health and Aging (CSHA), a population-based, prospective 5-year investigation of the epidemiology of dementia among Canadians aged 65+ years. The risk of an adverse cerebrovascular event (including vascular dementia, vascular cognitive impairment, or fatal stroke) during follow-up, was assessed according to serum folate quartiles among subjects with no evidence of dementia at baseline (n = 369). After adjusting for certain covariates, including cardiovascular disease and nutritional indices, education, smoking and baseline cognitive status, the risk estimate for an adverse cerebrovascular event associated with the lowest folate quartile compared with the highest quartile was OR 2.42 (95% CI 1.04-5.61). Results from stratified analyses also showed that relatively low serum folate was associated with a significantly higher risk of an adverse cerebrovascular event among female (OR 4.02, 95% CI 1.37-11.81) but not male (OR 1.02, 95% CI 0.25-4.13) subjects. Among the total sample, there was a consistent trend toward poorer health and cognitive outcomes during follow-up (including mortality, cognitive decline and dementia) among those in the lowest folate quartile compared with the highest quartile. Low serum folate levels are independently associated with a significantly higher risk of an adverse cerebrovascular event, including vascular dementia and stroke death, among older, cognitively vulnerable persons.