Together with vitamins B12 and B6, folic acid has been shown to reduce high plasma levels of homocysteine. Of the three, folate appears to have the strongest activity (Voutilainen et al 2001). Although elevated homocysteine has been implicated as a risk factor in cardiovascular disease (including atherosclerosis and coronary artery disease), cerebrovascular disease, peripheral vascular disease and venous thromboembolism (Clarke et al 1991, den Heijer 1996, Malinow et al 1989, Selhub 1995), exudative age-related macular degeneration, noise-related hearing loss, cognitive dysfunction, and adverse pregnancy outcomes (Gok et al 2004, Nowak et al 2005), cognitive dysfunction, and adverse pregnancy outcomes (Bjorke Monsen & Ueland 2003), clinical trials are currently underway to determine the clinical relevance of this association.
Cardiovascular protection Although folate adequacy remains protective against primary cardiovascular disease it may not be a useful intervention in those patients with established disease. In spite of promising results from earlier studies (Hendler & Rorvik 2001, Verhaar et al 2002), lowering homocysteine levels failed to exert a significant protective effect against cardiovascular events in a large study of 3749 men and women post-infarction. Combinations of 800 fjg of folate, 400 fjg B12 and 40 mg B6 were used in the 40-month study and appeared to increase risk (RR 1.22) (Bonaa et al 2006).
Alzheimer's dementia and impaired cognitive function in the elderly Findings such as the prevalence of folate deficiency in the elderly, increasing homocysteine levels with age and evidence of an inverse relationship total plasma homocysteine levels and cognitive function have attracted attempts to link the phenomena and provide an explanation for neuropsychiatry disorders in this population.
Currently, an abundance of epidemiological evidence and a limited number of studies have shown a positive correlation between folate status and dementia. For example, a 2002 review has estimated that 71 % of medical patients admitted acutely to hospital with severe folate deficiency have been observed with organic brain syndrome compared with 31% of controls (Reynolds 2002).
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A 2003 Cochrane review examined the effects of folic acid supplementation, with or without vitamin B12, in elderly healthy and demented people, in preventing cognitive impairment or retarding its progress (Malouf et al 2003). The review analysed data from four RCTand concluded that there was no beneficial effect of 750 fjg of folic acid/day on measures of cognition or mood in older healthy or cognitively impaired people. It also noted that the available studies are limited in size and scope and more studies are needed.
Renal transplant recipients Combination vitamin B treatment (folate, B12 and B6) may be of benefit in renal transplant patients, according to a RCT of 56 renal transplant patients, which found that vitamin supplementation with folic acid (5 mg/day), vitamin B6 (50 mg/day) and vitamin B12 (400 fjg/day] for 6 months reduced the progression of atherosclerosis, as evidenced by a significant decrease in carotid intima-média thickness. Additionally, a significant decrease in homocysteine levels was observed (Marcucci et al 2003).
Restenosis after percutaneous coronary intervention A RCT found that treatment with vitamin B12 (cyanocobalamin 400^g/day), folic acid (1 mg/day) and vitamin B6 (pyridoxine hydrochloride 10 mg/day) for 6 months significantly decreased the incidence of major adverse events, including restenosis, after percutaneous coronary intervention (Schnyder et al 2002). In contrast, a more recent trial demonstrated an increased risk of in-stent restenosis in those patients intravenously administered 1 mg of folic acid, 5 mg of vitamin B6, and 1 mg of vitamin B12 followed by daily oral doses of 1.2 mg of folic acid, 48 mg of vitamin B6, and 60 fjg of vitamin B12 for 6 months (Lange et al 2004). Further research with more consistent study designs are required to elucidate the true effects. Recurrent spontaneous miscarriage Maternal hyperhomocysteinemia and poor folate status are risk factors for recurrent embryo loss and for a first early embryo loss (George et al 2002). There has also been conflicting evidence in relation to the role of MTHFR polymorphism and pregnancy, although many studies point towards increased risk of recurrent spontaneous abortion. One explanation for the discrepant results may be that the numbers of study participants have been relatively small (Zetterberg 2004). Although researchers encourage the periconceptional use of both folate and B12 to reduce these risks, there is a lack of interventional studies in this area.
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