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B Vitamins, Homocysteine, Heart Disease and Cognitive Function

By Katherine Tucker, PhD

There are many aspects of ageing which are generally accepted as part of the process - we slow down, have more aches and pains, have more trouble seeing well, and start to forget things. Although ageing is inevitable, the past few decades have witnessed exciting advances in scientific understanding which suggest that at least some of these functional declines may be prevented, or at least delayed, through health behaviours. Thousands of papers have documented the value of smoking avoidance, drinking in moderation, regular physical activity and good dietary practices for health maintenance. We continue to find new aspects of dietary intake that may contribute to optimal health. Recent research has emphasized the role of specific dietary fatty acids, antioxidant vitamins, a variety of phytochemicals, and an emerging understanding of the important role of B vitamins.

B Vitamins and Homocysteine

One relatively new and very promising area of research highlights the importance of B vitamins in the prevention of vascular disease. Several studies have shown consistent and strong relationships between low concentrations of blood folate, vitamin B12 and vitamin B6, and high concentrations of homocysteine which, in turn, have been linked with heart disease, stroke and other vascular outcomes. Homocysteine is an amino acid that is created as an intermediate product during the process of protein metabolism. The breakdown of homocysteine to cysteine requires the vitamin B6 dependent enzyme, cystathionine beta synthase. Re-methylation to methionine requires a vitamin B12 dependent enzyme, with folate as a cofactor. The most common cause of homocysteine accumulation, therefore, is deficiency or low availability of folate, vitamin B12 or vitamin B6. The strong relationships between these nutrients and homocysteine concentrations have been noted in several studies and were clearly demonstrated in the Framingham Heart Study cohort1.

Homocysteine and Heart Disease

Lowering high homocysteine is thought to be important because of its strong and consistent relationship with heart disease. In case-control, cross-sectional and prospective cohort studies, high homocysteine has been linked with occurrence and mortality from heart disease - as well as with indicators of heart disease risk, including thickening of the carotid arteries and venous thrombosis, A recent case control study in nine European countries estimated that the associated risk of vascular disease associated with high homocysteine was approximately twice that of those with normal levels for both men and women2. Although the evidence for homocysteine as a causal risk factor is strong, it remains possible that low folate or some other strongly associated factor is primarily responsible. More definitive proof of causation awaits randomized controlled trials, several of which are now ongoing. Assuming the likely causal association between high homocysteine and/or associated low B vitamins is true, it has the potential to have enormous population importance. In the Framingham Heart Study's original cohort (aged 67-96 years), 29% were found to have high homocysteine concentrations (>14 mmol/L) and 64% of these were attributed to low B vitamin status, particularly to low folate status1.

Folate

Folate, or folic acid, has been gaining increasing recognition worldwide due to its protective effect against neural tube defects. Based mainly on this concern, it has been recommended that all women of child bearing age should consume 400 mg of folate per day and, in the United States, cereal grain products have recently been fortified at the level of 140 mg/100 grams product. In light of evidence that low folate intakes may contribute to risk of vascular disease, through elevated levels of plasma homocysteine, increased intake of folic acid is likely to benefit a much wider segment of the population. A recent analysis of data from the Framingham Offspring (aged 30-59 years at time of measurement), showed that fortification of the US flour supply with folic acid cut the prevalence of high homocysteine (defined as >13 mmol/L for this younger group) in half-from 19% prior to fortification, to about 10% after fortification3. If either folate or homocysteine is causing the increased risk of heart disease, as the data suggest, then we can expect to see declines in heart disease associated with this improved nutritional status in the future.

In countries where nutrient intakes are generally poor, and where there is no enrichment or fortification with B vitamins, it may be expected that low B vitamin status and high homocysteine concentrations may be even more prevalent. Major sources of dietary folate include most fruit and vegetables, particularly orange juice, green leafy vegetables, banana, and legumes. In the United States, fortified breakfast cereals are also an important contribution to total dietary intakes of this vitamin. In the Framingham study, we found that intake of approximately seven servings of fruit and vegetables per day, or 6-7 servings of fortified breakfast cereal per week, were associated with folate intake at the recommended level of 400 mg/day4. These intake patterns were also associated with significantly lower homocysteine when compared with those with lower intakes of these foods. Dietary changes to increase folate intake -more fruits, vegetables, and fortified breakfast cereals, where available-would have additional benefits, associated with the wide variety of healthful nutrients and non-nutrient factors balanced in these foods. However, while good diets are advisable for everyone, the majority of the population is unlikely to achieve this level of intake without added fortification,

Vitamin B12

The question of diet improvement vs. supplementation or fortification is particularly relevant for the elderly population. While the benefit to folate status and homocysteine concentrations is clear, there has been some concern about the possible masking of vitamin B12 deficiency with increased intakes of folic acid. Although results are not consistent, some studies have shown improvement in indicators of anaemia, but worsening of vitamin B12 related neurologic status with administration of folic acid, usually at doses greater than 1 mg/day (1000 mg). If undetected and left untreated, some of the neurologic consequences of vitamin B12 deficiency, including peripheral neuropathy, gait disturbances and dementia, could become permanent. In addition to masking neurological symptoms, it has been suggested that high folic acid intake may also precipitate these manifestations in some patients with vitamin B12 deficiency. Although true pernicious anaemia is not common, recent data suggest that the prevalence of vitamin B12 deficiency and associated neurologic symptoms may be more widespread than previously thought, affecting persons even at levels formerly considered borderline normal and among patients without anaemia or macrocytosis5.

Common symptoms in patients with diagnosed vitamin B12 deficiency include decreased vibration sense, impaired sense of touch, memory loss and fatigue. Many of these neurologic symptoms have been shown to improve with vitamin B12 therapy5. Low vitamin B12 status may also contribute to dementia through both the toxic effects of homocysteine on blood vessels, and because vitamin B12 is required for the production of myelin basic protein needed for the protection of nerves. Vitamin B12 status is related to adequacy of dietary intake, but to a lesser extent than is folate status. Studies of vitamin B12 status among older adults have consistently identified large segments of the population as either deficient or "low normal" despite apparently adequate dietary intakes. In the Framingham offspring study, about 16% of the population had vitamin B12 concentrations low enough to be at risk of inadequate vitamin B12 status, despite intakes generally above recommendations6. Vitamin B12 is found in all animal products. However, because of the need for several steps in the separation of vitamin B12 from food protein and preparation for absorption, many older individuals with otherwise adequate intakes have difficulty absorbing vitamin B12, resulting in inadequate status. Common causes of vitamin B12 deficiency include atrophic gastritis, gastric or intestinal surgery, vegetarianism or persistent use of antacids. For this reason, the most recent dietary reference intakes suggest that most of the vitamin B12 obtained by individuals aged 50 years and above come from supplements or fortified foods, where the vitamin is in a form which is more bioavailable than that bound to protein in food. The reversal of cognitive and neurological symptoms after vitamin B12 therapy appears to be related to duration of symptoms, suggesting that early identification and treatment of vitamin B12 deficiency is of critical importance. With the increased emphasis on folic acid in the food supply, greater attention should also be given to the risks of inadequate vitamin B12 status and its health effects.

Vitamin B6

Most of the studies examining homocysteine have measured fasting concentrations, which appears to be most effectively lowered by folic acid, with additional lowering with vitamin B12 when the status of this nutrient is inadequate. The third vitamin associated with homocysteine, vitamin B6, has generally been shown to have less of an effect on fasting homocysteine concentrations. However, because it works through a different biochemical pathway, it does have a significant effect on homocysteine levels' post-methionine load, or on the time it takes to clear the increased homocysteine concentrations that occur after a protein meal. While more research is needed to determine if this more transitory elevation in homocysteine is a causal factor in heart disease, it is interesting to note that epidemiologic studies have identified associations between vitamin B6 status and indicators of heart disease which are independent of fasting homocysteine concentrations2. Good dietary sources of vitamin B6 include banana, avocado, beef, poultry, fish, green leafy vegetables, and whole grains. Dietary surveys regularly show that large proportions of the population have diets that are low in this vitamin.

Homocysteine And Cognitive Function

Most recently, there is growing interest in the association between homocysteine and cognitive decline. Because hyperhomocysteinemia has been recognized as an independent risk factor for cerebral, coronary, and peripheral vascular disease, it may also be expected to relate to cerebrovascular dementia. Not surprisingly, cerebrovascular diseases and other cardiovascular diseases have been associated with an increased risk of cognitive impairment. Furthermore, several studies have shown that patients with dementia of vascular cause tend to have significantly higher plasma homocysteine concentrations than those without history of vascular disease. In a study of ageing men in Massachusetts, plasma homocysteine, folate and vitamin B12 were each associated with higher scores on cognitive functioning, and higher concentrations of vitamin B6 were associated with better performance on memory tests7.

It is well known that severe deficiencies of B vitamins can result in dementia - including, most notably, thiamin, niacin and vitamin B12. However, it is only recently that there has been a focus on the possible effects of even milder deficiencies of these and other nutrients - with some evidence of association with impaired cognitive function even at the "low normal" blood concentrations and dietary intakes. Although associations between homocysteine and cognitive impairment have theoretical support, most available data are cross-sectional and cannot, therefore, prove a causal relationship between nutritional status and cognitive function. In addition to evidence for a link with vascular dementia, elevated homocysteine concentrations and lower levels of folate and vitamin B12 have also been reported in Alzheimer's patients when compared with controls8. This, however, does not answer the question of whether the elevation in homocysteine is responsible for some of the cognitive impairments or whether it is a result of the impairment - through poorer diets or other mechanisms. More evidence of a causal direction is offered by the observation that in genetic disorders of methionine metabolism leading to high homocysteine, young individuals develop cerebrovascular disease and cognitive impairment. This suggests that the impairment is likely to be caused by elevated homocysteine or other closely associated factor. Still, the mechanisms of action for the effect of homocysteine on vascular disease remain unproven and it may be that the inadequacy of one or more of the vitamins, or even some other highly correlated factor, is primarily responsible for the vascular disease association.

There are a number of mechanisms by which elevated levels of homocysteine may cause cognitive impairment. Homocysteine is thought to cause abnormal adhesion of platelets to the endothelial wall (clotting) through a direct effect on the vessel wall. It may also have neurotoxic effects, leading to cell death. In one longitudinal study, higher homocysteine concentrations in Alzheimer's patients were associated with greater progression of brain atrophy as measured by medial temporal lobe thickness, as well as a similar (although non-significant) declines in cognitive test scores8.

Homocysteine has also been proposed to affect vascular systems through the promotion of oxidative damage and the enhancement of chronic inflammation. In addition to the effects of homocysteine, low concentrations of these B vitamins may also inhibit methylation reactions which may affect nerve myelin, neurotransmitters and membrane structures, which in turn, may lead to neuropathology and cognitive effects9. While these hypothesized mechanisms are plausible, research in this area remains limited, but is rapidly gaining attention.

Conclusion

The past decade has seen a new appreciation of the importance of folate, vitamin B12 and vitamin B6 to human health. Their association with homocysteine is clear. The evidence for an important role in the prevention of heart disease is becoming clearer, Ongoing clinical trials should provide further evidence of the causal nature of these relationships. A variety of mechanisms have been proposed to explain these associations and the next few years should offer more answers to these questions as well. An important result of this work is the realization that "low normal" intakes and blood concentrations may result in health impairments, suggesting that dietary intakes and clinical cutoff points should be higher than those used in the past. To date, much less work has been done to understand the possible roles of these vitamins in the prevention of cognitive decline. Initial associations look promising and hypothesized vascular and neurologic mechanisms associated with homocysteine and/or individual B vitamins are plausible. This is an exciting area of research that offers hope for future intervention to improve the quality of life of the ageing population.

References

1.

Selhub J, Jacques PF, Wilson PWF, Rush D, Rosenberg IH (1993) Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA. 270:2693-2698.



2.

Verhoef P, Meleady R, Daly LE, Graham IM, Robinson K, Boers GHJ, et al. (1999) Homocysteine, vitamin status and risk of vascular disease. European Heart Journal. 20:1234-1244.



3.

Jacques PJ, Selhub J, Bostom AG, Wilson PWF, Rosenberg IH (1999) The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med. 340:1449-1454.



4.

Tucker KL, Selhub J, Wilson PWD, Rosenberg IH (1996) Dietary intake pattern relates to plasma folate and homocysteine concentrations in the Framingham Heart Study. J Nutr. 125:3025-3031.



5.

Lindenbaum J, Healton EG, Savage DG, Brust JCM, Garrett TJ, Podell ER, et al. (1988) Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med. 318:1720-1728.



6.

Tucker KL, Rich S, Rosenberg IH, Jacques P, Wilson PWF, Dallal G, et al. (in press) Prevalent low vitamin B12 concentrations are associated with intake sources: the Framingham offspring study.



7.

Riggs KM, Spiro Al, Tucker K, Rush D (1996) Relations of vitamin B12, vitamin B6, folate and homocysteine to cognitive performance in the Normative Aging Study. Am J Clin Nutr. 63:306-314.



8.

Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM (1998) Folate, vitamin B12 and serum total homocysteine levels in confirmed Alzheimer's disease. Arch Neurol. 55:1449-1455.



9.

Rosenberg IH. Miller JW (1992) Nutritional factors in physical and cognitive functions of elderly people. Am J Clin Nutr. 55:1237S-1243S.


Dr Katherine Tucker, Epidemiology program, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, 711 Washington St, Boston MA 02111 USA; tel 617 556 3351; fax 617 556 3344; email tucker@hnrc.tufts.edu


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