Vitamin B12, Folic Acid, and the Prevention of Dementia
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《新英格兰医药杂志》
Finding treatments for the prevention of dementia is an important challenge for medical research.1 Dementia currently affects about 4.5 million persons in the United States, and many more have cognitive impairment. The disorder is characterized by an insidious and progressive loss of memory and higher intellectual function, which ultimately leads to the inability of affected persons to live independently. The population distribution of cognitive impairment shows a continuum of severity, with dementia at one extreme of the distribution.1 Longitudinal, population-based studies of people who are 70 years of age or older show that cognitive function declines abruptly and irreversibly at a younger age in some persons but remains intact in others until very old age.
The variability in the age at onset of dementia and the pattern of cognitive decline suggests that the condition is not an intrinsic feature of aging. One hypothesis is that it may arise in response to an event that interrupts blood supply to a critical region of the brain and triggers the onset of the disorder in susceptible persons. In 1998,2 my colleagues and I reported that patients with histologically confirmed Alzheimer's disease had higher concentrations of serum total homocysteine, a sulfur-containing amino acid previously linked to a risk of cardiovascular disease,3 as compared with age-matched controls, and postulated the "homocysteine hypothesis" of dementia. However, case–control studies are unable to rule out the possibility that the observed associations are due to the disease rather than being causal.2 More convincing evidence in support of the hypothesis was provided by an eight-year follow-up of 1092 dementia-free elderly participants in the Framingham study, which reported that persons with elevated homocysteine concentrations (>14 μmol per liter) had twice the risk of dementia, as compared with persons with lower homocysteine concentrations.4 Additional evidence was provided by the Rotterdam Scan Study — a population-based study of dementia-free elderly persons — which reported that elevated homocysteine concentrations were significantly and positively associated with radiologic evidence of white-matter lesions, silent brain infarcts,5 and atrophy of the cerebral cortex and hippocampus,6 in addition to being associated with cognitive impairment.7 Since homocysteine concentrations are easily lowered by dietary supplementation with folic acid and vitamin B12,8 it was suggested that these vitamins might prevent the onset of dementia.2
In this issue of the Journal, McMahon et al.9 report on the results of a trial examining the effects on cognitive function of homocysteine-lowering vitamin supplements in healthy elderly people. The trial involved 276 dementia-free persons in New Zealand who were randomly assigned to receive either a daily dietary supplement containing folate (1000 μg), vitamin B12 (500 μg), and vitamin B6 (10 mg) or placebo for a two-year period. Participants had a comprehensive assessment of cognitive function, including the Mini–Mental State Examination scores that assess global cognitive function, before and after treatment. Vitamin supplementation lowered plasma total homocysteine concentrations but had no detectable effects on cognitive function. The authors concluded that they could not provide support for the hypothesis that the lowering of homocysteine concentrations with B vitamins improved cognitive performance. However, since the trial included too few participants, the duration of treatment was too short, and cognitive-function scores in controls remained intact throughout the trial, it lacked the statistical power to refute the homocysteine hypothesis of dementia.
Randomized evidence for the effects of three to seven years of treatment with B vitamins on cognitive function should eventually be available on about 20,000 of the 50,000 participants with previous cardiovascular or renal disease in the 12 large homocysteine-lowering trials for the prevention of cardiovascular events.10 A meta-analysis of these trials, designed to have power sufficient to assess the relevance of B vitamins for the prevention of cardiovascular events, could also provide reliable evidence for the relevance of B vitamins for the maintenance of cognitive function.10
In 1998, the Department of Agriculture introduced mandatory fortification of all grain products with folic acid at a dose of 140 μg per 100 g of grain.11 The prevalence of low serum folate has decreased from a range of 16 to 22 percent before the fortification program to 0.5 to 1.7 percent after fortification; the actual level of fortification is about double what was originally intended.11 Concern has been expressed about the safety of such fortification in older people who have vitamin B12 deficiency, since persons with low vitamin B12 status appear to have a more rapid deterioration of cognitive function in the setting of a high intake of folate.12 Concern about the possible adverse effects of a high intake of folic acid on neurologic function in people with vitamin B12 deficiency has delayed the introduction of mandatory folic acid fortification in the United Kingdom. Vitamin B12 deficiency is common in older people, and the prevalence increases from about 5 percent at 65 years of age to 20 percent at the age of 80 years.13 Vitamin B12 is a more important determinant of elevated homocysteine concentrations in older people than is folate.13 Studies of older people indicate that only a small proportion of those identified with biochemical evidence of vitamin B12 deficiency have anemia or neuropathy or cognitive impairment.14
The Scientific Advisory Committee on Nutrition in the United Kingdom recognized that vitamin B12 deficiency is an important public health issue for older people and that a management strategy should be assessed, regardless of whether mandatory folic acid fortification is introduced.15 However, none of the large homocysteine-lowering trials for the prevention of cardiovascular events10 can distinguish the independent effects of vitamin B12 from those of folic acid. To address the treatment of the elderly population with biochemical evidence of vitamin B12 deficiency in the absence of symptoms, additional randomized evidence should be sought for the effects of daily oral dietary supplementation with 1000 μg of vitamin B12 in persons 70 years of age or older in the absence of previous vascular disease, anemia, or cognitive impairment. In addition to testing the relevance of vitamin B12 for the maintenance of cognitive function in a high-risk older population, trials adopting a factorial design could simultaneously assess the efficacy of other practicable treatments for the prevention of dementia and inform strategies for healthy aging.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford, United Kingdom.
References
Cummings JL. Alzheimer's disease. N Engl J Med 2004;351:56-67.
Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998;55:1449-1455.
Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991;324:1149-1155.
Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 2002;346:476-483.
Vermeer SE, van Dijk EJ, Koudstaal PJ, et al. Homocysteine, silent brain infarcts, and white matter lesions: the Rotterdam Scan Study. Ann Neurol 2002;51:285-289.
den Heijer T, Vermeer S, Clarke R, et al. Homocysteine and brain atrophy on MRI of non-demented elderly. Brain 2003;126:170-175.
Prins ND, Den Heijer T, Hofman A, et al. Homocysteine and cognitive function in the elderly: the Rotterdam Scan Study. Neurology 2002;59:1375-1380.
Homocysteine Lowering Trialists' Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr 2005;82:806-812.
McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, Williams SM. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med 2006;354:2764-2772.
B-Vitamin Treatment Trialists' Collaboration. Homocysteine-lowering trials for prevention of cardiovascular events: a review of the design and power of the large randomized trials. Am Heart J 2006;151:282-287.
Pfeiffer CM, Caudill SP, Gunter EW, Osterloh J, Sampson EJ. Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999-2000. Am J Clin Nutr 2005;82:442-450.
Morris MC, Evans DA, Bienias JL, et al. Dietary folate and vitamin B12 intake and cognitive decline among community-dwelling older persons. Arch Neurol 2005;62:641-645.
Clarke R, Grimley Evans J, Schneede J, et al. Vitamin B12 and folate deficiency in later life. Age Ageing 2004;33:34-41.
Hin H, Clarke R, Sherliker P, et al. Clinical relevance of low serum vitamin B12 concentrations in older people: Banbury B12 Study. Age Ageing 2006;35:416-422.
Department of Health. Folate and disease prevention. London: Scientific Advisory Committee on Nutrition, 2006.(Robert Clarke, M.D.)
The variability in the age at onset of dementia and the pattern of cognitive decline suggests that the condition is not an intrinsic feature of aging. One hypothesis is that it may arise in response to an event that interrupts blood supply to a critical region of the brain and triggers the onset of the disorder in susceptible persons. In 1998,2 my colleagues and I reported that patients with histologically confirmed Alzheimer's disease had higher concentrations of serum total homocysteine, a sulfur-containing amino acid previously linked to a risk of cardiovascular disease,3 as compared with age-matched controls, and postulated the "homocysteine hypothesis" of dementia. However, case–control studies are unable to rule out the possibility that the observed associations are due to the disease rather than being causal.2 More convincing evidence in support of the hypothesis was provided by an eight-year follow-up of 1092 dementia-free elderly participants in the Framingham study, which reported that persons with elevated homocysteine concentrations (>14 μmol per liter) had twice the risk of dementia, as compared with persons with lower homocysteine concentrations.4 Additional evidence was provided by the Rotterdam Scan Study — a population-based study of dementia-free elderly persons — which reported that elevated homocysteine concentrations were significantly and positively associated with radiologic evidence of white-matter lesions, silent brain infarcts,5 and atrophy of the cerebral cortex and hippocampus,6 in addition to being associated with cognitive impairment.7 Since homocysteine concentrations are easily lowered by dietary supplementation with folic acid and vitamin B12,8 it was suggested that these vitamins might prevent the onset of dementia.2
In this issue of the Journal, McMahon et al.9 report on the results of a trial examining the effects on cognitive function of homocysteine-lowering vitamin supplements in healthy elderly people. The trial involved 276 dementia-free persons in New Zealand who were randomly assigned to receive either a daily dietary supplement containing folate (1000 μg), vitamin B12 (500 μg), and vitamin B6 (10 mg) or placebo for a two-year period. Participants had a comprehensive assessment of cognitive function, including the Mini–Mental State Examination scores that assess global cognitive function, before and after treatment. Vitamin supplementation lowered plasma total homocysteine concentrations but had no detectable effects on cognitive function. The authors concluded that they could not provide support for the hypothesis that the lowering of homocysteine concentrations with B vitamins improved cognitive performance. However, since the trial included too few participants, the duration of treatment was too short, and cognitive-function scores in controls remained intact throughout the trial, it lacked the statistical power to refute the homocysteine hypothesis of dementia.
Randomized evidence for the effects of three to seven years of treatment with B vitamins on cognitive function should eventually be available on about 20,000 of the 50,000 participants with previous cardiovascular or renal disease in the 12 large homocysteine-lowering trials for the prevention of cardiovascular events.10 A meta-analysis of these trials, designed to have power sufficient to assess the relevance of B vitamins for the prevention of cardiovascular events, could also provide reliable evidence for the relevance of B vitamins for the maintenance of cognitive function.10
In 1998, the Department of Agriculture introduced mandatory fortification of all grain products with folic acid at a dose of 140 μg per 100 g of grain.11 The prevalence of low serum folate has decreased from a range of 16 to 22 percent before the fortification program to 0.5 to 1.7 percent after fortification; the actual level of fortification is about double what was originally intended.11 Concern has been expressed about the safety of such fortification in older people who have vitamin B12 deficiency, since persons with low vitamin B12 status appear to have a more rapid deterioration of cognitive function in the setting of a high intake of folate.12 Concern about the possible adverse effects of a high intake of folic acid on neurologic function in people with vitamin B12 deficiency has delayed the introduction of mandatory folic acid fortification in the United Kingdom. Vitamin B12 deficiency is common in older people, and the prevalence increases from about 5 percent at 65 years of age to 20 percent at the age of 80 years.13 Vitamin B12 is a more important determinant of elevated homocysteine concentrations in older people than is folate.13 Studies of older people indicate that only a small proportion of those identified with biochemical evidence of vitamin B12 deficiency have anemia or neuropathy or cognitive impairment.14
The Scientific Advisory Committee on Nutrition in the United Kingdom recognized that vitamin B12 deficiency is an important public health issue for older people and that a management strategy should be assessed, regardless of whether mandatory folic acid fortification is introduced.15 However, none of the large homocysteine-lowering trials for the prevention of cardiovascular events10 can distinguish the independent effects of vitamin B12 from those of folic acid. To address the treatment of the elderly population with biochemical evidence of vitamin B12 deficiency in the absence of symptoms, additional randomized evidence should be sought for the effects of daily oral dietary supplementation with 1000 μg of vitamin B12 in persons 70 years of age or older in the absence of previous vascular disease, anemia, or cognitive impairment. In addition to testing the relevance of vitamin B12 for the maintenance of cognitive function in a high-risk older population, trials adopting a factorial design could simultaneously assess the efficacy of other practicable treatments for the prevention of dementia and inform strategies for healthy aging.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford, United Kingdom.
References
Cummings JL. Alzheimer's disease. N Engl J Med 2004;351:56-67.
Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998;55:1449-1455.
Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991;324:1149-1155.
Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 2002;346:476-483.
Vermeer SE, van Dijk EJ, Koudstaal PJ, et al. Homocysteine, silent brain infarcts, and white matter lesions: the Rotterdam Scan Study. Ann Neurol 2002;51:285-289.
den Heijer T, Vermeer S, Clarke R, et al. Homocysteine and brain atrophy on MRI of non-demented elderly. Brain 2003;126:170-175.
Prins ND, Den Heijer T, Hofman A, et al. Homocysteine and cognitive function in the elderly: the Rotterdam Scan Study. Neurology 2002;59:1375-1380.
Homocysteine Lowering Trialists' Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr 2005;82:806-812.
McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, Williams SM. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med 2006;354:2764-2772.
B-Vitamin Treatment Trialists' Collaboration. Homocysteine-lowering trials for prevention of cardiovascular events: a review of the design and power of the large randomized trials. Am Heart J 2006;151:282-287.
Pfeiffer CM, Caudill SP, Gunter EW, Osterloh J, Sampson EJ. Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999-2000. Am J Clin Nutr 2005;82:442-450.
Morris MC, Evans DA, Bienias JL, et al. Dietary folate and vitamin B12 intake and cognitive decline among community-dwelling older persons. Arch Neurol 2005;62:641-645.
Clarke R, Grimley Evans J, Schneede J, et al. Vitamin B12 and folate deficiency in later life. Age Ageing 2004;33:34-41.
Hin H, Clarke R, Sherliker P, et al. Clinical relevance of low serum vitamin B12 concentrations in older people: Banbury B12 Study. Age Ageing 2006;35:416-422.
Department of Health. Folate and disease prevention. London: Scientific Advisory Committee on Nutrition, 2006.(Robert Clarke, M.D.)