Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification.
Journal: 2007/February - American Journal of Clinical Nutrition
ISSN: 0002-9165
PUBMED: 17209196
Abstract:
BACKGROUND
Historic reports on the treatment of pernicious anemia with folic acid suggest that high-level folic acid fortification delays the diagnosis of or exacerbates the effects of vitamin B-12 deficiency, which affects many seniors. This idea is controversial, however, because observational data are few and inconclusive. Furthermore, experimental investigation is unethical.
OBJECTIVE
We examined the relations between serum folate and vitamin B-12 status relative to anemia, macrocytosis, and cognitive impairment (ie, Digit Symbol-Coding score < 34) in senior participants in the 1999-2002 US National Health and Nutrition Examination Survey.
METHODS
The subjects had normal serum creatinine concentrations and reported no history of stroke, alcoholism, recent anemia therapy, or diseases of the liver, thyroid, or coronary arteries (n = 1459). We defined low vitamin B-12 status as a serum vitamin B-12 concentration < 148 pmol/L or a serum methylmalonic acid concentration>> 210 nmol/L-the maximum of the reference range for serum vitamin B-12-replete participants with normal creatinine.
RESULTS
After control for demographic characteristics, cancer, smoking, alcohol intake, serum ferritin, and serum creatinine, low versus normal vitamin B-12 status was associated with anemia [odds ratio (OR): 2.7; 95% CI: 1.7, 4.2], macrocytosis (OR: 1.8; 95% CI: 1.01, 3.3), and cognitive impairment (OR: 2.5; 95% CI: 1.6, 3.8). In the group with a low vitamin B-12 status, serum folate>> 59 nmol/L (80th percentile), as opposed to < or = 59 nmol/L, was associated with anemia (OR: 3.1; 95% CI: 1.5, 6.6) and cognitive impairment (OR: 2.6; 95% CI: 1.1, 6.1). In the normal vitamin B-12 group, ORs relating high versus normal serum folate to these outcomes were < 1.0 (P(interaction) < 0.05), but significantly < 1.0 only for cognitive impairment (0.4; 95% CI: 0.2, 0.9).
CONCLUSIONS
In seniors with low vitamin B-12 status, high serum folate was associated with anemia and cognitive impairment. When vitamin B-12 status was normal, however, high serum folate was associated with protection against cognitive impairment.
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Am J Clin Nutr 85(1): 193-200

Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification<sup><a href="#FN1" rid="FN1" class=" fn">1</a>,</sup><sup><a href="#FN2" rid="FN2" class=" fn">2</a>,</sup><sup><a href="#FN3" rid="FN3" class=" fn">3</a>,</sup><sup><a href="#FN4" rid="FN4" class=" fn">4</a></sup>

Abstract

Background

Historic reports on the treatment of pernicious anemia with folic acid suggest that high-level folic acid fortification delays the diagnosis of or exacerbates the effects of vitamin B-12 deficiency, which affects many seniors. This idea is controversial, however, because observational data are few and inconclusive. Furthermore, experimental investigation is unethical.

Objective

We examined the relations between serum folate and vitamin B-12 status relative to anemia, macrocytosis, and cognitive impairment (ie, Digit Symbol-Coding score <34) in senior participants in the 1999–2002 US National Health and Nutrition Examination Survey.

Design

The subjects had normal serum creatinine concentrations and reported no history of stroke, alcoholism, recent anemia therapy, or diseases of the liver, thyroid, or coronary arteries (n = 1459). We defined low vitamin B-12 status as a serum vitamin B-12 concentration <148 pmol/L or a serum methylmalonic acid concentration >210 nmol/L—the maximum of the reference range for serum vitamin B-12–replete participants with normal creatinine.

Results

After control for demographic characteristics, cancer, smoking, alcohol intake, serum ferritin, and serum creatinine, low versus normal vitamin B-12 status was associated with anemia [odds ratio (OR): 2.7; 95% CI: 1.7, 4.2], macrocytosis (OR: 1.8; 95% CI: 1.01, 3.3), and cognitive impairment (OR: 2.5; 95% CI: 1.6, 3.8). In the group with a low vitamin B-12 status, serum folate ≤59 nmol/L (80th percentile), as opposed to ≤59 nmol/L, was associated with anemia (OR: 3.1; 95% CI: 1.5, 6.6) and cognitive impairment (OR: 2.6; 95% CI: 1.1, 6.1). In the normal vitamin B-12 group, ORs relating high versus normal serum folate to these outcomes were <1.0 (Pinteraction <0.05), but significantly <1.0 only for cognitive impairment (0.4; 95% CI: 0.2, 0.9).

Conclusion

In seniors with low vitamin B-12 status, high serum folate was associated with anemia and cognitive impairment. When vitamin B-12 status was normal, however, high serum folate was associated with protection against cognitive impairment.

Keywords: Aging, anemia, cognition disorders, folate, fortified food, nutrition surveys, vitamin B-12 deficiency
Abstract

Footnotes

From the Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA.

Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views or policies of the US Department of Agriculture, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.

Supported by USDA agreement no. 58-1950-9-001 and NIH no. R03 AG021536-01.

Address reprint requests to MS Morris, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, 711 Washington Street, Room 901D, Boston, MA 02111. E-mail: ude.stfut@sirrom.ahtram.

Footnotes

References

  • 1. US Food and Drug Administration, Health and Human ServicesFood standards: amendment of standards of identity for enriched grain products to require addition of folic acid (final rule–21 CFR Part 101) Fed Reg. 1996;61:8781–97.[PubMed][Google Scholar]
  • 2. Rush DPericonceptional folate and neural tube defect. Am J Clin Nutr. 1994;59(suppl):511S–5S. discussion 515S–6S. [[PubMed][Google Scholar]
  • 3. Herbert V, Bigaouette JCall for endorsement of a petition to the Food and Drug Administration to always add vitamin B-12 to any folate fortification or supplement. Am J Clin Nutr. 1997;65:572–3.[PubMed][Google Scholar]
  • 4. Herbert V. Vitamin B12. In: Ziegler EE, Filer LJ, editors. Present knowledge in nutrition. 7. Washington, DC: International Life Sciences Institute Press; 1996. pp. 191–205. [PubMed]
  • 5. Rothenberg SPIncreasing the dietary intake of folate: pros and cons. Semin Hematol. 1999;36:65–74.[PubMed][Google Scholar]
  • 6. Koehler KM, Pareo-Tubbeh SL, Romero LJ, Baumgartner RN, Garry PJFolate nutrition and older adults: challenges and opportunities. J Am Diet Assoc. 1997;97:167–73.[PubMed][Google Scholar]
  • 7. Reynolds EH, Bottiglieri T, Laundy M, et al. Subacute combined degeneration with high serum vitamin B12 level and abnormal vitamin B12 binding protein. New cause of an old syndrome. Arch Neurol. 1993;50:739–42.[PubMed]
  • 8. Reynolds EHBenefits and risks of folic acid to the nervous system. J Neurol Neurosurg Psychiatry. 2002;72:567–71.[Google Scholar]
  • 9. Selhub J, Bagley LC, Miller J, Rosenberg IHB vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr. 2000;71(suppl):614S–20S.[PubMed][Google Scholar]
  • 10. Saltzman JR, Russell RMThe aging gut. Nutritional issues Gastroenterol Clin North Am. 1998;27:309–24.[PubMed][Google Scholar]
  • 11. Scott JMFolate and vitamin B12. Proc Nutr Soc. 1999;58:441–8.[PubMed][Google Scholar]
  • 12. Carmel RCobalamin, the stomach, and aging. Am J Clin Nutr. 1997;66:750–9.[PubMed][Google Scholar]
  • 13. FAO/WHO. Human vitamin and mineral requirements. Bangkok, Thailand: FAO/WHO; 2002. Human vitamin and mineral requirements. [PubMed]
  • 14. Scott JM, Weir DG. The methyl folate trap. A physiological response in man to prevent methyl group deficiency in kwashiorkor (methionine deficiency) and an explanation for folic-acid induced exacerbation of subacute combined degeneration in pernicious anaemia. Lancet. 1981;2:337–40.[PubMed]
  • 15. Dickinson CJNo reliable evidence that folate is harmful in B-12 deficiency. Br Med J. 1995;311:949.[Google Scholar]
  • 16. Dickinson CJDoes folic acid harm people with vitamin B12 deficiency? QJM. 1995;88:357–64.[PubMed][Google Scholar]
  • 17. Mills JL, Von Kohorn I, Conley MR, et al Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. Am J Clin Nutr. 2003;77:1474–7.[PubMed][Google Scholar]
  • 18. Dhar M, Bellevue R, Carmel RPernicious anemia with neuropsychiatric dysfunction in a patient with sickle cell anemia treated with folate supplementation. N Engl J Med. 2003;348:2204–7.[PubMed][Google Scholar]
  • 19. Metz J, McNeil AR, Levin MThe relationship between serum cobal-amin concentration and mean red cell volume at varying concentrations of serum folate. Clin Lab Haematol. 2004;26:323–5.[PubMed][Google Scholar]
  • 20. Liu S, West R, Randell E, et al A comprehensive evaluation of food fortification with folic acid for the primary prevention of neural tube defects. BMC Pregnancy Childbirth. 2004;4:20.[Google Scholar]
  • 21. Shane BFolate fortification: enough already? Am J Clin Nutr. 2003;77:8–9.[PubMed][Google Scholar]
  • 22. Rosenberg IHScience-based micronutrient fortification: which nutrients, how much, and how to know? Am J Clin Nutr. 2005;82:279–80.[PubMed][Google Scholar]
  • 23. National Center for Health Statistics. National Health and Nutrition Examination Survey. Version current 1 September 2005. Internet: (accessed 1 September 2005).[PubMed]
  • 24. National Center for Health Statistics. National Health and Nutrition Examination Survey. Version current 31 December 2005. Internet: (accessed 31 December 2005).[PubMed]
  • 25. National Center for Health Statistics. National Health and Nutrition Examination Survey. Version current 1 September 2005. Internet: (accessed 1 September 2005).[PubMed]
  • 26. WHO/UNICEF/UNU. Iron deficiency anaemia assessment, prevention, and control: a guide for programme managers. Geneva, Switzerland: World Health Organization; 2001. [PubMed]
  • 27. Wechsler D Wechsler Adult Intelligence Scale—III. San Antonio, TX: The Psychological Corporation; 1997. [PubMed][Google Scholar]
  • 28. Joy S, Kaplan E, Fein DSpeed and memory in the WAIS-III Digit Symbol–coding subtest across the adult lifespan. Arch Clin Neuropsychol. 2004;19:759–67.[PubMed][Google Scholar]
  • 29. National Center for Health Statistics, National Health and Nutrition Examination Survey. Household Interview Questionnaire. Version current 1 September 2005. Internet: (accessed 1 September 2005).[PubMed]
  • 30. Pfeiffer CM, Gunter EWAutomated assay for methylmalonic acid (MMA) in plasma. Clin Chem. 1999;45 (abstr 593) [PubMed][Google Scholar]
  • 31. Shipchandler MT, Moore EGRapid, fully automated measurement of plasma homocyst(e)ine with the Abbott IMx analyzer. Clin Chem. 1995;41:991–4.[PubMed][Google Scholar]
  • 32. Pfeiffer CM, Caudill SP, Gunter EW, Osterloh J, Sampson EJBiochemical 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;82:442–50.[PubMed][Google Scholar]
  • 33. Morris MS, Jacques PF, Rosenberg IH, Selhub JElevated serum methylmalonic acid concentrations are common among elderly Americans. J Nutr. 2002;132:2799–803.[PubMed][Google Scholar]
  • 34. Nordenberg D, Yip R, Binkin NJThe effect of cigarette smoking on hemoglobin levels and anemia screening. JAMA. 1990;264:1556–9.[PubMed][Google Scholar]
  • 35. Kelly P, McPartlin J, Goggins M, Weir DG, Scott JMUnmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr. 1997;65:1790–5.[PubMed][Google Scholar]
  • 36. Mills JLFortification of foods with folic acid–how much is enough? N Engl J Med. 2000;342:1442–5.[PubMed][Google Scholar]
  • 37. Weir DG, Scott JMBrain function in the elderly: role of vitamin B12 and folate. Br Med Bull. 1999;55:669–82.[PubMed][Google Scholar]
  • 38. Koury MJ, Ponka PNew insights into erythropoiesis: the roles of folate, vitamin B12, and iron. Annu Rev Nutr. 2004;24:105–31.[PubMed][Google Scholar]
  • 39. Wald NJ, Law MR, Morris JK, Wald DSQuantifying the effect of folic acid. Lancet. 2001;358:2069–73.[PubMed][Google Scholar]
  • 40. Oakley GP., Jr Let’s increase folic acid fortification and include vitamin B-12. Am J Clin Nutr. 1997;65:1889–90.[PubMed]
  • 41. Carmel RCurrent concepts in cobalamin deficiency. Annu Rev Med. 2000;51:357–75.[PubMed][Google Scholar]
  • 42. Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin and choline. Washington, DC: National Academy Press; 1998. [PubMed]
  • 43. Oakley GP., Jr Vitamin B-12 and folic acid supplementation (reply to V Herbert) Am J Clin Nutr. 1997;66:1479–80.[PubMed]
  • 44. Tucker KL, Mahnken B, Wilson PW, Jacques P, Selhub J. Folic acid fortification of the food supply. Potential benefits and risks for the elderly population. JAMA. 1996;276:1879–85.[PubMed]
  • 45. Choumenkovitch SF, Jacques PF, Nadeau MR, Wilson PW, Rosenberg IH, Selhub JFolic acid fortification increases red blood cell folate concentrations in the Framingham study. J Nutr. 2001;131:3277–80.[PubMed][Google Scholar]
  • 46. Choumenkovitch SF, Selhub J, Wilson PW, Rader JI, Rosenberg IH, Jacques PFFolic acid intake from fortification in United States exceeds predictions. J Nutr. 2002;132:2792–8.[PubMed][Google Scholar]
  • 47. D’Anci KE, Rosenberg IHFolate and brain function in the elderly. Curr Opin Clin Nutr Metab Care. 2004;7:659–64.[PubMed][Google Scholar]
  • 48. Ramos MI, Allen LH, Mungas DM, et al Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging. Am J Clin Nutr. 2005;82:1346–52.[PubMed][Google Scholar]
  • 49. Ravaglia G, Forti P, Maioli F, et al Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr. 2005;82:636–43.[PubMed][Google Scholar]
  • 50. Bryan J, Calvaresi E, Hughes DShort-term folate, vitamin B-12 or vitamin B-6 supplementation slightly affects memory performance but not mood in women of various ages. J Nutr. 2002;132:1345–56.[PubMed][Google Scholar]
  • 51. Garcia A, Zanibbi KHomocysteine and cognitive function in elderly people. CMAJ. 2004;171:897–904.[Google Scholar]
  • 52. Ellinson M, Thomas J, Patterson AA critical evaluation of the relationship between serum vitamin B, folate and total homocysteine with cognitive impairment in the elderly. J Hum Nutr Diet. 2004;17:371–83. (quiz 385–7). [[PubMed][Google Scholar]
  • 53. Schafer JH, Glass TA, Bolla KI, Mintz M, Jedlicka AE, Schwartz BSHomocysteine and cognitive function in a population-based study of older adults. J Am Geriatr Soc. 2005;53:381–8.[PubMed][Google Scholar]
  • 54. Garcia A, Haron Y, Pulman K, Hua L, Freedman MIncreases in homocysteine are related to worsening of stroop scores in healthy elderly persons: a prospective follow-up study. J Gerontol A Biol Sci Med Sci. 2004;59:1323–7.[PubMed][Google Scholar]
  • 55. 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;62:641–5.[PubMed][Google Scholar]
  • 56. Corrada MM, Kawas CH, Hallfrisch J, Muller D, Brookmeyer RReduced risk of Alzheimer’s disease with high folate intake: the Baltimore Longitudinal Study of Aging. Alz Dem J Alz Assoc. 2005;1:11–18.[Google Scholar]
  • 57. Kado DM, Karlamangla AS, Huang MH, et al Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur studies of successful aging. Am J Med. 2005;118:161–7.[PubMed][Google Scholar]
  • 58. Tucker KL, Qiao N, Scott T, Rosenberg I, Spiro A., III High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study. Am J Clin Nutr. 2005;82:627–35.[PubMed]
  • 59. Weir DG, Molloy AMMicrovascular disease and dementia in the elderly: are they related to hyperhomocysteinemia? Am J Clin Nutr. 2000;71:859–60.[PubMed][Google Scholar]
  • 60. Roman GCVascular dementia may be the most common form of dementia in the elderly. J Neurol Sci. 2002:203–204. 7–10.[PubMed][Google Scholar]
  • 61. Lokk JNews and views on folate and elderly persons. J Gerontol A Biol Sci Med Sci. 2003;58:354–61.[PubMed][Google Scholar]
  • 62. Scott JM, Weir DG, Molloy A, McPartlin J, Daly L, Kirke PFolic acid metabolism and mechanisms of neural tube defects. CIBA Found Symp. 1994;181:180–7. discussion 187–91. [[PubMed][Google Scholar]
  • 63. Shane B, Stokstad ELVitamin B12-folate interrelationships. Annu Rev Nutr. 1985;5:115–41.[PubMed][Google Scholar]
  • 64. Lumb M, Perry J, Deacon R, Chanarin IChanges in tissue folates accompanying nitrous oxide-induced inactivation of vitamin B12 in the rat. Am J Clin Nutr. 1981;34:2412–7.[PubMed][Google Scholar]
  • 65. Duthie SJ, Whalley LJ, Collins AR, Leaper S, Berger K, Deary IJHomocysteine, B vitamin status, and cognitive function in the elderly. Am J Clin Nutr. 2002;75:908–13.[PubMed][Google Scholar]
  • 66. Lindenbaum J, Rosenberg IH, Wilson PW, Stabler SP, Allen RHPrevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr. 1994;60:2–11.[PubMed][Google Scholar]
  • 67. Carmel R, Green R, Jacobsen DW, Rasmussen K, Florea M, Azen CSerum cobalamin, homocysteine, and methylmalonic acid concentrations in a multiethnic elderly population: ethnic and sex differences in cobalamin and metabolite abnormalities. Am J Clin Nutr. 1999;70:904–10.[PubMed][Google Scholar]
  • 68. Bjorkegren K, Svardsudd KSerum cobalamin, folate, methylmalonic acid and total homocysteine as vitamin B12 and folate tissue deficiency markers amongst elderly Swedes—a population-based study. J Intern Med. 2001;249:423–32.[PubMed][Google Scholar]
  • 69. Herrmann W, Schorr H, Bodis M, et al Role of homocysteine, cystathionine and methylmalonic acid measurement for diagnosis of vitamin deficiency in high-aged subjects. Eur J Clin Invest. 2000;30:1083–9.[PubMed][Google Scholar]
  • 70. Stabler SP, Allen RH, Fried LP, et al Racial differences in prevalence of cobalamin and folate deficiencies in disabled elderly women. Am J Clin Nutr. 1999;70:911–9.[PubMed][Google Scholar]
  • 71. Andres E, Loukili NH, Noel E, et al Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ. 2004;171:251–9.[Google Scholar]
  • 72. Herrmann W, Obeid R, Schorr H, Geisel JFunctional vitamin B12 deficiency and determination of holotranscobalamin in populations at risk. Clin Chem Lab Med. 2003;41:1478–88.[PubMed][Google Scholar]
  • 73. Clarke R, Refsum H, Birks J, et al Screening for vitamin B-12 and folate deficiency in older persons. Am J Clin Nutr. 2003;77:1241–7.[PubMed][Google Scholar]
  • 74. Mason JBBiomarkers of nutrient exposure and status in one-carbon (methyl) metabolism. J Nutr. 2003;133(suppl):941S–7S.[PubMed][Google Scholar]
  • 75. Carmel R, Green R, Rosenblatt DS, Watkins DUpdate on cobalamin, folate, and homocysteine. Hematology Am Soc Hematol Educ Program. 2003:62–81.[PubMed][Google Scholar]
  • 76. Elin RJ, Winter WEMethylmalonic acid: a test whose time has come? Arch Pathol Lab Med. 2001;125:824–7.[PubMed][Google Scholar]
  • 77. Carmel RSubtle cobalamin deficiency. Ann Intern Med. 1996;124:338–40.[PubMed][Google Scholar]
  • 78. Carmel RSubtle and atypical cobalamin deficiency states. Am J Hematol. 1990;34:108–14.[PubMed][Google Scholar]
  • 79. Carmel R, Sinow RM, Karnaze DS. Atypical cobalamin deficiency. Subtle biochemical evidence of deficiency is commonly demonstrable in patients without megaloblastic anemia and is often associated with protein-bound cobalamin malabsorption. J Lab Clin Med. 1987;109:454–63.[PubMed]
  • 80. Allen RH, Stabler SP, Lindenbaum JRelevance of vitamins, homocysteine and other metabolites in neuropsychiatric disorders. Eur J Pediatr. 1998;157(suppl):S122–6.[PubMed][Google Scholar]
  • 81. Stabler SPVitamins, homocysteine, and cognition. Am J Clin Nutr. 2003;78:359–60.[PubMed][Google Scholar]
  • 82. Eastley R, Wilcock GK, Bucks RSVitamin B12 deficiency in dementia and cognitive impairment: the effects of treatment on neuropsychological function. Int J Geriatr Psychiatry. 2000;15:226–33.[PubMed][Google Scholar]
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