Homocysteine Lowering and Cognitive Performance
http://www.100md.com
《新英格兰医药杂志》
To the Editor: McMahon et al. (June 29 issue)1 report that lowering plasma homocysteine concentrations by means of treatment with B vitamins did not improve the cognitive performance of healthy elderly volunteers with elevated homocysteine concentrations. Yet in the study population, there was little need to decrease homocysteine concentrations, no cognitive impairment to improve, and no association between elevated homocysteine concentrations and cognitive impairment to dissolve. What does it mean to improve an already quite normal cognitive performance and a mean score on the Mini–Mental State Examination of 29.2, given a possible score of 30? How can one define a clinically meaningful difference between two groups of healthy elderly volunteers? Whereas the usual definition of the upper limit of the normal range is 15 μmol per liter,2,3,4 McMahon et al. defined as "elevated" homocysteine concentrations as low as 13 μmol per liter. Thus, a good 62% of their healthy volunteers had elevated homocysteine concentrations, as compared with a reported prevalence of hyperhomocysteinemia of 18% among elderly New Zealand women.5 The already small sample was thus diluted by the large presence of elderly persons who were falsely classified as having hyperhomocysteinemia. Consistently, at baseline, the mean plasma folate and vitamin B12 concentrations were already rather high. Moreover, after baseline, the mean homocysteine concentration in the placebo group was below or near the upper limit of the normal range throughout the trial.
Ugo Lucca, M.Sc.
Mauro Tettamanti, Ph.D.
Istituto di Ricerche Farmacologiche Mario Negri
20157 Milan, Italy
lucca@marionegri.it
Pierluigi Quadri, M.D.
Ospedali Regionali of Mendrisio and Lugano
6850 Mendrisio, Switzerland
References
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.
Welch GN, Loscalzo J. Homocysteine and atherothombosis. N Engl J Med 1998;338:1042-1050.
Refsum H, Ueland PM, Nyg?rd O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med 1998;49:31-62.
Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet 1999;354:407-413.
de Jong N, Green TJ, Skeaff CM, et al. Vitamin B12 and folate status of older New Zealand women. Asia Pac J Clin Nutr 2003;12:85-91.
To the Editor: McMahon and colleagues examine whether there was a cognitive benefit of lowering serum homocysteine concentrations in healthy older people with the use of folate and vitamins B6 and B12. The hypothesis that lowering homocysteine concentrations would improve cognitive performance might not be supported by their results, however, and one has to ask whether the authors assessed this end point in the appropriate population.
Testing the a priori hypothesis of an association between cognitive impairment and higher concentrations of homocysteine seems to be rather difficult in the study population chosen. At enrollment, the participants did not have any cognitive dysfunction and had normal folate and B vitamin concentrations in combination with slightly increased homocysteine concentrations. Thus, one might assume that the "ceiling effect" in this sample of elderly persons did not permit the detection of clinical effects of lowering homocysteine concentrations.
As in other homocysteine trials focused on other diseases that have had at least deflating results,1 in this trial, the mechanisms of homocysteine reduction worked, but whether they afforded real clinical benefit seems to be debatable.
Michael Dettling, M.D.
Carolin Opgen-Rhein, M.D.
Ion-George Anghelescu, M.D.
Charité-University Medicine Berlin
14050 Berlin, Germany
michael.dettling@charite.de
References
Loscalzo J. Homocysteine trials -- clear outcomes for complex reasons. N Engl J Med 2006;354:1629-1632.
To the Editor: In their randomized, controlled study, McMahon and colleagues showed no association between homocysteine lowering and cognitive performance. There are, however, some methodologic limitations of the study that may have prevented the identification of a significant difference between the vitamin group and the placebo group. First, the duration of the study was only 2 years, potentially preventing the authors from seeing a significant difference in cognitive decline between the two groups. This possibility is supported by the finding that there was no significant cognitive decline detected in either group. One study cited by the authors referred to an increased incidence of Alzheimer's disease during an 8-year period among patients with elevated homocysteine levels.1 Perhaps if McMahon et al. had continued their study for a longer time, a significant difference might have been identified. The study merely indicates that there are no short-term benefits of homocysteine lowering with respect to cognitive decline. Therefore, the study should be viewed with caution until further studies with longer follow-up provide data that can more substantially establish a relationship between homocysteine levels and cognitive function.
Rajeev L. Narayan, M.D.
Columbia University College of Physicians and Surgeons
New York, NY 10032
rn2187@columbia.edu
References
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.
The authors reply: The transition from intact cognition to a demented state follows a continuum of declining cognitive ability, usually age-related. Thus, if lowering homocysteine concentrations reduces the risk of dementia in older people, it is reasonable to expect better cognitive function in those with lowered homocysteine concentrations, particularly before dementia appears, when cognitive function may be declining but is still within a normal range. Our trial tested the hypothesis that lowering the plasma homocysteine concentration improves cognitive function in healthy older people, and better cognitive performance in the group receiving vitamins would have had clinical relevance in this context. The trial was not designed to assess dementia as an end point.
We used a variety of tests to assess different aspects of cognition. Scores at baseline, with the exception of those for the Mini–Mental State Examination, were distributed over a range that ruled out the possibility of ceiling effects and were inversely correlated with age.1 The editorialist2 expected that scores on tests of cognition would decline over time in the placebo group and questioned the relevance of the overall results because no decline was apparent. Caution should be exercised, however, when interpreting the scores over time within either study group, because the administration of the same cognitive tests over time may promote learning and mask a decline in cognitive function. Furthermore, the alternative forms of the tests (e.g., different paragraphs, letters, word categories, or matrixes) that we used at the end of year 1 and year 2 to mitigate learning effects may have varied in difficulty and thus produced different mean scores. In a randomized, controlled trial such as ours, these confounding effects can be assumed to be similar for all participants, regardless of treatment, and the relevant comparison to determine the effect of homocysteine lowering on cognitive function is between the vitamin group and the placebo group.
The idea for our trial arose from a body of evidence suggesting an inverse association between homocysteine and cognitive performance, in the absence of dementia — an association that is reported to be independent of serum folate or vitamin B12 status.3 We could have recruited participants with higher plasma homocysteine concentrations, and in our report we acknowledge that such a group may have had a different cognitive response to homocysteine-lowering vitamins. Nevertheless, with a mean plasma homocysteine concentration of 16.6 μmol per liter at baseline, the participants in our study rank high in comparison with groups of similar age. For example, the 85th percentile for serum homocysteine concentrations among non-Hispanic whites 70 to 79 years of age in the United States — before folic acid fortification became mandatory — was 16.4 μmol per liter for men and 15.0 μmol per liter for women.4 In the Framingham Study cohort, the 75th percentile — associated with a higher risk of dementia — for those 70 to 74 years was 13.8 μmol per liter.5
C. Murray Skeaff, Ph.D.
Timothy J. Green, Ph.D.
Jennifer A. McMahon, Ph.D.
University of Otago
Dunedin 9054, New Zealand
murray.skeaff@stonebow.otago.ac.nz
References
Knight RG, McMahon J, Green TJ, Skeaff CM. Regression equations for predicting scores of persons over 65 on the Rey Auditory Verbal Learning Test, the Mini-Mental State Examination, the Trail Making Test and semantic fluency measures. Br J Clin Psychol 2006;45:393-402.
Clarke R. Vitamin B12, folic acid, and the prevention of dementia. N Engl J Med 2006;354:2817-2819.
Morris MS, Jacques PF, Rosenberg IH, Selhub J. Hyperhomocysteinemia associated with poor recall in the Third National Health and Nutrition Examination Survey. Am J Clin Nutr 2001;73:927-933.
Jacques PF, Rosenberg IH, Rogers G, et al. Serum total homocysteine concentrations in adolescent and adult Americans: results from the Third National Health and Nutrition Examination Survey. Am J Clin Nutr 1999;69:482-489.
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.
Ugo Lucca, M.Sc.
Mauro Tettamanti, Ph.D.
Istituto di Ricerche Farmacologiche Mario Negri
20157 Milan, Italy
lucca@marionegri.it
Pierluigi Quadri, M.D.
Ospedali Regionali of Mendrisio and Lugano
6850 Mendrisio, Switzerland
References
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.
Welch GN, Loscalzo J. Homocysteine and atherothombosis. N Engl J Med 1998;338:1042-1050.
Refsum H, Ueland PM, Nyg?rd O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med 1998;49:31-62.
Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet 1999;354:407-413.
de Jong N, Green TJ, Skeaff CM, et al. Vitamin B12 and folate status of older New Zealand women. Asia Pac J Clin Nutr 2003;12:85-91.
To the Editor: McMahon and colleagues examine whether there was a cognitive benefit of lowering serum homocysteine concentrations in healthy older people with the use of folate and vitamins B6 and B12. The hypothesis that lowering homocysteine concentrations would improve cognitive performance might not be supported by their results, however, and one has to ask whether the authors assessed this end point in the appropriate population.
Testing the a priori hypothesis of an association between cognitive impairment and higher concentrations of homocysteine seems to be rather difficult in the study population chosen. At enrollment, the participants did not have any cognitive dysfunction and had normal folate and B vitamin concentrations in combination with slightly increased homocysteine concentrations. Thus, one might assume that the "ceiling effect" in this sample of elderly persons did not permit the detection of clinical effects of lowering homocysteine concentrations.
As in other homocysteine trials focused on other diseases that have had at least deflating results,1 in this trial, the mechanisms of homocysteine reduction worked, but whether they afforded real clinical benefit seems to be debatable.
Michael Dettling, M.D.
Carolin Opgen-Rhein, M.D.
Ion-George Anghelescu, M.D.
Charité-University Medicine Berlin
14050 Berlin, Germany
michael.dettling@charite.de
References
Loscalzo J. Homocysteine trials -- clear outcomes for complex reasons. N Engl J Med 2006;354:1629-1632.
To the Editor: In their randomized, controlled study, McMahon and colleagues showed no association between homocysteine lowering and cognitive performance. There are, however, some methodologic limitations of the study that may have prevented the identification of a significant difference between the vitamin group and the placebo group. First, the duration of the study was only 2 years, potentially preventing the authors from seeing a significant difference in cognitive decline between the two groups. This possibility is supported by the finding that there was no significant cognitive decline detected in either group. One study cited by the authors referred to an increased incidence of Alzheimer's disease during an 8-year period among patients with elevated homocysteine levels.1 Perhaps if McMahon et al. had continued their study for a longer time, a significant difference might have been identified. The study merely indicates that there are no short-term benefits of homocysteine lowering with respect to cognitive decline. Therefore, the study should be viewed with caution until further studies with longer follow-up provide data that can more substantially establish a relationship between homocysteine levels and cognitive function.
Rajeev L. Narayan, M.D.
Columbia University College of Physicians and Surgeons
New York, NY 10032
rn2187@columbia.edu
References
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.
The authors reply: The transition from intact cognition to a demented state follows a continuum of declining cognitive ability, usually age-related. Thus, if lowering homocysteine concentrations reduces the risk of dementia in older people, it is reasonable to expect better cognitive function in those with lowered homocysteine concentrations, particularly before dementia appears, when cognitive function may be declining but is still within a normal range. Our trial tested the hypothesis that lowering the plasma homocysteine concentration improves cognitive function in healthy older people, and better cognitive performance in the group receiving vitamins would have had clinical relevance in this context. The trial was not designed to assess dementia as an end point.
We used a variety of tests to assess different aspects of cognition. Scores at baseline, with the exception of those for the Mini–Mental State Examination, were distributed over a range that ruled out the possibility of ceiling effects and were inversely correlated with age.1 The editorialist2 expected that scores on tests of cognition would decline over time in the placebo group and questioned the relevance of the overall results because no decline was apparent. Caution should be exercised, however, when interpreting the scores over time within either study group, because the administration of the same cognitive tests over time may promote learning and mask a decline in cognitive function. Furthermore, the alternative forms of the tests (e.g., different paragraphs, letters, word categories, or matrixes) that we used at the end of year 1 and year 2 to mitigate learning effects may have varied in difficulty and thus produced different mean scores. In a randomized, controlled trial such as ours, these confounding effects can be assumed to be similar for all participants, regardless of treatment, and the relevant comparison to determine the effect of homocysteine lowering on cognitive function is between the vitamin group and the placebo group.
The idea for our trial arose from a body of evidence suggesting an inverse association between homocysteine and cognitive performance, in the absence of dementia — an association that is reported to be independent of serum folate or vitamin B12 status.3 We could have recruited participants with higher plasma homocysteine concentrations, and in our report we acknowledge that such a group may have had a different cognitive response to homocysteine-lowering vitamins. Nevertheless, with a mean plasma homocysteine concentration of 16.6 μmol per liter at baseline, the participants in our study rank high in comparison with groups of similar age. For example, the 85th percentile for serum homocysteine concentrations among non-Hispanic whites 70 to 79 years of age in the United States — before folic acid fortification became mandatory — was 16.4 μmol per liter for men and 15.0 μmol per liter for women.4 In the Framingham Study cohort, the 75th percentile — associated with a higher risk of dementia — for those 70 to 74 years was 13.8 μmol per liter.5
C. Murray Skeaff, Ph.D.
Timothy J. Green, Ph.D.
Jennifer A. McMahon, Ph.D.
University of Otago
Dunedin 9054, New Zealand
murray.skeaff@stonebow.otago.ac.nz
References
Knight RG, McMahon J, Green TJ, Skeaff CM. Regression equations for predicting scores of persons over 65 on the Rey Auditory Verbal Learning Test, the Mini-Mental State Examination, the Trail Making Test and semantic fluency measures. Br J Clin Psychol 2006;45:393-402.
Clarke R. Vitamin B12, folic acid, and the prevention of dementia. N Engl J Med 2006;354:2817-2819.
Morris MS, Jacques PF, Rosenberg IH, Selhub J. Hyperhomocysteinemia associated with poor recall in the Third National Health and Nutrition Examination Survey. Am J Clin Nutr 2001;73:927-933.
Jacques PF, Rosenberg IH, Rogers G, et al. Serum total homocysteine concentrations in adolescent and adult Americans: results from the Third National Health and Nutrition Examination Survey. Am J Clin Nutr 1999;69:482-489.
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.