![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
3 Center for Biomedical Sciences, 4 Biomedical Brain Research Center, National Institute of Health, Eunpyeong-gu, Seoul 122-701, South Korea; and 5 Department of Neurology, 6 Department of Psychiatry and 7 Geriatric Health Clinic and Research Institute, Korea University Medical College, Ansan-city, Gyeonggi-do 425-707, South Korea
* To whom correspondence should be addressed. E-mail: inhojo{at}nih.go.kr.
 |
ABSTRACT |
|---|
 TOP ABSTRACT IntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
|---|
|
Introduction |
|---|
|
TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
|---|
An inverse relationship between plasma total homocysteine (tHcy) levels and cognitive function has been reported in case-control (4–6) and cross-sectional studies (7–9). Longitudinal studies have proposed that elevated plasma homocysteine may be a risk factor for Alzheimer's disease (10,11). However, data on the association between elevated tHcy levels and MCI are inconsistent (8,9,12–15). Furthermore, information on the risk of MCI in relation to elevated tHcy levels in the Asian population is very limited.
To the best of our knowledge, only 1 study has provided information on the relationship between elevated tHcy concentration and MCI in South Korea (14), even though South Korea is considered to have the most rapidly aging population in the world. However, this previous study did not include serum folate, vitamin B-12, or the apolipoprotein E (apoE) genotype, which are putative risk factors for cognitive decline, including Alzheimer's disease, in the statistical analysis (16). Furthermore, the sample in that study was medium sized, with 409 controls and 102 cases with MCI.
In this study, using a large, stratified, and randomized sample from the population-based Ansan Geriatric (AGE) cohort study, we investigated the relationship between elevated plasma tHcy levels and the risk of MCI in an elderly Korean population.
|
Subjects and Methods |
|---|
|
TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
|---|
60 y), for a baseline investigation, we constructed a first-wave sample from the AGE cohort study, as described previously (18). Briefly, all subjects received a telephone call and a letter at least 3 times inviting them to attend a comprehensive health screening at the Geriatric Health Clinic and Research Institute, Korea University Hospital, Ansan, Korea. Despite extensive efforts, however, a total of only 1391 subjects (595 men and 796 women) were randomly recruited between September 2004 and March 2006 and were regarded as the first-wave sample. The first-wave sample was evaluated by clinical and neuropsychological examinations and was subjected to genotyping for apoE 
4 polymorphism. In the first-wave sample, 64 subjects with no available data for neuropsychological examinations were excluded and a further 41 were excluded, because they were diagnosed with dementia at site examinations. Among the remaining 1286 subjects, 71 were excluded because they had insufficient information on health status, smoking status, serum vitamins, and apoE 4 genotype. Therefore, a total of 1215 elderly Korean subjects (520 men and 695 women; mean age, 68.7 ± 5.4 y; range, 60–85 y) were finally eligible for this analysis. Informed written consent for participation was obtained from each individual and the study protocol was approved by the institutional review board of the AGE study.
Cognitive function assessment.
MCI was diagnosed on the basis of the Mayo Clinic criteria (3), which include the following: 1) memory complaint, preferably corroborated by an informant; 2) objective memory impairment for age; 3) largely preserved general cognition; 4) essentially normal activities of daily living; and 5) no dementia. Diagnosis was made independently by a physician on the basis of all available information. The MCI group manifested memory or executive deficits compared with a normal score on the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet (19) according to age, sex, and education (score <mean – 1.5 SD) but with no impact on activities of daily living. The cut-off score of –1.5 SD below the mean was chosen to be consistent with published criteria for MCI (3). The final diagnosis was based upon a consensus meeting, attended by at least 1 neurologist, neuropsychologist, clinical neurophysiologist, geriatrician, and specialized nurse, at which all the available clinical data were considered. Symptoms of depression were determined according to the Korean version of the Geriatric Depression Scale (20). Depression was defined as a Geriatric Depression Scale score 18 (20).
Laboratory procedures.
Baseline blood samples were taken after an overnight fast. Blood samples for plasma homocysteine measurement were collected in tubes containing EDTA and centrifuged as soon as possible. The plasma was then separated from the cells after centrifugation, placed on ice, and kept in a refrigerator (–4°C) until analysis for homocysteine. Fasting plasma tHcy concentrations were measured with the automated ADVIA Centaur immunoassay (Bayer Healthcare) by a direct chemiluminescence method (21). We classified subjects into 4 groups in relation to plasma tHcy. We defined tHcy as severe hyperhomocysteinemia for concentrations of >100 µmol/L, intermediate for concentrations of >30 and 
100 µmol/L, moderate for concentrations of >15 and 30 µmol/L, and the reference total plasma tHcy range as 15 µmol/L (7,22). Blood samples for serum vitamin measurements were collected in separate tubes and sent to a biochemistry laboratory for analysis. Serum concentrations of folate and vitamin B-12 were measured using the Simul TRAC-SNB radioimmunoassay (ICN Biomedicals).
apoE genotypes.
Genomic DNA was obtained from EDTA-treated blood using a QIAmp DNA Blood Mini kit (Qiagen). apoE allele genotyping was performed by PCR. Subjects were divided into 2 groups based on the presence or absence of the apoE 4 allele.
Other measurements. The well-trained field survey team was composed of university students majoring in nursing and experienced interviewers. To ensure uniformity, all interviewers underwent 2 d of training before the survey was initiated and then the sociodemographic data were collected from the subjects. McNemar's test was used to assess the reliability between surveyors and showed no difference (P > 0.05) (23).
Detailed data on sociodemographic factors and personal characteristics were collected including age, sex, level of education, marital status, smoking, disease history, and dietary supplements. Marital status was categorized as married (cohabiting) or single (unmarried, widowed, divorced, or separated). Smoking behavior was classified as current smoker, ex-smoker (for at least 1 y), and nonsmoker, as previously described (24). Educational status was categorized as 6 y (elementary school completion), 7–12 y, and 13 y (college education level) in the Korean education system. Disease history was reported by subjects using a checklist that included 35 diseases and a residual category called "other diseases" and confirmed by reviewing medical records and medications (23). Information on dietary supplements was obtained from the subjects who answered the open-ended question: "Are you currently taking dietary supplements? If so, please write down or tell all the names." In this study, a total of 272 elderly subjects reported taking dietary supplements that included Chinese herbs (as a restorative), multivitamins, minerals such as calcium and iron, glucosamine, and others.
Statistical analysis. Data were expressed as means with SD (continuous) or number and percentage (categorical). Differences between normal subjects and those with MCI were evaluated using Student's t test or a chi-square test, as appropriate. Because of the skewed distributions of homocysteine, folate, and vitamin B-12, these variables were log-transformed before analysis. Differences among 3 groups according to the levels of plasma homocysteine were determined using general linear models (Duncan's test of multiple comparisons) or chi-square test, as appropriate. Multivariable-adjusted logistic regression analysis was conducted to examine the OR for MCI across a range of plasma homocysteine levels. Relationships between homocysteine and folate or vitamin B-12 were evaluated using Pearson's correlation analysis. Statistical analyses were performed with SAS software (SAS 9.1; SAS Institute). Statistical significance was defined as P < 0.05.
|
Results |
|---|
|
TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
|---|
|
15 µmol/L), moderate (15 < tHcy 30 µmol/L), or intermediate (30 < tHcy 100 µmol/L). Subjects with hyperhomocysteinemia were older, more likely to be men, current or ex-smokers, and more likely to have low serum folate and vitamin B-12 concentrations. Plasma homocysteine increased at each category of plasma homocysteine (P < 0.001) and serum folate and vitamin B-12 changed in the opposite direction (P < 0.001). As expected, subjects with hyperhomocysteinemia had higher prevalence of MCI (P = 0.009).
|
|
|
Discussion |
|---|
|
TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
|---|
15 µmol/L). This association appeared to be independent of other well-known putative risk factors for cognitive decline such as age, sex, education, smoking, marital status, and serum vitamin levels. Our results suggest that hyperhomocysteinemia may be an independent risk factor for MCI in elderly Korean subjects.
Our finding is consistent with previously reported results (9,14,25). In cross-sectional analyses from the Leiden 85-Plus study in the Netherlands in noninstitutionalized elderly subjects aged 85 y, cognitively impaired individuals had higher serum concentrations of homocysteine than did healthy subjects, as assessed by the Mini-Mental State Examination (MMSE) (9). A similar result was also reported from the longitudinal Veterans Affairs Normative Aging Study, which showed a causal relationship between elevated homocysteine levels and cognitive decline in American men aged 50–85 y (25). Furthermore, a case-control study using an elderly Korean population documented that plasma tHcy concentration was significantly greater in elderly subjects with MCI compared with healthy Korean subjects (14). Moreover, the authors of that study showed that subjects in the highest homocysteine tertile (12.3 µmol/L) had a 2.4-fold increase in risk for MCI compared with subjects in the lowest tertile (<10 µmol/L) after adjustment for age, sex, and education level. This result is fairly consistent with our study, showing that a plasma tHcy level in the highest quartile (18.45µmol/L) doubled the risk of MCI, after adjustment for confounding factors, compared with the lowest quartile (12.84 µmol/L; data not shown).
Nonetheless, some studies have also shown incompatible results. Among community-dwelling elderly subjects aged 55 y from the population-based Rotterdam study in the Netherlands, no relationship was found between tHcy levels and concurrent cognitive impairment, as assessed by the MMSE, or subsequent cognitive decline over 2.7 y, after adjustment for age, sex, and education level (12). Similarly, plasma homocysteine concentration did not differ between normal and MCI elderly subjects, as assessed by the Mayo Clinic criteria in a group of Polish subjects (13).
These inconsistent results may be attributable to differences in the ethnic origin of the study populations. In this regard, ethnic-specific differences in the prevalence of the apoE 4 allele should be considered, as the apoE 4 genotype may be associated with poorer performance in cognitive function, particularly memory (16). For example, the apoE 4 allele has a stronger effect on Alzheimer's disease in Japanese subjects than in Caucasians (26). None of the studies mentioned above, except for our current study, included apoE genotype as a confounding factor for analysis. Another possible reason for the incompatible results is the use of different criteria for MCI diagnosis, such as the Mayo Clinic criteria (this study) and the MMSE score (9). Petersen et al. (3) reported that the use of alternative criteria for MCI could lead to variable results for MCI outcome because of differences in the interpretation of cognitive impairment. Therefore, a direct comparison is not possible because of the many differences in the study conditions.
Several mechanisms for the effects of homocysteine on cognitive decline have been proposed. Elevated homocysteine levels may induce DNA damage in the central nervous system in addition to being implicated in vascular disease (27,28). Several authors have proposed that homocysteine-related impairment of glutathione metabolism and oxidative stress, impaired DNA methylation, and associated epigenetic mechanisms might increase amyloid-ß-peptide production and toxicity as, for example, in Alzheimer's disease (27–29). Increased concentrations of homocysteic acid, an N-methyl-D-aspartate receptor agonist and a metabolite of homocysteine, may result in neuronal dysfunction (30).
We found an inverse association between plasma tHcy and serum folate or vitamin B-12 concentration. This suggests that elevated homocysteine concentration may be reduced through folate or vitamin B-12 supplementation in patients with MCI. Some intervention studies have also suggested a beneficial effect of folate alone or in combination with vitamin B-12 supplementation on cognitive performance (31–33). Despite the correlation between plasma homocysteine and serum vitamin levels, serum folate and vitamin B-12 concentrations in our study did not differ between elderly subjects with and without MCI (Table 1). Overall, our data suggest that a shortage of these 2 vitamins, which are essential factors for the methylation of homocysteine to methionine, may contribute to the increase in plasma homocysteine concentrations rather than directly affect cognitive function. Several studies support this hypothesis (34,35). Oral folate plus vitamin B-12 for 12 wk decreased homocysteine concentration in patients aged 65 y with vascular disease but had no beneficial effect on cognitive performance (34). Similarly, vitamin B-12 alone or in combination with folate for 24 wk decreased plasma homocysteine concentration by 36%, but the vitamin supplementation did not improve cognitive function among subjects aged 70 y (35). Further research on the association between cognitive performance and folate or vitamin B supplementation should be undertaken in a large population with MCI, using sensitive measures of cognitive function.
Our study had several limitations that should be addressed in future studies. We observed an association between plasma tHcy and risk of MCI only in a cross-sectional setting. Therefore, we were unable to determine whether plasma tHcy is a cause or consequence of MCI. The causal relationship between plasma homocysteine levels and cognitive impairment should be evaluated in a follow-up study in the Korean population. Furthermore, because some of data used in the analyses were obtained from self-reports of subjects with MCI, these data may not be as accurate as those of normal subjects. However, the lack of difference in the discrepancy between self- and other-reported everyday functioning in the MCI groups compared with the normal subjects was previously reported (36), suggesting that the effect of any potential recall error from the MCI groups is likely to be small. Interviewer's help, particularly in the case of self-reported disease history from the MCI groups, may also significantly reduce these recall errors. Nevertheless, our study had several advantages. To date, this study has the largest sample size among studies of elderly subjects and the cohort was based on a stratified and random sample. Furthermore, the majority of putative risk factors for cognitive function, such as serum vitamins and apoE genotype, were included in the analysis.
In conclusion, our results suggest that hyperhomocysteinemia may be an independent risk factor for MCI in elderly Koreans. Large-scale intervention studies are needed to evaluate whether lowering blood homocysteine concentrations reduces the risk of cognitive impairment in elderly subjects.
|
FOOTNOTES |
|---|
2 Author disclosures: J. Kim, M. H. Park, E. Kim, C. Han, S. A. Jo, and I. Jo, no conflicts of interest.
8 J. Kim and M.H. Park contributed equally to this work.
9 Abbreviations used: AGE, Ansan Geriatric; apoE, apolipoprotein E; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; tHcy, total homocysteine.
Manuscript received 20 April 2007. Initial review completed 24 May 2007. Revision accepted 20 June 2007.
|
LITERATURE CITED |
|---|
|
TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
|---|
1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-IV). 4th ed. Washington: APA; 1994.
2. Morris JC, Storandt M, Miller JP, McKeel DW, Price JL, Rubin EH, Berg L. Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol. 2001;58:397–405.
3. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56:303–8.
4. 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;55:1449–55.
5. McCaddon A, Davies G, Hudson P, Tandy S, Cattell H. Total serum homocysteine in senile dementia of Alzheimer type. Int J Geriatr Psychiatry. 1998;13:235–9.[Medline]
6. Leblhuber F, Walli J, Artner-Dworzak E, Vrecko K, Widner B, Reibnegger G, Fuchs D. Hyperhomocysteinemia in dementia. J Neural Transm. 2000;107:1469–74.[Medline]
7. Ravaglia G, Forti P, Maioli F, Muscari A, Sacchetti L, Arnone G, Nativio V, Talerico T, Mariani E. Homocysteine and cognitive function in healthy elderly community dwellers in Italy. Am J Clin Nutr. 2003;77:668–73.
8. Quadri P, Fragiacomo C, Pezzati R, Zanda E, Forloni G, Tettamanti M, Lucca U. Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer disease, and vascular dementia. Am J Clin Nutr. 2004;80:114–22.
9. Mooijaart SP, Gussekloo J, Frolich M, Jolles J, Stott DJ, Westendorp RG, de Craen AJ. Homocysteine, vitamin B-12, and folic acid and the risk of cognitive decline in old age: the Leiden 85-Plus study. Am J Clin Nutr. 2005;82:866–71.
10. Ravaglia G, Forti P, Maioli F, Martelli M, Servadei L, Brunetti N, Porcellini E, Licastro F. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr. 2005;82:636–43.
11. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002;346:476–83.
12. Kalmijn S, Launer LJ, Lindemans J, Bots ML, Hofman A, Breteler MM. Total homocysteine and cognitive decline in a community-based sample of elderly subjects: the Rotterdam Study. Am J Epidemiol. 1999;150:283–9.
13. Religa D, Styczynska M, Peplonska B, Gabryelewicz T, Pfeffer A, Chodakowska M, Luczywek E, Wasiak B, Stepien K, et al. Homocysteine, apolipoprotein E and methylenetetrahydrofolate reductase in Alzheimer's disease and mild cognitive impairment. Dement Geriatr Cogn Disord. 2003;16:64–70.[Medline]
14. Cho SY, Kim SB, Lee MS, Kim HJ, Yun J, Kim K, Choi KG, Choi BO. Association between elevated homocysteine concentration and Alzheimer's disease, vascular disease, and mild cognitive impairment. J Korean Neurol Assoc. 2006;24:231–8 (Korean).
15. Kado DM, Karlamangla AS, Huang MH, Troen A, Rowe JW, Selhub J, Seeman TE. 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.[Medline]
16. Farlow MR, He Y, Tekin S, Xu J, Lane R, Charles HC. Impact of APOE in mild cognitive impairment. Neurology. 2004;63:1898–901.
17. Park MH, Jo SA, Jo I, Kim E, Eun SY, Han C, Park MK. No difference in stroke knowledge between Korean adherents to traditional and western medicine. The AGE study: an epidemiological study. BMC Public Health. 2006;6:153.[Medline]
18. Jo SA, Kim E, Park MH, Han C, Park HY, Jang Y, Song BJ, Jo IA. Glu487Lys polymorphism in the gene for mitochondria aldehyde dehydrogenase 2 is associated with myocardial infarction in elderly Korean men. Clin Chim Acta. 2007;382:43–7.[Medline]
19. Lee DY, Lee KU, Lee JH, Kim KW, Jhoo JH, Kim SY, Yoon JC, Woo SI, Ha J, et al. A normative study of the CERAD neuropsychological assessment battery in the Korean elderly. J Int Neuropsychol Soc. 2004;10:72–81.[Medline]
20. Bae JN, Cho MJ. Development of the Korean version of the Geriatric Depression Scale and its short form among elderly psychiatric patients. J Psychosom Res. 2004;57:297–305.[Medline]
21. Mindicino HJ, Carlsen J, Tewari P, Aagaard O, Zhang B, Conarpe C. An evaluation of an automated homocysteine method on the Bayer ADVIA Centaur automated chemiluminescent system. Clin Lab. 2002;48:493–6.[Medline]
22. Kang SS, Wong PW, Malinow MR. Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr. 1992;12:279–98.[Medline]
23. Woo EK, Han C, Jo SA, Park MK, Kim S, Kim E, Park MH, Lee J, Jo I. Morbidity and related factors among elderly people in South Korea: results from the Ansan Geriatric (AGE) cohort study. BMC Public Health. 2007;7:10.[Medline]
24. Jo I, Ahn Y, Lee J, Shin KR, Lee HK, Shin C. Prevalence, awareness, treatment, control and risk factors of hypertension in Korea: the Ansan study. J Hypertens. 2001;19:1523–32.[Medline]
25. 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.
26. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997;278:1349–56.
27. Irizarry MC, Gurol ME, Raju S, Diaz-Arrastia R, Locascio JJ, Tennis M, Hyman BT, Growdon JH, Greenberg SM, et al. Association of homocysteine with plasma amyloid beta protein in aging and neurodegenerative disease. Neurology. 2005;65:1402–8.
28. Kruman I, Kumaravel TS, Lohani A, Pedersen WA, Cutler RG, Kruman Y, Haughey N, Lee J, Evans M, et al. Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease. J Neurosci. 2002;22:1752–62.
29. Fuso A, Seminara L, Cavallaro RA, D'Anselmi F, Scarpa S. S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production. Mol Cell Neurosci. 2005;28:195–204.[Medline]
30. Gortz P, Hoinkes A, Fleischer W, Otto F, Schwahn B, Wendel U, Siebler M. Implications for hyperhomocysteinemia: not homocysteine but its oxidized forms strongly inhibit neuronal network activity. J Neurol Sci. 2004;218:109–14.[Medline]
31. Durga J, van Boxtel MP, Schouten EG, Kok FJ, Jolles J, Katan MB, Verhoef P. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet. 2007;369:208–16.[Medline]
32. Bryan J, Calvaresi E, Hughes D. Short-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.
33. 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;354:2764–72.
34. Stott DJ, MacIntosh G, Lowe GD, Rumley A, McMahon AD, Langhorne P, Tait RC, O'Reilly DS, Spilg EG, et al. Randomized controlled trial of homocysteine-lowering vitamin treatment in elderly patients with vascular disease. Am J Clin Nutr. 2005;82:1320–6.
35. Eussen SJ, de Groot LC, Joosten LW, Bloo RJ, Clarke R, Ueland PM, Schneede J, Blom HJ, Hoefnagels WH, et al. Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial. Am J Clin Nutr. 2006;84:361–70.
36. Farias ST, Mungas D, Jagust W. Degree of discrepancy between self and other-reported everyday functioning by cognitive status: dementia, mild cognitive impairment, and healthy elders. Int J Geriatr Psychiatry. 2005;20:827–34.[Medline]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
