NUTRITIONAL FACTORS AND COGNITIVE FUNCTION IN CHINESE OLDER ADULTS FENG LEI (BACHELOR OF MEDICINE) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PSYCHOLOGICAL MEDICINE NATIONAL UNIVERSITY OF SINGAPORE December, 2008 ACKNOWLEDGEMENT I am most grateful to Associate Professor Ng Tze Pin. As a knowledgeable and dedicated supervisor, he guided me through this exciting but hard journey of research and study. It is impossible for me to complete this PhD thesis without his expertise, encouragements, and concrete helps. I would like to express my sincere gratitude to my Co-Supervisor Prof. Kua Ee Heok, for his wise counsel and full supports. I benefited a lot from him, especially on geriatric psychiatry and Structured clinical psychiatric interview. I wish to give cordial thanks to all the team members of the Singapore Longitudinal Ageing Study (SLAS, NUS), the staffs in the Department of Psychological Medicine (PCM, NUS), the lecturers in the School Graduate Programme of Yoog Loo Lin School of Medicine (SOM, NUS), and the lecturers in the Centre for English Language Communication (CELC, NUS), for all your helps, supports, and instructions in the past four and half years. I would express my special thanks to Ms.Hin-Hiang Susan, for her heartening words, encouragements, and helps, especially during my low tide time. Finally, I would thanks to National University of Singapore, for awarding me the Research Scholarship, and thus make all those research works possible. I wish I will be able to contribute more to Singapore as well as the science world when I continue my academic life in this small but promising country. I CONTENTS ACKNOWLEDGEMENT ABSTRACT I V LIST OF TABLES VII LIST OF FIGURES VIII LIST OF ABBRIVIATIONS IX LIST OF APPENDICES XI 1. INTRODUCTION 1.1 Fast ageing population and its impact 1.2 Cognitive function and Cognitive decline in elderly population 1.3 Nutrition as potential modifiable cognitive risk/protective factor 1.4 Objectives of the current study 2. LITERATURE REVIEW 2.1 Nutritional status and Cognitive function 2.1.1 Diet and cognitive function 2.1.2 Albumin and cognitive function 2.1.3 Hemoglobin and cognitive function 2.1.4 Body mass index and cognitive function 2.2 Homocysteine, folate, vitamin B-12 and Cognitive function 17 2.2.1 Case-control studies 2.2.2 Cross-sectional studies 2.2.3 Cohort studies II 2.2.4 Clinical trials 2.3 Nutrition and cognitive function: the role of Apolipoprotein E Genotype 23 3. METHODS 3.1 Participants 25 3.2 Questionnaire interview and clinical measurements 29 3.2.1 Demographic data and substances use 3.2.2 Medical conditions and medication 3.2.3 Physical functional status 3.2.4 Global cognitive status 3.2.5 Other questionnaire data 3.2.6 Clinical measurements 3.3 Laboratory measurements 33 3.4 Neuropsychological assessment 34 3.5 Statistical analysis 36 3.5.1 Study I 3.5.2 Study II 3.5.3 Study III 3.5.4 Study IV 4. RESULTS 4.1 Study I 42 4.2 Study II 48 4.3 Study III 53 III 4.4 Study IV 60 5. DISCUSSION 5.1 Study I 64 5.2 Study II 67 5.3 Study III 72 5.4 Study IV 75 6. SUMMARY AND CONCLUSION 80 7. REFERENCES 85 8. LIST OF PUBLICATIONS 93 9. LIST OF CONFERENCE PRESENTATIONS 94 10. APPENDICES 95 IV ABSTRACT Background: Nutritional factors as modifiable cognitive protective/risk factors have been examined in recent years, published findings are inconsistent and/or insufficient. Few data are available for Asian population. Objective: To investigate aspects of the relationship between selected nutritional factors (albumin, hemoglobin, low body mass index, homocysteine, folate, and vitamin B-12), and cognitive performance, cognitive decline, and possible effect modification by Apolipoprotein E (APOE) genotype among Chinese older adults aged 55 and above. Methods: Population based study with both cross-sectional and longitudinal study designs. A group of Chinese older adults (N=2611) were assessed at baseline and were reassessed one to two years later. Cognitive performance was measured by Mini-Mental State Examination both at baseline and follow-up. Weight, height, serum albumin, hemoglobin, serum folate, serum vitamin B-12, plasma total homocysteine, and APOE genotype were measured at baseline. Data collected on confounding variables included cigarette smoking, alcohol consumption, cardiometabloic risk factors, activity of daily living, and depression. A comprehensive neuropsychological test battery was administered on a random subsample (N=841) at baseline. Study I investigated the relationships between body mass index, albumin, hemoglobin and cognitive performance. Study II investigated the effect of serum albumin on cognitive performance and cognitive decline and the effect modification by APOE genotype. Study III investigated the independent effects of folate, vitamin B-12, and homocysteine on specific cognitive functions. Study IV investigated the role of APOE ε4 as a genetic predisposing factor modulating the effect of vitamin B-12 on cognitive performance. V Results: Study I found that low hemoglobin in the bottom quintile (OR, 1.56; 95%CI, 1.00-2.47) and low BMI-with-chronic comorbidity (OR, 1.73; 95%CI, 1.02-2.95) were independently associated with poor cognitive performance (MMSE ≤ 23). Study II showed that decreasing levels of albumin were associated with an increased risk of cognitive impairment (P for trend=0.002), and with cognitive decline (P for trend=0.001). APOE- ε4 modified the association (P for interaction=0.049). Study III showed that homocysteine (log transformed) was inversely associated with performance on Block Design (β = -0.319, P=0.006) and Symbol Digit Modality Test written version (β= 0.129, P=0.031). Folate (log transformed) was significantly associated with Rey Auditory Verbal Learning Test delayed recall (β= 0.139, P=0.010), verbal learning (β= 0.112, P=0.038), percentage of forgetting (β= -0.139, P=0.013) and Categorical Verbal Fluency (β = 0.104, P=0.042). Study IV found that low vitamin B-12 was associated with poorer performance on several cognitive measures in APOE ε4 allele carriers but not in nonAPOE ε4 carriers. The interaction between low vitamin B-12 and APOE ε4 was significant for MMSE (P=0.007), Digit Span backward (P=0.006), and RAVLT immediate recall (P=0.02). Conclusions: Poor nutritional status was associated with poor cognitive performance. Low albumin was independently associated with cognitive decline, and its association was more pronounced in carriers of the APOE-ε4 allele. Folate and homocysteine was independently related with different cognitive domains. Vitamin B-12 was associated with cognitive performance in the presence of APOE ε4. VI LIST OF TABLES Study I Page 1. Prevalence of Risk factors for Cognitive Impairment by Quintiles of Haemoglobin and Albumin and Low BMI-with-chronic comorbidity 43 2. Multiple logistic regression model parameters: albumin, hemoglobin, low BMI, chronic comorbidity and low BMI * chronic comorbidity interaction. 44 3. Odds Ratios (95% CI) of Association of Quintiles of Haemoglobin and Albumin and low BMI-and-Chronic Illness with Cognitive Impairment 46 4. MMSE scores by Albumin, Hemoglobin, BMI and MICS categories in subset of participants with MMSE ≥24 (N=2252) 47 Study II 5. Baseline descriptive characteristics of participants by albumin categories 50 6. Cross-sectional and longitudinal analyses of association of serum albumin level (in tertiles) with cognitive function 51 7. Longitudinal association of serum albumin level (in tertiles) with cognitive decline in participants with MMSE≥24 at baseline 52 Study III 8. Demographic and laboratory test characteristics of study participants 54 9. Cognitive performance of study participants 55 10. Associations between natural log transformed homocysteine, folate, vitamin B-12 and cognitive test scores (model I) 57 11. Associations between natural log transformed homocysteine and cognitive test scores, adjusted for confounding in multivariable models 58 VII 12. Associations between natural log transformed folate and cognitive test scores, adjusted for confounding in multivariable models 59 Study IV 13. Baseline characteristics of the study sample 61 14. Natural log-transformed vitamin B-12, APOE ε4, and cognitive performance 62 15. Low vitamin B-12, APOE ε4 status, and cognitive performance 63 LIST OF FIGURES Figure1. Flow of participants in the Singapore Longitudinal Ageing Study 26 VIII LIST OF ABBREVIATIONS AD Alzheimer’s disease ADL Activity of Daily Living Aβ Amyloid β-peptid APOE Apolipoprotein E (gene) ApoE Apolipoprotein E (protein) BMI Body mass index CI Confidence Interval CSF Cerebrospinal fluid CV Coefficient of variation df Degree of freedom DSM Diagnostic and Statistical Manual of Mental Disorders GDS Geriatric Depression Scale HDL High density lipoproteins HR Hazard Ratio LDL Low density lipoproteins MCI Mild Cognitive Impairment MMSE Mimi-Mental State Examination OR Odds Ratio RAVLT Rey Auditory Verbal Learning Test RR Relative Risk SAM S-Adenosylmethionine IX REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. Kinsella K, Velkoff VA. U.S. Census Bureau, Series P95/01-1, An Aging World: 2001. Washington, DC: U.S. Government Printing Office, 2001. Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the Global Burden of Alzheimer's Disease. Alzheimer's and Dementia 2007;3.3:186191. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004;256:183-94. Park HL, O'Connell JE, Thomson RG. A systematic review of cognitive decline in the general elderly population. Int J Geriatr Psychiatry 2003;18:1121-34. Luchsinger JA, Mayeux R. Dietary factors and Alzheimer's disease. Lancet Neurol 2004;3:579-87. Van Dyk K, Sano M. The impact of nutrition on cognition in the elderly. Neurochem Res 2007;32:893-904. Huijbregts PP, Feskens EJ, Rasanen L, et al. Dietary patterns and cognitive function in elderly men in Finland, Italy and The Netherlands. Eur J Clin Nutr 1998;52:826-31. Correa Leite ML, Nicolosi A, Cristina S, Hauser WA, Nappi G. Nutrition and cognitive deficit in the elderly: a population study. Eur J Clin Nutr 2001;55:10538. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999;340:448-54. Barradas MA, Mikhailidis DP, Phillips AN. Albumin, haemostasis and cardiovascular disease. (Letter). Fibrinolysis 1991;5:131. Halliwell B. Albumin--an important extracellular antioxidant? Biochem Pharmacol 1988;37:569-71. Goldwasser P, Feldman J. Association of serum albumin and mortality risk. J Clin Epidemiol 1997;50:693-703. Nelson JJ, Liao D, Sharrett AR, et al. Serum albumin level as a predictor of incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol 2000;151:468-77. Folsom AR, Ma J, Eckfeldt JH, Nieto FJ, Metcalf PA, Barnes RW. Low serum albumin. Association with diabetes mellitus and other cardiovascular risk factors but not with prevalent cardiovascular disease or carotid artery intima-media thickness. The Atherosclerosis Risk in Communities (ARIC) Study Investigators. Ann Epidemiol 1995;5:186-91. Gillum RF, Ingram DD, Makuc DM. Relation between serum albumin concentration and stroke incidence and death: the NHANES I Epidemiologic Follow-up Study. Am J Epidemiol 1994;140:876-88. Klonoff-Cohen H, Barrett-Connor EL, Edelstein SL. Albumin levels as a predictor of mortality in the healthy elderly. J Clin Epidemiol 1992;45:207-12. Kuller LH, Eichner JE, Orchard TJ, Grandits GA, McCallum L, Tracy RP. The relation between serum albumin levels and risk of coronary heart disease in the Multiple Risk Factor Intervention Trial. Am J Epidemiol 1991;134:1266-77. 85 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. Phillips A, Shaper AG, Whincup PH. Association between serum albumin and mortality from cardiovascular disease, cancer, and other causes. Lancet 1989;2:1434-6. Maes M, DeVos N, Wauters A, et al. Inflammatory markers in younger vs elderly normal volunteers and in patients with Alzheimer's disease. J Psychiatr Res 1999;33:397-405. Cattin L, Bordin P, Fonda M, et al. Factors associated with cognitive impairment among older Italian inpatients. Gruppo Italiano di Farmacovigilanza nell'Anziano (G.I.F.A.). J Am Geriatr Soc 1997;45:1324-30. Zuccala G, Marzetti E, Cesari M, et al. Correlates of cognitive impairment among patients with heart failure: results of a multicenter survey. Am J Med 2005;118:496-502. La Rue A, Koehler KM, Wayne SJ, Chiulli SJ, Haaland KY, Garry PJ. Nutritional status and cognitive functioning in a normally aging sample: a 6-y reassessment. Am J Clin Nutr 1997;65:20-9. Dik MG, Jonker C, Hack CE, Smit JH, Comijs HC, Eikelenboom P. Serum inflammatory proteins and cognitive decline in older persons. Neurology 2005;64:1371-7. Ershler WB, Sheng S, McKelvey J, et al. Serum erythropoietin and aging: a longitudinal analysis. J Am Geriatr Soc 2005;53:1360-5. Eisenstaedt R, Penninx BW, Woodman RC. Anemia in the elderly: current understanding and emerging concepts. Blood Rev 2006;20:213-26. Beard CM, Kokmen E, O'Brien PC, Ania BJ, Melton LJ, 3rd. Risk of Alzheimer's disease among elderly patients with anemia: population-based investigations in Olmsted County, Minnesota. Ann Epidemiol 1997;7:219-24. Atti AR, Palmer K, Volpato S, Zuliani G, Winblad B, Fratiglioni L. Anaemia increases the risk of dementia in cognitively intact elderly. Neurobiol Aging 2006;27:278-84. Zamboni V, Cesari M, Zuccala G, et al. Anemia and cognitive performance in hospitalized older patients: results from the GIFA study. Int J Geriatr Psychiatry 2006;21:529-34. Argyriadou S, Vlachonikolis I, Melisopoulou H, Katachanakis K, Lionis C. In what extent anemia coexists with cognitive impairment in elderly: a cross-sectional study in Greece. BMC Fam Pract 2001;2:5. Elwood PC, Pickering J, Gallacher JE. Cognitive function and blood rheology: results from the Caerphilly cohort of older men. Age Ageing 2001;30:135-9. Denny SD, Kuchibhatla MN, Cohen HJ. Impact of anemia on mortality, cognition, and function in community-dwelling elderly. Am J Med 2006;119:327-34. Gustafson D. Adiposity indices and dementia. Lancet Neurol 2006;5:713-20. Gorospe EC, Dave JK. The risk of dementia with increased body mass index. Age Ageing 2007;36:23-9. Whitmer RA. The epidemiology of adiposity and dementia. Curr Alzheimer Res 2007;4:117-22. Whitmer RA, Gunderson EP, Quesenberry CP, Jr., Zhou J, Yaffe K. Body mass index in midlife and risk of Alzheimer disease and vascular dementia. Curr Alzheimer Res 2007;4:103-9. 86 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. Nourhashemi F, Deschamps V, Larrieu S, Letenneur L, Dartigues JF, BarbergerGateau P. Body mass index and incidence of dementia: the PAQUID study. Neurology 2003;60:117-9. Barrett-Connor E, Edelstein SL, Corey-Bloom J, Wiederholt WC. Weight loss precedes dementia in community-dwelling older adults. J Am Geriatr Soc 1996;44:1147-52. Stewart R, Masaki K, Xue QL, et al. A 32-year prospective study of change in body weight and incident dementia: the Honolulu-Asia Aging Study. Arch Neurol 2005;62:55-60. Buchman AS, Wilson RS, Bienias JL, Shah RC, Evans DA, Bennett DA. Change in body mass index and risk of incident Alzheimer disease. Neurology 2005;65:892-7. Kuo HK, Jones RN, Milberg WP, et al. Cognitive function in normal-weight, overweight, and obese older adults: an analysis of the Advanced Cognitive Training for Independent and Vital Elderly cohort. J Am Geriatr Soc 2006;54:97103. Munro HN. Nutrition of the elderly: Introduction. . In: Munro H N, Schlief G, Nestle A, eds. Nutrition of the Elderly. Nutrition Workshop Series. Vevey: Nestec/New York: Raven Press, 1992:1-5. Refsum H, Smith AD, Ueland PM, et al. Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem 2004;50:3-32. Klee GG. Cobalamin and folate evaluation: measurement of methylmalonic acid and homocysteine vs vitamin B(12) and folate. Clin Chem 2000;46:1277-83. 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. 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. McIlroy SP, Dynan KB, Lawson JT, Patterson CC, Passmore AP. Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland. Stroke 2002;33:2351-6. Quadri P, Fragiacomo C, Pezzati R, et al. Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer disease, and vascular dementia. Am J Clin Nutr 2004;80:114-22. Miller JW, Green R, Mungas DM, Reed BR, Jagust WJ. Homocysteine, vitamin B6, and vascular disease in AD patients. Neurology 2002;58:1471-5. Riggs KM, Spiro A, 3rd, Tucker K, Rush D. Relations of vitamin B-12, vitamin B6, folate, and homocysteine to cognitive performance in the Normative Aging Study. Am J Clin Nutr 1996;63:306-14. Lindeman RD, Romero LJ, Koehler KM, et al. Serum vitamin B12, C and folate concentrations in the New Mexico elder health survey: correlations with cognitive and affective functions. J Am Coll Nutr 2000;19:68-76. 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;73:927-33. 87 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. Robins Wahlin TB, Wahlin A, Winblad B, Backman L. The influence of serum vitamin B12 and folate status on cognitive functioning in very old age. Biol Psychol 2001;56:247-65. Prins ND, Den Heijer T, Hofman A, et al. Homocysteine and cognitive function in the elderly: the Rotterdam Scan Study. Neurology 2002;59:1375-80. Duthie SJ, Whalley LJ, Collins AR, Leaper S, Berger K, Deary IJ. Homocysteine, B vitamin status, and cognitive function in the elderly. Am J Clin Nutr 2002;75:908-13. Ravaglia G, Forti P, Maioli F, et al. Homocysteine and cognitive function in healthy elderly community dwellers in Italy. Am J Clin Nutr 2003;77:668-73. Miller JW, Green R, Ramos MI, et al. Homocysteine and cognitive function in the Sacramento Area Latino Study on Aging. Am J Clin Nutr 2003;78:441-7. Wright CB, Lee HS, Paik MC, Stabler SP, Allen RH, Sacco RL. Total homocysteine and cognition in a tri-ethnic cohort: the Northern Manhattan Study. Neurology 2004;63:254-60. Ravaglia G, Forti P, Maioli F, et al. Homocysteine and cognitive performance in healthy elderly subjects. Arch Gerontol Geriatr Suppl 2004:349-57. Schafer JH, Glass TA, Bolla KI, Mintz M, Jedlicka AE, Schwartz BS. Homocysteine and cognitive function in a population-based study of older adults. J Am Geriatr Soc 2005;53:381-8. Elias MF, Sullivan LM, D'Agostino RB, et al. Homocysteine and cognitive performance in the Framingham offspring study: age is important. Am J Epidemiol 2005;162:644-53. 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. Nurk E, Refsum H, Tell GS, et al. Plasma total homocysteine and memory in the elderly: the Hordaland Homocysteine Study. Ann Neurol 2005;58:847-57. Wang HX, Wahlin A, Basun H, Fastbom J, Winblad B, Fratiglioni L. Vitamin B(12) and folate in relation to the development of Alzheimer's disease. Neurology 2001;56:1188-94. 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;346:476-83. Dufouil C, Alperovitch A, Ducros V, Tzourio C. Homocysteine, white matter hyperintensities, and cognition in healthy elderly people. Ann Neurol 2003;53:214-21. 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. Tucker KL, Qiao N, Scott T, Rosenberg I, Spiro A, 3rd. 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. 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 highfunctioning adults: MacArthur Studies of Successful Aging. Am J Med 2005;118:161-7. 88 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. Crystal HA, Ortof E, Frishman WH, Gruber A, Hershman D, Aronson M. Serum vitamin B12 levels and incidence of dementia in a healthy elderly population: a report from the Bronx Longitudinal Aging Study. J Am Geriatr Soc 1994;42:9336. 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. Luchsinger JA, Tang MX, Shea S, Miller J, Green R, Mayeux R. Plasma homocysteine levels and risk of Alzheimer disease. Neurology 2004;62:1972-6. Mooijaart SP, Gussekloo J, Frolich M, et al. 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. 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. Sommer BR, Hoff AL, Costa M. Folic acid supplementation in dementia: a preliminary report. J Geriatr Psychiatry Neurol 2003;16:156-9. Seal EC, Metz J, Flicker L, Melny J. A randomized, double-blind, placebocontrolled study of oral vitamin B12 supplementation in older patients with subnormal or borderline serum vitamin B12 concentrations. J Am Geriatr Soc 2002;50:146-51. Clarke R, Harrison G, Richards S. Effect of vitamins and aspirin on markers of platelet activation, oxidative stress and homocysteine in people at high risk of dementia. J Intern Med 2003;254:67-75. Hvas AM, Juul S, Lauritzen L, Nexo E, Ellegaard J. No effect of vitamin B-12 treatment on cognitive function and depression: a randomized placebo controlled study. J Affect Disord 2004;81:269-73. Nilsson K, Gustafson L, Hultberg B. Improvement of cognitive functions after cobalamin/folate supplementation in elderly patients with dementia and elevated plasma homocysteine. Int J Geriatr Psychiatry 2001;16:609-14. Malouf R, Grimley Evans J. Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people. Cochrane Database Syst Rev 2008:CD004514. Malouf R, Areosa Sastre A. Vitamin B12 for cognition. Cochrane Database Syst Rev 2003:CD004326. Malouf R, Grimley Evans J. The effect of vitamin B6 on cognition. Cochrane Database Syst Rev 2003:CD004393. 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. Durga J, van Boxtel MP, Schouten EG, et al. 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. Mahley RW, Weisgraber KH, Huang Y. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease. Proc Natl Acad Sci U S A 2006;103:5644-51. 89 85. Roberson ED, Mucke L. 100 years and counting: prospects for defeating Alzheimer's disease. Science 2006;314:781-4. 86. Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A metaanalysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 1997;278:1349-56. 87. Bunce D, Kivipelto M, Wahlin A. Utilization of cognitive support in episodic free recall as a function of apolipoprotein E and vitamin B12 or folate among adults aged 75 years and older. Neuropsychology 2004;18:362-70. 88. Bunce D, Kivipelto M, Wahlin A. Apolipoprotein E, B vitamins, and cognitive function in older adults. J Gerontol B Psychol Sci Soc Sci 2005;60:P41-8. 89. Hu P, Bretsky P, Crimmins EM, Guralnik JM, Reuben DB, Seeman TE. Association between serum beta-carotene levels and decline of cognitive function in high-functioning older persons with or without apolipoprotein E alleles: MacArthur studies of successful aging. J Gerontol A Biol Sci Med Sci 2006;61:616-20. 90. Jorm AF. A short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): development and cross-validation. Psychol Med 1994;24:14553. 91. Mahoney FI, Barthel DW. Functional Evaluation: The Barthel Index. Md State Med J 1965;14:61-5. 92. Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 1969;9:179-86. 93. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-98. 94. Ng T-P, Niti M, Chiam P-C, Kua E-H. Ethnic and Educational Differences in Cognitive Test Performance on Mini-Mental State Examination in Asians. Am. J. Geriatr. Psychiatry 2007;15:130-139. 95. Sheikh JI, Yesavage JA. Geriatric Depression Scale (GDS): Recent evidence and development of a shorter version. Clinical Gerontology : A Guide to Assessment and Intervention. NY: The Haworth Press, 1986:165-173. 96. Lim PP, Ng LL, Chiam PC, Ong PS, Ngui FT, Sahadevan S. Validation and comparison of three brief depression scales in an elderly Chinese population. Int J Geriatr Psychiatry 2000;15:824-30. 97. Posner BM, Jette AM, Smith KW, Miller DR. Nutrition and health risks in the elderly: the nutrition screening initiative. Am J Public Health 1993;83:972-8. 98. Revision of body mass index (BMI) cut-offs in Singapore. Available at: http://www.hpb,gov.sg/hpb/default.asp. Accessed August 4, 2006. 99. Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 1990;31:545-8. 100. Wechsler D. WAIS-III administration and scoring manual. San Antonio, TX: The Psychological Corporation, 1997. 101. Wechsler D. WMS-III dministration and scoring manual. San Antonio, TX: The Psychological Corporation, 1997. 90 102. Rey A. L’examen clinique en psychologie. Paris: Presses Universitaires de France, 1964. 103. Delis DC, Kaplan E, Kramer JH. The Delis-Kaplan Executive Function System. San Antonio, TX: The Psychological Corporation, 2001. 104. Smith A. Symbol Digit Modality Test. Los Angeles: Western Psychological Services, 1991. 105. Reitan RM, Wolfson D. The Halstead-Reitan neuropsychological test battery: Theory and clinical interpretation. ed. S. Tucson, AZ: Neuropsychology Press, 1993. 106. Kutlay S, Nergizoglu G, Duman N, et al. Recognition of neurocognitive dysfunction in chronic hemodialysis patients. Ren Fail 2001;23:781-7. 107. Tuppo EE, Arias HR. The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol 2005;37:289-305. 108. Means RT, Jr. Pathogenesis of the anemia of chronic disease: a cytokine-mediated anemia. Stem Cells 1995;13:32-7. 109. Yeh SS, Schuster MW. Geriatric cachexia: the role of cytokines. Am J Clin Nutr 1999;70:183-97. 110. Kalantar-Zadeh K, Ikizler TA, Block G, Avram MM, Kopple JD. Malnutritioninflammation complex syndrome in dialysis patients: causes and consequences. Am J Kidney Dis 2003;42:864-81. 111. Belayev L, Zhao W, Pattany PM, et al. Diffusion-weighted magnetic resonance imaging confirms marked neuroprotective efficacy of albumin therapy in focal cerebral ischemia. Stroke 1998;29:2587-99. 112. Singh S, Mulley GP, Losowsky MS. Why are Alzheimer patients thin? Age Ageing 1988;17:21-8. 113. Wilson CJ, Finch CE, Cohen HJ. Cytokines and cognition--the case for a head-totoe inflammatory paradigm. J Am Geriatr Soc 2002;50:2041-56. 114. Doweiko JP, Nompleggi DJ. The role of albumin in human physiology and pathophysiology, Part III: Albumin and disease states. JPEN J Parenter Enteral Nutr 1991;15:476-83. 115. Davies KJ. Intracellular proteolytic systems may function as secondary antioxidant defenses: an hypothesis. J Free Radic Biol Med 1986;2:155-73. 116. Akiyama H, Barger S, Barnum S, et al. Inflammation and Alzheimer's disease. Neurobiol Aging 2000;21:383-421. 117. Roman GC. Vascular dementia may be the most common form of dementia in the elderly. J Neurol Sci 2002;203-204:7-10. 118. Pearson TA. New tools for coronary risk assessment: what are their advantages and limitations? Circulation 2002;105:886-92. 119. Zoellner H, Hofler M, Beckmann R, et al. Serum albumin is a specific inhibitor of apoptosis in human endothelial cells. J Cell Sci 1996;109 ( Pt 10):2571-80. 120. Keaney JF, Jr., Simon DI, Stamler JS, et al. NO forms an adduct with serum albumin that has endothelium-derived relaxing factor-like properties. J Clin Invest 1993;91:1582-9. 121. Cohen RM, Small C, Lalonde F, Friz J, Sunderland T. Effect of apolipoprotein E genotype on hippocampal volume loss in aging healthy women. Neurology 2001;57:2223-8. 91 122. Moffat SD, Szekely CA, Zonderman AB, Kabani NJ, Resnick SM. Longitudinal change in hippocampal volume as a function of apolipoprotein E genotype. Neurology 2000;55:134-6. 123. Bookheimer SY, Strojwas MH, Cohen MS, et al. Patterns of Brain Activation in People at Risk for Alzheimer's Disease. N Engl J Med 2000;343:450-456. 124. Burggren AC, Small GW, Sabb FW, Bookheimer SY. Specificity of brain activation patterns in people at genetic risk for Alzheimer disease. Am J Geriatr Psychiatry 2002;10:44-51. 125. Herrmann W, Geisel J. Vegetarian lifestyle and monitoring of vitamin B-12 status. Clin Chim Acta 2002;326:47-59. 126. Refsum H, Smith AD. Low vitamin B-12 status in confirmed Alzheimer's disease as revealed by serum holotranscobalamin. J Neurol Neurosurg Psychiatry 2003;74:959-61. 127. Mattson MP, Shea TB. Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci 2003;26:137-46. 128. Morris MS. Homocysteine and Alzheimer's disease. Lancet Neurol 2003;2:425-8. 129. Hassing L, Wahlin A, Winblad B, Backman L. Further evidence on the effects of vitamin B12 and folate levels on episodic memory functioning: a population-based study of healthy very old adults. Biol Psychiatry 1999;45:1472-80. 130. Garcia A, Haron Y, Pulman K, Hua L, Freedman M. Increases 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. 131. Persson J, Lind J, Larsson A, et al. Altered brain white matter integrity in healthy carriers of the APOE epsilon4 allele: a risk for AD? Neurology 2006;66:1029-33. 132. Haan MN, Shemanski L, Jagust WJ, Manolio TA, Kuller L. The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons. JAMA 1999;282:40-6. 133. Whalley LJ, Deary IJ, Starr JM, et al. n-3 Fatty acid erythrocyte membrane content, APOE varepsilon4, and cognitive variation: an observational follow-up study in late adulthood. Am J Clin Nutr 2008;87:449-54. 134. Lee BK, Glass TA, Wand GS, et al. Apolipoprotein E Genotype, Cortisol, and Cognitive Function in Community-Dwelling Older Adults. Am J Psychiatry 2008;165:1456-1464. 135. Buttini M, Orth M, Bellosta S, et al. Expression of human apolipoprotein E3 or E4 in the brains of Apoe-/- mice: isoform-specific effects on neurodegeneration. J Neurosci 1999;19:4867-80. 136. Mahley RW, Huang Y, Weisgraber KH. Detrimental effects of apolipoprotein E4: potential therapeutic targets in Alzheimer's disease. Curr Alzheimer Res 2007;4:537-40. 137. Vogiatzoglou A, Refsum H, Johnston C, et al. Vitamin B12 status and rate of brain volume loss in community-dwelling elderly. Neurology 2008;71:826-32. 138. Elias MF, Robbins MA, Budge MM, et al. Homocysteine and cognitive performance: modification by the ApoE genotype. Neurosci Lett 2008;430:64-9. 139. Flicker L, Martins RN, Thomas J, et al. B-vitamins reduce plasma levels of beta amyloid. Neurobiol Aging 2008;29:303-5. 92 LIST OF PUBLICATIONS 1. Feng L, Ng TP, Chuah L, Niti M, Kua EH. Homocysteine, folate, and vitamin B12 and cognitive performance in older Chinese adults: findings from the Singapore Longitudinal Ageing Study. Am J Clin Nutr. 2006 Dec; 84(6):1506-12. 2. Ng TP, Feng L, Niti M, Yap KB. Albumin, hemoglobin, BMI and cognitive performance in older adults. Age Ageing. 2008 Jul; 37(4):423-9. 3. Ng TP, Feng L, Niti M, Kua EH, Yap KB. Tea consumption and cognitive impairment and decline in older Chinese adults. Am J Clin Nutr. 2008 Jul; 88 (1): 224-231. 4. Ng TP, Niti M, Feng L, Kua EH, Yap KB. Albumin, APOE- ε4 and Cognitive Decline in Community-Dwelling Chinese Older Adults. J Am Geriatr Soc. 2008 Nov 19. [Epub ahead of print] 5. Ng TP, Feng L, Niti M, Kua EH, Yap KB. Folate, Vitamin B-12, Homocysteine and Depressive Symptoms in a Population Sample of Chinese Older Adults. J Am Geriatr Soc. [Accepted for publication] 6. Ng TP, Feng L, Gwee X, Kua EH. Cognitive functioning associated with tea consumption in cognitively well functioning Chinese older adults in the Singapore Longitudinal Ageing Study Cohort. [Submitted] 7. Feng L, Li J, Yap KB, Kua EH, Ng TP. Vitamin B-12, Apolipoprotein E genotype and cognitive performance in community-living older adults: evidence of gene-micronutrient interaction [Submitted] 8. Gao Q, Ng TP, Feng L, Niti M, Kua EH. Omega-3 polyunsaturated fatty acid supplements and cognitive decline: Singapore Longitudinal Aging Studies [drafted] 93 LIST OF CONFERENCE PRESENTATIONS 1. Homocysteine, Folate, Vitamin B-12 and Cognitive Performance in Older Chinese Adults. Podium Session. Society for Geriatric Medicine 8th Scientific Meeting. September 16 -17, 2006. Tan Tock Seng Hospital, Singapore. 2. Vitamin B-12 APOE genotype and Cognitive Performance. Poster Session. Alzheimer's Association Prevention of Dementia conference. June 9-12, 2007. Washington DC, USA 3. Tea Consumption and Cognitive Impairment and Decline. Poster session. 11th International Conference on Alzheimer’s disease. July 26-31, 2008. Chicago, USA. 94 Appendix SLAS Mini-Mental State Examination 95 96 97 98 99 100 [...]... important to find modifiable risk and protective factors for cognitive impairment and decline, in order to prevent cognitive impairment, slow cognitive decline, and delay the onset of dementia This thesis focused on aspects of the relationship between cognitive function, cognitive decline and selected nutritional factors in community-living Chinese older adults, namely albumin, hemoglobin, body mass index,... strategies to maintain and promote cognitive health of the elderly population On the other hand, even small increments in delaying in dementia onset and progression can significantly reduce the global burden of the disease.(2) Therefore, a better understanding of cognitive function and cognitive decline in the elderly population is clearly needed 1.2 Cognitive function and cognitive decline in elderly population... the link between homocysteine, folate, vitamin B-12 and the risk of dementia and cognitive impairment in older adults The thiol-containing amino acid homocysteine links the methionine cycle with the folate cycle and is a sensitive marker for folate and vitamin B-12 deficiency (42, 43) In the methionine cycle, folate 17 and vitamin B-12 are important cofactors for the remethylation of homocysteine to... serum albumin and global cognitive decline (measured by MMSE) and its effect modification by APOE-ε4 among community-living older adults Study III: To examine the independent associations between homocysteine, folate, vitamin B-12 and cognitive performance (measured by MMSE and neuropsychological tests) in community-dwelling elderly Chinese with generally well cognitive (Mini-Mental State Examination... the understanding of the roles of nutritional factors on cognitive functioning in older adults It could provide the evidence 5 and rationale for the design of future clinical trials and the establishment of a prevention and intervention framework for cognitive impairment Furthermore, the introduction of APOE genotype in this study could expand our knowledge of gene-environmental interaction in the development... score equal or above 24) and physical functioning (fully independent on Activities of Daily Living) Study IV: To examine the role of APOE ε4 as a genetic predisposing factor modulating the effect of vitamin B-12 on cognitive function (measured by MMSE and neuropsychological tests) in “cognitively normal” community-dwelling elderly Chinese (no cognitive impairment and cognitive decline) Hopefully, this... mobility, and agerelated physiological and social changes (41), establishing the relationship between cognitive and nutritional status using nutritional markers such as BMI thus has practical significance Body mass index, albumin, and hemoglobin could be examined together to reveal the possible independent effects 2.2 Homocysteine, folate, vitamin B-12 and cognitive function Recent research has investigated... selected nutritional factors: albumin, hemoglobin, low body mass index, folate, homocysteine and vitamin B-12 and potential effect modification by APOE genotype Among these factors, albumin, hemoglobin and 4 body mass index are conventionally considered as clinical markers of general nutritional status while the two B-vitamins are closely associated with homocysteine in one-carbon metabolism Accordingly,... not included in order to preserve integrity and coherence of the thesis as a whole 7 CHAPTER 2 LITERATURE REVIEW The literature review focuses on clinical and epidemiological studies that are related to this thesis 2.1 Nutritional status and cognitive function In the past, both overall dietary intake and conventional clinical markers of nutritional status (albumin, hemoglobin and body mass index) have... important factors (e.g defective dentition, gastrointestinal maldigestion and malabsorption, food-drug interactions) have not been taken into account For that reason, biochemical or anthropometric markers have been utilized to represent nutritional status in other studies As such, literatures on albumin, hemoglobin and body mass index are reviewed in the following sections 2.1.2 Albumin and cognitive function . 2.1 Nutritional status and Cognitive function 8 2.1.1 Diet and cognitive function 2.1.2 Albumin and cognitive function 2.1.3 Hemoglobin and cognitive function 2.1.4 Body mass index and cognitive. between cognitive function, cognitive decline and selected nutritional factors in community-living Chinese older adults, namely albumin, hemoglobin, body mass index, homocysteine, folate, and vitamin. investigate aspects of the relationship between selected nutritional factors (albumin, hemoglobin, low body mass index, homocysteine, folate, and vitamin B-12), and cognitive performance, cognitive