Homocysteine and Cognitive Function

Homocysteine and Cognitive Function Aron Troen, Ph.D., 1 and Irwin Rosenberg, M.D. 1 ABSTRACT The prevention and treatment of age-related cognitive impairment and dementia is one of the greatest and most elusive challenges of our time. The prevalence of dementia increases exponentially with age, as does the prevalence of those with micronutrient deficiency. Several studies have shown that elevated homocysteine is correlated with cognitive decline and with cerebral atrophy and that it predicts the subsequent development of dementia in cognitively intact middle-aged and elderly individuals. If elevated homocysteine promotes cognitive dysfunction, then lowering homocysteine by means of B-vitamin supplementation may protect cognitive function by arresting or slowing the disease process. KEYWORDS: Homocysteine, cognitive function, dementia Q1 Educational Objectives: Q1 The prevention and treatment of age-related cognitive impairment and dementia is one of the greatest and most elusive challenges of our time. The prevalence of dementia increases exponentially with age from less than 1% at age 60 years to one in every three individuals by age 85. 1 In addition, many other people experience less severe manifestations of mild cognitive impairment without progressing to frank dementia. The onset of dementia is insidious, and the underlying pathologies are believed to be active for many years before the cognitive loss becomes apparent; however, once apparent, brain damage may be irreversible. 2 It is therefore of the utmost importance to evaluate strategies to prevent or slow agerelated cognitive decline. Several studies have reported that elevated homocysteine is correlated with cognitive decline and with cerebral atrophy, 3 and it predicts the subsequent development of dementia 4 in cognitively normal, middle-aged and elderly individuals. If indeed homocysteine promotes cognitive dysfunction, then lowering homocysteine levels by means of B-vitamin supplementation may protect cognitive function by arresting or slowing the disease process. 5 Many studies have reported associations between elevated plasma homocysteine and cognitive dysfunction. Elevated plasma total homocysteine (thcy) has consistently and convincingly been linked with diseases of the aging brain, including subtle age-related cognitive decline, cerebrovascular disease and stroke, 7 10 Vascular Dementia, 11,12 and Alzheimer disease. 4,13 The appearance of homocysteine as a common denominator in several age-related central nervous system disorders indicates that homocysteine may represent a common pathophysiological pathway in these conditions. ELEVATED thcy AND STROKE Many case control and cross-sectional studies have reported a positive association between hyperhomocysteinemia 204 Homocysteine, B-Vitamins, and Risk of Cardiovascular Disease; Editor in Chief, Jan Jacques Michiels, M.D., Ph.D.; Guest Editors, Robert Clarke, M.D., Yvo Smulders, Ph.D., Brian Fowler, Ph.D., and Coen D.A. Stehouwer, M.D. Seminars in Vascular Medicine, Volume 5, Number 2, 2005. Address for correspondence and reprint requests: Aron Troen, Ph.D., Nutrition and Neurocognition Laboratory and Vitamin Metabolism and Aging Laboratory, The Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts. 1 Nutrition and Neurocognition Laboratory and Vitamin Metabolism and Aging Laboratory, The Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111. Copyright # 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001 USA. Tel: +1(212)584-4662. 1528-9648,p;2005,05,02,204,209,ftx,en;svm00236x.

HOMOCYSTEINE AND COGNITIVE FUNCTION/TROEN, ROSENBERG 205 and stroke and heart disease. A metaanalysis of 27 case control studies reported an odds ratio for cerebrovascular disease of 1.9 per 5 mm increase in thcy, 10 whereas another reported an odds ratio of 3.97 for a thcy level above the 95th percentile. 14 Although some prospective studies failed to confirm these observations, 15 17 most reported significant associations between elevated homocysteine and risk of stroke. 8,18 20 The Framingham study of 1947 older people reported an odds ratio of 1.82 (95% confidence interval [CI] 1.14 2.91) for the highest compared with the lowest quartile of homocysteine in a 9.9-year follow up. 8 A metaanalysis of the C677T polymorphism for the methyletetrahydrofolate reductase gene and risk of stroke involving 13,928 individuals reported an odds ratio of 1.26 for those with the TT genotype compared with those with the CC genotype. This TT genotype results in a higher homocysteine level, which provides some support for causality. 21 ELEVATED thcy AND DEMENTIA The publication of three cross-sectional studies in 1997 1998 that reported on the association of elevated homocysteine with Alzheimer disease prompted a substantial increase in interest in the homocysteine hypothesis of Alzheimer disease. 13,22,23 Since then, a small number of studies have not observed this association, 24 26 but many more studies have confirmed these observations. 27 31 The strongest associations were reported by Clarke et al. in a longitudinal case control study comparing homocysteine levels taken during life from 76 cases with a histological diagnosis of Alzheimer disease made postmortem and 108 controls without cognitive impairment. 13 Clarke et al. reported an odds ratio of 4.5 (95% CI 2.2 9.2) for histologically confirmed Alzheimer disease associated with homocysteine in the upper compared with the lower third, after controlling for age, sex, smoking, social class, and ApoE genotype. When folate and B 12 were controlled for, in addition to the other variables, the odds ratio increased to 5.1, indicating that the effects of homocysteine may be independent of vitamin status. In the latter study, homocysteine values were measured annually and were found to be relatively stable during follow-up, compared with values at enrollment, and homocysteine levels appeared to be independent of the duration of illness or severity of dementia before enrollment. Moreover, elevated homocysteine predicted the extent of medial temporal lobe atrophy, as assessed on a computed tomography scan of dementia patients. 13 Several studies of clinically diagnosed Alzheimer disease correlated homocysteine with the severity of cognitive impairment; 23,29 however, without histological confirmation, one cannot exclude the possibility that the more severely impaired cases did not have concomitant vascular disease. Indeed, Alzheimer and cerebrovascular disease frequently overlap, 32 36 and the presence of vascular pathology contributes synergistically to the severity of cognitive impairment beyond what would be predicted on the basis of the Alzheimer pathology alone. 37 High levels of homocysteine are also found in studies of non- Alzheimer-type Vascular Dementia. 7,11,29,30,38 Given its association with other forms of cardiovascular and peripheral vascular disease, homocysteine might play a role in the pathogenesis of vascular dementia through brain infarctions or white-matter changes (leukoencephalopathy) from small vessel disease. 12 Fassbender et al. found that mean plasma thcy was higher in subcortical vascular encephalopathy that was associated with what he defined as microvessel disease (mean 18.2 8.5 SD mm thcy) than in association with large-vessel disease (mean 13.8 7.6 mm). 39 In this study, plasma homocysteine was a stronger risk factor for subcortical vascular dementia than was age, hypertension, diabetes, or smoking, with an odds ratio of 5.7 (95% CI 2.5 12.9). 11 The most compelling evidence to date comes from a prospective study of 1092 dementia-free elderly individuals from the Framingham cohort. This study reported that baseline hyperhomocysteinemia (thcy > 14 mm) was associated with almost double the risk of dementia and of Alzheimer s disease over an 8-year follow-up period. 4 Using multivariate proportional hazards regression analysis to adjust for age, sex, apolipoprotein-e genotype, and vascular risk factors other than homocysteine and plasma levels of folate and vitamins B 12 and B 6, the relative risk for dementia was 1.4 (95% CI 1.1 1.8) per standard deviation increase in either baseline or follow-up plasma homocysteine. The corresponding relative risks for Alzheimer disease were even higher, at 1.7 (95% CI 1.2 2.4) for baseline and 1.5 (95% CI 1.1 2.0) for follow-up. In other words, a 5-mM increase in plasma homocysteine levels at baseline increased the risk of development of dementia by 40 70%. The risk of Alzheimer disease attributable to a plasma thcy in the highest age-specific quartile of our population was 16%, which is comparable to the population-attributable risk of having at least one apolipoprotein-e e4 allele (22%). 40 Nevertheless, these data have yet to be replicated. A recent attempt to do so in 679 subjects of the Washington Heights Inwood Columbia Aging study found no association between baseline homocysteine and subsequent risk of dementia or cognitive decline. 25 However, in comparison to the Framingham study, subjects had lower educational levels, a higher prevalence of diabetes, a narrower range of homocysteine levels, and a shorter mean follow-up time, all of which might have lessened the likelihood of detecting a significant association. HOMOCYSTEINE AND MILD COGNITIVE IMPAIRMENT Several cross-sectional studies conducted by our group 41 43 and many others 29,44 46 in dementia-free

206 SEMINARS IN VASCULAR MEDICINE/VOLUME 5, NUMBER 2 2005 subjects have shown a correlation between elevated plasma homocysteine and poor performance on neuropsychological tests. One study of 156 community-dwelling, self-caring, nondemented elderly found that Cambridge Cognitive Examination scores were inversely related to thcy values, even after correction for age, gender, IQ, and depression (r 2 ¼ 0.11, r ¼ 0.33, p ¼.002). 44 Our colleagues investigated the associations between plasma concentrations of folate, vitamin B 12, vitamin B 6, and homocysteine and scores on a battery of cognitive tests in 70 men, aged 54 81 years, participating in the Normative Aging Study. 42 Lower folate and vitamin B 12 concentrations were associated with poorer spatial copying skills (r ¼ 0.25 and 0.35, respectively). In addition, plasma homocysteine concentration, which is inversely correlated with plasma folate and vitamin B 12 concentrations, was a stronger predictor of spatial copying performance than either vitamin (r ¼ 0.39, p ¼.0009). In a population-based study of 1270 subjects aged over 60 years, Morris et al. (2001) found that the odds of passing a simple memory (word recall) test were reduced by 70% for thcy > 13.7 mm (odds ratio 0.3; 95% CI 0.2 0.7). 41 In a Scottish study of two cohorts born in 1921 and 1936, only the older cohort showed significant inverse correlations between homocysteine and performance on the Raven s Progressive Matrices (r ¼ 0.22), Block Design (r ¼ 0.27), and Digit Span tests (r ¼ 0.25). 45 The study by Bell et al. is notable for showing that elderly patients with depression who had lower cognitive screening test scores had significantly higher homocysteine concentrations than did either younger depression patients or elderly depression patients with normal cognitive screening test scores. 43 Several prospective studies reported an association between baseline homocysteine and subsequent cognitive decline in nondemented individuals. An early analysis of the relation of homocysteine to change in cognitive scores in the Rotterdam study failed to detect an association of baseline homocysteine and cognitive decline. 47 However, this early study used the relatively insensitive Mini Mental Status Examination and a short 3-year follow up. Subsequent analysis at after 6 years with more rigorous neuropsychological testing 48 revealed a highly significant association of baseline homocysteine with subsequent decline in discrete cognitive domains of attention and information processing and verbal learning and memory. In contrast, blood folate correlated only with Delayed Recall verbal learning and memory at baseline, and no correlations were observed for vitamin B 12. In a small study of 32 community adults greater than 65 years old in Wales, McCaddon et al. reported that high baseline thcy predicted follow-up cognitive scores on word recall and constructional praxis tests at a 5-year follow up, independent of age, sex renal function, B-vitamins, smoking, or hypertension. 49 Another recent longitudinal study of 499 people aged 70 79 years, from the MacArthur Studies of Successful Aging, who were initially selected as high-functioning older adults, found that high baseline homocysteine and low folate, vitamin B 12, or vitamin B 6 status were each associated with worse baseline cognitive performance on a battery of tests that included confrontation naming, word recall, figure copying, and a test of conceptual reasoning. However, in the longitudinal follow-up, those in the lowest quartile of folate had a 1.6-fold increased risk of being in the worst quartile of cognitive decline, independent of homocysteine, whereas the association between homocysteine and cognitive decline was largely accounted for by low levels of folate. 50 HOMOCYSTIENE, BRAIN ATROPHY, AND WHITE-MATTER LESIONS Structural brain imaging has provided important information on the relation of homocysteine to functional cognitive dysfunction and to underlying cerebrovascular and neurodegenerative changes. The initial case control study of homocysteine and Alzheimer disease by Clarke et al. was prompted by the observation of rapid medial temporal lobe atrophy on x-ray computed tomography scans of patients with Alzheimer disease. 12 In a subsequent analysis of the same cohort, Clarke et al. reported a high correlation between thcy and leukoaraiosis on computed tomography scan of the brains of these patients. 51 The white-matter lesions were more pronounced in the deep white matter and were most prevalent in individuals with Alzheimer disease. Such associations appear to depend on the age, gender, and condition of the subjects examined. For example, in a cross-sectional study of homocysteine and brain atrophy, Sachdev 52 compared associations of white-matter hyperintensities with cognition in a case control study of stroke patients and of a healthy group of 60 64-year-old adults. Contrary to expectations, general brain atrophy was not associated with homocysteine in stroke patients. Instead, the severity of deep whitematter hyperintensity was significantly correlated with homocysteine (r ¼ 0.167). Higher homocysteine was also associated with poorer measures of attention and executive function in both cases and controls (particularly on the Trails-B test). Overall cognitive performance was significantly correlated with white-matter hyperintensities, stroke number, and stroke volume, but homocysteine was only associated with stroke number and not the extent of lesions. In healthy 60 64-yearold men and women, homocysteine showed a weak but significant correlation with the volume of deep whitematter hyperintensities (r ¼ 0.135), but again, it did not correlate with brain atrophy. These correlations were driven by male gender and, when analyzed separately, did not reach significance in the women, possibly because on average, women had more severe white-matter

HOMOCYSTEINE AND COGNITIVE FUNCTION/TROEN, ROSENBERG 207 damage but lower homocysteine concentrations. Another small study of psychogeriatric inpatients examined the relationship of homocysteine, folate, and vitamin B 12 with magnetic resonance imaging (MRI) markers of neuropathology. 53 Here, too, homocysteine was associated with severity of white-matter hyperintensity, but not with measures of brain volume or atrophy. Intriguingly, folate was associated with hippocampal and amygdalar volume and was negatively associated with whitematter damage, even though no individuals were clinically vitamin deficient. In the Rotterdam Brain Scan Study of 1077 men and women aged 60 90 years, plasma homocysteine concentrations were associated with risk of severe deep and periventricular white-matter lesions and of silent brain infarcts in a cross-sectional analysis of MRI scans. 54 These lesions were three times more common in individuals in the top quintile of homocysteine values compared with the lowest four quintiles. The severity of the white-matter lesions increased with increasing homocysteine levels, and the association remained significant even after adjustment for atherosclerotic disease and the presence of silent infarcts. A subsequent study in the same cohort found region-specific atrophy in the cortex and hippocampus, but not in the amygdala. 55 Crosssectional neuropsychological test scores of participants were significantly associated with elevated plasma homocysteine with an adjusted difference of 0.26 (95% CI 0.37 to 0.14) for psychomotor speed, 0.13 (95% CI 0.27 to 0.01) for memory function, and 0.20 (95% CI 0.30 to 0.11) for global cognitive function for the top quintile, compared with the lower four quintiles of Hcy, respectively. These associations were not mediated by structural brain changes in white matter or global atrophy on MRI. 56 A similar analysis was conducted in the prospective Epidemiology of Vascular aging cohort (EVA). 57 Baseline homocysteine concentrations of more than 15 mm increased the risk of cognitive deterioration up to 4 years later by a factor of 2.7, on MMSE scores and the digit symbol coding and Trail making tests of executive function and attention, although in this cohort the Trails test did not reach significance. High homocysteine was also correlated with poor performance on cognitive tests in cross-sectional analyses. These results were not changed when the analyses were adjusted for MRI white-mater ratings, indicating that in this cohort, the cognitive impairment was not mediated by whitematter damage. In the Framingham Offspring study of 1539 men and women aged 26 81 years (mean age 55 10 years) who were free of clinical stroke, dementia, multiple sclerosis, and brain injury, higher plasma homocysteine concentrations were related to global brain atrophy as determined by MRI by measuring the ratio of the total brain volume to total cranial volume. 3 Greater atrophy was associated with poorer performance on neuropsychological tests of executive function and attention (including the Trails B test). Higher homocysteine was also directly related to poorer performance on tests of attention and concentration. CONCLUSION Most of the available evidence supports an association of homocysteine with a wide spectrum of central nervous system dysfunction and pathology. Moreover, the strong graded associations between plasma homocysteine levels and the risk of developing not only cerebrovascular disease, brain atrophy, and dementia but also cognitive decline over time in otherwise healthy older adults are consistent with a causal role for homocysteine in cognitive deterioration. Although the use of different tests and populations makes it difficult to compare studies directly, the weight of the evidence is consistent with an involvement of homocysteine in impairing discrete areas of cognitive function including visuospatial skills, memory, nonverbal intelligence, and speed of information processing. Interestingly, these patterns of cognitive deficits are consistent with what would be predicted to result from a subcortical vascular pathology. Nevertheless, such compelling epidemiological data cannot establish causality, and although there are plausible mechanisms to account for the associations, it remains to be demonstrated whether elevated homocysteine mediates or is merely an indicator of metabolic abnormalities that accelerate brain aging. Although epidemiological studies can try to isolate the relationships of homocysteine to functional and structural measures of central nervous system integrity from those of its metabolic determinants, homocysteine is never biologically independent of its determinants, and any rise in plasma homocysteine is preceded by a metabolic or physiologic change. Isolating homocysteine as cause or effect requires the use of experimental models. 58 Identifying brain lesions and cognitive domains that are specifically determined by homocysteine in human studies may prove similarly challenging. Even so, the finding that high baseline homocysteine predicts incident dementia long before the manifestation of cognitive decline 4 indicates that homocysteine is an early marker for the incipient disease process. Ultimately, clinical trials of B-vitamin supplementation will have to determine whether homocysteine lowering can prevent or slow the progression of age-related cognitive decline. The solution to this challenge is eagerly anticipated. ACKNOWLEDGMENTS This work was supported by a grant from the Alzheimer s Association (NIRG-02 4119) and by the U.S. Department of Agriculture under cooperative

208 SEMINARS IN VASCULAR MEDICINE/VOLUME 5, NUMBER 2 2005 Q2 Q3 Q4 Q5 agreement No.58-1950-9-001. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the U.S. Department of Agriculture. REFERENCES 1. Katzman R, Kawas C. The epidemiology of dementia and Alzheimer disease. In: Terry RD, Katzman R, Bick KL, eds. Alzheimer Disease. New York: Rave Press; 1994 Q2 2. Smith AD. Homocysteine, B vitamins and cognitive deficit in the elderly.. Am J Clin Nutr 2002 Q3 ;75:908 913 3. Beiser A, Au R, DeCarli C, et al. Higher levels of plasma homocysteine are associated with subsequent lower brain volume and poorer performance on tests of attention and concentration: the Framingham offspring study. The 8th International Conference on Alzheimer s Disease and Related Disorders. Stockholm, Sweden, 2002 Q4 4. 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 5. Selhub J, Bagley LC, Miller J, Rosenberg IH. B vitamins, homocyseine, and neurocognitive function in the elderly. Am J Clin Nutr 2000;71:614S 620S 6. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 1969 Q5 ;56:111 128 7. Yoo JH, Chung CS, Kang SS. Relation of plasma homocyst(e)ine to cerebral infarction and cerebral atherosclerosis. Stroke 1998;29:2478 2483 8. Bostom AG, Rosenberg IH, Silbershatz H, et al. Nonfasting plasma total homocysteine levels and stroke incidence in elderly persons: the Framingham Study. Ann Intern Med 1999;131:352 355 9. Brattstrom LE, Hardevo JE, Hultverg BL. Moderate homocysteinemia a possible risk factor for arteriosclerotic cerebrovascular disease. Stroke 1984;15:1012 1016 10. Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995;274:1049 1057 11. Fassbender K, Mielke O, Bertsch T, Nafe B, Froschen S, Hennerici M. Homocysteine in cerebral macroangiography and microangiopathy. Lancet 1999;353:1586 1587 12. Hogervorst E, Ribeiro HM, Molyneux A, Budge M, Smith AD. Plasma homocysteine levels, cerebrovascular risk factors, and cerebral white matter changes (leukoaraiosis) in patients with Alzheimer disease. Arch Neurol 2002;59:787 793 13. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998;55:1449 1455 14. Moller J, Nielsen GM, Tvedegaard KC, Andersen NT, Jorgensen PE. A meta-analysis of cerebrovascular disease and hyperhomocysteinaemia. Scand J Clin Lab Invest 2000;60: 491 499 15. Alfthan G, Pekkanen J, Jauhiainen M, et al. Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis 1994;106:9 19 16. Fallon UB, Elwood P, Ben-Shlomo Y, Ubbink JB, Greenwood R, Smith GD. Homocysteine and ischaemic stroke in men: the Caerphilly study. J Epidemiol Community Health 2001;55:91 96 17. Verhoef P, Hennekens CH, Malinow MR, Kok FJ, Willett WC, Stampfer MJ. A prospective study of plasma homocyst(e)ine and risk of ischemic stroke. Stroke 1994;25:1924 1930 18. Bots ML, Launer LJ, Lindemans J, et al. Homocysteine and short-term risk of myocardial infarction and stroke in the elderly: the Rotterdam Study. Arch Intern Med 1999;159:38 44 19. Perry IJ, Refsum H, Morris RW, Ebrahim SB, Ueland PM, Shaper AG. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995;346:1395 1398 20. Ridker PM, Manson JE, Buring JE, Shih J, Matias M, Hennekens CH. Homocysteine and risk of cardiovascular disease among postmenopausal women. JAMA 1999;281: 1817 1821 21. Casas J, Bautista L, Smeeth L, Sharma P, Hingorani A. Homocysteine and stroke: evidence on a causal link from mendelian randomization. Lancet 2005;365:224 232 22. Joosten E, Lesaffre E, Riezler R, et al. Is metabolic evidence for vitamin B-12 and folate deficiency more frequent in elderly patients with Alzheimer s disease? J Gerontol A Biol Sci Med Sci 1997;52:M76 M79 23. McCaddon A, Davies G, Hudson P, Tandy S, Cattell H. Total serum homocysteine in senile dementia of Alzheimer type. Int J Geriatr Psychiatry 1998;13:235 239 24. Miller JW, Green R, Mungas DM, Reed BR, Jagust WJ. Homocysteine, vitamin B6, and vascular disease in AD patients. Neurology 2002;58:1471 1475 25. Luchsinger JA, Tang MX, Shea S, Miller J, Green R, Mayeux R. Plasma homocysteine levels and risk of Alzheimer disease. Neurology 2004;62:1972 1976 26. Ravaglia G, Forti P, Maioli F, et al. Elevated plasma homocysteine levels in centenarians are not associated with cognitive impairment. Mech Ageing Dev 2000;121:251 261 27. Storey SG, Suryadevara V, Aronow WS, Ahn C. Association of plasma homocysteine in elderly persons with atherosclerotic vascular disease and dementia, atherosclerotic vascular disease without dementia, dementia without atherosclerotic vascular disease, and no dementia or atherosclerotic vascular disease. J Gerontol A Biol Sci Med Sci 2003;58:M1135 M1136 28. Religa D, Styczynska M, Peplonska B, et al. Homocysteine, apolipoprotein E and methylenetetrahydrofolate reductase in Alzheimer s disease and mild cognitive impairment. Dement Geriatr Cogn Disord 2003;16:64 70 29. Lehmann M, Gottfries CG, Regland B. Identification of cognitive impairment in the elderly: homocysteine is an early marker. Dement Geriatr Cogn Disord 1999;10:12 20 30. Leblhuber F, Walli J, Artner-Dworzak E, et al. Hyperhomocysteinemia in dementia. J Neural Transm 2000;107: 1469 1474 31. Nilsson K, Gustafson L, Hultberg B. Plasma homocysteine concentration relates to the severity but not to the duration of Alzheimer s disease. Int J Geriatr Psychiatry 2004;19:666 672 32. de la Torre JC. Cerebromicrovascular pathology in Alzheimer s disease compared to normal aging. Gerontology 1997;43:26 43 33. Kalaria RN, Ballard C. Overlap between pathology of Alzheimer disease and vascular dementia. Alzheimer Dis Assoc Disord 1999;13:S115 S123 34. Moody DM, Brown WR, Challa VR, Ghazi-Birry HS, Reboussin DM. Cerebral microvascular alterations in aging,

HOMOCYSTEINE AND COGNITIVE FUNCTION/TROEN, ROSENBERG 209 leukoaraiosis, and Alzheimer s disease. Ann N Y Acad Sci 1997;826:103 116 35. Morris JH. Vascular dementia. In: Esiri MM, Morris JH, eds. The Neuropathology of Dementia. Cambridge: Cambridge University Press; 1997:137 173 36. O Brien MD. Vascular dementia is underdiagnosed. Arch Neurol 1988;45:797 798 37. Nagy Z, Esiri MM, Jobst KA, et al. The effects of additional pathology on the cognitive deficit in Alzheimer disease. J Neuropathol Exp Neurol 1997;56:165 170 38. Pollak RD, Pollak A, Idelson M, Bejarano-Achache I, Doron D, Blumenfeld A. The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and vascular dementia. J Am Geriatr Soc 2000;48:664 668 39. Fassbender K, Mielke O, Bertsch T, Nafe B, Fröschen S, Hennerici M. Homocysteine in cerebral macroangiography and microangiopathy. Lancet 1999;353:1586 1587 40. Brookmeyer R, Curriero FC. Survival curve estimation with partial non-random exposure information. Stat Med 2002; 21:2671 2683 41. 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 42. Riggs KM, Spiro Ar, Tucker K, Rush D. Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study. Am J Clin Nutr 1996;63:306 314 43. Bell IR, Edman JS, Selhub J, et al. Plasma homocysteine in vascular disease and in nonvascular dementia of depressed elderly people. Acta Psychiatr Scand 1992;86:386 390 44. Budge M, Johnston C, Hogervorst E, et al. Plasma total homocysteine and cognitive performance in a volunteer elderly population. Ann N Y Acad Sci 2000;903:407 410 45. 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;75:908 913 46. 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;78:441 447 47. 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;150:283 289 48. Teunissen CE, Blom AH, Van Boxtel MP, et al. Homocysteine: a marker for cognitive performance? A longitudinal follow-up study. J Nutr Health Aging 2003;7:153 159 49. McCaddon A, Hudson P, Davies G, Hughes A, Williams JH, Wilkinson C. Homocysteine and cognitive decline in healthy elderly. Dement Geriatr Cogn Disord 2001;12:309 313 50. Kado D, Karlamangla A, Huang M, et al. Homocysteine versus the vitamins folate, B6 and B12 as predictors of cognitive function and cognitive decline in older high functioning adults: MacArthur studies of successful aging. Am J Med 2005: In press 51. Clarke R, Joachim C, Esiri M, et al. Leukoaraiosis at presentation and disease progression during follow-up in histologically confirmed cases of dementia. Ann N Y Acad Sci 2000;903:497 500 52. Sachdev P. Homocysteine, cerebrovascular disease and brain atrophy. J Neurol Sci 2004;226:25 29 53. Scott TM, Tucker KL, Bhadelia A, et al. Homocysteine and B vitamins relate to brain volume and white-matter changes in geriatric patients with psychiatric disorders. Am J Geriatr Psychiatry 2004;12:631 638 54. Vermeer SE, van Dijk EJ, Koudstaal PJ, et al. Homocysteine, silent brain infarcts, and white matter lesions: The Rotterdam Scan Study. Ann Neurol 2002;51:285 289 55. den Heijer T, Vermeer SE, Clarke R, et al. Homocysteine and brain atrophy on MRI of non-demented elderly. Brain 2003;126:170 175 56. Prins ND, Den Heijer T, Hofman A, et al. Homocysteine and cognitive function in the elderly: the Rotterdam Scan Study. Neurology 2002;59:1375 1380 57. Dufouil C, Alperovitch A, Ducros V, Tzourio C. Homocysteine, white matter hyperintensities, and cognition in healthy elderly people. Ann Neurol 2003;53:214 221 58. Troen AM, Lutgens E, Smith DE, Rosenberg IH, Selhub J. The atherogenic effect of excess methionine intake. Proc Natl Acad Sci USA 2003;100:15089 15094