Jacob Selhub

BACKGROUND: In cross-sectional studies, elevated plasma homocysteine levels have been associated with poor cognition and dementia. Studies of newly diagnosed dementia are required in order to establish whether the elevated homocysteine levels precede the onset of dementia or result from dementia-related nutritional and vitamin deficiencies. METHODS: A total of 1092 subjects without dementia (667 women and 425 men; mean age, 76 years) from the Framingham Study constituted our study sample. We examined the relation of the plasma total homocysteine level measured at base line and that measured eight years earlier to the risk of newly diagnosed dementia on follow-up. We used multivariable proportional-hazards regression to adjust for age, sex, apolipoprotein E genotype, vascular risk factors other than homocysteine, and plasma levels of folate and vitamins B12 and B6. RESULTS: Over a median follow-up period of eight years, dementia developed in 111 subjects, including 83 given a diagnosis of Alzheimer's disease. The multivariable-adjusted relative risk of dementia was 1.4 (95 percent confidence interval, 1.1 to 1.9) for each increase of 1 SD in the log-transformed homocysteine value either at base line or eight years earlier. The relative risk of Alzheimer's disease was 1.8 (95 percent confidence interval, 1.3 to 2.5) per increase of 1 SD at base line and 1.6 (95 percent confidence interval, 1.2 to 2.1) per increase of 1 SD eight years before base line. With a plasma homocysteine level greater than 14 micromol per liter, the risk of Alzheimer's disease nearly doubled. CONCLUSIONS: An increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer's disease.

OBJECTIVE: To describe the distribution of plasma homocysteine concentrations in an elderly population and to analyze the relationship between homocysteine level and intake of vitamins and serum levels of vitamins that serve as coenzymes in homocysteine metabolism. DESIGN: Cross-sectional analysis of homocysteine levels and vitamin blood levels and intake in elderly participants in the Framingham Study. SETTING: Population-based cohort in Framingham, Mass. PARTICIPANTS: A total of 1160 adult survivors, aged 67 to 96 years, from the original Framingham Heart Study cohort. MAIN OUTCOME MEASURES: Plasma homocysteine concentration correlated with plasma folate, vitamin B12, pyridoxal-5'-phosphate (PLP), and oral intakes of these vitamins, and the contribution of these vitamins to the prevalence of elevated homocysteine in the population. RESULTS: Homocysteine levels were positively correlated with age after controlling for vitamin concentrations. After controlling for age, sex, and levels of other vitamins, homocysteine exhibited a strong inverse association with plasma folate. When subjects were grouped by deciles of plasma folate, mean homocysteine was significantly higher in the lowest two folate deciles (15.6 and 13.7 mumol/L, respectively) than in the highest decile (11.0 mumol/L). Homocysteine demonstrated weaker, inverse associations with plasma vitamin B12 and PLP. Similar inverse associations were demonstrated between homocysteine and intakes of folate and vitamin B6, but not vitamin B12. Prevalence of high homocysteine (> 14 mumol/L) was 29.3% in this cohort, and was greatest among subjects with low folate status. Inadequate plasma concentrations of one or more B vitamins appear to contribute to 67% of the cases of high homocysteine. CONCLUSIONS: These results indicate a strong association between homocysteine concentration and folate, vitamin B12, and vitamin B6 status, as well as age. It is possible that a substantial majority of the cases of high homocysteine in this older population can be attributed to vitamin status.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) synthesizes 5-methyltetrahydrofolate, the major carbon donor in remethylation of homocysteine to methionine. A common MTHFR mutation, an alanine-to-valine substitution, renders the enzyme thermolabile and may cause elevated plasma levels of the amino acid homocysteine. METHODS AND RESULTS: To assess the potential interaction between this mutation and vitamin coenzymes in homocysteine metabolism, we screened 365 individuals from the NHLBI Family Heart Study. Among individuals with lower plasma folate concentrations ( < 15.4 nmol/L), those with the homozygous mutant genotype had total fasting homocysteine levels that were 24% greater (P<.05) than individuals with the normal genotype. A difference between genotypes was not seen among individuals with folate levels > or = 15.4 nmol/L. CONCLUSIONS: Individuals with thermolabile MTHFR may have a higher folate requirement for regulation of plasma homocysteine concentrations; folate supplementation may be necessary to prevent fasting hyperhomocysteinemia in such persons.

BACKGROUND: Few investigations have evaluated the incremental usefulness of multiple biomarkers from distinct biologic pathways for predicting the risk of cardiovascular events. METHODS: We measured 10 biomarkers in 3209 participants attending a routine examination cycle of the Framingham Heart Study: the levels of C-reactive protein, B-type natriuretic peptide, N-terminal pro-atrial natriuretic peptide, aldosterone, renin, fibrinogen, D-dimer, plasminogen-activator inhibitor type 1, and homocysteine; and the urinary albumin-to-creatinine ratio. RESULTS: During follow-up (median, 7.4 years), 207 participants died and 169 had a first major cardiovascular event. In Cox proportional-hazards models adjusting for conventional risk factors, the following biomarkers most strongly predicted the risk of death (each biomarker is followed by the adjusted hazard ratio per 1 SD increment in the log values): B-type natriuretic peptide level (1.40), C-reactive protein level (1.39), the urinary albumin-to-creatinine ratio (1.22), homocysteine level (1.20), and renin level (1.17). The biomarkers that most strongly predicted major cardiovascular events were B-type natriuretic peptide level (adjusted hazard ratio, 1.25 per 1 SD increment in the log values) and the urinary albumin-to-creatinine ratio (1.20). Persons with "multimarker" scores (based on regression coefficients of significant biomarkers) in the highest quintile as compared with those with scores in the lowest two quintiles had elevated risks of death (adjusted hazard ratio, 4.08; P<0.001) and major cardiovascular events (adjusted hazard ratio, 1.84; P=0.02). However, the addition of multimarker scores to conventional risk factors resulted in only small increases in the ability to classify risk, as measured by the C statistic. CONCLUSIONS: For assessing risk in individual persons, the use of the 10 contemporary biomarkers that we studied adds only moderately to standard risk factors.

BACKGROUND: Epidemiologic studies have identified hyperhomocysteinemia as a possible risk factor for atherosclerosis. We determined the risk of carotid-artery atherosclerosis in relation to both plasma homocysteine concentrations and nutritional determinants of hyperhomocysteinemia. METHODS: We performed a cross-sectional study of 1041 elderly subjects (418 men and 623 women; age range, 67 to 96 years) from the Framingham Heart Study. We examined the relation between the maximal degree of stenosis of the extracranial carotid arteries (as assessed by ultrasonography) and plasma homocysteine concentrations, as well as plasma concentrations and intakes of vitamins involved in homocysteine metabolism, including folate, vitamin B12, and vitamin B6. The subjects were classified into two categories according to the findings in the more diseased of the two carotid vessels: stenosis of 0 to 24 percent and stenosis of 25 to 100 percent. RESULTS: The prevalence of carotid stenosis of > or = 25 percent was 43 percent in the men and 34 percent in the women. The odds ratio for stenosis of > or = 25 percent was 2.0 (95 percent confidence interval, 1.4 to 2.9) for subjects with the highest plasma homocysteine concentrations (> or = 14.4 mumol per liter) as compared with those with the lowest concentrations (< or = 9.1 mumol per liter), after adjustment for sex, age, plasma high-density lipoprotein cholesterol concentration, systolic blood pressure, and smoking status (P < 0.001 for trend). Plasma concentrations of folate and pyridoxal-5'-phosphate (the coenzyme form of vitamin B6) and the level of folate intake were inversely associated with carotid-artery stenosis after adjustment for age, sex, and other risk factors. CONCLUSIONS: High plasma homocysteine concentrations and low concentrations of folate and vitamin B6, through their role in homocysteine metabolism, are associated with an increased risk of extracranial carotid-artery stenosis in the elderly.