Folate is essential for the de novo biosynthesis of purines and thymidylate, and is an important ... more Folate is essential for the de novo biosynthesis of purines and thymidylate, and is an important mediator in the transfer of methyl groups for DNA methylation. Folate deficiency, Nutr 1997;65:46-52. KEY WORDS Folate, DNA methylation, DNA damage, PS3' carcinogenesis i From the Vitamin Bioavailability Laboratory, Jean Mayer US Department of Agriculture
The quality oflife ofaging individuals depends profoundly on their capacity for physical mobility... more The quality oflife ofaging individuals depends profoundly on their capacity for physical mobility, mental alert-
The plasma homocysteine response to mcthionine loading was assessed in vitamin B-6-and folate-def... more The plasma homocysteine response to mcthionine loading was assessed in vitamin B-6-and folate-deficient sponses to methioninc loading in humans.
The catabolism ofhomocysteine through cysconcentrations are not a good indicator of vitamin B-6 s... more The catabolism ofhomocysteine through cysconcentrations are not a good indicator of vitamin B-6 status.
Catecholamine autoxidation produces reactive oxygen species that have been implicated in the loss... more Catecholamine autoxidation produces reactive oxygen species that have been implicated in the loss of dopaminergic neurons in the nigrostriatal region of the brain that occurs during normal aging and in Parkinson's disease. In the present study, the potential protective effects of catecholamine O-methylation and of melatonin against catecholamine autoxidation-induced protein damage were assessed in vitro using the oxygen radical absorbance capacity (ORAC) assay. The rate of oxidation of the fluorescent protein porphyridium cruentum fl-phycoerythrin (/3-PE) caused by the oxidizing agent CuSO4 was shown to be accelerated by addition of the catecholamines dopamine and L-dopa. Replacement of dopamine and L-dopa in the assay with their O-methylated metabolites 3-O-methyldopamine and 3-O-methyldopa significantly decreased the rate of fl-PE oxidation. When melatonin was added to the ORAC assay in combination with dopamine or L-dopa, the rate of/3-PE oxidation was decreased as well. These findings were consistent with the following interpretations: (1) O-methylated catecholamines are less susceptible to autoxidation than their nonmethylated precursors, and (2) melatonin, which has recently been shown to be a powerful antioxidant, is capable of scavenging free radicals produced during catecholamine autoxidation. These findings suggest that O-methylation and melatonin may be important components of the brain's antioxidant defenses against catecholamine autoxidation and may protect against consequent dopaminergic neurodegeneration.
Background: Elevated plasma homocysteine (hyperhomocysteinemia), an independent risk factor for v... more Background: Elevated plasma homocysteine (hyperhomocysteinemia), an independent risk factor for vascular disease, has been reported to be inversely correlated with objective measures of cognitive function in patients with Alzheimer disease and in community-dwelling older adults. Objective: We evaluated the cross-sectional relation between total plasma homocysteine concentration and cognitive function in elderly Latinos (aged ≥ 60 y; n = 1789) participating in the Sacramento Area Latino Study on Aging. Design: Global cognitive function was assessed by using the Modified Mini-Mental State Examination, and specific cognitive functions were assessed by using 6 instruments developed for crosscultural and multilingual neuropsychological evaluation of older persons. Associations between the cognitive function scores and total plasma homocysteine concentrations were then measured by multiple regression analysis with control for potential confounding by nutrient status (red blood cell folate, plasma vitamin B-12), kidney function (serum creatinine), demographic variables (age, sex, education, acculturation), and depressive symptoms. Results: Modest inverse associations were found between homocysteine concentrations and several indexes of cognitive function, including the global Modified Mini-Mental State Examination assessment and the picture-association, verbal attention-span, and pattern-recognition tests (P ≤ 0.05). Demographic variables, particularly age and education, were more strongly associated with cognitive function scores than was homocysteine. Conclusions: Homocysteine is a modest independent predictor of cognitive function in community-dwelling elderly Latinos. Reducing plasma homocysteine concentrations by administering B-vitamin supplements may provide some protection against cognitive decline in this and other elderly populations, but the effect may be limited.
Background: High concentrations of homocysteine have been linked to a greater risk of Alzheimer d... more Background: High concentrations of homocysteine have been linked to a greater risk of Alzheimer disease, dementia, and cognitive decline. Objective: We evaluated the association between homocysteine and 4.5-y combined incidences of dementia and cognitive impairment without dementia (CIND) in a cohort of 1779 Mexican Americans aged 60 -101 y. Design: Homocysteine, red blood cell (RBC) folate, and plasma vitamin B-12 were measured at baseline. New cases of dementia or CIND were ascertained by neuropsychological and clinical examinations and expert adjudication. We used proportional hazards models to estimate the risk of homocysteine-associated dementia or CIND and the influence of RBC folate and plasma vitamin B-12 on that association. Results: High homocysteine concentrations were associated with a greater risk of dementia or CIND: hazard ratio (HR): 2.39; 95% CI: 1.11, 5.16. Plasma vitamin B-12 modified the association between homocysteine and the outcome. The rates of dementia or CIND associated with homocysteine for those in the lowest and highest tertiles of vitamin B-12, respectively, were significantly higher (HR: 1.61, P ҃ 0.04) and lower (HR: 0.94, P ҃ 0.015) than the risk for those in the middle tertile. Conclusions: Homocysteine is an independent risk factor for both dementia and CIND. Higher plasma vitamin B-12 may reduce the risk of homocysteine-associated dementia or CIND.
A common polymorphism (775G>C) in the vitamin B12 transport protein, transcobalamin II (TCII), ha... more A common polymorphism (775G>C) in the vitamin B12 transport protein, transcobalamin II (TCII), has been identified in which proline replaces arginine at codon 259. We determined the influence of TCII genotype on indices of B12 status, including total serum B12, the amount of B12 bound to TCII (holoTCII), methylmalonic acid, and homocysteine, in 128 healthy older adults (ages 40-88 years). Mean total B12 and homocysteine concentrations were not significantly different among the 3 genotypes. Mean holoTCII concentration was significantly higher in those subjects homozygous for the proline form of TCII (PP) compared with those homozygous for the arginine form (RR) and heterozygotes (PR) (P < .006). In addition, mean methylmalonic acid concentrations were significantly lower in the PP and PR groups compared with the RR group (P < .02). The PP genotype may be more efficient in delivering B12 to tissues, resulting in enhanced B12 functional status. TCII genotype may thus influence susceptibility to B12 deficiency. (Blood. 2002;100:718-720)
It has previously been shown that choline deficiency causes depletion of hepatic folate concen tr... more It has previously been shown that choline deficiency causes depletion of hepatic folate concen tration in rats. Two separate experiments were under taken to investigate the converse phenomenon: whether folate deficiency would lead to depletion of hepatic choline. In Experiment 1, severe folate deficiency was induced in rats by feeding an amino acid-defined diet containing (per kg diet) 1.4 g choline, O mg folate and 10 g succinylsulfathiazole. Control rats were fed the same diet containing 8 mg folate/kg. After 4 wk, plasma and hepatic folate concentrations were significantly depleted in the severely folate-defident rats compared with controls (P < 0.001), and hepatic choline and phosphocholine concentrations were 65 and 80% lower, respectively (P < 0.001). In Experiment 2, moderate folate deficiency was induced in rats by feeding the same diet as described above, but with the succinylsul fathiazole omitted. After 24 wk, significant systemic folate deficiency was present in the moderately folatedeficient rats compared with controls (P < 0.001). A modest reduction (36%, P = 0.087) in hepatic choline concentration was observed in the moderately folatedeficient rats compared with controls. No significant differences in hepatic phosphocholine concentrations were detected between the two groups. These results indicate that severe folate deficiency causes secondary hepatic choline deficiency in rats. J. Nutr. 124: 2197Nutr. 124: -2203Nutr. 124: , 1994.
Background: Higher intake of folate and vitamins B 6 (pyridoxine hydrochloride) and B 12 (cyanoco... more Background: Higher intake of folate and vitamins B 6 (pyridoxine hydrochloride) and B 12 (cyanocobalamin) may decrease the risk of Alzheimer disease (AD) through the lowering of homocysteine levels.
Folate plays a key role in nucleic acid synthesis. As a consequence, the most conspicuous complic... more Folate plays a key role in nucleic acid synthesis. As a consequence, the most conspicuous complication of folate deficiency or of derangements of folate metabolism is megaloblastic macrocytic anemia caused by interdiction of normal proliferation of rapidly dividing bone marrow cells. Other rapidly dividing cells, including those in the gastrointestinal tract, may also be affected by the megaloblastic process. This may result in malabsorption. However, there is mounting evidence to indicate that there are other earlier manifestations of folate deficiency or of longstanding suboptimal folate nutrition. Chief among these manifestations of folate deficiency are an increased predisposition to occlusive vascular disease and thrombosis, which have been linked to increased levels of homocysteine found in folate deficiency and abnormal states of folate metabolism. In addition, folate deficiency, previously considered free of neurological consequences, is now known to be associated with disturbances of mood, and even spinal cord syndromes similar to those seen in vitamin B12 deficiency. Finally, there is both experimental and clinical evidence to suggest that folate deficiency may interfere with immunologic status and may be associated with an increased predisposition to neoplasia. Nutritional as well as genetic factors may contribute to these various nonhematological manifestations of folate insufficiency.
Background: Low folate status is associated with poor cognitive function and dementia in the elde... more Background: Low folate status is associated with poor cognitive function and dementia in the elderly. Since 1998, grain products in the United States have been fortified with folic acid, which has reduced the prevalence of folate deficiency and hyperhomocysteinemia. Objective: We investigated whether folate status is associated with cognitive function and dementia in a cohort of elderly Latinos (aged ͧ 60 y; n ҃ 1789) exposed to folic acid fortification. Design: Global cognitive function was assessed by the Modified Mini-Mental State Examination (3MSE) and specific cognitive functions by cross-culturally validated neuropsychological tests. Dementia was diagnosed according to the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 3rd edition revised, and California Alzheimer Disease Diagnostic and Treatment criteria. Red blood cell (RBC) folate was measured by automated chemiluminescence and total plasma homocysteine by HPLC. Results: The prevalence of folate deficiency (RBC folate ͨ 160 ng/mL) was 1%. After control for confounding by homocysteine, vitamin B-12, creatinine, demographic variables, and depressive symptom score, RBC folate was directly associated with 3MSE (P ҃ 0.005) and delayed recall (P ҃ 0.007) scores. In addition, adjusted odds ratios for low 3MSE score (ͨ78) and dementia diagnosis per unit increase in RBC folate were significantly below unity (P ͨ 0.008), which indicated that the relative risks of cognitive impairment and dementia decreased with increasing RBC folate concentration. In contrast, adjusted odds ratios for low 3MSE score and dementia diagnosis per unit increase in homocysteine were not significant. Conclusion: RBC folate is directly associated with cognitive function scores and is inversely associated with dementia in elderly Latinos despite folic acid fortification.
A renewed interest in the sulfur-containing amino acid, homocysteine, has emerged over the past f... more A renewed interest in the sulfur-containing amino acid, homocysteine, has emerged over the past few years due to increasingly convincing data that it is associated with, and probably a causative factor of, accelerated occlusive vascular disease.'-' The fact that vitamins Biz, B6, and folate all play important roles as either coenzymes or substrates in the metabolism of h o m o c y~t e i n e~.~ has greatly added to the interest in this amino acid because deficiencies of these three vitamins, or supplementation with them, have been found to have substantial impact on circulating concentrations of homocysteine in selected situations.
Folate is essential for the de novo biosynthesis of purines and thymidylate, and is an important ... more Folate is essential for the de novo biosynthesis of purines and thymidylate, and is an important mediator in the transfer of methyl groups for DNA methylation. Folate deficiency, Nutr 1997;65:46-52. KEY WORDS Folate, DNA methylation, DNA damage, PS3' carcinogenesis i From the Vitamin Bioavailability Laboratory, Jean Mayer US Department of Agriculture
The quality oflife ofaging individuals depends profoundly on their capacity for physical mobility... more The quality oflife ofaging individuals depends profoundly on their capacity for physical mobility, mental alert-
The plasma homocysteine response to mcthionine loading was assessed in vitamin B-6-and folate-def... more The plasma homocysteine response to mcthionine loading was assessed in vitamin B-6-and folate-deficient sponses to methioninc loading in humans.
The catabolism ofhomocysteine through cysconcentrations are not a good indicator of vitamin B-6 s... more The catabolism ofhomocysteine through cysconcentrations are not a good indicator of vitamin B-6 status.
Catecholamine autoxidation produces reactive oxygen species that have been implicated in the loss... more Catecholamine autoxidation produces reactive oxygen species that have been implicated in the loss of dopaminergic neurons in the nigrostriatal region of the brain that occurs during normal aging and in Parkinson's disease. In the present study, the potential protective effects of catecholamine O-methylation and of melatonin against catecholamine autoxidation-induced protein damage were assessed in vitro using the oxygen radical absorbance capacity (ORAC) assay. The rate of oxidation of the fluorescent protein porphyridium cruentum fl-phycoerythrin (/3-PE) caused by the oxidizing agent CuSO4 was shown to be accelerated by addition of the catecholamines dopamine and L-dopa. Replacement of dopamine and L-dopa in the assay with their O-methylated metabolites 3-O-methyldopamine and 3-O-methyldopa significantly decreased the rate of fl-PE oxidation. When melatonin was added to the ORAC assay in combination with dopamine or L-dopa, the rate of/3-PE oxidation was decreased as well. These findings were consistent with the following interpretations: (1) O-methylated catecholamines are less susceptible to autoxidation than their nonmethylated precursors, and (2) melatonin, which has recently been shown to be a powerful antioxidant, is capable of scavenging free radicals produced during catecholamine autoxidation. These findings suggest that O-methylation and melatonin may be important components of the brain's antioxidant defenses against catecholamine autoxidation and may protect against consequent dopaminergic neurodegeneration.
Background: Elevated plasma homocysteine (hyperhomocysteinemia), an independent risk factor for v... more Background: Elevated plasma homocysteine (hyperhomocysteinemia), an independent risk factor for vascular disease, has been reported to be inversely correlated with objective measures of cognitive function in patients with Alzheimer disease and in community-dwelling older adults. Objective: We evaluated the cross-sectional relation between total plasma homocysteine concentration and cognitive function in elderly Latinos (aged ≥ 60 y; n = 1789) participating in the Sacramento Area Latino Study on Aging. Design: Global cognitive function was assessed by using the Modified Mini-Mental State Examination, and specific cognitive functions were assessed by using 6 instruments developed for crosscultural and multilingual neuropsychological evaluation of older persons. Associations between the cognitive function scores and total plasma homocysteine concentrations were then measured by multiple regression analysis with control for potential confounding by nutrient status (red blood cell folate, plasma vitamin B-12), kidney function (serum creatinine), demographic variables (age, sex, education, acculturation), and depressive symptoms. Results: Modest inverse associations were found between homocysteine concentrations and several indexes of cognitive function, including the global Modified Mini-Mental State Examination assessment and the picture-association, verbal attention-span, and pattern-recognition tests (P ≤ 0.05). Demographic variables, particularly age and education, were more strongly associated with cognitive function scores than was homocysteine. Conclusions: Homocysteine is a modest independent predictor of cognitive function in community-dwelling elderly Latinos. Reducing plasma homocysteine concentrations by administering B-vitamin supplements may provide some protection against cognitive decline in this and other elderly populations, but the effect may be limited.
Background: High concentrations of homocysteine have been linked to a greater risk of Alzheimer d... more Background: High concentrations of homocysteine have been linked to a greater risk of Alzheimer disease, dementia, and cognitive decline. Objective: We evaluated the association between homocysteine and 4.5-y combined incidences of dementia and cognitive impairment without dementia (CIND) in a cohort of 1779 Mexican Americans aged 60 -101 y. Design: Homocysteine, red blood cell (RBC) folate, and plasma vitamin B-12 were measured at baseline. New cases of dementia or CIND were ascertained by neuropsychological and clinical examinations and expert adjudication. We used proportional hazards models to estimate the risk of homocysteine-associated dementia or CIND and the influence of RBC folate and plasma vitamin B-12 on that association. Results: High homocysteine concentrations were associated with a greater risk of dementia or CIND: hazard ratio (HR): 2.39; 95% CI: 1.11, 5.16. Plasma vitamin B-12 modified the association between homocysteine and the outcome. The rates of dementia or CIND associated with homocysteine for those in the lowest and highest tertiles of vitamin B-12, respectively, were significantly higher (HR: 1.61, P ҃ 0.04) and lower (HR: 0.94, P ҃ 0.015) than the risk for those in the middle tertile. Conclusions: Homocysteine is an independent risk factor for both dementia and CIND. Higher plasma vitamin B-12 may reduce the risk of homocysteine-associated dementia or CIND.
A common polymorphism (775G>C) in the vitamin B12 transport protein, transcobalamin II (TCII), ha... more A common polymorphism (775G>C) in the vitamin B12 transport protein, transcobalamin II (TCII), has been identified in which proline replaces arginine at codon 259. We determined the influence of TCII genotype on indices of B12 status, including total serum B12, the amount of B12 bound to TCII (holoTCII), methylmalonic acid, and homocysteine, in 128 healthy older adults (ages 40-88 years). Mean total B12 and homocysteine concentrations were not significantly different among the 3 genotypes. Mean holoTCII concentration was significantly higher in those subjects homozygous for the proline form of TCII (PP) compared with those homozygous for the arginine form (RR) and heterozygotes (PR) (P < .006). In addition, mean methylmalonic acid concentrations were significantly lower in the PP and PR groups compared with the RR group (P < .02). The PP genotype may be more efficient in delivering B12 to tissues, resulting in enhanced B12 functional status. TCII genotype may thus influence susceptibility to B12 deficiency. (Blood. 2002;100:718-720)
It has previously been shown that choline deficiency causes depletion of hepatic folate concen tr... more It has previously been shown that choline deficiency causes depletion of hepatic folate concen tration in rats. Two separate experiments were under taken to investigate the converse phenomenon: whether folate deficiency would lead to depletion of hepatic choline. In Experiment 1, severe folate deficiency was induced in rats by feeding an amino acid-defined diet containing (per kg diet) 1.4 g choline, O mg folate and 10 g succinylsulfathiazole. Control rats were fed the same diet containing 8 mg folate/kg. After 4 wk, plasma and hepatic folate concentrations were significantly depleted in the severely folate-defident rats compared with controls (P < 0.001), and hepatic choline and phosphocholine concentrations were 65 and 80% lower, respectively (P < 0.001). In Experiment 2, moderate folate deficiency was induced in rats by feeding the same diet as described above, but with the succinylsul fathiazole omitted. After 24 wk, significant systemic folate deficiency was present in the moderately folatedeficient rats compared with controls (P < 0.001). A modest reduction (36%, P = 0.087) in hepatic choline concentration was observed in the moderately folatedeficient rats compared with controls. No significant differences in hepatic phosphocholine concentrations were detected between the two groups. These results indicate that severe folate deficiency causes secondary hepatic choline deficiency in rats. J. Nutr. 124: 2197Nutr. 124: -2203Nutr. 124: , 1994.
Background: Higher intake of folate and vitamins B 6 (pyridoxine hydrochloride) and B 12 (cyanoco... more Background: Higher intake of folate and vitamins B 6 (pyridoxine hydrochloride) and B 12 (cyanocobalamin) may decrease the risk of Alzheimer disease (AD) through the lowering of homocysteine levels.
Folate plays a key role in nucleic acid synthesis. As a consequence, the most conspicuous complic... more Folate plays a key role in nucleic acid synthesis. As a consequence, the most conspicuous complication of folate deficiency or of derangements of folate metabolism is megaloblastic macrocytic anemia caused by interdiction of normal proliferation of rapidly dividing bone marrow cells. Other rapidly dividing cells, including those in the gastrointestinal tract, may also be affected by the megaloblastic process. This may result in malabsorption. However, there is mounting evidence to indicate that there are other earlier manifestations of folate deficiency or of longstanding suboptimal folate nutrition. Chief among these manifestations of folate deficiency are an increased predisposition to occlusive vascular disease and thrombosis, which have been linked to increased levels of homocysteine found in folate deficiency and abnormal states of folate metabolism. In addition, folate deficiency, previously considered free of neurological consequences, is now known to be associated with disturbances of mood, and even spinal cord syndromes similar to those seen in vitamin B12 deficiency. Finally, there is both experimental and clinical evidence to suggest that folate deficiency may interfere with immunologic status and may be associated with an increased predisposition to neoplasia. Nutritional as well as genetic factors may contribute to these various nonhematological manifestations of folate insufficiency.
Background: Low folate status is associated with poor cognitive function and dementia in the elde... more Background: Low folate status is associated with poor cognitive function and dementia in the elderly. Since 1998, grain products in the United States have been fortified with folic acid, which has reduced the prevalence of folate deficiency and hyperhomocysteinemia. Objective: We investigated whether folate status is associated with cognitive function and dementia in a cohort of elderly Latinos (aged ͧ 60 y; n ҃ 1789) exposed to folic acid fortification. Design: Global cognitive function was assessed by the Modified Mini-Mental State Examination (3MSE) and specific cognitive functions by cross-culturally validated neuropsychological tests. Dementia was diagnosed according to the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 3rd edition revised, and California Alzheimer Disease Diagnostic and Treatment criteria. Red blood cell (RBC) folate was measured by automated chemiluminescence and total plasma homocysteine by HPLC. Results: The prevalence of folate deficiency (RBC folate ͨ 160 ng/mL) was 1%. After control for confounding by homocysteine, vitamin B-12, creatinine, demographic variables, and depressive symptom score, RBC folate was directly associated with 3MSE (P ҃ 0.005) and delayed recall (P ҃ 0.007) scores. In addition, adjusted odds ratios for low 3MSE score (ͨ78) and dementia diagnosis per unit increase in RBC folate were significantly below unity (P ͨ 0.008), which indicated that the relative risks of cognitive impairment and dementia decreased with increasing RBC folate concentration. In contrast, adjusted odds ratios for low 3MSE score and dementia diagnosis per unit increase in homocysteine were not significant. Conclusion: RBC folate is directly associated with cognitive function scores and is inversely associated with dementia in elderly Latinos despite folic acid fortification.
A renewed interest in the sulfur-containing amino acid, homocysteine, has emerged over the past f... more A renewed interest in the sulfur-containing amino acid, homocysteine, has emerged over the past few years due to increasingly convincing data that it is associated with, and probably a causative factor of, accelerated occlusive vascular disease.'-' The fact that vitamins Biz, B6, and folate all play important roles as either coenzymes or substrates in the metabolism of h o m o c y~t e i n e~.~ has greatly added to the interest in this amino acid because deficiencies of these three vitamins, or supplementation with them, have been found to have substantial impact on circulating concentrations of homocysteine in selected situations.
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