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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 60:1190-1201 (2005)
© 2005 The Gerontological Society of America

REVIEW ARTICLE

The Role of Homocysteine in Multisystem Age-Related Problems: A Systematic Review

Hsu-Ko Kuo1,2,6,7, Farzaneh A. Sorond1,2,3,6, Jen-Hau Chen1,2,6,7, Ardeshir Hashmi1,2, William P. Milberg4,5,6 and Lewis A. Lipsitz1,2,6,

1 Hebrew Rehabilitation Center for Aged, Boston, Massachusetts.
2 Beth Israel Deaconess Medical Center, Boston, Massachusetts.
3 Brigham and Women's Hospital, Boston, Massachusetts.
4 Geriatric Neuropsychology Laboratory, Geriatric, Research, Education and Clinical Center (GRECC), Brockton/West Roxbury Department of Veterans Affairs Medical Center, Boston, Massachusetts.
5 Department of Psychiatry
6 Division of Aging, Harvard Medical School, Boston, Massachusetts.
7 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Address correspondence to Lewis A. Lipsitz, MD, Hebrew Rehabilitation Center for Aged, 1200 Centre Street, Boston, MA 02131. E-mail: lipsitz{at}mail.hrca.harvard.edu


   Abstract
Top
 Abstract
Homocysteine Metabolism and...
 Methods of Article...
 Homocysteine and Age-Related...
 Homocysteine-Lowering Therapy:...
 References
 
Homocysteine is a sulfur-containing amino acid that is involved in one-carbon metabolism. Hyperhomocysteinemia is a common phenomenon among elderly people. There is growing evidence of an association between hyperhomocysteinemia and geriatric multisystem problems, including coronary artery disease, stroke, peripheral vascular disease, cognitive impairment, dementia, depression, osteoporotic fractures, and functional decline. The proposed mechanisms of the association include angiotoxicity, neurotoxicity, and inhibition of collagen cross-linking. A homocysteine-lowering strategy may prevent or slow the development of these age-related problems. Vitamin supplementation and folic acid fortification of grain foods have been shown to decrease plasma homocysteine concentrations. More research is needed to investigate whether lifelong homocysteine lowering can prevent the development of late-life morbidity.

HYPERHOMOCYSTEINEMIA and homocystinuria due to abnormal homocysteine metabolism were first described by Carson and Neill in 1962 (1). Patients with this inborn error of metabolism usually manifest mental retardation, lens dislocation, skeletal abnormalities, and early thrombotic events (2). In 1969, McCully proposed that hyperhomocysteinemia may be a vascular risk factor. This proposition was based on autopsy evidence in two children with hyperhomocysteinemia and homocystinuria who had widespread arteriosclerotic changes (3). McCully's hypothesis was supported by subsequent studies (4,5) linking hyperhomocysteinemia to peripheral vascular, cerebrovascular, and coronary artery disease (CAD). Recently, elevations in plasma homocysteine have also been shown to be associated with common problems seen with aging, such as cognitive impairment, dementia, depression, osteoporotic fractures, and functional decline. In this article we will review this evidence, and argue that public attention to lowering plasma homocysteine throughout life may reduce much of the morbidity and mortality associated with aging.

The normal range of plasma homocysteine level is 5–15 µmol/L. Hyperhomocysteinemia is defined as a plasma homocysteine level >15 µmol/L and is classified as moderate (15–30 µmol/L), intermediate (30–100 µmol/L), or severe (>100 µmol/L) (4). The prevalence of hyperhomocysteinemia in the general population is between 5% and 10% (6). However, the rate may be as high as 30% in the elderly population (older than 65 years), according to the Framingham Study (7). The prevalence of hyperhomocysteinemia may have declined in the United States since dietary fortification with folic acid began in 1996. Data from the Framingham Offspring Study cohort showed that the prevalence of hyperhomocysteinemia in individuals evaluated after the widespread institution of folate fortification has decreased by approximately 50% (8).


   HOMOCYSTEINE METABOLISM AND DETERMINANTS OF HOMOCYSTEINE LEVELS
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 Homocysteine Metabolism and...
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 Homocysteine and Age-Related...
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Homocysteine is a sulfur-containing amino acid derived from the metabolism of methionine, an essential amino acid. Homocysteine is metabolized by one of two pathways: remethylation or transulfuration (Figure 1). Plasma homocysteine levels are determined by several factors described below.



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  		Figure 1. Homocysteine metabolism. In the remethylation pathway, methionine synthase (MS), a vitamin B12-dependent enzyme, catalyses the transfer of a methyl group from N5-methyl-tetrahydrolate to homocysteine, forming methionine and tetrahydrofolate. Tetrahydrolate accepts single carbon units from serine to form N5,N10-methylene-tetrahydrolate and glycine. N5,N10-methylene-tetrahydrolate reductase (MTHFR) catalyses N5,N10-methylene-tetrahydrolate to form N5-methyl-tetrahydrolate, the methyl donor in the remethylation cycle. In the transulfuration pathway, homocysteine reacts with serine, under action of vitamin B6-dependent enzyme cystathione ß-synthase (CBS), to form cystathionine. Cystathionine is then catalysed by cystathionase to form cysteine, a rate-limiting precursor for glutathione synthesis. MS = methionine synthase

 
Lifestyle and Physiologic Determinants
Homocysteine levels increase with age, are higher in men than in women (9), and are influenced by renal function (10). Renal impairment raises plasma homocysteine levels by reducing homocysteine clearance (11). The Hordaland Homocysteine Study was the first population-based study to reveal homocysteine-determining lifestyle factors. The study showed that male sex, smoking status, high coffee consumption, lack of exercise, and older age are associated with elevated homocysteine levels (12). Alcohol intake and serum creatinine levels were two additional determinants according to the Framingham Offspring Study (13).

Nutrition
Nutritional deficiencies in vitamin cofactors required for homocysteine metabolism, such as folate, vitamin B12, and vitamin B6, may lead to hyperhomocysteinemia (Figure 1). The Hordaland Homocysteine Study assessed nutrient intake in 11,941 healthy participants aged 40–67 years by using nutrition questionnaires. They demonstrated that intake of folate was a strong negative determinant of homocysteine levels (12). The Framingham Offspring Study further examined the correlation between homocysteine levels and intake of different vitamin nutrients by using a validated food-frequency questionnaire. Dietary intake of B vitamins (including folate, vitamin B6, and riboflavin) and regular use of vitamin B supplements were inversely associated with homocysteine levels (13). Selhub and colleagues (7) examined the Framingham Study cohort and concluded that plasma concentrations of folate, vitamin B12, and vitamin B6 (as well as their intake) were primary determinants of plasma homocysteine levels in older adults, explaining 67% of the cases of hyperhomocysteinemia.

Genetic Determinants
A thermolabile variant of N5,N10-methylene-tetrahydrofolate reductase (MTHFR), caused by a cytosine (C) to thymine (T) point mutation at nucleotide 677 (C677T), leads to the substitution of valine for alanine (14). This mutation reduces MTHFR activity by 50%, predisposing to hyperhomocysteinemia. Homozygosity for MTHFR C677T has been found in 8% of Caucasian, 1.5% of African-American, and 13% of Hispanic people (15). Individuals homozygous for the T allele with folate levels above the median do not demonstrate hyperhomocysteinemia (16). Under conditions of folate deficiency, this mutation causes mild-to-moderate hyperhomocysteinemia (17), indicating a gene–nutrient interaction. Other genetic defects, including cystathione ß-synthase deficiency and MTHFR deficiency, will result in severe hyperhomocysteinemia and homocystinuria. Their occurrences are extremely rare.

Other Associations
Hypothyroidism raises plasma homocysteine levels, which may be attributed in part to reduced renal function in hypothyroidism (18). Hyperhomocysteinemia has been described in patients with rheumatoid arthritis (19), psoriasis (20), and cancer, including breast, ovarian, and pancreatic cancer, and acute lymphoblastic leukemia (21). The underlying mechanisms are not clear. Numerous drugs can increase homocysteine levels through interference with the vitamin cofactors in homocysteine metabolism. Methotrexate depletes folate, causing hyperhomocysteinemia (22). Anticonvulsants, such as phenytoin, carbamazepine, and valproic acid, also impair folate metabolism and lead to hyperhomocysteinemia (23). Several other drugs, such as theophylline, isoniazid, and hydralazine, may increase plasma homocysteine by inhibiting the synthesis of vitamin B6 (24). Nitrous oxide, an anesthetic agent, inhibits methionine synthase activity and raises homocysteine levels (20).


   METHODS OF ARTICLE IDENTIFICATION FOR RELATIONSHIP BETWEEN HOMOCYSTEINE AND AGE-RELATED PROBLEMS
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We searched the MEDLINE (January 1966 through March 2004) databases by using combinations of the following terms: "cardiovascular diseases," "peripheral vascular diseases," "dementia," "cognitive impairment," "cognition disorders," "depression," "falls," "physical function," "functional decline," "musculoskeletal equilibrium," "osteoporotic fracture," and "homocysteine," both as key words and mapped to relevant Medical Subject Headings (MeSH) terms when possible. Only English-language journals were examined. Additional references were found by reviewing bibliographies from identified articles.

Individual articles had to meet the following criteria to be included: (1) articles examining the relationship between homocysteine and age-related problems, including CAD, stroke, carotid artery disease, peripheral arterial disease, cognitive impairment, depression, functional decline, and osteoporotic fracture; and (2) studies or reviews based on older adults (age 55 years of older). Information of relevant articles was retrieved according to a standardized format.


   HOMOCYSTEINE AND AGE-RELATED PROBLEMS
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 Abstract
 Homocysteine Metabolism and...
 Methods of Article...
 Homocysteine and Age-Related...
Homocysteine-Lowering Therapy:...
 References
 
The various systems affected by homocysteine elevation and the proposed mechanisms underlying these effects are summarized in Figure 2 and discussed below.



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  		Figure 2. Pathophysiological roles of homocysteine and its multisystem effects

 
Vascular Diseases
Traditional cardiovascular risk factors explain about 50%–60% of the variation in vascular disease occurrence (25). Hyperhomocysteinemia is an independent risk factor for CAD (26) and myocardial infarction (MI) (27). Elevated homocysteine level is a strong independent predictor of cardiac events and mortality in patients with angiographically confirmed CAD (28,29) and acute coronary syndromes (30). Hyperhomocysteinemia plays an important role in development of cerebrovascular disease (31) and cerebral small-vessel disease or leukoaraiosis (32,33). In addition, several meta-analyses concluded that homocysteine is an independent risk factor for CAD (34,35), cerebrovascular disease (34–36), and peripheral arterial disease (34). However, the majority of these studies were conducted in middle-aged individuals. Data from older people are relatively sparse. The major longitudinal studies examining the association between homocysteine and vascular disease in older adults are summarized in Table 1.


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  		Table 1. Major Longitudinal Studies of Homocysteine as a Risk Factor for Vascular Diseases in Older Adults.

 
CAD and MI.-- Cross-sectionally, elevated homocysteine level has been shown to be associated with increased baseline prevalence of CAD in a group of long-term care patients (37) and community-dwelling elderly people (38). The Zutphen Elderly Study (39) showed that an elevated homocysteine level was associated with an increased prevalence of MI. Several prospective studies suggested that hyperhomocysteinemia has a causal role in the development of CAD (40) and MI (41,42). Additionally, elevated homocysteine levels predicted cardiovascular hospitalization (43) and both cardiovascular death and all-cause mortality among elderly people (44–46).

Stroke.-- In several cross-sectional studies, an elevated homocysteine level was associated with the prevalence of stroke (39,47), silent brain infarcts (48,49), cerebral white matter lesions (leukoaraiosis) (48,50), and cardiovascular disease risk including history of stroke or MI (51,52). Several longitudinal follow-up studies suggested a causal role of hyperhomocysteinemia in stroke. The Framingham Study (53), the Rotterdam Study (41), and Aronow and colleagues (54) showed that elevated homocysteine level was an independent risk factor for incident stroke. In the longitudinal Zutphen Elderly Study, hyperhomocysteinemia was found to be a strong predictor for fatal cerebrovascular disease in normotensive men. The Rotterdam Scan Study showed that an elevated homocysteine level was marginally associated with new silent brain infarcts in persons without prevalent infarcts (55). In another study of 1039 stroke patients, plasma homocysteine measured within 24 hours of acute stroke independently predicted recurrent stroke within 15 months (56).

Carotid artery disease and peripheral arterial disease.-- A significant cross-sectional association between elevated homocysteine levels and extracranial carotid artery disease has been established by several western studies (52,57–59). Two studies conducted in Japanese elderly people also supported this notion (60,61). Two cross-sectional studies, Aronow and Ahn (62) and Darius and colleagues (63), found that elevated homocysteine plasma levels were related to peripheral arterial disease in older adults. The Rotterdam Study found that persons with elevated homocysteine levels had a lower ankle–arm index (52), indicating peripheral atherosclerosis. No prospective studies have been conducted to examine the potential causal relationship between hyperhomocysteinemia and either carotid artery disease or peripheral arterial disease.

Pathophysiologic mechanisms of vascular disease in hyperhomocysteinemia.-- Several mechanisms have been proposed for the development of vascular disease in patients with hyperhomocysteinemia. These arise from observations in patients with homocystinuria, animal experiments, and in vitro studies. Targets of homocysteine include endothelial cells, platelets, vascular smooth muscle cells, blood lipids, coagulation factors, and nitric oxide. Homocysteine-induced arteriosclerosis is characterized by endothelial injury followed by significant platelet activation and thrombus formation (64). Homocysteine is rapidly auto-oxidized in plasma, and potent oxidative products including superoxide and hydrogen peroxide are generated (65). These oxidative products promote endothelial damage (65) and oxidative modification of low-density lipoprotein (66), resulting in the formation of foam cells. Homocysteine promotes proliferation of vascular smooth muscle cells by inducing cyclin A gene expression (67) and hence contributes to atherosclerosis. Homocysteine also creates a prothrombotic environment by activating factor V (68), reducing protein C activation (69), inactivating expression of thrombomodulin (70), inducing expression of tissue factor (71), suppressing anticoagulant heparin sulfate expression (72), and blocking tissue plasminogen activator binding to endothelial cells (73). Finally, homocysteine depletes endothelium-derived nitric oxide and reduces its production (74), further impairing endothelial function.

In conclusion, hyperhomocysteinemia is a risk indicator for vascular diseases in older adults. A causal association between hyperhomocysteinemia and carotid and/or peripheral artery disease in elderly people remains to be established.

Cognitive Impairment
Progressive cognitive decline and dementia are common in old age. The prevalence of dementia in those aged 65 or older is estimated to range from 6% to 10% (75). Alzheimer's disease (AD) and vascular dementia (VaD) are the two most common forms of dementia, comprising approximately 70% and 20%, respectively, of all dementia cases (75,76). Homocysteine has been proposed as a neurotoxin (77), and the notion that homocysteine may be an important risk factor for cognitive impairment has recently attracted research interest. Follow-up studies of the association between homocysteine and cognition in older adults are summarized in Table 2.


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  		Table 2. Major Longitudinal Studies of Homocysteine as a Risk Factor for Cognitive Impairment in Older Adults.

 
Dementia.-- Hyperhomocysteinemia is a common finding in psychogeriatric patients (78). In case–control studies by Joosten and colleagues (79) and McCaddon and colleagues (80), patients with AD had significantly higher homocysteine levels than did controls. More convincing evidence for the association was reported by Clarke and colleagues (81), who found that patients in the upper third of the serum homocysteine distribution had a 5-fold elevated risk of histologically confirmed AD compared with patients in the bottom third of the distribution.

In addition to AD, many case–control studies have demonstrated that elevated homocysteine levels are associated with VaD. Leblhuber (82), Bottiglieri (83), Nagga (84) and their colleagues showed that homocysteine levels were significantly higher in patients with VaD and AD than in controls. However, these studies were criticized because they did not adjust for cardiovascular risk factors and determinants of homocysteine levels. McIlroy and colleagues (85), by appropriately controlling for potential confounders, concluded that moderately high homocysteine levels are independently associated with VaD and AD.

Although there is a cross-sectional association between hyperhomocysteinemia and dementia (78–85), this association does not indicate causation. Seshadri and colleagues (86) followed the Framingham Study cohort over a median of 8 years and concluded that an increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and AD.

Global cognition and individual cognitive domains.-- Elevation of plasma homocysteine has been reported to affect global cognition as well as specific cognitive domains. Many population-based cross-sectional studies (87–92) have shown that plasma homocysteine levels are inversely related to global cognitive function. Certain cognitive domains, such as executive function, are selectively impaired by cardiovascular risk factors (93,94). Budge and colleagues (89) and Morris and colleagues (95) reported a cross-sectional association between elevated homocysteine levels and memory impairment. More studies have reported a negative relationship between homocysteine levels and executive function (including psychomotor speed and attention, abstract thinking, mental flexibility, and multitasking) or visuospatial performance (such as spatial copying skill, spatial organization ability, and pattern recognition ability), both of which require intact frontal–subcortical circuits and are sensitive to increased loads of cardiovascular risk. The Sacramento Area Latino Study on Aging (SALSA) (91) suggested that homocysteine levels were inversely related to both executive functions and visuospatial performance. Another population-based study by Duthie and colleagues (96) supported this finding by examining a group of individuals born in 1921. The Normative Aging Study (97) found a negative association between homocysteine levels and visuospatial performance, while the Rotterdam Scan Study (90) suggested that homocysteine was inversely related to executive function.

Several prospective studies have suggested a causal relation between hyperhomocysteinemia and impairment in global and selective cognitive functions. McCaddon and colleagues (98) found that homocysteine independently predicted global cognition, word recall, orientation, and constructional praxis scores over a 5-year period. The Epidemiology of Vascular Aging Study (92) found that elevated plasma homocysteine was a significant predictor for decline in both global cognition and executive function for over 4 years. The Rotterdam Study by Kalmijn and colleagues (99), however, did not show a significant association between elevated homocysteine levels and cognitive decline, but their follow-up period of 2.7 years was relatively short.

Mechanism of hyperhomocysteinemia-related cognitive impairment.-- Homocysteine exhibits angiotoxicity that may lead to large- or small-vessel disease in the brain, eventually causing cognitive impairment. Additionally, hyperhomocysteinemia may cause cognitive impairment via direct neurotoxicity. Recent studies have shown that homocysteine can be directly toxic to cultured human and murine neuronal cells (77,100). Homocysteine stimulates N-methyl-D-aspartate (NMDA) receptors, resulting in calcium influx and excitotoxicity (100). Excitotoxicity may also be enhanced via homocysteine-related potentiation of glutamate neurotoxicity (100). Homocysteine also enhances ß-amyloid toxicity (101) and causes tau hyperphosphorylation (102). It has also been reported to impair DNA repair in hippocampal neurons (103) and induce apoptosis by eliciting DNA damage (77). Anatomically, hyperhomocysteinemia is associated with cerebral cortical and hippocampal atrophy (104,105), potentially resulting in cognitive decline.

In conclusion, hyperhomocysteinemia is associated with cognitive decline and increased risk of dementia in elderly people. Although most of the studies have controlled for nutritional markers, including folate and vitamin B status, elevated homocysteine levels could be a consequence of deficiencies in other nutritional factors associated with cognitive disorders.

Depression
Depression is a common disorder in elderly people with a major impact on public health. Between 1% and 2% of elderly persons carry a diagnosis of major depression (106). However, the prevalence of depressive symptoms not meeting criteria for a major depression is high in elderly people (average prevalence 13.5%) (107). When a depressive episode occurs in late life, a cerebrovascular cause may be more common than genetic or psychological causes. Some studies (108,109) have demonstrated an association between cardiovascular conditions (such as hypertension or transient ischemic attacks) and depression. Homocysteine, by acting as a cardiovascular risk factor, may be associated with, or even lead to, depressive symptoms in old age.

Several studies examined the association between homocysteine and depression in older adults. Investigators in the Women's Health and Aging Study (110) enrolled 700 physically disabled women (mean age 77.3 years, range 65–100 years) and found that women with higher grades of depression tended to have higher homocysteine levels, although this observation did not achieve statistical significance. However, this study was restricted to physically disabled women, raising the issue of generalizability. The population-based Rotterdam Study (111) screened 3884 elderly people (mean age 72.9 years) and did not find any association between elevated homocysteine levels and depression after multivariable adjustment. Another population-based study, the Hordaland Homocysteine Study (112), cross-sectionally examined the association between homocysteine and depression in 5948 persons aged 46–49 years (mean 47.4 years) and 70–74 years (mean 71.9 years) and found that homocysteine was significantly associated with depression in 4338 elderly persons (70–74 years) after controlling for age and sex.

Depression may be accompanied by anorexia, which may lead to poor nutrition and hyperhomocysteinemia. Hence, the importance of adequate adjustment for possible confounders to pursue an independent association cannot be overemphasized. Because the association between homocysteine and depression is not consistent across all cross-sectional studies in older adults, additional prospective studies are needed.

Osteoporotic Fracture
Osteoporosis is characterized by low bone mineral density, or deterioration of bone microarchitecture, resulting in increased risk of fracture. Osteoporotic fracture is becoming a major public health issue as the population ages, and is associated with increased morbidity, mortality, and economic costs. Elevated homocysteine level has been proposed as a potential risk factor for osteoporosis based on the observation that there is an increased prevalence of skeletal deformities, including generalized osteoporosis, in patients with autosomal recessive homocystinuria (113).

Two recent population-based prospective studies support the notion that homocysteine is an important risk factor for osteoporotic fractures in older persons. In the study from The Netherlands, van Meurs and colleagues (114) examined 2406 individuals aged 55 years or older, and found that the risk of osteoporotic fracture increased by 40% for each increase of 1 standard deviation in the homocysteine level after multivariable adjustment. Additionally, a serum homocysteine level in the highest quartile doubled the risk of fracture (114). McLean and colleagues followed 1999 elderly persons in the Framingham Study cohort for more than 10 years, and suggested that plasma homocysteine concentrations were associated with the risk of hip fracture in both men and women. After controlling for potential confounders, the risk ratios for hip fractures in men and women were 3.84 (95% confidence interval [CI], 1.38–10.70) and 1.92 (95% CI, 1.18–3.10), respectively, comparing persons in the highest quartile of homocysteine levels to those in the lowest quartile (115). In the study from The Netherlands, moreover, the effect of high homocysteine levels on the risk of fractures was comparable in magnitude to some well established risk factors of fractures, including low bone mineral density, cognitive impairment, and recent falls (114). These findings can be attributed to the fact that increased homocysteine levels could interfere with collagen cross-linking (116,117), important for the stability and strength of the collagen network, and thus could lead to an increased risk of fracture.

Physical Function
Decline in physical function is a common geriatric problem. The incidence of walking difficulty is as high as 40% in noninstitutionalized adults aged 85 and older; among older nursing home residents, it reaches 60% or higher (118). Given the fact that homocysteine is associated with many age-related illnesses, it is reasonable to hypothesize that there is an association between hyperhomocysteinemia and functional decline.

There is one study supporting this notion. The MacArthur Study of Successful Aging was a longitudinal study of successful aging (119) that followed 499 healthy and highly functional community-dwelling people (aged 70–79 years) over 3 years (120). Physical performance was based on gait, balance, lower body strength and coordination, and manual dexterity. People with elevated plasma homocysteine levels had an increased risk of functional decline over 3 years. With each standard deviation increase in homocysteine levels, there was a 50% higher risk of being in the worst quartile of physical function (odds ratio = 1.5; 95% CI, 1.2–1.9) after multivariable adjustment. The mechanism of this relationship is thought to be linked to oxidative damage of endothelial cells, protein, and deoxyribonucleic acid, and accelerated telomere loss (120). Another explanation is that hyperhomocysteinemia is a risk factor for leukoaraiosis (32), which may (a) interrupt frontal lobe circuits responsible for normal gait and balance (121) and (b) interfere with descending motor fibers arising from medial cortical areas, which are important for lower extremity motor control (122).


   HOMOCYSTEINE-LOWERING THERAPY: OPPORTUNITIES FOR PREVENTION?
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 Homocysteine Metabolism and...
 Methods of Article...
 Homocysteine and Age-Related...
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Ample evidence indicates that hyperhomocysteinemia is associated with several common age-related syndromes, but proof of causality can only be established by showing that lowering homocysteine can prevent these problems. Plasma homocysteine levels can be lowered by therapy with B vitamins, such as vitamin B12 and folate, or by folic acid fortification of grain foods. A previous meta-analysis (123) indicated that daily supplementation with both 0.5–5.0 mg of folic acid and 0.5 mg of vitamin B12 could be expected to reduce homocysteine concentrations by about one-quarter to one-third. Folic acid fortification of grain foods, fully implemented since January 1, 1998, has been shown to improve folate status and reduce mean homocysteine levels by 7% in the Framingham Heart Study cohort (8). This policy has been advocated as a cost-effective public health strategy for the prevention of CAD (124). Although homocysteine levels can be lowered effectively, more studies are required to determine whether multivitamin therapy or the folic acid fortification policy can prevent the development of vascular disease, cognitive impairment, dementia, depression, or functional decline in old age.

Homocysteine-lowering therapy has been shown to improve arterial endothelial function. Woo and colleagues (125) found that folic acid supplementation significantly improved endothelium-dependent flow-mediated dilation in asymptomatic hyperhomocysteinemic adults. Chambers and colleagues (126) found that supplementation with folic acid and vitamin B12 improved vascular endothelial function in male CAD patients. By improving arterial endothelial function in humans, folic acid-based vitamin therapy may have therapeutic potential for vascular protection.

Observational studies (127–129) have shown that an increase in folic acid intake by vitamin supplementation and fruit and vegetable intake can reduce the risk of stroke and CAD. A randomized, controlled trial (130) showed that multivitamin combination therapy (folate, vitamin B12, and pyridoxine) for 6 months was effective in reducing the rate of cardiovascular events and coronary restenosis in 205 patients after successful percutaneous angioplasty. A recent homocysteine-lowering trial, known as the Vitamin Intervention for Stroke Prevention (VISP) (117), showed no reduction in cardiovascular events in patients with ischemic stroke. The results of the Vitamins to Prevent Stroke (VITATOPS) (131) trial, another ongoing international homocysteine-lowering trial enrolling patients at high risk for cardiovascular and stroke events, are eagerly awaited.

The effect of a folic acid-based supplement on cognitive function was examined by Nilsson and colleagues (132) in an open label trial. They found that patients with mild-to-moderate dementia and hyperhomocysteinemia improved clinically on the Mini-Mental Status Examination and the Short Performance Test, a short cognitive test for assessing memory and attention, after vitamin substitution. Bryan and colleagues (133) conducted a randomized, controlled trial showing that folate, vitamin B12, or vitamin B6 supplementation had a positive effect on memory measures in a group of healthy women aged 20–94 years. Two other randomized, controlled trials (134,135) studying patients with dementia or cognitive impairment did not find cognitive benefit after folic acid supplementation; however, the sample sizes in the two studies were small, and large-scale trials are required to investigate the effect of homocysteine-lowering therapy on cognition. No evidence was found regarding folic acid-based supplementation in the prevention of depression. However, folic acid has been shown to enhance antidepressant action (136) and hasten recovery from episodes of major depression (137). With regard to the association between homocysteine and risk of osteoporotic fracture or functional decline, a causal relationship cannot easily be ascertained because interventional homocysteine-lowering studies with functional decline or fracture as outcomes are still lacking. In summary, the evidence discussed so far has not yet supported a role for homocysteine-lowering therapy in the prevention of functional decline, osteoporotic fractures, and neuropsychiatric disorders.

Conclusion
Homocysteine has been found to have multisystem effects in older adults, and elevated levels may play a pathophysiologic role in vascular diseases, cognitive decline, dementia, depression, osteoporotic fracture, and functional decline. The proposed mechanisms of these associations include angiotoxicity, neurotoxicity, and inhibition of collagen cross-linking. Hence, homocysteine-lowering agents, such as folic acid and vitamin B12, seem reasonable choices for the prevention and management of these problems.

Currently, there is no consensus regarding regular screening for homocysteine levels in the asymptomatic, elderly population. Folic acid supplements and folic acid fortification in food products seem to show promise for the prevention of cardiovascular disease. More studies are needed to document the role of our folic acid fortification policy and vitamin supplementation in primary and secondary prevention of age-related illnesses.


   Acknowledgments
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Dr. Kuo is supported by the Men's Associates Fellowship from the Hebrew Rehabilitation Center for Aged, Boston, MA. Dr. Lipsitz holds the Irving and Edyth S. Usen and Family Chair in Geriatric Medicine at the Hebrew Rehabilitation Center for Aged, Boston, MA. The work was supported in part by the National Institutes of Health Grants A604390 and A608812, the National Institute on Aging K12 Grant AG00294, and the Department of Veterans Affairs Medical Research Service.

The authors thank Dr. Yau-Hua Yu for editorial assistance and support.


   Footnotes
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 Homocysteine and Age-Related...
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Decision Editor: John E. Morley, MB, BCh

Received July 23, 2004

Accepted August 31, 2004


   References
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  1. Carson NA, Neill DW. Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland. Arch Dis Child. 1962;37:505-513.
  2. Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet. 1985;37:1-31.[Medline]
  3. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol. 1969;56:111-28.[Medline]
  4. Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med. 1998;49:31-62.[Medline]
  5. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med. 1998;338:1042-1050.[Free Full Text]
  6. Booth GL, Wang EE. Preventive health care, 2000 update: screening and management of hyperhomocysteinemia for the prevention of coronary artery disease events. The Canadian Task Force on Preventive Health Care. CMAJ. 2000;163:21-29.[Abstract/Free Full Text]
  7. Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA. 1993;270:2693-2698.[Abstract/Free Full Text]
  8. Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med. 1999;340:1449-1454.[Abstract/Free Full Text]
  9. Nygard O, Vollset SE, Refsum H, et al. Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA. 1995;274:1526-1533.[Abstract/Free Full Text]
  10. Bostom AG, Lathrop L. Hyperhomocysteinemia in end-stage renal disease: prevalence, etiology, and potential relationship to arteriosclerotic outcomes. Kidney Int. 1997;52:10-20.[Medline]
  11. Guttormsen AB, Ueland PM, Svarstad E, Refsum H. Kinetic basis of hyperhomocysteinemia in patients with chronic renal failure. Kidney Int. 1997;52:495-502.[Medline]
  12. Nygard O, Refsum H, Ueland PM, Vollset SE. Major lifestyle determinants of plasma total homocysteine distribution: the Hordaland Homocysteine Study. Am J Clin Nutr. 1998;67:263-270.[Abstract]
  13. Jacques PF, Bostom AG, Wilson PW, Rich S, Rosenberg IH, Selhub J. Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am J Clin Nutr. 2001;73:613-621.[Abstract/Free Full Text]
  14. Kang SS, Zhou J, Wong PW, Kowalisyn J, Strokosch G. Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet. 1988;43:414-421.[Medline]
  15. Conroy JM, Trivedi G, Sovd T, Caggana M. The allele frequency of mutations in four genes that confer enhanced susceptibility to venous thromboembolism in an unselected group of New York State newborns. Thromb Res. 2000;99:317-324.[Medline]
  16. Jacques PF, Bostom AG, Williams RR, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996;93:7-9.[Abstract/Free Full Text]
  17. Harmon DL, Woodside JV, Yarnell JW, et al. The common ‘thermolabile’ variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia. QJM. 1996;89:571-577.[Abstract/Free Full Text]
  18. Hussein WI, Green R, Jacobsen DW, Faiman C. Normalization of hyperhomocysteinemia with L-thyroxine in hypothyroidism. Ann Intern Med. 1999;131:348-351.[Abstract/Free Full Text]
  19. Roubenoff R, Dellaripa P, Nadeau MR, et al. Abnormal homocysteine metabolism in rheumatoid arthritis. Arthritis Rheum. 1997;40:718-722.[Medline]
  20. Ueland PM, Refsum H. Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. J Lab Clin Med. 1989;114:473-501.[Medline]
  21. Refsum H, Wesenberg F, Ueland PM. Plasma homocysteine in children with acute lymphoblastic leukemia: changes during a chemotherapeutic regimen including methotrexate. Cancer Res. 1991;51:828-835.[Abstract/Free Full Text]
  22. Refsum H, Ueland PM. Clinical significance of pharmacological modulation of homocysteine metabolism. Trends Pharmacol Sci. 1990;11:411-416.[Medline]
  23. Schwaninger M, Ringleb P, Winter R, et al. Elevated plasma concentrations of homocysteine in antiepileptic drug treatment. Epilepsia. 1999;40:345-350.[Medline]
  24. Ubbink JB, van der Merwe A, Delport R, et al. The effect of a subnormal vitamin B-6 status on homocysteine metabolism. J Clin Invest. 1996;98:177-184.[Medline]
  25. Smith SC, Jr, Amsterdam E, Balady GJ, et al. Prevention Conference V: Beyond secondary prevention: identifying the high-risk patient for primary prevention: tests for silent and inducible ischemia: Writing Group II. Circulation. 2000;101:E12-E16.
  26. Pancharuniti N, Lewis CA, Sauberlich HE, et al. Plasma homocyst(e)ine, folate, and vitamin B-12 concentrations and risk for early-onset coronary artery disease. Am J Clin Nutr. 1994;59:940-948.[Abstract/Free Full Text]
  27. Stampfer MJ, Malinow MR, Willett WC, et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA. 1992;268:877-881.[Abstract/Free Full Text]
  28. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med. 1997;337:230-236.[Abstract/Free Full Text]
  29. Anderson JL, Muhlestein JB, Horne BD, et al. Plasma homocysteine predicts mortality independently of traditional risk factors and C-reactive protein in patients with angiographically defined coronary artery disease. Circulation. 2000;102:1227-1232.[Abstract/Free Full Text]
  30. Stubbs PJ, Al-Obaidi MK, Conroy RM, et al. Effect of plasma homocysteine concentration on early and late events in patients with acute coronary syndromes. Circulation. 2000;102:605-610.[Abstract/Free Full Text]
  31. 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.[Medline]
  32. Hassan A, Hunt BJ, O'Sullivan M, et al. Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction. Brain. 2004;127:(Pt 1): 212-219.[Abstract/Free Full Text]
  33. Fassbender K, Mielke O, Bertsch T, Nafe B, Froschen S, Hennerici M. Homocysteine in cerebral macroangiography and microangiopathy. Lancet. 1999;353:1586-1587.[Medline]
  34. Boushey CJ, Beresford SA, 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.[Abstract/Free Full Text]
  35. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002;288:2015-2022.[Abstract/Free Full Text]
  36. 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.[Medline]
  37. Aronow WS, Ahn C. Association between plasma homocysteine and coronary artery disease in older persons. Am J Cardiol. 1997;80:1216-1218.[Medline]
  38. Lindeman RD, Romero LJ, Yau CL, Koehler KM, Baumgartner RN, Garry PJ. Serum homocysteine concentrations and their relation to serum folate and vitamin B12 concentrations and coronary artery disease prevalence in an urban, bi-ethnic community. Ethn Dis. 2003;13:178-185.[Medline]
  39. Stehouwer CD, Weijenberg MP, van den Berg M, Jakobs C, Feskens EJ, Kromhout D. Serum homocysteine and risk of coronary heart disease and cerebrovascular disease in elderly men: a 10-year follow-up. Arterioscler Thromb Vasc Biol. 1998;18:1895-1901.[Abstract/Free Full Text]
  40. Aronow WS, Ahn C. Increased plasma homocysteine is an independent predictor of new coronary events in older persons. Am J Cardiol. 2000;86:346-347.[Medline]
  41. 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.[Abstract/Free Full Text]
  42. 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.[Abstract/Free Full Text]
  43. Nurk E, Tell GS, Vollset SE, Nygard O, Refsum H, Ueland PM. Plasma total homocysteine and hospitalizations for cardiovascular disease: the Hordaland Homocysteine Study. Arch Intern Med. 2002;162:1374-1381.[Abstract/Free Full Text]
  44. Bostom AG, Silbershatz H, Rosenberg IH, et al. Nonfasting plasma total homocysteine levels and all-cause and cardiovascular disease mortality in elderly Framingham men and women. Arch Intern Med. 1999;159:1077-1080.[Abstract/Free Full Text]
  45. Kark JD, Selhub J, Adler B, et al. Nonfasting plasma total homocysteine level and mortality in middle-aged and elderly men and women in Jerusalem. Ann Intern Med. 1999;131:321-330.[Abstract/Free Full Text]
  46. Vollset SE, Refsum H, Tverdal A, et al. Plasma total homocysteine and cardiovascular and noncardiovascular mortality: the Hordaland Homocysteine Study. Am J Clin Nutr. 2001;74:130-136.[Abstract/Free Full Text]
  47. Kawamoto R, Kajiwara T, Oka Y, Takagi Y. An association between plasma homocysteine concentrations and ischemic stroke in elderly Japanese. J Atheroscler Thromb. 2002;9:121-125.[Medline]
  48. 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.[Medline]
  49. Matsui T, Arai H, Yuzuriha T, et al. Elevated plasma homocysteine levels and risk of silent brain infarction in elderly people. Stroke. 2001;32:1116-1119.[Abstract/Free Full Text]
  50. Bertsch T, Mielke O, Holy S, et al. Homocysteine in cerebrovascular disease: an independent risk factor for subcortical vascular encephalopathy. Clin Chem Lab Med. 2001;39:721-724.[Medline]
  51. Kario K, Duell PB, Matsuo T, et al. High plasma homocyst(e)ine levels in elderly Japanese patients are associated with increased cardiovascular disease risk independently from markers of coagulation activation and endothelial cell damage. Atherosclerosis. 2001;157:441-449.[Medline]
  52. Bots ML, Launer LJ, Lindemans J, Hofman A, Grobbee DE. Homocysteine, atherosclerosis and prevalent cardiovascular disease in the elderly: The Rotterdam Study. J Intern Med. 1997;242:339-347.[Medline]
  53. 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.[Abstract/Free Full Text]
  54. Aronow WS, Ahn C, Gutstein H. Increased plasma homocysteine is an independent predictor of new atherothrombotic brain infarction in older persons. Am J Cardiol. 2000;86:585-586, A10.[Medline]
  55. Vermeer SE, Den Heijer T, Koudstaal PJ, Oudkerk M, Hofman A, Breteler MM. Incidence and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study. Stroke. 2003;34:392-396.[Abstract/Free Full Text]
  56. Boysen G, Brander T, Christensen H, Gideon R, Truelsen T. Homocysteine and risk of recurrent stroke. Stroke. 2003;34:1258-1261.[Abstract/Free Full Text]
  57. Aronow WS, Ahn C, Schoenfeld MR. Association between plasma homocysteine and extracranial carotid arterial disease in older persons. Am J Cardiol. 1997;79:1432-1433.[Medline]
  58. Tsai MY, Arnett DK, Eckfeldt JH, Williams RR, Ellison RC. Plasma homocysteine and its association with carotid intimal-medial wall thickness and prevalent coronary heart disease: NHLBI Family Heart Study. Atherosclerosis. 2000;151:519-524.[Medline]
  59. Selhub J, Jacques PF, Bostom AG, et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med. 1995;332:286-291.[Abstract/Free Full Text]
  60. Kawamoto R, Doi T, Tokunaga H. Association of plasma homocysteine concentrations with carotid atherosclerosis in elderly Japanese. Intern Med. 2001;40:1189-1194.[Medline]
  61. Okamura T, Kitamura A, Moriyama Y, et al. Plasma level of homocysteine is correlated to extracranial carotid-artery atherosclerosis in non-hypertensive Japanese. J Cardiovasc Risk. 1999;6:371-377.[Medline]
  62. Aronow WS, Ahn C. Association between plasma homocysteine and peripheral arterial disease in older persons. Coron Artery Dis. 1998;9:49-50.[Medline]
  63. Darius H, Pittrow D, Haberl R, et al. Are elevated homocysteine plasma levels related to peripheral arterial disease? Results from a cross-sectional study of 6880 primary care patients. Eur J Clin Invest. 2003;33:751-757.[Medline]
  64. Harker LA, Slichter SJ, Scott CR, Ross R. Homocystinemia. Vascular injury and arterial thrombosis. N Engl J Med. 1974;291:537-543.
  65. Welch GN, Upchurch G, Jr, Loscalzo J. Hyperhomocyst(e)inemia and atherothrombosis. Ann N Y Acad Sci. 1997;811:48-58 discussion 58–59.[Medline]
  66. Loscalzo J. The oxidant stress of hyperhomocyst(e)inemia. J Clin Invest. 1996;98:5-7.[Medline]
  67. Tsai JC, Wang H, Perrella MA, et al. Induction of cyclin A gene expression by homocysteine in vascular smooth muscle cells. J Clin Invest. 1996;97:146-153.[Medline]
  68. Rodgers GM, Kane WH. Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest. 1986;77:1909-1916.
  69. Rodgers GM, Conn MT. Homocysteine, an atherogenic stimulus, reduces protein C activation by arterial and venous endothelial cells. Blood. 1990;75:895-901.[Abstract/Free Full Text]
  70. Lentz SR, Sadler JE. Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. J Clin Invest. 1991;88:1906-1914.
  71. Fryer RH, Wilson BD, Gubler DB, Fitzgerald LA, Rodgers GM. Homocysteine, a risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells. Arterioscler Thromb. 1993;13:1327-1333.[Abstract/Free Full Text]
  72. Nishinaga M, Ozawa T, Shimada K. Homocysteine, a thrombogenic agent, suppresses anticoagulant heparan sulfate expression in cultured porcine aortic endothelial cells. J Clin Invest. 1993;92:1381-1386.
  73. Hajjar KA. Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J Clin Invest. 1993;91:2873-2879.
  74. Stamler JS, Osborne JA, Jaraki O, et al. Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. J Clin Invest. 1993;91:308-318.
  75. Leifer BP. Early diagnosis of Alzheimer's disease: clinical and economic benefits. J Am Geriatr Soc. 2003;51:(5 Suppl Dementia): S281-S288.[Medline]
  76. Roman GC. Vascular dementia: distinguishing characteristics, treatment, and prevention. J Am Geriatr Soc. 2003;51:(5 Suppl Dementia): S296-S304.[Medline]
  77. Kruman II, Culmsee C, Chan SL, et al. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci. 2000;20:6920-6926.[Abstract/Free Full Text]
  78. Nilsson K, Gustafson L, Faldt R, et al. Hyperhomocysteinaemia–a common finding in a psychogeriatric population. Eur J Clin Invest. 1996;26:853-859.[Medline]
  79. 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.
  80. 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.[Medline]
  81. 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.[Abstract/Free Full Text]
  82. Leblhuber F, Walli J, Artner-Dworzak E, et al. Hyperhomocysteinemia in dementia. J Neural Transm. 2000;107:1469-1474.
  83. Bottiglieri T, Parnetti L, Arning E, et al. Plasma total homocysteine levels and the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene: a study in an Italian population with dementia. Mech Ageing Dev. 2001;122:2013-2023.[Medline]
  84. Nagga K, Rajani R, Mardh E, Borch K, Mardh S, Marcusson J. Cobalamin, folate, methylmalonic acid, homocysteine, and gastritis markers in dementia. Dement Geriatr Cogn Disord. 2003;16:269-275.[Medline]
  85. 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;33:2351-2356.[Abstract/Free Full Text]
  86. 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.[Abstract/Free Full Text]
  87. Stewart R, Asonganyi B, Sherwood R. Plasma homocysteine and cognitive impairment in an older British African-Caribbean population. J Am Geriatr Soc. 2002;50:1227-1232.[Medline]
  88. Ravaglia G, Forti P, Maioli F, et al. Homocysteine and cognitive function in healthy elderly community dwellers in Italy. Am J Clin Nutr. 2003;77:668-673.[Abstract/Free Full Text]
  89. Budge MM, de Jager C, Hogervorst E, Smith AD. Total plasma homocysteine, age, systolic blood pressure, and cognitive performance in older people. J Am Geriatr Soc. 2002;50:2014-2018.[Medline]
  90. 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.[Abstract/Free Full Text]
  91. 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.[Abstract/Free Full Text]
  92. Dufouil C, Alperovitch A, Ducros V, Tzourio C. Homocysteine, white matter hyperintensities, and cognition in healthy elderly people. Ann Neurol. 2003;53:214-221.[Medline]
  93. Kuo HK, Sorond FA, Iloputaife I, Gagnon M, Milberg WP, Lipsitz LA. Effect of blood pressure on cognitive functions in the elderly. J Gerontol A Biol Sci Med Sci. 2004;54:1191-1194.
  94. Pugh KG, Kiely DK, Milberg WP, Lipsitz LA. Selective impairment of frontal-executive cognitive function in African Americans with cardiovascular risk factors. J Am Geriatr Soc. 2003;51:1439-1444.[Medline]
  95. 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.[Abstract/Free Full Text]
  96. 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.[Abstract/Free Full Text]
  97. Riggs KM, Spiro A, III, 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.[Abstract/Free Full Text]
  98. 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.[Medline]
  99. 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.[Abstract/Free Full Text]
  100. Lipton SA, Kim WK, Choi YB, et al. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A. 1997;94:5923-5928.[Abstract/Free Full Text]
  101. Ho PI, Collins SC, Dhitavat S, et al. Homocysteine potentiates beta-amyloid neurotoxicity: role of oxidative stress. J Neurochem. 2001;78:249-253.[Medline]
  102. Vafai SB, Stock JB. Protein phosphatase 2A methylation: a link between elevated plasma homocysteine and Alzheimer's disease. FEBS Lett. 2002;518:(1–3): 1-4.[Medline]
  103. Kruman, II, Kumaravel TS, Lohani A, et al. Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease. J Neurosci. 2002;22:1752-1762.[Abstract/Free Full Text]
  104. den Heijer T, Vermeer SE, Clarke R, et al. Homocysteine and brain atrophy on MRI of non-demented elderly. Brain. 2003;126:(Pt 1): 170-175.
  105. Williams JH, Pereira EA, Budge MM, Bradley KM. Minimal hippocampal width relates to plasma homocysteine in community-dwelling older people. Age Ageing. 2002;31:440-444.[Abstract/Free Full Text]
  106. Blazer D, Hughes DC, George LK. The epidemiology of depression in an elderly community population. Gerontologist. 1987;27:281-287.[Medline]
  107. Beekman AT, Copeland JR, Prince MJ. Review of community prevalence of depression in later life. Br J Psychiatry. 1999;174:307-311.[Abstract/Free Full Text]
  108. Krishnan KR. Organic bases of depression in the elderly. Annu Rev Med. 1991;42:261-266.[Medline]
  109. Rao R. Depression after transient ischemic attack: a clinically distinct subtype of vascular depression? Arch Gen Psychiatry. 1998;55:753-754.[Free Full Text]
  110. Penninx BW, Guralnik JM, Ferrucci L, Fried LP, Allen RH, Stabler SP. Vitamin B(12) deficiency and depression in physically disabled older women: epidemiologic evidence from the Women's Health and Aging Study. Am J Psychiatry. 2000;157:715-721.[Abstract/Free Full Text]
  111. Tiemeier H, van Tuijl HR, Hofman A, Meijer J, Kiliaan AJ, Breteler MM. Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study. Am J Psychiatry. 2002;159:2099-2101.[Abstract/Free Full Text]
  112. Bjelland I, Tell GS, Vollset SE, Refsum H, Ueland PM. Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry. 2003;60:618-626.[Abstract/Free Full Text]
  113. Morreels CL, Jr, Fletcher BD, Weilbaecher RG, Dorst JP. The roentgenographic features of homocystinuria. Radiology. 1968;90:1150-1158.[Medline]
  114. van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM, et al. Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med. 2004;350:2033-2041.[Abstract/Free Full Text]
  115. McLean RR, Jacques PF, Selhub J, et al. Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med. 2004;350:2042-2049.[Abstract/Free Full Text]
  116. Jackson SH. The reaction of homocysteine with aldehyde: an explanation of the collagen defects in homocystinuria. Clin Chim Acta. 1973;45:215-217.[Medline]
  117. Lubec B, Fang-Kircher S, Lubec T, Blom HJ, Boers GH. Evidence for McKusick's hypothesis of deficient collagen cross-linking in patients with homocystinuria. Biochim Biophys Acta. 1996;1315:159-162.[Medline]
  118. Alexander NB. Gait disorders in older adults. J Am Geriatr Soc. 1996;44:434-451.[Medline]
  119. Berkman LF, Seeman TE, Albert M, et al. High, usual and impaired functioning in community-dwelling older men and women: findings from the MacArthur Foundation Research Network on Successful Aging. J Clin Epidemiol. 1993;46:1129-1140.[Medline]
  120. Kado DM, Bucur A, Selhub J, Rowe JW, Seeman T. Homocysteine levels and decline in physical function: MacArthur Studies of Successful Aging. Am J Med. 2002;113:537-542.[Medline]
  121. Masdeu JC, Wolfson L, Lantos G, et al. Brain white-matter changes in the elderly prone to falling. Arch Neurol. 1989;46:1292-1296.[Abstract/Free Full Text]
  122. Baloh RW, Ying SH, Jacobson KM. A longitudinal study of gait and balance dysfunction in normal older people. Arch Neurol. 2003;60:835-839.[Abstract/Free Full Text]
  123. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. BMJ. 1998;316:894-898.[Abstract/Free Full Text]
  124. Tice JA, Ross E, Coxson PG, et al. Cost-effectiveness of vitamin therapy to lower plasma homocysteine levels for the prevention of coronary heart disease: effect of grain fortification and beyond. JAMA. 2001;286:936-943.[Abstract/Free Full Text]
  125. Woo KS, Chook P, Lolin YI, Sanderson JE, Metreweli C, Celermajer DS. Folic acid improves arterial endothelial function in adults with hyperhomocystinemia. J Am Coll Cardiol. 1999;34:2002-2006.[Abstract/Free Full Text]
  126. Chambers JC, Ueland PM, Obeid OA, Wrigley J, Refsum H, Kooner JS. Improved vascular endothelial function after oral B vitamins: an effect mediated through reduced concentrations of free plasma homocysteine. Circulation. 2000;102:2479-2483.[Abstract/Free Full Text]
  127. Joshipura KJ, Hu FB, Manson JE, et al. The effect of fruit and vegetable intake on risk for coronary heart disease. Ann Intern Med. 2001;134:1106-1114.[Abstract/Free Full Text]
  128. Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA. 1998;279:359-364.[Abstract/Free Full Text]
  129. Bazzano LA, He J, Ogden LG, et al. Dietary intake of folate and risk of stroke in US men and women: NHANES I Epidemiologic Follow-up Study. National Health and Nutrition Examination Survey. Stroke. 2002;33:1183-1188.[Abstract/Free Full Text]
  130. Schnyder G, Roffi M, Pin R, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med. 2001;345:1593-1600.[Abstract/Free Full Text]
  131. The VITATOPS (Vitamins to Prevent Stroke) Trial: rationale and design of an international, large, simple, randomised trial of homocysteine-lowering multivitamin therapy in patients with recent transient ischaemic attack or stroke. Cerebrovasc Dis. 2002;13:120-126.[Medline]
  132. 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;16:609-614.[Medline]
  133. 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;132:1345-1356.[Abstract/Free Full Text]
  134. Sommer BR, Hoff AL, Costa M. Folic acid supplementation in dementia: a preliminary report. J Geriatr Psychiatry Neurol. 2003;16:156-159.[Abstract]
  135. 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.[Medline]
  136. Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord. 2000;60:121-130.[Medline]
  137. Procter A. Enhancement of recovery from psychiatric illness by methylfolate. Br J Psychiatry. 1991;159:271-272.[Abstract/Free Full Text]



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L. Cordain and M. S Hickey
Ultraviolet radiation represents an evolutionary selective pressure for the south-to-north gradient of the MTHFR 677TT genotype.
Am. J. Clinical Nutrition, November 1, 2006; 84(5): 1243 - 1243.
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H. Refsum, E. Nurk, A. D. Smith, P. M. Ueland, C. G. Gjesdal, I. Bjelland, A. Tverdal, G. S. Tell, O. Nygard, and S. E. Vollset
The Hordaland Homocysteine Study: A Community-Based Study of Homocysteine, Its Determinants, and Associations with Disease
J. Nutr., June 1, 2006; 136(6): 1731S - 1740S.
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