Vitamin B12, folate,and homocysteine in depression: the Rotterdam Study

OBJECTIVE: The associations of vitamin B(12), folate, and homocysteine with depression were examined in a population-based study. METHOD: The authors screened 3,884 elderly people for depressive symptoms. Subjects with positive screening results had psychiatric workups. Folate, vitamin B(12), and homocysteine blood levels were compared in 278 persons with depressive symptoms, including 112 with depressive disorders, and 416 randomly selected reference subjects. Adjustments were made for age, gender, cardiovascular disease, and functional disability. RESULTS: Hyperhomocysteinemia, vitamin B(12) deficiency, and to a lesser extent, folate deficiency were all related to depressive disorders. For folate deficiency and hyperhomocysteinemia, the association with depressive disorders was substantially reduced after adjustment for functional disability and cardiovascular disease, but for vitamin B(12) this appeared independent. CONCLUSIONS: The association of vitamin B(12) and folate with depressive disorders may have different underlying mechanisms. Vitamin B(12) may be causally related to depression, whereas the relation with folate is due to physical comorbidity.     

Homocysteine and folate deficiency sensitize oligodendrocytes to the cell death-promoting effects of a presenilin-1 mutation and amyloid beta-peptide

Although damage to white matter occurs in the brains of patients with Alzheimer's disease (AD), the underlying mechanisms are unknown. Recent findings suggest that individuals with elevated levels of homocysteine are at increased risk of AD. Here we show that oligodendrocytes from mice expressing a mutant form of presenilin-1 (PS1) that causes familial AD exhibit increased sensitivity to death induced by homocysteine compared to oligodendrocytes from wild-type control mice. Homocysteine also sensitized oligodendrocytes to the cytotoxicity of amyloid beta-peptide. Folate deficiency, which is known to result in elevated levels of homocysteine in vivo, also sensitized oligodendrocytes to the cell-death-promoting actions of mutant PS1 and amyloid beta-peptide. Inhibitors of poly (ADP-ribose) polymerase and p53 protected oligodendrocytes against cell death induced by homocysteine and amyloid beta-peptide, consistent with a role for a DNA-damage response in the cell death process. These findings demonstrate an adverse effect of homocysteine on oligodendrocytes, and suggest roles for homocysteine and folate deficiency in the white matter damage in AD and related neurodegenerative disorders.     

Homocysteine and folate deficiency sensitize oligodendrocytes to the cell death-promoting effects of a presenilin-1 mutation and amyloid β-peptide

Although damage to white matter occurs in the brains of patients with Alzheimer’s disease (AD), the underlying mechanisms are unknown. Recent findings suggest that individuals with elevated levels of homocysteine are at increased risk of AD. Here we show that oligodendrocytes from mice expressing a mutant form of presenilin-1 (PS1) that causes familial AD exhibit increased sensitivity to death induced by homocysteine compared to oligodendrocytes from wild-type control mice. Homocysteine also sensitized oligodendrocytes to the cytotoxicity of amyloid β-peptide. Folate deficiency, which is known to result in elevated levels of homocysteine in vivo, also sensitized oligodendrocytes to the cell-death-promoting actions of mutant PS1 and amyloid β-peptide. Inhibitors of poly (ADP-ribose) polymerase and p53 protected oligodendrocytes against cell death induced by homocysteine and amyloid β-peptide, consistent with a role for a DNA-damage response in the cell death process. These findings demonstrate an adverse effect of homocysteine on oligodendrocytes, and suggest roles for homocysteine and folate deficiency in the white matter damage in AD and related neurodegenerative disorders.     

Homocysteine, folate, methylation, and monoamine metabolism in depression

OBJECTIVES: Previous studies suggest that folate deficiency may occur in up to one third of patients with severe depression, and that treatment with the vitamin may enhance recovery of the mental state. There are, however, difficulties in interpreting serum and red cell folate assays in some patients, and it has been suggested that total plasma homocysteine is a more sensitive measure of functional folate (and vitamin B12) deficiency. Other studies suggest a link between folate deficiency and impaired metabolism of serotonin, dopamine, and noradrenaline (norepinephrine), which have been implicated in mood disorders. A study of homocysteine, folate, and monoamine metabolism has, therefore, been undertaken in patients with severe depression. METHODS: In 46 inpatients with severe DSM III depression, blood counts, serum and red cell folate, serum vitamin B12, total plasma homocysteine, and, in 28 patients, CSF folate, S-adenosylmethionine, and the monoamine neurotransmitter metabolites 5HIAA, HVA, and MHPG were examined. Two control groups comprised 18 healthy volunteers and 20 patients with neurological disorders, the second group undergoing CSF examination for diagnostic purposes. RESULTS: Twenty four depressed patients (52%) had raised total plasma homocysteine. Depressed patients with raised total plasma homocysteine had significant lowering of serum, red cell, and CSF folate, CSF S-adenosylmethionine and all three CSF monoamine metabolites. Total plasma homocysteine was significantly negatively correlated with red cell folate in depressed patients, but not controls. CONCLUSIONS: Utilising total plasma homocysteine as a sensitive measure of functional folate deficiency, a biological subgroup of depression with folate deficiency, impaired methylation, and monoamine neurotransmitter metabolism has been identified. Detection of this subgroup, which will not be achieved by routine blood counts, is important in view of the potential benefit of vitamin replacement.     

Homocysteine effects on brain volumes mapped in 732 elderly individuals

Elevated homocysteine levels are a known risk factor for Alzheimer's disease and vascular disorders. Here we applied tensor-based morphometry to brain magnetic resonance imaging scans of 732 elderly individuals from the Alzheimer's Disease Neuroimaging Initiative study, to determine associations between homocysteine and brain atrophy. Those with higher homocysteine levels showed greater frontal, parietal, and occipital white matter atrophy in the entire cohort, irrespective of diagnosis, age, or sex. This association was also found when considering mild cognitive impairment individuals separately. Vitamin B supplements, such as folate, may help prevent homocysteine-related atrophy in Alzheimer's disease by possibly reducing homocysteine levels. These atrophy profiles may, in the future, offer a potential biomarker to gauge the efficacy of interventions using dietary folate supplementation.     

Serum folate and homocysteine levels in patients with obsessive-compulsive disorder

Previous studies have shown that folate deficiency, increased homocysteine, impaired metylation have been identified in depressive disorder. Recently, growing research has resulted in the biological association between obsessive-compulsive disorder (OCD) and affective disorders. Therefore, in the present study it was evaluated whether or not folate and homocysteine levels changed. Serum folate and homocysteine concentrations were measured in 23 patients with OCD and in same number of controls. In addition, all patients were assessed by Yale-Brown Obsession Compulsion Scale (Y-BOCS). Serum folate values were significantly lower in OCD patients than in controls, while homocysteine concentrations were higher in patients compared with controls. Serum folate values were significantly and negatively related to Y-BOCS scores. Total serum homocysteine concentrations were positively correlated to Y-BOCS scores and the duration of illness. There was a trend toward a negative correlation between the concentrations of serum folate and homocysteine. In conclusion, we identified that a group of patients with OCD might have folate deficiency, higher homocysteine levels and probable impaired metylation and monoamine metabolism.     

Moderate hyperhomocysteinaemia and immune activation in Parkinson's disease

Moderate hyperhomocysteinaemia has been linked to an increased risk for cardiovascular diseases. Increased homocysteine concentrations may follow folate depletion due to insufficient dietary intake of the vitamin, but there is also some indication that immune activation could play a role. In this preliminary study, homocysteine, folate, and vitamin B(12) concentrations were measured in 19 patients with Parkinson's disease, 61-90 years of age, and compared to a healthy control group of similar age and to neopterin concentrations as an indicator of immune activation. A subgroup of patients presented with increased homocysteine and low folate concentrations. Homocysteine levels correlated inversely with vitamins folate and B(12) and positively with neopterin concentrations. Disturbed homocysteine metabolism in Parkinson's disease may be associated with vitamin deficiency and with immune system activation which may underlie folate depletion.     

Leukoencephalopathies associated with disorders of cobalamin and folate metabolism

Disorders of cobalamin and folate intracellular metabolism that result in defective remethylation of homocysteine to methionine are associated with leukodystrophy, whereas disorders of cobalamin transport generally are not. Cobalamin derivatives are needed for only two reactions in man; remethylation of homocysteine to methionine, with methylcobalamin as a cofactor for methionine synthase, and the conversion of methylmalonyl-coenzyme A to succinyl coenzyme A by methylmalonyl-CoA mutase, with adenosylcobalamin as a cofactor. Mutations at various metabolic steps affect the synthesis of adenosylcobalamin (CblA, CblB, and CblD2), methylcobalamin (CblE, CblG, and CblD1), or both of these (CblF, CblD, and CblC). The most common disorder of folate metabolism, 5,10-methylenetetrahydrofolate deficiency, also affects remethylation and presents with leukodystrophy. Pathways of cobalamin and folate metabolism intersect at one site, methionine synthase. Patients with the remethylating disorders present acutely or chronically with significant neurologic, hematologic, vascular, and other symptoms. Circulating levels of cobalamin and folate are usually normal in these disorders, and initial diagnosis is aided by measurement of homocysteine and methylmalonic acid in blood or urine, together with hematologic tests. Current diagnosis is often by newborn screening. These disorders all show autosomal recessive inheritance, and all are treatable, although with variable outcome.     

Elevated plasma homocysteine levels in patients treated with levodopa: association with vascular disease

BACKGROUND: Hyperhomocysteinemia is a risk factor for vascular disease and potentially for dementia and depression. The most common cause of elevated homocysteine levels is deficiency of folate or vitamin B(12). However, patients with Parkinson disease (PD) may have elevated homocysteine levels resulting from methylation of levodopa and dopamine by catechol O-methyltransferase, an enzyme that uses S-adenosylmethionine as a methyl donor and yields S-adenosylhomocysteine. Since S-adenosylhomocysteine is rapidly converted to homocysteine, levodopa therapy may put patients at increased risk for vascular disease by raising homocysteine levels. OBJECTIVES: To determine whether elevations in plasma homocysteine levels caused by levodopa use are associated with increased prevalence of coronary artery disease (CAD), and to determine what role folate and vitamin B(12) have in levodopa-induced hyperhomocysteinemia. DESIGN/METHODS: Subjects included 235 patients with PD followed up in a movement disorders clinic. Of these, 201 had been treated with levodopa, and 34 had not. Blood samples were collected for the measurement of homocysteine, folate, cobalamin, and methylmalonic acid levels. A history of CAD (prior myocardial infarctions, coronary artery bypass grafting, or coronary angioplasty procedures) was prospectively elicited. We analyzed parametric data by means of 1-way analysis of variance or the t test, and categorical data by means of the Fisher exact test or chi(2) test. RESULTS: Mean +/- SD plasma homocysteine levels were significantly higher in patients treated with levodopa (16.1 +/- 6.2 micro mol/L), compared with levodopa-na?ve patients (12.2 +/- 4.2 micro mol/L; P<.001). We found no difference in the plasma concentration of folate, cobalamin, or methylmalonic acid between the 2 groups. Patients whose homocysteine levels were in the higher quartile (>or=17.7 micro mol/L) had increased prevalence of CAD (relative risk, 1.75; 95% confidence interval, 1.08-2.70;P=.04). CONCLUSIONS: Levodopa therapy, rather than PD, is a cause of hyperhomocysteinemia in patients with PD. Deficiency of folate or vitamin B(12) levels does not explain the elevated homocysteine levels in these patients. To our knowledge, this is the first report that levodopa-related hyperhomocysteinemia is associated with increased risk for CAD. These findings have implications for the treatment of PD in patients at risk for vascular disease, and potentially for those at risk for dementia and depression.     

Homocysteine and folate metabolism in depression

Homocysteine is a sensitive marker of folate and vitamin B12 deficiency. Numerous studies have confirmed the association between folate deficiency and depression. It is not completely understood whether homocysteine is solely a marker for folate deficiency or if it may play a more direct role in the expression of mood disorders. This review describes the biochemical, neurochemical and clinical correlations of folate deficiency and hyperhomocysteinemia in relation to depression.     

Homocysteine in neuropsychiatric disorders of the elderly

OBJECTIVE: There is increasing interest in homocysteine as a risk factor for neuropsychiatric disorders such as stroke, dementia, depression and Parkinson's disease. This article reviews the current literature on the relationship between homocysteine and these disorders to ascertain if any clinical recommendations can be made. METHOD: A MEDLINE and EMBASE search was made for English language publications between 1966 and 2002 using the search terms 'Homocysteine' and 'Stroke', 'Dementia', 'Vascular Dementia', 'Alzheimer's dementia', 'Cognition disorders or cognitive decline or memory disorders', 'Depression or depressive disorders' or 'Parkinson's disease'. In addition, individual articles were hand searched for relevant references. RESULTS: Cross-sectional studies consistently suggest that elevated homocysteine increases the risk of stroke, and may also increase the risk of leukoariosis, vascular dementia (VaD), cognitive impairment and Alzheimer's disease (AD). Longitudinal studies of homocysteine as a risk factor are few and inconsistently supportive of these associations. No intervention trials to determine the effect of lowering homocysteine levels have yet been published. The pathological mechanisms for homocysteine-mediated disease await complete elucidation. Mild hyperhomocysteinemia is common in the elderly population, and folate supplementation can decrease homocysteine levels. CONCLUSION: The epidemiological evidence for homocysteine as a risk factor for neuropsychiatric disease is an emerging area of great interest. Screening the population for hyperhomocysteinemia cannot be recommended at this stage, but individuals at increased risk of cerebrovascular disease or cognitive impairment should be investigated and treated for elevated homocysteine levels.     

Cobalamin, folate, methylmalonic acid, homocysteine, and gastritis markers in dementia

The prevalence of dementia disorders, cobalamin and/or folate deficiency as well as gastritis increases with age. To investigate whether there is an association between these conditions, plasma homocysteine (Hcy), serum methylmalonic acid, serum cobalamin and blood folate concentrations were measured. Gastritis was indirectly diagnosed by measuring serum antibodies against H,K-ATPase, HELICOBACTER PYLORI and intrinsic factor, using enzyme-linked immunosorbent assays. The studied groups consisted of 47 patients with Alzheimer's disease (AD), 9 with AD pathology in combination with additive vascular lesions, 59 with vascular dementia, 8 who were cognitively impaired, and 101 control cases. Plasma Hcy concentrations were significantly elevated in the dementia groups, with the highest levels in patients with vascular pathology. We conclude that hyperhomocysteinemia is a common finding in patients with dementia disorders of different etiologies. The markers for gastritis did not contribute to an elucidation of a possible connection between this condition, dementia disorders, or cobalamin/folate deficiency.     

Homocysteine and Parkinson's disease: a dangerous liaison?

Homocysteine, a sulphur-containing amino acid formed by demethylation of methionine, is involved in numerous processes of methyl group transfer, all playing pivotal roles in the biochemistry of the human body. Increased levels of plasma homocysteine (hyperhomocysteinemia) - which may result from a deficiency of folate, vitamin B6 or B12 or mutations in enzymes regulating the catabolism of homocysteine - are associated with a wide range of clinical manifestations, mostly affecting the central nervous system (e.g., mental retardation, cerebral atrophy and epileptic seizures). Recent evidence suggests that changes in the metabolic fate of homocysteine, leading to hyperhomocysteinemia, may also play a role in the pathophysiology of neurodegenerative disorders, particularly Parkinson's disease (PD). The nervous system might be particularly sensitive to homocysteine, due to the excitotoxic-like properties of the amino acid. However, experimental findings have shown that homocysteine does not seem to posses direct, cytotoxic activity, while the amino acid has proven able to synergize with more specific neurotoxic insults. Hyperhomocysteinemia has been repeatedly reported in PD patients; the increase, however, seems mostly related to the methylated catabolism of l-Dopa, the main pharmacological treatment of PD. Therefore, hyperhomocysteinemia may not be specific to movement disorders or other neurological diseases, the condition being, in fact, rather the result of the combinations of different factors, mainly metabolic, but also genetic and pharmacological, intervening in the neurodegenerative process.     

Plasma homocysteine levels in multiple sclerosis

BACKGROUND: There is evidence that homocysteine contributes to various neurodegenerative disorders, and elevated plasma homocysteine levels have been observed in patients with multiple sclerosis (MS). OBJECTIVE: To investigate if and why plasma homocysteine levels are increased in MS, and whether they play a role in the disease course. METHODS: We compared plasma levels of homocysteine in 88 patients with MS and 57 healthy controls. In the MS group, 28 had a benign course, 37 were secondary progressive, and 23 primary progressive. To explore the underlying mechanisms, we measured serum levels of vitamins B6 and B12, folate, interleukin (IL)-12, tumour necrosis factor (TNF)-alpha, leukocyte nitric oxide production, and plasma diene conjugate levels (measure of oxidative stress). RESULTS: Mean (SD) plasma homocysteine concentration was higher in patients (13.8 (4.9) micromol/l) than in controls (10.1 (2.5) micromol/l; p<0.0001). However, there were no significant differences in homocysteine levels between the three clinical subgroups of MS. Serum concentrations of vitamin B6, vitamin B12, and folate were not different between patients with MS and controls. In the MS group, there were no correlations between plasma homocysteine levels and the serum concentrations of IL-12 or TNF-alpha, leukocyte nitric oxide production, or plasma diene conjugate levels. CONCLUSIONS: Elevated plasma homocysteine occurs in both benign and progressive disease courses of MS, and seems unrelated to immune activation, oxidative stress, or a deficiency in vitamin B6, vitamin B12, or folate.     

Homocysteine and neurologic disease

Over the last 10 years, there has been an explosion of interest in homocysteine, a sulfur-containing amino acid that occupies a central location in the metabolic pathways of thiol compounds. This interest is primarily because of the realization that hyperhomocysteinemia is an important risk factor for vascular disease, including stroke, independent of long-recognized factors such as hyperlipidemia, hypertension, diabetes mellitus, and smoking. Since elevated homocysteine levels can often be normalized by supplementing the diet with folic acid (folate), pyridoxine hydrochloride (vitamin B(6)), and cyanocobalamin (vitamin B(12)), these observations raise the exciting possibility that this inexpensive and well-tolerated therapy may be effective in decreasing the incidence of vascular disease. In addition to its association with cerebrovascular disease, homocysteine may play a role in neurodegenerative disorders, even if only as a marker of functional vitamin B(12) deficiency. Homocysteine is also important to neurologists since most anticonvulsants raise homocysteine levels, an effect that may explain the teratogenic effects of these drugs. Practical knowledge concerning some details of homocysteine metabolism, the diagnosis of hyperhomocysteinemia, and the use of polyvitamin therapy to lower homocysteine levels will be increasingly important in the treatment of patients with neurologic disease. Arch Neurol. 2000;57:1422-1428     

Homocysteine metabolism and various consequences of folate deficiency

Homocysteine is a neurotoxic non-proteinogenic amino acid, an abnormal increase of which in plasma has been implicated in many pathological conditions including cardiovascular diseases, neural tube defects and is now recognized and Alzheimer's disease. Homocysteine elimination is regulated by the transmethylation and the transsulfuration pathways and is modulated by folate, a member of the B-vitamin family. A metabolic product of folate, 5 methyltetrahydrofolate, provides a methyl group that is used to reconvert homocysteine back to methionine through the transmethylation pathway. The efficiency of folate metabolism has an impact on the availability of S-adenosylmethionine (SAM), a compound that is known to activate homocysteine flux through the transsulfuration pathway. SAM is also necessary for utilization of the antioxidant glutathione via glutathione S-transferase. In this review, I will elaborate on different biochemical reactions that are implicated in the regulation of homocysteine elimination through the transmethylation and the transsulfuration pathways and on various consequences of folate deficiency on homocysteine metabolism.     

Gene--nutrition interactions in coronary artery disease: correlation between the MTHFR C677T polymorphism and folate and homocysteine status in a Korean population

INTRODUCTION: Elevated plasma total homocysteine is a major risk for coronary artery disease (CAD). Methyltetrahydrofolate reductase (MTHFR) is a main regulatory enzyme in homocysteine metabolism; a common C677T mutation in the MTHFR gene results in decreased enzyme activity, and contributes to increased homocysteine levels and decreased folate levels. We investigated the frequency of MTHFR C677T alleles in a Korean population, determined the genotype-specific threshold levels of folate or vitamin B12, and investigated the relationship between the TT genotype and the risk of CAD. MATERIALS AND METHODS: We enrolled a study population of 163 CAD patients and 50 control subjects, and screened the MTHFR C677T polymorphism using real-time PCR with melting point analysis. Levels of plasma homocysteine, folate and vitamin B12 were also determined. We then defined the genotype-specific threshold values of folate and vitamin B12 required to keep homocysteine levels in a normal range for individuals of each MTHFR C677T genotype. RESULTS: The frequency of the TT genotype was 18% in control subjects and 26% in patients group (P>0.05). Individuals homozygous for the TT genotype had significantly elevated homocysteine levels (P<0.05). The genotype-specific folate threshold level was significantly higher in TT individuals than in the CC or CT genotypes. The OR of individuals with low folate status and the TT genotype to estimate the relative risk of CAD was 2.2 and the OR of those with high folate status and the TT genotype was 1.5 (95% CI, 0.5-9.6 and 0.7-3.2, respectively). CONCLUSION: We were able to define a gene-nutrient interaction that shows a higher risk for CAD based on specific threshold folate levels required by different MTHFR C677T genotypes in a Korean population.     

Folate deficiency inhibits proliferation of adult hippocampal progenitors

Neurogenesis in the adult hippocampus may play important roles in learning and memory, and in recovery from injury. As recent findings suggest, the perturbance of homocysteine/folate or one-carbon metabolism can adversely affect both the developing and the adult brain, and increase the risk of neural tube defects and Alzheimer's disease. We report that dietary folic acid deficiency dramatically increased blood homocysteine levels and significantly reduced the number of proliferating cells in the dentate gyrus of the hippocampus in adult mice. In vitro, the perturbance of one-carbon metabolism repressed proliferation of cultured embryonic multipotent neuroepithelial progenitor cells and affected cell cycle distribution. Our results suggest that dietary folate deficiency inhibits proliferation of neuronal progenitor cells in the adult brain and thereby affects neurogenesis.     

Homocysteine and dementia

Homocysteine is a vascular risk factor including cerebral macroangiopathy and microangiopathy. Furthermore, there might also be an association with cognitive disorders including vascular dementia and Alzheimer's disease. Hyperhomocysteinemia linked with cognitive impairment might be an indirect marker for low concentrations of vitamin B 12, vitamin B 6 or folate, resulting from low intake or from an impaired transport of the vitamins to the brain. Another possibility is a direct harmful effect of homocysteine to cognition via vascular and neurotoxic pathophysiologic mechanisms. Because hyperhomocysteinemia is a potentially reversible risk factor and can be identified early, it should be investigated by prospective intervention studies whether lowering homocysteine levels by vitamin supplementation could reduce incidence and progression of cognitive disorders.     

Homocysteine, vitamin B12, and folic acid levels in Alzheimer's disease, mild cognitive impairment, and healthy elderly: baseline characteristics in subjects of the Australian Imaging Biomarker Lifestyle study

There is some debate regarding the differing levels of plasma homocysteine, vitamin B12 and serum folate between healthy controls (HC), mild cognitive impairment (MCI), and Alzheimer's disease (AD). As part of the Australian Imaging Biomarker Lifestyle (AIBL) study of aging cohort, consisting of 1,112 participants (768 HC, 133 MCI patients, and 211 AD patients), plasma homocysteine, vitamin B12, and serum and red cell folate were measured at baseline to investigate their levels, their inter-associations, and their relationships with cognition. The results of this cross-sectional study showed that homocysteine levels were increased in female AD patients compared to female HC subjects (+16%, p-value < 0.001), but not in males. Red cell folate, but not serum folate, was decreased in AD patients compared to HC (-10%, p-value = 0.004). Composite z-scores of short- and long-term episodic memory, total episodic memory, and global cognition all showed significant negative correlations with homocysteine, in all clinical categories. Increasing red cell folate had a U-shaped association with homocysteine, so that high red cell folate levels were associated with worse long-term episodic memory, total episodic memory, and global cognition. These findings underscore the association of plasma homocysteine with cognitive deterioration, although not unique to AD, and identified an unexpected abnormality of red cell folate.