Serum Folate and Homocysteine, Mood Disorders, and Aging
Larry H. Bernstein, MD, FCAP, Curator
LPBI
Dietary Folate and the Risk of Depression in Finnish MiddleAged Men
Tolmunen T, et al.
PSYCHOTHER AND PSYCHOSOM · OCT 2004; 73:334-339 DOI: http://dx.doi.org:/10.1159/000080385
Serum Folate, Vitamin B-12, and Homocysteine and Their Association With Depressive Symptoms Among U.S. Adults
M.A. BEYDOUN, M.R. SHROFF, H.A. BEYDOUN AND A.B. ZONDERMAN
PSYCHOSOM MED · NOV 2010; DOI: http://dx.doi.org:/10.1097/PSY.0b013e3181f61863
Objective: To examine, in a nationally representative sample of U.S. adults, the associations of serum folate, vitamin B-12, and total homocysteine (tHcy) levels with depressive symptoms. Several nutritional and physiological factors have been linked to depression in adults, including low folate and vitamin B-12 and elevated tHcy levels.
Methods: Data on U.S. adults (age, 20–85 years; n 2524) from the National Health and Nutrition Examination Survey during the period 2005 to 2006 were used. Depressive symptoms were measured with the Patient Health Questionnaire (PHQ), and elevated symptoms were defined as a PHQ total score of 10. Serum folate, vitamin B-12, and tHcy were mainly expressed as tertiles. Multiple ordinary least square (OLS), logistic, and zero-inflated Poisson regression models were conducted in the main analysis.
Results: Overall, mean PHQ score was significantly higher among women compared with men. Elevated depressive symptoms (PHQ score of 10) were inversely associated with folate status, particularly among women (fully adjusted odds ratio [tertiles T3 versus T1] 0.37; 95% confidence interval, 0.17–0.86), but not significantly related to tHcy or vitamin B-12. No interaction was noted between the three exposures in affecting depressive symptoms. In older adults (50 years) and both sexes combined, tHcy was positively associated with elevated depressive symptoms (fully adjusted odds ratio [tertiles T2 versus T1] 3.01; 95% confidence interval, 1.01–9.03), although no significant dose-response relationship was found. Conclusions: Future interventions to improve mental health outcomes among U.S. adults should take into account dietary and other factors that would increase levels of serum folate.
Key words: depression, folate, vitamin B-12, homocysteine, adults.
Relationship of homocysteine, folic acid and vitamin B12 depression in a middle-aged community sample
P.S. SACHDEV, et al. PSYCHOL MED · MAY 2005; 35, 529–538 http://dx.doi.org: /10.1017/S0033291704003721
Background. Case control studies have supported a relationship between low folic acid and vitamin B12 and high homocysteine levels as possible predictors of depression. The results from epidemiological studies are mixed and largely from elderly populations.
Method. A random subsample of 412 persons aged 60–64 years from a larger community sample underwent psychiatric and physical assessments, and brain MRI scans. Subjects were assessed using the PRIME-MD Patient Health Questionnaire for syndromal depression and severity of depressive symptoms. Blood measures included serum folic acid, vitamin B12, homocysteine and creatinine levels, and total antioxidant capacity. MRI scans were quantified for brain atrophy, subcortical atrophy, and periventricular and deep white-matter hyperintensity on T2-weighted imaging.
Results. Being in the lowest quartile of homocysteine was associated with fewer depressive symptoms, after adjusting for sex, physical health, smoking, creatinine, folic acid and B12 levels. Being in the lowest quartile of folic acid was associated with increased depressive symptoms, after adjusting for confounding factors, but adjustment for homocysteine reduced the incidence rate ratio for folic acid to a marginal level. Vitamin B12 levels did not have a significant association with depressive symptoms. While white-matter hyperintensities had significant correlations with both homocysteine and depressive symptoms, the brain measures and total antioxidant capacity did not emerge as significant mediating variables. Conclusions. Low folic acid and high homocysteine, but not low vitamin B12 levels, are correlates of depressive symptoms in community-dwelling middle-aged individuals. The effects of folic acid and homocysteine are overlapping but distinct.
Association of folate intake with the occurrence of depressive episodes in middle-aged French men and women
P. Astorg, et al. BRIT J NUTR · AUG 2008; 100, 183–18 http://dx.doi.org:/10.1017/S0007114507873612
A low folate intake or a low folate status have been found to be associated with a higher frequency of depression in populations, but the existence and the direction of a causal link between folate intake or status and depression is still uncertain. The aim of this study was to seek the relation between the habitual folate intake in middle-aged men and women and the occurrence of depressive episodes. In a subsample of 1864 subjects (809 men and 1055 women) from the French SU.VI.MAX cohort, dietary habits have been measured at the beginning of the follow-up (six 24 h records) and declarations of antidepressant prescription, taken as markers of depressive episodes, have been recorded during the 8-year follow-up. No significant association was observed between folate intake and the risk of any depressive episode or of a single depressive episode during the follow-up, in both men and women. In contrast, the risk of experiencing recurrent depressive episodes (two or more) during the follow-up was strongly reduced in men with high folate intake (OR 0·25 (95% CI 0·06, 0·98) for the highest tertile v. the lowest, P for trend 0·046). This association was not observed in women. These results suggest that a low folate intake may increase the risk of recurrent depression in men. Folate: Depression: Cohort studies
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.
Faux NG1, Ellis KA, Porter L, Fowler CJ,…, Ames D, Masters CL, Bush AI.
J Alzheimers Dis. 2011; 27(4):909-22. http://dx.doi.org:/10.3233/JAD-2011-110752.
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.
Homocysteine and folate as risk factors for dementia and Alzheimer disease1,2,3
Giovanni Ravaglia, Paola Forti, Fabiola Maioli, …., Nicoletta Brunetti, Elisa Porcellini, and Federico Licastro
Am J Clin Nutr Sept 2005; 82(3): 636-643
Background: In cross-sectional studies, elevated plasma total homocysteine (tHcy) concentrations have been associated with cognitive impairment and dementia. Incidence studies of this issue are few and have produced conflicting results.
Objective: We investigated the relation between high plasma tHcy concentrations and risk of dementia and Alzheimer disease (AD) in an elderly population.
Design: A dementia-free cohort of 816 subjects (434 women and 382 men; mean age: 74 y) from an Italian population-based study constituted our study sample. The relation of baseline plasma tHcy to the risk of newly diagnosed dementia and AD on follow-up was examined. A proportional hazards regression model was used to adjust for age, sex, education, apolipoprotein E genotype, vascular risk factors, and serum concentrations of folate and vitamin B-12.
Results: Over an average follow-up of 4 y, dementia developed in 112 subjects, including 70 who received a diagnosis of AD. In the subjects with hyperhomocysteinemia (plasma tHcy > 15 μmol/L), the hazard ratio for dementia was 2.08 (95% CI: 1.31, 3.30; P = 0.002). The corresponding hazard ratio for AD was 2.11 (95% CI: 1.19, 3.76; P = 0.011). Independently of hyperhomocysteinemia and other confounders, low folate concentrations (≤11.8 nmol/L) were also associated with an increased risk of both dementia (1.87; 95% CI: 1.21, 2.89; P = 0.005) and AD (1.98; 95% CI: 1.15, 3.40; P = 0.014), whereas the association was not significant for vitamin B-12.
Conclusions: Elevated plasma tHcy concentrations and low serum folate concentrations are independent predictors of the development of dementia and AD.
In Western societies, the prevalence and economic costs of Alzheimer disease (AD) are soaring in step with the increased number of elders in the population (1). Therefore, it is important to identify modifiable risk factors for this disease. The sulfur amino acid homocysteine is a unique candidate for this role because of its direct neurotoxicity (2–4) and its association with cerebrovascular disease (5), which is currently believed to play a significant role in AD etiology (6). Moreover, elevated concentrations of plasma total homocysteine (tHcy) are an indicator of inadequate folate and vitamin B-12 status (7) and can directly affect brain function via altered methylation reactions (8).
An association between AD and elevated tHcy concentrations has been reported in case-control (9, 10) and cross-sectional (11, 12) studies. Moreover, in nondemented elderly populations, plasma tHcy is inversely associated with poor performance at simultaneously performed tests of global cognitive function (13–15) and specific cognitive skills (13, 16). However, cross-sectional studies cannot determine causality. Only 2 longitudinal studies investigated the relation between hyperhomocysteinemia and risk of incident AD, but their results were inconsistent; the Framingham Study reported a strong association (17), and the Washington Heights–Inwood Columbia Ageing Project (WHICAP) reported no association (18). Clarification of this issue is important because consistent evidence of a prospective association between homocysteine and AD would more strongly support the need for intervention trials testing the effectiveness of homocysteine-lowering vitamin therapy in preventing dementia.
Therefore, we examined baseline plasma tHcy in relation to risk of incident dementia and AD in the Conselice Study of Brain Aging (CSBA), an Italian population-based study of older persons.
Study population
The CSBA is a population-based survey, already described in detail elsewhere (19,20), the principal aim of which is to provide data about epidemiology and risk factors for dementia in the elderly. Its design includes both cross-sectional and longitudinal components. The study was approved by the Institutional Review Board of the Department of Internal Medicine, Cardioangiology, and Hepatology, University of Bologna, and written informed consent was obtained from all participants.
Briefly, in 1999–2000, 1016 (75%) of the 1353 individuals aged ≥65 y residing in the Italian municipality of Conselice (province of Ravenna, Emilia Romagna region) participated in the prevalence study. Data on cognitive status at the follow-up examination in 2003–2004 were collected for 861 of the 937 participants free of dementia at baseline. A flow chart detailing the derivation of the incidence sample used in this study is reported in Figure 1⇓.
This prospective population-based study was the first to replicate previous findings from the Framingham Study (17), indicating that hyperhomocysteinemia doubles the risk of developing dementia and AD independently of several major confounders. Our results disagree with the negative findings recently reported in the WHICAP study (18). Possible explanations for this difference are the acknowledged insufficient statistical power of the WHICAP study, the rather homogeneously high tHcy concentrations of its sample—which did not permit enough variability to detect an association—and methodologic issues related to the prolonged time between blood sample collection and processing, which could have affected tHcy measurements.
Inconsistent results were also given by the only 2 studies that examined the association between homocysteine and cognitive decline at follow-up as measured with the MMSE (30, 31). These studies, however, differed in sample size and in which confounders were taken into account. Moreover, MMSE is a reliable global screening measure of cognitive function but was not developed to estimate changes in cognitive function or to diagnose dementia (32).
The substantial evidence that tHcy is an independent vascular risk factor (5) supports the role of hyperhomocysteinemia in AD. Subjects with vascular risk factors and cerebrovascular disease have an increased risk of AD (6), and hyperhomocysteinemia has been related to cerebral macro- and microangiopathy, endothelial dysfunction, impaired nitric oxide activity, and increased oxidative stress (33–35). Moreover, as shown in cell cultures, homocysteine can directly cause brain damage through several mechanisms: increased glutamate excitoxicity via activation of N-methyl-D-aspartate receptors (2), enhancement of β-amyloid peptide generation (4), impairment of DNA repair, and sensitization of neurons to amyloid toxicity (3).
On the basis of cross-sectional observations, some authors have suggested that elevated plasma tHcy concentrations are not a causative factor in dementia and AD but are only a marker for concomitant vascular disease, independently of cognitive status (36, 37). Results from other cross-sectional investigations (9, 12, 38), as well as those from the present investigation and the Framingham Study (17), argue against this interpretation, but only intervention trials can give the ultimate proof of a causal relation between hyperhomocysteinemia and AD.
In contrast with both the Framingham (17) and WHICAP (18) studies, we also found that, independent of homocysteine and other confounders (including vitamin B-12), low serum folate is associated with an increased risk of incident dementia and AD. Mandatory folate fortification of food might partially explain the negative results of the US studies, whereas in Italy, where folate fortification is not practiced, relative folate deficiency may be endemic among the elderly population. Nondemented patients with poor cognitive performance and AD patients often exhibit poor folate status (reviewed in 8), but only one study specifically examined B vitamins in relation to incident dementia. In a selected sample of nondemented Swedish elderly participants in the Kungsholmen Study, low serum folate and vitamin B-12 were predictive of AD at 3 y of follow-up (39). The sample, however, was small (370 subjects), and a clear association was detected only when both vitamins were taken into account.
Biologic explanatory mechanisms relating folate deficiency to dementia include impaired methylation reactions in the central nervous system, with a consequent insufficient supply of methyl groups, which are required for the synthesis of myelin, neurotransmitters, membrane phospholipids, and DNA (8). However, because of the study design and the relatively short follow-up time, we cannot definitely establish whether the independent association between low folate and dementia risk indicates an actual effect of folate status on cognitive function or, on the contrary, that subtle functional alterations may affect the dietary intake of folate in the early preclinical stages of dementia.
Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor
Stuart A. Lipton*†, Won-Ki Kim‡, Yun-Beom Choi*,…, Derrick R. Arnelle§, and Jonathan S. Stamler
PNAS 1997; 94(11):5923–5928 http://www.pnas.org/content/94/11/5923.abstract
Severely elevated levels of total homocysteine (approximately millimolar) in the blood typify the childhood disease homocystinuria, whereas modest levels (tens of micromolar) are commonly found in adults who are at increased risk for vascular disease and stroke. Activation of the coagulation system and adverse effects of homocysteine on the endothelium and vessel wall are believed to underlie disease pathogenesis. Here we show that homocysteine acts as an agonist at the glutamate binding site of the N-methyl-D-aspartate receptor, but also as a partial antagonist of the glycine coagonist site. With physiological levels of glycine, neurotoxic concentrations of homocysteine are on the order of millimolar. However, under pathological conditions in which glycine levels in the nervous system are elevated, such as stroke and head trauma, homocysteine’s neurotoxic (agonist) attributes at 10–100 μM levels outweigh its neuroprotective (antagonist) activity. Under these conditions neuronal damage derives from excessive Ca2+ influx and reactive oxygen generation. Accordingly, homocysteine neurotoxicity through overstimulation of N-methyl-D-aspartate receptors may contribute to the pathogenesis of both homocystinuria and modest hyperhomocysteinemia.
Vitamin B12 and folate in relation to the development of Alzheimer’s disease
H-X. Wang, Å. Wahlin, H. Basun, …, B. Winblad, and L. Fratiglioni
Neurology May 8, 2001; 56(9):1188-1194 http://dx.doi.org/10.1212/WNL.56.9.1188
Objective: To explore the associations of low serum levels of vitamin B12 and folate with AD occurrence.
Methods: A population-based longitudinal study in Sweden, the Kungsholmen Project. A random sample of 370 nondemented persons, aged 75 years and older and not treated with B12 and folate, was followed for 3 years to detect incident AD cases. Two cut-off points were used to define low levels of vitamin B12 (≤150 and ≤250 pmol/L) and folate (≤10 and ≤12 nmol/L), and all analyses were performed using both definitions. AD and other types of dementia were diagnosed by specialists according to DSM-III-R criteria.
Results: When using B12 ≤150pmol/L and folate ≤10 nmol/L to define low levels, compared with people with normal levels of both vitamins, subjects with low levels of B12or folate had twice higher risks of developing AD (relative risk [RR] = 2.1, 95% CI = 1.2 to 3.5). These associations were even stronger in subjects with good baseline cognition (RR = 3.1, 95% CI = 1.1 to 8.4). Similar relative risks of AD were found in subjects with low levels of B12or folate and among those with both vitamins at low levels. A comparable pattern was detected when low vitamin levels were defined as B12 ≤250 pmol/L and folate ≤12 nmol/L.
Conclusions: This study suggests that vitamin B12 and folate may be involved in the development of AD. A clear association was detected only when both vitamins were taken into account, especially among the cognitively intact subjects. No interaction was found between the two vitamins. Monitoring serum B12 and folate concentration in the elderly may be relevant for prevention of AD.
Assessing the association between homocysteine and cognition: reflections on Bradford Hill, meta-analyses, and causality
Hyperhomocysteinemia is a recognized risk factor for cognitive decline and incident dementia in older adults. Two recent reports addressed the cumulative epidemiological evidence for this association but expressed conflicting opinions. Here, the evidence is reviewed in relation to Sir Austin Bradford Hill’s criteria for assessing “causality,” and the latest meta-analysis of the effects of homocysteine-lowering on cognitive function is critically examined. The meta-analysis included 11 trials, collectively assessing 22 000 individuals, that examined the effects of B vitamin supplements (folic acid, vitamin B12, vitamin B6) on global or domain-specific cognitive decline. It concluded that homocysteine-lowering with B vitamin supplements has no significant effect on cognitive function. However, careful examination of the trials in the meta-analysis indicates that no conclusion can be made regarding the effects of homocysteine-lowering on cognitive decline, since the trials typically did not include individuals who were experiencing such decline. Further definitive trials in older adults experiencing cognitive decline are still urgently needed.
Mouse model for deficiency of methionine synthase reductase exhibits short-term memory impairment and disturbances in brain choline metabolism
Nafisa M. Jadavji, Renata H. Bahous, Liyuan Deng, Olga Malysheva, Marilyn Grand’maison, Barry J. Bedell, Marie A. Caudill, Rima Rozen
Hyperhomocysteinaemia can contribute to cognitive impairment and brain atrophy. MTRR (methionine synthase reductase) activates methionine synthase, which catalyses homocysteine remethylation to methionine. Severe MTRR deficiency results in homocystinuria with cognitive and motor impairments. An MTRR polymorphism may influence homocysteine levels and reproductive outcomes. The goal of the present study was to determine whether mild hyperhomocysteinaemia affects neurological function in a mouse model with Mtrr deficiency. Mtrr+/+, Mtrr+/gt and Mtrrgt/gtmice (3 months old) were assessed for short-term memory, brain volumes and hippocampal morphology. We also measured DNA methylation, apoptosis, neurogenesis, choline metabolites and expression of ChAT (choline acetyltransferase) and AChE (acetylcholinesterase) in the hippocampus. Mtrrgt/gt mice exhibited short-term memory impairment on two tasks. They had global DNA hypomethylation and decreased choline, betaine and acetylcholine levels. Expression of ChAT and AChE was increased and decreased respectively. At 3 weeks of age, they showed increased neurogenesis. In the cerebellum, mutant mice had DNA hypomethylation, decreased choline and increased expression of ChAT. Our work demonstrates that mild hyperhomocysteinaemia is associated with memory impairment. We propose a mechanism whereby a deficiency in methionine synthesis leads to hypomethylation and compensatory disturbances in choline metabolism in the hippocampus. This disturbance affects the levels of acetylcholine, a critical neurotransmitter in learning and memory.
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