Influences of Folate Supplementation on Homocysteine and Cognition in Patients with Folate Deficiency and Cognitive Impairment.

Although folate deficiency was reported to be associated with hyperhomocysteinemia, influence of folate supplementation on cognition remains controversial. Therefore, we explored the effects of folate supplementation on the cognition and Homocysteine (Hcy) level in relatively short periods in patients with folate deficiency and cognitive impairment. Enrolled 45 patients (mean age of 79.7 ± 7.9 years old) with folate deficiency (<3.6 ng/mL) with cognitive impairment underwent Mini-Mental State Examination (MMSE), and laboratory examinations, including folate, vitamin B12, and Hcy. The degree of hippocampal atrophy in MRI was estimated using a voxel-based specific regional analysis system for Alzheimer's disease (VSRAD). Patients were administrated folate (5 mg/day), then Hcy, and MMSE score were re-examined after 28 to 63 days. Mean Hcy significantly decreased from 25.0 ± 18.0 to 11.0 ± 4.3 nmol/mL (p < 0.001). Average MMSE scores also significantly changed from 20.1 ± 4.7 to 22.2 ± 4.3 (p < 0.001). The degree of change in the MMSE score and basic Hcy or Hcy change was significantly positively correlated, while degree of hippocampal atrophy in MRI did not. Although several factors should be taken into account, folate supplementation ameliorated cognitive impairment, at least for a short period, in patients with folate deficiency.

Folic acid consumption based on the theory of planned behaviour in pregnant women.

Folic Acid reduces the risk of neural tube defects. This study was aimed to investigate the consumption of folic acid to prevent deficiency anaemia based on the theory of planned behaviour on pregnant women in Neyshabur, Iran. This study included 180 pregnant women, who were gathered from 12 healthcare centres in the city of Neyshabur, Iran in 2018. Using a questionnaire and blood lab exam (folat) were measured and analysed. The average rates of knowledge, attitude, perceived behavioural control, intention, behaviour in the education group were meaningfully increased (p value < .05); however, these changes were not meaningful in the control group (p value > .05). Also, no statistically meaningful difference was obtained in subjective norm between the groups after the intervention (p = .924). It is suggested that folic acid supplementation promotion workshops should be held in health centres with the aim of preventing folic acid deficiency anaemia.Impact statementWhat is already known on this subject? The results of this study showed that by using education based on the theory of planned behaviour that emphasises the important psychological factors of behaviour or change, folic acid can be consumed in pregnant women. That women receive adequate and proper knowledge, along with a positive attitude toward taking folic acid, and feel that taking folic acid is at their discretion in terms of environmental factors (facilities and barriers), increases intent to use folic acid.What do the results of this study add? The results of this study also showed that the amount of folic acid intake during pregnancy increased by pregnant women and anaemia decreased.What are the implications of these findings for clinical practice and/or further research? The study showed the importance of the role of education based on theory of planned behaviour in consumption promoting folic acid.

[Folic acid and vitamin B12 determination in the assessment of cognitive disorders : Overview and data analysis from a university outpatient memory clinic]. / Folsäure- und Vitamin-B12-Bestimmung in der Diagnostik kognitiver Störungen : Übersicht und Datenanalyse einer universitären Gedächtnisambulanz.

Vitamin B12 and folic acid deficiencies are particularly frequent conditions in older people. Since these metabolic disorders represent relevant dyscognitive factors, the assessment of vitamin B12 and folic acid levels is essential in the diagnostic approach of cognitive disorders, such as mild cognitive impairment and dementia in an outpatient memory clinic. This article summarizes the relevant diagnostic and therapeutic aspects of vitamin B12 and folic acid deficiencies and their effects on cognition. The literature review is supplemented by a data analysis of a naturalistic cohort of 250 patients from this outpatient memory clinic.

Nutrition research in cognitive impairment/dementia, with a focus on soya and folate.

Observational studies and treatment trials investigating nutrition and cognitive function, with a focus on folate and soya and dementia, were reviewed. Data suggested that effects of folic acid based interventions may only be shown before cognitive decline is evident and/or if people are folate deficient. In older people in Indonesia, Hawai'i and China, tofu, which can contain high levels of phytoestrogens, was found to increase dementia risk. This association was not mediated by a vegetarian diet, socioeconomic status, formaldehyde, thyroid function, or loss of teeth. On the other hand, human observational and animal treatment studies suggested that tempe, a fermented soya product containing phytoestrogens and folate, reduced dementia risk and improved memory. High oestrogen levels were found to increase dementia risk in older women. However, in women with adequate serum folate, high oestrogen levels did not confer additional dementia risk and may protect ageing neurons. In conclusion, reviews seem to suggest that folic acid interventions are only effective on cognitive outcomes in people who are folate deficient and do not have cognitive impairment. Frequent consumption of tofu may have detrimental effects on memory and increase dementia risk in older East Asian people, while tempe may reduce these risks. Possibly folate in tempe offsets the potential negative effects of oestrogenic compounds on ageing neurons.

Reduced nerve growth factor levels in stress-related brain regions of folate-deficient mice.

Folate deficiency has been linked to neurodegenerative and stress-related diseases such as stroke, dementia and depression. The role of the neurotrophins nerve growth factor (NGF) and neurotrophin-3 (NT-3) in stress-related disorders and neurodegeneration has garnered increasing attention in recent years. Uracil misincorporation is involved in the neuropsychiatric dysfunction induced by experimental folate deprivation. However, the effects of folate deficiency on the expression of NGF and NT-3 in brain tissue have not yet been investigated. In a 2×2 design, aged mice lacking uracil-DNA N-glycosylase (Ung(-/-)) versus wild-type (Ung(+/+)) controls were subjected to a folate-deficient diet versus a regular diet for three months. Independent of genotype, folate deficiency led to decreased NGF protein levels in the frontal cortex and amygdala. In the hippocampus, NGF levels were increased in UNG(-/-) mice on the normal diet, but not under folate deficiency, while in UNG(+/+) mice, folate deprivation did not affect hippocampal NGF content. NT-3 protein concentrations were neither affected by genotype nor by folate deficiency. Altogether, the results of our study show that folate deficiency affects NGF levels in the frontal cortex, amygdala and hippocampus. The decrease in NGF content in the hippocampus in response to folate deficiency in Ung(-/-) mice may contribute to their phenotype of enhanced anxiety and despair-like behavior as well as to selective hippocampal neurodegeneration.

Supplementation with apple juice can compensate for folate deficiency in a mouse model deficient in methylene tetrahydrofolate reductase activity.

Folate insufficiency promotes developmental as well as age-related disorders of the nervous system. The C677T variant of 5',10' methylene tetrahydrofolate reductase (MTHFR; which utilizes folate to regenerate methionine from homocysteine) displays reduced activity, and therefore promotes functional folate deficiency. Mice heterozygously lacking this gene (MTHFR+/- mice) represent a useful model for analysis of the impact of MTHFR deficiency and potential compensatory approaches. Since consumption of apple products has benefited mouse models subjected to dietary and/or genetically-induced folate deficiency, we compared the impact of supplementation with apple juice on cognitive and neuromuscular performance of mice MTHFR+/+ and +/- mice with and without dietary folate deficiency. Mice were maintained for 1 month on a standard, complete diet, or a challenge diet lacking folate, and vitamin E and containing a 50 g iron/500 g total diet as a pro-oxidant. Additional groups received apple juice concentrate (AJC) diluted to 0.5% (vol/vol) in their sole source of drinking water. MTHFR+/- mice demonstrated significantly impaired cognitive performance in standard reward-based T maze and the non-reward-based Y maze tests as compared to MTHFR+/+ when maintained on the complete diet; supplementation with AJC improved the performance of MTHFR+/- to the level observed for MTHFR+/+ mice. Maintenance for 1 month on the deficient diet reduced the performance of both genotypes in both tests, but supplementation with AJC prevented these reductions. MTHFR+/+ and +/- displayed virtually identical neuromuscular performance in the standard paw grip endurance test when maintained on the complete diet, and displayed similar, non-significant declines in performance when maintained on the deficient diet. Supplementation of either diet with AJC dramatically improved the performance of both genotypes. The findings presented herein indicate that supplementation with AJCs can compensate for genetic as well as dietary insufficiency in folate in a murine model of genetic folate compromise, and support the notion that dietary supplementation may be more critical under conditions of latent genetic compromise.

Folic acid supplementation in pregnant women.

INTRODUCTION: Folic acid (FA) deficiency is associated with neural tube defects (NTD). In a non-risk pregnancy, The Danish National Board of Health recommends FA supplementation from planned pregnancy until three months after conception. We explored pregnant women's knowledge about and actual supplementation with FA and related this to education, number of pregnancies and age. MATERIAL AND METHODS: Eighty-four consecutive pregnant women with a midwife consultation were included in the period 25-28 August 2008. All filled in a unified questionnaire. RESULTS: 82% had knowledge of FA supplementation and 89% received FA supplementation. 51% followed national recommendations. We found a statistically significant correlation between higher educational level and knowledge about FA supplementation, actual supplementation of FA and FA supplementation in accordance with national recommendations. No statistical associations were found between number of pregnancies or age and any FA-related parameters. Family, friends, general practitioner (GP) and the internet were the main information sources. CONCLUSION: Correct FA supplementation is quite low; conversely, knowledge about and actual FA supplementation are fairly high. Further intervention is necessary to increase the level of correct FA supplementation. Women with a low educational level--which may herald low socio-economic status--seem to form a suitable target group for information campaigns. Multiple pregnancies or higher age should not be perceived as indicators of a higher information level. Dissemination of information to the pregnant women including family, friends, GPs or the internet is recommended.

Cognitive impairment in folate-deficient rats corresponds to depleted brain phosphatidylcholine and is prevented by dietary methionine without lowering plasma homocysteine.

Poor folate status is associated with cognitive decline and dementia in older adults. Although impaired brain methylation activity and homocysteine toxicity are widely thought to account for this association, how folate deficiency impairs cognition is uncertain. To better define the role of folate deficiency in cognitive dysfunction, we fed rats folate-deficient diets (0 mg FA/kg diet) with or without supplemental L-methionine for 10 wk, followed by cognitive testing and tissue collection for hematological and biochemical analysis. Folate deficiency with normal methionine impaired spatial memory and learning; however, this impairment was prevented when the folate-deficient diet was supplemented with methionine. Under conditions of folate deficiency, brain membrane content of the methylated phospholipid phosphatidylcholine was significantly depleted, which was reversed with supplemental methionine. In contrast, neither elevated plasma homocysteine nor brain S-adenosylmethionine and S-adenosylhomocysteine concentrations predicted cognitive impairment and its prevention by methionine. The correspondence of cognitive outcomes to changes in brain membrane phosphatidylcholine content suggests that altered phosphatidylcholine and possibly choline metabolism might contribute to the manifestation of folate deficiency-related cognitive dysfunction.

Folic acid for the prevention of neural tube defects: the Danish experience.

Evidence from controlled trials suggests that ingestion of 0.4 mg of folic acid per day in the periconceptional period is effective in preventing neural tube defects (NTD). For this reason, most countries recommend that women planning pregnancy take folic acid supplements in the periconceptional period, and some countries even fortify stable foods with folic acid. Denmark exemplifies a country with a relatively conservative attitude with respect to taking action in these matters. In 1999, a national information campaign was launched that recommended women planning pregnancy take 0.4 mg of folic acid periconceptionally, but with the moderation that women who eat a healthy diet do not need to take folic acid supplement. The campaign was repeated during 2001. The results of the latter campaign were evaluated by using data from a national survey among pregnant women conducted simultaneously with the campaign by the Danish National Birth Cohort. An increase in the proportion of folic acid users took place concomitantly with the launching of the information events, but the increase was limited. Among women who did not plan their pregnancy, a small proportion had taken folic acid supplements periconceptionally, and this proportion did not change concomitantly with the campaign. Young age and low education were factors associated with low likelihood of taking folic acid. It seems that different and more efficient actions are needed if a more substantial proportion of Danish women and their fetuses are going to benefit from the knowledge that folic acid supplementation in the periconceptional period can prevent NTD.

A randomised double-blind placebo-controlled trial of folic acid supplementation of cholinesterase inhibitors in Alzheimer's disease.

OBJECTIVES: (1) to assess the effect of 1 mg folic acid supplementation of cholinesterase inhibitors (ChI) in a 6 month double-blind placebo-controlled study of patients with Alzheimer's Disease (AD) and (2) to assess whether outcome measures were affected by changes in homocysteine levels. METHOD: Fifty-seven consecutive outpatients with probable AD were treated concurrently with a ChI and either folic acid or placebo. None had conditions or medication known to interfere with folate metabolism. Fasting folate and homocysteine levels were measured prior to commencing ChI and 6 months later. Response was categorised using criteria of the National Institute of Clinical Excellence (NICE). RESULTS: Twelve males and 29 females completed treatment (mean age 76.27 SD 6.23 years, Mini-Mental State Examination (MMSE) 23.49 SD 3.53, baseline homocysteine 18.39 SD 4.62 micromoles per litre). 23 received folic acid and 18 placebo. There were no significant baseline differences or use of individual ChI between the two arms. After 6 months a significant difference was seen in the change from baseline in combined Instrumental Activities of Daily Living and Social Behaviour scores between arms (folate+1.50 (SD 5.32) vs placebo -2.29 (SD 6.16) (p=0.03) but not change in MMSE scores. Sixteen of 23 subjects receiving folic acid and 7/18 placebo subjects were classified as NICE responders (p=0.05). CONCLUSION: This pilot double blind study suggests that response to ChI in patients with AD may be improved by the use of folic acid. The relationship between any change in homocysteine levels and response to treatment is discussed.

Apple juice concentrate maintains acetylcholine levels following dietary compromise.

Oxidative stress contributes to age-related cognitive decline. In some instances, consumption of fruits and vegetables rich in antioxidant can provide superior protection than supplementation with purified antioxidants. Our prior studies have shown that supplementation with apple juice concentrate (AJC) alleviates oxidative damage and cognitive decline in adult (9-12 months) mice lacking ApoE (as a model of increased oxidative stress) and in normal aged (2-2.5 years) mice when challenged with a vitamin-deficient, oxidative stress-promoting diet. Here, we demonstrate that AJC, administered in drinking water, maintains acetylcholine levels that otherwise decline when adult and aged mice are maintained on the above deficient diet. Normal mice aged either 9-10 months or 2-2.5 years and ApoE-/- mice aged 9-10 months were maintained for 1 month on a complete diet or a diet lacking folate and vitamin E and containing iron as a pro-oxidant, and additional groups received 0.5% AJC ad libitum in drinking water. Spectrophotometric assay of acetylcholine levels revealed a significant decline in homogenates of combined frontal cortex and hippocampus for all mice maintained on the deficient diet, and a prevention of this decline in mice maintained on the deficient diet when supplemented with AJC. These findings provide a likely mechanism by which consumption of antioxidant-rich foods such as apples can prevent the decline in cognitive performance that accompanies dietary and genetic deficiencies and aging.

Mediterranean diet and depression.

OBJECTIVE: The adherence to a Mediterranean Dietary Pattern ensures an adequate intake of B vitamins and w-3 fatty acids. A protective role on depression has been suggested for both nutrients. DESIGN: Cross-sectional analysis from the SUN (Seguimiento Universidad de Navarra) prospective cohort study. Data from 9670 participants (4211 men and 5459 women) were analised. Logistic regression analyses were fitted to assess the association between B-vitamins and w-3 fatty acids intake (quintiles) and the prevalence of depression. RESULTS: Folate intake was inversely associated with depression prevalence among men, especially smokers. Among women, B12 vitamin intake was inversely associated with depression, especially among smokers and physically active women. No significant associations were observed for w-3 fatty acids intake. CONCLUSIONS: The adherence to a Mediterranean Dietary Pattern ensures an adequate intake of fruits, nuts, vegetables, cereals, legumes or fish, important sources of nutrients linked to depression prevention.

Vitamin B12 and folate depletion in cognition: a review.

In cross-sectional studies, low levels of folate and B12 have been shown to be associated with cognitive decline and dementia Evidence for the putative role of folate, vitamin B12 in neurocognitive and other neurological functions comes from reported cases of severe vitamin deficiencies, particularly pernicious anemia, and homozygous defects in genes that encode for enzymes of one-carbon metabolism. The neurological alterations seen in these cases allow for a biological role of vitamins in neurophysiology. Results are quite controversial and there is an open debate in literature, considering that the potential and differential role of folate and B12 vitamin in memory acquisition and cognitive development is not completely understood or accepted. What is not clear is the fact that vitamin B12 and folate deficiency deteriorate a pre-existing not overt pathological situation or can be dangerous even in normal subjects. Even more intriguing is the interaction between B12 and folate, and their role in developing hyperhomocysteinemia. The approach to the rehabilitation of the deficiency with adequate vitamin supplementation is very confusing. Some authors suggest it, even in chronic situations, others deny any possible role. Starting from these quite confusing perspectives, the aim of this review is to report and categorize the data obtained from the literature. Despite the plausible biochemical mechanism, further studies, based on clinical, neuropsychological, laboratory and (lastly) pathological features will be necessary to better understand this fascinating biochemical riddle.

Depression and folate status in the US Population.

BACKGROUND: Folate deficiency and low folate status have been linked in clinic studies to depression, persistent depressive symptoms, and poor antidepressant response. These relationships have not been demonstrated in general populations. This study examined associations between depression and folate status indicators in an ethnically diverse general US population sample aged 15-39 years. METHODS: Healthy subjects whose red blood cell (RBC) folate concentrations had been measured were determined to have no depression (n = 2,526), major depression (n = 301), or dysthymia (n = 121) using a diagnostic interview schedule. Serum concentrations of folate and total homocysteine (tHcy) were also measured. RESULTS: After adjustment for sociodemographic factors, serum vitamin B(12) concentration, alcohol consumption over the past year and current status as to overweight and use of vitamin/mineral supplements, cigarettes and illegal drugs, subjects who met criteria for a lifetime diagnosis of major depression had folate concentrations in serum and RBCs that were lower than those of subjects who had never been depressed. Subjects who met criteria for dysthymia alone had lower RBC folate concentrations than never-depressed subjects, but the serum folate concentrations of the two groups were comparable. Serum tHcy concentration was not related to lifetime depression diagnoses. Low folate status was found to be most characteristic of recently recovered subjects, and a large proportion of such subjects were folate deficient. CONCLUSIONS: Low folate status was detectable in depressed members of the general US population. Folate supplementation may be indicated during the year following a depressive episode.

Behavioral and neurochemical changes in folate-deficient mice.

Weanling mice were fed an amino acid-based diet supplemented with 0 or 11.3 mumol folic acid/kg diet for approximately 38 days to study behavior and neurochemistry in folate deficiency. After approximately 5 wk, mice fed the unsupplemented diet weighted approximately 70% as much those fed the supplemented diet. After 2 wk, mice fed the unsupplemented diet consistently discarded (spilled) more food, and after approximately 5 wk, they had spilled 3 times more than mice fed the supplemented diet. Serum folate, brain folate and brain S-adenosylmethionine of mice fed the unsupplemented diet were 4, 53, and 60% as high, respectively, as those of mice fed the supplemented diet. Pathologic changes were not evident in brain, spinal cord, or skeletal muscle of folate-deficient mice. The hypothalamic 5-hydroxyindole acetic acid/serotonin ratio and caudate dopamine, homovanillic acid, and 3,4-dihydroxyphenylacetic acid concentrations were lower in deficient than control mice. Folate-deficient mice develop a behavioral activity, food spilling, which may have a neurochemical basis in the serotonin and dopamine systems.

Vitamins in psychiatry. Do they have a role?

Deficiencies of specific vitamins produce consistent symptoms of psychiatric disorder. Thiamine deficiency, which is common in alcoholism, can produce confusion and psychotic symptoms, in addition to neurological signs. Vitamin B12 and folate deficiency may contribute symptoms of disorientation, depression or psychosis; their measurement is a part of routine dementia work-ups. Pyridoxine deficiency results in seizures, although the effects of exogenously administered pyridoxine are not clearly understood in depression and anxiety - the disorders in which it is most frequently used clinically. The use of vitamins has been most prominent in psychiatry in the treatment of schizophrenia, where large doses of nicotinic acid were initially given alone and later combined with other vitamins and minerals. Several theoretical models were described to support the use of vitamins in schizophrenia. These included: the parallels of schizophrenia to the psychiatric symptoms of pellagra; hypotheses of a defect in adrenaline metabolism; and the accumulation of psychotoxic substances which produce psychotic symptoms. Initially, positive results were reported over 30 years ago, but have not been replicated by thorough investigations. An extensive series of comprehensive placebo-controlled trials failed to show efficacy for any of the vitamin therapies tested. Although clearly less effective than antipsychotic drug treatment, vitamin therapy is not without risks - adverse effects have been reported with nicotinic acid, pyridoxine and vitamin C.(ABSTRACT TRUNCATED AT 250 WORDS)

The Wechsler subtests in mild organic brain damage associated with folate deficiency.

Forty-nine patients with low serum and cerebrospinal fluid folate levels completed the Ottawa-Wechsler Scale after 7-11 months of folate supplementation (10 mg daily). Twelve patients exhibited major neurological symptoms, while 37 patients displayed depression and minor neurological signs. After folate therapy, Verbal, Performance and Full Wechsler scores were significantly improved (P less than 0.001). The order of improvement in scores on the Wechsler subtests (from the statistically most significant to the least as measured by the t-statistics) was: Block Design, Digit Symbol, Similarities, Picture Completion, Picture Arrangement, Arithmetic, Object Assembly, Digit Span, Information, and Comprehension.