Low Serum Folate Research Articles

Maternal folate deficiency causes inhibition of mTOR signaling, down-regulation of placental amino acid transporters and fetal growth restriction in mice

Maternal folate deficiency is linked to restricted fetal growth, however the underlying mechanisms remain to be established. Here we tested the hypothesis that mTOR functions as a folate sensor in vivo in mice and that maternal folate deficiency inhibits placental mTOR signaling and amino acid transporter activity and causes fetal growth restriction. Folate deficient mice had lower serum folate (−60%). In late pregnancy, fetal weight in the folate deficient group was decreased (−17%, p < 0.05), whereas placental weight, litter size and crown rump length were unaltered. Maternal folate deficiency inhibited placental mTORC1 and mTORC2 signaling and decreased trophoblast plasma membrane System A and L amino acid transporter activities and transporter isoform expression. Folate deficiency also caused a decrease in phosphorylation of specific functional readouts of mTORC1 and mTORC2 signaling in multiple maternal and fetal tissues. We have identified a novel specific molecular link between maternal folate availability and fetal growth, involving regulation of placental mTOR signaling by folate, resulting in changes in placental nutrient transport. mTOR folate sensing may have broad biological significance because of the critical role of folate in normal cell function and the wide range of disorders, including cancer, that have been linked to folate availability.

Serum folate concentration and the incidence of lung cancer.

BackgroundLung cancer is a leading cause of cancer-related mortality globally. Folate helps to maintain DNA integrity and to regulate gene expression. Serum folate levels may affect the risk of several cancers, including lung cancer. In this study we evaluated the association between serum folate concentration and variations in genes involved in folate metabolism with lung cancer incidence in Poland.MethodsThe study included 366 lung cancer patients and 366 control subjects. We measured serum folate concentration and genotyped six variants in MTHFR, MTR and MTRR genes. The odds ratios of being diagnosed with lung cancer were calculated using conditional univariable and multivariable logistic regression with respect to folate level and genotypes.ResultsThe mean serum folate level was lower in lung cancer cases than in control group (20.07 nmol/l vs. 22.52 nmol/l, p = 0.002). The odds ratio for lung cancer declined with increasing serum content of the folate. The folate concentration of >25.71 nmol/l (IVth quartile) in comparison to <15.92 nmol/l (Ist quartile) was associated with an odds ratio of 0.61 (95%CI 0.40–0.95, p = 0.03). The analysis of variations in MTHFR, MTR and MTRR genes did not reveal any significant difference between lung cancer cases and controls in univariable and multivariable analyses.ConclusionIn this case-control study, lower serum folate concentrations were associated with a higher risk of lung cancer diagnosis. Although previous findings have been somewhat mixed, our results add to the evidence that circulating folate levels may be an indicator of lung cancer risk.

Role of folate in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of chronic liver conditions that are characterized by steatosis, inflammation, fibrosis, and liver injury. The global prevalence of NAFLD is rapidly increasing in proportion to the rising incidence of obesity and type 2 diabetes. Because NAFLD is a multifaceted disorder with many underlying metabolic abnormalities, currently, there is no pharmacological agent that is therapeutically approved for the treatment of this disease. Folate is a water-soluble B vitamin that plays an essential role in one-carbon transfer reactions involved in nucleic acid biosynthesis, methylation reactions, and sulfur-containing amino acid metabolism. The liver is the primary organ responsible for storage and metabolism of folates. Low serum folate levels have been observed in patients with obesity and diabetes. It has been reported that a low level of endogenous folates in rodents perturbs folate-dependent one-carbon metabolism, and may be associated with development of metabolic diseases such as NAFLD. This review highlights the biological role of folate in the progression of NAFLD and its associated metabolic complications including obesity and type 2 diabetes. Understanding the role of folate in metabolic disease may position this vitamin as a potential therapeutic for NAFLD.

Status of serum vitamin B12 and folate in patients with inflammatory bowel disease in China.

Background/AimsInflammatory bowel disease (IBD) primarily involves the intestinal tract and can affect vitamin absorption. This study was designed to assess the prevalence of vitamin B12 and folate deficiencies in patients with IBD, and to identify the risk factors associated with abnormal serum vitamin B12 and folate levels.MethodsWe evaluated the medical records of 195 patients with Crohn's disease (CD) and 62 patients with ulcerative colitis (UC), and selected 118 healthy subjects for the control group.ResultsThere were more CD patients with vitamin B12 deficiency than UC patients (14.9% vs. 3.2%, P=0.014) and controls (14.9% vs. 4.2%, P=0.003). The prevalence of folate deficiency was higher in CD patients than in controls (13.3% vs. 3.4%, P=0.004). There were no significant differences in the serum vitamin B12 and folate statuses of the UC and control groups. Patients with prior ileal or ileocolic resection showed a higher prevalence of abnormal vitamin B12 levels than those without prior resection (n=6/16, n=23/179; P=0.018). A disease duration within 5 years was a risk factor of abnormal folate levels in CD patients.ConclusionsThis study showed that vitamin B12 and folate deficiencies were more common in patients with CD than in UC patients and controls. Prior ileal or ileocolonic resection was a risk factor of serum vitamin B12 abnormalities, and a disease duration within 5 years was a risk factor of low serum folate levels in CD patients.

The evaluation of serum homocysteine, folic acid, and vitamin B12 in patients complicated with preeclampsia.

IntroductionIncreased plasma homocysteine may be associated with adverse pregnancy outcomes, such as preeclampsia. The aim of this study was to determine the plasma homocysteine, serum folate, and vitamin B12 levels in preeclamptic pregnant women.MethodsThis case-control study was conducted in 2016 in Ahwaz on 51 pregnant women with preeclampsia and 51 healthy pregnant women of the same gestational age, who served as controls. The case group also was subdivided into severe and non-severe preeclampsia. Patients’ data were collected through a questionnaire and medical records. Serum homocysteine, folic acid, and vitamin B12 were analyzed using chemiluminescent assay. The results were compared between two groups. Statistical analyses were done using IBM-SPSS 20.0. A Kolmogorov-Smirnov test, independent samples t-test, Mann-Whitney test, and Chi-square test were used for data analysis.ResultsNo different demographic characteristics were found among the groups. Pregnant women complicated with preeclampsia displayed significantly higher serum homocysteine levels (p < 0.001) and lower serum folate (p = 0.005) and vitamin B12 levels (p < 0.001) compared to controls. A statistically significant inverse correlation was evident between serum homocysteine and serum folate levels in preeclamptic patients (p = 0.005; r = −0.389). In addition, an inverse correlation was identified between homocysteine and serum vitamin B12, but it was not statistically significant (p = 0.160; r = −0.200). Significant differences occurred in serum homocysteine and folate levels between the severe and non-severe subgroups (p < 0.001, p < 0.001).ConclusionWomen complicated with preeclampsia displayed higher maternal serum homocysteine and lower serum folate and vitamin B12. Further studies are needed to confirm if the prescription of folic acid and vitamin B12 in women with a deficiency of these vitamins could decrease the level of serum homocysteine and, therefore, reduce the risk of preeclampsia or, if it occurred, its severity.

People with low serum folate levels have higher risk of colorectal adenoma/advanced colorectal adenoma occurrence and recurrence in China.

ObjectiveTo investigate the potential association between serum folate levels and colorectal adenoma (CRA) occurrence and recurrence.MethodsThis prospective study measured baseline serum folate levels in outpatients who were screened for CRA using colonoscopy. Participants were then randomly selected to produce one group with CRA and one without CRA. These two subgroups underwent further follow-up observations of colonoscopy to determine the occurrence of new and recurrent CRA.ResultsA total of 1310 participants were screened at baseline: 888 were healthy subjects without CRA; and 422 had CRA. Two subgroups were randomly selected (n = 200 per group) for follow-up. In the overall population, baseline serum folate levels were significantly lower in patients with CRA or advanced CRA (A-CRA) compared with healthy participants without CRA. Similar findings were shown for the follow-up study in terms of the association between CRA and A-CRA occurrence and recurrence and baseline serum folate levels. After controlling for confounders, increased serum folate was associated with a reduced risk of occurrence of CRA (odds ratio [OR] 0.993, 95% confidence interval [CI] 0.924, 1.066) and recurrence of CRA (OR 0.749, 95% CI 0.322, 1.742).ConclusionsHigher serum folate levels may be protective against CRA and/or A-CRA.

Association of serum vitamin B12 and folate with mortality in incident hemodialysis patients

Vitamin B12 (B12) and folate are essential vitamins that play important roles in physiological processes. In the general population, many studies have evaluated the association of these vitamins with clinical outcomes, yet this association in hemodialysis (HD) patients remains unclear. We examined the association of serum folate and B12 with mortality in a 5-year cohort of 9517 (folate) and 12 968 (B12) HD patients using Cox models with hierarchical adjustment for sociodemographics, comorbidities, and laboratory variables associated with the malnutrition and inflammation complex syndrome. The associations of baseline B12 and folate (separately) with all-cause mortality were evaluated across five categories of B12 [<400 (reference), 400-<550, 550-<650, 650-<750 and ≥750 pg/mL] and folate [<6.2, 6.2-<8.4, 8.4-<11 (reference), 11-<14.3 and ≥14.3 ng/mL]. The study cohort with B12 measurements had a mean ± standard deviation age of 63 ± 15 years, among whom 43% were female, 33% were African-American, and 57% were diabetic. Higher B12 concentrations ≥550 pg/mL were associated with a higher risk of mortality after adjusting for sociodemographic and laboratory variables. However, only lower serum folate concentrations <6.2 ng/mL were associated with a higher risk of all-cause mortality when adjusted for sociodemographic variables [adjusted hazard ratio (95% confidence-interval): 1.18 (1.03-1.35)]. Higher B12 concentrations are associated with higher all-cause mortality in HD patients independent of sociodemographics and laboratory variables, whereas lower folate concentrations were associated with higher all-cause mortality after accounting for sociodemographic variables. Further studies are warranted to determine the optimal B12 and folate level targets in this population.

Associations of pregnancy folate and choline status with parental cancer risk factors and offspring's stem cell markers

Aims of the study were to investigate the associations of pregnant folate and choline status with parental diseases risks and stem cell markers which may involve in metabolic programming for offspring's susceptibility to cancer diseases. Fifty pregnant women were recruited from multiple clinic centers and NTU hospital to participate through the study. Blood samples from the first trimester pregnant women were collected for measurements of serum folate, choline, betaine and B12 levels. Lymphocytic DNAs were extracted for methylenetetrahydrofolate reductase (MTHFR) genotyping and for methylated promoter status of sonic hedgehog (SHH), insulin‐like growth factor‐2 (IGF2) and LINE‐1 (long interspersed nucleotide elements). Dietary data were collected by qFFQ and analyzed for nutrient intakes. The data revealed that deficiency rates of total choline (&lt; 50% AI) and folate intake (&lt; EAR) among the pregnant women were 11% and 14%, respectively. MTHFR 677CT/TT genotypes in relative to CC wild type were associated with higher intakes of phosphotidylcholine and total choline, and with lower serum folate (P = 0.049) and betaine (P = 0.023) levels. Historical parental obesity in relative to normal‐weight parents was associated with higher intake levels of folate (P = 0.002) and total choline (P = 0.048), and with significantly lower plasma free choline levels (P = 0.049) in pregnant off springs. Serum choline and folate levels of pregnant offspring were differentially associated with lymphocytic methylation status of SHH, IGF2 and LINE‐1 and their parental cancer risk factors.

Lower Maternal Serum Folate in First Trimester Associated with Higher Autism Risk in Offspring

BackgroundEpidemiologic evidence suggests that periconceptional maternal folate intake is associated with decreased risk for autism spectrum disorder (ASD), but the biochemical underpinnings of this relationship and direct maternal folate measurement have not been reported.ObjectiveTo examine the association between first trimester in utero maternal metabolic risk factors (including methyl donors and folate metabolites, markers of oxidative stress and inflammation, and maternal BMI) and risk of ASD at age 4–7years.MethodsUsing a case‐control design, we identified 44 four to seven year old children with an ADOS‐confirmed diagnosis of Autism Spectrum Disorder treated at Maine Medical Center Developmental Behavioral Pediatrics Clinic (Portland, ME). Archived maternal blood samples from the first trimester of pregnancy (11–13 weeks gestational age) were identified for these cases at the Foundation for Blood Research in Scarborough, ME. 44 control samples from the biorepository were identified based on five matching criteria (sex of child, maternal age, maternal smoking status, age of sample, gestational age of sample collection.) All samples were linked with birth certificate data to identify covariates. We measured unmetabolized folic acid (FA), 5‐methyl tetrahydrofolate (MTHF), vitamin B12, homocysteine and high Sensitivity C Reactive protein (CRP) from the samples. We examined the associations between these factors in pregnancy and diagnosis of ASD with logistic regression using SAS version 9.2.ResultsMaternal and infant characteristics for cases and controls are shown in table 1. Although in other cohorts maternal obesity has been associated with increased risk of ASD, maternal obesity was not associated with ASD diagnosis in our cohort, although our power for this comparison was low. As shown in table 2, maternal first trimester serum concentration of 5‐MTHF in the lower 2 tertiles (T1, T2) (compared to the highest tertile, T3) was associated with increased odds of ASD diagnosis in offspring [OR (95% CI) T1: 6.04 (1.25, 29.30) and T2: 7.10 (1.38, 36.46)]. Maternal CRP, FA, vitamin B12, and homocysteine were not significantly associated with risk of ASD (Table 2).ConclusionsLower first trimester serum maternal 5‐MTHF concentration was associated with increased risk of developing autism in offspring in an unadjusted analysis. Analysis of markers of oxidative stress and products of folate catabolism in these samples as well as adjustment for potential confounders is underway. If these findings are confirmed in larger cohorts, this may present an opportunity for prenatal intervention to reduce the risk for autism.Support or Funding InformationThe Alden Trust Characteristics of mother‐infant pairs of ASD cases and controls. Characteristic Cases (n= 44) Controls (n= 44) p n (%) Mother's BMI at blood draw &lt;25 kg/m2 14 (32%) 17 (39%) 0.61 25–&lt;30 kg/m2 12 (27%) 14 (32%) 30–&lt;35kg/m2 7 (16%) 9 (20%) 35+ kg/m2 11 (25%) 4 (9%) Gestational age at birth &lt;37 weeks 7 (16%) 6 (14%) 0.43 37–40 weeks 36 (82%) 33 (75%) &gt;40 weeks 1 (2%) 5 (11%) Maternal tobacco use No 35 (81%) 36 (83%) 0.32 Yes 8 (19%) 7 (17%) Unknown 1 1 Gestational diabetes No 42 (95%) 43 (98%) 0.56 Yes 2 (5%) 1 (2%) Maternal Education HS or less 13 (30%) 11 (25%) 0.26 Some college or degree 22 (50%) 22 (50%) Post college 9 (20%) 11 (25%) Paternal Education HS or less 13 (52%) 8 (32%) 0.09 Some college or degree 4 (16%) 11 (44%) Post college 8 (32%) 6 (24%) Missing 18 16 Mother's Race/ethnicity Black 2 (5%) 0 (0%) White 40 (91%) 43 (98%) Asian 2 (5%) 1 (2%) Gestational Age at blood draw (wks) 11 12 (27%) 10 (23%) 0.57 12 18 (41%) 18 (41%) 13 14 (32%) 16 (36%) Year of blood draw 2008 9 (20%) 8 (18%) 0.90 2009 11 (25%) 12 (27%) 2010 16 (36%) 14 (32%) 2011 8 (18%) 10 (23%) Infant Male Sex 30 (68%) 30 (68%) 1.00 Odds ratios (OR) and 95% CIs for associations between first trimester maternal metabolic markers and ASD diagnosis at 4–7 years compared to controls. Maternal Metabolic Marker OR (95% CI) Unmetabolized Folic Acid (FA) nmol/L &lt;0.293 1.06 (0.36, 3.13) 0.293–&lt;1.89 1.28 (0.40, 4.08) 1.89+ 1.00 (Referent) Serum 5‐Methyl THF nmol/L &lt;19.3 6.04 (1.25, 29.30) 19.3–&lt;27.4 7.10 (1.38, 36.46) 27.4+ 1.00 (Referent) Serum Vitamin B12 pg/ml &lt;450 0.74 (0.25, 2.18) 450–&lt;702 0.72 (0.26,1.96) 702+ 1.00 (Referent) Homocysteine micromol/L &lt;3.09 0.65 (0.22, 1.96) 3.09–&lt;3.68 1.25 (0.41, 3.81) 3.68+ 1.00 (Referent) Serum High Sensitivity CReactive protein (CRP) mg/L &lt;1.7 1.00 (Referent) 1.7–&lt;7.2 0.84 (0.29, 2.47) 7.2+ 0.68 (0.20, 2.32)

Association between folate status and cervical intraepithelial neoplasia.

Background/Objectives:To investigate the effect of folate status on cervical intraepithelial neoplasia (CIN) progression and its relationship with high-risk human papillomavirus (hrHPV).Subjects/Methods:We evaluated 20 000 sexually active women aged <65 years in Yangqu County by using a questionnaire; the subjects were also screened using the ThinPrep cytologic test (TCT). Patients with abnormal TCT results (other than glandular cell abnormalities) who were willing to provide informed consent were further diagnosed using colposcopy and histopathological examination. We investigated 247 cases of low-grade cervical squamous intraepithelial lesions (LSIL), 125 cases of high-grade cervical squamous intraepithelial lesions (HSIL) and 877 controls. A 24-item food frequency questionnaire was filled out by the investigator to estimate the consumption of dietary folate. Positivity for hrHPV from residual exfoliated cervical cells was tested; serum folate was also measured.Results:The hrHPV infection rate in HSIL patients (77.6%) was higher than that in LSIL (33.2%) and control (32.0%) patients. Dietary folate intakes in controls, LSIL and HSIL were 306.9±176.6, 321.8±168.0 and 314.7±193.8 μg/kcal, respectively. The levels of serum folate in controls, LSIL and HSIL were 18.2±7.9, 15.9±7.1 and 14.3±7.5 nmol/l, respectively. Increased CIN correlated with higher rates of hrHPV infection and lower levels of serum folate.Conclusions:Low levels of serum folate may increase the risk of CIN progression. Furthermore, potential synergy may exist between low serum folate levels and hrHPV infection to promote CIN development.

The Effect of Trimethoprim on Serum Folate Levels in Humans: A Randomized, Double-Blind, Placebo-Controlled Trial.

Trimethoprim antagonize the actions of folate by inhibition of dihydrofolate reductase. This could diminish serum folate levels in humans and causes folate deficiency in some patients. We conducted a randomized, double-blind, placebo-controlled trial, to investigate the effect of trimethoprim on serum folate levels in healthy participants after a 7-day trial period. Thirty young, healthy males were randomly allocated to receive trimethoprim, 200 mg twice daily, and 30 were randomly allocated to placebo. Before trial initiation, participant numbers were given randomly generated treatment allocations within sealed opaque envelopes. Participants and all staff were kept blinded to treatment allocations during the trial. Serum folate was measured at baseline and at end of trial. In the 58 participants analyzed (30 in the trimethoprim group and 28 in the placebo group), 8 had folate deficiency at baseline. Within the trimethoprim group, serum folate was significantly decreased (P = 0.018) after the trial. We found a mean decrease in serum folate among trimethoprim exposed of 1.95 nmol/L, compared with a 0.21 nmol/L mean increase in the placebo group (P = 0.040). The proportion of folate-deficient participants increased significantly within the trimethoprim group (P = 0.034). No serious adverse events were observed. In conclusion, we found that a daily dose of 400 mg trimethoprim for 7 days significantly lowered serum folate levels in healthy study participants.

Folic Acid Supplementation in Pregnancy and the Risk of Pre-Eclampsia-A Cohort Study.

This prospective cohort study designed to assess the effect of folic acid supplementation in pregnancy on the risk of preeclampsia (PE) took place in Ottawa, ON and Kingston, ON, Canada, from September 1, 2002 to August 31, 2008. Pregnant women, less than 20 weeks gestational age were recruited and delivered in the Ottawa region and the Kingston General Hospital. Demographic characteristics of the study participants and the patterns of supplementation of folic acid were described and occurrence of PE between women with folic acid supplementation during pregnancy and women without were compared. Multiple logistic regression was used in the estimation of the independent effect of supplementation of folic acid. Additional analyses assessing the effect of low RBC and serum folate and dose-response relationship were performed. Analyses were performed in all study participants, and then in high risk and low risk sub-groups, respectively. A total of 7,669 participants were included in the final analysis. Ninety five percent of the study participants were taking folic acid supplementation in early second trimester. The rate of PE was lower in the supplementation group than in the no supplementation group, and the difference was statistically significant in high risk women. Similar patterns of associations were observed in analysis by RBC and serum folate levels and in dose-response analysis. Folic acid supplementation in pregnancy may reduce PE risk in pregnant women, especially in those women with increased risk of developing PE.

Folic Acid Supplementation Mitigates Alzheimer's Disease by Reducing Inflammation: A Randomized Controlled Trial.

Background/Aims. Low serum folate levels can alter inflammatory reactions. Both phenomena have been linked to Alzheimer's disease (AD), but the effect of folic acid on AD itself is unclear. We quantified folate supplementation's effect on inflammation and cognitive function in patients with AD over the course of 6 months. Methods. Patients newly diagnosed with AD (age > 60 years; n = 121; mild to severe; international criteria) and being treated with donepezil were randomly assigned into two groups with (intervention group) or without (control group) supplemental treatment with folic acid (1.25 mg/d) for 6 months. The Mini-Mental State Examination (MMSE) was administered to all patients at baseline and follow-up, and blood samples were taken before and after treatment. We quantified serum folate, amyloid beta (Aβ), interleukin-6 (IL-6), tumor necrosis factor α (TNFα), plasma homocysteine (Hcy), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and the mRNA levels of presenilin (PS), IL-6, and TNFα in leukocytes. Data were analyzed using a repeated-measures mixed model. Results. The mean MMSE was slightly increased in the intervention group compared to that in the control group (P < 0.05). Posttreatment, plasma SAM and SAM/SAH levels were significantly higher (P < 0.05), while Aβ 40, PS1-mRNA, and TNFα-mRNA levels were lower in the intervention group than in the control group (P < 0.05). The Aβ 42/Aβ 40 ratio was also higher in the intervention group (P < 0.05). Conclusions. Folic acid is beneficial in patients with AD. Inflammation may play an important role in the interaction between folic acid and AD. This trial is registered with clinical trial registration number ChiCTR-TRC-13003246.

Maintenance of activities of daily living despite risk from genetic polymorphism in hemodialysis patients under nutritional management who survived an average of 30 years

Only 4 % of hemodialysis (HD) patients survive over 25 years after their initiation of HD even in Japan. To elucidate their clinical characteristics, we investigated their lifestyle and genetic factor. TT genotype of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism was reported as a high-risk factor for cardiovascular event and poor survival in CKD patients. Seventy-eight of Japanese patients receiving HD more than 30 years were enrolled. Their daily lifestyle and activity were evaluated with diet history questionnaires (DHQ), geriatric nutritional risk index (GNRI), and basic activity of daily living (BADL) scores. MTHFR C677T was genotyped by PCR-restriction fragment length polymorphism (RFLP). The mean dietary intake of energy was 30.6 ± 9.3 kcal/kg of ideal body weight (IBW), protein 1.1 ± 0.4 g/kg of IBW and their adequacy ratios for Japanese guideline 2007 were 97.7 and 101.9 %, respectively. BADL was 90, and daily activities were highly maintained in patients. The frequency of TT genotype was 26.9 % and it was almost twice as that in the general population. The patients with TT genotype had lower serum folate and higher serum homocysteine than those with the CC or CT genotypes, though there was no significant difference in dietary folate intake among them. Although the frequency of TT genotype was higher than healthy population, our patients showed longer survival with high QOL and nutritional status. It is suggested that the proper lifestyle might overcome the genetic risk factors in patients receiving HD.

The impact of MTHFR 677 C/T genotypes on folate status markers: a meta-analysis of folic acid intervention studies.

Methylenetetrahydrofolate reductase (MTHFR) is a key folate pathway enzyme with the T variant of the MTHFR gene increasing the risk of low folate status, particularly coupled with low folate intake. As genetic variability of MTHFR influences folate status, it is important to ensure an adequate intake that overrides genetic effects but minimises any adverse effects. Our aim was to assess the influence of MTHFR genotype on folate status followed by response to supplementation. We performed a meta-analysis of ten folate intervention studies to assess the degree to which MTHFR C677T genotype influenced plasma homocysteine and serum folate levels as measures of folate status. We then examined response after supplementation at intake values up to the upper tolerable limit. The MTHFR 677TT genotype was associated with higher plasma homocysteine (2.7μmol/L, TT vs. CT/CC; 2.8μmol/L, TT vs. CC) and lower serum folate (2.5nmol/L, TT vs. CT/CC; 3.6nmol/L, TT vs. CC). In two studies, the TT groups had mean plasma Hcy>15μmol/L. Serum folate levels were >7nmol/L for all genotype groups. After supplementation of 400 up to 1670μg DFEs of folic acid or folic acid+fortified foods and/or natural food folates for a minimum of 4weeks, there were no significant differences in plasma homocysteine levels; however, individuals with the TT genotype had a lower serum folate response to supplementation (7.2nmol/L, TT vs. CT/CC; 8.7nmol/L, TT vs. CC). This meta-analysis confirms observations from observational and intervention studies that MTHFR TT genotype is associated with increased plasma homocysteine and lowered serum folate and less response to short-term supplementation. The results can be used for modelling and guiding personalised intake recommendations for the nutrient folate.

B vitamins related to homocysteine metabolism in adults celiac disease patients: a cross-sectional study.

BackgroundThe only treatment for celiac disease is the gluten-free diet. Few studies have assessed the nutritional adequacy of this diet, especially of B vitamins related to homocysteine metabolism. The aim of this study was to assess the nutritional status and serum concentrations of B vitamins involved in homocysteine metabolism, and to determine whether the dietary intake of these vitamins are meeting Dietary Reference Intakes in celiac patients.MethodsA cross-sectional study enrolled a total of 20 celiac patients (36.3 ± 13.7 years old; 65 % women), following strict gluten-free diet (GFD) and 39 healthy controls matched by sex and age. The dietary intake was assessed by 3-day food records, and serum concentrations of homocysteine and vitamins B6, B12, and folate were determined after overnight fasting. Comparisons between the two groups were performed by Student’s t test or Mann–Whitney U-test, for continuous variables. Pearson’s chi-square test or Fisher’s exact test was used for categorical variables. An alpha level of 5 % were considered significant.ResultsCeliac patients had lower serum folate concentrations (7.7 ± 3.5 ng/mL, P < 0.05) than controls. All celiac patients had folate intake below the Estimated Average Requirement (EAR) (130.8 ± 53.6 μg/d). However, only a small proportion of celiac patients had hyperhomocysteinemia.ConclusionsCeliac patients treated with GFD presented inadequacy of dietary folate intake and low-serum concentrations of folate, suggesting that more attention should be given to the quality of the nutrients offered by the GFD, as it constitutes a lifelong treatment.

Long-term omega-3 fatty acid supplementation prevents expression changes in cochlear homocysteine metabolism and ameliorates progressive hearing loss in C57BL/6J mice

Omega-3 polyunsaturated fatty acids (PUFAs) are essential nutrients well known for their beneficial effects, among others on cognitive development and maintenance, inflammation and oxidative stress. Previous studies have shown an inverse association between high plasma levels of PUFAs and age-related hearing loss, and the relationship between low serum folate and elevated plasma homocysteine levels and hearing loss. Therefore, we used C57BL/6J mice and long-term omega-3 supplementation to evaluate the impact on hearing by analyzing their auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) thresholds. The omega-3 group showed significantly lower ABR hearing thresholds (~25 dB sound pressure level) and higher DPOAE amplitudes in mid–high frequencies when compared to the control group. These changes did not correlate with alterations between groups in plasma homocysteine or serum folate levels as measured by high-performance liquid chromatography and a microbiological method, respectively. Aging in the control group was associated with imbalanced cytokine expression toward increased proinflammatory cytokines as determined by quantitative reverse transcriptase polymerase chain reaction; these changes were prevented by omega-3 supplementation. Genes involved in homocysteine metabolism showed decreased expression during aging of control animals, and only alterations in Bhmt and Cbs were significantly prevented by omega-3 feeding. Western blotting showed that omega-3 supplementation precluded the CBS protein increase detected in 10-month-old controls but also produced an increase in BHMT protein levels. Altogether, the results obtained suggest a long-term protective role of omega-3 supplementation on cochlear metabolism and progression of hearing loss.

Poor micronutrient intake and status is a public health problem among adolescent Mozambican girls

Micronutrient deficiencies can damage the health of adolescent girls and their offspring. There is a lack of population-based data on the micronutrient status of adolescents in Sub-Saharan Africa. We conducted a cross-sectional, population-based study to examine the biochemical status, prevalence of deficiency, dietary intake, and food sources of selected micronutrients among adolescent girls in Central Mozambique. Separate groups of study participants were recruited in 2 seasons in 2010. The participants were girls between 14 and 19 years of age (n = 551) from 1 urban area and 2 rural districts. Micronutrient status indicators were analyzed from blood and urine samples. Twenty-four-hour dietary recalls were also carried out. The overall prevalence with 95% confidence interval (calculated using sampling weights) among nonpregnant girls was 42.4% (37.2%-47.8%; n = 466) for anemia, 27.4% (23.1%-32.2%; n = 427) for low serum ferritin, 32.7% (27.7%-38.1%; n = 423) for low serum zinc, 14.7% (11.2%-19.0%; n = 426) for low plasma retinol, and 4.1% (2.9%-5.8%; n = 448) for low serum folate. The selenium status was considered sufficient. Mild to moderate iodine deficiency was found in the rural districts, whereas the iodine status of urban girls was adequate. Significantly lower serum folate concentrations were found in the urban area compared to the rural districts. The seasonal differences in vitamin A intake were significant. The intakes of micronutrients from animal source foods were small. In summary, adolescent Mozambican girls are at risk of several micronutrient deficiencies. This raises concern especially because adolescent motherhood is common in the region. Actions need to be taken to prevent and control micronutrient deficiencies.

Effects of antiepileptic drug monotherapy on one-carbon metabolism and DNA methylation in patients with epilepsy.

PurposeThe aim of this study was to compare the serum levels of one-carbon metabolism (OCM) nutrients (e.g., folate, homocysteine and vitamin B12) and peripheral blood DNA methylation in epileptic patients under treatment with antiepileptic drugs (AEDs) and in healthy controls.MethodsIn this cross-sectional study, 60 patients with epilepsy who were receiving valproate (VPA) (n = 30) or lamotrigine (LTG) (n = 30) monotherapy were enrolled. Thirty age and sex matched healthy subjects served as the controls. Serum concentrations of OCM nutrients and peripheral blood DNA methylation status were measured.ResultsCompared to the control group, the VPA group had higher serum levels of homocysteine (p<0.05). No difference in homocysteine concentration was observed in the LTG group. Patients receiving VPA or LTG had significantly lower serum folate levels in comparison with controls (p<0.001). The level of methylation of long interspersed nucleotide element-1 (LINE-1) in peripheral blood was not significantly different between the AED monotherapy group and healthy controls. A difference in the methylation levels of methylenetetrahydrofolate reductase (MTHFR) amplicon was observed between AED-treated patients with epilepsy and controls (p<0.01). A positive correlation between serum folate levels and peripheral blood MTHFR amplicon methylation status was also observed (r = 0.25, p = 0.023).ConclusionOur findings suggest that the effects of AED monotherapy on OCM may induce specific regions of DNA hypomethylation.

Neuropsychiatric Symptoms Implicated in Conversion From MCI to Dementia

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessNeuropsychiatric Symptoms Implicated in Conversion From MCI to DementiaMark MoranMark MoranSearch for more papers by this authorPublished Online:3 Apr 2015https://doi.org/10.1176/appi.pn.2015.3b9AbstractNeuropsychiatric symptoms may be etiologic for dementia through neuroendocrine axis activation, or they may interact synergistically with a biological factor; either of these suggests that treating neuropsychiatric symptoms might delay dementia onset.Neuropsychiatric symptoms in the presence of mild cognitive impairment (MCI), including depression, appear to significantly increase the risk of conversion to dementia—either amnestic or Alzheimer’s type dementia—according to a report published February 20 in AJP in Advance.Researchers at Johns Hopkins University School of Medicine and in the United Kingdom searched PubMed (from 1946) and Web of Knowledge (from 1900) through May 22, 2013 (updated June 5, 2014), using a variety of terms such as “mild cognitive,” “cognitive impairment,” and “age associated cognitive decline” included in longitudinal studies reporting potentially modifiable risk factors for incident dementia in people with MCI. There were 76 eligible articles reporting epidemiologic and clinical studies.A principal finding from the study was that diabetes, prediabetes, metabolic syndrome, and low serum folate levels increased risk of conversion from amnestic MCI to Alzheimer’s dementia and from any type or nonamnestic MCI to all-cause dementia. But the researchers also found that the presence of neuropsychiatric symptoms predicted conversion to all-cause dementia. Among the findings are the following:There is evidence that more depressive symptoms predict conversion from any-type MCI to all-cause dementia from epidemiologic studies, but the evidence is inconsistent in clinical studies; it is also inconsistent as to whether depressive symptoms predict conversion from amnestic MCI to Alzheimer’s dementia or to any-cause dementia. There is evidence from clinical studies that the presence of neuropsychiatric symptoms in people with any-type MCI, but not their overall levels of symptoms, predicts conversion to all-cause dementia. There is inconsistent evidence about whether anxiety symptoms are associated with conversion from amnestic MCI to Alzheimer’s dementia and about whether apathy predicts the risk of conversion from amnestic MCI to Alzheimer’s dementia or from any-type MCI to dementia.“A third to three-quarters of people with MCI have neuropsychiatric symptoms, most commonly depression, anxiety, apathy, and irritability,” the researchers stated. “Neuropsychiatric symptoms predicted conversion from any-type MCI to all-cause dementia. Neuropsychiatric symptoms may be etiologic for dementia, for example through neuroendocrine axis activation, or they may interact synergistically with a biological factor, such as genetic predisposition. Either of these putative relationships suggests that treating neuropsychiatric symptoms could theoretically delay dementia.” Dilip Jeste, M.D., said that between 35 percent and 45 percent of people with mild cognitive impairment develop dementia within three years and that the financial costs of dementia exceed those of heart disease and cancer.Dilip Jeste, M.D.Dilip Jeste, M.D., a past APA president and a professor of psychiatry and neurosciences and the Estelle and Edgar Levi Chair in Aging at the University of California, San Diego, said that the costs associated with dementia make identification of risk factors a valuable public-health task. “This is an important paper based on a careful meta-analysis of 76 published articles reporting longitudinal studies on potentially modifiable risk factors for development of dementia in persons with mild cognitive impairment, or MCI,” he told Psychiatric News. “In DSM-5, dementia and MCI are labeled major and minor neurocognitive disorders, respectively. In general, between 35 percent and 45 percent of people with MCI develop dementia within three years. The total financial cost of dementia exceeds that of heart disease and cancer. Therefore, identifying and controlling risk factors for developing dementia among older adults with MCI is of clear public-health significance.“These authors report that diabetes, pre-diabetes, metabolic syndrome, neuropsychiatric symptoms including depression, and lower serum folate levels were associated with variably increased risk of dementia, whereas the Mediterranean diet seemed to reduce the risk of developing dementia in patients with MCI,” Jeste added. “These findings suggest that control and prevention of diabetes, treatment of depressive and other neuropsychiatric symptoms, and use of a Mediterranean diet and of folate supplements may be helpful in lowering the risk of dementia in persons with MCI. A word of caution in interpreting the present results is that they are not based on large, randomized, controlled trials in individuals with MCI. Associations do not necessarily indicate causality or even directionality. Nonetheless, the recommendations should be helpful in at least some people and are consistent with good clinical practice.” ■“Modifiable Predictors of Dementia in Mild Cognitive Impairment: A Systematic Review and Meta-Analysis” can be accessed here. ISSUES NewArchived