Folate status and health: challenges and opportunities

AbstractEach year approximately 2400 pregnancies develop folic acid-preventable spina bifida and anencephaly in Europe. Currently, 70% of all affected pregnancies are terminated after prenatal diagnosis. The prevalence of neural tube defects (NTDs) has been significantly lowered in more than 70 countries worldwide by applying fortification with folic acid. Periconceptional supplementation of folic acid also reduces the risk of congenital heart diseases, preterm birth, low birth weight, and health problems associated with child mortality and morbidity. All European governments failed to issue folic acid fortification of centrally processed and widely eaten foods in order to prevent NTDs and other unwanted birth outcomes. The estimated average dietary intake of folate in Germany is 200 μg dietary folate equivalents (DFE)/day. More than half of German women of reproductive age do not consume sufficient dietary folate to achieve optimal serum or red blood cell folate concentrations (&gt;18 or 1000 nmol/L, respectively) necessary to prevent spina bifida and anencephaly. To date, targeted supplementation is recommended in Europe, but this approach failed to reduce the rate of NTDs during the last 10 years. Public health centers for prenatal care and fortification with folic acid in Europe are urgently needed. Only such an action will sufficiently improve folate status, prevent at least 50% of the NTD cases, reduce child mortality and morbidity, and alleviate other health problems associated with low folate such as anemia.</jats:p

Algoritmo para el diagnóstico precoz de la deficiencia de vitamina B12 en ancianos

Background: The elderly population is particularly at risk for developing vitamin B12-deficiency. Serum cobalamin does not necessarily reflect a normal B12 status. The determination of methylmalonic acid is not available in all laboratories. Issues of sensitivity for holotranscobalamin and the low specificity of total homocysteine limit their utility. The aim of the present study is to establish a diagnostic algorithm by using a combination of these markers in place of a single measurement. Methods: We compared the diagnostic efficiency of these markers for detection of vitamin B12 deficiency in a population (n = 218) of institutionalized elderly (median age 80 years). Biochemical, haematological and morphological data were used to categorize people with or without vitamin B12 deficiency. Results: In receiver operating curves characteristics for detection on vitamin B12 deficiency using single measurements, serum folate has the greatest area under the curve (0.87) and homocysteine the lowest (0.67). The best specificity was observed for erythrocyte folate and methylmalonic acid (100% for both) but their sensitivity was very low (17% and 53%, respectively). The highest sensitivity was observed for homocysteine (81%) and serum folate (74%). When we combined these markers, starting with serum and erythrocyte folate, followed by holotranscobalamin and ending by methylmalonic acid measurements, the overall sensitivity and specificity of the algorithm were 100% and 90%, respectively. Conclusion: The proposed algorithm, which combines erythrocyte folate, serum folate, holotranscobalamin and methylmalonic acid, but eliminate B12 and tHcy measurements, is a useful alternative for vitamin B12 deficiency screening in an elderly institutionalized cohort.Introducción: Los mayores son una población que presenta un riesgo importante de desarrollar una deficiencia de vitamina B12, pero las concentraciones de cobalamina en suero no reflejan necesariamente un estado abnormal en el estado de B12 . Existen biomarcadores asociados a la vitamina B12: el ácido metilmalónico no está disponible en todos los laboratorios, la holotranscobalamina es poco sensible y la homocisteína presenta una baja especificidad. El objetivo del presente estudio es establecer un algoritmo de diagnóstico mediante el uso de una combinación de estos biomarcadores en lugar de la medición de uno sólo de ellos. Métodos: Se comparó la eficacia diagnóstica de estos marcadores para la detección de deficiencia de vitamina B12 en una población (n = 218) de ancianos institucionalizados (edad media 80 años). Los parámetros bioquímicos, hematológicos y morfológicos fueron utilizados para clasificar a los sujetos con o sin deficiencia de vitamina B12. Resultados: Se establecieron las curvas ROC (Receiver Operating Curves) para determinar la eficacia diagnóstica de cada parámetro, tomado individualmente. El folato sérico tenía la mayor área bajo la curva (0,87) y la homocisteína la más baja (0,67). Se observó que la mejor especificidad la presentaba el folato eritrocitario y el ácido metilmalónico (100% para ambos), pero sus sensibilidades eran muy bajas (17% y 53%, respectivamente). Y se observó que la sensibilidad más alta la presentaba la homocisteína (81%) y el folato sérico (74%), pero en contrapartida una especificidad baja. Cuando se combinaron estos marcadores, iniciando las determinaciones con el folato sérco y eritrocitario, seguido por holotranscobalamina y terminando por las mediciones de ácido metilmalónico, la sensibilidad y especificidad global del algoritmo fueron 100% y 90%, respectivamente. Conclusión: El algoritmo propuesto, que combina la determinación de folato sérico y eritrocitario, holotranscobalamina y ácido metilmalónico, sin necesidad de evaluar la vitamina B12 y la homocisteína, es una alternativa útil para la detección de un estado abnormal del estado de vitamina B12 en una población de ancianos institucionalizados

Pharmacokinetics of Sodium and Calcium Salts of (6S)-5-Methyltetrahydrofolic Acid Compared to Folic Acid and Indirect Comparison of the Two Salts

(6S)-5-Methyltetrahydrofolic acid ((6S)-5-Methyl-THF) salts and folic acid may differ in their abilities to raise plasma (6S)-5-Methyl-THF levels. We compared the area under the curve (AUC), Cmax, and Tmax of plasma (6S)-5-Methyl-THF after intakes of (6S)-5-Methyl-THF-Na salt (Arcofolin®) and folic acid. Moreover, we compared the AUCs after intakes of (6S)-5-Methyl-THF-Na and the calcium salt, (6S)-5-Methyl-THF-Ca, that were tested against folic acid in two independent studies. The study was randomized, double blind, and cross over. Twenty-four adults (12 men and 12 women) received a single oral dose of 436 µg (6S)-5-Methyl-THF-Na and an equimolar dose of folic acid (400 µg) on two kinetic days with two weeks washout period in between. The plasma concentrations of (6S)-5-Methyl-THF were measured at 9 time points between 0 and 8 h. We found that the AUC0–8 h of plasma (6S)-5-Methyl-THF (mean (SD) = 126.0 (33.6) vs. 56.0 (25.3) nmol/L*h) and Cmax (36.8 (10.8) vs. 11.1 (4.1) nmol/L) were higher after administration of (6S)-5-Methyl-THF-Na than after the administration of folic acid (p < 0.001 for both). These differences were present in men and women. Only administration of folic acid resulted in a transient increase in plasma unmetabolized folic acid (2.5 (2.0) nmol/L after 0.5 h and 4.7 (2.9) nmol/L after 1 h). Intake of (6S)-5-Methyl-THF-Na was safe. The ratios of the AUC0–8 h for (6S)-5-Methyl-THF-Na and (6S)-5-Methyl-THF-Ca to the corresponding folic acid reference group and the delta of these AUC0–8 h did not differ between the studies. In conclusion, a single oral dose of (6S)-5-Methyl-THF-Na caused higher AUC0–8 h and Cmax of plasma (6S)-5-Methyl-THF compared to folic acid. The Na- and Ca- salts of (6S)-5-Methyl-THF are not likely to differ in their pharmacokinetics. Further studies may investigate whether supplementation of the compounds for a longer time will lead to differences in circulating or intracellular/tissue folate concentrations

Homocysteine, folate and vitamin B12 in neuropsychiatric diseases: review and treatment recommendations

In Europe, neuropsychiatric diseases currently make up approximately a third of the total burden of disease. In 2004, 27% of the overall population was affected by at least one of the most frequent neuropsychiatric diseases such as Alzheimer's dementia, Parkinson's disease, stroke or depression. The annual costs of care exceed those of cancer, cardiovascular conditions and diabetes. In order to delay the onset or course of neurodegenerative diseases, the available potential should be utilized. As well as improving quality of life of patients and relatives, this may reduce the great financial burden caused by neurodegenerative disorders. However, the availability of established drugs or therapeutic agents is very limited. This paper reviews the state of current knowledge as to how homocysteine metabolism is relevant for neurodegenerative and other neuropsychiatric diseases, with particular emphasis on the evidence for prophylactic and therapeutic strategies. In the European countries, many people do not take the recommended daily minimum amount of folate and vitamin B12. Deficiency of these vitamins and secondary changes in the concentrations of associated metabolites, such as methylmalonic acid and homocysteine, may contribute to the onset and progression of neuropsychiatric diseases. This paper reviews the evidence regarding whether substitution of folate and vitamin B12 is beneficial, for example, in cerebrovascular disease, dementia and depression

Health Risk, Functional Markers and Cognitive Status in Institutionalized Older Adults: A Longitudinal Study

A Follow-up of vitamin B12 and lipids status is essential in older people, being closely related to non-communicable diseases. Their relationships with cognitive and physical status are not clear. The aim was to analyze the evolution of vitamin B12 and related parameters, lipid and hematological profiles, and their relationships with cognitive and physical status among institutionalized elderly. Sixty residents, ranged from 62 to 99, were evaluated. Biomarkers (vitamin B12 and related parameters, lipid and hematological profiles), functional capacity (handgrip, arm and leg strength), and cognitive status (Mini-Mental State Examination) were evaluated four times at 4-month intervals. At the beginning of the study, 63% and 70% of the sample showed abnormal homocysteine and folate values, respectively. At the end of the year, abnormal homocysteine increased to 68%, abnormal folate values decreased to 50%. Throughout the year, serum folate showed a significant increase (14.9 vs. 16.3 nmol/L), (p &lt; 0.05). Serum cobalamin (299 vs. 273 pmol/L). HDL-cholesterol (49.9 vs. 47.0 mg/dL) and triglyceride levels (102.4 vs. 123.2 mg/dL) showed a significant decrease and increase respectively in mean values (all p &lt; 0.05). Serum cobalamin and HDL-cholesterol were the most important biomarkers associated with cognitive function (both p &lt; 0.05). The most relevant biomarkers associated with poor physical strength depending on the body part analyzed were low concentrations of HDL-cholesterol, LDL-cholesterol, apolipoprotein A1, and albumin (all p &lt; 0.05). The evolution of lipid biomarkers, their significance with cognitive values, and association with handgrip, point to the importance of the handgrip measurement, a very simple test, as an important health marker. Both serum albumin and physical strength are important health markers in older people

Growth regulation of rat thyrocytes (FRTL-5 cells) by the secreted ectodomain of beta-amyloid precursor-like proteins

The TSH-dependent expression of amyloid precursor-like proteins and the secretion of their ectodomain (sAPP) in rat thyroids coincide with increased rates of thyrocyte proliferation. To analyze whether the secretion of sAPP and the proliferation of thyrocytes are regulatorily linked, we employed [H-3]thymidine or 5-bromo-2&#039;-deoxyuridine assays and found that conditioned culture medium stimulated the proliferation of FRTL-5 cells depending on the content of sAPP. These observations prompted experiments with sAPP-derived peptides known to stimulate the growth of APP-deficient fibroblasts. Using autoradiography and radiochemical assays, we observed that an iodinated 19-mer sAPP peptide was bound specifically to the surface of FRTL-5 cells. Binding of this peptide was followed by a 2- to 8-fold increase in cell proliferation, which reached a plateau at 1 mM. This effect was significant only when cells were cultured in nonconfluent monolayers, and contact inhibition did not interfere. Our observations indicate that sAPP and sAPP-derived peptides increased the proportion of proliferation-competent FRTL-5 cells and suggest that sAPP may be a new member in the family of peptides involved in the growth regulation of thyrocytes

Pharmacokinetics of sodium and calcium salts of (6S)-5-methyltetrahydrofolic acid compared to folic acid and indirect comparison of the two salts

(6S)-5-Methyltetrahydrofolic acid ((6S)-5-Methyl-THF) salts and folic acid may differ in their abilities to raise plasma (6S)-5-Methyl-THF levels. We compared the area under the curve (AUC), Cmax, and Tmax of plasma (6S)-5-Methyl-THF after intakes of (6S)-5-Methyl-THF-Na salt (Arcofolin®) and folic acid. Moreover, we compared the AUCs after intakes of (6S)-5-Methyl-THF-Na and the calcium salt, (6S)-5-Methyl-THF-Ca, that were tested against folic acid in two independent studies. The study was randomized, double blind, and cross over. Twenty-four adults (12 men and 12 women) received a single oral dose of 436 µg (6S)-5-Methyl-THF-Na and an equimolar dose of folic acid (400 µg) on two kinetic days with two weeks washout period in between. The plasma concentrations of (6S)-5-Methyl-THF were measured at 9 time points between 0 and 8 h. We found that the AUC0–8 h of plasma (6S)-5-Methyl-THF (mean (SD) = 126.0 (33.6) vs. 56.0 (25.3) nmol/L*h) and Cmax (36.8 (10.8) vs. 11.1 (4.1) nmol/L) were higher after administration of (6S)-5-Methyl-THF-Na than after the administration of folic acid (p < 0.001 for both). These differences were present in men and women. Only administration of folic acid resulted in a transient increase in plasma unmetabolized folic acid (2.5 (2.0) nmol/L after 0.5 h and 4.7 (2.9) nmol/L after 1 h). Intake of (6S)-5-Methyl-THF-Na was safe. The ratios of the AUC0–8 h for (6S)-5-Methyl-THF-Na and (6S)-5-Methyl-THF-Ca to the corresponding folic acid reference group and the delta of these AUC0–8 h did not differ between the studies. In conclusion, a single oral dose of (6S)-5-Methyl-THF-Na caused higher AUC0–8 h and Cmax of plasma (6S)-5-Methyl-THF compared to folic acid. The Na-and Ca-salts of (6S)-5-Methyl-THF are not likely to differ in their pharmacokinetics. Further studies may investigate whether supplementation of the compounds for a longer time will lead to differences in circulating or intracellular/tissue folate concentrations