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Iron deficiency is known to aggravate the prognosis of patients with heart failure. Iron has functions in the mitochondrial respiratory chain. In patients with reduced mitochondrial respiration, the mitochondrial ratio between the level of nicotinamide adenine dinucleotide and its reduced form decreases. Due to the mitochondrial-lysosomal interplay, decreased mitochondrial respiration also leads to inhibition of lysosomal hydrolysis. As a result, cobalamin and iron will be trapped in lysosomes. This will, even if iron and cobalamin have been consumed and absorbed in sufficient amounts, lead to their functional deficiencies.1 Functional iron deficiency can further impede mitochondrial respiration. Increased plasma levels of methylmalonic acid were shown to predict all-cause and cardiovascular mortality in the general population. Treatments targeting mitochondrial and lysosomal function may correct the functional deficiencies and improve prognosis in a subgroup of patients with heart failure, notably those with skeletal muscle wasting. Methylmalonic acid levels may be used for monitoring response to treatment, thereby identifying patients of the subgroup in which disease outcome may improve., Graphical abstract Dysfunction of the mitochondrial respiratory chain leads to lysosomal trapping of iron and cobalamin. The plasma methylmalonic acid level increases and forms an indicator.Image 1, Highlights • Iron deficiency hampers mitochondrial respiration, and this aggravates heart failure. • Mitochondrial respiration oxidizes NADH and is required for lysosomal hydrolysis. • Reduced respiration will therefore trap cobalamin and iron in lysosomes. • Plasma methylmalonic acid levels will increase and can be used as a marker. • NAD + precursors may liberate iron and cobalamin and improve mitochondrial respiration.

Vitamin B12 deficiency is commonly associated with dementia in patients over the age of 65 years; however, it can affect people of all ages. Recognizing the clinical sequelae of subacute combined degeneration is essential for the timely diagnosis and treatment of vitamin B12 deficiency. In this report, we describe a case of a young man presenting with several months of neuropathy, depression, and abdominal symptoms. His initial vitamin B12 levels were within normal limits, but an elevated methylmalonic acid level and subacute combined degeneration of his spine on MRI confirmed the diagnosis of vitamin B12 deficiency. The patient later tested positive for autoantibodies associated with pernicious anemia. His symptoms improved with intramuscular injections of cyanocobalamin. This case highlights the importance of recognizing vitamin B12 deficiency in patients of all age groups even in the setting of apparently "normal" B12 levels.

Older people are at risk for cobalamin (vitamin B12) deficiency because of a number of common disorders (e.g. autoimmune gastritis) and drugs (e.g. antacids) that may alter its absorption and utilization. The prevalence of cobalamin deficiency increases with age, resulting particularly elevated in frail and institutionalized subjects. At variance with common sense, the diagnosis is far from simple and requires a high degree of suspicion, due to heterogeneity and non-specificity of the signs and symptoms, ranging from macrocytosis (with or without anemia) to neuropsychiatric manifestations, that characterize several other aging-related disorders, like hematological malignancies, diabetes, hypothyroidism or vasculopathies. Furthermore, the detection of low levels of serum vitamin B12 appears poorly sensitive and specific. Other biomarkers, like serum homocysteine or methylmalonic acid, have improved the diagnostic possibilities but are expensive, not widely available and may be influenced by some confounders (e.g. folate deficiency, or chronic renal failure). Early recognition and treatment are crucial, since a proportion of patients develop severe complications, such as bone marrow failure and irreversible neurological impairment. High-dose oral treatment has proven to be as effective as the parenteral route even in subjects with malabsorption, ensuring the complete resolution in the majority of cases. In this review, we trace the essential role of cobalamin in humans, the possible causes and impact of deficiency, the diagnostic challenges and the therapeutic options, between old and emerging concepts, with a particular focus on the elderly.

Thrombotic thrombocytopenic purpura (TTP) can often be life threatening and requires timely diagnosis and prompt initiation of plasmapharesis. Cobalamin deficiency can closely mimic TTP and distinguishing between the two diseases can prove to be a diagnostic challenge. Previously, cobalamin-related pseudo-TTP has been associated with pernicious anemia, dietary insufficiency and hereditary disorders of cobalamin activation. Here in, we discuss the first case of suspected metformin-induced cobalamin deficiency causing pseudo-TTP. Our patient was a 36-year-old female with type 2 diabetes mellitus on metformin for eight years who presented with hemolytic anemia, thrombocytopenia, schistocytes and mild acute renal failure. The initial impression was TTP; however, further workup revealed very low serum cobalamin levels and elevated methylmalonic acid levels. Apart from metformin use, no other cause of cobalamin deficiency was identified. We recommended upper gastrointestinal endoscopy to definitively rule out pernicious anemia.

Background Vitamin B12 deficiency occurs frequently, especially among the elderly. However, screening for vitamin B12 deficiency is hampered by poor sensitivity of the existing total vitamin B12 assay. Methylmalonic acid (MMA) is considered as the most representative indicator of metabolic vitamin B12 deficiency and is used as such in this study. The aim of this study was to validate the clinical usefulness of holotranscobalamin (holoTC) as an initial screening assay for metabolic vitamin B12 deficiency in a mixed patient population. Methods Three hundred and sixty blood samples were collected by five Dutch hospitals. Vitamin B12 and holoTC in serum were measured (AxSYM; Abbott). MMA in serum was measured by tandem mass spectrometry (LC-MS/MS). Results Receiver operating curve (ROC) analysis demonstrated a greater area under the curve (AUC) for holoTC than for vitamin B12 in detecting vitamin B12 deficiency characterized by three predefined cut-off levels of MMA. A cut-off value of 32 pmol/L of holoTC resulted in the highest sensitivity (83%) with acceptable specificity (60%) in detecting MMA concentrations above 0.45 μmol/L. The combination of vitamin B12 and holoTC did not improve diagnostic accuracy at this cut-off level. Conclusions HoloTC has a better diagnostic accuracy than vitamin B12 and can replace the existing vitamin B12 assay as a primary screening test in patients suspected of vitamin B12 deficiency. Critical evaluation of cut-off values of holoTC indicated that a cut-off value of 32 pmol/L can be considered in screening for metabolic vitamin B12 deficiency (defined by MMA > 0.45 μmol/L) in a mixed patient population.

Objective: Vitamin B12 deficiency is frequently observed in developing countries. Herein we report the long-term clinical and laboratory outcomes in 45 children presented with various symptoms of vitamin B12 deficiency. Materials and Methods: Symptoms and physical findings, and percentiles for weight, height, and head circumference at presentation were recorded. The educational level of the patients' mothers, vitamin B12 deficiency-related diseases and family income data were collected. Complete blood count, serum vitamin B12, folate, iron, iron binding capacity and ferritin, and plasma homocysteine levels were recorded measured at presentation. The patients were treated with vitamin B12, as follows: 1 mg/d IM for 1 week, followed by 1 mg IM QWK for 2 weeks, and then monthly 1mg injections. Patients were neurologically and hematologically re-evaluated after treatment. The visual evoked potential (VEP) test was used to examine the integrity and function of the visual pathway. Brainstem evoked potential (BAEP) responses were used to analyze auditory function. Neuromotor development was assessed using Denver II Development Screening Test. Results: The mean age of 20 male and 25 female patients was 5.6 +/- 5.9 years (range: 1.4 months-17 years). The most common symptoms at presentation were weakness, failure to thrive, and hematologic manifestations (pallor, petechiae, ecchymosis). Abnormal neurologic findings at presentation were observed in 20% of the patients, and were more commonly observed in those

Hyperhomocysteinemia may contribute to the development of osteoporosis. The relationship of Hcy and vitamin B12 with bone turnover markers, BUA, and fracture incidence was studied in 1267 subjects of the Longitudinal Aging Study Amsterdam. High Hcy and low vitamin B12 concentrations were significantly associated with low BUA, high markers of bone turnover, and increased fracture risk. Introduction: Hyperhomocysteinemia may contribute to the development of osteoporosis. Vitamin B12 is closely correlated to homocysteine (Hcy). The main objective of our study was to examine the association of Hcy and vitamin B12 status and the combined effect of these two with broadband ultrasound attenuation (BUA), bone turnover markers, and fracture. Materials and Methods: Subjects were 615 men and 652 women with a mean age of 76 ± 6.6 (SD) years of the Longitudinal Aging Study Amsterdam (LASA). At baseline (1995/1996), blood samples were taken after an overnight fast for dairy products. Plasma Hcy was measured with IMx, serum vitamin B 12 with competitive immunoassay (IA) luminescence, serum osteocalcin (OC) with immunoradiometric assay (IRMA), and urinary excretion of deoxypyridinoline (DPD) with competitive IA and corrected for creatinine (Cr) concentration. CVs were 4%, 5%, 8%, and 5%, respectively. BUA was assessed in the heel bone twice in both the right and left calcaneus. Mean BUA value was calculated from these four measurements. CV was 3.4%. After baseline measurements in 1995, a 3-year prospective follow-up of fractures was carried out until 1998/1999. Subjects were grouped by using two different approaches on the basis of their vitamin B12 concentration, normal versus low (15 μM) or highest quartile (Q4) versus normal quartiles (Q1-Q3). Analysis of covariance was performed to calculate mean values of BUA, OC, and DPD/Crurine based on the specified categories of Hcy and vitamin B12 and adjusted for several confounders (potential confounders were age, sex, body weight, body height, current smoking [yes/no], mobility, cognition). The relative risk (RR) of any fracture was assessed with Cox regression analysis. Quartiles were used when Hcy and vitamin B12 were separately studied in their relationship with fracture incidence. Results: Fourteen percent of the men and 9% of the women had high Hcy (>15 μM) and low vitamin B12 (12 levels 15 μM had lower BUA, higher DPD/Cr, and higher OC concentrations than their counterparts. In men, no differences were found between the different Hcy and vitamin B12 categories in adjusted means of BUA, OC, or DPD/Crurine. Twenty-eight men and 43 women sustained a fracture during the 3-year follow-up period. The adjusted RR for fractures (95% CI) for men with high Hcy and/or low vitamin B12 concentrations was 3.8 (1.2-11.6) compared with men with normal Hcy and vitamin B12 concentrations. Women with high Hcy and/or low vitamin B 12 concentrations had an adjusted RR for fractures of 2.8 (1.3-5.7). Conclusions: High Hcy and low vitamin B12 concentrations were significantly associated with low BUA, high markers of bone turnover, and increased fracture risk.

Background Supplementation with high doses of oral cobalamin is as effective as cobalamin administered by intramuscular injection to correct plasma markers of vitamin B12 deficiency, but the effects of lower oral doses of cobalamin on such markers are uncertain. Methods We conducted a randomized, parallel-group, double-blind, dose-finding trial to determine the lowest oral dose of cyanocobalamin required to normalize biochemical markers of vitamin B12 deficiency in older people with mild vitamin B12 deficiency, defined as a serum vitamin B12 level of 100 to 300 pmol/L (135-406 pg/mL) and a methylmalonic acid level of 0.26 µmol/L or greater. We assessed the effects of daily oral doses of 2.5, 100, 250, 500, and 1000 µg of cyanocobalamin administered for 16 weeks on biochemical markers of vitamin B12 deficiency in 120 people. The main outcome measure was the dose of oral cyanocobalamin that produced 80% to 90% of the estimated maximal reduction in the plasma methylmalonic acid concentration. Results Supplementation with cyanocobalamin in daily oral doses of 2.5, 100, 250, 500, and 1000 µg was associated with mean reductions in plasma methylmalonic acid concentrations of 16%, 16%, 23%, 33%, and 33%, respectively. Daily doses of 647 to 1032 µg of cyanocobalamin were associated with 80% to 90% of the estimated maximum reduction in the plasma methylmalonic acid concentration. Conclusion The lowest dose of oral cyanocobalamin required to normalize mild vitamin B12 deficiency is more than 200 times greater than the recommended dietary allowance, which is approximately 3 µg daily

Methylmalonic acid (MMA) and total homocysteine (tHCYS) concentrations are used to detect acquired and inborn errors of cobalamin (vitamin B12, Cbl) metabolism and to evaluate the effect of therapeutic interventions. Dried blood spot sampling offers a patient-friendly and easy alternative to plasma sampling. However, dried blood spot concentrations are not necessarily equal to plasma concentrations. Therefore, the objective of this work was to establish the relationship between MMA and tHYS dried blood spot and plasma concentrations to facilitate clinical implementation of dried blood spot sampling. MMA and tHCYS in both plasma and DBS were validated on ultra performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS). While position of the punch (in DBS) did affect tHCYS concentration, no influence of hematocrit (Ht) and blood volume on both MMA and tHCYS concentrations was observed. The plasma assay performed better than the DBS assay by most criteria. However, the DBS matrix was superior for tHCYS stability. Paired plasma and DBS samples were obtained from patients suspected for Cbl deficiency and from patients with a known inborn error of metabolism affecting MMA or tHCYS concentration. Based on the strong correlation of tHCYS in both matrices ( y = 0.46 ± 1.12 ( r 2 = 0.91)), determination of tHCYS in plasma can be replaced by tHCYS in DBS. However, for MMA, a correlation in the higher (pathological) range of MMA exist, but no correlation was observed in the lower ranges. Therefore the added value of MMA concentrations in DBS is currently unknown and should be further investigated.

Background: Lack of cobalamin may lead to neurologic disorders, which have been reported in strict vegetarians. Objective: The objective of this study was to investigate whether cognitive functioning is affected in adolescents (aged 10-16 y) with marginal cobalamin status as a result of being fed a macrobiotic diet up to an average age of 6 y. Design: Data on dietary intake, psychological test performance, and biochemical variables of cobalamin status were collected from 48 adolescents who consumed macrobiotic (vegan type) diets up to the age of 6 y, subsequently followed by lactovegetarian or omnivorous diets, and from 24 subjects (aged 10-18 y) who were fed omnivorous diets from birth onward. Thirty-one subjects from the previously macrobiotic group were cobalamin deficient according to their plasma methylmalonic acid concentrations. Seventeen previously macrobiotic subjects and all control subjects had normal cobalamin status. Results: The control subjects performed better on most psychological tests than did macrobiotic subjects with low or normal cobalamin status. A significant relation between test score and cobalamin deficiency (P = 0.01) was observed for a test measuring fluid intelligence (correlation coefficient: -0.28; 95% CI: -0.48, -0.08). This effect became more pronounced (P = 0.003) within the subgroup of macrobiotic subjects (correlation coefficient: -0.38; 95% CI: -0.62, - 0.14). Conclusion: Our data suggest that cobalamin deficiency, in the absence of hematologic signs, may lead to impaired cognitive performance in adolescents.

Background: Cobalamin deficiency has been described in children consuming macrobiotic diets. Objective: We investigated whether moderate consumption of animal products is sufficient for achieving normal cobalamin function in 73 adolescents who had received a macrobiotic diet until 6 y of age and had then switched to a lactovegetarian, lactoovovegetarian, or omnivorous diet (macrobiotic adolescents). Design: Hematologic indexes and serum concentrations of methylmalonic acid (MMA), total homocysteine (tHcy), and folate were measured. Current consumption frequency of animal products and cobalamin intake from dairy products were assessed by questionnaire. Data from 94 age-matched adolescents who received an omnivorous diet from birth were used as a reference. Results: Serum cobalamin concentrations were significantly lower and concentrations of MMA and folate and mean corpuscular volume (MCV) were significantly higher in macrobiotic adolescents than in control adolescents: of macrobiotic adolescents, 21% had abnormal MMA concentrations (> 0.41 mmol/L), 37% had abnormal cobalamin concentrations ( 12.8 mmol/L), and 15% had abnormal MCV (> 89 fL). In macrobiotic adolescents, dairy products (200 g milk or yogurt and 22 g cheese/d) supplied on average 0.95 mg cobalamin/d; additionally, these adolescents consumed fish, meat, or chicken 2‐3 times/wk. In girls, meat consumption contributed more to cobalamin status than the consumption of dairy products, whereas in boys these food groups were equally important. Conclusions: A substantial number of the formerly strict macrobiotic adolescents still had impaired cobalamin function. Thus, moderate consumption of animal products is not sufficient for restoring normal cobalamin status in subjects with inadequate cobalamin intake during the early years of life. Am J Clin Nutr 1999;69:664‐71.

A combination of high folate with low vitamin B12plasma status has been associated with cognitive impairment in a population exposed to mandatory folic acid fortification. The objective of the present study was to examine the interactions between plasma concentrations of folate and vitamin B12markers in relation to cognitive performance in Norwegian elderly who were unexposed to mandatory or voluntary folic acid fortification. Cognitive performance was assessed by six cognitive tests in 2203 individuals aged 72–74 years. A combined score was calculated using principal component analysis. The associations of folate concentrations, vitamin B12markers (total vitamin B12, holotranscobalamin (holoTC) and methylmalonic acid (MMA)) and their interactions in relation to cognitive performance were evaluated by quantile regression and least-squares regression, adjusted for sex, education, apo-ɛ4 genotype, history of CVD/hypertension and creatinine. Cross-sectional analyses revealed an interaction (P= 0·009) between plasma concentrations of folate and vitamin B12in relation to cognitive performance. Plasma vitamin B12concentrations in the lowest quartile ( 18·5 nmol/l) were associated with a reduced risk of cognitive impairment compared with plasma concentrations in the middle quartiles of both vitamins (OR 0·22, 95 % CI 0·05, 0·92). The interaction between folate and holoTC or MMA in relation to cognitive performance was not significant. In conclusion, this large study population unexposed to mandatory folic acid fortification showed that plasma folate, but not plasma vitamin B12, was associated with cognitive performance. Among the elderly participants with vitamin B12concentrations in the lower range, the association between plasma folate and cognitive performance was strongest.

Background Supplementation with high doses of oral cobalamin is as effective as cobalamin administered by intramuscular injection to correct plasma markers of vitamin B12 deficiency, but the effects of lower oral doses of cobalamin on such markers are uncertain. Methods We conducted a randomized, parallel-group, double-blind, dose-finding trial to determine the lowest oral dose of cyanocobalamin required to normalize biochemical markers of vitamin B12 deficiency in older people with mild vitamin B12 deficiency, defined as a serum vitamin B12 level of 100 to 300 pmol/L (135-406 pg/mL) and a methylmalonic acid level of 0.26 µmol/L or greater. We assessed the effects of daily oral doses of 2.5, 100, 250, 500, and 1000 µg of cyanocobalamin administered for 16 weeks on biochemical markers of vitamin B12 deficiency in 120 people. The main outcome measure was the dose of oral cyanocobalamin that produced 80% to 90% of the estimated maximal reduction in the plasma methylmalonic acid concentration. Results Supplementation with cyanocobalamin in daily oral doses of 2.5, 100, 250, 500, and 1000 µg was associated with mean reductions in plasma methylmalonic acid concentrations of 16%, 16%, 23%, 33%, and 33%, respectively. Daily doses of 647 to 1032 µg of cyanocobalamin were associated with 80% to 90% of the estimated maximum reduction in the plasma methylmalonic acid concentration. Conclusion The lowest dose of oral cyanocobalamin required to normalize mild vitamin B12 deficiency is more than 200 times greater than the recommended dietary allowance, which is approximately 3 µg daily

Background: Cobalamin deficiency is prevalent in vegetarians and has been associated with increased risk of osteoporosis. Aim of the study: To examine the association between cobalamin status and bone mineral density in adolescents formerly fed a macrobiotic diet and in their counterparts. Methods: In this cross-sectional study bone mineral density (BMD) and bone mineral content (BMC) were determined by DEXA in 73 adolescents (9-15 y) who were fed a macrobiotic diet up to the age of 6 years followed by a lacto-(-ovo-) vegetarian or omnivorous diet. Data from 94 adolescents having consumed an omnivorous diet throughout their lives were used as controls. Serum concentrations of cobalamin, methylmalonic acid (MMA) and homocysteine were measured and calcium intake was assessed by questionnaire. Analysis of covariance (MANCOVA) was performed to calculate adjusted means for vitamin B12 and MMA for low and normal BMC and BMD groups. Results: Serum cobalamin concentrations were significantly lower (geometric mean (GM) 246 pmol/L vs. 469 pmol/L) and MMA concentrations were significantly higher (GM 0.27 μmol/L vs. 0.16 μmol/L) in the formerly macrobiotic-fed adolescents compared to their counterparts. In the total study population, after adjusting for height, weight, bone area, percent lean body mass, age, puberty and calcium intake, serum MMA was significantly higher in subjects with a low BMD (p = 0.0003) than in subjects with a normal BMD. Vitamin B12 was significantly lower in the group with low BMD (p = 0.0035) or BMC (p = 0.0038) than in the group with normal BMD or BMC. When analyses were restricted to the group of formerly macrobiotic-fed adolescents, MMA concentration remained higher in the low BMD group compared to the normal BMD group. Conclusions: In adolescents, signs of an impaired cobalamin status, as judged by elevated concentrations of methylmalonic acid, were associated with low BMD. This was especially true in adolescents fed a macrobiotic diet during the first years of life, where cobalamin deficiency was more prominent. © Steinkopff Verlag 2004.

Background: Cobalamin deficiency is prevalent in vegetarians and has been associated with increased risk of osteoporosis. Aim of the study: To examine the association between cobalamin status and bone mineral density in adolescents formerly fed a macrobiotic diet and in their counterparts. Methods: In this cross-sectional study bone mineral density (BMD) and bone mineral content (BMC) were determined by DEXA in 73 adolescents (9-15 y) who were fed a macrobiotic diet up to the age of 6 years followed by a lacto-(-ovo-) vegetarian or omnivorous diet. Data from 94 adolescents having consumed an omnivorous diet throughout their lives were used as controls. Serum concentrations of cobalamin, methylmalonic acid (MMA) and homocysteine were measured and calcium intake was assessed by questionnaire. Analysis of covariance (MANCOVA) was performed to calculate adjusted means for vitamin B12 and MMA for low and normal BMC and BMD groups. Results: Serum cobalamin concentrations were significantly lower (geometric mean (GM) 246 pmol/L vs. 469 pmol/L) and MMA concentrations were significantly higher (GM 0.27 μmol/L vs. 0.16 μmol/L) in the formerly macrobiotic-fed adolescents compared to their counterparts. In the total study population, after adjusting for height, weight, bone area, percent lean body mass, age, puberty and calcium intake, serum MMA was significantly higher in subjects with a low BMD (p = 0.0003) than in subjects with a normal BMD. Vitamin B12 was significantly lower in the group with low BMD (p = 0.0035) or BMC (p = 0.0038) than in the group with normal BMD or BMC. When analyses were restricted to the group of formerly macrobiotic-fed adolescents, MMA concentration remained higher in the low BMD group compared to the normal BMD group. Conclusions: In adolescents, signs of an impaired cobalamin status, as judged by elevated concentrations of methylmalonic acid, were associated with low BMD. This was especially true in adolescents fed a macrobiotic diet during the first years of life, where cobalamin deficiency was more prominent. © Steinkopff Verlag 2004.

Background: The reason for the high prevalence of mild cobalamin (vitamin B-12) deficiency in the elderly is poorly understood. Objective: We aimed to determine the reason for this high prevalence. Design: We examined cobalamin intake, the presence and severity of atrophic gastritis, the presence of Helicobacter pylori infection, and plasma cobalamin and methylmalonic acid (MMA) concentrations in 105 healthy, free-living, older subjects aged 74‐80 y. Results: Mild cobalamin deficiency, ie, low to low-normal plasma cobalamin concentrations ( 0.32 mmol/L), were found in 23.8% of subjects; 25.7% of subjects were not cobalamin deficient (plasma cobalamin ♢ 260 pmol/L and plasma MMA ≤ 0.32 mmol/L). Six subjects (5.8%), including 1 with mild cobalamin deficiency, had dietary cobalamin intakes below the Dutch recommended dietary intake of 2.5 mg/d. Mildly cobalamin-deficient subjects had lower total (diet plus supplements) cobalamin intakes (median: 4.9 mg/d; 25th and 75th percentiles: 3.9, 6.4) than did non-cobalamin-deficient subjects (median: 6.3 mg/d; 25th and 75th percentiles: 5.4, 7.9) ( P = 0.0336), mainly because of less frequent use of cobalamin supplements (8% compared with 29.6%; x 2 = 3.9, P = 0.048). Atrophic gastritis was found in 32.4% of the total study group: mild to moderate in 19.6% and severe in 12.7%. The prevalence of severe atrophic gastritis, but not mild-to-moderate atrophic gastritis, was higher in mildly cobalamin-deficient subjects (25%) than in non-cobalamin-deficient subjects (3.7%) (x 2 = 4.6, P = 0.032). The prevalence of immunoglobulin G antibodies to H. pylori was similar in mildly cobalamin-deficient subjects (54.2%) and in non-cobalamin-deficient subjects (44.4%) (x 2 = 0.5, P = 0.5). Conclusions: The high prevalence of mild cobalamin deficiency in healthy, free-living, older Dutch subjects could be explained by inadequate cobalamin intake or severe atrophic gastritis in only 28% of the study population. Other mechanisms explaining mild cobalamin deficiency in older people must be sought. Am J Clin Nutr 1998;68:328‐34.

Contains fulltext : 50233.pdf (Publisher’s version ) (Closed access) BACKGROUND: Vitamin B-12 deficiency is associated with cognitive impairment in older people. However, evidence from randomized trials of the effects of vitamin B-12 supplementation on cognitive function is limited and inconclusive. OBJECTIVE: The objective was to investigate whether daily supplementation with high doses of oral vitamin B-12 alone or in combination with folic acid has any beneficial effects on cognitive function in persons aged >/=70 y with mild vitamin B-12 deficiency. DESIGN: In a double-blind, placebo-controlled trial, 195 subjects were randomly assigned to receive 1000 microg vitamin B-12, 1000 microg vitamin B-12 + 400 microg folic acid, or placebo for 24 wk. Vitamin B-12 status was assessed on the basis of methylmalonic acid, total homocysteine (tHcy), and holotranscobalamin (holoTC) concentrations before and after 12 and 24 wk of treatment. Cognitive function was assessed before and after 24 wk of treatment with the use of an extensive neuropsychologic test battery that included the domains of attention, construction, sensomotor speed, memory, and executive function. RESULTS: Vitamin B-12 status did not change significantly after treatment in the placebo group; however, oral vitamin B-12 supplementation corrected mild vitamin B-12 deficiency. Vitamin B-12 + folic acid supplementation increased red blood cell folate concentrations and decreased tHcy concentrations by 36%. Improvement in memory function was greater in the placebo group than in the group who received vitamin B-12 alone (P = 0.0036). Neither supplementation with vitamin B-12 alone nor that in combination with folic acid was accompanied by any improvement in other cognitive domains. CONCLUSION: Oral supplementation with vitamin B-12 alone or in combination with folic acid for 24 wk does not improve cognitive function.