title: Effects of vitamin B-12 supplementation on neurologic and cognitive function in older people: a randomized controlled trial12 Genomic DNA methylation decreases in response to moderate folate depletion in elderly women. Short-term folate, vitamin B-12 or vitamin B-6 supplementation slightly affects memory performance but not mood in women of various ages. Influence of folate status and polyphenol intake on thiamin status of Irish women. The effect of folic acid supplementation on carotid intima-media thickness in patients with cardiovascular risk: a randomized, placebo-controlled trial. High prevalence of cobalamin deficiency in elderly outpatients. Clinical Trial of the Effect of Vitamin B12 in Elderly Subjects with Low Serum B12 Levels Effects of folic acid supplementation on psychomotor performance and hemorheology in healthy elderly subjects. Oral vitamin B12 for patients suspected of subtle cobalamin deficiency: a multicentre pragmatic randomised controlled trial Effect of 3 y of folic acid supplementation on the progression of carotid intima-media thickness and carotid arterial stiffness in older adults. The effect of folic acid supplementation on plasma homocysteine in an elderly population. A randomized, double-blind, placebo-controlled study of oral vitamin B12 supplementation in older patients with subnormal or borderline serum vitamin B12 concentrations. Vitamin B12 and folate and the risk of anemia in old age: the Leiden 85-Plus Study. Efficacy of short-term oral cobalamin therapy for the treatment of cobalamin deficiencies related to food-cobalamin malabsorption: a study of 30 patients. Use of Folic Acid-Fortified Milk in the Elderly Population
abstract: Background : Moderate vitamin B-12 deficiency is relatively common in older people . However , there is little robust evidence on the effect of vitamin B-12 supplementation on neurologic and cognitive outcomes in later life . Objective : We investigated whether vitamin B-12 supplementation benefits neurologic and cognitive function in moderately vitamin B-12–deficient older people . Design : We conducted a double-blind , r and omized , placebo-controlled trial in 7 general practice s in South East Engl and , United Kingdom . Study participants were aged ≥75 y and had moderate vitamin B-12 deficiency ( serum vitamin B-12 concentrations : 107–210 pmol/L ) in the absence of anemia and received 1 mg crystalline vitamin B-12 or a matching placebo as a daily oral tablet for 12 mo . Peripheral motor and sensory nerve conduction , central motor conduction , a clinical neurologic examination , and cognitive function were assessed before and after treatment . Results : A total of 201 participants were enrolled in the trial , and 191 subjects provided outcome data . Compared with baseline , allocation to vitamin B-12 was associated with a 177 % increase in serum concentration of vitamin B-12 ( 641 compared with 231 pmol/L ) , a 331 % increase in serum holotranscobalamin ( 240 compared with 56 pmol/L ) , and 17 % lower serum homocysteine ( 14.2 compared with 17.1 μmol/L ) . In intention-to-treat analysis of covariance models , with adjustment for baseline neurologic function , there was no evidence of an effect of supplementation on the primary outcome of the posterior tibial compound muscle action potential amplitude at 12 mo ( mean difference : −0.2 mV ; 95 % CI : –0.8 , 0.3 mV ) . There was also no evidence of an effect on any secondary peripheral nerve or central motor function outcome , or on cognitive function or clinical examination . Conclusion : Results of the trial do not support the hypothesis that the correction of moderate vitamin B-12 deficiency , in the absence of anemia and of neurologic and cognitive signs or symptoms , has beneficial effects on neurologic or cognitive function in later life . This trial was registered at www.is rct n.com as IS RCT N54195799 BACKGROUND Methylation of genomic DNA is dependent on an adequate supply of folate coenzymes . Previous data support the hypothesis that abnormal DNA methylation plays an integral role in carcinogenesis . To date , no studies assessing the effect of inadequate folate status on DNA methylation in older women ( aged > 63 y ) have been reported . OBJECTIVE The effect of moderate folate depletion followed by folate repletion on leukocyte genomic DNA methylation was investigated in elderly women ( aged 60 - 85 y ) to evaluate whether DNA methylation could be used as a functional indicator of folate status . DESIGN Healthy , postmenopausal women ( n = 33 ) consumed a moderately folate-depleted diet ( 118 microg folate/d ) for 7 wk , followed by 7 wk of folate repletion with 200 or 415 microg/d , each provided as 2 different dietary treatments for a total of 4 treatment groups ( n = 30 ) . Leukocyte DNA methylation was determined on the basis of the ability of DNA to incorporate [(3)H]methyl groups from labeled S:-adenosylmethionine in an in vitro assay . RESULTS Incorporation of [(3)H]methyl groups increased significantly ( P : = 0.0025 ) in response to folate depletion , suggesting undermethylation of DNA . No significant changes were detected in [(3)H]methyl incorporation in any group over the 7-wk repletion period compared with postdepletion values . CONCLUSIONS DNA methylation status may be used as a functional indicator of moderately depleted folate status . The slow response to the repletion diets observed suggests that normalization of DNA methylation after moderate folate depletion may be delayed in older women Based on research demonstrating associations between folate , B-12 and B-6 vitamins and cognition and mood , we investigated the effects of short-term supplementation in 211 healthy younger , middle-aged and older women who took either 750 microg of folate , 15 microg of vitamin B-12 , 75 mg of vitamin B-6 or a placebo daily for 35 d. In addition , we examined associations between dietary intake of these vitamins and cognition and mood . Usual dietary intake status was estimated using a retrospective , self-report , quantified food frequency question naire . Participants completed alternate forms of st and ardized tests of cognitive processing re sources , memory , executive function , verbal ability and self-report mood measures before and after supplementation . Supplementation had a significant positive effect on some measures of memory performance only , and no effect on mood . Dietary intake status was associated with speed of processing , recall and recognition and verbal ability The relationship of folate status and polyphenol intake to thiamin status was studied in 80 r and omly selected elderly and young Irish women , with key variables affecting thiamin nutrition controlled for .  Folate , thiamin , and polyphenol intakes  were measured during a 4-wk baseline ( elderly and young ) and 6-wk double-blind ( elderly ) supplementation period . Only elderly subjects were r and omly assigned to placebo , folic acid ( 400 micrograms ) , thiamin ( 10 mg ) , or folic-acid-plus-thiamin groups .  Thiamin status ( TPP effect ) was not affected by folate status ( plasma and erythrocyte folate ) during the baseline period or with folic acid supplementation alone . Polyphenol intake was not correlated with thiamin status . Only thiamin intake and thiamin supplementation significantly affected thiamin status . Because the majority of subjects ( 102 of 160 ) were initially thiamin deficient , enrichment of Irish grain products with thiamin is recommended INTRODUCTION Observational studies have suggested a causal relationship between hyperhomocysteinemia and cardiovascular complications such as stroke and ischemic heart disease . The Homocysteine Lowering Trialists ' Collaboration has shown that daily administration of folic acid can significantly decrease homocysteine levels up to 25 % . Aim of this study was to investigate the effect of daily supplementation of folic acid ( 5 mg ) on IMT after 18 months of treatment in patients with at least one cardiovascular risk factor . METHODS We enrolled 103 patients with at least one cardiovascular risk factor who were r and omized to receive either a daily dose of 5 mg folic acid ( group I , n=53 ) or placebo ( group II , n=50 ) for 18 months . RESULTS After 18 months of folic acid supplementation , homocysteine levels were significantly reduced in the active treatment group compared to a non-significant increase in the placebo group . Folic acid levels were markedly increased in the former group and non-significantly reduced in the latter . Significant regression of carotid IMT was observed ( 0.961+/-0.092 to 0.933+/-0.077 mm , p<0.001 ) compared to significant IMT progression in the placebo group ( 0.964+/-0.099 to 0.984+/-0.094 mm ) . CONCLUSION Folic acid supplementation results in significant IMT reduction after 18 months in patients with at least one cardiovascular risk OBJECTIVE To measure the prevalence of cobalamin ( vitamin B12 ) deficiency in geriatric out patients as documented by both low serum cobalamin levels and elevations of serum methylmalonic acid and homocysteine and to determine the response to cobalamin treatment . DESIGN Prospect i ve study screening elderly subjects for cobalamin deficiency using radiodilution cobalamin assays as well as stable isotope dilution gas chromatography-mass spectrometry methylmalonic acid and homocysteine assays . In patients with serum cobalamin levels < or = 300 pg/mL , the response to cobalamin treatment in the group with levels of methylmalonic acid and /or homocysteine > 3 st and ard deviations ( SD ) above the mean for normals was compared with that of those without such elevations . SETTING Outpatient geriatric clinics at the VA Medical Center and University Health Sciences Center , Denver , CO . PATIENTS One-hundred and fifty-two consecutive out patients , ages 65 to 99 , were screened . Twenty-nine subjects with serum cobalamin levels < or = 300 pg/mL were prospect ively evaluated and treated with cobalamin . MAIN OUTCOME MEASURES Cobalamin , methylmalonic acid , homocysteine , complete blood counts , neurologic examination , and neuropsychological testing . RESULTS The prevalence of cobalamin deficiency as defined by a serum cobalamin level < or = 300 pg/mL and levels of serum methylmalonic acid and /or homocysteine elevated to > 3 SD was 14.5 % of the screened out patients . A similar proportion of patients with low normal serum cobalamin levels ( between 201 and 300 pg/mL ) demonstrated elevated metabolites > 3 SD ( 56 % ) compared with patients with low serum cobalamin levels ( < or = 200 pg/mL ) ( 62 % ) . Cobalamin therapy caused a marked fall or complete correction of the elevated methylmalonic acid and homocysteine levels in each patient who was treated prospect ively . Results for complete blood count , lactate dehydrogenase , bilirubin , baseline neurologic score , and baseline neuropsychologic scores did not differ in the group of patients with elevated metabolites compared with those with normal metabolites . The mean red cell volume fell significantly in the patients with elevated metabolites after 6 months of cobalamin treatment . One patient with elevated metabolites had marked improvement in his neurologic abnormalities after 6 months of cobalamin treatment . CONCLUSION There was a high ( 14.5 % ) prevalence of cobalamin deficiency as demonstrated by elevations in serum methylmalonic acid and homocysteine in addition to low or low normal serum cobalamin levels in elderly out patients . The serum cobalamin level was insensitive for screening since similar numbers of patients with low normal serum cobalamin levels of 201 - 300 pg/mL compared with patients with low cobalamin levels ( < or = 200 pg/mL ) had markedly elevated metabolites which fell with cobalamin treatment . Additional studies will be required to define the full clinical benefit from treatment with Cbl in elderly subjects A clinical trial of the effect of vitamin B12 therapy was conducted in 39 elderly subjects who had been found , in a community screening survey , to have low levels of serum B12 without a macrocytic anaemia or neuropathy . The study produced no evidence which suggests that in such subjects B12 is superior to placebo in effecting an improvement in psychiatric state or general well-being . There was a clear tendency for all the subjects to show an improvement during the trial , but this probably represents the therapeutic effect of involvement in a research exercise of this kind Cognitive impairment is associated with increased blood concentrations of homocysteine and high blood viscosity . Previous studies have shown that vitamin B supplementation reduces homocysteine and enhances cognitive function in patients with mild dementia and low serum folic acid . However , whether folic acid enhances cognitive function in elderly subjects without dementia and normal serum folic acid is unknown . Twenty-four healthy elderly subjects ( age 73.0+/-5.6 years , mean+/-S.D. ) with normal serum folic acid ( 6.3+/-2.4 microg/l ) and Mini Mental State Examination ( MMSE ) > 27/30 were r and omized to 4-week treatment with folic acid 5mg/day or placebo  in a r and omized , placebo-controlled , parallel-group study . Continuous Attention Test ( CAT ) , Four-Choice Reaction Time ( FCRT ) , Digit-Symbol Substitution ( DSS ) , Scanning Memory Sets ( SMS ) , and blood viscosity for different shear rates were measured before and after treatment . Folic acid supplementation induced a significant increase in serum folic acid levels ( + 13.8 versus + 1.6 microg/l , p<0.001 ) and fall in homocysteine levels ( -1.91 versus -0.41 micromol/l , p=0.05 ) compared to placebo . However , there was no significant change in CAT , FCRT , DSS , SMS , and blood viscosity between the two groups . Short-term folic acid supplementation does not enhance psychomotor performance or reduce blood viscosity in healthy elderly subjects with normal serum folic acid levels and preserved cognitive function Background Evidence regarding the effectiveness of oral vitamin B12 in patients with serum vitamin B12 levels between 125 - 200 pM/l is lacking . We compared the effectiveness of one-month oral vitamin B12 supplementation in patients with a subtle vitamin B12 deficiency to that of a placebo . Methods This multicentre ( 13 general practice s , two nursing homes , and one primary care center in western Switzerl and ) , parallel , r and omised , controlled , closed-label , observer-blind trial included 50 patients with serum vitamin B12 levels between 125 - 200 pM/l who were r and omized to receive either oral vitamin B12 ( 1000 μg daily , N = 26 ) or placebo ( N = 24 ) for four weeks . The institution 's pharmacist used simple r and omisation to generate a table and allocate treatments . The primary outcome was the change in serum methylmalonic acid ( MMA ) levels after one month of treatment . Secondary outcomes were changes in total homocysteine and serum vitamin B12 levels . Blood sample s were central ised for analysis and adherence to treatment was verified by an electronic device ( MEMS ; Aardex Europe , Switzerl and ) . Trial registration : IS RCT N 22063938 . Results Baseline characteristics and adherence to treatment were similar in both groups . After one month , one patient in the placebo group was lost to follow-up . Data were evaluated by intention-to-treat analysis . One month of vitamin B12 treatment ( N = 26 ) lowered serum MMA levels by 0.13 μmol/l ( 95%CI 0.06 - 0.19 ) more than the change observed in the placebo group ( N = 23 ) . The number of patients needed to treat to detect a metabolic response in MMA after one month was 2.6 ( 95 % CI 1.7 - 6.4 ) . A significant change was observed for the B12 serum level , but not for the homocysteine level , hematocrit , or mean corpuscular volume . After three months without active treatment ( at four months ) , significant differences in MMA levels were no longer detected . Conclusions Oral vitamin B12 treatment normalised the metabolic markers of vitamin B12 deficiency . However , a one-month daily treatment with1000 μg oral vitamin B12 was not sufficient to normalise the deficiency markers for four months , and treatment had no effect on haematological signs of B12 deficiency BACKGROUND Observational studies have shown that low folate and elevated homocysteine concentrations are risk factors for vascular disease in the general population . R and omized controlled trials in vascular patients have failed to show that folic acid reduces the risk of recurrent vascular disease , whereas such trials are lacking in the general population . OBJECTIVE The objective was to determine whether folic acid supplementation reduces the progression of atherosclerosis as measured by common carotid intima-media thickness (CIMT)-a vali date d marker of atherosclerosis and predictor of vascular disease risk . DESIGN A r and omized , double-blind , placebo-controlled study in 819 men and postmenopausal women aged 50 - 70 y , free-living in the Netherl and s , and with a total homocysteine concentration ≥13 μmol/L at screening was conducted . Participants received either 800 μg folic acid or placebo daily for 3 y. Rate of change in CIMT and arterial distensibility were the primary and secondary outcomes , respectively . RESULTS Compared with placebo , serum folate increased by 577 % and plasma total homocysteine concentrations decreased by 26 % after 3 y of folic acid supplementation . The mean ( ±SE ) rate of change in CIMT was 1.9 ± 0.9 μm/y in the folic acid arm and 1.3 ± 0.8 μm/y in the placebo arm ( mean difference : 0.7 μm/y ; 95 % CI : -1.8 , 3.1 μm/y ; P = 0.59 ) . No difference was observed ( P = 0.23 ) between the rates of change in distensibility in the folic acid arm ( -0.53 ± 0.06 × 10(-3 ) kPa(-1 ) ) and in the placebo arm ( -0.62 ± 0.06 × 10(-3 ) kPa(-1 ) ) . CONCLUSION Despite a considerable increase in folate concentrations and a reduction in total homocysteine concentrations , 3-y folic acid supplementation did not slow down atherosclerotic progression or arterial stiffening . This trial was registered at clinical trials.gov as NCT00110604 BACKGROUND Increased plasma homocysteine is associated with coronary artery disease , peripheral vascular disease and venous thrombosis . Folic acid is the most effective therapy for reducing homocysteine levels . The lowest effective supplement of folic acid is not known , particularly for the elderly who have the highest prevalence of these conditions . AIM To explore the effects of daily supplements of 0 , 50 , 100 , 200 , 400 and 600 microg folic acid on plasma homocysteine in an elderly population . DESIGN R and omized double-blind placebo-controlled trial . METHODS Participants ( n=368 ) aged 65 - 75 years were r and omly allocated to receive one of the treatments for 6 weeks .  Plasma homocysteine was recorded after 3 weeks and 6 weeks of supplementation . RESULTS Only the 400 microg and 600 microg groups had significantly lower homocysteine levels compared to placebo ( p=0.038 and p<0.001 , respectively ) . Using multiple linear regression and each individual 's total folic acid intake ( diet plus supplement ) , a total daily folic acid intake of 926 microg per day would be required to ensure that 95 % of the elderly population would be without cardiovascular risk from folate deficiency . DISCUSSION A daily folic acid intake of 926 microg is unlikely to be achieved by diet alone . Individual supplementation or fortification of food with folic acid will be required to reach this target OBJECTIVES To determine the effect of small doses of oral cyanocobalamin supplements in older patients with low or borderline serum vitamin B12 concentrations but no other evidence of pernicious anemia ( PA ) . DESIGN R and omized , double-blind , placebo-controlled study assessing the efficacy of oral cyanocobalamin 10 microg and 50 microg daily for 1 month . SETTING Two geriatric hospitals in the North Western Health Care Network , Melbourne , Australia . PARTICIPANTS Thirty-one in patients with serum vitamin B12 levels between 100 and 150 pmol/L , without PA , other malabsorption disorders , or progressive neurological or terminal illness . The mean age was 81.4 years . INTERVENTION After informed consent , a medical and drug history was taken and the Mini-Mental State Examination ( MMSE ) completed . A dietitian made assessment of oral cobalamin intake . Blood was taken for serum vitamin B12 , serum and red cell folate assay , full blood examination , fasting serum gastrin , parietal and intrinsic factor antibodies , fasting serum homocysteine , and creatinine . Patients were then r and omized to receive 10 microg oral cyanocobalamin , 50 microg oral cyanocobalamin , or placebo treatment for 1 month , after which the investigations and clinical examinations were repeated . MEASUREMENTS Percentage change in the level of vitamin B12 , homocysteine , folate , and red cell parameters and absolute changes in MMSE were calculated and compared between groups . The groups were compared on the number of responders who improved their level of B12 by 20 % . Chi-square calculations on changes in serum vitamin B12 concentration were also performed . RESULTS Mean serum vitamin B12 + /- st and ard deviation improved by 51.7 + /- 47.1 % in the 50-microg group , 40.2 + /- 34.4 % in the 10-microg group , and 11.7 + /- 24.5 % in the placebo group . The change in the 50-microg cyanocobalamin group was significantly greater than that in the placebo group ( P=.044 ) . The change in the 10-microg cyanocobalamin group was not significantly different from that in the placebo group ( P=.186 ) . Eight of 10 subjects in each treatment group were classified as responders , compared with two of 11 in the placebo group ( P=.004 ) . Homocysteine levels fell in patients receiving cyanocobalamin , but this fall failed to reach statistical significance . There were no significant changes in the other parameters measured . CONCLUSION Cyanocobalamin supplementation of 50 microg but not 10 microg daily produced a significant increase in serum vitamin B12 . This result has implication s for the management of patients with subnormal or borderline serum vitamin B12 concentrations and for food fortification with vitamin B12 BACKGROUND Screening for deficiencies in vitamin B(12 ) and folate is advocated to prevent anemia in very elderly individuals . However , the effects of vitamin B(12 ) and folate deficiency on the development of anemia in old age have not yet been established . METHODS The current study is embedded in the Leiden 85-Plus Study , a population -based prospect i ve study of subjects aged 85 years . Levels of vitamin B(12 ) , folate , and homocysteine were determined at baseline . Hemoglobin levels and mean corpuscular volume ( MCV ) were determined annually during 5 years of follow-up . RESULTS We analyzed data from 423 subjects who did not use any form of cyanocobalamin , hydroxocobalamin , or folic acid supplementation , neither at baseline nor during follow-up . Folate deficiency ( < 7 nmol/L ; n = 34 ) and elevated homocysteine levels ( > 13.5 mumol/L ; n = 194 ) were associated with anemia at baseline ( adjusted odds ratio [ OR ] , 2.44 ; 95 % confidence interval [ CI ] , 1.06 - 5.61 ; and adjusted OR , 1.82 ; 95 % CI , 1.08 - 3.06 , respectively ) , but vitamin B(12 ) deficiency ( < 150 pmol/L ; n = 68 ) was not ( adjusted OR , 1.51 ; 95 % CI , 0.79 - 2.87 ) . Furthermore , vitamin B(12 ) deficiency was not associated with the development of anemia during follow-up ( adjusted HR , 0.92 ; 95 % CI , 0.46 - 1.82 ) or with changes in MCV ( adjusted linear mixed model ; P = .77 ) . Both folate deficiency and elevated homocysteine levels were associated with the development of anemia from age 85 years onward ( adjusted HR , 3.33 ; 95 % CI , 1.55 - 7.14 ; and adjusted HR , 1.70 ; 95 % CI , 1.01 - 2.88 , respectively ) , but not with an increase in MCV over time ( P > .30 ) . CONCLUSION In the general population of very elderly individuals , anemia in 85-year-old subjects is associated with folate deficiency and elevated homocysteine levels but not with vitamin B(12 ) deficiency BACKGROUND It has been suggested that oral cobalamin ( vitamin ( B12 ) ) therapy may be an effective therapy for treating cobalamin deficiencies related to food-cobalamin malabsorption . However , the duration of this treatment was not determined . PATIENTS AND METHOD In an open-label , nonplacebo study , we studied 30 patients with established cobalamin deficiency related to food-cobalamin malabsorption , who received between 250 and 1000 microg of oral crystalline cyanocobalamin per day for at least 1 month .  ENDPOINTS Blood counts , serum cobalamin and homocysteine levels were determined at baseline and during the first month of treatment . RESULTS During the first month of treatment , 87 % of the patients normalized their serum cobalamin levels ; 100 % increased their serum cobalamin levels ( mean increase , + 167 pg/dl ; P < 0.001 compared with baseline ) ; 100 % had evidence of medullary regeneration ; 100 % corrected their initial macrocytosis ; and 54 % corrected their anemia . All patients had increased hemoglobin levels ( mean increase , + 0.6 g/dl ) and reticulocyte counts ( mean increase , + 35 x 10(6)/l ) and decreased erythrocyte cell volume ( mean decrease , 3 fl ; all P < 0.05 ) . CONCLUSION Our findings suggest that crystalline cyanocobalamin , 250 - 1000 microg/day , given orally for 1 month , may be an effective treatment for cobalamin deficiencies not related to pernicious anemia Folic acid deficiency is common in the elderly population , result ing in anaemia , dementia , many neurological sequelae and an indirect role in atheromatous disease . An increase in natural food folate is relatively ineffective at increasing folate status and the use of folate fortification of foodstuffs is recommended . The aim of our study was to assess the benefits of folic acid-fortified milk to the folate status of an elderly institutionalised population . 49 subjects received  fortified milk  as part of their daily diet for at least 6 months ( active group ) and 40 subjects received unfortified milk ( control group ) . Our results showed a mean serum folate level in the active group of 5.81 ( 1.1–17.6 ) µg/l compared to the control group mean of 2.16 ( 0.5–9.4 ) µg/l ( p < 0.001 ; normal range for serum folate 2.7–20 µg/l ) . Similarly the mean red cell folate level in the active group of 316.5 ( 130–905 ) µg/l was significantly higher than the control group mean of 196.1 ( 95–490 ) µg/l ( p < 0.001 ; normal range for red cell folate 150–1,000 µg/l ) . Our results suggest that folic acid-fortified milk is an efficacious and acceptable method of administration of folic acid in the elderly population and we recommend the use of folic acid-fortified milk in the regular daily diet of the elderly population
target: The effects did not differ by sex or by age group .
  Conclusions Evidence on the effects of supplementation of low concentrations of vitamin B12 and folate on haematological parameters in community-dwelling older people is inconclusive .
background: Background / objectives Low vitamin B12 and folate levels in community-dwelling older people are usually corrected with supplements .
  However , the effect of this supplementation on haematological parameters in older persons is not known .