Biochemical indicators of vitamin B12 and folate insufficiency and cognitive decline

Tangney, C.C., Tang, Y., Evans, D.A., and Morris,

M.C.Neurology – 27-JAN-2009; 72(4): 361-7

Objectives: The goal of the study was to determine which parameters—serum concentrations of Vitamin B₁₂ or B₁₂ metabolites were most closely correlated with cognitive decline.

Methods: A stratified random sampling selected 516 subjects from the Chicago Health and Aging Project. Linear mixed models were used to examine the association of homocysteine, methylmalonic acid, 2-methylcitric acid, and cystathionine to a change in cognitive scores. The time frame of the study was over 6 years. Every three years during this period, cognitive function was assessed by the East Boston tests of immediate and delayed recall, the Mini-Mental State Examination, and the Symbol Digit Modalities Test. On each test, scores were expressed as z-scores and averaged. An approximately normally distributed global measure of cognitive function was obtained. The statistical analysis reduced the “floor and ceiling effects” as well as other potential measurement errors inherent in each test. Results were expressed as the sum of the standardized scores.

Results: Vitamin B₁₂ deficiency was seen in 14.2% of the participants. Increased serum homocysteine was noted in 19.2% while increased methylmalonic (MMA) acid levels were noted in 36.4% of participants. The higher MMA values were correlated with faster cognitive decline (p = 0.004). Conversely, higher B₁₂ concentrations were associated with slower rates of cognitive decline. (p = 0.005) There was no detectable relationship between homocysteine levels and cognition.

Conclusions: The most important risk factors for cognitive decline in older populations are high serum methylmalonic acid and low vitamin B₁₂ concentrations. Supplementation with folic acid, in food or as a supplement, may be contraindicated in this population.

Effects of cyanocobalamin on immunity in patients with pernicious anemia.

Erkurt, M.A., Aydogdu, I., Dikilita,Å.Ÿ., Kuku, I., Kaya, E., Bayraktar, N., Ozhan, O., Ozkan, I.,and Sonmez, A. Med Princ Pract – 01-JAN-2008; 17(2): 131-5

Objectives: To evaluate patients with pernicious anemia regarding the role of Vitamin B₁₂ in both cellular and humoral immunity.

Methods: A prospective study was conducted. Changes in T and B lymphocyte subpopulations, Natural Killer (NK) cell number, serum C3/C4 and levels of immunoglobulins G, M and A were measured before and during treatment of Vitamin B₁₂deficient patients with cyanocobalamin.

Results: Pre-treatment, the absolute numbers of CD⁴⁺ and CD⁸⁺ lymphocytes was decreased as was NK cell activity. The CD⁴⁺/ CD⁸⁺was also decreased. After treatment with cyanocobalamin, these values were restored to normal levels. Serum levels of C3, C4 and immunoglobulins G, M and A were increased post-treatment.

Conclusions: Vitamin B₁₂ plays an important role in cellular and humoral immunity and immunoregulation. In patients with pernicious anemia, immune parameters were restored after treatment with cyanocobalamin.

Homocysteine Lowering and Cognition in CKD: The Veterans Affairs Homocysteine Study

Brady, C.B., Gaziano, J.M. Czypoliski, R.A., Guarino, P.D., Kaufman, J.S., Warren, S.R., Hartigan, P., Goldfarb, D.S. and Jamison, R.L.

Objectives: The study was designed to investigate the relationship of the high homocysteine levels associated with chronic kidney disease and decreased cognitive function. Potential treatment by supplementation with high dose Vitamin B was investigated as well.

Methods: A randomized, double blind controlled study was conducted with 659 patients (mean age, 67.3 +/- 11.7 years) diagnosed with chronic kidney disease (CKD) or end-stage renal disease (ESRD) with coexisting high plasma total homocysteine levels (≥15μmol/L). Cognitive assessment by Telephone Interview of Cognitive Status-modified (TICSm) and supplemented with attention, working memory and executive function tests was initiated after implementation of Vitamin B treatment. The treatment consisted of either a daily high dose Vitamin B capsule (40 mg of folic acid, 100 mg of vitamin B₆ , and 2 mg of vitamin B₁₂) or placebo.

Results: Approximately 19% of patients had some level of cognitive impairment at the onset of the assessment, regardless of treatment assignment (vitamin or placebo) or kidney disease status. The treatment with high dose Vitamin B resulted in a decrease of tHcy levels by 26.7%. 1 year analysis (adjusted and unadjusted) showed no improvement in cognitive outcomes with treatment.

Conclusions: Cognitive outcomes were not affected significantly by treatment with high dose Vitamin B. A major limitation of this study was that cognitive assessment was begun after vitamin treatment was instituted. High dose daily Vitamin B supplementation was positively correlated with decreased tHcy levels.

Effect of L-dopa on plasma homocysteine in PD patients.Relationship to B-vitamin status

Miller, J.W., Selhub,J., Nadeau, M.R., Thomas, C.A., Feldman, R.G., and Wolf, P.A. Neurology – 8-APR-2003; 60(7): 1125-9.

Objectives: l-dopa is used in the treatment of Parkinson’s disease (PD) and is known to increase both the cellular synthesis and plasma levels of homocysteine. The objective of this study was to determine the effect of supplementation with folate, and Vitamins B₁₂ and B₆ on plasma concentrations of homocyteine in l-dopa treated and control PD patients.

Methods: 40 patients were enrolled in this study on an out-patient basis. Both men and women diagnosed with idiopathic PD who showed at least two of the three cardinal criteria were included. The cardinal criteria were rigidity, resting tremor and bradykinesia. Specific exclusion criteria included pregnancy, dietary restrictions, and a history of neurodegenerative disorders other than PD, drug or alcohol abuse, depression or other major medical disorders also correlated with a Vitamin B deficiency status. 20 of the patients were concurrently treated with the standard l-dopa/carbidopa combination (treatment group) and 20 were l-dopa-naïve (control group). Levels of plasma homocysteine, folate, Vitamins B₁₂ and B₆ were measured and correlated with the treatment and control groups.

Results: Higher plasma levels of homocysteine and lower plasma levels of the vitamin were found with the l-dopa/carbidopa group. In the control group, similar plasma levels of B vitamins were not associated with higher levels of homocysteine. (P<.001)

Conclusions: PD patients treated with l-dopa should be monitored for their homocysteine levels as these can increase with treatment. The extent of the plasma hyperhomocysteinemia is inversely related to B-vitamin status. Supplementation of PD patients on l-dopa with B-vitamins should be considered.

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A single-center, double-blinded, randomized controlled study to evaluate the relative efficacy of sublingual and oral vitamin B-complex administration in reducing total serum homocysteine levels

Yazaki, Y., Chow, G., and Mattie, M.J Altern Complement Med – 01-NOV-2006; 12(9): 881-5.

Objectives: Sublingual versus oral B-complex, each containing 1000mcg of Vitamin B₁₂, was studied in a double blinded, randomized and placebo controlled test to determine the relative efficacies in reducing serum total homocysteine levels (tHcy). The ultimate goal of the study is the clinical use of B-complex vitamins in the treatment of atherosclerosis.

Methods: 41 patients (ages 50-80 years) were randomized into a control (placebo) group, a sublingual group and an oral group. The patients were selected on the basis of serum tHcy concentrations greater than 11μmol/L. The treatment groups underwent a 6 week trial of Vitamin B complex, containing 1000mcg of B₁₂, 400 mcg folic acid, and 5 mg of Vitamin B₆. Each treatment group also received the corresponding placebo (e.g. the oral group received a placebo sublingual preparation and the sublingual group received an oral placebo).

Results: Both the sublingual and the oral groups experienced significant reduction in serum tHcy levels (P < .0001) during the treatment period. There was no statistically significant difference between the two dosing regimens.

Conclusions Sublingual b12 and oral B complex preparations containing 1000mcg of B₁₂, 400 mcg folic acid, and 5 mg of Vitamin B₆ are effective at decreasing tHcy levels. The results indicated that the use of Vitamin B complex may be indicated in the treatment of atherosclerosis

Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route.

Sharabi, A., Cohen, E., Sulkes, J., and Garty, M.Br J Clin Pharmacol – 01-DEC-2003; 56(6): 635-8.

Objectives: Sublingual and oral administration of 500mcg of Vitamin B12 (cobalamin) were compared in cobalamin deficient patients.

Methods: 30 cobalamin deficient patients were randomized into 3 groups: sublingual B₁₂, oral B₁₂ and B-complex vitamin treatment. Serum levels of cobalamin were measured at the beginning of the study and at 4 weeks. Each group received 500 mcg of cobalamin or its equivalent, daily.

Results: All three groups exhibited a significant and similar increase in serum cobalamin levels at the end of the 4 week period. (P<0.0001, 95% CI)

Conclusions: Serum cobalamin deficiency may be corrected by 500 mcg daily of sublingual B12, oral B₁₂ or B-complex vitamin equivalent. No significant difference in the three groups was noted.

Effectiveness of vitamin B12 in treating recurrent aphthous stomatitis: a randomized, double-blind, placebo-controlled trial.

Volkov, I., Rudoy, I., Freud, T., Sardal, G., Naimer, S., Peleg, R., and Press, Y.J Am Board Fam Med – 01-JAN-2009; 22(1): 9-16.

Objectives: Recurrent aphthous stomatitis is the most common oral lesion seen in primary care practice and occurs in an estimated 25% of the general population. The objective of the current study was to validate and confirm previous observations on the benefits of Vitamin B₁₂ for the treatment of this patient population.

Methods: 58 patients were randomly divided into a treatment group (N=31) and a control (placebo) group (N=27). The treatment group received 1000mcg of sublingual Vitamin B12 for 6 months. The control group received placebo for the same time period. Clinicians were blinded to group assignment. Clinical parameters measured were pain, number of ulcers, outbreak frequency, and duration of outbreak. 87% of the treatment group and 93% of the control group completed the study.

Results: During the last 2 months of the study, 15 patients (55.6%) from the treatment group and 4 patients (16%) from the control group were clinically determined to have reached the endpoint “no aphthous ulcers status” (P < .01). The treatment group also had fewer outbreaks (P < .0001), less painful lesions (P < .0001) and shorter duration of outbreak (P < .0001).

Conclusions: Sublingual B12 at 1000mcg/d is an effective, safe and inexpensive treatment of recurrent aphthous stomatitis.

Successful Treatment of Chronic Erythema Nodosum with Vitamin B12

Volkov,I., Rudoy, I., and Press, Y.J Am Board Fam Pract 2005;18:567–9.

Objectives: To present a case study of a patient successfully treated with Vitamin B₁₂ for painful chronic erythema nodosum refractory to NSAIDs.

Methods: A 38 year old female vegetarian patient was diagnosed with chronic erythema nodosum, numbness in extremities and a sub-clinical deficiency of Vitamin B12. The patient was treated with biweekly intramuscular injections of 1000 mcg B12 for 4 weeks. This was followed by sublingual vitamin B12 (1000mcg, biweekly).

Results: The numbness and rash began to show clinical signs of improvement within 2 weeks of treatment initiation. No recurrence of symptoms were reported.

Conclusions: Physicians should check for subclinical deficiency of B₁₂ in patients presenting with erythema nodosum or extremity numbness.