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Vitamin B12 (Cobalamin) and folate are interconnected cofactors/coenzymes which participate in the normal functioning of the “folate” and “methionine” cycles within the body. The “folate” cycle is needed for DNA and RNA synthesis as well as for the metabolism of homocysteine to methionine. This methionine is utilized in the “methionine” cycle which is needed for methylation of DNA, RNA, proteins and lipids. According to Kennedy increased homocysteine levels have been linked to decreased cognitive function, Alzheimer’s disease (AD) and dementia.1

Understanding the role vitamin B12, folate and total homocysteine (tHcy) levels in the body have on cognition during different stages in life and the effects supplementing these B vitamins can produce can help with prevention of mental deterioration and with mental development.

Introduction

Effects on Early Development & Long-Term Cognitive Abilities

Associations between Alzheimer's Disease and Blood Homocysteine,

Vitamin B12, and Folate: A Case-Control Study

Chen H, Liu S, Ji L, et al. Associations between Alzheimer’s Disease and Blood Homocysteine, Vitamin B12, and Folate: A Case-Control Study. Current Alzheimer Research. 2015; 12:88-94.

Effects on Impaired Cognitive Function

Objective

Investigate the correlation between Alzheimer’s Disease (AD) and tHcy, vitamin B12 and folate levels in the blood.

Pressure to control the increasing burden of AD

Methods

Case–control study

115 case subjects with AD were matched 1:1 (for age ± 3 yrs. & sex) with 115 control subjects

Serum folate and vitamin B12 were collected and measured via automated immunoassay analyzer

Plasma tHcy was measured using high-performance liquid chromatography

Self-reported questionnaire, BMI, & use of folic acid and vitamin B12 supplements

Cognitive function was evaluated using a version of MMSE (dementia-screening instrument) and 20 ADL questions were asked

Findings

No significant differences (P≥0.05) between education, handedness, living with others, B12 supplement use, or folate supplement use

Significant differences (P≤0.05) between marital status, BMI, smoking, alcohol use, comorbid diseases, family history, MMSE score and ADL score

AD cases possessed higher tHcy levels (P=0.000) , lower serum vitamin B12 levels (P=0.000) and lower serum folate levels (P=0.000)

Association between intake of B vitamins and cognitive function in elderly Koreans

with cognitive impairment Kim H, Kim G, Jang W, Kim SY, Chang N. Association between intake of B vitamins and cognition function in elderly Koreans with cognitive impairment. Nutrition Journal. 2014; 13:118.

Effects of Vitamin B12 Supplementation

Effects of vitamin B-12 supplementation and neurologic and cognitive function in older people: a randomized controlled trial

Dangour AA, Allen E, Clarke R, et al. Effects of vitamin B-12 supplementation on neurological and cognitive function in older people: a randomized

controlled trial. Am J Clin Nur. 2015; 102:639-47.

Objective

Conclude if daily supplementation of 1 mg of vitamin B12 for a duration of 12 months impacts cognitive and neurological function in elderly people who possess a moderate B12 deficiency

Little research on subjects who already possess a deficiency

Methods

Double-blind, randomized, placebo-controlled clinical trial

191 subjects aged ≥75 y with moderate vitamin B12 deficiency (serum vitamin B12 concentrations: 107-210 pmol/L) with absence of anemia

99 of the subjects were treated with 1 mg of vitamin B12 daily, 120 subjects were give a placebo

Data on diet, alcohol consumption, psychological health, education, medical history, current prescribed medication , weight, height, and mobility were recorded at baseline & after 12 mo.

Neurologic function was assessed at baseline and after 12 mo.

Cognitive function was assessed at baseline and after 12 mo.

At baseline and after 12 mo. blood was sampled from subjects and serum concentrations of vitamin B12, holotranscobalamin, tHcy and folate were measured

Findings

Vitamin B12 serum levels increased 177% after 12 mo. in treated subjects

Holotranscobalamin serum levels increased 331% after 12 mo. in treated subjects

Serum tHcy levels decreased 17% after 12 mo. in treated subjects

No significant difference in neurological function with the allocated treatment at 12 mo.

No significant difference in cognitive function or other secondary outcomes with the allocated treatment at 12 mo.

Conclusion

Vitamin B12, folate and homocysteine levels may have been shown to have lasting effects on brain development and cognitive function if issues arise at the neonatal life stages.

People with cognitive impairment such as AD and/or MCI may have lower serum levels of B12 and folate, increased levels of tHcy and have decreased numbers of dietary and supplemental intake

Supplementing B12 in those with mild B12 deficiencies may not improve cognitive/neurological function.

More research on specific stages during pregnancy, serum levels and dietary trends over development of cognitive impairment, and supplementation of various combinations of B vitamins is needed in the future. B vitamins are strongly interrelated in their cellular processes and research on a wider range of B vitamins is needed.

Prenatal folate, homocysteine and vitamin B12 levels and child brain volumes, cognitive development and psychological functioning: the Generation R Study

Ars CL, Nijs IM, Marroun HE, et al. Prenatal folate, homocysteine and vitamin B12 levels and child brain volumes, cognitive development and psychological functioning: the Generation R Study. Br J Nutr. 2016; 1:1-9.

Human Nutrition and Chronic Disease, North Carolina State University

Kelsey M. Hall

Vitamin B-12 and Folate as Related to Cognitive Function

Objective Discover if a link between folate insufficiency, high total homocysteine levels and low vitamin

B12 levels in pregnant women were associated with abnormal brain morphology & cognitive/psychological function in their offspring

Methods Nested case-control study within the Generation R Study 62 Dutch children, 6-8 yrs., whose mothers had insufficient (<8 nmol/l) plasma folate during

early pregnancy and 194 similar controls with normal (<8 nmol/l) maternal plasma folate levels Maternal folate and tHcy concentrations analysis Evaluation of emotional and behavior issues IQ, neurocognitive abilities, and structural MRI data was collected

Findings An over-all decreased brain volume was found in the cases with low maternal plasma folate

(P≤0.017) Emotional and behavioral problems were not significantly correlated IQ was significantly lower (7 points) in the cases with maternal tHcy concentrations of >9.1

µmol/l Cases with lower maternal plasma folate levels scored lower on neurocognitive abilities

Objective Examine the relationship between B vitamin

intake (dietary and supplementation) and cognitive function

With cognitive impairment South Korea = most rapidly aging pop.

Methods Case-control study 100 cases with mild cognitive impairment

(MCI), 100 case with AD, and 121 controls All subjects older than 60

Subjects completed the Korean version of the Consortium to Establish a Registry for AD (CERAD-K) assessment packet

Dietary assessment through 24 hour recall of all food and supplements consumed was collected and analyses

Plasma folate, vitamin B12 and tHcy concentrations were analyzed

Findings Dietary and total B vitamins intake was

negatively associated with tHcy levels and positively with cognitive function

A connection between B vitamins intake and cognitive function was stronger in AD cases and MCI cases than in the controls

AD cases also showed a stronger connection than MCI

Maternal pregnancy tHcy level and IQ in Offspring

Figure 2. Shows a significant correlation (P≤0.05) between high tHcy concentration (>9.1 µmol/l) and lower IQ . B, b value. 95% confidence interval.

tHcy (n 240) B 95% CI P

Model 1 -8.02 -12.11, -3.93 0.000*

Model 2 -7.05 -11.04, -3.06 0.001*

Model 3 -6.91 -10.92, -2.90 0.001*

Odds ratios for the association between AD and combined blood tHcy, vitamin B12 and folate levels

Group Crude OR (95% CI)

Crude OR P

Adjusted OR (95% CI)

Adjusted OR P

1 1.0 1.0

2 2.0(0.8-4.8) 0.120 2.2(0.9-5.5) 0.082

3 4.6(1.7-12.9) 0.003 4.6(1.6-13.2) 0.004

4 4.4(1.4-14.2) 0.013 4.3(1.3-14.6) 0.019

5 5.8(1.8-19.0) 0.004 6.4(1.9-21.6) 0.003

6 14.1(4.8-41.5) 0.000 17.0(5.4-53.4) 0.000

7 27.8(9.2-83.8) 0.000 30.5(9.7-95.9) 0.000 Figure 3. Various combinations of low and high values of tHcy, folate and vitamin B12 were combined into different groups and analyzed. Results indicated that high tHcy combined with low vitamin B12 were related to AD development.

Correlation coefficients between B vitamins intake and plasma tHcy levels among

AD cases, MCI cases and the control

Total AD tHcy (µmol/L)

MCI tHcy (µmol/L)

Control tHcy (µmol/L)

Vitamin B2(mg/d) Diet only

-0.172** 0.069 -0.204 0.053

Vitamin B2 (mg/d) Total

-0.185*** -0.182 -0.208* -0.133

Vitamin B6 (mg/d) Diet only

-0.168** 0.075 0.098 0.015

Vitamin B6(mg/d) Total

-0.183** -0.216* -0.130 -0.141

Vitamin B12(µg/d) Diet only

-0.115* -0.111 -0.053 -0.019

Vitamin B12(µg/d) Total

-0.127* -0.173 0.069 -0.143

Folate (µg DFE/d) Diet only

-0.036 -0.093 0.102 -0.031

Folate (µg DFE/d) Total

-0.151** -0.121 -0.104 -0.063

(*p<0.05, **p<0.01, ***p<0.001)

Figure 4. Plasma tHcy was negatively correlated with total intake of vitamin B2, (p<0.001), vitamin B6 (p<0.01), vitamin B12 (p<0.05) and folate (p<0.01).

Figure 1. Folate & Methionine Cycles 1

CVLT: California Verbal Learning Test

Treated (n=91) Mean ± SE

Placebo (n=93) Mean ± SE

Unadjusted effect size Mean difference (95% CI)

Adjusted effect size Mean difference (95% CI) *adjusted for age and sex*

CVLT: Total words correct in 3 trials, n

23.9 ± 0.7 24.6 ± 0.7 -1.4 (-2.9, 0.1) -1.4 (-2.9, 0.1)

CVLT: Words recalled at delayed recall, n

7.5 ± 0.3 7.7 ± 0.4 -0.4 (-1.0, 0.2) -0.4 (-1.0, 0.2)

Symbol letter modality, n correct

39.6 ± 1.1 40.1 ± 1.2 -1.3 (-3.2, 0.6) -1.3 (-3.2, 0.6)

Reaction time, s Simple

0.3 ± 0.01 0.3 ± 0.01 0.01 (-0.02, 0.04) 0.01 (-0.02, 0.04)

Reaction time, s Choice

0.7 ± 0.01 0.7 ± 0.02 -0.003 (-0.03, 0.02) -0.003 (-0.03, 0.02)

Verbal fluency, n animals named

20.8 ± 0.5 19.9 ± 0.6 1.1 (-0.1, 2.2) 1.1 (-0.1, 2.2)

30-item General Health Question score *n=5 in treated & n=11 in placebo*

2.4 ± 0.5 2.7 ± 0.5 -0.1 (-1.2, 1.0) -0.1 (-1.3, 1.1)

Effects of vitamin B12 on cognitive and psychological function outcomes at 12 mo.

Figure 5. Difference between treated and placebo after 12 mo. were minimal as indicated by mean

differences. Results of the trial did not support the hypothesis.

1. Kennedy D. B Vitamins and the Brain: Mechanisms, Dose and Efficacy – A Review. Nutrients. 2016; 8: 1-69.