Effects of Folic Acid and Vitamin B12, Alone and in Combination on Cognitive Function and Inflammatory Factors in the Elderly with Mild Cognitive Impairment: A Single-blind Experimental Design

Author(s): Fei Ma, Xuan Zhou, Qing Li, Jiangang Zhao, Aili Song, Peilin An, Yue Du, Weili Xu, Guowei Huang*.

Journal Name: Current Alzheimer Research

Volume 16 , Issue 7 , 2019

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Abstract:

Background: Folate and vitamin B12 are well-known as essential nutrients that play key roles in the normal functions of the brain. Inflammatory processes play at least some role in the pathology of AD. Effective nutritional intervention approaches for improving cognitive deficits that reduce the peripheral inflammatory cytokine levels have garnered special attention.

Objective: The present study aimed to determine whether supplementation with folic acid and vitamin B12, alone and in combination improves cognitive performance via reducing levels of peripheral inflammatory cytokines.

Methods: 240 participants with MCI were randomly assigned in equal proportion to four treatment groups: folic acid alone, vitamin B12 alone, folic acid plus vitamin B12 or control without treatment daily for 6 months. Cognition was measured with WAIS-RC. The levels of inflammatory cytokines were measured using ELISA. Changes in cognitive function or blood biomarkers were analyzed by repeatedmeasure analysis of variance or mixed-effects models. This trial has been registered with trial number ChiCTR-ROC-16008305.

Results: Compared with control group, the folic acid plus vitamin B12 group had significantly greater improvements in serum folate, homocysteine, vitamin B12 and IL-6, TNF-α, MCP-1. The folic acid plus vitamin B12 supplementation significantly changed the Full Scale IQ (effect size d = 0.169; P = 0.024), verbal IQ (effect size d = 0.146; P = 0.033), Information (d = 0.172; P = 0.019) and Digit Span (d = 0.187; P = 0.009) scores. Post hoc Turkey tests found that folic acid and vitamin B12 supplementation was significantly more effective than folic acid alone for all endpoints.

Conclusions: The combination of oral folic acid plus vitamin B12 in MCI elderly for six months can significantly improve cognitive performance and reduce the levels of inflammatory cytokines in human peripheral blood. The combination of folic acid and vitamin B12 was significantly superior to either folic acid or vitamin B12 alone.

Keywords: Mild cognitive impairment, folic acid, vitamin B12, peripheral inflammatory cytokines, single-blind experimental design, Alzheimer's disease.

[1]
Rajesh R, Tampi DJ, Tampi SC, Ambreen Ghori MD. Mild cognitive impairment: a comprehensive review. Healthy Aging Res 4: 1-11. (2015)
[2]
Crous-Bou M, Minguillón C, Gramunt N, Molinuevo JL. Alzheimer’s disease prevention: from risk factors to early intervention. Alzheimers Res Ther 9(1): 71. (2017)
[http://dx.doi.org/10.1186/s13195-017-0297-z] [PMID: 28899416]
[3]
Zhang YP, Miao R, Li Q, Wu T, Ma F. Effects of DHA supplementation on hippocampal volume and cognitive function in older adults with mild cognitive impairment: a 12-month randomized, double-blind, placebo-controlled trial. J Alzheimers Dis 55(2): 497-507. (2017)
[http://dx.doi.org/10.3233/JAD-160439] [PMID: 27716665]
[4]
Ma F, Wu T, Zhao J, Ji L, Song A, Zhang M, et al. Plasma homocysteine and serum folate and vitamin B12 levels in mild cognitive impairment and Alzheimer’s disease: a case-control study. Nutrients 9(7): 725. (2017)
[http://dx.doi.org/10.3390/nu9070725] [PMID: 28698453]
[5]
Lucock MD, Daskalakis IG, Wild J, Anderson A, Schorah CJ, Lean ME, et al. The influence of dietary folate and methionine on the metabolic disposition of endotoxic homocysteine. Biochem Mol Med 59(2): 104-11. (1996)
[http://dx.doi.org/10.1006/bmme.1996.0074] [PMID: 8986631]
[6]
Refsum H. Folate, vitamin B12 and homocysteine in relation to birth defects and pregnancy outcome. Br J Nutr 85(2): S109-13. (2001)
[http://dx.doi.org/10.1079/BJN2000302] [PMID: 11509098]
[7]
Ng TP, Feng L, Nyunt MS, Feng L, Gao Q, Lim ML, et al. Metabolic syndrome and the risk of mild cognitive impairment and progression to dementia: follow-up of the Singapore Longitudinal Ageing Study Cohort. JAMA Neurol 73(4): 456-63. (2016)
[http://dx.doi.org/10.1001/jamaneurol.2015.4899] [PMID: 26926205]
[8]
de Lau LM, Refsum H, Smith AD, Johnston C, Breteler MM. Plasma folate concentration and cognitive performance: Rotterdam Scan Study. Am J Clin Nutr 86(3): 728-34. (2007)
[http://dx.doi.org/10.1093/ajcn/86.3.728] [PMID: 17823439]
[9]
Ravaglia G, Forti P, Maioli F, Martelli M, Servadei L, Brunetti N, et al. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr 82(3): 636-43. (2005)
[http://dx.doi.org/10.1093/ajcn/82.3.636] [PMID: 16155278]
[10]
McCaddon A, Regland B, Hudson P, Davies G. Functional vitamin B(12) deficiency and Alzheimer disease. Neurology (2002); 58(9): 1395-9.
[http://dx.doi.org/10.1212/WNL.58.9.1395] [PMID: 12011287]
[11]
Bozoglu E, Isik AT, Doruk H, Kilic S. The effects of early vitamin B12 replacement therapy on the cognitive and functional status of elderly subjects. Klinik Psikofarmakoloji Bülteni-Bulletin of Clinical Psychopharmacology 20(2): 120-4. (2010)
[http://dx.doi.org/10.1080/10177833.2010.11790645]
[12]
Agrawal A, Ilango K, Singh PK, Karmakar D, Singh GP, Kumari R, et al. Age dependent levels of plasma homocysteine and cognitive performance. Behav Brain Res 283: 139-44. (2015)
[http://dx.doi.org/10.1016/j.bbr.2015.01.016] [PMID: 25601573]
[13]
Guest J, Bilgin A, Hokin B, Mori TA, Croft KD, Grant R. Novel relationships between B12, folate and markers of inflammation, oxidative stress and NAD(H) levels, systemically and in the CNS of a healthy human cohort. Nutr Neurosci 18(8): 355-64. (2015)
[http://dx.doi.org/10.1179/1476830515Y.0000000041] [PMID: 26263423]
[14]
Heppner FL, Ransohoff RM, Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci 16(6): 358-72. (2015)
[http://dx.doi.org/10.1038/nrn3880] [PMID: 25991443]
[15]
Rubio-Perez JM, Morillas-Ruiz JM. A review: inflammatory process in Alzheimer’s disease, role of cytokines. ScientificWorldJournal 2012756357 (2012)
[http://dx.doi.org/10.1100/2012/756357] [PMID: 22566778]
[16]
Holmes C, Cunningham C, Zotova E, Culliford D, Perry VH. Proinflammatory cytokines, sickness behavior, and Alzheimer disease. Neurology 77(3): 212-8. (2011)
[http://dx.doi.org/10.1212/WNL.0b013e318225ae07] [PMID: 21753171]
[17]
Berk M, Wadee AA, Kuschke RH, O’Neill-Kerr A. Acute phase proteins in major depression. J Psychosom Res 43(5): 529-34. (1997)
[http://dx.doi.org/10.1016/S0022-3999(97)00139-6] [PMID: 9394269]
[18]
Dansokho C, Aucouturier P, Dorothée G. Beneficial effect of interleukin-2-based immunomodulation in Alzheimer-like pathology. Brain 140(7)e39 (2017)
[http://dx.doi.org/10.1093/brain/awx108] [PMID: 28498909]
[19]
Zheng C, Zhou XW, Wang JZ. The dual roles of cytokines in Alzheimer’s disease: update on interleukins, TNF-α, TGF-β and IFN-γ. Transl Neurodegener 5: 7. (2016)
[http://dx.doi.org/10.1186/s40035-016-0054-4] [PMID: 27054030]
[20]
Bettcher BM, Fitch R, Wynn MJ, Lalli MA, Elofson J, Jastrzab L, et al. MCP-1 and eotaxin-1 selectively and negatively associate with memory in MCI and Alzheimer’s disease dementia phenotypes. Alzheimers Dement (Amst) 3: 91-7. (2016)
[http://dx.doi.org/10.1016/j.dadm.2016.05.004] [PMID: 27453930]
[21]
Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 256(3): 183-94. (2004)
[http://dx.doi.org/10.1111/j.1365-2796.2004.01388.x] [PMID: 15324362]
[22]
Ritchie K, Artero S, Touchon J. Classification criteria for mild cognitive impairment: a population-based validation study. Neurology 56(1): 37-42. (2001)
[http://dx.doi.org/10.1212/WNL.56.1.37] [PMID: 11148233]
[23]
Perneczky R, Pohl C, Sorg C, Hartmann J, Komossa K, Alexopoulos P, et al. Complex activities of daily living in mild cognitive impairment: conceptual and diagnostic issues. Age Ageing 35(3): 240-5. (2006)
[http://dx.doi.org/10.1093/ageing/afj054] [PMID: 16513677]
[24]
Yao-xian G. Revision of wechsler’s adult intelligence scale in china. Acta Psychol Sin 3: 18. (2002)
[25]
Durga J, van Boxtel MP, Schouten EG, Kok FJ, Jolles J, Katan MB, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet 369(9557): 208-16. (2007)
[http://dx.doi.org/10.1016/S0140-6736(07)60109-3] [PMID: 17240287]
[26]
Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C, Agacinski G, et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS One 5(9)e12244 (2010)
[http://dx.doi.org/10.1371/journal.pone.0012244] [PMID: 20838622]
[27]
Almeida OP, Marsh K, Alfonso H, Flicker L, Davis TM, Hankey GJ. B-vitamins reduce the long-term risk of depression after stroke: The VITATOPS-DEP trial. Ann Neurol 68(4): 503-10. (2010)
[http://dx.doi.org/10.1002/ana.22189] [PMID: 20976769]
[28]
Coley N, Andrieu S, Gardette V, Gillette-Guyonnet S, Sanz C, Vellas B, et al. Dementia prevention: methodological explanations for inconsistent results. Epidemiol Rev 30: 35-66. (2008)
[http://dx.doi.org/10.1093/epirev/mxn010] [PMID: 18779228]
[29]
Jia X, McNeill G, Avenell A. Does taking vitamin, mineral and fatty acid supplements prevent cognitive decline? A systematic review of randomized controlled trials. J Hum Nutr Diet 21(4): 317-36. (2008)
[http://dx.doi.org/10.1111/j.1365-277X.2008.00887.x] [PMID: 18721399]
[30]
Malouf R, Grimley Evans J. Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people. Cochrane Database Syst Rev (4): CD004514 (2008)
[http://dx.doi.org/10.1002/14651858.CD004514.pub2] [PMID: 18843658]
[31]
Raman G, Tatsioni A, Chung M, Rosenberg IH, Lau J, Lichtenstein AH, et al. Heterogeneity and lack of good quality studies limit association between folate, vitamins B-6 and B-12, and cognitive function. J Nutr 137(7): 1789-94. (2007)
[http://dx.doi.org/10.1093/jn/137.7.1789] [PMID: 17585032]
[32]
Ma F, Wu T, Zhang J, Han F, Marseglia A, Liu H, et al. Effects of six-month folic acid supplementation on cognitive function and blood biomarkers in Mild Cognitive Impairment: a randomized controlled trial in China. J Gerontol A Biol Sci Med Sc 71: 1376-83. (2016)
[33]
Morris MS, Jacques PF, Rosenberg IH, Selhub J. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr 85(1): 193-200. (2007)
[http://dx.doi.org/10.1093/ajcn/85.1.193] [PMID: 17209196]
[34]
Smith AD, Refsum H. Homocysteine, B vitamins, and cognitive impairment. Annu Rev Nutr 36: 211-39. (2016)
[http://dx.doi.org/10.1146/annurev-nutr-071715-050947] [PMID: 27431367]
[35]
Hannibal L, Blom HJ. Homocysteine and disease: causal associations or epiphenomenons? Mol Aspects Med 53: 36-42. (2017)
[http://dx.doi.org/10.1016/j.mam.2016.11.003] [PMID: 27876556]
[36]
Schaffer A, Verdoia M, Cassetti E, Marino P, Suryapranata H, De Luca G. Relationship between homocysteine and coronary artery disease. Results from a large prospective cohort study. Thromb Res 134(2): 288-93. (2014)
[http://dx.doi.org/10.1016/j.thromres.2014.05.025] [PMID: 24928335]
[37]
Ray L, Khemka VK, Behera P, Bandyopadhyay K, Pal S, Pal K, et al. Cerum homocysteine, dehydroepiandrosterone sulphate and lipoprotein (a) in alzheimer’s disease and vascular dementia. Aging Dis 4(2): 57-64. (2013)
[PMID: 23696950]
[38]
Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging 21(3): 383-421. (2000)
[http://dx.doi.org/10.1016/S0197-4580(00)00124-X] [PMID: 10858586]
[39]
Krabbe KS, Pedersen M, Bruunsgaard H. Inflammatory mediators in the elderly. Exp Gerontol 39(5): 687-99. (2004)
[http://dx.doi.org/10.1016/j.exger.2004.01.009] [PMID: 15130663]
[40]
Nicklas BJ, Brinkley TE. Exercise training as a treatment for chronic inflammation in the elderly. Exerc Sport Sci Rev 37(4): 165-70. (2009)
[PMID: 19955865]
[41]
Dalal S, Parkin SM, Homer-Vanniasinkam S, Nicolaou A. Effect of homocysteine on cytokine production by human endothelial cells and monocytes. Ann Clin Biochem 40(Pt 5): 534-41. (2003)
[http://dx.doi.org/10.1258/000456303322326452] [PMID: 14503991]
[42]
Coppola A, Astarita C, Liguori E, Fontana D, Oliviero M, Esposito K, et al. Impairment of coronary circulation by acute hyperhomocysteinaemia and reversal by antioxidant vitamins. J Intern Med 256(5): 398-405. (2004)
[http://dx.doi.org/10.1111/j.1365-2796.2004.01389.x] [PMID: 15485475]
[43]
Herrmann W, Quast S, Schultze H, Ullrich M, Geisel J. The importance of hyperhomocysteinemia in high age people. Atherosclerosis 134: 1005-9. (1997)
[http://dx.doi.org/10.1016/S0021-9150(97)88909-5]
[44]
Refsum H, Smith AD, Ueland PM, Nexo E, Clarke R, McPartlin J, et al. Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem 50(1): 3-32. (2004)
[http://dx.doi.org/10.1373/clinchem.2003.021634] [PMID: 14709635]


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Article Details

VOLUME: 16
ISSUE: 7
Year: 2019
Page: [622 - 632]
Pages: 11
DOI: 10.2174/1567205016666190725144629
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