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Providing perspectives on recent research into vitamins and nutritionals


Vitamin B12, the Microstructure of the Hippocampus, and Learning in Older Women

By Julia Bird

Vitamin B12 is required for the proper functioning of the brain. There are various ways in which an adequate vitamin B12 status supports neurological function. Vitamin B12 is required for the synthesis of DNA building blocks, and the integrity of DNA, and has epigenetic effects on DNA methylation in the brain (see Feng and Fan, and review paper from Reynolds). In addition, levels of homocysteine rise when functional vitamin B12 deficiency is present, which may damage neurons. Clinical vitamin B12 deficiency causes neurological symptoms: fatigue, numbness and tingling in the hands and feet, confusion and poor memory. However, there is a lack of consensus about the best biomarker and cut-off point to use to define deficiency (Bailey et al.).

Some people have low vitamin B12 levels yet the functional marker of vitamin B12 deficiency (methylmalonic acid: MMA) is normal, while others have a normal vitamin B12 level yet show signs of a functional vitamin B12 deficit with elevated MMA. These anomalies may arise from differences between individuals such as genetics or hormones changing the way that vitamin B12 is metabolized, or interactions between other vitamin, in particular folate. Sometimes, neurological complaints are present despite no obvious changes in blood parameters, as described by Lindenbaum and colleagues. As vitamin B12 is needed for many different processes in the body, it is also likely that various symptoms gradually develop as vitamin B12 concentrations decline. The study group lead by Köbe described a study to determine the effect of low-normal (≥150 and <300 pmol/L) and high normal (≥300 pmol/L) vitamin B12 concentrations on cognitive performance and the microstructure of the hippocampus, in other words the connectivity between brain cells, and the integrity of various cell types in the part of the brain associated with forming new memories.

The authors used data available from 100 women aged 50 to 80 with mild cognitive impairment that included problems with memory, who were attending a memory clinic. The participants’ vitamin B12 status (including vitamin B12, MMA, homocysteine, folate and creatinine) was determined, subjects underwent cognitive testing, and magnetic resonance imaging was used to estimate the volume and microstructure of the hippocampus in the brain. The women were divided into two approximately equal groups for the low- and high-normal vitamin B12 levels.

The authors found some evidence of functional deficiency in the low-normal group: their holotranscobalamin levels were lower, and their homocysteine and MMA levels were higher than the high-normal group, although the low-normal group also had a poorer folate status. The cognitive testing consisted of testing participants’ ability to learn and remember words. People with low-normal vitamin B12 levels were able to learn 5 out of 75 fewer words, remember 1 out of 15 fewer words, and recognize 3 out of 15 fewer words than the group with high-normal levels, and this was a statistically significant difference for the learning and recognition tasks. The difference remained after adjustment for sex, age, education and other potential modifiers. Although there was no difference in the volume of the hippocampus, the microstructure of the hippocampus was worse in the low-normal group. Further analyses showed that the poorer hippocampus integrity was responsible for the performance difference between the two groups. While this study was cross-sectional, its results could be used to design a clinical trial to test whether supplementation of older adults with low-normal vitamin B12 levels can improve the structure of the hippocampus and improve memory.

Main citation:

Theresa Köbe, A Veronica Witte, Ariane Schnelle, Ulrike Grittner, Valentina A Tesky, Johannes Pantel, Jan Philipp Schuchardt, Andreas Hahn, Jens Bohlken, Dan Rujescu, and Agnes Flöel. Vitamin B-12 concentration, memory performance, and hippocampal structure in patients with mild cognitive impairment. Am J Clin Nutr ajcn116970; First published online February 24, 2016. doi:10.3945/ajcn.115.116970.

Supporting citations:

Bailey RL, Carmel R, Green R, Pfeiffer CM, Cogswell ME, Osterloh JD, Sempos CT, Yetley EA. Monitoring of vitamin B-12 nutritional status in the United States by using plasma methylmalonic acid and serum vitamin B-12. Am J Clin Nutr. 2011 Aug;94(2):552-61. doi: 10.3945/ajcn.111.015222. Epub 2011 Jun 15.

Jian Feng, Guoping Fan. Chapter 4 – The Role of DNA Methylation in the Central Nervous System and Neuropsychiatric Disorders. In: International Review of Neurobiology. Volume 89, 2009, Pages 67–84. Novel Approaches to Studying Basal Ganglia and Related Neuropsychiatric Disorders.

Edward Reynolds, Vitamin B12, folic acid, and the nervous system, The Lancet Neurology, Volume 5, Issue 11, November 2006, Pages 949-960, ISSN 1474-4422,