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Posted by on Sep 9, 2008 in Neurology, Neuropsychiatry

Low-Normal B12 Associated With Brain Atrophy

Low-Normal B12 Associated With Brain Atrophy

Vitamin B12 deficiency (typically defined as a serum level <150 pmol/L, but usually much lower) is a well-documented cause of nervous system injury, traditionally in the form of subacute combined degeneration. Whether low-normal serum levels of B12 pose a risk for milder forms of CNS dysfunction, like cognitive impairment, is less clear.

In this week’s Neurology, physicians from the Oxford Project to Investigate Memory and Aging (OPTIMA) report a statistical association between low-normal B12 levels (ie, <308 pmol/L) and brain atrophy in 107 elderly, cognitively intact,* community-dwelling volunteers during a 5-year period.

By using annual, serial MRI studies, investigators assessed the potential associations between brain atrophy (the percentage of whole brain-volume loss per year) and known markers of vitamin B12 status: plasma B12, transcobalamin (TC), holotranscolbalamin (holoTC), methymalonic acid (MMA), and total homocysteine (tHcy). The mean B12 level at baseline was 363 pmol/L, and no subject had a B12 level below 150. Approximately 6% of subjects were receiving oral or injectable B12 supplementation. It is important to note that associations between B12 markers and cognitive function were not examined in this study.

After adjustment for a number of factors (age, sex, creatinine, education, initial brain volume, etc), reduced brain volume was significantly more likely in those subjects with lower B12 and holoTC levels at baseline. Also subjects with B12, holoTC, or TC saturation levels in the bottom third were significantly more likely to demonstrate brain atrophy (but note that confidence intervals for odds ratios were very wide; see Table). While MMA and tHcy are believed to be more sensitive indicators of B12 deficiency, high levels of these metabolites were not associated with loss of brain volume in this study.

B12 Variable

OR, Adjusted (95% CI)

P Value

B12, pmol/L




1.00 (ref)



4.39 (1.01, 19.03)



6.17 (1.25, 30.47)


HoloTC, pmol/L




1.00 (ref)



2.63 (0.63, 10.92)



5.99 (1.21, 29.81)


TC saturation, %




1.00 (ref)



6.64 (1.31, 33.73)



6.63 (1.22, 36.05)


The authors appropriately caution that their findings must be confirmed by larger studies in different populations, and that cognitive impairment is yet to be correlated with B12-associated brain atrophy. Also the utility of early B12 supplementation to prevent observed brain loss merits study.  

* Cambridge Cognitive Assessment (CAMCOG) score >80; Mini-Mental State Examination (MMSE) score >24.

bmartin (1130 Posts)

A native East Tennessean, Barbara Martin is a formerly practicing, board-certified neurologist who received her BS (psychology, summa cum laude) and MD from Duke University before completing her postgraduate training (internship, residency, fellowship) at the Hospital of the University of Pennsylvania in Philadelphia. She has worked in academia, private practice, medical publishing, drug market research, and continuing medical education (CME). For the last 3 years, she has worked in a freelance capacity as a medical writer, analyst, and consultant. Follow Dr. Barbara Martin on and Twitter.