Vitamin B12 Status Linked to Cognitive Decline and MRI Changes

S. Andrew Josephson, MD


AccessMedicine from McGraw-Hill 

Guidelines suggest serum B12 measurement in patients with suspected dementia in order to screen for severe B12 deficiency as a potentially treatable cause of cognitive decline. There remains a concern that some individuals with more modestly low levels of B12 may also experience cognitive decline that may be made clinically worse by high levels of serum folate, a more common occurrence in the United States since the introduction of mandatory folic acid grain supplementation. A recent study (Tangney et al., 2011) aimed to examine the relationship between cognitive decline, MRI changes, and levels of B12 and other biochemical markers of B12 deficiency, namely serum homocysteine and methylmalonic acid (MMA).

Participants in the study were part of the Chicago Health and Aging Project, a longitudinal cohort study of 6158 persons. At baseline, all patients received in-home interviews that included cognitive testing repeated in 3-year cycles. Stratified random sampling of patients at each cycle triggered both a clinical neurologic evaluation and phlebotomy. The present study includes 121 of these randomly selected patients who underwent cognitive testing followed by brain MRI on average 4.6 years later. The average age of the patients included was 79 years, and 51% were women. Of the group, 17.5% demonstrated elevated serum homocysteine values (>14 µmol/L) and 15.2% had elevated MMA (>271 nmol/L).

The authors found that both homocysteine and MMA were significantly associated with poorer cognitive testing across multiple domains; B12 levels demonstrated no such association. For each 1-µmol/L increase in homocysteine, for example, the global cognitive score decreased by 0.03 standardized units (p = .04). Examination of MRI measures demonstrated that serum homocysteine concentration was significantly associated with an increased volume of white matter hyperintensities even after adjustment for age, sex, race, education, dementia, and APOE4 status. Higher levels of homocysteine and MMA were each significantly associated with decreased total brain volume (a measure of atrophy) even after adjustment. Interestingly, the association of homocysteine with cognitive function was no longer significant after adjustment for white matter volume or cerebral infarcts, and the association of MMA with cognitive function was no longer significant after adjustment for total brain volume.

This study is not the first to examine these relationships, but it does paint a tantalizing picture that modest amounts of B12 deficiency, as noted by elevation of MMA and homocysteine, may either lead to or speed the rate of cognitive decline in elderly patient populations. The model that emerges is that elevated MMA (a more specific marker for B12 deficiency) may affect cognition through reduction in total brain volume, and homocysteine (which can also be elevated in folate deficiency and other conditions) may mediate effects on cognition through increased white matter hyperintensities and cerebral infarcts. For the clinician, it is reasonable to encourage adequate B12 intake among the elderly, but future studies are needed to determine whether B12 levels should be measured routinely (perhaps via serum MMA or homocysteine levels) in patients without cognitive decline and then supplementation initiated in hopes of preventing decline.