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EDITORIAL |
1 From the Deptartment of Medical Pathology and Laboratory Medicine, University of California, Davis, CA
2 Address correspondence to JW Miller, UC Davis Medical Center, Research 3, Room 3200A, 4645 Second Avenue, Sacramento, CA 95817. E-mail: jwmiller{at}ucdavis.edu.
See corresponding article on page 1406.
It is well established that the clinical manifestations of overt, severe vitamin B-12 deficiency include both hematologic (macrocytic or megaloblastic anemia) and neurologic (subacute combined degeneration of the spinal cord, peripheral neuropathy, cognitive impairment) sequelae. The neurologic consequences are of particular concern, because they can occur in the absence of hematologic symptoms (1) and can become permanent if vitamin B-12 replacement therapy is not initiated within a year of the onset of symptoms (2, 3). It therefore is incumbent on clinicians to recognize vitamin B-12 deficiency at an early stage, before the neurologic health of a person is irreversibly affected.
The most common screening test for vitamin B-12 deficiency is the measurement of total plasma or serum vitamin B-12. Although cutoffs vary among assays and laboratories, a total vitamin B-12 concentration <148 pmol/L (<200 pg/mL) is commonly considered indicative of vitamin B-12 deficiency. However, measurement of total vitamin B-12 does have limitations in that individuals may present with vitamin B-12–responsive metabolic or neurologic abnormalities despite having a total vitamin B-12 concentration within the normal range (>148 pmol/L) (1, 4, 5). The limited usefulness of total vitamin B-12 is also indicated by population-based cohort studies of the associations between vitamin B-12 status and cognitive function in older adults, in whom both vitamin B-12 deficiency and cognitive impairment are of significant concern. Whereas some studies have shown direct associations between total vitamin B-12 and cognitive function test scores (6), other studies have found no significant correlations, either cross-sectionally or prospectively (7). To make matters more confusing, studies have found inverse associations between total vitamin B-12 and cognitive function scores (8, 9). Taken together, these findings suggest that total vitamin B-12 may not be the best screening measure for vitamin B-12 status, at least with respect to cognitive function in the elderly.
Alternatives to total vitamin B-12 in screening for vitamin B-12 deficiency include holotranscobalamin (holoTC; the amount of total vitamin B-12 in serum bound to the transport protein transcobalamin) and methylmalonic acid and homocysteine, 2 metabolites that become elevated in the blood in vitamin B-12 deficiency. Of these 3, homocysteine has received the most attention and has been associated in many studies with poor cognitive function and increased risk of dementia (10, 11). Elevated homocysteine is not specific to vitamin B-12 deficiency, however. It becomes elevated in various conditions, including folate and vitamin B-6 deficiencies, renal insufficiency, and hypothyroidism. Thus, homocysteine is not a particularly useful indicator of vitamin B-12 status in and of itself. Methylmalonic acid and holoTC are considered more specific measures of vitamin B-12 status than is homocysteine, but there have been only a handful of studies that have assessed the associations between these analytes and cognitive function in older adults. One of these studies appears in this issue of the Journal.
McCracken et al (12) measured total vitamin B-12, holoTC, and methylmalonic acid concentrations in 84 nondemented elderly subjects (42 men and 42 women aged 69–93 y) living in North Wales. Homocysteine was not measured. Cognitive function was assessed by using the Mini-Mental State Examination (MMSE) and the Cognitive Section of the Cambridge Mental Disorders of the Elderly Examination (CAMCOG). Regardless of the measurement applied, low vitamin B-12 status was highly prevalent in this cohort: the median total vitamin B-12 concentration was 146 pmol/L, with 20% of the subjects having very low total vitamin B-12 values (<96 pmol/L); 26% had low holoTC concentrations (<37 pmol/L), and 43% had elevated methylmalonic acid concentrations (>0.42 µmol/L), which is suggestive of metabolically significant vitamin B-12 deficiency. Of the 3 analytes, only methylmalonic acid was correlated with cognitive function scores. Methylmalonic acid was inversely associated with total MMSE score, as well as with several cognitive domains evaluated with the CAMCOG assessment, including language comprehension, language expression, ideational praxis, and total praxis. These results suggest that methylmalonic acid better reflects vitamin B-12 status and is a better predictor of cognitive function in older adults than is total vitamin B-12 or holoTC. This provides support for increased use of methylmalonic acid in screening for vitamin B-12 deficiency in older adults.
This conclusion, however, is not completely supported by the literature. The few studies that have measured associations between methylmalonic acid and cognitive function have not been consistent. As reviewed by McCracken et al (12), some have found elevated methylmalonic acid concentrations in dementia patients, whereas others have not, and some have found significant correlations between methylmalonic acid and cognitive function scores, whereas others have not. Thus, as for total vitamin B-12, methylmalonic acid may have limited utility as a screening test for vitamin B-12 deficiency and associated cognitive deficits in older adults.
The reasons for inconsistent findings relating vitamin B-12 status measures to cognitive function are difficult to discern. One possibility is that no single analyte is sufficient to provide a definitive determination of vitamin B-12 status. This may be due to a variety of factors, including imprecision of the assays used to measure each analyte and confounding conditions that affect analyte concentrations independent of vitamin B-12 status. An important example of the latter is renal insufficiency, which can affect serum concentrations of all 4 of the analyte indicators of vitamin B-12 status cited above. With this in mind, several investigators have proposed screening strategies for vitamin B-12 deficiency that use combinations of analytes. The use of these strategies allows persons to be classified as vitamin B-12 deficient only if they have 
2 analytes outside the reference ranges, such as low concentrations of total vitamin B-12 or holoTC and elevated concentrations of methylmalonic acid or homocysteine (13, 14) or low concentrations of both total vitamin B-12 and holoTC (15). These strategies hold promise for improved capacity to distinguish persons who are at risk of vitamin B-12 deficiency from those who are not at risk. The challenge now for investigators is to use these multiple analyte strategies in cohort studies to determine whether they improve the ability to predict cognitive deficits in older adults. Perhaps this can be accomplished by using existing data from studies such as that of McCracken et al (12) or by incorporating multiple analyte strategies for assessing vitamin B-12 status into the design of future studies.
ACKNOWLEDGMENTS
The author reports no conflict of interest with respect to this editorial.
REFERENCES
T mutation correlate with cognitive performance. Neurobiol Aging 2006;27:334–43.[Medline]Related articles in AJCN:
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