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The fraction of total plasma vitamin B^sub 12^ bound to transcobalamin (holoTC/B12 ratio) may reflect tissue levels of the vitamin, but its clinical relevance is unclear. We assessed associations between cognitive function and total B12, holoTC, and holoTC/B12 ratio in a cohort of elderly Latinos (n = 1089, age 60-101 years). We assessed cognitive function using the Modified Mini-Mental State Examination (3MSE) and a delayed recall test; we diagnosed clinical cognitive impairment by neuropsychological and clinical exam with expert adjudication; and we assessed depressive symptoms using the Center for Epidemiological Studies Depression Scale (CES-D). We measured total B12 and holoTC using radioassays. HoloTC/B12 ratio was directly associated with 3MSE score (P = 0.026) but not delayed recall score. Interactions between holoTC/B12 and CES-D score were observed for 3MSE (P = 0.026) and delayed recall scores (P = 0.013) such that associations between the ratio and cognitive function scores were confined to individuals with CES-D ≥16. For individuals with CES-D ≥16, the odds ratio for clinical cognitive impairment for the lowest holoTC/B12 tertile was 3.6 (95% CI 1.2-11.2) compared with the highest tertile (P = 0.03). We observed no associations between cognitive function and total B12 or holoTC alone, except between holoTC and 3MSE score (P = 0.021), and no interactions between holoTC or total B12 and CES-D score on cognitive function. HoloTC/B12 ratio is associated with cognitive function in elderly Latinos with depressive symptoms and may better reflect the adequacy of B12 for nervous system function than either holoTC or total B12 alone.

Discussion

In this elderly Latino population, a low ratio of holoTC to total B12 was associated with low 3MSE and low delayed recall scores and an increased odds ratio for clinical cognitive impairment (diagnosis of dementia or CIND) among those who also had increased depressive symptom scores. In contrast, neither holoTC nor total B12, when considered separately, were significantly associated with global cognitive function or clinical cognitive impairment regardless of depressive symptom score. These results suggest that the proportion of total B12 on TC may better reflect B12 status in the brain than either holoTC or total B12 alone, one possible interpretation of these findings is that a low holoTC/B12 ratio is indicative of suboptimal supply of B12 to the brain, which results in a global effect characterized by both depressive symptoms and cognitive impairment. However, because this is a cross-sectional study, it is not possible to draw any conclusions about cause and effect, and the possibility of reverse causation cannot be dismissed.

Clinically, vitamin B12 deficiency is known to affect the nervous system, resulting in peripheral neuropathy, gait ataxia, depression, cognitive impairment, and dementia (2, 3). Although low plasma B12 status has been associated with cognitive impairment and dementia in case-control studies (29, 30), both crosssectional and prospective cohort studies have shown mixed associations of plasma B12 concentration with specific measures of cognitive function. In a crosssectional assessment of 1000 free-living adults age 75 years and older, low serum B12 concentrations (≤133 pmol/L) were associated with a 2- to 4-fold increased risk of cognitive impairment as indicated by low MiniMental State Examination (MMSE) scores (31). In contrast, no correlation between serum B12 concentrations and cognitive performance was observed on several tests including the MMSE in cross-sectional (n = 559) analyses of participants of the Leiden 85-Plus Study (32). In addition, in a subsample of this same cohort (n = 341), serum B12 levels did not predict cognitive decline longitudinally (32). To further complicate the issue, in some studies, high rather than low plasma B12 concentrations were associated with poor cognitive function. One study, using cross-sectional data from 818 individuals 50-70 years old, found plasma B12 concentrations to be inversely associated with specific functions of memory and sensorimotor speed (33). However, this study excluded individuals with B12 deficiency, which may explain, in part, the inverse associations observed. In a case-control study of 30 primary Alzheimer-type dementia patients, a significant association was observed between declining Cambridge Cognitive Examination scores and increasing total serum B12 concentrations (34). The authors suggested that these paradoxical findings might be explained by the fact that total B12 consists of B12 bound in serum to both haptocorrin and TC, implying that an increased total B12 may be due to an increase in haptocorrin and therefore not all the B12 would be available to extrahepatic tissues.

One possible explanation for the disparate findings among epidemiological studies is that depressive symptoms generally have not been taken into consideration as a potential effect modifier of the association between B12 and cognitive function. Though limited, there is evidence that the associations between plasma vitamin B12 and cognitive function test scores are stronger in depressive patients than in nondepressive patients (35). This is consistent with the present study in which the significant association between holoTC/ B12 and cognitive function was confined to those participants with depressive symptoms. Thus, we hypothesize that patients exhibiting concurrently depressive symptoms and cognitive impairment may be those most likely to respond to B12 supplementation, particularly if the holoTC/B12 ratio is low. However, it cannot be ruled out that cognitive impairment causes both depressive symptoms and reduced holoTC/B12 ratio by unrecognized pathophysiological mechanisms or by behavioral modifications affecting dietary intake of B12.

The disparate findings among epidemiological studies may also be explained by variations in sensitivity and accuracy of assessments used to determine the degree of cognitive function in individuals, or by difficulties in accurately assessing B12 status. Typically, B12 status is assessed using a single measurement of total plasma OT serum B12. However, the use of only 1 measure to establish a deficient or suboptimal state allows for potential misclassification. Other assays used in conjunction with total B12, such as methylmalonic acid, homocysteine, and holoTC, may allow for better discrimination of B12 status than total B12 alone (11, 14, 36, 37), but inherent limitations in these assays may still lead to misclassification of B12 status. It remains to be seen if various combinations of metabolic assays, using consistent cutoff values, will further improve the ability to detect an association between B12 status and cognitive function in epidemiological studies.

In this study, we have introduced the concept of combining holoTC and total B12 measurements in a ratio. We propose that this ratio may provide a better reflection of cellular delivery and tissue B12 status, at least for the brain, than any of the current measures used, including holoTC and total B12 alone. The use of holoTC in a ratio to assess B12 status has been reported, but usually in the context of the percentage of total TC that has bound B12 or percent TC saturation (a calculated value that is distinct from the holoTC/ B12 ratio). Percent TC saturation, in combination with holoTC, has been suggested as a better measure of change in B12 status than holoTC alone (W, Ð, 38). Whereas this information may be useful in diagnosing malabsorption, holoTC/B12 may better reflect the availability of circulating B12 to tissues, and therefore intracellular B12 status. The use of TC saturation as a measure of B12 status may be analogous to what has been reported for circulating iron in which the ratio of serum iron to total iron binding capacity (transferrin saturation) provides informative evidence of tissue iron supply (39). However, because there are 2 distinct plasma B12 transport proteins, TC and haptocorrin, a measure of the distribution of total B12 between these proteins, i.e., the holoTC/B12 ratio, may better reflect the functional efficiency of B12 delivery to extrahepatic tissues than does TC saturation. Moreover, there is some evidence to suggest that plasma concentrations of TC (but not holoTC) rise as an acute phase reactant in association with infection or inflammatory disease (40). The usefulness of TC saturation might therefore be compromised in individuals with inflammatory conditions.