This report describes the associations of serum vitamin B12 and vitamin B12–related metabolites to cognitive performance at cycle 2 and to MRI measurements on average 4.6 years later. Associations are observed for concentrations of vitamin B12 and related markers that are considered reflective of adequate vitamin status.
The finding of associations between several of the vitamin B12 markers and global cognitive scores is consistent with our previous report of 516 CHAP subjects7
as well as that of others,21–25
but not all.26
Associations between brain MRI measures (in particular, TBV and WMHV) and global cognition as well as performance in multiple domains have been reported previously by our group, but not in relation to vitamin B12 status.1
In the present report, we did not observe associations between the vitamin B12 markers and cerebral infarcts. This observation is in contrast to reports by other groups who have described a greater number of infarcts and more WMH burden with higher homocysteine concentrations.27–29
Absence of an association in our study may be due to the few subjects. The observation of effect modification by APOE
4 on the association of cystathionine and TBV is consistent with evidence that the genotype and low B vitamin status confers greater vulnerability to cognitive deficits.30
In the present study, the potential mediation of MRI measures on the relation of vitamin B12– related markers to cognition has been investigated. Serum homocysteine levels were associated with cognitive performance which was independent of TBV. Others have noted a relationship between homocysteine and cognition31,32
but not simultaneously with brain MRI measures. In a British cohort where mandatory folate fortification is in place, a comprehensive set of vitamin B12 markers were examined in association with brain atrophy over 5 years in 107 older adults. After adjustment for confounders, neither homocysteine nor MMA was predictive of brain atrophy, though vitamin B12 and its carrier, holotranscobalamin, were.6
In the VITACOG trial, treatment with a supplement containing vitamin B6, vitamin B12, and folate for 2 years reduced homocysteine levels and slowed brain atrophy in British adults with mild cognitive impairment, but concomitant changes in cognitive scores were not reported.33
Associations between several vitamin B12 indicators and white matter lesions and with cognitive function were reported in the Rotterdam Scan Study but potential mediation effects were not examined.26
Our data suggest that both vascular and nonvascular mechanisms play a role in vitamin B12 status. The vascular mechanism is consistent with the attenuation of the relation between homocysteine and cognitive performance when cerebral infarcts were entered in the model. For the nonvascular contribution, small differences in vitamin B12 markers may alter the integrity of white matter, specifically by modifying the extent of myelin damage. Areas of demyelination on brain MRI have been described in vitamin B12–deficient patients or in those with diseases that affect vitamin B12 metabolism.33–35
Thus, our findings lend support for the contention that poor vitamin B12 status is a risk factor for brain atrophy and possibly WMHV which in turn may contribute to cognitive impairment. The single MRI measure in the present study prevents direct investigation of whether poor vitamin B12 status results in cognitive decline by promoting faster rates of total brain atrophy or demyelination in selected white matter areas. On the basis of repeated MRI scans, brain atrophy associated with cognitive decline appears to be a slow process; brain atrophy rates among adults aged 70 years or more ranged from 0.7% to 1.1% per year.6,33
A distinct contribution made by our group is a comprehensive study of the metabolic indicators of vitamin B12 status and the possible role it has on both cognitive performance and brain measures. Both homocysteine and MMA accumulate when insufficient vitamin B12 is available as a cofactor for 2 separate reactions; cystathionine and 2-methylcitric acid also accumulate.11,12
Folate and vitamin B6 status may also contribute to elevated cystathionine and 2-methylcitric acid, however. Only MMA accumulates specifically in response to low vitamin B12 status. A limitation to this study is the absence of serum folate and vitamin B6 determinations. Strengths of this study include a sensitive imaging method to assess WMHV and TBV at the same MRI facility, a well-characterized biracial cohort of older adults, and use of validated measures of cognitive function.
Marginal vitamin B12 status in older age36
is frequently missed by measurement of serum vitamin B12 levels alone. Our findings suggest that MMA, the specific marker of B12 deficiency, may affect cognition by reducing TBV whereas the effect of homocysteine on cognition may be mediated through increased WMHV and cerebral infarcts. Vitamin B12 status as reflected by functional markers such as homocysteine and MMA concentrations and the relations to brain changes on MRI and cognitive testing deserves further examination.