Folate and vitamin B₁₂-related biomarkers in relation to brain volumes

Aim: We investigated cross-sectional associations between circulating homocysteine, folate, biomarkers of vitamin B₁₂ status and brain volumes. We furthermore compared brain volumes of articipants who received daily folic acid and vitamin B₁₂ supplementation with participants who did not. Methods: Participants of the B-PROOF study (n = 2919) were assigned to 400 μg folic acid and 500 μg vitamin B₁₂, or a placebo. After two years of intervention, T₁-weighted magnetic resonance imaging (MRI) scans were made in a random subsample (n = 218) to obtain grey and white matter volume, and total brain volume (TBV). Plasma homocysteine, serum folate, vitamin B₁₂, holotranscobalamin, and methylmalonic acid concentrations were measured. Results: Multiple linear regression analyses showed inverse associations between plasma homocysteine with TBV (β = -0.91, 95% CI-1.85-0.03, p = 0.06) and between serum folate and TBV (β = -0.20, 95% CI -0.38, -0.02, p = 0.03). No significant associations were observed for serum vitamin B₁₂ and holotranscobalamin. Fully adjusted ANCOVA models showed that the group that received B-vitamins had a lower TBV (adjusted mean 1064, 95% CI 1058-1069 mL) than the non-supplemented group (1072, 95% CI 1067-1078 mL, p = 0.03). Conclusions: Results were contradictory, with higher Hcy levels associated with lower TBV, but also with higher folate levels associated with lower TBV. In addition, the lack of a baseline measurement withholds us from giving recommendations on whether folic acid and vitamin B₁₂ supplementation will be beneficial above and beyond normal dietary intake for brain health.