Vitamin D, Folate, and Cobalamin Serum Concentrations Are Related to Brain Volume and White Matter Integrity in Urban Adults

Abstract

Background and objectives: Lower vitamin status has been linked to cognitive deficits, pending mechanistic elucidation. Serum 25-hydroxyvitamin D [25(OH)D], folate and cobalamin were explored against brain volumes and white matter integrity (WMI). Methods: Three prospective waves from Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) study were used [Baltimore, City, MD, 2004-2015, N = 183-240 urban adults (Age_v1: 30-64 years)]. Serum vitamin 25-hydroxyvitamin D [25(OH)D], folate and cobalamin concentrations were measured at visits 1 (v₁: 2004-2009) and 2 (v₂: 2009-2013), while structural and diffusion Magnetic Resonance Imaging (sMRI/dMRI) outcomes were measured at v_scan: 2011-2015. Top 10 ranked adjusted associations were corrected for multiple testing using familywise Bonferroni (FWER <0.05) and false discovery rates (FDR, q-value < 0.10). Results: We found statistically significant (FWER < 0.05; β±SE) direct associations of 25(OH)D(v₁) with WM volumes [overall: +910 ± 336/males: +2,054 ± 599], occipital WM; [overall: +140 ± 40, males: +261 ± 67 and Age_v1 > 50 years: +205 ± 54]; parietal WM; [overall: +251 ± 77, males: +486 ± 129 and Age_v1 > 50 years: +393 ± 108] and left occipital pole volume [overall: +15.70 ± 3.83 and above poverty: 19.0 ± 4.3], findings replicated for 25(OH)D (v₂-v₁) annualized exposure, which was also linked with greater WMI (fractional anisotropy, FA) in the anterior limb of the internal capsule (ALIC); FWER < 0.05 [Overall: +0.0020 ± 0.0004; Whites: +0.0024 ± 0.0004] and in the cingulum (hippocampus) [Overall: +0.0016 ± 0.0004]. Only trends were detected for cobalamin exposures (q < 0.10), while serum folate (v₁) was associated with lower mean diffusivity (MD) in ALIC, reflecting greater WMI, overall. Conclusions: Among urban adults, serum 25(OH)D status and increase were consistently linked to larger occipital and parietal WM volumes and greater region-specific WMI. Pending longitudinal replication of our findings, randomized controlled trials of vitamin D supplementation should be conducted against brain marker outcomes.

Keywords: 25-hydroxyvitamin D; brain volumes; cobalamin; cognitive aging; folate; health disparities; white matter integrity.

Figure 1

Study participant schematic: HANDLS 2004–2013 and HANDLS-SCAN 2011–2015^a. 25(OH)D, 25-hydroxyvitamin D; B-12, Vitamin B-12 (cobalamin); dMRI, Diffusion magnetic resonance imaging; HANDLS, Healthy Aging in Neighborhoods of Diversity Across the Life Span; k, average number of repeats; sMRI, Structural/volumetric magnetic resonance imaging. ^aVisit 1 refers to HANDLS 2004–2009; Visit 2 refers to HANDLS 2009–2013; and HANDLS-SCAN visit (v_scan) was carried out between 2011 and 2015.

Figure 2

ROI-wide brain dMRI association with v₁ serum 25(OH)D, folate and cobalamin in total population: volcano plots and brain image visualization for HANDLS 2004–2009 and HANDLS-SCAN 2011–2015^a,b. ^aVolcano plots display Log₁₀(p-values) for each set of models against the standardized effect (b) on the X-axis, highlighting findings with larger effect sizes. Associations with P < 0.05 are presented in red, whereas those with both P < 0.05 and effect size in absolute value >0.20 are presented in green. ^bBrain visualization using FSLeyes program is focused on standardized effect sizes (b) and direction, with negative effects (b < 0) shown in cold colors and positive effects (b > 0) shown in warmer colors. The range is between −0.3 and +0.3 with lighter colors indicating stronger effects in either direction. Only ROIs with uncorrected p-value < 0.05 are presented.