Vitamin D deficiency is associated with reduced hippocampal volume and disrupted structural connectivity in patients with mild cognitive impairment

Abstract

Vitamin D deficiency may exacerbate adverse neurocognitive outcomes in the progression of diseases such as Parkinson's, Alzheimer's, and other dementias. Mild cognitive impairment (MCI) is prodromal for these neurocognitive disorders and neuroimaging studies suggest that, in the elderly, this cognitive impairment is associated with a reduction in hippocampal volume and white matter structural integrity. To test whether vitamin D is associated with neuroanatomical correlates of MCI, we analyzed an existing structural and diffusion MRI dataset of elderly patients with MCI. Based on serum 25-OHD levels, patients were categorized into serum 25-OHD deficient (<12 ng/mL, n = 27) or not-deficient (>12 ng/mL, n = 29). Freesurfer 6.0 was used to parcellate the whole brain into 164 structures and segment the hippocampal subfields. Whole-brain structural connectomes were generated using probabilistic tractography with MRtrix. The network-based statistic (NBS) was used to identify subnetworks of connections that significantly differed between the groups. We found a significant reduction in total hippocampal volume in the serum 25-OHD deficient group especially in the CA1, molecular layer, dentate gyrus, and fimbria. We observed a connection deficit in 13 regions with the right hippocampus at the center of the disrupted network. Our results demonstrate that low vitamin D is associated with reduced volumes of hippocampal subfields and connection deficits in elderly people with MCI, which may exacerbate neurocognitive outcomes. Longitudinal studies are now required to determine if vitamin D can serve as a biomarker for Alzheimer's disease and if intervention can prevent the progression from MCI to major cognitive disorders.

Keywords: MRI; cognition; older adults; vitamin D.

Figure 1

Histogram showing the frequency of serum 25‐OHD level of the participants (N = 56). Mean serum 25‐OHD level was 15.41 ng/mL. The participants were divided into two groups (dotted line): deficient 25‐OHD (n = 27) and not‐deficient 25‐OHD (n = 29) based on Institute of Medicine specifications (Ross et al., 2011)

Figure 2

Hippocampal subfield segmentation using Freesurfer v 6.0 overlaid on a structural MRI scan to provide anatomical context. Three sections are shown: sagittal view of the left hippocampus (top left), coronal view of the both hippocampi (top right), and axial view of both hippocampi (bottom left). Each subfield is colored distinctly (bottom right). CA, Cornu Ammonis; GC‐DG, granular cell layer within the dentate gyrus; HATA, hippocampus–amygdaloid transition area [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 3

Processing pipeline of probabilistic tractography and connectome preparation. DWI, diffusion‐weighted image; GM, grey matter; SIFT, spherical‐deconvolution informed filtering of tractograms; WM, white matter [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 4

Serum vitamin D (25‐OHD) levels (N = 56) and hippocampal subfield volumes (N = 54) in deficient and not‐deficient serum 25‐OHD groups. Significant differences between deficient and not‐deficient groups were found for levels of 25‐OHD (a) MMSE score (b), and total hippocampal volume (c), with no effect of laterality (d) or brain/head size (e). Hippocampal subfield volume analysis revealed a significant difference in the CA1 region, the molecular layer, the dentate gyrus, and the fimbria (f). Smaller volumes in the subiculum, CA3 and CA4 did not reach significance. CA, Cornu Ammonis; GC‐DG, granular cell layer within the dentate gyrus; HATA, hippocampus–amygdaloid transition area. ^* p < .05; ^*** p < .001; ^# p < .06. Data present as mean ± SEM (standard error of mean). Family‐wise error rate (FWER) corrected. MRI data are missing for two patients in the deficient group

Figure 5

Disrupted intra‐ and interhemispheric connectivity in serum deficient 25‐OHD MCI patients (n = 25). This disrupted network was found at threshold t = 3.5. (a) Axial view. (b) Coronal view. (c) Sagittal view. The figure made using BrainNet Viewer (Xia, Wang, & He, 2013). In total, 13 nodes and 12 edges were disrupted in the brains of MCI patients with vitamin D deficiency. The 3D view of this disrupted network is available in Supporting Information, Video S2 [Color figure can be viewed at http://wileyonlinelibrary.com]