Systemic inflammation in non-demented elderly human subjects: brain microstructure and cognition

Abstract

The purpose of this study was to test the hypothesis that higher levels of systemic inflammation in a community sample of non-demented subjects older than seventy years of age are associated with reduced diffusion anisotropy in brain white matter and lower cognition. Ninety-five older persons without dementia underwent detailed clinical and cognitive evaluation and magnetic resonance imaging, including diffusion tensor imaging. Systemic inflammation was assessed with a composite measure of commonly used circulating inflammatory markers (C-reactive protein and tumor necrosis factor-alpha). Tract-based spatial statistics analyses demonstrated that diffusion anisotropy in the body and isthmus of the corpus callosum was negatively correlated with the composite measure of systemic inflammation, controlling for demographic, clinical and radiologic factors. Visuospatial ability was negatively correlated with systemic inflammation, and diffusion anisotropy in the body and isthmus of the corpus callosum was shown to mediate this association. The findings of the present study suggest that higher levels of systemic inflammation may be associated with lower microstructural integrity in the corpus callosum of non-demented elderly individuals, and this may partially explain the finding of reduced higher-order visual cognition in aging.

Figure 1. Regions of the white matter skeleton with a significant negative correlation between FA and the composite measure of systemic inflammation are shown in dark blue (controlling for age, sex, level of education, and presence of WMHs).

(A) Axial (radiological convention), (B) sagittal (left to right) and (C) coronal (posterior to anterior) views are presented for better localization. In order to ensure high contrast, the same dark blue color is assigned to all voxels with p<0.05 after correction for multiple comparisons. Mean FA maps of the IIT Human Brain Atlas (v.3) (grayscale), and the corresponding white matter skeleton (green color) are shown in the background. No part of the white matter skeleton showed a significant positive correlation between FA and the composite measure of inflammation.

Figure 2. Plot of the mean FA (after correction for the effects of age, sex, level of education, and presence of WMHs) of the corpus callosum voxels that showed a significant negative correlation between FA and systemic inflammation in voxel-wise analysis (Fig. 1), as a function of the composite measure of systemic inflammation.

Figure 3. Results of probabilistic tractography in the HARDI template of the IIT Human Brain Atlas (v.3) for a seed region covering the mid-sagittal section of the corpus callosum cluster that showed significant negative correlation between FA and systemic inflammation.

(A) Location of the seed used for probabilistic tractography, overlaid on the mid-sagittal slice of the mean T₁-weighted template of the atlas. (B–E) Three-dimensional renderings of track-density maps of fibers that cross through the body and isthmus of the corpus callosum, where FA was shown to be significantly negatively correlated with the composite measure of systemic inflammation. (B) View of the lateral side of the left hemisphere. (C) View of the lateral side of the right hemisphere. (D) View of the medial aspect of the right hemisphere. (E) View of the medial aspect of the left hemisphere.