Cerebral white matter integrity and resting-state functional connectivity in middle-aged patients with type 2 diabetes

Abstract

Early detection of brain abnormalities at the preclinical stage can be useful for developing preventive interventions to abate cognitive decline. We examined whether middle-aged type 2 diabetic patients show reduced white matter integrity in fiber tracts important for cognition and whether this abnormality is related to preestablished altered resting-state functional connectivity in the default mode network (DMN). Diabetic and nondiabetic participants underwent diffusion tensor imaging, functional magnetic resonance imaging, and cognitive assessment. Multiple diffusion measures were calculated using streamline tractography, and correlations with DMN functional connectivity were determined. Diabetic patients showed lower fractional anisotropy (FA) (a measure of white matter integrity) in the cingulum bundle and uncinate fasciculus. Control subjects showed stronger functional connectivity than patients between the posterior cingulate and both left fusiform and medial frontal gyri. FA of the cingulum bundle was correlated with functional connectivity between the posterior cingulate and medial frontal gyrus for combined groups. Thus, middle-aged patients with type 2 diabetes show white matter abnormalities that correlate with disrupted functional connectivity in the DMN, suggesting that common mechanisms may underlie structural and functional connectivity. Detecting brain abnormalities in middle age enables implementation of therapies to slow progression of neuropathology.

Figure 1

Schematic overview of ROI placement and tract reconstruction. For the CB, four ROI sets were strategically placed on color-by-orientation maps to reconstruct the dorsal and ventral portions of the CB in each hemisphere. The anterior dorsal ROI (#1) is outlined on three consecutive coronal slices in which the anterior commissure is most notable. The posterior dorsal ROI (#2) and posterior ventral ROI (#3) are outlined in the same view on two consecutive coronal slices at the posterior disjunction of the corpus callosum in the first two slices in which the corpus callosum appears disjointed. Finally, the first coronal slice showing the middle cerebellar peduncle was selected for outlining the anterior ventral ROI (#4). Tractography was filtered through a midline exclusion region to exclude any interhemispheric fibers (mostly corpus callosum). For the UF, two ROI sets were drawn on FA maps on a single coronal slice adjacent to the most anterior point of the fornix and placed in the stem of the anterior temporal lobe and around the white matter of the anterior floor of the external/extreme capsule. By retaining only those tracts with paths that connected both regions of interest (the “and” approach), we ensured that fibers were selected that exclusively belonged to the UF. For the SLF, the most dorsal part was identified in the axial view on color-by-orientation maps, usually one or two slices above the body of the corpus callosum. The SLF was then outlined from the superior-to-inferior direction in approximately five consecutive axial slices.

Figure 2

Tractography results of the CB (red color), UF (green color), and SLF (blue color) of a representative subject in this study.

Figure 3

FA of the CB, UF, and SLF in people with type 2 diabetes (□) and nondiabetic healthy control subjects (■). The error bars represent mean ± SD. Compared with control subjects, people with type 2 diabetes showed lower FA in all tracts; statistically significant for the CB and UF corrected for multiple comparisons and adjusted for age, gender, IQ, verbal fluency, and memory performance. *P < 0.05.

Figure 4

Correlation between FA of the CB and strength of functional connectivity (β weight) between the medial frontal gyrus (MedFG) and the PCC, components of the DMN. Groups are combined, and each point represents one individual.