Alterations of White Matter Integrity and Hippocampal Functional Connectivity in Type 2 Diabetes Without Mild Cognitive Impairment

Qian Sun, Guan-Qun Chen, Xi-Bin Wang, Ying Yu, Yu-Chuan Hu, Lin-Feng Yan, Xin Zhang, Yang Yang, Jin Zhang, Bin Liu, Cong-Cong Wang, Yi Ma, Wen Wang, Ying Han, Guang-Bin Cui, Qian Sun, Guan-Qun Chen, Xi-Bin Wang, Ying Yu, Yu-Chuan Hu, Lin-Feng Yan, Xin Zhang, Yang Yang, Jin Zhang, Bin Liu, Cong-Cong Wang, Yi Ma, Wen Wang, Ying Han, Guang-Bin Cui

Abstract

Aims: To investigate the white matter (WM) integrity and hippocampal functional connectivity (FC) in type 2 diabetes mellitus (T2DM) patients without mild cognitive impairment (MCI) by using diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (rs-fMRI), respectively. Methods: Twelve T2DM patients without MCI and 24 age, sex and education matched healthy controls (HC) were recruited. DTI and rs-fMRI data were subsequently acquired on a 3.0T MR scanner. Tract-based spatial statistics (TBSS) combining region of interests (ROIs) analysis was used to investigate the alterations of DTI metrics (fractional anisotropy (FA), mean diffusivity (MD), λ1 and λ23) and FC measurement was performed to calculate hippocampal FC with other brain regions. Cognitive function was evaluated by using Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Brain volumes were also evaluated among these participants. Results: There were no difference of MMSE and MoCA scores between two groups. Neither whole brain nor regional brain volume decrease was revealed in T2DM patients without MCI. DTI analysis revealed extensive WM disruptions, especially in the body of corpus callosum (CC). Significant decreases of hippocampal FC with certain brain structures were revealed, especially with the bilateral frontal cortex. Furthermore, the decreased FA in left posterior thalamic radiation (PTR) and increased MD in the splenium of CC were closely related with the decreased hippocampal FC to caudate nucleus and frontal cortex. Conclusions: T2DM patients without MCI showed extensive WM disruptions and abnormal hippocampal FC. Moreover, the WM disruptions and abnormal hippocampal FC were closely associated. Highlights -T2DM patients without MCI demonstrated no obvious brain volume decrease.-Extensive white matter disruptions, especially within the body of corpus callosum, were revealed with DTI analysis among the T2DM patients.-Despite no MCI in T2DM patients, decreased functional connectivity between hippocampal region and some critical brain regions were detected.-The alterations in hippocampal functional connectivity were closely associated with those of the white matter structures in T2DM patients. This trial was registered to ClinicalTrials.gov (NCT02420470, https://www.clinicaltrials.gov/).

Keywords: functional connectivity (FC); hippocampal; resting-state functional magnetic resonance imaging (rs-fMRI); tract-based spatial statistics (TBSS); type 2 diabetes mellitus (T2DM).

Figures

Figure 1
Figure 1
Group difference based on voxel-based morphometry (VBM) analysis. (A,B) Difference of the mean gray matter volume (GMV), white matter volume (WMV), total brain volume (TBV) and proportion of cerebrospinal fluid (CSF) in type 2 diabetes mellitus (T2DM) and healthy control (HC) subjects. (C) Difference of regional atrophy between T2DM and HC groups. Neither whole brain (A,B) nor regional brain (C) volume reduction was observed in T2DM patients. All P > 0.05.
Figure 2
Figure 2
Differences in tract-based spatial statistics (TBSS) analysis results of fractional anisotropy (FA), mean diffusivity (MD), λ1, and λ23 images between T2DM and HC groups (axial images). Green regions represent the mean FA skeleton of all subjects. Red regions represent tracts with decreased FA, Deep-blue regions represent tracts with increased MD, Light-blue regions represent tracts with increased axial diffusivity (λ1), and Yellow regions represent tracts with increased radial diffusivity (λ23) in T2DM patients compared with HC subjects (P < 0.05, family wise error (FWE) corrected). There were significant differences in extensive white matter (WM) tracts in T2DM patients.
Figure 3
Figure 3
Mean diffusion metrics and group differences of region of interests (ROIs) analysis between T2DM and HC groups. (A) Regions with decreased FA in T2DM groups; (B) regions with increased MD in T2DM groups; (C) regions with increased λ1 in T2DM groups; (D) regions with increased λ23 in T2DM patients. All the ROIs showed in the figure were significantly different (all P < 0.05). GCC, genu of corpus callosum; BCC, body of corpus callosum; SCC, splenium of corpus callosum; CST, corticospinal tract. SCP, superior cerebellar peduncle; PTR, posterior thalamic radiation. ACR, anterior corona radiata. PCR, posterior corona radiata. SCR, superior corona radiata. R, right, L, left.
Figure 4
Figure 4
Significant difference in the functional connectivity (FC) of hippocampal region between T2DM and HC groups. The color scale represents the strength of hippocampal FC (decreasing strength from green to red) in axial images. The threshold was set as P < 0.05, AlphaSim corrected.
Figure 5
Figure 5
The relationships between WM diffusion metrics and hippocampal FC measures in T2DM. The mean FA values in PTR_L was positively associated with the average coefficient of FC between the left hippocampal region and (A) left frontal cortex; (B) right frontal cortex; (C) left caudate nucleus; The mean MD values in SCC was negatively associated with the average coefficient of FC between the right hippocampal region and (D) right frontal cortex; (E) right cingulate cortex; (F) left caudate nucleus. R, right; L, left. r value means Pearson’s correlation coefficient. P value < 0.05 was considered to be statistically significant.

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