Voxel-based morphometry reveals the correlation between gray matter volume and serum P-tau-181 in type 2 diabetes mellitus patients with different HbA1c levels

INTRODUCTION: Emerging evidence suggested widespread decreased gray matter volume (GMV) and tau hyperphosphorylation were associated with type 2 diabetes mellitus (T2DM). Insulin resistance is one of the mechanisms of neuron degeneration in T2DM; it can decrease the activity of protein kinase B and increase the activity of glycogen synthesis kinase-3β, thus promoting the hyperphosphorylation of tau protein and finally leading to neuronal degeneration. However, the association between GMV and serum tau protein phosphorylated at threonine 181 (P-tau-181) in T2DM patients lacks neuroimaging evidence. We aimed to investigate the difference in brain GMV between T2DM patients with different glycated hemoglobin A1c (HbA1c) levels and healthy control (HC) subjects and the correlation between serum P-tau-181 and GMV in T2DM patients. METHODS: Clinical parameters, biochemical indicators, and MRI data were collected for 41 T2DM patients with high glycosylated hemoglobin level (HGL), 17 T2DM patients with normal glycosylated hemoglobin level (NGL), and 42 HC subjects. Voxel-based morphometry (VBM) method was applied to investigate GMV differences among groups, and multiple regression analysis was used to examine the correlation between serum P-tau-181 and GMV. RESULTS: Compared with HC subjects, the T2DM patients with HGL or NGL all showed significantly decreased GMV. Briefly, the GMV decreased in T2DM patients with HGL was mainly in the bilateral parahippocampal gyrus (PHG), right middle temporal gyrus (MTG), temporal pole (TPOmid), hippocampus (HIP), and left lingual gyrus. The GMV reduction in T2DM patients with NGL was in the right superior temporal gyrus (STG), and there was no significant difference in GMV between the two diabetic groups. The GMV values of bilateral PHG, right MTG, TPOmid, HIP, and STG can significantly (p < 0.0001) distinguish T2DM patients from HC subjects in ROC curve analysis. In addition, we found that serum P-tau-181 levels were positively correlated with GMV in the right superior and middle occipital gyrus and cuneus, and negatively correlated with GMV in the right inferior temporal gyrus in T2DM patients. CONCLUSION: Our study shows that GMV atrophy can be used as a potential biological indicator of T2DM and also emphasizes the important role of P-tau-181 in diabetic brain injury, providing new insights into the neuropathological mechanism of diabetic encephalopathy.