Analysis of white matter tract integrity using diffusion kurtosis imaging reveals the correlation of white matter microstructural abnormalities with cognitive impairment in type 2 diabetes mellitus.

Background: This study aimed to identify disruptions in white matter integrity in type 2 diabetes mellitus (T2DM) patients by utilizing the white matter tract integrity (WMTI) model, which describes compartment-specific diffusivities in the intra- and extra-axonal spaces, and to investigate the relationship between WMTI metrics and clinical and cognitive measurements. Methods: A total of 73 patients with T2DM and 57 healthy controls (HCs) matched for age, sex, and education level were enrolled and underwent diffusional kurtosis imaging and cognitive assessments. Tract-based spatial statistics (TBSS) and atlas-based region of interest (ROI) analysis were performed to compare group differences in diffusional metrics, including fractional anisotropy (FA), mean diffusivity (MD), axonal water fraction (AWF), intra-axonal diffusivity (Daxon), axial extra-axonal space diffusivity (De,//), and radial extra-axonal space diffusivity (De,⊥) in multiple white matter (WM) regions. Relationships between diffusional metrics and clinical and cognitive functions were characterized. Results: In the TBSS analysis, the T2DM group exhibited decreased FA and AWF and increased MD, De,∥, and De,⊥ in widespread WM regions in comparison with the HC group, which involved 56.28%, 32.07%, 73.77%, 50.47%, and 75.96% of the mean WM skeleton, respectively (P < 0.05, TFCE-corrected). De,⊥ detected most of the WM changes, which were mainly located in the corpus callosum, internal capsule, external capsule, corona radiata, posterior thalamic radiations, sagittal stratum, cingulum (cingulate gyrus), fornix (stria terminalis), superior longitudinal fasciculus, and uniform fasciculus. Additionally, De,⊥ in the genu of the corpus callosum was significantly correlated with worse performance in TMT-A (ß = 0.433, P < 0.001) and a longer disease duration (ß = 0.438, P < 0.001). Conclusions: WMTI is more sensitive than diffusion tensor imaging in detecting T2DM-related WM microstructure abnormalities and can provide novel insights into the possible pathological changes underlying WM degeneration in T2DM. De,⊥ could be a potential imaging marker in monitoring disease progression in the brain and early intervention treatment for the cognitive impairment in T2DM.

Unraveling the underlying mechanisms of reduced amyloidogenic properties in human calcitonin via double mutations.

The therapeutic efficacy of peptide-based drugs is commonly hampered by the intrinsic propensity to aggregation. A notable example is human calcitonin (hCT), a peptide hormone comprising 32 amino acids, which is synthesized and secreted by thyroid gland parafollicular cells (C cells). This hormone plays a vital role in regulating blood calcium levels and upholding bone integrity. Despite its physiological importance, utilizing hCT as a drug is hampered by its inclination to form amyloid. To address this limitation, an alternative is provided by salmon calcitonin (sCT), which possesses a lower aggregation propensity. Although sharing the same disulfide bond at the N terminus as hCT, sCT differs from hCT at a total of 16 amino acid positions. However, due to the dissimilarity in sequences, using sCT as a clinical replacement occasionally results in adverse side effects in patients. Earlier investigations have highlighted the significant roles of Tyr-12 and Asn-17 in inducing the formation of amyloid fibrils. By introducing double mutations at these sites, the ability to hinder aggregation can be significantly augmented. This study delves into the oligomerization and helical structure formation of the hCT double mutant (Y12LN17H hCT, noted as DM hCT), as well as two single mutants (Y12L and N17H), aiming to elucidate the mechanism behind hCT fibrillization. In addition, computational prediction tools were employed again to identify potential substitutes. Although the results yielded were not entirely satisfactory, a comparison between the newly examined and previously found hCT double mutants provides insights into the reduced aggregation propensity of the latter. This research endeavor holds the promise of informing the design of more effective therapeutic peptide drugs in the future.