Microstructural Changes in the Corpus Callosum in Different Forms of Sporadic Age-Related Cerebral Small Vessel...

Background/Objectives: Cerebral small vessel disease (SVD) is a heterogeneous condition in which similar conventional MRI findings may be associated with different clinical manifestations and pathogenetic mechanisms. Previously, hierarchical clustering of structural MRI features in patients with severe white matter hyperintensities (Fazekas 3) identified two MRI phenotypes, designated MRI Type 1 and MRI Type 2. Diffusion MRI (dMRI) may provide additional information about the microstructural differences between these phenotypes. To compare white matter microstructure between MRI Type 1 and MRI Type 2 of sporadic age-related SVD using signal-based and biophysical dMRI models. Methods: This cross-sectional study included 75 patients with SVD and 36 age- and sex-matched healthy controls. Among the patients with SVD, 43 had MRI Type 1 and 32 had MRI Type 2. All participants underwent structural and multi-shell dMRI on a 3 Tesla MRI scanner. Diffusion metrics were derived using multiple models: Diffusion Tensor Imaging (DTI), Diffusion Kurtosis Imaging (DKI), Neurite Orientation Dispersion and Density Imaging (NODDI), White Matter Tract Integrity (WMTI), and the Multi-compartment Spherical Mean Technique (MC-SMT). Tract-profile analysis was performed in three corpus callosum segments: the forceps major, forceps minor, and body. Group differences were assessed using age- and sex-adjusted general linear models with correction for multiple comparisons. The combined discriminative value of dMRI metrics was evaluated using regularized Elastic Net logistic regression with repeated nested five-fold cross-validation. Results: After adjustment for age and sex, the overall group effect remained significant for 45 of 48 global dMRI measures following Benjamini-Hochberg correction. Compared with MRI Type 2, MRI Type 1 showed lower fractional anisotropy (FA), neurite density index (NDI), intra-axonal volume fraction (INTRA), axonal water fraction (AWF), mean kurtosis (MK), axial kurtosis (AK), and radial kurtosis (RK), and higher mean diffusivity (MD), radial diffusivity (RD), extra-axonal mean diffusivity (EXTRA_MD), extra-axonal transverse diffusivity (EXTRA_TRANS), and extra-axonal radial diffusivity (radEAD). These differences were generally most pronounced in the body of the corpus callosum. In the segmental analysis, 131 of 144 values showed a significant overall group effect after correction, and 108 demonstrated significant differences between MRI Type 1 and MRI Type 2. The largest effects were observed in the 60-80% interval of the corpus callosum body, particularly for AWF, MK, INTRA, EXTRA_TRANS, RK, FA, RD, radEAD, and MD. An Elastic Net model combining age, sex, and 48 global dMRI measures discriminated MRI Type 1 from MRI Type 2 with an internally validated area under the curve of 0.866 (95% CI, 0.762-0.953), accuracy of 86.7%, sensitivity of 75.0%, and specificity of 95.3%. Ten dMRI features showed a selection frequency of at least 70% across repeated model construction. Conclusions: MRI Type 1 is characterized by more severe and spatially extensive corpus callosum microstructural abnormalities than MRI Type 2, despite broadly similar vascular risk-factor profiles. The findings support the heterogeneity of sporadic age-related SVD and indicate that combined signal-based and biophysical dMRI metrics may improve MRI phenotyping. The observed associations should be interpreted as indirect markers of tissue microstructure and require confirmation in larger, independent, and longitudinal cohorts.