Mechanistic insights into age- and vascular-related microstructure differences in the corpus callosum using...

Corpus callosum microstructure is a proposed risk biomarker for vascular contributions to cognitive impairment. This study compared corpus callosum microstructure measures from the "Standard Model" biophysical diffusion model with diffusion tensor and kurtosis imaging (DTI, DKI) measures for differences related to age and cerebral small vessel disease (cSVD) in a population-based sample of cognitively unimpaired older adults (n = 112, mean age 69.9). Standard Model measures included axonal water fraction (f) and intra-axonal diffusivity (D_a), proposed as markers related to axonal density and integrity, respectively, and extra-axonal parallel (D_e^∥)_and perpendicular diffusivities(D_e^⟂), proposed as markers sensitive to neuroinflammation and demyelination, respectively. These were compared with DTI and DKI measures regarding their association with age or white matter hyperintensity (WMH) volume on T2w MRI, a proxy for cSVD burden. Of Standard Model measures, D_e^⟂ and D_a were associated with age, and D_e^⟂ of genu and body was associated with both WMH volume and age, suggesting that demyelination may be an important mechanism in age and cSVD-related microstructural differences in the corpus callosum. Sensitivity to age and WMH volume was overall similar to DTI and DKI measures. Mediation analyses showed that D_e^⟂ mediated the relationship between mean and axial kurtosis in the genu and body, respectively, when evaluating associations with WMH volume, suggesting that demyelination is a potential important mechanism underlying microstructural differences quantified by kurtosis in cSVD. Overall, the Standard Model-derived measures provides compartment-specific biophysical insight into aging and cSVD, with high sensitivity comparable to conventional DTI and DKI.