In search of a unifying theory of white matter aging: improving the understanding of tract-wise degeneration using multi-parametric signatures of morphometry and microstructure

ABSTRACT While tract-wise differences in volume and microstructure are common targets of investigation in age-related changes in the white matter (WM), there has been relatively little exploration into other attributes of tract morphometry or its relation to microstructure in vivo, and limited understanding on how they jointly inform the interpretation of the WM aging trajectory. This study examines ten WM tracts for tract-wise differences in morphometry (i.e. volume, length, and volume-to-length ratio) and microstructural integrity (i.e. fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) using diffusion MRI data from the Human Connectome Project in Aging (HCP-A) with the goal of laying the foundation for a unified model of age-related WM microstructure-morphometry trajectories with a special focus on sex differences. Results indicated widely heterogeneous patterns of decline and morphometry-microstructural associations across tracts. Multi-parametric signatures of decline suggest stages or mechanisms of degeneration that differ between sexes. This work highlights the value of integrating microstructural and morphometric measures of WM health instead of observing them separately, suggesting multiple modes of WM degeneration.