1 Rotman Research Institute, 3560 Bathurst Street Baycrest, Toronto, Ontario, M6A 2E1, Canada. trobinson@research.baycrest.org.
2 Rotman Research Institute, 3560 Bathurst Street Baycrest, Toronto, Ontario, M6A 2E1, Canada.
3 Physics, Concordia University, Montreal, Quebec, Canada.
4 Rotman Research Institute, 3560 Bathurst Street Baycrest, Toronto, Ontario, M6A 2E1, Canada. jchen@research.baycrest.org.
5 Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. jchen@research.baycrest.org.
6 Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada. jchen@research.baycrest.org.

One of the most promising interventional targets for brain health is cerebral perfusion, but its link to white matter (WM) aging remains unclear. Motivated by existing literature demonstrating links between declining cortical perfusion and the development of WM hyperintensities, we posit that regional WM hypoperfusion precedes deteriorating WM integrity. Using the Human Connectome Project Aging (HCP-A) data set, we examine tract-wise associations between WM microstructural integrity (i.e. fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) and perfusion (i.e. cerebral blood flow and arterial transit time) in ten major bilateral WM tracts. Results show that tracts displaying the largest CBF decline in aging do not necessarily display the largest ATT decline, and vice versa. Moreover, significant WM perfusion-microstructure canonical correlations were found in all tracts, but the drivers of these correlations vary by both tract and sex, with female subjects demonstrating more tracts with large microstructural variations contributing to the correlations. Importantly, age-effects on arterial transit time peak at a younger age than those of all other parameters investigated, preceding age-related microstructural differences and CBF in several tracts. This study contributes compelling evidence to the vascular hypothesis of WM degeneration and highlights the utility of blood-flow timing as an early marker of aging.