In search of a unifying theory of white matter aging: associations with age in perfusion detectable in advance of microstructure

Abstract

ABSTRACTOne 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 WM perfusion-microstructure relationships vary by both tract and sex. Moreover, we identify multiple distinct stages of deterioration, with female subjects demonstrating more tracts in advanced stages of decline. Additionally, arterial transit time appears to be the earliest indicator of WM declines, preceding age-related microstructural differences 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.