In search of a unifying theory of white matter aging: tract perfusion-microstructure relationships

Age-related degeneration of white matter (WM) tissue in the brain has been found to underlie progressive cognitive declines in healthy populations. Understanding and predicting these changes is necessary to building a more unified model of the aging brain and improving interventions. We posit that regional hypoperfusion in the WM precedes deteriorating WM integrity, as evidenced by studies demonstrating relationships between declining cortical perfusion and the development of WM hyperintensities. This remains an understudied area of WM aging, in part due to technical challenges in quantifying WM perfusion. This study seeks to examine tract-wise associations between WM microstructural integrity and perfusion parameters in the Human Connectome Project - Aging (HCP-A) participants. Perfusion was measured by cerebral blood flow (CBF) and arterial transit time (ATT), while microstructural integrity was measured by fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Their associations are assessed in ten major bilateral WM tracts. Results show that WM perfusion-microstructure relationships vary both by tract and by sex. We identify consistent patterns of associations between perfusion and microstructure that suggest the presence of multiple distinct stages of deterioration, with female subjects demonstrating more tracts in advanced stages of decline. Additionally, ATT appears to be the earliest indicator of WM declines, preceding age-related differences in WM microstructure in several tracts. This study contributes compelling evidence to the vascular hypothesis of WM degeneration, and highlights the utility of blood-flow timing rather than CBF as an early marker of aging. ### Competing Interest Statement The authors have declared no competing interest.