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

Abstract

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.

Developmental order, fibre caliber, and vascularization predict tract-wise declines: Testing retrogenesis and physiological predictions in white matter aging

“…While between-tract differences demonstrate meaningful patterns within both this study and previous research (Robinson et al, 2023), within-tract comparisons represent an additional axis of comparisons that has received relatively little attention. Given the considerable differences in rates and patterns of development across tracts in all stages of WM growth and maturation, comparing regions within tracts along a developmental gradient may further clarify our understanding of retrogenesis as a process.…”

“…While existing research has focused largely on microstructural measures of WM integrity (Slater et al, 2019), microvascular measures of WM declines have remained an underrepresented area of research on WM aging, due in part to the previous difficulty of imaging perfusion in the WM directly (Bernbaum et al, 2015; Chen et al, 2013). The importance of neurovascular health in maintaining tissue integrity in aging is increasingly recognized, as associations have been observed between cortical perfusion and the development of WM lesions (Chen et al, 2013), as well as between WM perfusion and microstructural integrity in the aging WM directly (Robinson et al, 2023). As a result, growing evidence of regional differences in white matter (WM) perfusion is poised to join established literature on WM differences in aging trajectories.…”

“…Huang et al, 2020). Our recent findings suggest that WM degeneration may also vary by both axonal diameter and perfusion (Robinson et al, 2023). As a result, incorporating physiological differences between tracts can be considered both a component of, and a complement to, developmental retrogenesis models.…”