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

ABSTRACT

To understand the consistently observed spatial distribution of white-matter (WM) aging, developmentally driven theories of retrogenesis have gained traction, positing that the order WM development predicts declines. Regions that develop first are often expected to deteriorate the last, i.e. "last-in-first-out". Alternatively, regions which develop most rapidly may also decline most rapidly in aging, or the "gains-predict-loss" model. The validity of such theories remains uncertain, in part due to lack of clarity on the definition of developmental order. Our recent findings also suggest that WM degeneration may vary by physiological parameters such as perfusion. Furthermore, it is informative to link perfusion to fibre metabolic need, which varies with fibre size. Here we address the question of whether WM degeneration is determined by development trajectory or physiological state across both microstructural and perfusion measures using data drawn from the Human Connectome Project in Aging (HCP-A). Our results indicate that developmental order of tract myelination provides the strongest support for the retrogenesis hypothesis, with the last to complete myelination the first to decline. Moreover, higher mean axon diameter and lower macrovascular density are associated with lower degrees of WM degeneration across measures. Tract perfusion, in turn also tends to be higher and the arterial transit time longer for tracts that appear first. These findings suggest that WM degeneration in different tracts may be governed by their developmental trajectories and physiology, and ultimately influenced by each tract's metabolic demand.