Testing retrogenesis and physiological explanations for tract-wise white matter aging: links to developmental order, fiber calibre, and vascularization.

To understand observed spatial distributions of white-matter (WM) aging, developmentally driven theories termed "retrogenesis" have gained traction, positing that WM tract development order predicts order of declines, with later developing regions expected to deteriorate first, i.e., "last-in-first-out." Alternatively, regions that develop most rapidly may decline most rapidly in aging, i.e., "gains-predict-loss." The validity of such theories remains uncertain, partly due to lack of clarity in defining developmental order. Recent findings suggest that WM aging is also associated with physiological parameters such as perfusion and fiber size. Here, we address the extent to which degrees of WM aging are determined by development trajectory (i.e., retrogenesis) and/or physiological states. We obtained microstructural and perfusion data from the Human Connectome Project in Aging (HCP-A), complemented by a meta-analysis involving maps of fiber calibre and macrovascular volume. Our results suggest (1) myelination development order explains more associations with WM health than prenatal emergence order; (2) earlier-myelinating tracts exhibit higher microstructural integrity and less susceptibility to microstructural deterioration in aging but lower perfusion and longer arterial-transit times (ATT), suggestive of collateral blood supply; (3) earlier-emerging tracts show longest ATT and greatest ATT increase across aging; (4) tracts with larger axons and higher macrovascular density in young adulthood show longer ATT and less susceptibility to microstructure/perfusion degeneration irrespective of developmental order; and (5) negligible support for "gains-predict-loss." These findings were sex-dependent in a tract-specific manner. Future work will investigate the role of macrovascular collateral flow and tract-wise influences of metabolic demand.