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

To understand the consistently observed spatial distribution of white-matter (WM) aging, developmentally driven theories termed "retrogenesis" have gained traction, positing that the order of WM tract development predicts the order of declines. Regions that develop first are 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 "gains-predict-loss". The validity of such theories remains uncertain, in part due to lack of clarity on the definition of developmental order. Importantly, our recent findings suggest that WM aging is also associated with physiological parameters such as perfusion, which may be linked to fibre metabolic need, which in turn varies with fibre size. Here we address the extent to which the degree of WM aging is determined by development trajectory (i.e. retrogenesis) and/or by physiological state. We obtained microstructural and perfusion measures using data from the Human Connectome Project in Aging (HCP-A), complemented by a meta-analysis involving maps of fibre calibre and macrovascular volume. Our results suggest that (1) while tracts that appear last or finish myelinating first in development display the slowest aging, the pattern of aging is not fully explained by retrogenesis; in fact, time courses of tract emergence and myelination give rise to opposite associations with WM decline; (2) tracts that appear earlier also have higher mean axon calibre and are also associated with lower degrees of WM microstructural aging; (3) such tracts also tend to exhibit relatively sustained CBF with a higher rate of lengthening of the arterial transit times (ATT), suggestive of collateral blood supply. These findings were also sex dependent in a tract-specific manner. Future work will investigate whether these are ultimately influenced by each tract's metabolic demand and the role of macrovascular collateral flow.

Fiber-specific age-related differences in the white matter of healthy adults uncovered by fixel-based analysis.

Diffusion magnetic resonance imaging studies often investigate white matter (WM) microstructural degeneration in aging by probing WM regions that exhibit negative age associations of fractional anisotropy (FA). However, WM regions in which FA is unassociated with age are not necessarily "spared" in aging. Besides the confound of inter-participant heterogeneity, FA conflates all intravoxel fiber populations and does not allow the detection of individual fiber-specific age associations. In this study of 541 healthy adults aged 36-100 years, we use fixel-based analysis to investigate age associations among each "fixel" within a voxel, representing individual fiber populations. We find age associations of fixel-based measures that indicate age-related differences in individual fiber populations amid complex fiber architectures. Different crossing fiber populations exhibit different slopes of age associations. Our findings may provide evidence of selective degeneration of intravoxel WM fibers in aging, which does not necessarily manifest as a change in FA and therefore escapes notice if conventional voxel-based analyses are relied upon alone.