Fixel-Based Analysis of Visual Pathway White Matter in Primary Open-Angle Glaucoma

Purpose: White matter (WM) degeneration of the visual pathways in primary open-angle glaucoma (POAG) is well documented, but its exact pathophysiology remains unclear. To date, glaucomatous WM degeneration has been exclusively studied using diffusion tensor imaging (DTI) only. However, DTI measures lack direct biological interpretation, and the approach itself suffers from multiple technical limitations. Fixel-based analysis (FBA) is a novel framework for studying WM degeneration, overcoming DTI's technical limitations and providing biologically meaningful metrics. FBA measures fiber density (FD), representing early microstructural changes, and fiber-bundle cross section (FC), representing late macrostructural changes. In this study, we use FBA to study glaucomatous degeneration of the pregeniculate optic tracts (OTs) and postgeniculate optic radiation (ORs) in POAG.Methods: This was a cross-sectional case-control study with 12 POAG patients and 16 controls. Multi-shell diffusion-weighted images were acquired. FBA was used to produce a population template, and probabilistic tractography was used to track the OTs and ORs in template space. Finally, FD and FC of the tracts of interest were compared between the two groups.Results: Compared with the controls, the OTs of the patients exhibited a significant (familywise error corrected P < 0.05) decrease in FD and FC, whereas their ORs exhibited a significant decrease in FD but not in FC.Conclusions: FBA provides sensitive measures to assess WM changes in glaucoma. Our findings suggest that the OTs of glaucoma patients exhibit signs of more advanced WM degeneration compared with the ORs. This potentially implicates anterograde trans-synaptic propagation as the primary cause of glaucomatous spread along the visual pathways.