Investigating changes in axonal density and morphology of glaucomatous optic nerves using fixel-based analysis

PURPOSE: To characterize neurodegeneration of glaucomatous optic nerves (ONs) in terms of changes in axonal density and morphology using fixel-based analysis (FBA), a novel framework for analyzing diffusion-weighted MRI (DWI). Furthermore, we aimed to explore the potential of FBA measures as biomarkers of glaucomatous ON degeneration. METHODS: DWI scans were obtained from 15 glaucoma patients and 15 controls. ONs were tracked and segmented into their three anatomical segments; intraorbital (IO), intracanalicular (ICAN) and intracranial (ICRAN). For each segment, FBA measures were computed, which included fiber density (FD; a measure of axonal density), fiber-bundle cross-section (FC; an estimate of morphological changes), and fiber density and cross-section (FDC). Peripapillary retinal nerve fiber layer (pRNFL) thickness and visual field mean deviation (VFMD) were assessed for glaucoma patients. ANCOVA was used to compare FBA values between the two groups, and Spearman's correlation analysis was used to test the correlation between FBA measures and pRNFL thickness and VFMD. RESULTS: All glaucomatous ON segments showed a significant loss of FD and FDC compared to the controls, while a loss of FC was found in the IO and ICRAN segments only. FD and FDC values of the IO and ICAN segments of glaucomatous ONs showed significant correlations with pRNFL thickness and VFMD. CONCLUSIONS: Glaucomatous ONs exhibit lower FD and FC compared to controls, indicating axonal loss and gross atrophy. The correlation between FBA measures of glaucomatous ONs and established clinical tests of glaucoma demonstrates the potential of FBA measures as biomarkers of glaucomatous ON degeneration