Spatial Decomposition of Longitudinal RNFL Maps Reveals Distinct Modes of Glaucomatous Progression with Structure Function and Genetic Signatures

PurposeTo determine whether spatial decomposition of longitudinal retinal nerve fiber layer (RNFL) change maps reveals distinct modes of glaucomatous progression masked by conventional averaging, and to validate these modes through structure-function mapping and genetic association analysis. MethodsPixel-wise RNFL rates of change were computed from longitudinal optic disc OCT scans of 15,242 eyes (8,419 adults with primary open-angle glaucoma [POAG]; Massachusetts Eye and Ear, 1998-2023). A loss-only constraint zeroed all thickening values, reflecting the biological prior that adult RNFL does not regenerate. Non-negative matrix factorization decomposed these maps into spatial progression components (80% training set). Components were evaluated in a held-out set (20%) for retinotopic structure-function concordance, visual field (VF) progressor classification against global and quadrant RNFL rates, and enrichment of genetic association signals at established POAG loci. ResultsSix anatomically distinct progression patterns emerged, including diffuse circumferential loss, focal peripapillary defects, and arcuate bundle degeneration. Pattern-based models significantly outperformed global RNFL rate for classifying VF progressors (area under the curve, 0.750 [95% CI, 0.709-0.790] vs. 0.702; P = .0096) and explained additional variance in functional decline (Nagelkerke pseudo-R{superscript 2}, 0.301 vs. 0.198; P = .0011). Structure-function mapping confirmed retinotopic coherence. Spatial phenotypes recovered stronger genetic signals than global rates at 85.3% of established POAG loci, suggesting they capture more biologically homogeneous endophenotypes of progression. ConclusionsGlaucomatous structural progression occurs through spatially distinct modes with independent structure-function and genetic signatures that conventional RNFL averaging obscures.