Spatial Signatures of Retinal Neurodegeneration in Glaucoma, Alzheimer's Disease, and Carotid Stenosis

Purpose: To compare spatial and topographical signatures of inner retinal alterations across primary open-angle glaucoma (POAG), Alzheimer's disease (AD), and carotid artery stenosis (CAS). Methods: This multicenter cross-sectional study included 1380 participants: 695 healthy controls (HCs), 331 with POAG, 105 with AD, and 249 with CAS. Peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell layer (GCL) thicknesses were measured using optical coherence tomography (OCT). Spatial dispersion metrics, including vertical asymmetry, maximum–minimum (Max–Min) difference, and coefficient of variation, were derived to characterize intraeye spatial heterogeneity. Results: POAG showed profound global pRNFL and GCL thinning, whereas AD and CAS had preserved global pRNFL thickness. Spatial analysis revealed distinct anatomic patterns. POAG was characterized by marked compression of the pRNFL sectoral thickness range (reduced Max–Min difference; P < 0.001). In contrast, AD and CAS maintained or increased pRNFL spatial variability. AD showed selective temporal pRNFL thinning (P = 0.002) without significant macular GCL thinning, whereas CAS showed generalized macular GCL thinning with temporal pRNFL vulnerability (both P < 0.05). The pRNFL Max–Min difference showed high apparent discrimination for differentiating POAG from HC, AD, and CAS, outperforming conventional global thickness metrics, but requires external validation. Conclusions: Retinal neurodegeneration exhibits etiology-specific spatial architectures. Intraeye spatial heterogeneity metrics may help distinguish glaucomatous optic neuropathy from central neurodegenerative and chronic ischemic conditions, although validation in independent and early-stage cohorts is needed. Translational Relevance: Spatial OCT metrics may aid differentiation of glaucomatous and nonglaucomatous retinal neurodegeneration.