Histopathological findings and knowledge gaps in glaucomatous neurodegeneration

Abstract Glaucoma is the leading cause of irreversible blindness globally, characterized by progressive retinal ganglion cell dysfunction and death resulting in remodeling of the optic nerve head and optic nerve degeneration. Whilst substantial progress has been made in understanding basic mechanisms of glaucomatous neurodegeneration in animal models, significant knowledge gaps remain regarding the histopathological substrate of this disease in human tissue. This review synthesizes current understanding of established histopathological findings in glaucomatous eyes, including retinal ganglion cell degeneration, synaptic pathology, axonal transport dysfunction, lamina cribrosa remodeling, glial cell responses, extracellular matrix changes, and structure-function relationships. We end by identifying major gaps in our knowledge regarding cellular heterogeneity in retinal ganglion cell vulnerability, circuit-level retinal remodeling, the temporal sequence of pathological events, the functional consequences of astrocyte and microglial activation, and the mechanisms linking structural pathology to functional vision loss. Addressing these gaps requires integrated approaches combining classical histology with modern molecular profiling, greater access to human post-mortem tissue with rigorous disease staging, and systematic investigation of retinal ganglion cell subtype-specific pathology in the human retina and optic nerve.