Targeting Molecular Markers of Neurodegeneration for Early Therapeutic Intervention in the Pathophysiology and Progression of Diabetic Retinopathy

Retinal neuronal dysfunction and degeneration emerge early in the pathogenesis of diabetic retinopathy (DR), preceding visible microvascular abnormalities. These neuronal alterations driven by chronic hyperglycemia initiate a cascade of mitochondrial failure, neuroinflammation, and synaptic disruption, which ultimately contribute to vascular breakdown and vision loss. A growing body of evidence identifies specific biomarkers that reflect these early neurodegenerative processes. Structural changes such as ganglion cell complex thinning and disorganization of the retinal inner layers (DRIL), functional impairments in flicker-induced vasodilation and oscillatory potentials, and molecular signals including caspase-3, Glial Fibrillary Acidic Protein (GFAP), and neurofilament light chain are quantifiable indicators of retinal neuronal injury. Emerging candidates such as miRNAs, retinal extracellular vesicle content, and semaphorin 3A provide additional insights into axonal transport defects and protein misfolding. Advances in artificial intelligence particularly in Optical Coherence Tomography (OCT), Optical Coherence Tomography Angiography (OCTA) image analysis, and pupillometry analysis have shown promise in enhancing the sensitivity and precision of early biomarker detection, enabling more objective risk prediction and monitoring. This review synthesizes current findings on neurodegeneration-related biomarkers in DR, emphasizing their potential for early diagnosis, risk stratification, and therapeutic monitoring. Broader clinical application will require non-invasive detection platforms, standardized protocols, and biomarker-driven trials aimed at shifting DR management toward proactive neuroprotection.