Deciphering the Connection Between Microvascular Damage and Neurodegeneration in Early Diabetic Retinopathy.

Diabetic retinopathy (DR), a common diabetes complication leading to vision loss, presents early clinical signs linked to retinal vasculature damage, affecting the neural retina at advanced stages. However, vascular changes and potential effects on neural cells before clinical diagnosis of DR are less well understood. To study the earliest stages of DR, we performed histological phenotyping and quantitative analysis on postmortem retinas from 10 donors with diabetes and without signs of DR (e.g., microaneurysms, hemorrhages), plus three control eyes and one donor eye with DR. We focused on capillary loss in the deeper vascular plexus (DVP) and superficial vascular plexus (SVP), and on neural retina effects. The eye with advanced DR had profound vascular and neural damage, whereas those of the 10 randomly selected donors with diabetes appeared superficially normal. The SVP was indistinguishable from those of the control eyes. In contrast, more than half of the retinas from donors with diabetes had capillary dropout in the DVP and increased capillary diameter. However, we could not detect any localized neural cell loss in the vicinity of dropout capillaries. Instead, we observed a subtle pan-retinal loss of inner nuclear layer cells in all diabetes cases (P < 0.05), independent of microvascular damage. In conclusion, our findings demonstrate a novel histological biomarker for early-stage diabetes-related damage in the human postmortem retina; the biomarker is common in people with diabetes before clinical DR diagnosis. Furthermore, the mismatch between capillary dropout and neural loss leads us to question the notion of microvascular loss directly causing neurodegeneration at the earliest stages of DR, so diabetes may affect the two readouts independently.