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 (such as microaneurysms and haemorrhages), plus 3 controls and 1 DR case, focusing on capillary loss in the deeper (DVP) and superficial vascular plexuses (SVP) and neural retina effects. The advanced DR case exhibited profound vascular and neural damage, whereas the ten randomly selected donors with diabetes appeared superficially normal. The SVP was indistinguishable from the controls. In contrast, over half of the retinas from donors with diabetes showed capillary dropout in the DVP and increased capillary diameter. However, we could not detect any localised neural cell loss in the vicinity of dropout capillaries. Instead, we observed a subtle pan-retinal loss of inner nuclear layer (INL) 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 human postmortem retina, common in people with diabetes before clinical DR diagnosis. Furthermore, the mismatch between capillary dropout and neural loss questions the notion of microvascular loss directly causing neurodegeneration at the earliest stages of DR, so diabetes may affect the two readouts independently.