ABSTRACT Aim Diabetic retinopathy (DR) is a common complication of diabetes mellitus and can result in vision loss. Early clinically diagnosed signs of DR are linked to vascular damage, impacting on the neural retina typically at later stages. However, vascular changes and potential effects on neural cells before clinical diagnosis of DR are less understood. Methods To learn more about the earliest stages of DR we studied postmortem retina from diabetic donors who did not have clinical DR. Histological phenotyping and quantitative analysis were carried out on retina from 14 donors (3 controls, 10 diabetics, and 1 DR case) to examine capillary loss in the deeper vascular plexus (DVP) and the superficial vascular plexus (SVP) of the retinal vasculature and to study effects on the neural retina. Result The advanced DR case exhibited profound vascular and neural damage as expected, whereas none of the ten randomly selected diabetic donors had any DR signs that would have been diagnosed clinically. Within that group, two showed very minor capillary dropout in the SVP, whilst in the remaining diabetic cases the SVP was indistinguishable from the controls. In contrast, over half of the diabetic retinas showed capillary dropout in the DVP and increased capillary diameter. Furthermore, a pan retinal loss of inner nuclear layer cells was observed in those diabetics with capillary dropout compared to the controls (p&lt;0.05), but there was no local spatial correlation between neural cell loss and capillary dropout. Conclusions Our study has established a novel histological biomarker for diabetes related tissue damage at the earliest stages of DR in human postmortem retina, which appears to be common in people with diabetes before DR can be clinically diagnosed. Furthermore, the spatial mismatch between local capillary dropout and the diffuse neural loss in the INL suggests that at this very early stage of DR, microvascular loss may not causally be directly connected to neurodegeneration and that diabetes may affect the two readouts independently. RESEARCH IN CONTEXT What is already known about this subject? Early DR is currently clinically defined by visible microvascular changes. Tests of retinal function in people with diabetes imply neuroretinal impairments in early DR. Clinical imaging in people with diabetes suggests reduced perfusion in the deep retinal vasculature plexus. What is the key question? (one bullet point only; formatted as a question) How does retinal microvascular damage relate to neuronal damage? What are the new findings? We have developed a sensitive histological biomarker for microvascular damage in postmortem retinal tissue. Early vascular changes in the deeper plexus occur in diabetes even in the absence of manifest DR. Neurodegenerative changes are distributed throughout the retina in diabetes and do not spatially correlate with microvascular nonperfusion. How might this impact on clinical practice in the foreseeable future? Deeper plexus perfusion can be a useful early biomarker to assess DR.

Disconnection Between Microvascular Damage and Neurodegeneration in Early Diabetic Retinopathy