Reversed Neurovascular Coupling on Optical Coherence Tomography Angiography Is the Earliest Detectable Abnormality before Clinical Diabetic Retinopathy

Diabetic retinopathy (DR) has traditionally been viewed as either a microvasculopathy or a neuropathy, though neurovascular coupling deficits have also been reported and could potentially be the earliest derangement in DR. To better understand neurovascular coupling in the diabetic retina, we investigated retinal hemodynamics by optical coherence tomography angiography (OCTA) in individuals with diabetes mellitus (DM) but without DR (DM no DR) and mild non-proliferative DR (mild NPDR) compared to healthy eyes. Using an experimental design to monitor the capillary responses during transition from dark adaptation to light, we examined 19 healthy, 14 DM no DR and 11 mild NPDR individuals. We found that the only structural vascular abnormality in the DM no DR group was increased superficial capillary plexus (SCP) vessel density (VD) compared to healthy eyes, while mild NPDR eyes showed significant vessel loss in the SCP at baseline. There was no significant difference in inner retinal thickness between the groups. During dark adaptation, the deep capillary plexus (DCP) VD was lower in mild NPDR individuals compared to the other two groups, which may leave the photoreceptors more susceptible to ischemia in the dark. When transitioning from dark to ambient light, both diabetic groups showed a qualitative reversal of VD trends in the SCP and middle capillary plexus (MCP), with significantly decreased SCP at 5 min and increased MCP VD at 50 s compared to healthy eyes, which may impede metabolic supply to the inner retina during light adaptation. Mild NPDR eyes also demonstrated DCP dilation at 50 s and 5 min and decreased adjusted flow index at 5 min in light. Our results show altered neurovascular responses in all three macular vascular plexuses in diabetic subjects in the absence of structural neuronal changes on high resolution imaging, suggesting that neurovascular uncoupling may be a key mechanism in the early pathogenesis of DR, well before the clinical appearance of vascular or neuronal loss.