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

Abstract

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.

Longitudinal Microvascular and Neuronal Retinal Evaluation in Patients With Diabetes Mellitus Types 1 and 2 and Good Glycemic Control

“…An early increase in retinal blood flow in the SCP in DM with no DR, as observed in this study, has been already reported in recent studies 5–7 and interpreted as a compensatory effect to initial capillary occlusion, maybe due to regulatory mechanisms separate from those of deeper vessels and capable of preserving flow at this level. 6 Similarly, Ashraf et al 27 found no correlation between changes observed in the SCP and in the DCP in different DR stages, thus suggesting that these changes may be at least partially independent.…”

“…D iabetic retinopathy (DR) was recently defined as a "highly tissue-specific neurovascular complication" of both Type 1 and Type 2 diabetes mellitus (DM1/DM2) 1 and subclinical evidence of both neuronal and microvascular damage before clinically evident DR has been widely reported. [2][3][4][5][6][7] Even if diabetes mellitus (DM), and especially DM2, prevalence is increasing, 8 most evidence indicates that patients with DM can significantly reduce the risk of diabetes-related complications by maintaining an optimal long-term metabolic control with low glycated hemoglobin (HbA1c) variability. [9][10][11] Current recommendations indicate a target HbA1c level # 6.5% in DM1 and #7% in DM2 to minimize the risk of long-term vascular complications.…”

“…Diabetic retinopathy (DR) was recently defined as a “highly tissue-specific neurovascular complication” of both Type 1 and Type 2 diabetes mellitus (DM1/DM2) 1 and subclinical evidence of both neuronal and microvascular damage before clinically evident DR has been widely reported. 2–7…”

Initiation of L-DOPA Treatment After Detection of Diabetes-Induced Retinal Dysfunction Reverses Retinopathy and Provides Neuroprotection in Rats

“…[7][8][9][10][11][12][13][14][15] Diabetes-induced changes in the ERG may be attributed to neuronal dysfunction, 7,11,16,17 changes in the levels of neurotransmitters, [17][18][19][20] and cell death in the neural retina. 18 In addition, early vascular changes, such as increased vascular permeability as early as 1 week after hyperglycemia in diabetic rodents, 21,22 or structural vascular abnormalities detected with optical coherence tomography angiography in patients with diabetes and no visible microvascular fundus changes [23][24][25] may alter neuronal function owing to neurovascular coupling.…”

CSANet: a lightweight channel and spatial attention neural network for grading diabetic retinopathy with optical coherence tomography angiography

“…As Figure 3A-3F shows, compared with normal eyes, mild NPDR eyes had a small amount of non-perfusion and microvascular tumors in the wide-field OCTA (WF-OCTA) images ( 44 ). As DR progresses from moderate to severe NPDR, the number of non-perfusion areas and microaneurysms increases, and blood vessels become distorted and dilated ( 45 ) ( Figure 3G-3I ).…”