Functional OCT angiography reveals early retinal neurovascular dysfunction in diabetes with capillary resolution

Altered retinal neurovascular coupling may contribute to the development and progression of diabetic retinopathy (DR) but remains highly challenging to measure due to limited resolution and field of view of the existing functional hyperemia imaging. Here, we present a novel modality of functional OCT angiography (fOCTA) that allows a 3D imaging of retinal functional hyperemia across the entire vascular tree with single-capillary resolution. In fOCTA, functional hyperemia was evoked by a flicker light stimulation, recorded by a synchronized time-lapse OCTA (i.e., 4D), and extracted precisely from each capillary segment (space) and stimulation period (time) in the OCTA time series. The high-resolution fOCTA revealed that the retinal capillaries, particularly the intermediate capillary plexus, exhibited apparent hyperemic response in normal mice, and significant functional hyperemia loss (P < 0.001) at an early stage of DR with few overt signs of retinopathy and visible restoration after aminoguanidine treatment (P < 0.05). Retinal capillary functional hyperemia has strong potential to provide sensitive biomarkers of early DR, and retinal fOCTA would provide new insights into the pathophysiology, screening and treatment of early DR.