Purpose. To evaluate the presence of hyperreflective spots (HRS) in diabetic patients without clinically detectable retinopathy (no DR) or with nonproliferative mild to moderate retinopathy (DR) without macular edema, and compare the results to controls. Methods. 36 subjects were enrolled: 12 with no DR, 12 with DR, and 12 normal subjects who served as controls. All studied subjects underwent full ophthalmologic examination and spectral domain optical coherence tomography (SD-OCT). SD-OCT images were analyzed to measure and localize HRS. Each image was analyzed by two independent, masked examiners. Results. The number of HRS was significantly higher in both diabetics without and with retinopathy versus controls ( ) and in diabetics with retinopathy versus diabetics without retinopathy ( ). The HRS were mainly located in the inner retina layers (inner limiting membrane, ganglion cell layer, and inner nuclear layer). The intraobserver and interobserver agreement was almost perfect ( ). Conclusions. SD-OCT hyperreflective spots are present in diabetic eyes even when clinical retinopathy is undetectable. Their number increases with progressing retinopathy. Initially, HRS are mainly located in the inner retina, where the resident microglia is present. With progressing retinopathy, HRS reach the outer retinal layer. HRS may represent a surrogate of microglial activation in diabetic retina. 1. Introduction An increasing body of evidence suggests that retinal neurodegeneration and inflammation occur in human diabetes even before the development of clinical signs of diabetic retinopathy (DR) [1]. Retinal neural cell loss (neurodegeneration) has already been demonstrated in vivo (as thinning of retinal nerve fiber and ganglion cell layers), both in type 1 and 2 diabetes [2–7]. Retinal microglia activation has been recognized as the main responsible for the initial inflammatory response, even though the exact mechanism through which inflammatory cytokines are released remains poorly known [8]. Some experimental studies have shown that retinal inflammation occurring during the course of diabetes mellitus is a relatively early event and that it precedes both vascular dysfunction and neuronal degeneration [1, 8]. Joussen at al. demonstrated in animal models of diabetes mellitus that ICAM-1- and CD18-mediated leukocyte adhesion is increased in the retinal vasculature and accounts for many of the signature lesions of DR [1]. Ibrahim et al. demonstrated in rats that the accumulation of Amadori-glycated albumin (AGA) within the 8-week diabetic retina elicits microglial
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