High-Resolution Adaptive Optics in Vivo Autofluorescence Imaging in Stargardt Disease

Abstract

Targeting the early pathogenic steps in Stargardt disease type 1 (STGD1) is critical to advance our understanding of this condition and to develop potential therapies. Lipofuscin precursors may accumulate within photoreceptors, leading to photoreceptor damage and preceding retinal pigment epithelial (RPE) cell death. Fluorescence adaptive optics scanning light ophthalmoscopy can provide autofluorescence (AF) images in vivo with microscopic resolution to elucidate the cellular origin of AF abnormalities in STGD1.OBJECTIVE To study the spatial distribution of photoreceptor, RPE, and AF abnormalities in patients with STGD1 at a cellular level. DESIGN, SETTING, AND PARTICIPANTSCross-sectional study using fluorescence adaptive optics scanning light ophthalmoscopy to compare the cones, rods, and RPE cells between 3 patients with STGD1 and 1 control individual. Imaging sessions were conducted at the University of Rochester. Further image analyses were performed at Beijing Tongren Eye Center and the University of Pittsburgh. Data were collected from August 2015 to February 2016, and analysis began in March 2016. MAIN OUTCOMES AND MEASURESStructural appearance of cones, rods, and AF structures at different retinal locations.RESULTS Two women and 1 man with macular atrophy phenotype of STGD1 and visual acuity loss ranging from 20/30 to 20/150 and 1 woman without STGD1 with 20/20 visual acuity were analyzed. Cone and rod spacing was increased in all 3 patients at all locations where photoreceptors were detectable; most cones had a dark appearance. Autofluorescence was low contrast but contained structures consistent with RPE cells in the periphery. In the transition zone peripheral to the foveal atrophic lesion, the structural pattern of AF was more consistent with photoreceptors than RPE cells. The microscopic AF was disrupted within areas of clinically detectable atrophy.CONCLUSIONS AND RELEVANCE Adaptive optics high-resolution images of cones, rods, and RPE cells at the leading disease front of STGD1 macular atrophy show an AF pattern that appears to colocalize with photoreceptors or may result from a combination of AF signals from both RPE cells and photoreceptors. This in vivo observation is consistent with histologic reports of fluorescence arising from photoreceptors in STGD1. The detection of bisretinoid accumulation in the photoreceptors may represent an early pathologic step in STGD1 and can provide an in vivo imaging tool to act as a biomarker of disease progression.

Abnormal Visual Function Outside the Area of Atrophy Defined by Short-Wavelength Fundus Autofluorescence in Stargardt Disease

“…Adaptive optics reflectance and SW-AF imaging suggests that there may be photoreceptor abnormality in areas of only subtle RPE changes. 21 NIR-AF that visualizes RPE atrophy using a loss of the melanin signal yields a larger dark lesion than does SW-AF, and in some cases corresponded to or even exceeded the zone of EZ loss in OCT scans. 22,23 Near infrared SW-AF may be a better measure of RPE integrity, and may show larger areas of involvement, but whether it captures the full dense scotoma remains to be determined.…”

“…Adaptive optics reflectance and SW-AF imaging suggests that there may be photoreceptor abnormality in areas of only subtle RPE changes. 21 …”

Computational Model-Based Estimation of Mouse Eyeball Structure From Two-Dimensional Flatmount Microscopy Images

“…Therefore this method can promote development of RPE cell in situ morphology analysis without loss of 3D eyeball structures and facilitate histopathology image analysis for enhanced studies of RPE cell morphometry for eye-related diseases. 6,21 Notably, a large number of in situ noninvasive fundus imaging technologies have emerged recently, including adaptive optics optical coherence tomography, 40,41 adaptive optics scanning laser ophthalmoscopy, [42][43][44] and fluorescence adaptive optics scanning light ophthalmoscopy, 45,46 among others. With advances in these imaging technologies, RPE morphometry analyses become more important in eye disease research, diagnosis, and treatment.…”

Imaging in inherited retinal disorders

“…Dark spaces in the cone mosaics on AO are correlated with disease severity (Figure 3). 66,67 North-Carolina macular dystrophy. North Carolina macular dystrophy (NCMD) is a rare AD congenital or infantile onset disorder with complete penetrance.…”