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Investigating Biomarkers for USH2A Retinopathy Using Multimodal Retinal Imaging

Gill, JS; Theofylaktopoulos, V; Mitsios, A; Houston, S; Hagag, AM; Dubis, AM; Moosajee, M; (2022) Investigating Biomarkers for USH2A Retinopathy Using Multimodal Retinal Imaging. International Journal of Molecular Sciences , 23 (8) , Article 4198. 10.3390/ijms23084198. Green open access

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Abstract

Pathogenic mutations in USH2A are a leading cause of visual loss secondary to non-syndromic or Usher syndrome-associated retinitis pigmentosa (RP). With an increasing number of RP-targeted clinical trials in progress, we sought to evaluate the photoreceptor topography under-lying patterns of loss observed on clinical retinal imaging to guide surrogate endpoint selection in USH2A retinopathy. In this prospective cross-sectional study, twenty-five patients with molecularly confirmed USH2A-RP underwent fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT) and adaptive optics scanning laser ophthalmoscopy (AOSLO) retinal imaging. Analysis comprised measurement of FAF horizontal inner (IR) and outer (OR) hyperautofluorescent ring diameter; SD-OCT ellipsoid zone (EZ) and external limiting membrane (ELM) width, normalised EZ reflectance; AOSLO foveal cone density and intact macular photoreceptor mosaic (IMPM) diam-eter. Thirty-two eyes from 16 patients (mean age ± SD, 36.0 ± 14.2 years) with USH2A-associated Usher syndrome type 2 (n = 14) or non-syndromic RP (n = 2) met the inclusion criteria. Spatial align-ment was observed between IR-EZ and OR-ELM diameters/widths (p <0.001). The IMPM border occurred just lateral to EZ loss (p < 0.001), although sparser intact photoreceptor inner segments were detected until ELM disruption. EZ width and IR diameter displayed a biphasic relationship with cone density whereby slow cone loss occurred until retinal degeneration reached ~1350 µm from the fovea, beyond which greater reduction in cone density followed. Normalised EZ reflectance and cone density were significantly associated (p <0.001). As the strongest correlate of cone density (p < 0.001) and best-corrected visual acuity (p <0.001), EZ width is the most sensitive biomarker of structural and functional decline in USH2A retinopathy, rendering it a promising trial endpoint.

Type: Article
Title: Investigating Biomarkers for USH2A Retinopathy Using Multimodal Retinal Imaging
Open access status: An open access version is available from UCL Discovery
DOI: 10.3390/ijms23084198
Publisher version: https://doi.org/10.3390/ijms23084198
Language: English
Additional information: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
Keywords: USH2A; retinitis pigmentosa; Usher syndrome; fundus autofluorescence; spectral-domain optical coherence tomography; adaptive optics scanning laser ophthalmoscopy
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10147539
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