Photoreceptor (PR) degeneration, gliosis, and relation to supporting tissues in geographic atrophy (GA) of age-related macular degeneration (AMD)

Abstract

Purpose : To inform the interpretation of optical coherence tomography (OCT), we histologically characterize GA and surrounding tissues, including quantification of structures contributing to PR-attributable bands in OCT, at standard distances from a GA border defined by the descent of the external limiting membrane (ELM) towards Bruch’s membrane (BrM). Findings are correlated to retinal pigment epithelium (RPE), choriocapillaris endothelium, BrM, and extracellular deposits.

Methods : Submicrometer epoxy sections of 13 eyes of 12 Caucasian donors were scanned under oil and assessed for published and newly defined cellular and laminar phenotypes at ±500 and ±100 µm from the ELM descent in central and superior macula (170 locations). Trends across this boundary were assessed with generalized estimating equations and logit models.

Results : Neurosensory retina: towards the ELM descent (GA border), PR nuclei appeared in the Henle fiber layer (HFL), resulting in dyslamination (indistinguishable ONL and HFL) at 40.3% of locations 100 µm from the ELM descent. Inner segment myoids (ISmy) shortened. PR nuclei and mitochondria translocated inward. Across the ELM descent and into the GA area, ISmy and ONL thickness declined to zero (p=0.039; 0.009); the distance between outer plexiform layer (OPL) and ELM declined from 56.7±22.1 µm to 27.2±18.7 µm, p=0.038), but not to zero, because Müller cells filled this space. Supporting tissues: towards the ELM descent, the RPE-basal laminar deposit (BLamD) complex thickened. In the GA area, BLamD persisted. From -500 µm (outside GA) to +500 µm (within GA) choriocapillary endothelium density along BrM decreased from 0.45 to 0.21 (p=0.0474). BrM thinned due to loss of intercapillary pillars (1.87 to 1.14 µm, p=0.0446).

Conclusions : Representing the scrolling of PR by Müller cells in advance of spreading RPE demise, the ELM descent sharply delimits an area of marked gliosis and near-total PR depletion clinically defined as GA. In contrast, degeneration of support tissues across this boundary is gradual. Segmentation of the HFL-ONL band may be complicated by reflectivity profiles of dyslamination and mitochondrial translocation. Data encourage the identification of novel AMD clinical trial endpoints, representing earlier stages in GA progression, before intense gliosis impedes intervention.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.