Increased Fundus Autofluorescence and Progression of Geographic Atrophy Secondary to Age-Related Macular Degeneration: The GAIN Study

Biarnés, Marc; Arias, Luís; Alonso, Jordi; Garcia, Míriam; Hijano, M; Rodríguez, Anabel; Serrano, A; Badal, Josep; Muhtaseb, H Al; Verdaguer, Paula; Monés, Jordi

doi:10.1016/j.ajo.2015.05.009

Cited by 53 publications

(54 citation statements)

References 32 publications

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“…In RPE flat mounts of AMD eyes, cells are seen to redistribute, aggregate, and overall lose autofluorescent granules in concert with cytoskeletal stress, as they degenerate. 9 Topographically precise longitudinal imaging in GA patients has shown that hyperAF indicates disease activity but does not predict atrophy on either a fine-grain 24 or population 95 basis. In AMD patients imaged with quantitative AF, which standardizes across populations via a fluorescent reference material in the light path, 96 FAF intensities decrease rather than increase.…”

Section: Discussionmentioning

confidence: 99%

Visualizing Retinal Pigment Epithelium Phenotypes in the Transition to Geographic Atrophy in Age-Related Macular Degeneration

Zanzottera

Ach

Huisingh

et al. 2016

Retina

136

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Purpose To inform the interpretation of clinical optical coherence tomography and fundus autofluorescence?imaging in geographic atrophy (GA) of age-related macular degeneration (AMD) by determining the distribution of retinal pigment epithelium (RPE) phenotypes in the transition from health to atrophy (GA) in donor eyes. Method In RPE-Bruch’s membrane flat mounts of 2 GA eyes the terminations of organized RPE cytoskeleton and autofluorescent material were compared. In high-resolution histological sections of 13 GA eyes, RPE phenotypes were assessed at ±500 and ±100 µm from the descent of the external limiting membrane (ELM) towards Bruch’s membrane. The ELM descent was defined as curved, reflected, or oblique in shape. Thicknesses of RPE, basal laminar deposit (BLamD), and RPE+BLamD were measured. Results A border of atrophy that can be precisely delimited is the ELM descent, as opposed to the termination of the RPE layer itself, because of dissociated RPE in the atrophic area. Approaching the ELM descent, the percentage of abnormal RPE morphologies increases, the percentage of age-normal cells decreases, overall RPE thickens, and BLamD does not thin. The combination of RPE plus BLamD is 19.7% thicker at −100 µm from the ELM descent than at −500 µm (23.1 ± 10.7 vs 19.3 ± 8.2 µm; p=0.05). Conclusion The distribution of RPE phenotypes at the GA transition support the idea that these morphologies represent defined stages of a degeneration sequence. The idea RPE dysmorphia including rounding and stacking helps explain variable autofluorescence patterns in GA 14 is reinforced. The ELM descent and RPE+BLamD thickness profile may have utility as SDOCT metrics in clinical trials.

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Section: Discussionmentioning

confidence: 99%

Visualizing Retinal Pigment Epithelium Phenotypes in the Transition to Geographic Atrophy in Age-Related Macular Degeneration

Zanzottera

Ach

Huisingh

et al. 2016

Retina

136

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“…An abnormal accumulation of lipofuscin is a major risk factor implicated in different forms of macular degeneration (Delori et al, 1995a; Marmorstein et al, 2002; Gerth et al, 2007; Biarnes et al, 2015), and also the most notable and consistent pathological finding in BEST1 -linked maculopathies, serving as an indirect biomarker of metabolic activity between the photoreceptor outer segment (POS) turnover and RPE phagocytosis (Bakall et al, 2007; Piñeiro-Gallego et al, 2011; Lei et al, 2013; Singh et al, 2013a). Recent advances with noninvasive retinal imaging modalities have enabled detailed mapping and quantification of fundus autofluorescence (FAF) in vivo , and its correlation with increased levels of lipofuscin components in the aged and diseased retinae (Delori et al, 1995a, 1995b; Brunk and Terman, 2002; Boon et al, 2008; Duncker et al, 2014); however, the polymorphous nature of lipofuscin material and consequences of its buildup in the retina are still controversial.…”

Section: Introductionmentioning

confidence: 99%

Bestrophinopathy: An RPE-photoreceptor interface disease

Guziewicz

Sinha

Gómez

et al. 2017

Progress in Retinal and Eye Research

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Bestrophinopathies, one of the most common forms of inherited macular degenerations, are caused by mutations in the BEST1 gene expressed in the retinal pigment epithelium (RPE). Both human and canine BEST1-linked maculopathies are characterized by abnormal accumulation of autofluorescent material within RPE cells and bilateral macular or multifocal lesions; however, the specific mechanism leading to the formation of these lesions remains unclear. We now provide an overview of the current state of knowledge on the molecular pathology of bestrophinopathies, and explore factors promoting formation of RPE-neuroretinal separations, using the first spontaneous animal model of BEST1-associated retinopathies, canine Best (cBest). Here, we characterize the nature of the autofluorescent RPE cell inclusions and report matching spectral signatures of RPE-associated fluorophores between human and canine retinae, indicating an analogous composition of endogenous RPE deposits in Best Vitelliform Macular Dystrophy (BVMD) patients and its canine disease model. This study also exposes a range of biochemical and structural abnormalities at the RPE-photoreceptor interface related to the impaired cone-associated microvillar ensheathment and compromised insoluble interphotoreceptor matrix (IPM), the major pathological culprits responsible for weakening of the RPE-neuroretina interactions, and consequently, formation of vitelliform lesions. These salient alterations detected at the RPE apical domain in cBest as well as in BVMD- and ARB-hiPSC-RPE model systems provide novel insights into the pathological mechanism of BEST1-linked disorders that will allow for development of critical outcome measures guiding therapeutic strategies for bestrophinopathies.

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“…2, 18–20 The autofluorescent intracellular organelles containing these sources, lipofuscin (L), have further been implicated beyond biomarker status as an agent of AMD and Stargardt disease, and yet strong clinical evidence refutes this hypothesis. 18, 21, 22 _ENREF_19_ENREF_16 Clearly, the chemical composition of L is important to understanding human retinal disease.…”

Section: Introductionmentioning

confidence: 99%

Hyperspectral Autofluorescence Imaging of Drusen and Retinal Pigment Epithelium in Donor Eyes With Age-Related Macular Degeneration

Tong

Ami

Hong

et al. 2016

Retina

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Purpose To elucidate the molecular pathogenesis of age-related macular degeneration (AMD) and interpretation of fundus autofluorescence (AF) imaging, we identified spectral AF characteristics of drusen and retinal pigment epithelium (RPE) in donor eyes with AMD. Methods Macular RPE/Bruch’s membrane (BrM) flat mounts were prepared from 5 donor eyes with AMD. In 12 locations (1–3/eye), hyperspectral AF images in 10-nm-wavelength steps were acquired at 2 excitation wavelengths (λex 436 nm, 480 nm). A non-negative tensor factorization algorithm was used to recover 5 abundant emission spectra and their corresponding spatial localizations. Results At λex 436 nm, we consistently localized a novel spectrum (SDr) with a peak emission near 510 nm in drusen and sub-RPE deposits. Abundant emission spectra seen previously (S0 in BrM and S1, S2, and S3 in RPE lipofuscin/melanolipofuscin (L/ML), respectively), also appeared in AMD eyes, with the same shapes and peak wavelengths as in normal tissue. L/ML spectra localizations in AMD eyes varied widely in their overlap with drusen, ranging from none to complete. Conclusions An emission spectrum peaking at ~510 nm (λex 436 nm) appears to be sensitive and specific for drusen and sub-RPE deposits. One or more abundant spectra from RPE organelles exhibit characteristic relationships with drusen.

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Increased Fundus Autofluorescence and Progression of Geographic Atrophy Secondary to Age-Related Macular Degeneration: The GAIN Study

Abstract: FAF patterns, baseline area of atrophy, and time of follow-up were associated with GA progression. However, FAF patterns seem to be a consequence (not a cause) of enlarging atrophy and their effect on GA progression seems mostly driven by baseline area of atrophy.

Cited by 53 publications

References 32 publications

Visualizing Retinal Pigment Epithelium Phenotypes in the Transition to Geographic Atrophy in Age-Related Macular Degeneration

Visualizing Retinal Pigment Epithelium Phenotypes in the Transition to Geographic Atrophy in Age-Related Macular Degeneration

Bestrophinopathy: An RPE-photoreceptor interface disease

Hyperspectral Autofluorescence Imaging of Drusen and Retinal Pigment Epithelium in Donor Eyes With Age-Related Macular Degeneration

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