Stages of Drusen-Associated Atrophy in Age-Related Macular Degeneration Visible via Histologically Validated Fundus Autofluorescence

Chen, Ling; Messinger, Jeffrey D.; Ferrara, Daniela; Freund, K. Bailey; Curcio, Christine A.

doi:10.1016/j.oret.2020.11.006

Cited by 31 publications

(27 citation statements)

References 40 publications

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“…Here we focused on a transition to MNV; a transition to MA is described elsewhere. 40,[100][101][102] We extend this proposal by showing that drusen and SDD topographies reflect those of cone and rod photoreceptors in control eyes as well as AMD. Linking progression to molecular pathways that sustain cones and rods also links AMD to the evolutionary biology of vision, a radically simplifying idea.…”

Section: Discussionsupporting

confidence: 62%

Biometrics, Impact, and Significance of Basal Linear Deposit and Subretinal Drusenoid Deposit in Age-Related Macular Degeneration

Chen

Messinger

Kar

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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Basal linear deposit (BLinD) is a thin layer of soft drusen material. To elucidate the biology of extracellular deposits conferring age-related macular degeneration (AMD) progression risk and inform multimodal clinical imaging based on optical coherence tomography (OCT), we examined lipid content and regional prevalence of BLinD, soft drusen, pre-BLinD, and subretinal drusenoid deposit (SDD) in AMD and non-AMD aged eyes. We estimated BLinD volume and illustrated its relation to type 1 macular neovascularization (MNV).METHODS. Donor eyes were classified as early to intermediate AMD (n = 25) and agematched controls (n = 54). In high-resolution histology, we assessed BLinD/soft drusen thickness at 836 and 1716 locations in AMD and control eyes, respectively. BLinD volume was estimated using solid geometry in donor eyes, one clinically characterized. RESULTS.BLinD, drusen, type 1 MNV, and fluid occupy the sub-RPE-basal laminar space. BLinD volume in a 3-mm diameter circle may be as much as 0.0315 mm 3 . Osmophilic lipid was more concentrated in BLinD/drusen than SDD. In the fovea, BLinD/drusen was prevalent in AMD eyes; pre-BLinD was prevalent in control eyes. SDD was low in the fovea and high in perifovea, especially in AMD eyes. CONCLUSIONS.Although invisible, BLinD may presage type 1 MNV. BLinD volume approaches the criterion OCT drusen volume of 0.03 mm 3 for AMD progression risk. BLinD culminates years of subfoveal lipid accumulation. SDD is detected relatively late in life, with currently unknown precursors. Deposit topography suggests one outer retinal lipid recycling system serving specialized cone and rod physiology, and its dysregulation in AMD is due to impaired transfer to the circulation.

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Section: Discussionsupporting

confidence: 62%

Biometrics, Impact, and Significance of Basal Linear Deposit and Subretinal Drusenoid Deposit in Age-Related Macular Degeneration

Chen

Messinger

Kar

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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“… 7 , 62 This topographic difference in GA expansion rate and GA distribution suggests that GA onset may be driven by different biological processes from GA expansion. Previous histological studies have suggested that GA lesions typically begin over drusen, 63 – 65 consistent with the similar topographic variation between the soft drusen height53 and the percentage area affected by GA in our study. In comparison, GA expansion is unlikely to be driven by drusen, as the atrophic lesions are commonly not surrounded by drusen.…”

Section: Discussionsupporting

confidence: 92%

Local Progression Kinetics of Geographic Atrophy Depends Upon the Border Location

Shen

Sun

Ahluwalia

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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“…These include descent and curving of the external limiting membrane (border of atrophy), reactive gliosis, adherent glial seal in areas of photoreceptor depletion, and invasion of individual drusen. 31 , 44 , 70 , 71 CRALBP immunohistochemistry confirmed HFL fiber geometry as well as retinoid capacity of Müller glia, still supported by retinal circulation late in disease. Single and grouped RPE organelles paralleling Müller glia 7 , 72 are presumably carried intracellularly.…”

Section: Discussionmentioning

confidence: 67%

Hyperreflective Foci, Optical Coherence Tomography Progression Indicators in Age-Related Macular Degeneration, Include Transdifferentiated Retinal Pigment Epithelium

Cao

Leong

Messinger

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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Purpose By optical coherence tomography (OCT) imaging, hyperreflective foci (HRF) indicate progression risk for advanced age-related macular degeneration (AMD) and are in part attributable to ectopic retinal pigment epithelium (RPE). We hypothesized that ectopic RPE are molecularly distinct from in-layer cells and that their cross-retinal course follows Müller glia. Methods In clinical OCT (61 eyes, 44 patients with AMD, 79.4 ± 7.7 years; 29 female; follow-up = 4.7 ± 0.9 years), one HRF type, RPE plume (n = 129 in 4 morphologies), was reviewed. Twenty eyes of 20 donors characterized by ex vivo OCT were analyzed by histology (normal, 4; early/intermediate AMD, 7; geographic atrophy, 6; neovascular AMD, 3). Cryosections were stained with antibodies to retinoid (RPE65, CRALPB) and immune (CD68, CD163) markers. In published RPE cellular phenotypes, red immunoreactivity was assessed semiquantitatively by one observer (none, some cells, all cells). Results Plume morphology evolved over time and many resolved (40%). Trajectories of RPE plume and cellular debris paralleled Müller glia, including near atrophy borders. RPE corresponding to HRF lost immunoreactivity for retinoid markers and gained immunoreactivity for immune markers. Aberrant immunoreactivity appeared in individual in-layer RPE cells and extended to all abnormal phenotypes. Müller glia remained CRALBP positive. Plume cells approached and contacted retinal capillaries. Conclusions HRF are indicators not predictors of overall disease activity. Gain and loss of function starts with individual in-layer RPE cells and extends to all abnormal phenotypes. Evidence for RPE transdifferentiation, possibly due to ischemia, supports a proposed process of epithelial–mesenchyme transition. Data can propel new biomarkers and therapeutic strategies for AMD.

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Stages of Drusen-Associated Atrophy in Age-Related Macular Degeneration Visible via Histologically Validated Fundus Autofluorescence

Cited by 31 publications

References 40 publications

Biometrics, Impact, and Significance of Basal Linear Deposit and Subretinal Drusenoid Deposit in Age-Related Macular Degeneration

Biometrics, Impact, and Significance of Basal Linear Deposit and Subretinal Drusenoid Deposit in Age-Related Macular Degeneration

Local Progression Kinetics of Geographic Atrophy Depends Upon the Border Location

Hyperreflective Foci, Optical Coherence Tomography Progression Indicators in Age-Related Macular Degeneration, Include Transdifferentiated Retinal Pigment Epithelium

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