Correlation of Histologic Features with In Vivo Imaging of Reticular Pseudodrusen

Greferath, Ursula; Guymer, Robyn H.; Vessey, Kirstan A.; Brassington, Kate; Fletcher, Erica L.

doi:10.1016/j.ophtha.2016.02.009

Cited by 110 publications

(122 citation statements)

References 32 publications

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“…70–73 An equivalent population has not yet been described in normal aged human eyes, although microglia appear in atrophic areas 61, 69, 70 and in association with advanced subretinal drusenoid deposits. 74 Alternatively, several mouse models involving targeted disruption of mechanistically diverse pathways also exhibit ‘sloughed’ RPE 75–80 , supporting the concept that RPE stress responses are a final common pathway to multiple different stressors. What molecular signals prompt RPE to assume migratory behaviors in human GA eyes is unspecified.…”

Section: Discussionmentioning

confidence: 96%

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: 96%

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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“…10 In a more recent histologic study, Greferath and colleagues reported SDD in the outer nuclear layer juxtaposed to photoreceptor outer segments, along with overlying photoreceptor disruption and loss. 46 Although Greferath reported a lack of choroidal changes in association with RPD, this study focused on cross-sections of larger vessels in the choroid and provided no quantitative flatmount studies or detailed endothelial immunohistochemical or electron microscopic methods that would be necessary to evaluate the integrity of the choriocapillaris.…”

Section: Discussionmentioning

confidence: 99%

Choriocapillaris Nonperfusion is Associated With Poor Visual Acuity in Eyes With Reticular Pseudodrusen

Nesper

Soetikno

Fawzi

2017

American Journal of Ophthalmology

119

124

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Purpose To study choriocapillaris blood flow in age-related macular degeneration (AMD) using optical coherence tomography angiography (OCTA) and study its correlation to vision (VA) in eyes with reticular pseudodrusen (RPD) versus those with drusen without RPD (drusen). Design Cross-sectional study Methods Patients with either drusen or RPD in early AMD underwent OCTA imaging of the superior, inferior, and/or nasal macula. We quantified “percent choriocapillaris area of non-perfusion” (PCAN) in eyes with RPD versus those with drusen. We assessed the repeatability of PCAN and its correlations with VA. Results Twenty-nine eyes of 26 patients with RPD and 21 eyes of 16 age-matched AMD patients with drusen were included. Qualitatively, the choriocapillaris in areas with RPD showed focal dark regions without flow signal on OCTA (non-perfusion). The repeatability coefficient of PCAN was 0.49%. Eyes with RPD had significantly greater PCAN compared to eyes with drusen (7.31% and 3.88%, respectively; P < 0.001). We found a significant correlation between PCAN and VA for the entire dataset (r = 0.394, P = 0.005). When considering eyes with RPD separately, this correlation was stronger (r = 0.474, P = 0.009) but lost significance when considering eyes with drusen separately (r = 0.175, P = 0.45). Conclusions Eyes with RPD have significantly larger areas of choriocapillaris non-perfusion compared to eyes with drusen and no RPD. The correlation between PCAN and VA in this RPD population provides a potential mechanistic explanation for vision compromise in RPD compared to other forms of drusen in AMD.

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“…This hypothesis is supported by experimental studies in mouse models, in which subretinal microglia are active in aging 59,60 compared to intermediate disease and worse in humans. 61, 62 Notably in human GA, pigmented cells resembling ‘sloughed’ and ‘intraretinal’ RPE express an inflammatory marker (CD163, a haptoglobin-hemoglobin scavenger) typical of bone marrow-derived macrophages, suggesting a new range of activities. 61 Transdifferentiation is the changing of a cell from one differentiated state to another.…”

Section: Discussionmentioning

confidence: 99%

Histologic and Optical Coherence Tomographic Correlates in Drusenoid Pigment Epithelium Detachment in Age-Related Macular Degeneration

et al. 2017

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Purpose Drusenoid pigment epithelium detachment (D-PED) is a known precursor to geographic atrophy in age-related macular degeneration (AMD). We sought histological correlates for spectral-domain optical coherence tomography (SD-OCT) signatures in D-PED and determined the frequency and origin of these OCT signatures in a clinical cohort of D-PED eyes. Design Laboratory imaging-histology comparison; Retrospective, observational cohort study. Participants Four donor eyes with histopathologic diagnosis of AMD (2 non-neovascular D-PED and 2 neovascular PED); 49 eyes of 33 clinic patients with non-neovascular D-PED > 2 mm in diameter. Method Donor eyes underwent multimodal ex vivo imaging including SD-OCT then processing for high-resolution histology. All clinic patients were imaged with SD-OCT, near-infrared reflectance and color photography. Main Outcome Measures Histologic correlates for SD-OCT signatures in D-PED; Estimate of coverage by different RPE phenotypes in the D-PED surface; Frequency and origin of histologically-verified SD-OCT signatures in a clinical cohort of D-PED eyes; Comparisons of histological features between neovascular PED and D-PED due to AMD. Results Intraretinal and subretinal hyperreflective foci as seen on SD-OCT correlated to RPE cells on histology. Hypertransmission of light below the RPE+basal lamina band correlated with dissociated RPE. Subretinal hyperreflective material due to acquired vitelliform lesions corresponded to regions of apically expelled RPE organelles. In the clinical cohort, all histologically verified reflectivity signatures were visible and quantifiable. The appearance of intraretinal hyperreflective foci was preceded by thickening of the RPE-basal lamina band. Compared to PEDs associated with neovascular AMD, D-PEDs had different crystallization patterns, no lipid-filled cells, and thinner basal laminar deposits. Conclusion Multiple RPE fates in AMD, including intraretinal cells that are highly prognostic for progression, can be reliably followed and quantified using eye-tracked serial SD-OCT. This information may be particularly useful for obtaining an accurate timeline of incipient geographic atrophy in clinic populations and for quantifying anatomic endpoints and response to therapy in AMD clinical trials.

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Correlation of Histologic Features with In Vivo Imaging of Reticular Pseudodrusen

Abstract: Reticular pseudodrusen represent subretinal deposits that extend through the outer nuclear layer, affect photoreceptor integrity, and are associated with retinal gliosis and RPE damage.

Cited by 110 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

Choriocapillaris Nonperfusion is Associated With Poor Visual Acuity in Eyes With Reticular Pseudodrusen

Histologic and Optical Coherence Tomographic Correlates in Drusenoid Pigment Epithelium Detachment in Age-Related Macular Degeneration

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