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Nature Communications Dec 2021Age-related Macular Degeneration (AMD), a blinding eye disease, is characterized by pathological protein- and lipid-rich drusen deposits underneath the retinal pigment...
Age-related Macular Degeneration (AMD), a blinding eye disease, is characterized by pathological protein- and lipid-rich drusen deposits underneath the retinal pigment epithelium (RPE) and atrophy of the RPE monolayer in advanced disease stages - leading to photoreceptor cell death and vision loss. Currently, there are no drugs that stop drusen formation or RPE atrophy in AMD. Here we provide an iPSC-RPE AMD model that recapitulates drusen and RPE atrophy. Drusen deposition is dependent on AMD-risk-allele CFH(H/H) and anaphylatoxin triggered alternate complement signaling via the activation of NF-κB and downregulation of autophagy pathways. Through high-throughput screening we identify two drugs, L-745,870, a dopamine receptor antagonist, and aminocaproic acid, a protease inhibitor that reduce drusen deposits and restore RPE epithelial phenotype in anaphylatoxin challenged iPSC-RPE with or without the CFH(H/H) genotype. This comprehensive iPSC-RPE model replicates key AMD phenotypes, provides molecular insight into the role of CFH(H/H) risk-allele in AMD, and discovers two candidate drugs to treat AMD.
Topics: Alleles; Aminocaproic Acid; Complement Factor H; Drug Evaluation, Preclinical; Humans; Induced Pluripotent Stem Cells; Macular Degeneration; Models, Biological; Phenotype; Pyridines; Pyrroles; Retinal Pigment Epithelium
PubMed: 34911940
DOI: 10.1038/s41467-021-27488-x -
Taiwan Journal of Ophthalmology 2022A wide spectrum of phenotypic manifestations characterizes age-related macular degeneration (AMD). Drusen is considered the hallmark of AMD and is located underneath the... (Review)
Review
A wide spectrum of phenotypic manifestations characterizes age-related macular degeneration (AMD). Drusen is considered the hallmark of AMD and is located underneath the retinal pigment epithelium (RPE). In contrast, subretinal drusenoid deposits (SDDs), also known as reticular pseudodrusens, are located in the subretinal space, on top of the RPE. SDDs are poorly detected by clinical examination and color fundus photography. Multimodal imaging is required for their proper diagnosis. SDDs are topographically and functionally related to rods. SDDs cause a deep impairment in retinal sensitivity and dark adaptation. SDDs are dynamic structures that may grow, fuse with each other, or regress over time. An intermediate step in some eyes is the development of an acquired vitelliform lesion. The presence of SDD confers an eye a high risk for the development of late AMD. SDD leads to macular neovascularization, particularly type 3, geographic atrophy, and outer retinal atrophy.
PubMed: 35813798
DOI: 10.4103/tjo.tjo_18_22 -
Eye (London, England) May 2018The first descriptions of ageing macula disorder (AMD), be it under other names, appeared in 1855 and 1868. The earliest accounts of AMD linked the presence of drusen... (Review)
Review
The first descriptions of ageing macula disorder (AMD), be it under other names, appeared in 1855 and 1868. The earliest accounts of AMD linked the presence of drusen with visual loss. It took a century before these connections between drusen and AMD were generally accepted by medical science and in clinical articles. The first signs of AMD appear in the region of the choriocapillaris, Bruch's membrane and the retinal pigment epithelium. The pathogenesis of drusen and of AMD is still uncertain. This is reflected in the wide variation in nomenclature of both, since the first publications.
Topics: History, 19th Century; History, 20th Century; History, 21st Century; Humans; Macular Degeneration; Retinal Drusen; Terminology as Topic
PubMed: 29424832
DOI: 10.1038/eye.2017.298 -
Clinical Ophthalmology (Auckland, N.Z.) 2017Age-related macular degeneration (AMD) is a leading cause of vision loss in patients >50 years old. The hallmark of the disease is represented by the accumulation of... (Review)
Review
Age-related macular degeneration (AMD) is a leading cause of vision loss in patients >50 years old. The hallmark of the disease is represented by the accumulation of extracellular material between retinal pigment epithelium and the inner collagenous layer of Bruch's membrane, called drusen. Although identified almost 30 years ago, reticular pseudodrusen (RPD) have been recently recognized as a distinctive phenotype. Unlike drusen, they are located in the subretinal space. RPD are strongly associated with late AMD, especially geographic atrophy, type 2 and 3 choroidal neovascularization, which, in turn, are less common in typical AMD. RPD identification is not straightforward at fundus examination, and their identification should employ at least 2 different imaging modalities. In this narrative review, we embrace all aspects of RPD, including history, epidemiology, histology, imaging, functional test, natural history and therapy.
PubMed: 29033536
DOI: 10.2147/OPTH.S130165 -
Scientific Reports Apr 2022This study aimed to describe the clinical characteristics of age-related macular degeneration (AMD) eyes with both cuticular drusen (CD) and reticular pseudodrusen...
This study aimed to describe the clinical characteristics of age-related macular degeneration (AMD) eyes with both cuticular drusen (CD) and reticular pseudodrusen (RPD). Clinical records of patients diagnosed with CD or RPD with multimodal imaging was reviewed for patients diagnosed with both CD and RPD. The distribution patterns of CD (macular and diffuse type) and RPD (localized, intermediate, and diffuse type), presence of soft drusen, large drusen (> 200 µm), variant subretinal drusenoid deposits, and macular complications were investigated. Of the 220 eyes of 110 patients diagnosed with CD and 926 eyes of 463 patients diagnosed with RPD, 13 eyes of seven patients met the diagnostic criteria for both CD and RPD. The mean age at initial presentation was 71.4 ± 8.8 years and six patients were female. The mean subfoveal choroidal thickness was 143.8 ± 25.1 µm. The distribution of CD was of the macular type in all eyes. Distribution of RPD was localized in 11 eyes (84.6%) and intermediate in two eyes (15.4%). Soft drusen, large drusen, and variant subretinal drusenoid deposits were present in 13 (100%), 12 (92.3%) and, seven (53.8%) eyes, respectively. Macular neovascularization was observed in two eyes (15.4%). CD and RPD can coexist in eyes with AMD. Multimodal imaging should be used for AMD eyes with features suggestive of CD and RPD, considering the high likelihood of developing late AMD.
Topics: Choroid; Female; Fluorescein Angiography; Humans; Macular Degeneration; Retina; Retinal Drusen; Tomography, Optical Coherence
PubMed: 35383241
DOI: 10.1038/s41598-022-09608-9 -
Translational Vision Science &... Dec 2020To investigate the structure-function relationship in eyes with drusen with mesopic and scotopic microperimetry.
PURPOSE
To investigate the structure-function relationship in eyes with drusen with mesopic and scotopic microperimetry.
METHODS
We analyzed structural and functional data from 43 eyes with drusen. Functional data were acquired with mesopic and scotopic two-color (red and cyan) microperimetry. Normative values were calculated using data from 56 healthy eyes. Structural measurements were green autofluorescence and dense macular optical coherence tomography scans. The latter were used to calculate the retinal pigment epithelium elevation (RPE-E) and the photoreceptor reflectivity ratio (PRR). The pointwise structure-function relationship was measured with linear mixed models having the log-transformed structural parameters as predictors and the sensitivity loss (SL, deviation from normal) as the response variable.
RESULTS
In the univariable analysis, the structural predictors were all significantly correlated ( < 0.05) with the SL in the mesopic and scotopic tests. In a multivariable model, mesopic microperimetry yielded the best structure-function relationship. All predictors were significant ( < 0.05), but the predictive power was weak (best = 0.09). The relationship was improved when analyzing locations with abnormal RPE-E (best = 0.18).
CONCLUSIONS
Mesopic microperimetry shows better structure-function relationship compared to scotopic microperimetry; the relationship is weak, likely due to the early functional damage and the small number of tested locations affected by drusen. The relationship is stronger when locations with drusen are isolated for the mesopic and scotopic cyan test.
TRANSLATIONAL RELEVANCE
These results could be useful to devise integrated structure-function methods to detect disease progression in intermediate age-related macular degeneration.
Topics: Humans; Macular Degeneration; Retina; Retinal Drusen; Tomography, Optical Coherence; Visual Field Tests
PubMed: 33442497
DOI: 10.1167/tvst.9.13.43 -
PloS One 2022The purpose of this study was to examine the ocular and systemic risk profile of the fundus phenotype ≥ 20 small hard (macular) drusen (< 63 μm in diameter).
PURPOSE
The purpose of this study was to examine the ocular and systemic risk profile of the fundus phenotype ≥ 20 small hard (macular) drusen (< 63 μm in diameter).
METHODS
This single-center, cross-sectional study of 176 same-sex twin pairs aged 30 to 80 (median 60) years was a component of a framework study of the transition from not having age-related macular degeneration to having early AMD. Drusen categories assessed using fundus photography and optical coherence tomography included small hard drusen (diameter < 63 μm), intermediate soft drusen (63-125 μm), and large soft drusen (> 125 μm), of which the soft drusen are compatible with a diagnosis of AMD.
RESULTS
Having ≥ 20 small hard drusen within or outside the macula was associated with increasing age, lower body mass index, shorter axial length, hyperopia, female sex, increasing high-density lipoprotein (HDL), high alcohol consumption, and with the presence of soft drusen.
CONCLUSIONS
Having ≥ 20 small hard drusen was associated with some AMD-related risk factors, but not with smoking, increasing body mass index, and higher blood pressure. Having ≥ 20 small hard drusen was also associated with soft drusen, in agreement with previous studies. These findings suggest that small hard drusen are not an early manifestation of AMD but the product of a distinct process of tissue alteration that promotes the development of AMD or some subtype thereof.
Topics: Female; Humans; Cross-Sectional Studies; Retinal Drusen; Macular Degeneration; Retina; Risk Factors; Tomography, Optical Coherence
PubMed: 36548342
DOI: 10.1371/journal.pone.0279279 -
Soft Drusen in Age-Related Macular Degeneration: Biology and Targeting Via the Oil Spill Strategies.Investigative Ophthalmology & Visual... Mar 2018AMD is a major cause of legal blindness in older adults approachable through multidisciplinary research involving human tissues and patients. AMD is a... (Review)
Review
AMD is a major cause of legal blindness in older adults approachable through multidisciplinary research involving human tissues and patients. AMD is a vascular-metabolic-inflammatory disease, in which two sets of extracellular deposits, soft drusen/basal linear deposit (BLinD) and subretinal drusenoid deposit (SDD), confer risk for end-stages of atrophy and neovascularization. Understanding how deposits form can lead to insights for new preventions and therapy. The topographic correspondence of BLinD and SDD with cones and rods, respectively, suggest newly realized exchange pathways among outer retinal cells and across Bruch's membrane and the subretinal space, in service of highly evolved, eye-specific physiology. This review focuses on soft drusen/BLinD, summarizing evidence that a major ultrastructural component is large apolipoprotein B,E-containing, cholesterol-rich lipoproteins secreted by the retinal pigment epithelium (RPE) that offload unneeded lipids of dietary and outer segment origin to create an atherosclerosis-like progression in the subRPE-basal lamina space. Clinical observations and an RPE cell culture system combine to suggest that soft drusen/BLinD form when secretions of functional RPE back up in the subRPE-basal lamina space by impaired egress across aged Bruch's membrane-choriocapillary endothelium. The soft drusen lifecycle includes growth, anterior migration of RPE atop drusen, then collapse, and atrophy. Proof-of-concept studies in humans and animal models suggest that targeting the "Oil Spill in Bruch's membrane" offers promise of treating a process in early AMD that underlies progression to both end-stages. A companion article addresses the antecedents of soft drusen within the biology of the macula.
Topics: Apolipoproteins B; Apolipoproteins E; Humans; Macular Degeneration; Retinal Drusen; Retinal Pigment Epithelium
PubMed: 30357336
DOI: 10.1167/iovs.18-24882 -
Scientific Reports Apr 2021The natural history and clinical significance of pachydrusen is unclear. This study aims to compare the longitudinal changes of eyes with pachydrusen and soft drusen and...
The natural history and clinical significance of pachydrusen is unclear. This study aims to compare the longitudinal changes of eyes with pachydrusen and soft drusen and progression to exudative macular neovascularisation (MNV). Patients with a diagnosis of MNV in one eye only and the fellow eye was selected as the study eye. Study eyes were required to have pachydrusen or soft drusen on fundus photographs and follow up of at least 2 years or until exudative MNV occurred. Systematic grading was performed at baseline and change in drusen area and onset of exudative MNV recorded over the period of follow up. A total of 75 eyes from 75 patients (29 with pachydrusen and 46 with soft drusen) were included. There was no difference in the rate of progression to exudative MNV in the soft and pachydrusen groups (13.3% versus 24.1%, p = 0.38). Pachydrusen, as compared to soft drusen, was associated with polypoidal choroidal vasculopathy subtype (85.7% versus 16.7%, p < 0.01) and the location of exudation was co-localised with soft drusen but not with pachydrusen. There was a higher rate of increase in soft drusen area compared to pachydrusen area (27.7 ± 31.9%/year versus 8.7 ± 12.4%/year respectively, p < 0.01). We found no difference in the proportion of eyes that developed exudative MNV in this study however characterisation of drusen evolution patterns revealed a strong association with exudative MNV subtype.
Topics: Aged; Choroidal Neovascularization; Disease Progression; Female; Humans; Macular Degeneration; Male; Retinal Drusen; Tomography, Optical Coherence
PubMed: 33820941
DOI: 10.1038/s41598-021-87083-4 -
Journal of Biological Engineering May 2022Age-related macular degeneration (AMD) is a progressive, degenerative disease of the macula, leading to severe visual loss in the elderly population. There are two types... (Review)
Review
Age-related macular degeneration (AMD) is a progressive, degenerative disease of the macula, leading to severe visual loss in the elderly population. There are two types of AMD: non-exudative ('dry') AMD and exudative ('wet') AMD. Non-exudative AMD is characterized by drusen formation and macular atrophy, while the blood vessels are not leaky. Exudative AMD is a more advanced form of the disease, featured with abnormal blood vessel growth and vascular leakage. Even though anti-angiogenic therapies have been effective in treating wet AMD by normalizing blood vessels, there is no treatment available to prevent or treat dry AMD. Currently, the mechanisms of drusen formation and macular atrophy in the dry AMD are poorly understood, in part because the currently available in vivo models of AMD could not decouple and isolate the complex biological and biophysical factors in the macular region for a detailed mechanism study, including the complement system, angiogenesis factors, extracellular matrix, etc. In the present review article, we describe the biological background of AMD and the key cells and structures in AMD, including retinal epithelium, photoreceptor, Bruch's membrane, and choriocapillaris. We also discuss pre-clinical animal models of AMD and in vivo tissue-engineered approaches, including cell suspension injection and organoid-derived cell sheet transplantation. We also discuss in vitro tissue-engineered models for AMD research. Specifically, we evaluate and compare currently available two- and three-dimensional AMD tissue-engineered models that mimic key anatomical players in AMD progression, including pathophysiological characteristics in Bruch's membrane, photoreceptor, and choriocapillaris. Finally, we discuss the limitation of current AMD models and future directions.
PubMed: 35578246
DOI: 10.1186/s13036-022-00291-y