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Investigative Ophthalmology & Visual... Feb 2021To refine estimates of macular soft drusen abundance in eyes with age-related macular degeneration (AMD) and evaluate hypotheses about drusen biogenesis, we investigated... (Observational Study)
Observational Study
PURPOSE
To refine estimates of macular soft drusen abundance in eyes with age-related macular degeneration (AMD) and evaluate hypotheses about drusen biogenesis, we investigated topographic distribution and growth rates of drusen by optical coherence tomography (OCT). We compared results to retinal features with similar topographies (cone density and macular pigment) in healthy eyes.
METHODS
In a prospective study, distribution and growth rates of soft drusen in eyes with AMD were identified by human observers in OCT volumes and analyzed with computer-assistance. Published histologic data for macular cone densities (n = 12 eyes) and in vivo macular pigment optical density (MPOD) measurements in older adults with unremarkable maculae (n = 31; 62 paired eyes, averaged) were revisited. All values were normalized to Early Treatment Diabetic Retinopathy Study (ETDRS) subfield areas.
RESULTS
Sixty-two eyes of 44 patients were imaged for periods up to 78 months. Soft drusen volume per unit volume at baseline is 24.6-fold and 2.3-fold higher in the central ETDRS subfield than in outer and inner rings, respectively, and grows most prominently there. Corresponding ratios (central versus inner and central versus outer) for cone density in donor eyes is 13.3-fold and 5.1-fold and for MPOD, 24.6 and 23.9-fold, and 3.6 and 3.6-fold.
CONCLUSIONS
Normalized soft drusen volume in AMD eyes as assessed by OCT is ≥ 20-fold higher in central ETDRS subfields than in outer rings, paralleling MPOD distribution in healthy eyes. Data on drusen volume support this metric for AMD risk assessment and clinical trial outcome measure. Alignment of different data modalities support the ETDRS grid for standardizing retinal topography in mechanistic studies of drusen biogenesis.
Topics: Aged; Aged, 80 and over; Disease Progression; Female; Fluorescein Angiography; Follow-Up Studies; Fovea Centralis; Fundus Oculi; Humans; Macular Degeneration; Male; Middle Aged; Prospective Studies; Retinal Drusen; Retinal Pigment Epithelium; Tomography, Optical Coherence
PubMed: 33605982
DOI: 10.1167/iovs.62.2.26 -
The British Journal of Ophthalmology Oct 2021To evaluate the various patterns of subretinal fluid (SRF) in eyes with age-related macular degeneration (AMD) in the absence of macular neovascularisation (MNV) and to...
PURPOSE
To evaluate the various patterns of subretinal fluid (SRF) in eyes with age-related macular degeneration (AMD) in the absence of macular neovascularisation (MNV) and to assess the long-term outcomes in these eyes.
METHODS
This retrospective study included only eyes with non-neovascular AMD and associated SRF. Eyes with evidence of MNV were excluded. Spectral-domain optical coherence tomography (SD-OCT) was obtained at baseline and at follow-up, and qualitative and quantitative SD-OCT analysis of macular drusen including drusenoid pigment epithelial detachment (PED) and associated SRF was performed to determine anatomic outcomes.
RESULTS
Forty-five eyes (45 patients) were included in this analysis. Mean duration of follow-up was 49.7±36.7 months. SRF exhibited three different morphologies: crest of fluid over the apex of the drusenoid PED, pocket of fluid at the angle of a large druse or in the crypt of confluent drusen or drape of low-lying fluid over confluent drusen. Twenty-seven (60%) of the 45 eyes with fluid displayed collapse of the associated druse or drusenoid PED and 24 (53%) of the 45 eyes developed evidence of complete or incomplete retinal pigment epithelial and outer retinal atrophy.
CONCLUSION
Non-neovascular AMD with SRF is an important clinical entity to recognise to avoid unnecessary anti-vascular endothelial growth factor therapy. Clinicians should be aware that SRF can be associated with drusen or drusenoid PED in the absence of MNV and may be the result of retinal pigment epithelial (RPE) decompensation and RPE pump failure.
Topics: Angiogenesis Inhibitors; Fluorescein Angiography; Follow-Up Studies; Humans; Intravitreal Injections; Macular Degeneration; Retinal Detachment; Retinal Drusen; Retinal Pigments; Retrospective Studies; Subretinal Fluid; Tomography, Optical Coherence; Vascular Endothelial Growth Factor A; Visual Acuity; Wet Macular Degeneration
PubMed: 32920528
DOI: 10.1136/bjophthalmol-2020-317326 -
Acta Ophthalmologica Aug 2016Age-related macular degeneration (AMD), the most common cause of visual loss after the age of 65, displays a degeneration of the retinal pigment epithelial (RPE) cells... (Review)
Review
Age-related macular degeneration (AMD), the most common cause of visual loss after the age of 65, displays a degeneration of the retinal pigment epithelial (RPE) cells and photoreceptors in the retinal centre (macula). The central macula (fovea) that contains mostly cone photoreceptors mediates the high visual acuity. Drusen maculopathy may lead to visual deterioration. Drusen are extracellular deposits of debris that accumulate on Bruch's membrane. Drusen attract inflammatory, immunological and vasoactive stimuli. RPE and photoreceptor cells overlying drusen exhibit biochemical and morphological signs of degeneration. Strong and intermittent light exposure (photons) induces the formation of free radicals in the very high oxygen tension milieu of the retina. The negative effects of irradiation stimulate accumulation of lipofuscin in RPE and photoreceptor cells leading to mitochondrial dysfunction and apoptotic cell death. A hydrophobic barrier is built up in Bruch's membrane reducing diffusion to the choroid. Hereditary and inflammatory factors modify the risk for AMD. There is a genetic dysregulation of the complement system leading to inappropriate complement activation. The genetic polymorphism of complement factor H (CFH) and age-related maculopathy susceptibilty 2 (ARMS2) increase the risk of progression to advanced AMD. The photoelectric effect creates free radicals, resulting in a continuous increase of lipofuscin formation and impairing mitochondrial activity. In addition, inflammation and complement dysregulation contribute to the formation of drusen and vasoproliferative reactions with neovascularization. Antioxidants neutralize reactive oxygen species and reduce lipofuscin accumulation in RPE and photoreceptor cells. For prophylactic treatment of drusen maculopathy, high doses of antioxidants such as vitamins C and E, lutein, zeaxanthine and zinc are used according to the Age-Related Eye Disease Study 2 (AREDS 2). The risk of developing advanced AMD was reduced by 27% at 10 years follow-up. No adverse events were noted.
Topics: Antioxidants; Humans; Macular Degeneration; Photoreceptor Cells, Vertebrate; Retinal Drusen; Retinal Pigment Epithelium; Risk Factors; Vision Disorders
PubMed: 27009526
DOI: 10.1111/aos.13011 -
Retina (Philadelphia, Pa.) Mar 2020To investigate the prevalence of pachydrusen, soft drusen, and subretinal drusenoid deposits in eyes with different neovascular age-related macular degeneration (nAMD)...
PURPOSE
To investigate the prevalence of pachydrusen, soft drusen, and subretinal drusenoid deposits in eyes with different neovascular age-related macular degeneration (nAMD) subtypes, determine the relationship between each drusen type and the choroidal thickness, and analyze the distinct features of each nAMD subtype according to the drusen type.
METHODS
Medical records involving 454 eyes from 454 patients with nAMD were retrospectively reviewed. The prevalence of each drusen type and the choroidal thickness and choroidal characteristics were evaluated according to the nAMD subtype.
RESULTS
Pachydrusen were prevalent in the typical nAMD (40.4%) and polypoidal choroidal vasculopathy (47.8%) groups and were not detected in the retinal angiomatous proliferation group. No significant drusen were detected in 24.3% of typical nAMD, 43.3% of polypoidal choroidal vasculopathy, and 0% of retinal angiomatous proliferation groups. Regardless of the nAMD subtype, pachydrusen, soft drusen, and subretinal drusenoid deposits were associated with a thick, moderately thick, and thin choroid, respectively. For eyes with typical nAMD, the prevalence of choroidal vascular hyperpermeability and extrafoveal neovascularization was significantly higher in the pachydrusen group than in the other groups. By contrast, the prevalence of Type 2 neovascularization was significantly lower in the pachydrusen group than in the subretinal drusenoid deposit group (P < 0.001 for all).
CONCLUSION
The prevalence of various drusen differed according to the nAMD subtypes, and each drusen type was strongly associated with the choroidal thickness. Typical nAMD showed distinct features according to the accompanying drusen type.
Topics: Aged; Aged, 80 and over; Choroid; Female; Fluorescein Angiography; Follow-Up Studies; Fundus Oculi; Humans; Incidence; Male; Middle Aged; Republic of Korea; Retina; Retinal Drusen; Retrospective Studies; Tomography, Optical Coherence; Visual Acuity; Wet Macular Degeneration
PubMed: 30550531
DOI: 10.1097/IAE.0000000000002419 -
Journal of Clinical Medicine Jun 2020The emergence of pachychoroid disease is changing the concept of age-related macular degeneration (AMD). The concept of pachychoroid diseases was developed through... (Review)
Review
The emergence of pachychoroid disease is changing the concept of age-related macular degeneration (AMD). The concept of pachychoroid diseases was developed through clinical observation of multimodal images of eyes with AMD and central serous chorioretinopathy; however, recent genetic studies have provided a proof of concept for pachychoroid spectrum disease, which should be differentiated from drusen-driven AMD. The genetic confirmation of pachychoroid concept further provides novel viewpoints to decode previously reported findings, which facilitates an understanding of the true nature of pachychoroid diseases and AMD. The purpose of this review was to elucidate the relationship between pachychoroid diseases and AMD by interpreting previous findings on pachychoroid diseases and AMD from the novel viewpoints of genetic associations. We confirmed that previous genetic studies supported the concept of pachychoroid diseases. From a genetic viewpoint, the presence of thick choroid and the presence of choroidal vascular hyperpermeability were important characteristics of pachychoroid spectrum diseases. Previous studies have also suggested the classification of polypoidal choroidal vasculopathy (PCV) into two subtypes, pachychoroid neovasculopathy and drusen-driven PCV. Genetic viewpoints will be beneficial to rearrange subtypes of drusen-driven AMD and pachychoroid spectrum diseases. Further genetic studies are needed to investigate pachyvessels, pachydrusen and the significance of polypoidal lesions in pachychoroid neovasculopathy and drusen-driven AMD/PCV.
PubMed: 32610483
DOI: 10.3390/jcm9072034 -
Histology and Histopathology Feb 2024With aging and age-related macular dystrophy (AMD), proteolytic fragments are deposited in extracellular drusen located between the RPE and Bruch's membrane. Localized...
PURPOSE
With aging and age-related macular dystrophy (AMD), proteolytic fragments are deposited in extracellular drusen located between the RPE and Bruch's membrane. Localized hypoxia may be a risk factor for AMD. Our hypothesis is that following hypoxia, activation of proteolytic enzymes called calpains may cause proteolysis/degeneration of retinal cells and RPE. No direct evidence has yet demonstrated activation of calpains in AMD. The purpose of the present study was to identify calpain-cleaved proteins in drusen.
METHODS
Seventy-six (76) drusen were analyzed in human eye sections from six normal and twelve AMD human donor eyes. The sections were subjected to immunofluorescence for the calpain-specific 150 kDa breakdown product from α-spectrin, SBDP150 - a marker for calpain activation, and for recoverin - a marker for photoreceptor cells.
RESULTS
Among 29 nodular drusen, 80% from normal eyes and 90% from AMD eyes stained positive for SBDP150. Among 47 soft drusen, mostly from AMD eyes, 72% stained positive for SBDP150. Thus, the majority of both soft and nodular drusen from AMD donors contained SBDP150.
CONCLUSIONS
SBDP150 was detected for the first time in soft and nodular drusen from human donors. Our results suggest that calpain-induced proteolysis participates in the degeneration of photoreceptors and/or RPE cells during aging and AMD. Calpain inhibitors may ameliorate AMD progression.
Topics: Humans; Calpain; Retina; Macular Degeneration; Retinal Drusen; Hypoxia
PubMed: 37314158
DOI: 10.14670/HH-18-635 -
PloS One 2021Drusen are known to be the important hallmark to predict the development of age-related macular degeneration (AMD). The prevalence of drusen is lower in Asians compared...
Drusen are known to be the important hallmark to predict the development of age-related macular degeneration (AMD). The prevalence of drusen is lower in Asians compared with Caucasians so that the role of signs constituting early AMD is not well established in Asian populations as in Western countries. In this study, we retrospectively investigated clinical characteristics and 5-year incidence of neovascular AMD (nAMD) in the fellow eye of unilateral nAMD patients. Of 296 consecutive unilateral nAMD patients who had been followed up more than 5 years, 170 typical AMD, 119 polypoidal choroidal vasculopathy, and 7 retinal angiomatous proliferation were included. To examine factors associated with nAMD occurrence in the fellow eye, drusen and pigmentary abnormality in the fellow eye were classified into 4 categories; Category 1: no or small drusen < 63 μm (37.2%), Category 2: 63-125 μm medium drusen or pigmentary abnormality (22.2%), Category 3: large drusen > 125 μm (25.0%), Category P: pachydrusen (15.5%). The mean sub-foveal choroidal thickness (SFCT) was Category 1: 276 μm, Category 2: 308 μm, Category 3: 246 μm, and Category P: 302 μm, respectively. Of note, SFCT in Category 2 and Category P was significantly larger than those of Category 3. Finally, the 5-year incidence of nAMD in the fellow eye was 32/296 (10.8%); Category 1: 0/110 (0%), Category 2: 12/66 (18.2%), Category 3: 20/74 (27.0%), and Category P: 0/46 (0%). Thus, signs of intermediate AMD (large drusen) as well as those of early AMD, especially the pigmentary abnormality, may contribute to development of bilateral nAMD in Japanese patients.
Topics: Aged; Choroid; Female; Humans; Incidence; Japan; Macular Degeneration; Male; Middle Aged; Retina; Retinal Drusen; Retrospective Studies; Tomography, Optical Coherence
PubMed: 34314466
DOI: 10.1371/journal.pone.0255213 -
Journal of Extracellular Vesicles Nov 2021Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. Drusen are key contributors to the etiology of AMD and the ability to modulate drusen...
Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. Drusen are key contributors to the etiology of AMD and the ability to modulate drusen biogenesis could lead to therapeutic strategies to slow or halt AMD progression. The mechanisms underlying drusen biogenesis, however, remain mostly unknown. Here we demonstrate that under homeostatic conditions extracellular vesicles (EVs) secreted by retinal pigment epithelium (RPE) cells are enriched in proteins associated with mechanisms involved in AMD pathophysiology, including oxidative stress, immune response, inflammation, complement system and drusen composition. Furthermore, we provide first evidence that drusen-associated proteins are released as cargo of extracellular vesicles secreted by RPE cells in a polarised apical:basal mode. Notably, drusen-associated proteins exhibited distinctive directional secretion modes in homeostatic conditions and, differential modulation of this directional secretion in response to AMD stressors. These observations underpin the existence of a finely-tuned mechanism regulating directional apical:basal sorting and secretion of drusen-associated proteins via EVs, and its modulation in response to mechanisms involved in AMD pathophysiology. Collectively, our results strongly support an active role of RPE-derived EVs as a key source of drusen proteins and important contributors to drusen development and growth.
Topics: Cell Polarity; Cells, Cultured; Extracellular Vesicles; Humans; Induced Pluripotent Stem Cells; Macular Degeneration; Nicotine; Organoids; Oxidative Stress; Phagocytosis; Proteins; Reactive Oxygen Species; Retinal Drusen; Retinal Pigment Epithelium; Secretome; Signal Transduction
PubMed: 34750957
DOI: 10.1002/jev2.12165 -
Clinical & Experimental Ophthalmology Dec 2014Reticular macular lesions, also known as 'reticular macular disease', 'reticular drusen', 'reticular pseudodrusen', or 'subretinal drusenoid deposits', are a pattern of... (Review)
Review
Reticular macular lesions, also known as 'reticular macular disease', 'reticular drusen', 'reticular pseudodrusen', or 'subretinal drusenoid deposits', are a pattern of lesions commonly found in age-related macular degeneration and best visualized using at least two imaging techniques in combination. Reticular lesions have four stages of progression observable on spectral domain optical coherence tomography, but they do not show the usual signs of regression of soft drusen (calcification and pigment changes). Furthermore, reticular lesions correlate histologically with subretinal drusenoid deposits localized between the retinal pigment epithelium and the inner segment ellipsoid band. Reticular lesions are most commonly seen in older age groups of female patients with age-related macular degeneration and are usually bilateral. They are not clearly associated with known age-related macular degeneration genes and are highly associated with late-stage age-related macular degeneration and an increased mortality rate. They are also associated with alterations in the neural retina and choroid.
Topics: Fluorescein Angiography; Humans; Multimodal Imaging; Phenotype; Retina; Retinal Drusen; Terminology as Topic; Tomography, Optical Coherence
PubMed: 24803342
DOI: 10.1111/ceo.12353 -
Retina (Philadelphia, Pa.) Oct 2023To enable in vivo analysis of drusen composition and lifecycle, the macular nodular and cuticular drusen were assessed using histology.
PURPOSE
To enable in vivo analysis of drusen composition and lifecycle, the macular nodular and cuticular drusen were assessed using histology.
METHODS
Median and interquartile range of base widths of single (nonconfluent) nodular drusen in three sources were determined histologically: 43 eyes of 43 clinically undocumented donors, in an online resource; one eye with punctate hyperfluorescence in fluorescein angiography; and two eyes of one patient with bilateral "starry sky" cuticular drusen. All tissues were processed for high-resolution epoxy-resin histology and for cuticular drusen, transmission electron microscopy.
RESULTS
All drusen localized between the retinal pigment epithelium basal lamina and inner collagenous layer of the Bruch membrane. They were solid, globular, homogeneously stained with toluidine blue, and uncovered by basal laminar deposit and basal mounds. Median base widths were 13.0 µ m (Source 1, N = 128 drusen, interquartile range 7.7, 20.0 µ m), 15.3 µ m (Source 2, N = 87, interquartile range 10.6, 20.5 µ m), and 7.3 µ m (Source 3, N = 78, interquartile range 3.9, 14.1 µ m).
CONCLUSION
In three samples, >90% of solitary nodular drusen were <30 µ m, the visibility threshold in color fundus photography; these drusen are hyperfluorescent in fluorescein angiography. Whether these progress to soft drusen, known as high-risk from epidemiology studies and hypofluorescent, may be determinable from multimodal imaging datasets that include fluorescein angiography.
Topics: Humans; Bruch Membrane; Retinal Drusen; Macular Degeneration; Fluorescein Angiography; Fluoresceins; Staining and Labeling
PubMed: 37399252
DOI: 10.1097/IAE.0000000000003871