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Ophthalmology Jun 2022To determine the prognostic significance and impact on visual function of the cuticular drusen phenotype in a cohort with intermediate age-related macular degeneration... (Observational Study)
Observational Study
PURPOSE
To determine the prognostic significance and impact on visual function of the cuticular drusen phenotype in a cohort with intermediate age-related macular degeneration (AMD).
DESIGN
Longitudinal, observational study.
PARTICIPANTS
Participants aged 50 years or older, with bilateral large conventional drusen, without late AMD.
METHODS
Multimodal imaging (MMI) and microperimetry were performed at baseline and then every 6 months for up to 3 years. Eyes were graded for the MMI-based presence of cuticular drusen at baseline. Color fundus photographs were used to grade for the presence of pigmentary abnormalities. OCT scans were used to calculate drusen volume. The associations between cuticular drusen and progression to MMI-defined late AMD (including OCT signs of atrophy) and the impact on visual sensitivity were examined with and without adjustment for the confounders of baseline age, pigmentary abnormalities, and drusen volume.
MAIN OUTCOME MEASURES
Time to develop MMI-defined late AMD and change in mean visual sensitivity.
RESULTS
A total of 280 eyes from 140 participants were included, with 70 eyes from 35 individuals (25%) having cuticular drusen at baseline. Cuticular drusen were not significantly associated with an increased rate of progression to late AMD with and without adjustment for confounders (P ≥ 0.784 for both). In an adjusted model, cuticular drusen were not associated with lower baseline visual sensitivity (P = 0.758) or a faster rate of visual sensitivity decline (P = 0.196).
CONCLUSIONS
In a cohort with bilateral large conventional drusen, individuals with the cuticular drusen phenotype had neither a higher nor lower risk of developing late AMD over 3 years and were not associated with a difference in rate of visual sensitivity decline compared with those without this phenotype. As such, individuals with this phenotype currently warrant similar monitoring strategies as those with conventional drusen.
Topics: Bruch Membrane; Disease Progression; Eye Diseases, Hereditary; Humans; Macular Degeneration; Retinal Drusen; Tomography, Optical Coherence
PubMed: 35120992
DOI: 10.1016/j.ophtha.2022.01.028 -
Retina (Philadelphia, Pa.) Feb 2020Cuticular drusen (CD) have been associated with manifestations of age-related macular degeneration such as atrophy and neovascularization in the macula. In this study,...
PURPOSE
Cuticular drusen (CD) have been associated with manifestations of age-related macular degeneration such as atrophy and neovascularization in the macula. In this study, eyes with CD were followed and investigated for the estimated 5-year risk of progression to sequelae of age-related macular degeneration such as geographic atrophy (GA) and macular neovascularization (MNV).
METHODS
A consecutive series of patients with CD were followed for the development of GA and MNV. Whenever possible, they were also studied retrospectively. The patients with CD were categorized into three phenotypic groups. Phenotype 1: eyes had concentrated, densely populated CD in the macular and paramacular area, Phenotype 2: eyes showed scattered CD in the posterior fundus, and Phenotype 3: involved eyes with CD mixed with large drusen (>200 µm). The 5-year incidence of progression was then estimated using a Kaplan-Meier estimator.
RESULTS
A total of 63 eyes from 38 patients (35 women with a mean age at presentation of 58.9 ± 14.2 years) were studied and followed for a mean of 40 ± 18 months. Thirteen patients had single eyes with GA (84.5%; 11/13) or MNV (15.5%; 2/13) in one eye at presentation and were subsequently excluded. Geographic atrophy developed in 19.0% (12/63) of eyes and MNV in 4.8% (3/63) of eyes. The cumulative estimated 5-year risk of GA and MNV was 28.4% and 8.7%, respectively. The estimated 5-year incidence of MNV or GA was 12.6%, 50.0%, and 51.6% in Phenotype 1, Phenotype 2, and Phenotype 3, respectively (P = 0.0015, log-rank test). No difference in risk was found in the development of GA or MNV (P = 0.11) between the subgroup of patients presenting with GA or MNV in their fellow eye and those with both eyes included.
CONCLUSION
When patients with CD are followed longitudinally, there was a significant risk of progression to GA or MNV for Phenotype 2 and Phenotype 3. Patients with CD are commonly first diagnosed in the fifth decade of life, and there is a female predominance. Clinicians should use multimodal imaging to detect and be aware of the risk of progression to manifestations of GA and MNV. These risks of GA and MNV suggest that patients with CD may be part of the overall spectrum of age-related macular degeneration.
Topics: Adult; Aged; Aged, 80 and over; Bruch Membrane; Eye Diseases, Hereditary; Female; Fluorescein Angiography; Follow-Up Studies; Fundus Oculi; Geographic Atrophy; Humans; Incidence; Macula Lutea; Male; Middle Aged; New York; Retinal Drusen; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Tomography, Optical Coherence; Wet Macular Degeneration
PubMed: 31972795
DOI: 10.1097/IAE.0000000000002399 -
Acta Ophthalmologica Sep 2022The retina has enormous lipids demands and must meet those needs. Retinal lipid homeostasis appears to be based on the symbiosis between neurons, Müller glial cells...
PURPOSE
The retina has enormous lipids demands and must meet those needs. Retinal lipid homeostasis appears to be based on the symbiosis between neurons, Müller glial cells (MGC), and retinal pigment epithelium (RPE) cells, which can be impacted in several retinal diseases. The current research challenge is to better understand lipid-related mechanisms involved in retinal diseases, such as age-related macular degeneration (AMD) and glaucoma.
RESULTS
In a first axis, in vitro and focus on Müller glial cell, we aimed to characterize whether the 24S-hydroxycholesterol (24S-OHC), an overexpressed end-product of cholesterol elimination pathway in neural tissue and likely produced by suffering retinal ganglion cells in glaucoma, may modulate MGC membrane organization, such as lipid rafts, to trigger cellular signalling pathways related to retinal gliosis. We have found that lipid composition appears to be a key factor of membrane architecture, especially for lipid raft microdomain formation, in MGC. However, 24S-OHC did not appear to trigger retinal gliosis via the modulation of lipid or protein composition within lipid rafts microdomains. This study provided a better understanding of the complex mechanisms involved in the pathophysiology of glaucoma. On a second clinical ax, we focused on the lipid-related mechanisms involved in the dysfunction of aging RPE and the appearance of drusenoid deposits in AMD. Using the Montrachet population-based study, we intend to report the frequency of reticular pseudodrusen (RPD) and its ocular and systemic risk factors, particularly related to lipid metabolisms, such as plasma lipoprotein levels, carotenoids levels, and lipid-lowering drug intake. Our study showed that RPD was less common in subjects taking lipid-lowering drugs. Lipid-lowering drugs, such as statins, may reduce the risk of RPD through their effect on the production and function of lipoproteins. This observation highlights the potential role of retinal lipid trafficking via lipoproteins between photoreceptors and retinal pigment epithelium cells in RPD formation. Those findings have been complemented with preliminary results on the analysis of plasma fatty acid (FA) profile, a surrogate marker of short-term dietary lipid intake, according to the type of predominant drusenoid deposit, soft drusen or RPD, in age-related maculopathy.
CONCLUSION
Further research on lipid metabolism in retinal diseases is warranted to better understand the pathophysiology of retinal diseases and develop new promising diagnostic, prognostic, and therapeutic tools for our patients.
Topics: Carotenoids; Cholesterol; Fatty Acids; Glaucoma; Gliosis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipid Metabolism; Macular Degeneration; Retinal Drusen
PubMed: 36117363
DOI: 10.1111/aos.15226 -
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 -
Clinical & Experimental Optometry Sep 2019Reticular pseudodrusen (RPD), also known as subretinal drusenoid deposits, represent a morphological change to the retina distinct from other subtypes of drusen by being... (Review)
Review
Reticular pseudodrusen (RPD), also known as subretinal drusenoid deposits, represent a morphological change to the retina distinct from other subtypes of drusen by being located above the level of the retinal pigment epithelium. Although they can infrequently appear in individuals with no other apparent pathology, their highest rates of occurrence are in association with age-related macular degeneration (AMD), for which they hold clinical significance by being highly correlated with end-stage disease sub-types, choroidal neovascularisation and geographic atrophy. Reticular pseudodrusen are also found in other diseases, most notably Sorsby's fundus dystrophy, pseudoxanthoma elasticum and acquired vitelliform lesions. They are found more frequently in females, with increased age and more commonly bilaterally than unilaterally. Increased risk of RPD formation is conveyed by genetic variants known to increase risk of AMD development, including complement factor H, age-related maculopathy susceptibility 2, and high-temperature requirement A serine peptidase 1; however, to date, no genetic factor has been found to predispose to RPD independent of those that carry risks for AMD. They have typical features visible on multimodal imaging, identifiable either as single lesions or more commonly in yellowish-white net-like patterns on colour fundus photography and are particularly distinguishable using spectral domain optical coherence tomography, fundus auto-fluorescence, and near infrared reflectance imaging. On histological examination, RPD have been shown to have distinct compositions in comparison to typical drusen, suggesting different pathways of pathogenesis. Although their aetiology remains unclear, presence of opsin within lesions, a high topographic association with areas of highest rod-photoreceptor concentration and functional deficits most pronounced within the scotopic range, has implicated rod photoreceptor dysfunction as a component of RPD.
Topics: Choroidal Neovascularization; Geographic Atrophy; Humans; Macular Degeneration; Multimodal Imaging; Retinal Drusen
PubMed: 30298528
DOI: 10.1111/cxo.12842 -
Graefe's Archive For Clinical and... Jun 2023Geographic atrophy (GA) is a late-stage form of age-related macular degeneration (AMD) characterized by the expansion of atrophic lesions in the outer retina. There are... (Review)
Review
PURPOSE
Geographic atrophy (GA) is a late-stage form of age-related macular degeneration (AMD) characterized by the expansion of atrophic lesions in the outer retina. There are currently no approved pharmacological treatments to prevent or slow the progression of GA. This review describes the progression and assessment of GA, predictive imaging features, and complement-targeting investigational drugs for GA.
METHODS
A literature search on GA was conducted.
RESULTS
Expansion of atrophic lesions in patients with GA is associated with a decline in several measures of visual function. GA lesion size has been moderately associated with measures obtained through microperimetry, whereas GA lesion size in the 1-mm diameter area centered on the fovea has been associated with visual acuity. Optical coherence tomography (OCT) can provide 3-dimensional quantitative assessment of atrophy and is useful for identifying early atrophy in GA. Features that have been found to predict the development of GA include certain drusen characteristics and pigmentary abnormalities. Specific OCT features, including hyper-reflective foci and OCT-reflective drusen substructures, have been associated with AMD disease progression. Lesion characteristics, including focality, regularity of shape, location, and perilesional fundus autofluorescence patterns, have been identified as predictors of faster GA lesion growth. Certain investigational complement-targeting drugs have shown efficacy in slowing the progression of GA.
CONCLUSION
GA is a progressive disease associated with irreversible vision loss. Therefore, the lack of treatment options presents a significant unmet need. OCT and drugs under investigation for GA are promising future tools for disease management.
Topics: Humans; Geographic Atrophy; Macular Degeneration; Fundus Oculi; Fovea Centralis; Tomography, Optical Coherence; Atrophy; Disease Progression; Fluorescein Angiography
PubMed: 36520185
DOI: 10.1007/s00417-022-05931-z -
Annals of Eye Science Mar 2021Soft drusen and basal linear deposit (BLinD) are two forms of the same extracellular lipid rich material that together make up an Oil Spill on Bruch's membrane (BrM)....
BACKGROUND
Soft drusen and basal linear deposit (BLinD) are two forms of the same extracellular lipid rich material that together make up an Oil Spill on Bruch's membrane (BrM). Drusen are focal and can be recognized clinically. In contrast BLinD is thin and diffusely distributed, and invisible clinically, even on highest resolution OCT, but has been detected on hyperspectral autofluorescence (AF) imaging . We sought to optimize histologic hyperspectral AF imaging and image analysis for recognition of drusen and sub-RPE deposits (including BLinD and basal laminar deposit), for potential clinical application.
METHODS
Twenty locations specifically with drusen and 12 additional locations specifically from fovea, perifovea and mid-periphery from RPE/BrM flatmounts from 4 AMD donors underwent hyperspectral AF imaging with 4 excitation wavelengths (λ 436, 450, 480 and 505 nm), and the resulting image cubes were simultaneously decomposed with our published non-negative matrix factorization (NMF). Rank 4 recovery of 4 emission spectra was chosen for each excitation wavelength.
RESULTS
A composite emission spectrum, sensitive and specific for drusen and presumed sub-RPE deposits (the SDr spectrum) was recovered with peak at 510-520 nm in all tissues with drusen, with greatest amplitudes at excitations λ 436, 450 and 480 nm. The RPE spectra of combined sources Lipofuscin (LF)/Melanolipofuscin (MLF) were of comparable amplitude and consistently recapitulated the spectra S1, S2 and S3 previously reported from all tissues: tissues with drusen, foveal and extra-foveal locations.
CONCLUSIONS
A clinical hyperspectral AF camera, with properly chosen excitation wavelengths in the blue range and a hyperspectral AF detector, should be capable of detecting and quantifying drusen and sub-RPE deposits, the earliest known lesions of AMD, before any other currently available imaging modality.
PubMed: 33791592
DOI: 10.21037/aes-20-12 -
Clinical Ophthalmology (Auckland, N.Z.) 2021Cuticular drusen are part of the spectrum of age-related macular degeneration (AMD) with particular clinical and multimodal imaging characteristics. This drusen... (Review)
Review
Cuticular drusen are part of the spectrum of age-related macular degeneration (AMD) with particular clinical and multimodal imaging characteristics. This drusen subpopulation shares several high-risk single nucleotide polymorphisms with AMD. Despite this feature, they can manifest at a relatively young age, presenting with a female preponderance. Multimodal imaging is essential for characterizing such lesions, using a combination of color fundus photographs, optical coherence tomography (OCT), fluorescein angiography (FA), and fundus autofluorescence (FAF). The classic starry-sky pattern visible on FA and the typical central hypoautofluorescent lesion with hyperautofluorescent rim on FAF is considered the result of a central retinal pigment epithelium (RPE) erosion from these triangular elevations of the RPE-basal lamina. This finding may also be responsible for the typical choroidal hypertransmission appreciated through OCT. The clinical course of cuticular drusen may be relatively benign at early stages, with small drusen presenting at a young age. However, the presence of clinical phenotypes characterized by diffuse involvement and/or accompanying large drusen in patients older than 60 years may confer a significant risk for either macular neovascularization or geographic atrophy.
PubMed: 34584401
DOI: 10.2147/OPTH.S272345 -
Cureus Feb 2023Age-related macular degeneration (AMD) is a highly prevalent macular condition that primarily affects the older population. It is the primary cause of blindness amongst... (Review)
Review
Age-related macular degeneration (AMD) is a highly prevalent macular condition that primarily affects the older population. It is the primary cause of blindness amongst the elderly population. It is an inflammatory disease that characteristically shows choroidal neovascularization and geographic atrophy. The exact pathomechanism of developing AMD is not known. However, certain factors such as increased age, smoking, genetic factors and certain environmental factors are usually associated with the development of the disease. AMD also involves oxidative stress-mediated destruction of retinal pigment epithelial cells and, consequently, that of retinal photoreceptors. Alzheimer's disease (AD) is a degenerative disorder involving the nervous system that usually affects people aged 65 and over. Both AMD and AD are age-related, degenerative conditions that have several similarities and share many of the same risk factors such as vascular conditions like arteriosclerosis, high blood pressure and obesity. It is believed that the early emergence of the clinical manifestations of AMD and AD may also be significantly influenced by oxidative stress and genetic polymorphism in complement factor H. A common pathogenic pathway between AD and AMD is quite likely. Amyloid-β is an aberrant protein that accumulates within the brains of Alzheimer's patients and appears as plaques on magnetic resonance imaging (MRI). These plaques are a pathognomonic sign of Alzheimer's disease. Similar to this, amyloid-β deposits are reported to build up beneath the retina of AMD patients, which appear as tiny clusters of protein-lipid substances known as drusen. It has also been found that individuals suffering from AMD exhibit an increased chance of developing AD than those with no AMD.
PubMed: 36938233
DOI: 10.7759/cureus.34920 -
Graefe's Archive For Clinical and... Mar 2020To provide an integrate multimodal imaging characterization of peripheral drusen in the eyes with and without macular signs of age-related macular degeneration (AMD) and...
PURPOSE
To provide an integrate multimodal imaging characterization of peripheral drusen in the eyes with and without macular signs of age-related macular degeneration (AMD) and to analyze their association with macular findings.
METHODS
In this retrospective, cross-sectional study, subjects with peripheral drusen were imaged with the Optos (Optos PLC, Dunfermline, Scotland, UK) and Spectralis devices to obtain referenced spectral domain optical coherence tomography (SD-OCT) images. Two experienced graders independently graded the ultra-widefield (UWF) pseudocolor and fundus autofluorescence (FAF) images for the presence of peripheral drusen and analyzed peripheral druse features using OCT. Main outcome measures included quantitative and qualitative assessment of peripheral drusen.
RESULTS
Fifty-seven eyes (30 subjects) were included in the analysis. Mean ± SD age was 77.6 ± 9.2 years (range 54-97 years). On pseudocolor images, graders identified the presence of drusen in all the enrolled eyes (Cohen's kappa was 1.0). On FAF images, Cohen's kappa was 0.71. In the topographical assessment, peripheral drusen were detected in 23 cases in the temporal region, in 40 cases in the nasal region, in 40 cases in the inferior region, and in 42 cases in the superior region. On SD-OCT images, peripheral drusen had a high reflective core in 97.1% of cases, while remaining drusen were characterized by a low reflective core. The macula was affected by early/intermediate AMD in 23 eyes (43.5%) and late AMD in 6 eyes (10.5%).
CONCLUSIONS
We provided an integrate multimodal imaging assessment of peripheral drusen in the eyes with and without AMD. Peripheral drusen were characterized by distinguished features that may suggest that these lesions constitute a distinct disease, rather than representing an expansion of AMD.
Topics: Aged; Aged, 80 and over; Cross-Sectional Studies; Female; Fluorescein Angiography; Fundus Oculi; Humans; Male; Middle Aged; Multimodal Imaging; Reproducibility of Results; Retina; Retinal Drusen; Retrospective Studies; Tomography, Optical Coherence
PubMed: 31900644
DOI: 10.1007/s00417-019-04586-7