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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 -
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 -
Acta Ophthalmologica Dec 2023Globally age-related macular degeneration (AMD) is a leading cause of blindness with a significant impact on quality of life. Geographic atrophy (GA) is the atrophic... (Review)
Review
Globally age-related macular degeneration (AMD) is a leading cause of blindness with a significant impact on quality of life. Geographic atrophy (GA) is the atrophic late form of AMD and its prevalence increases markedly with age with around 1 in 5 persons aged 85 and above having GA in at least one eye. Bilateral GA leads to severe visual impairment thus posing a significant burden on patients, careers and health providers. The incidence and prevalence of GA varies across different geographic regions, with the highest rates in those of European ancestry. Although heterogeneity in definitions of GA and reporting strategy can explain some of the discrepancies, the data overall are consistent in showing a lower prevalence in other ethnicities such as those of Asian heritage. This is at present unexplained but thought to be due to the existence of protective factors such as differences in eye pigmentation, diet, environmental exposures and genetic variability. This review covers key aspects of the prevalence and incidence of the ocular precursor features of GA (large drusen, pigmentary abnormalities and reticular pseudo-drusen), the late stage of GA and factors that have been known to be associated with modifying risk including systemic, demographic, environment, genetic and ocular. Understanding the global epidemiology scenario is crucial for the prevention of and management of patients with GA.
Topics: Humans; Geographic Atrophy; Retinal Drusen; Quality of Life; Macular Degeneration; Retina
PubMed: 37933608
DOI: 10.1111/aos.15767 -
Frontiers in Bioscience (Elite Edition) Jan 2017There is growing evidence of epidemiological, genetic, molecular and clinical links between Alzheimer's disease (AD) and age-related macular degeneration (AMD). Major... (Review)
Review
There is growing evidence of epidemiological, genetic, molecular and clinical links between Alzheimer's disease (AD) and age-related macular degeneration (AMD). Major interest in the relationship between AD and AMD has derived from the evidence that beta-amyloid, the main component of senile plaques, the hallmark of AD, is also an important component of drusen, the hallmark of AMD. This finding has a great potential in the present era of anti-amyloid agents for the treatment of AD. The connection between AD and AMD is also supported by the evidence that the two diseases share other pathophysiological factors, such as oxidative stress and neuroinflammation. Accordingly, a few clinical trials have evaluated the efficacy of antioxidants on visual and cognitive performance in patients presenting both disorders. In this review, we summarize the pathophysiological and clinical evidence of the relationship between these two age-related disorders. Considering the increasing prevalence of both conditions along with the aging of the population, further investigations of this important issue are highly needed.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Clinical Trials as Topic; Humans; Macular Degeneration; Oxidative Stress; Prevalence; Retinal Drusen; Risk Factors
PubMed: 27814598
DOI: 10.2741/e794 -
Ophthalmology Science Dec 2021To elucidate the prevalence of soft drusen, pseudodrusen, and pachydrusen and their 5-year changes in a Japanese population.
PURPOSE
To elucidate the prevalence of soft drusen, pseudodrusen, and pachydrusen and their 5-year changes in a Japanese population.
DESIGN
Longitudinal population-based cohort study conducted from 2013 through 2017.
PARTICIPANTS
Residents 40 years of age or older.
METHODS
Nonmydriatic color fundus photographs were used to grade drusen subtypes and retinal pigment epithelium (RPE) abnormalities according to the Three Continent Age-Related Macular Degeneration Consortium. The 5-year changes of each drusen were investigated.
MAIN OUTCOME MEASURES
The prevalence of each drusen subtype and the 5-year changes of each drusen.
RESULTS
Among 1731 participants, 1660 participants had gradable photographs that were assessed. The age-adjusted prevalence of soft drusen, pachydrusen, and pseudodrusen was 4.3% (95% confidence interval [CI], 3.2%-5.8%), 7.7% (95% CI, 6.2%-9.7%), and 2.8% (95% CI, 1.7%-4.2%), respectively. Pachydrusen accounted for 82.0% (n = 50) of the extramacular drusen (n = 61). Pigment abnormalities were seen in 28.3% and 8.3% of eyes with soft drusen and pachydrusen, respectively ( < 0.0001). Longitudinal changes were investigated in 1444 participants with follow-up examinations, which showed an increase in size in 8.3% and 3.7% and regression in 1.7% and 5.5% for eyes with soft drusen and pachydrusen, respectively. No participants demonstrated RPE atrophy after pachydrusen regression.
CONCLUSIONS
The prevalence of pachydrusen was higher than that of soft drusen and pseudodrusen combined. Pachydrusen may regress over time and typically is not associated with RPE atrophy as detected using color fundus photographs.
PubMed: 36246945
DOI: 10.1016/j.xops.2021.100081 -
Kidney International Reports Apr 2022Complement has been implicated in systemic lupus erythematosus (SLE) pathogenesis on the basis of the associations with inherited complement defects and genome-wide...
INTRODUCTION
Complement has been implicated in systemic lupus erythematosus (SLE) pathogenesis on the basis of the associations with inherited complement defects and genome-wide association study risk alleles, glomerular deposits, reduced serum levels, and occasional reports of retinal drusen. This study examined drusen in SLE and their clinical significance.
METHODS
This cross-sectional observational study compared individuals with SLE recruited from renal and rheumatology clinics with hospital controls. Participants were reviewed for clinical features and underwent imaging with a nonmydriatic retinal camera. Deidentified images were examined by 2 trained graders for drusen number and size using a grid overlay.
RESULTS
The cohort with SLE ( 65) comprised 55 women (85%) and 10 men (15%) with a median age of 47 years (interquartile range 35-59), where 23 (35%) were of southern European or Asian ancestry, and 32 (49%) had biopsy-proven lupus nephritis. Individuals with SLE had higher mean drusen numbers than controls (27 ± 60, 3 ± 9, respectively, = 0.001), more drusen counts ≥10 (31, 48% and 3, 5%, respectively, < 0.001), and more medium-large drusen (14, 22% and 3, 5%, respectively, < 0.001). In SLE, mean drusen counts were higher, and drusen were larger, with an estimated glomerular filtration rate (eGFR) <90 ml/min per 1.73 m ( = 0.02, = 0.02, respectively) or class IV nephritis ( = 0.03, = 0.02).
CONCLUSION
Drusen composition resembles that of glomerular immune deposits. CFH controls complement activation in the extracellular matrix and risk variants are shared by drusen in macular degeneration and by SLE. CFH represents a possible treatment target for SLE especially with renal impairment.
PubMed: 35497809
DOI: 10.1016/j.ekir.2022.01.1063 -
American Journal of Ophthalmology Jan 2024Retinal drusen have been described in people with IgA nephropathy. We examined the frequency of drusen in IgA nephropathy and compared their location and composition...
PURPOSE
Retinal drusen have been described in people with IgA nephropathy. We examined the frequency of drusen in IgA nephropathy and compared their location and composition with those for drusen in age-related macular degeneration.
DESIGN
Immunohistological case series of eyes of patients with IgA nephropathy, and a comparison eye with age-related macular degeneration.
METHODS
Donor eyes from 4 individuals (3 male, 1 female, aged 40-80 years) with biopsy-proven IgA nephropathy and kidney failure were examined for the presence of drusen, and location and composition using antibodies for vitronectin, IgA, IgM, IgG, C3, and C1q. Results were compared with those for drusen in macular degeneration without IgA nephropathy.
RESULTS
All 4 donors had sparse, subretinal pigment epithelium drusen of 55-65 mm diameter that stained for vitronectin but not for IgA or complement. All donors had retinal capillaries and choriocapillaris staining for IgA. The youngest donor (female, 40) had rare deposits in the outer nuclear layer that stained for IgA, but not for vitronectin. The oldest donor (male, 82) had large cystlike spaces in the inner nuclear and plexiform layers, and smaller cysts in the outer nuclear layer, with no staining for IgA or complement.
CONCLUSIONS
Retinal drusen are uncommon in IgA nephropathy, even with kidney failure. Drusen in IgA nephropathy resemble drusen found in age-related macular degeneration. IgA-staining deposits in the outer nuclear layer were likely due to systemic deposition of IgA and complement activation. The nature of cystic spaces is unknown. Further analysis of the retinas of people with glomerulonephritis is recommended.
Topics: Humans; Male; Female; Retinal Drusen; Glomerulonephritis, IGA; Vitronectin; Macular Degeneration; Renal Insufficiency; Immunoglobulin A
PubMed: 37757996
DOI: 10.1016/j.ajo.2023.09.019 -
Ophthalmologica. Journal International... 2022The transition from a normal fundus to one with early drusen (≥20 small hard drusen) to age-related macular degeneration (AMD) in the form of drusen ≥63 μm in...
INTRODUCTION
The transition from a normal fundus to one with early drusen (≥20 small hard drusen) to age-related macular degeneration (AMD) in the form of drusen ≥63 μm in diameter is of interest, because small hard drusen may be precursors of large drusen. Study of AMD precursor lesions may provide valuable insight into factors that initiate AMD. Here, the progression of drusen was studied over an interval of 20 years in a population-based twin cohort.
METHODS
Single-center, 20-year follow-up of 138 twins include biometry, fundus optical coherence tomography, and fundus photography. Macular characteristics were hierarchically classified as (per eye) (1) <20 small hard drusen, (2) ≥20 small hard drusen, (3) drusen ≥63 μm, or (4) ≥20 small hard drusen combined with drusen ≥63 μm. Additive and dominant genetic effects as well as shared and nonshared environmental effects were analyzed in a bivariate biprobit model with a classic liability-threshold approach and polygenic modeling with random effects.
RESULTS
Median participant age was 59 (range 41-66) years. Of 25 (18%) cases of incident macular drusen, 7 had ≥20 small hard drusen, and 18 had drusen ≥63 μm at follow-up, whereas no participant had developed both traits simultaneously. Smoking was associated with incident ≥20 small hard drusen (p = 0.04) and incident drusen ≥63 μm (p = 0.003). Having ≥20 small hard drusen at baseline was associated with incident drusen ≥63 μm at follow-up (p = 0.02). Development of drusen ≥63 μm was attributable to 49% genetic effects and 51% environmental effects.
CONCLUSION
The risk of progressing from 0 to 19 small hard macular drusen per eye to having ≥20 small hard drusen or drusen ≥63 μm at follow-up was associated with smoking and genetic predisposition. Having ≥20 small hard drusen in the absence of drusen ≥63 μm at baseline was associated with incident drusen ≥63 μm when examined 20 years later. The study confirms that small hard macular drusen is a forewarning of AMD and that progression to AMD may be hindered by avoidance of smoking.
Topics: Adult; Aged; Humans; Middle Aged; Cohort Studies; Follow-Up Studies; Macular Degeneration; Retinal Drusen; Risk Factors; Tomography, Optical Coherence
PubMed: 35878587
DOI: 10.1159/000525652 -
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 -
EClinicalMedicine Jan 2022The hematopoietic stem cell disorders, myeloproliferative neoplasms (MPNs), are characterised by chronic low-grade inflammation (CLI). Recently, we showed that patients...
BACKGROUND
The hematopoietic stem cell disorders, myeloproliferative neoplasms (MPNs), are characterised by chronic low-grade inflammation (CLI). Recently, we showed that patients with MPNs have an increased prevalence of drusen and age-related macular degeneration (AMD), and drusen prevalence seemed associated with higher CLI. Studying MPNs may reveal more about drusen pathophysiology. This study investigated CLI further by measuring cytokine levels and complement system markers, comparing these between patients with MPNs and AMD.
METHODS
This cross-sectional study, between July 2018 and November 2020 conducted at Zealand University Hospital (ZUH) - Roskilde, Denmark, included 29 patients with neovascular AMD (nAMD), 28 with intermediate-stage AMD (iAMD), 62 with MPNs (35 with drusen - MPNd and 27 with healthy retinas - MPNn). With flow cytometry, we measured complement-regulatory-proteins (Cregs). With immunoassays, we investigated cytokine levels combined into a summary-inflammation-score (SIS).
FINDINGS
The MPNd and nAMD groups had similar SIS, significantly higher than the MPNn and iAMD groups. Additionally, we found SIS to increase over the MPN biological continuum from early cancer stage, essential thrombocytaemia (ET), over polycythaemia vera (PV) to the late-stage primary myelofibrosis (PMF). MPNs showed signs of complement dysregulation, with Cregs expression lower in PV than ET and PMF and even lower in PV patients with drusen.
INTERPRETATION
This study suggests that MPNd have a higher CLI than MPNn and may indicate systemic CLI to play a greater part in, and even initiate drusen formation. We suggest using MPNs as a "Human Inflammation Model" of drusen development. The CLI in MPNs elicits drusen formation, triggering more CLI creating a vicious cycle, increasing the risk of developing AMD.
FUNDING
Fight for Sight, Denmark, and Region Zealand's research promotion fund.
PubMed: 35128362
DOI: 10.1016/j.eclinm.2021.101248