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New Beckman staging of age-related macular degeneration and how it compares to Age-Related Eye Disease Study (AREDS) simplified grading scores and AREDS classification
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While the development of anti-vascular endothelial growth factor (anti-VEGF) as a therapy for neovascular age-related macular degeneration (AMD) was a great success, the pathologic processes underlying dry AMD that eventually leads to photoreceptor dysfunction, death, and vision loss remain elusive to date, with a lack of effective therapies and in...
Citations
... The etiopathology of age-related macular degeneration is still not fully understood [3,5]. It is suggested that the disease process begins mainly at the level of the outer retinal layer and is associated with the senescence of retinal pigment epithelial cells. ...
The main aim of this study was to characterize the retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thickness in the macular area eyes affected by wet age-related macular degeneration (wAMD) treated with anti-VEGF and compare the results with the control of fellow untreated eyes affected by early stages of dry age-related macular degeneration (dAMD). Additionally, we aimed to estimate if the number of injections received and other factors, including age, best-corrected visual acuity (BCVA), or sex, may affect the differences in the obtained measurements of retinal nerve fiber layer thickness. We prospectively included 106 eyes of 53 patients with unilateral wet age-related macular degeneration. The fellow eyes with non-advanced dry age-related macular degeneration served as a control group in a cross-sectional study. RNFL and GCL in the macular region were evaluated using optical coherence tomography, with outcomes expressed as differences in the thickness of both examined layers between the study and control groups. We found thinner GCL in wAMD vs. dAMD (p < 0.001). In turn, the RNFL layer did not show any statistically significant differences between the two groups (p = 0.409). Similarly, we found a statistically significant correlation between the number of injections and the layer thickness (p = 0.106). Among all assessed parameters, age over 73 was the only factor significantly affecting the thickness of the retinal nerve fiber layer in both groups (p = 0.042). The morphology of the inner layers of the retina in dry and wet AMD seems to differ, possibly due to differences in the etiopathogenesis of these two forms of the disease. In our study, the retinal ganglion cell layer was thinner in the treated vs. fellow eye (with dry AMD), while the nerve fiber layer was not significantly different between the groups. The number of anti-VEGF injections had no effect on the thickness of the macular nerve fiber layer.
... Numerous studies demonstrate that PMX500FI, a synthetic bioavailable L-carnitine-conjugated ALA derivative [288], crosses the blood-brain barrier, the blood-retinal barrier [14], inhibits histone deacetylase activity [258,289], improves mitochondrial function and expresses superior pharmacokinetics in vivo compared to ALA [290][291][292][293][294][295][296][297]. In an ophthalmic indication of unmet therapeutic need, Chen et al. [298] showed that in a mouse model of photoreceptor cell death that occurs after their separation from the RPE [299,300], intraperitoneal administration [301] of PMX500FI led to a meaningful reduction of TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)-positive (apoptotic) cells in the photoreceptor layer [302] compared to a vehicle group (p = 0.009) at 24 h after RD (Fig. 6) [298]. ...
Pathological deterioration of mitochondrial function is increasingly linked with multiple degenerative illnesses as a mediator of a wide range of neurologic and age-related chronic diseases, including those of genetic origin. Several of these diseases are rare, typically defined in the United States as an illness affecting fewer than 200,000 people in the U.S. population, or about one in 1,600 individuals. Vision impairment due to mitochondrial dysfunction in the eye is a prominent feature evident in numerous primary mitochondrial diseases and is common to the pathophysiology of many of the familiar ophthalmic disorders, including age-related macular degeneration, diabetic retinopathy, glaucoma and retinopathy of prematurity — a collection of syndromes, diseases and disorders with significant unmet medical needs. Focusing on metabolic mitochondrial pathway mechanisms, including the possible roles of cuproptosis and ferroptosis in retinal mitochondrial dysfunction, we shed light on the potential of α-lipoyl-L-carnitine in treating eye diseases. α-Lipoyl-L-carnitine is a bioavailable mitochondria-targeting lipoic acid prodrug that has shown potential in protecting against retinal degeneration and photoreceptor cell loss in ophthalmic indications.
... Age-related macular degeneration (AMD) is one of the leading causes of central vision loss among individuals aged 50 years and older (1)(2)(3)(4)(5)(6)(7)(8)(9). As the aging population increases, the increased prevalence of AMD continues to be a health concern. ...
... The non-exudative non-neovascular AMD (also known as "dry" AMD) affecting about 85% of the AMD population, and the exudative/neovascular AMD, also known as "wet" AMD affecting 15% of the AMD population. Though there has been good success in treating neovascular AMD (4, 10-12) the same cannot be told for the nonexudative "dry" AMD (6). Non-exudative AMD in its early and intermediate stages is characterized by sub-retinal pigment epithelium (RPE) deposits called drusen under the neuroretina (13) and RPE pigmentary variation with mild to moderate visual disturbances, while in its advanced atrophic stage is characterized by loss of photoreceptor/RPE/choriocapillaries complex and significant vision loss (9,14,15). ...
... It is well accepted that AMD is complex multi-factorial disease (6,9,(16)(17)(18)(19). Despite successes in the identification of genes and molecular/cellular processes that contribute to AMD risk, mechanisms by which specific genetic variants contribute to AMD progression remain a matter of debate (20)(21)(22)(23)(24)(25)(26)(27). ...
Age-Related Macular Degeneration (AMD) is a bilateral ocular condition resulting in irreversible vision impairment caused by the progressive loss of photoreceptors in the macula, a region at the center of the retina. The progressive loss of photoreceptor is a key feature of dry AMD but not always wet AMD, though both forms of AMD can lead to loss of vision. Regression-based biological age clocks are one of the most promising biomarkers of aging but have not yet been used in AMD. Here we conducted analyses to identify regression-based biological age clocks for the retina and explored their use in AMD using transcriptomic data consisting of a total of 453 retina samples including 105 Minnesota Grading System (MGS) level 1 samples, 175 MGS level 2, 112 MGS level 3 and 61 MGS level 4 samples, as well as 167 fibroblast samples. The clocks yielded good separation among AMD samples with increasing severity score viz., MGS1-4, regardless of whether clocks were trained in retina tissue, dermal fibroblasts, or in combined datasets. Clock application to cultured fibroblasts, embryonic stem cells, and induced Pluripotent Stem Cells (iPSCs) were consistent with age reprograming in iPSCs. Moreover, clock application to in vitro neuronal differentiation suggests broader applications. Interesting, many of the age clock genes identified include known targets mechanistically linked to AMD and aging, such as GDF11, C16ORF72, and FBN2. This study provides new observations for retina age clocks and suggests new applications for monitoring in vitro neuronal differentiation. These clocks could provide useful markers for AMD monitoring and possible intervention, as well as potential targets for in vitro screens.
... Despite the possibilities offered by ultrastructural analysis of retinal layers with OCT, there is currently no consensus on the mechanisms of irreversible changes in photoreceptors and RPE during the natural course of nAMD and under the anti-VEGF therapy. 7 It is also evident that the identification of structural biomarkers based on OCT is relevant not only for monitoring of disease progression and response to treatment of patients with nAMD but also for understanding the mechanism of irreversible retinal changes. 8,9 As it was demonstrated in earlier works, with a help of mathematical analysis methods that consider not only the morphometric characteristics of retinal tissue but also its physical parameters derived experimentally, one can reliably describe the changes to the retina and optic disc associated with myopic foveoschisis and glaucoma optic neuropathy. ...
Purpose:
To construct a realistic physical model of viscoelastic retinal stretching and, on its basis, derive a universal quantitative criterion of irreversible retinal deformations during age-related macular degeneration.
Methods:
In this work, standard methods of nonlinear fracture mechanics of ductile and viscoelastic materials were applied to study the evolution of retinal deformation progress in patients with neovascular age-related macular degeneration in the area of large druses or subretinal or sub-retinal pigment epithelium fluid accumulation. A two-dimensional rhombic model of viscoelastic Kelvin-Feucht primitives was used to reconstruct the parameters included in the approximation of the creep strain growth rate. A clinical case of a patient with age-related macular degeneration and retinal pigment epithelium detachment in the macula was taken as a basis for theoretical research. The patient underwent retinal optical coherent tomography on DRI Swept-Source OCT.
Results:
A closed realistic theoretical model of retinal stretching in the projection of retinal pigment epithelium elevation due to its detachment or drusen based on a two-dimensional rhombic Kelvin-Feucht primitives model was constructed. The calculation of stress in the retinal tissue with consistent consideration of creep effects was performed.
Conclusions:
The time of critical retinal loading - a new quantitative criterion for the irreversibility of retinal stretching in age-related macular degeneration is proposed. This criterion allows the prediction of the functional outcome of antiangiogenic therapy in patients with age-related macular degeneration with identical initial retinal morphometric parameters.
... Inflammation is a critical mediator of AMD progression 56 . In our apoB100 mice, local and systemic inflammation appear to play a role, as indicated by assessments of the circulating cytokine profiles and visualization of F4/80-positive macrophages concentrated in the sub-retinal space, which worsened with age. ...
Apolipoprotein B100 (apoB100) is the structural protein of cholesterol carriers including low-density lipoproteins. It is a constituent of sub-retinal pigment epithelial (sub-RPE) deposits and pro-atherogenic plaques, hallmarks of early dry age-related macular degeneration (AMD), an ocular neurodegenerative blinding disease, and cardiovascular disease, respectively. Herein, we characterized the retinal pathology of transgenic mice expressing mouse apoB100 in order to catalog their functional and morphological ocular phenotypes as a function of age and establish measurable endpoints for their use as a mouse model to test potential therapies. ApoB100 mice were found to exhibit an age-related decline in retinal function, as measured by electroretinogram (ERG) recordings of their scotopic a-wave, scotopic b-wave; and c-wave amplitudes. ApoB100 mice also displayed a buildup of the cholesterol carrier, apolipoprotein E (apoE) within and below the supporting extracellular matrix, Bruch's membrane (BrM), along with BrM thickening, and accumulation of thin diffuse electron-dense sub-RPE deposits, the severity of which increased with age. Moreover, the combination of apoB100 and advanced age were found to be associated with RPE morphological changes and the presence of sub-retinal immune cells as visualized in RPE-choroid flatmounts. Finally, aged apoB100 mice showed higher levels of circulating and ocular pro-inflammatory cytokines, supporting a link between age and increased local and systemic inflammation. Collectively, the data support the use of aged apoB100 mice as a platform to evaluate potential therapies for retinal degeneration, specifically drugs intended to target removal of lipids from Bruch's membrane and/or alleviate ocular inflammation.
... AMD is thought to globally affect over 8 million people (Flaxman et al., 2017) and RP is the most common retinal inherited disease, approximately 1 in 5,000 worldwide (Huang, 2018). Currently, clinical treatments are limited to delaying the progress of RDs, such as pharmacotherapy and gene therapy (Scholl et al., 2016;Miller et al., 2017). But there is no available way to restore dysfunctional photoreceptors once substantial photoreceptor damage occurs. ...
Stem cell-based cell therapies are considered to be promising treatments for retinal disorders with dysfunction or death of photoreceptors. However, the enrichment of human photoreceptors suitable for transplantation has been highly challenging so far. This study aimed to generate a photoreceptor-specific reporter human induced pluripotent stem cell (hiPSC) line using CRISPR/Cas9 genome editing, which harbored an enhanced green fluorescent protein ( eGFP ) sequence at the endogenous locus of the pan photoreceptor marker recoverin ( RCVRN ) . After confirmation of successful targeting and gene stability, three-dimensional retinal organoids were induced from this reporter line. The RCVRN-eGFP reporter faithfully replicated endogenous protein expression of recoverin and revealed the developmental characteristics of photoreceptors during retinal differentiation. The RCVRN-eGFP specifically and steadily labeled photoreceptor cells from photoreceptor precursors to mature rods and cones. Additionally, abundant eGFP-positive photoreceptors were enriched by fluorescence-activated cell sorting, and their transcriptome signatures were revealed by RNA sequencing and data analysis. Moreover, potential clusters of differentiation (CD) biomarkers were extracted for the enrichment of photoreceptors for clinical applications, such as CD133 for the positive selection of photoreceptors. Altogether, the RCVRN-eGFP reporter hiPSC line was successfully established and the first global expression database of recoverin-positive photoreceptors was constructed. These achievements will provide a powerful tool for dynamically monitoring photoreceptor cell development and purification of human photoreceptors, thus facilitating photoreceptor cell therapy for advanced retinal disorders.
... To date, the only approved treatment for intermediate AMD is supplementation of antioxidant micronutrients (AREDS2 formula), which has been demonstrated only to modestly reduce the rate of progression to advanced AMD [6]. Studies investigating the underlying pathophysiologic processes behind GA have suggested multiple pathways including oxidative stress, lipid dysregulation, inflammation, and complement that could be targeted with traditional small molecules and antibody treatments [24][25][26][27][28]. After numerous negative clinical trials, an anti-C5 agent and anti-C3 agent have recently shown promising results in phase 3 clinical trials in terms of slowing the growth of geographic atrophy [29,30]. ...
Age-related macular degeneration (AMD) is a progressive neurodegenerative disease that is the world’s leading cause of blindness in the aging population. Although the clinical stages and forms of AMD have been elucidated, more specific prognostic tools are required to determine when patients with early and intermediate AMD will progress into the advanced stages of AMD. Another challenge in the field has been the appropriate development of therapies for intermediate AMD and advanced atrophic AMD. After numerous negative clinical trials, an anti-C5 agent and anti-C3 agent have recently shown promising results in phase 3 clinical trials, in terms of slowing the growth of geographic atrophy, an advanced form of AMD. Interestingly, both drugs appear to be associated with an increased incidence of wet AMD, another advanced form of the disease, and will require frequent intravitreal injections. Certainly, there remains a need for other therapeutic agents with the potential to prevent progression to advanced stages of the disease. Investigation of the role and clinical utility of non-coding RNAs (ncRNAs) is a major advancement in biology that has only been minimally applied to AMD. In the following review, we discuss the clinical relevance of ncRNAs in AMD as both biomarkers and therapeutic targets.
... The incidence and progression of AMD increase significantly with age. Multiple conditions accelerate the development of AMD, including dysregulated complement system, oxidative stress, impaired autophagy clearance, and inflammation of endothelial cells [3,7,8]. Transcription factor forkhead box protein P1 (Foxp1) is a key regulator of endothelial cell inflammation and plays an important role in heart development [9,10]. ...
Background
The exudative form of age-related macular degeneration (AMD) is characterized by abnormal blood vessel growth, which is stimulated by vascular endothelial growth factor (VEGF) released from retinal pigment epithelium (RPE). The angiogenic behaviors of vascular endothelial cells in vitro depend on forkhead box protein P1 (Foxp1), a transcription repressor widely expressed in human and murine tissues during development. In this study, we aimed to determine whether loss of Foxp1 affects laser-induced choroidal neovascularization (CNV) in mouse.
Methods
Eye-selective deletion of Foxp1 was obtained by crossing Foxp1 flox/flox with Six3-Cre mice. Laser photocoagulation was delivered to six- to eight-week-old mice to induce CNV. The expression of Foxp1 and Cre was determined by immunofluorescence in cryostat sections of the eyes. Fundus fluorescein angiography (FFA), optical coherence tomography (OCT), and B4 isolectin staining were applied to analyze the leakage, bulge height, and area of CNV lesions, respectively. RPE-choroid tissues were isolated for the determination of VEGF and pigment epithelium derived factor (PEDF) by Western blotting.
Results
Foxp1 was expressed in retinal ganglion cells, RPE, and the choroidal endothelial cells. Laser photocoagulation increased the number of Foxp1 ⁺ -endothelial cells and induced CNV. Six3-Cre reduced Foxp1 expression in RPE but not the endothelium, leading to a lower level of VEGF in the RPE-choroid. Foxp1 knockout inhibited pathological angiogenesis and vascular leakage of the laser-induced CNV lesions.
Conclusions
Foxp1 regulates the expression of VEGF in the RPE, and inhibition of Foxp1 could potentially be a novel strategy for the prevention and therapy of neovascularization related to AMD.
... Four landmark studies identified a strong association between AMD and the Y402H common variant of the CFH gene. 9e12 These and numerous subsequent studies have established a clear link between immune dysregulation and AMD pathogenesis, 13 which have led to recent studies investigating the possible strategy of complement inhibition to slow GA progression. The initial studies have yielded null results. ...
Topic
To evaluate whether there are differences in systemic complement activation profiles in patients with early/intermediate nonexudative age-related macular degeneration (AMD) or geographic atrophy (GA) compared to non-AMD controls.
Clinical Relevance
Complement inhibition has emerged as a therapeutic strategy for GA, although clinical trials to date have yielded mixed results. Despite these efforts, there is no clear consensus regarding what portions of the complement pathway are dysregulated in AMD or when this dysregulation occurs relative to AMD stage. Although past studies have compared systemic complement activation profiles in patients with AMD versus non-AMD controls, differences in AMD case definition and differing analytical approaches complicate their interpretation.
Methods
We performed a systematic review by identifying articles from database inception to October 11, 2020 that reported systemic complement activation profiles in patients with early/intermediate nonexudative AMD or GA versus non-AMD controls by searching PubMed, Google Scholar, and Embase. Risk of bias was assessed using a modified Newcastle-Ottawa score.
Results
The eight reviewed studies included 2,131 independent participants. Most studies report significantly higher systemic levels of products associated with complement activation and significantly lower systemic levels of products associated with complement inhibition in patients with early and advanced nonexudative AMD compared with non-AMD controls.
Conclusion
There is evidence that systemic complement over-activation is a feature of early/intermediate and advanced nonexudative AMD. However, given significant heterogeneity, these findings are not conclusive and warrant further investigation.
... Traditionally, color fundus photography and slit lamp biomicroscopy have been the mainstay for the ophthalmic examination of fundus lesions associated with AMD [15,59,60]. Several disease classification systems have been developed over the years, from population studies [61][62][63] and clinical-based trials, of which the Age-Related Eye Disease Study (AREDS) clinical severity scale (Table 1) and its simplified severity scale are most notable [64][65][66][67]. ...
Age-related macular degeneration (AMD) remains a leading cause of modifiable vision loss in older adults. Chronic oxidative injury and compromised antioxidant defenses represent essential drivers in the development of retinal neurodegeneration. Overwhelming free radical species formation results in mitochondrial dysfunction, as well as cellular and metabolic imbalance, which becomes exacerbated with increasing age. Thus, the depletion of systemic antioxidant capacity further proliferates oxidative stress in AMD-affected eyes, resulting in loss of photoreceptors, neuroinflammation, and ultimately atrophy within the retinal tissue. The aim of this systematic review is to examine the neuroprotective potential of the xanthophyll carotenoids lutein, zeaxanthin, and meso-zeaxanthin on retinal neurodegeneration for the purpose of adjunctive nutraceutical strategy in the management of AMD. A comprehensive literature review was performed to retrieve 55 eligible publications, using four database searches from PubMed, Embase, Cochrane Library, and the Web of Science. Epidemiology studies indicated an enhanced risk reduction against late AMD with greater dietary consumption of carotenoids, meanwhile greater concentrations in macular pigment demonstrated significant improvements in visual function among AMD patients. Collectively, evidence strongly suggests that carotenoid vitamin therapies offer remarkable synergic protection in the neurosensory retina, with the potential to serve as adjunctive nutraceutical therapy in the management of established AMD, albeit these benefits may vary among different stages of disease.
