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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 -
Journal of Neuro-ophthalmology : the... Jun 2022Optic disc drusen (ODD) are calcified deposits at the anterior optic nerve that are often detectable by ophthalmic imaging, including optical coherence tomography and...
Optic disc drusen (ODD) are calcified deposits at the anterior optic nerve that are often detectable by ophthalmic imaging, including optical coherence tomography and fundus autofluorescence imaging. Multicolor (MC) imaging is a novel modality that captures reflectance of blue, green, and near-infrared laser lights with confocal scanning laser ophthalmoscopy to rapidly acquire high-resolution reflectance images of the optic disc and retina. Here, we show an eye with 3 MC imaging features of ODD, including prominent green hyperreflectance of the optic disc, green sheathing of the papillary and peripapillary vasculature (arterioles > venules), and presence of orange superficial ODD. MC imaging can provide rapid high-resolution assessment of eyes with optic nerve head elevation to help distinguish pseudopapilledema vs papilledema in children and adults without dilation, and future large studies incorporating MC imaging will help determine its contribution in the diagnosis and monitoring of ODD and assessment of other causes of optic nerve head elevation.
Topics: Adult; Child; Humans; Nerve Fibers; Optic Disk Drusen; Optic Nerve Diseases; Papilledema; Retinal Ganglion Cells; Tomography, Optical Coherence
PubMed: 35482433
DOI: 10.1097/WNO.0000000000001470 -
Turkish Journal of Ophthalmology Feb 2023To investigate choriocapillaris flow voids (FV) with a new optical coherence tomography angiography (OCTA) image processing strategy that can eliminate artifacts caused...
OBJECTIVES
To investigate choriocapillaris flow voids (FV) with a new optical coherence tomography angiography (OCTA) image processing strategy that can eliminate artifacts caused by vitreous opacities, sub-retinal pigment epithelium fluid and deposits, and subretinal fluid (SRF) by thresholding the en-face OCT image of the outer retina.
MATERIALS AND METHODS
We retrospectively reviewed medical records of patients with drusen and patients with active central serous chorioretinopathy (CSC). FV number (FVn), average area (FVav), and maximum area (FVmax) and the percentage of nonperfused choriocapillaris area (PNPCA) obtained using the proposed strategy were compared with those obtained by removing only artifacts caused by the superficial capillary plexus (SCP).
RESULTS
The SRF group included 21 eyes with active CSC and the drusen group included 29 eyes with nonexudative age-related macular degeneration. FVav, FVmax, FVn, and PNPCA obtained using the algorithm were significantly lower than those obtained by removing only SCP-related artefacts in both groups (all p<0.05). The algorithm was also able to remove 96.9% of artifacts secondary to vitreous opacities and all artifacts secondary to serous pigment epithelial detachments.
CONCLUSION
Choriocapillaris nonperfusion areas on OCTA images may be overestimated in eyes with RPE abnormalities and SRF due to artifacts. These artifact areas on choriocapillaris OCTA images can be removed using thresholded images of the outer retina en-face OCT scans. Our new artifact-removal strategy is useful in the assessment of choriocapillaris FV in eyes with SRF, drusen, drusen-like deposits, and pigment epithelial detachment.
Topics: Humans; Artifacts; Retrospective Studies; Choroid; Retina; Retinal Detachment
PubMed: 36847632
DOI: 10.4274/tjo.galenos.2022.23855 -
Ophthalmic & Physiological Optics : the... Jul 2023The purpose of this study was to build an automated age-related macular degeneration (AMD) colour fundus photography (CFP) recognition method that incorporates...
INTRODUCTION
The purpose of this study was to build an automated age-related macular degeneration (AMD) colour fundus photography (CFP) recognition method that incorporates confounders (other ocular diseases) and normal age-related changes by using drusen masks for spatial feature supervision.
METHODS
A range of clinical sources were used to acquire 7588 CFPs. Contrast limited adaptive histogram equalisation was used for pre-processing. ResNet50 was used as the backbone network, and a spatial attention block was added to integrate prior knowledge of drusen features into the backbone. The evaluation metrics used were sensitivity, specificity and F1 score, which is the harmonic mean of precision and recall (sensitivity) and area under the receiver-operating characteristic (AUC). Fivefold cross-validation was performed, and the results compared with four other methods.
RESULTS
Excellent discrimination results were obtained with the algorithm. On the public dataset (n = 6565), the proposed method achieved a mean (SD) sensitivity of 0.54 (0.09), specificity of 0.99 (0.00), F1 score of 0.62 (0.06) and AUC of 0.92 (0.02). On the private dataset (n = 1023), the proposed method achieved a sensitivity of 0.92 (0.02), specificity of 0.98 (0.01), F1 score of 0.92 (0.01) and AUC of 0.98 (0.01).
CONCLUSION
The proposed drusen-aware model outperformed baseline and other vessel feature-based methods in F1 and AUC on the AMD/normal CFP classification task and achieved comparable results on datasets that included other diseases that often confound classification. The method also improved results when a five-category grading protocol was used, thereby reflecting discriminative ability of the algorithm within a real-life clinical setting.
Topics: Humans; Retinal Drusen; Macular Degeneration; Retina; Algorithms; ROC Curve
PubMed: 36786498
DOI: 10.1111/opo.13108 -
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 -
Ophthalmology and Therapy Dec 2023Age-related macular degeneration (AMD) is a leading cause of severe vision loss worldwide, with a global prevalence that is predicted to substantially increase.... (Review)
Review
Age-related macular degeneration (AMD) is a leading cause of severe vision loss worldwide, with a global prevalence that is predicted to substantially increase. Identifying early biomarkers indicative of progression risk will improve our ability to assess which patients are at greatest risk of progressing from intermediate AMD (iAMD) to vision-threatening late-stage AMD. This is key to ensuring individualized management and timely intervention before substantial structural damage. Some structural biomarkers suggestive of AMD progression risk are well established, such as changes seen on color fundus photography and more recently optical coherence tomography (drusen volume, pigmentary abnormalities). Emerging biomarkers identified through multimodal imaging, including reticular pseudodrusen, hyperreflective foci, and drusen sub-phenotypes, are being intensively explored as risk factors for progression towards late-stage disease. Other structural biomarkers merit further research, such as ellipsoid zone reflectivity and choriocapillaris flow features. The measures of visual function that best detect change in iAMD and correlate with risk of progression remain under intense investigation, with tests such as dark adaptometry and cone-specific contrast tests being explored. Evidence on blood and plasma markers is preliminary, but there are indications that changes in levels of C-reactive protein and high-density lipoprotein cholesterol may be used to stratify patients and predict risk. With further research, some of these biomarkers may be used to monitor progression. Emerging artificial intelligence methods may help evaluate and validate these biomarkers; however, until we have large and well-curated longitudinal data sets, using artificial intelligence effectively to inform clinical trial design and detect outcomes will remain challenging. This is an exciting area of intense research, and further work is needed to establish the most promising biomarkers for disease progression and their use in clinical care and future trials. Ultimately, a multimodal approach may yield the most accurate means of monitoring and predicting future progression towards vision-threatening, late-stage AMD.
PubMed: 37773477
DOI: 10.1007/s40123-023-00807-9 -
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 -
Ophthalmology. Retina Oct 2023To elucidate the clinical characteristics and progression rate of geographic atrophy (GA) associated with age-related macular degeneration (AMD) in a Japanese population. (Observational Study)
Observational Study
PURPOSE
To elucidate the clinical characteristics and progression rate of geographic atrophy (GA) associated with age-related macular degeneration (AMD) in a Japanese population.
DESIGN
Retrospective, multicenter, observational study.
PARTICIPANTS
A total of 173 eyes from 173 patients from 6 university hospitals in Japan were included. Of 173 study eyes, 101 eyes from 101 patients were included in the follow-up group. All patients were Japanese, aged ≥ 50 years and had definite GA associated with AMD in at least 1 eye.
METHODS
The GA area was measured semiautomatically using fundus autofluorescence (FAF) images. In the follow-up group followed for > 6 months with FAF images, the GA progression rate was calculated by 2 methods: mm per year and mm per year using the square-root transformation (SQRT) strategy. Simple and multiple linear regression analyses were used to identify the baseline factors associated with the GA progression rate.
MAIN OUTCOME MEASURES
Clinical characteristics of GA and the GA progression rate.
RESULTS
The mean age was 76.8 ± 8.8 years, and 109 (63.0%) were males. Sixty-two (35.8%) patients had bilateral GA. The mean GA area was 3.06 ± 4.00 mm (1.44 ± 1.00 mm [SQRT]). Thirty-eight eyes (22.0%) were classified as having pachychoroid GA. Drusen and reticular pseudodrusen were detected in 115 (66.5%) and 73 (42.2%) eyes, respectively. The mean subfoveal choroidal thickness was 194.7 ± 105.5 μm. In the follow-up group (follow-up period: 46.2 ± 28.9 months), the mean GA progression rate was 1.01 ± 1.09 mm per year (0.23 ± 0.18 mm/year [SQRT]). In the multivariable analysis, the baseline GA area (SQRT; P = 0.002) and the presence of reticular pseudodrusen (P < 0.001) were significantly associated with a greater GA progression rate (SQRT).
CONCLUSIONS
Certain clinical characteristics of GA in Asian populations may differ from those in White populations. Asian patients with GA showed male dominance and relatively thicker choroid than White patients. There was a group with GA without drusen but with features of pachychoroid. The GA progression rate in this Asian population was relatively lower than that in White populations. Large GA and reticular pseudodrusen were associated with a greater GA progression rate.
FINANCIAL DISCLOSURE(S)
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Topics: Humans; Male; Aged; Aged, 80 and over; Female; Geographic Atrophy; Retrospective Studies; East Asian People; Fluorescein Angiography; Macular Degeneration; Retinal Drusen
PubMed: 37302656
DOI: 10.1016/j.oret.2023.06.004 -
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 -
Ophthalmology and Therapy Dec 2023Photobiomodulation (PBM) relies on the pathophysiological mechanism whereby red to near-infrared light can target mitochondrial activity and promote ATP synthesis.... (Review)
Review
BACKGROUND
Photobiomodulation (PBM) relies on the pathophysiological mechanism whereby red to near-infrared light can target mitochondrial activity and promote ATP synthesis. Preclinical and clinical studies have shown promising results in treating intermediate age-related macular degeneration (AMD), since PBM can produce photochemical reactions in endogenous retinal chromophores. Currently, PBM is approved by the Food and Drug Administration and by the European Medicines Agency for the treatment of intermediate AMD. This narrative review aimed to evaluate the available evidence on the effectiveness and safety of PBM in treating intermediate AMD.
METHODS
A comprehensive search was conducted using the PubMed database, employing the keywords "photobiomodulation" and "age-related macular degeneration." All English-language studies published up to June 2023 were reviewed, and the search was expanded to include relevant references from selected articles. The included publications were analyzed for this review.
RESULTS
The available studies on PBM in AMD demonstrated promising but inconsistent results. PBM showed potential in improving best-corrected visual acuity (BCVA) and contrast sensitivity (CS) in patients with AMD. Some studies also suggested a reduction in AMD lesions, such as drusen volume. However, the long-term efficacy and optimal treatment parameters of PBM in AMD remained to be fully determined due to the limitations of the available studies. These included variations in irradiation techniques, wavelengths, exposure times, and treatment sessions, making it challenging to generalize the effectiveness of PBM. Furthermore, the lack of accurate classification of AMD phenotypes in the available studies hindered the understanding of which phenotypes could truly benefit from this treatment. Finally, the strength of evidence varied among studies, with limited sample sizes, unpublished results, and only three randomized sham-controlled trials.
CONCLUSIONS
Currently, the effectiveness of PBM in promoting drusen resorption or preventing progression to advanced forms of AMD, as observed in the cited studies, remains uncertain.
PubMed: 37768527
DOI: 10.1007/s40123-023-00812-y