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Disease Models & Mechanisms Apr 2024Mechanical stimulation as a mimic of drusen formation in the eye increases the expression of angiogenic factors in retinal pigment epithelial (RPE) cells, but the...
Mechanical stimulation as a mimic of drusen formation in the eye increases the expression of angiogenic factors in retinal pigment epithelial (RPE) cells, but the underlying molecular mechanisms remain unclear. We investigated and characterized the effects of mechanical stimulation on the expression of angiogenic factors in RPE cells both in vitro and in a mouse model. Mechanical stimulation increased the expression of vascular endothelial growth factor (VEGF, encoded by VEGFA) and other angiogenesis-related genes in cultured RPE1 cells. The presence of hypoxia-inducible factor 1α (HIF-1α, encoded by HIF1A) was also increased, and both knockdown of HIF-1α and treatment with the HIF-1α inhibitor CAY10585 attenuated the effect of mechanical stimulation on angiogenesis factor gene expression. Signaling by the tyrosine kinase SRC and p38 mitogen-activated protein kinase was involved in HIF-1α activation and consequent angiogenesis-related gene expression induced by mechanical stimulation. Our results suggest that SRC-p38 and HIF-1α signaling are involved in the upregulation of angiogenic factors in RPE cells by mechanical stimulation. Such in vivo suppression of upregulated expression of angiogenesis-related genes by pharmacological inhibitors of HIF-1α suggests a new potential approach to the treatment of age-related macular degeneration.
Topics: Retinal Pigment Epithelium; Hypoxia-Inducible Factor 1, alpha Subunit; Animals; Up-Regulation; p38 Mitogen-Activated Protein Kinases; Mice, Inbred C57BL; src-Family Kinases; Vascular Endothelial Growth Factor A; Stress, Mechanical; Signal Transduction; Mice; Cell Line; Angiogenesis Inducing Agents; Epithelial Cells; Humans
PubMed: 38691000
DOI: 10.1242/dmm.050640 -
Graefe's Archive For Clinical and... Apr 2024Geographic atrophy (GA) is an advanced, irreversible, and progressive form of age-related macular degeneration (AMD). Structural optical coherence tomography (OCT) and... (Review)
Review
BACKGROUND
Geographic atrophy (GA) is an advanced, irreversible, and progressive form of age-related macular degeneration (AMD). Structural optical coherence tomography (OCT) and OCT angiography (OCTA) have been largely used to characterize this stage of AMD and, more importantly, to define biomarkers associated with the development and progression of GA in AMD.
METHODS
Articles pertaining to OCT and OCTA biomarkers related to the development and progression of GA with relevant key words were used to search in PubMed, Researchgate, and Google Scholar. The articles were selected based on their relevance, reliability, publication year, published journal, and accessibility.
RESULTS
Previous reports have highlighted various OCT and OCTA biomarkers linked to the onset and advancement of GA. These biomarkers encompass characteristics such as the size, volume, and subtype of drusen, the presence of hyperreflective foci, basal laminar deposits, incomplete retinal pigment epithelium and outer retinal atrophy (iRORA), persistent choroidal hypertransmission defects, and the existence of subretinal drusenoid deposits (also referred to as reticular pseudodrusen). Moreover, biomarkers associated with the progression of GA include thinning of the outer retina, photoreceptor degradation, the distance between retinal pigment epithelium and Bruch's membrane, and choriocapillaris loss.
CONCLUSION
The advent of novel treatment strategies for GA underscores the heightened need for prompt diagnosis and precise monitoring of individuals with this condition. The utilization of structural OCT and OCTA becomes essential for identifying distinct biomarkers associated with the initiation and progression of GA.
PubMed: 38689123
DOI: 10.1007/s00417-024-06497-8 -
Investigative Ophthalmology & Visual... Apr 2024To longitudinally assess the impact of high-risk structural biomarkers for natural disease progression in non-exudative age-related macular degeneration (AMD) on...
PURPOSE
To longitudinally assess the impact of high-risk structural biomarkers for natural disease progression in non-exudative age-related macular degeneration (AMD) on spatially resolved mesopic and scotopic fundus-controlled perimetry testing.
METHODS
Multimodal retinal imaging data and fundus-controlled perimetry stimuli points were semiautomatically registered according to landmark correspondences at each annual visit over a period of up to 4 years. The presence of sub-RPE drusen, subretinal drusenoid deposits, pigment epithelium detachments (PEDs), hyper-reflective foci (HRF), vitelliform lesions, refractile deposits, and incomplete RPE and outer retinal atrophy (iRORA) and complete RPE and outer retinal atrophy (cRORA) were graded at each stimulus position and visit. Localized retinal layer thicknesses were extracted. Mixed-effect models were used for structure-function correlation.
RESULTS
Fifty-four eyes of 49 patients with non-exudative AMD (mean age, 70.7 ± 9.1 years) and 27 eyes of 27 healthy controls (mean age, 63.4 ± 8.9 years) were included. During study course, presence of PED had the highest functional impact with a mean estimated loss of -1.30 dB (P < 0.001) for mesopic and -1.23 dB (P < 0.001) for scotopic testing, followed by HRF with -0.89 dB (mesopic, P = 0.001) and -0.87 dB (scotopic, P = 0.005). Subretinal drusenoid deposits were associated with a stronger visual impairment (mesopic, -0.38 dB; P = 0.128; scotopic, -0.37 dB; P = 0.172) compared with sub-RPE drusen (-0.22 dB, P = 0.0004; -0.18 dB, P = 0.006). With development of c-RORA, scotopic retinal sensitivity further significantly decreased (-2.15 dB; P = 0.02). Thickening of the RPE-drusen-complex and thinning of the outer nuclear layer negatively impacted spatially resolved retinal sensitivity.
CONCLUSIONS
The presence of PED and HRF had the greatest prognostic impact on progressive point-wise sensitivity losses. Higher predominant rod than cone-mediated localized retinal sensitivity losses with early signs of retinal atrophy development indicate photoreceptor preservation as a potential therapeutic target for future interventional AMD trials.
Topics: Humans; Female; Aged; Male; Middle Aged; Tomography, Optical Coherence; Visual Field Tests; Disease Progression; Visual Acuity; Visual Fields; Macular Degeneration; Retinal Drusen; Biomarkers; Follow-Up Studies; Retinal Pigment Epithelium; Night Vision; Retina; Aged, 80 and over; Fluorescein Angiography
PubMed: 38687492
DOI: 10.1167/iovs.65.4.45 -
Investigative Ophthalmology & Visual... Apr 2024Complement dysregulation is a key component in the pathogenesis of age-related macular degeneration (AMD) and related diseases such as early-onset macular drusen (EOMD)....
PURPOSE
Complement dysregulation is a key component in the pathogenesis of age-related macular degeneration (AMD) and related diseases such as early-onset macular drusen (EOMD). Although genetic variants of complement factor H (CFH) are associated with AMD risk, the impact of CFH and factor H-like protein 1 (FHL-1) expression on local complement activity in human retinal pigment epithelium (RPE) remains unclear.
METHODS
We identified a novel CFH variant in a family with EOMD and generated patient induced pluripotent stem cell (iPSC)-derived RPE cells. We assessed CFH and FHL-1 co-factor activity through C3b breakdown assays and measured complement activation by immunostaining for membrane attack complex (MAC) formation. Expression of CFH, FHL-1, local alternative pathway (AP) components, and regulators of complement activation (RCA) in EOMD RPE cells was determined by quantitative PCR, western blot, and immunostaining. Isogenic EOMD (cEOMD) RPE was generated using CRISPR/Cas9 gene editing.
RESULTS
The CFH variant (c.351-2A>G) resulted in loss of CFH and FHL-1 expression and significantly reduced CFH and FHL-1 protein expression (∼50%) in EOMD iPSC RPE cells. These cells exhibited increased MAC deposition upon exposure to normal human serum. Under inflammatory or oxidative stress conditions, CFH and FHL-1 expression in EOMD RPE cells paralleled that of controls, whereas RCA expression, including MAC formation inhibitors, was elevated. CRISPR/Cas9 correction restored CFH/FHL-1 expression and mitigated alternative pathway complement activity in cEOMD RPE cells.
CONCLUSIONS
Identification of a novel CFH variant in patients with EOMD resulting in reduced CFH and FHL-1 and increased local complement activity in EOMD iPSC RPE supports the involvement of CFH haploinsufficiency in EOMD pathogenesis.
Topics: Humans; Complement Factor H; Haploinsufficiency; Retinal Pigment Epithelium; Macular Degeneration; Male; Female; Induced Pluripotent Stem Cells; Complement C3b Inactivator Proteins; Complement Activation; Pedigree; Blotting, Western; Complement System Proteins; Retinal Drusen; Middle Aged; Muscle Proteins; Intracellular Signaling Peptides and Proteins; LIM Domain Proteins
PubMed: 38683564
DOI: 10.1167/iovs.65.4.43 -
Bioengineering (Basel, Switzerland) Mar 2024Artificial intelligence has been used effectively in medical diagnosis. The objective of this project is to examine the application of a collective AI model using...
Artificial intelligence has been used effectively in medical diagnosis. The objective of this project is to examine the application of a collective AI model using weighted fusion of predicted probabilities from different AI architectures to diagnose various retinal conditions based on optical coherence tomography (OCT). A publicly available Noor dataset, comprising 16,822, images from 554 retinal OCT scans of 441 patients, was used to predict a diverse spectrum of age-related macular degeneration (AMD) stages: normal, drusen, or choroidal neovascularization. These predictions were compared with predictions from ResNet, EfficientNet, and Attention models, respectively, using precision, recall, F1 score, and confusion matric and receiver operating characteristics curves. Our collective model demonstrated superior accuracy in classifying AMD compared to individual ResNet, EfficientNet, and Attention models, showcasing the effectiveness of using trainable weights in the ensemble fusion process, where these weights dynamically adapt during training rather than being fixed values. Specifically, our ensemble model achieved an accuracy of 91.88%, precision of 92.54%, recall of 92.01%, and F1 score of 92.03%, outperforming individual models. Our model also highlights the refinement process undertaken through a thorough examination of initially misclassified cases, leading to significant improvements in the model's accuracy rate to 97%. This study also underscores the potential of AI as a valuable tool in ophthalmology. The proposed ensemble model, combining different mechanisms highlights the benefits of model fusion for complex medical image analysis.
PubMed: 38671722
DOI: 10.3390/bioengineering11040300 -
Ophthalmology. Retina Apr 2024Swept-source OCT angiography (SS-OCTA) scans of eyes with age-related macular degeneration (AMD) were used to replace color, autofluorescence, infrared reflectance, and...
PURPOSE
Swept-source OCT angiography (SS-OCTA) scans of eyes with age-related macular degeneration (AMD) were used to replace color, autofluorescence, infrared reflectance, and dye-based fundus angiographic imaging for the diagnosis and staging of AMD. Through the use of different algorithms with the SS-OCTA scans, both structural and angiographic information can be viewed and assessed using both cross sectional and en face imaging strategies.
DESIGN
Presented at the 2022 Charles L. Schepens, MD, Lecture at the American Academy of Ophthalmology Retina Subspecialty Day, Chicago, Illinois, on September 30, 2022.
PARTICIPANTS
Patients with AMD.
METHODS
Review of published literature and ongoing clinical research using SS-OCTA imaging in AMD.
MAIN OUTCOME MEASURES
Swept-source OCT angiography imaging of AMD at different stages of disease progression.
RESULTS
Volumetric SS-OCTA dense raster scans were used to diagnose and stage both exudative and nonexudative AMD. In eyes with nonexudative AMD, a single SS-OCTA scan was used to detect and measure structural features in the macula such as the area and volume of both typical soft drusen and calcified drusen, the presence and location of hyperreflective foci, the presence of reticular pseudodrusen, also known as subretinal drusenoid deposits, the thickness of the outer retinal layer, the presence and thickness of basal laminar deposits, the presence and area of persistent choroidal hypertransmission defects, and the presence of treatment-naïve nonexudative macular neovascularization. In eyes with exudative AMD, the same SS-OCTA scan pattern was used to detect and measure the presence of macular fluid, the presence and type of macular neovascularization, and the response of exudation to treatment with vascular endothelial growth factor inhibitors. In addition, the same scan pattern was used to quantitate choriocapillaris (CC) perfusion, CC thickness, choroidal thickness, and the vascularity of the choroid.
CONCLUSIONS
Compared with using several different instruments to perform multimodal imaging, a single SS-OCTA scan provides a convenient, comfortable, and comprehensive approach for obtaining qualitative and quantitative anatomic and angiographic information to monitor the onset, progression, and response to therapies in both nonexudative and exudative AMD.
FINANCIAL DISCLOSURE(S)
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
PubMed: 38641006
DOI: 10.1016/j.oret.2024.04.012 -
Frontiers in Aging Neuroscience 2024The intricate parallels in structure and function between the human retina and the central nervous system designate the retina as a prospective avenue for understanding... (Review)
Review
The intricate parallels in structure and function between the human retina and the central nervous system designate the retina as a prospective avenue for understanding brain-related processes. This review extensively explores the shared physiopathological mechanisms connecting age-related macular degeneration (AMD) and proteinopathies, with a specific focus on tauopathies. The pivotal involvement of oxidative stress and cellular senescence emerges as key drivers of pathogenesis in both conditions. Uncovering these shared elements not only has the potential to enhance our understanding of intricate neurodegenerative diseases but also sets the stage for pioneering therapeutic approaches in AMD.
PubMed: 38633983
DOI: 10.3389/fnagi.2024.1371745 -
Frontiers in Immunology 2024To determine and compare the serum levels of complement Factor H (FH), monomeric C-Reactive Protein (mCRP) and pentameric C-Reactive protein (pCRP) in patients with... (Observational Study)
Observational Study
PURPOSE
To determine and compare the serum levels of complement Factor H (FH), monomeric C-Reactive Protein (mCRP) and pentameric C-Reactive protein (pCRP) in patients with age-related macular degeneration (AMD) and to correlate them with clinical, structural and functional parameters.
METHODS
Cross-sectional observational study. One hundred thirty-nine individuals (88 patients and 51 healthy controls) from two referral centers were included and classified into three groups: early or intermediate AMD (n=33), advanced AMD (n=55), and age and sex matched healthy controls (n=51). Serum levels of FH, mCRP, and pCRP were determined and correlated with clinical and imaging parameters.
RESULTS
Patients with intermediate AMD presented FH levels significantly lower than controls [186.5 (72.1-931.8) µg/mL vs 415.2 (106.1-1962.2) µg/mL; p=0.039] and FH levels <200 µg/mL were associated with the presence of drusen and pigmentary changes in the fundoscopy (p=0.002). While no differences were observed in pCRP and mCRP levels, and mCRP was only detected in less than 15% of the included participants, women had a significantly higher detection rate of mCRP than men (21.0% vs. 3.8%, p=0.045). In addition, the ratio mCRP/FH (log) was significantly lower in the control group compared to intermediate AMD (p=0.031). Visual acuity (p<0.001), macular volume (p<0.001), and foveal thickness (p=0.034) were significantly lower in the advanced AMD group, and choroidal thickness was significantly lower in advanced AMD compared to early/intermediate AMD (p=0.023).
CONCLUSION
Intermediate AMD was associated in our cohort with decreased serum FH levels together with increased serum mCRP/FH ratio. All these objective serum biomarkers may suggest an underlying systemic inflammatory process in early/intermediate AMD patients.
Topics: Female; Humans; Male; Biomarkers; C-Reactive Protein; Complement Factor H; Cross-Sectional Studies; Macular Degeneration
PubMed: 38633250
DOI: 10.3389/fimmu.2024.1330913 -
Ophthalmology. Retina Apr 2024This study aims to define the characteristics of acquired vitelliform lesions (AVLs) in patients with intermediate age-related macular degeneration (iAMD).
PURPOSE
This study aims to define the characteristics of acquired vitelliform lesions (AVLs) in patients with intermediate age-related macular degeneration (iAMD).
DESIGN
Retrospective, observational, cross sectional study.
SUBJECTS
This study included 217 eyes with AVLs associated with iAMD, and an equivalent number of control patients.
METHODS
OCT scans were evaluated for qualitative and quantitative parameters at both the eye and lesion level. Eye-level parameters included the presence of: hyporeflective core drusen, intraretinal hyperreflective foci (IHRF), subretinal drusenoid deposits, macular pachyvessels, central retinal thickness, and central choroidal thickness. Lesion-level qualitative parameters included the presence of ellipsoid zone (EZ) and external limiting membrane disruption overlying the AVL, IHRF overlying the AVL, AVL overlying drusen, pachyvessels under the AVL, a solid core within AVL, and AVL location. Lesion-level quantitative characteristics included AVL height and width, AVL distance from the fovea, and sub-AVL choroidal thickness.
MAIN OUTCOME MEASURES
The primary outcomes assessed included the frequency of IHRF, the presence of macular pachyvessels, central choroidal thickness, and the dimensions (both height and width) of AVLs.
RESULTS
Comparing the AVL and control groups, the frequency of IHRF (AVL: 49.3% vs. control: 26.3%) and macular pachyvessels (37.3% vs. 6.9%) was significantly higher in the AVL case group, and the central choroidal thickness (256.8 ± 88 μm vs. 207.1± 45 μm) was thicker in the AVL group. Acquired vitelliform lesions located over drusen, with overlying IHRF, or situated subfoveally, and AVL lesions with EZ disruption were found to have a greater lesion height and width compared with AVL lesions lacking these characteristics (P value < 0.001 for all). Additionally, a significant negative correlation was observed between the distance from the fovea and AVL height (Spearman rho: -0.19, P = 0.002) and width (Spearman rho: -0.30, P = 0.001).
CONCLUSIONS
This study represents the largest reported cohort of AVL lesions associated with iAMD. Novel findings include the higher frequency of pachyvessels in addition to the presence of a thicker choroid in these eyes, as well as the greater height and width of AVL closer to the foveal center. These findings may offer insights into pathophysiologic mechanisms underlying the development of AVL.
FINANCIAL DISCLOSURE(S)
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
PubMed: 38631656
DOI: 10.1016/j.oret.2024.04.009 -
Scientific Reports Apr 2024The objective of this study is to define structure-function relationships of pathological lesions related to age-related macular degeneration (AMD) using microperimetry...
The objective of this study is to define structure-function relationships of pathological lesions related to age-related macular degeneration (AMD) using microperimetry and multimodal retinal imaging. We conducted a cross-sectional study of 87 patients with AMD (30 eyes with early and intermediate AMD and 110 eyes with advanced AMD), compared to 33 normal controls (66 eyes) recruited from a single tertiary center. All participants had enface and cross-sectional optical coherence tomography (Heidelberg HRA-2), OCT angiography, color and infra-red (IR) fundus and microperimetry (MP) (Nidek MP-3) performed. Multimodal images were graded for specific AMD pathological lesions. A custom marking tool was used to demarcate lesion boundaries on corresponding enface IR images, and subsequently superimposed onto MP color fundus photographs with retinal sensitivity points (RSP). The resulting overlay was used to correlate pathological structural changes to zonal functional changes. Mean age of patients with early/intermediate AMD, advanced AMD and controls were 73(SD = 8.2), 70.8(SD = 8), and 65.4(SD = 7.7) years respectively. Mean retinal sensitivity (MRS) of both early/intermediate (23.1 dB; SD = 5.5) and advanced AMD (18.1 dB; SD = 7.8) eyes were significantly worse than controls (27.8 dB, SD = 4.3) (p < 0.01). Advanced AMD eyes had significantly more unstable fixation (70%; SD = 63.6), larger mean fixation area (3.9 mm; SD = 3.0), and focal fixation point further away from the fovea (0.7 mm; SD = 0.8), than controls (29%; SD = 43.9; 2.6 mm; SD = 1.9; 0.4 mm; SD = 0.3) (p ≤ 0.01). Notably, 22 fellow eyes of AMD eyes (25.7 dB; SD = 3.0), with no AMD lesions, still had lower MRS than controls (p = 0.04). For specific AMD-related lesions, end-stage changes such as fibrosis (5.5 dB, SD = 5.4 dB) and atrophy (6.2 dB, SD = 7.0 dB) had the lowest MRS; while drusen and pigment epithelial detachment (17.7 dB, SD = 8.0 dB) had the highest MRS. Peri-lesional areas (20.2 dB, SD = 7.6 dB) and surrounding structurally normal areas (22.2 dB, SD = 6.9 dB) of the retina with no AMD lesions still had lower MRS compared to controls (27.8 dB, SD = 4.3 dB) (p < 0.01). Our detailed topographic structure-function correlation identified specific AMD pathological changes associated with a poorer visual function. This can provide an added value to the assessment of visual function to optimize treatment outcomes to existing and potentially future novel therapies.
Topics: Humans; Cross-Sectional Studies; Prospective Studies; Macular Degeneration; Tomography, Optical Coherence; Fluorescein Angiography; Structure-Activity Relationship
PubMed: 38622152
DOI: 10.1038/s41598-024-54619-3