Geographic atrophy: Mechanism of disease, pathophysiology, and role of the complement system

Bakri, Sophie J.; Bektas, Meryem; Sharp, Darcie; Luo, Roger T.; Sarda, Sujata P.; Khan, Shahnaz

doi:10.18553/jmcp.2023.29.5-a.s2

Cited by 15 publications

(15 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 24 In AMD, particularly GA, inflammation plays a crucial role in the degenerative process. 25 , 26 Our control showed that retinal microglia are mainly located in the GCL and IPL. However, we observed the migration of macrophages and microglia into the ONL layer at all time points in NaIO 3 -injected rats.…”

Section: Discussionmentioning

confidence: 80%

Histologic and Immunohistochemical Characterization of GA-Like Pathology in the Rat Subretinal Sodium Iodate Model

Naik,

Grebe,

Bhutto

et al. 2024

Trans. Vis. Sci. Tech.

View full text Add to dashboard Cite

Purpose Geographic atrophy (GA) is an advanced form of dry age-related macular degeneration with multifactorial etiology and no well-established treatment. A model recapitulating the hallmarks would serve as a key to understanding the underlying pathologic mechanisms better. In this report, we further characterized our previously reported subretinal sodium iodate model of GA. Methods Retinal degeneration was induced in rats (6–8 weeks old) by subretinal injections of NaIO 3 as described previously. Animals were sacrificed at 3, 8 and 12 weeks after injection and eyes were fixed or cryopreserved. Some choroids were processed as flatmounts while other eyes were cryopreserved, sectioned, and immunolabeled with a panel of antibodies. Finally, some eyes were prepared for transmission electron microscopic (TEM) analysis. Results NaIO 3 subretinal injection resulted in a well-defined focal area of retinal pigment epithelium (RPE) degeneration surrounded by viable RPE. These atrophic lesions expanded over time. RPE morphologic changes at the border consisted of hypertrophy, multilayering, and the possible development of a migrating phenotype. Immunostaining of retinal sections demonstrated external limiting membrane descent, outer retinal tubulation (ORT), and extension of Müller cells toward RPE forming a glial membrane in the subretinal space of the atrophic area. TEM findings demonstrated RPE autophagy, cellular constituents of ORT, glial membranes, basal laminar deposits, and defects in Bruch's membrane. Conclusions In this study, we showed pathologic features of a rodent model resembling human GA in a temporal order through histology, immunofluorescence, and TEM analysis and gained insights into the cellular and subcellular levels of the GA-like phenotypes. Translational Relevance Despite its acute nature, the expansion of atrophy and the GA-like border in this rat model makes it ideal for studying disease progression and provides a treatment window to test potential therapeutics for GA.

show abstract

Section: Discussionmentioning

confidence: 80%

Histologic and Immunohistochemical Characterization of GA-Like Pathology in the Rat Subretinal Sodium Iodate Model

Naik,

Grebe,

Bhutto

et al. 2024

Trans. Vis. Sci. Tech.

View full text Add to dashboard Cite

show abstract

“…With age, RPE dysfunction progresses, leading to drusen and lipofuscin deposition [11,39]. Drusen and lipofuscin components, as well as other oxidative stress products, such as advanced glycation end products, have been reported to induce inflammation through multiple pathways, including via the complement cascade [39][40][41][42]. When regulatory components in these pathways are compromised, especially by genetic risk factors, initiation of chronic inflammation (para-inflammation) may lead to damage and, ultimately, retinal cell death, which is a typical feature of GA [11,42].…”

Section: Discussionmentioning

confidence: 99%

Circulating Anti-Endothelial Cell Antibodies in Patients with Geographic Atrophy Related to Dry Age-Related Macular Degeneration

Żuber-Łaskawiec,

Wilańska,

Karska-Basta

et al. 2024

Medicina

View full text Add to dashboard Cite

Background and Objectives: Age-related macular degeneration (AMD) is one of the leading causes of central vision loss among elderly patients, and its dry form accounts for the majority of cases. Although several causes and mechanisms for the development and progression of AMD have previously been identified, the pathogenesis of this complex disease is still not entirely understood. As inflammation and immune system involvement are strongly suggested to play a central role in promoting the degenerative process and stimulating the onset of complications, we aimed to analyze the frequency of serum anti-retinal (ARAs) and anti-endothelial cell antibodies (AECAs) in patients with dry AMD and to determine their relationship with the clinical features of the disease, notably the area of geographic atrophy (GA). Materials and Methods: This study included 41 patients with advanced-stage dry AMD and 50 healthy controls without AMD, matched for gender and age. ARAs were detected by indirect immunofluorescence using monkey retina as an antigen substrate, and the presence of AECAs was determined using cultivated human umbilical vein endothelial cells and primate skeletal muscle. Results: ARAs were detected in 36 (87.8%) AMD patients (titers ranged from 1:20 to 1:320) and in 16 (39.0%) (titers ranged from 1:10 to 1:40) controls (p = 0.0000). Twenty of the forty-one patients (48.8%) were positive for AECAs, while in the control group, AECAs were present only in five sera (10.0%). The titers of AECAs in AMD patients ranged from 1:100 to 1:1000, and in the control group, the AECA titers were 1:100 (p = 0.0001). There were no significant correlations between the presence of AECAs and disease activity. Conclusions: This study demonstrates a higher prevalence of circulating AECAs in patients with dry AMD; however, no correlation was found between the serum levels of these autoantibodies and the area of GA.

show abstract

“…Retinal pathology problems that were investigated in this study were: retinal pigmented epithelium (RPE) change, drusen, geographic atrophy (GA), HTR, nonproliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), choroidal neovascularization (CNV), central retinal artery occlusion (CRAO), myopic retinopathy (MR), branch retinal vein occlusion (BRVO), and central retinal vein occlusion (CRVO). Each evaluated retinal pathology is defined in Table 1 [14][15][16][17][18][19][20][21][22][23][24] . Statistical Analysis The prevalence of retinal pathologies is reported as percentage and 95% confidence interval.…”

Section: Subjects and Methods Ethical Approvalmentioning

confidence: 99%

“…Drusen Yellow deposits under the retina [14] Retinal pigmented epithelium change Change in the pigmentation of the RPE [15] Geographic atrophy Atrophic lesions in the macula [16] Choroidal neovascularization New blood vessels originating from the choroid [17] Nonproliferative diabetic retinopathy The presence of at least one sign including microaneurysms, dot and blot and intraretinal hemorrhages, hard exudates, cotton-wool spots, and venous beading in diabetic patients [18][19] Proliferative diabetic retinopathy The presence of new vessels with or without intravitreal hemorrhages in diabetic patients [19] Hypertensive retinopathy 1 or more signs including generalized arteriolar narrowing, focal arteriolar narrowing, arteriovenous nicking, arteriolar wall opacity, retinal hemorrhage (blot, dot, flame-shaped), microaneurysm, cotton wool spot, hard exudate, moderate retinopathy plus optic disc swelling in patients with hypertension [20]…”

Section: Retinal Pathologies Definitionmentioning

confidence: 99%

Prevalence of retinal pathologies in people over 60 years: the Tehran Geriatrics Eye Study

Mortazavi,

Jamali,

Hashemi

et al. 2024

Int J Ophthalmol

View full text Add to dashboard Cite

AIM: To determine the prevalence of some retinal pathologies in people over 60y and their association with demographic and ocular factors. METHODS: A cross-sectional study was conducted in Tehran using multistage cluster sampling. After selecting subjects aged 60 and over, optometric, and ophthalmic examinations were done. For retinal examination, a 90 D lens was used and indirect ophthalmoscopy was performed after instilling tropicamide drops. Biometry was done using the IOL Master for all participants. RESULTS: Of 3791 people that were invited through cluster sampling, 3310 participated in the study (response rate=82%). The prevalence of retinal pigmented epithelium (RPE) change, drusen, geographic atrophy (GA), hypertensive retinopathy (HTR), nonproliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), choroidal neovascularization (CNV), central retinal artery occlusion (CRAO), myopic retinopathy (MR), branch retinal vein occlusion (BRVO), and central retinal vein occlusion (CRVO) was 27.42%, 11.08%, 4.52%, 3.03%, 4.05%, 0.54%, 0.82%, 0.39%, 0.20%, 0.49%, and 0.19%, respectively. After removing the effect of age, the odds of NPDR were 1.68 times higher in women compared to men (P=0.014). After removing the effect of sex, the odds of drusen, RPE change, GA, CNV, BRVO, and CRVO increased with age. CONCLUSION: There is a higher prevalence of RPE change, drusen, GA, CNV and a lower prevalence of MR and CRAO in the elderly population of Tehran aged over 60y compared to global average values. Considering the correlation of most of the diseases with age and their effects on vision, attention should be paid to these diseases and the related screening programs to prevent vision impairment.

show abstract

Geographic atrophy: Mechanism of disease, pathophysiology, and role of the complement system

Cited by 15 publications

References 43 publications

Histologic and Immunohistochemical Characterization of GA-Like Pathology in the Rat Subretinal Sodium Iodate Model

Histologic and Immunohistochemical Characterization of GA-Like Pathology in the Rat Subretinal Sodium Iodate Model

Circulating Anti-Endothelial Cell Antibodies in Patients with Geographic Atrophy Related to Dry Age-Related Macular Degeneration

Prevalence of retinal pathologies in people over 60 years: the Tehran Geriatrics Eye Study

Contact Info

Product

Resources

About