Progression from Early/Intermediate to Advanced Forms of Age-Related Macular Degeneration in a Large UK Cohort: Rates and Risk Factors

Chakravarthy, Usha; Bailey, Clare; Scanlon, Peter H; McKibbin, Martin; Khan, Rehna; Mahmood, Sajjad; Downey, Louise; Dhingra, Narendra; Brand, Christopher; Brittain, Christopher; Willis, Jeffrey R.; Venerus, Alessandra; Muthutantri, Anushini; Cantrell, Ronald A.

doi:10.1016/j.oret.2020.01.012

Cited by 49 publications

(38 citation statements)

References 35 publications

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“…Age-related macular degeneration (AMD) is a leading cause of irreversible blindness worldwide. 1 The pathophysiology underlying development of AMD is multifactorial. 2 Previous studies have linked cardiovascular disease and its risk factors, such as cigarette smoking, obesity, and hypertension, to the development and progression of AMD.…”

Section: Introductionmentioning

confidence: 99%

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Increased Systemic C-Reactive Protein Is Associated With Choroidal Thinning in Intermediate Age-Related Macular Degeneration

Chen

Palestine

Lynch

et al. 2021

Trans. Vis. Sci. Tech.

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Purpose C-reactive protein (CRP) and decreased choroidal thickness (CT) are risk factors for progression to advanced age-related macular degeneration (AMD). We examined the association between systemic levels of CRP and CT in patients with intermediate AMD (iAMD). Methods Patients with iAMD in the Colorado AMD Registry were included. Baseline serum samples and multimodal imaging including spectral domain–optical coherence tomography (SD-OCT), fundus photography, and autofluorescence were obtained. Medical and social histories were surveyed. CT was obtained by manual segmentation of OCT images. High-sensitivity CRP levels were quantified in serum samples. Univariate and multivariable linear regression models accounting for the intrasubject correlation of two eyes were fit using log-transformed CT as the outcome. Results The study included 213 eyes from 107 patients with a mean age of 76.8 years (SD, 6.8). Median CT was 200.5 µm (range, 86.5–447.0). Median CRP was 1.43 mg/L (range, 0.13–17.10). Higher CRP was associated with decreased CT in the univariate model ( P = 0.01). Older age and presence of reticular pseudodrusen (RPD) were associated with decreased CT ( P < 0.01), whereas gender, body mass index, and smoking were not associated with CT. Higher CRP remained significantly associated with decreased CT after adjustment for age and RPD ( P = 0.01). Conclusions Increased CRP may damage the choroid, leading to choroidal thinning and increased risk of progression to advanced AMD. Alternatively, CRP may be a marker for inflammatory events that mediate ocular disease. The results of this study further strengthen the association between inflammation and AMD. Translational Relevance Increased CRP is associated with choroidal thinning, a clinical risk factor for AMD.

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Section: Introductionmentioning

confidence: 99%

“…2 Previous studies have linked cardiovascular disease and its risk factors, such as cigarette smoking, obesity, and hypertension, to the development and progression of AMD. 1 – 4 …”

Section: Introductionmentioning

confidence: 99%

Increased Systemic C-Reactive Protein Is Associated With Choroidal Thinning in Intermediate Age-Related Macular Degeneration

Chen

Palestine

Lynch

et al. 2021

Trans. Vis. Sci. Tech.

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“…Two major advanced stages of AMD can occur simultaneously in one patient or even in a single eye: Choroidal neovascularization (CNV) and geographic atrophy (GA) [ 15 , 16 ]. These completely different disease patterns cause either disruption or loss of the retinal pigment epithelium (RPE).…”

Section: Introductionmentioning

confidence: 99%

Properdin Modulates Complement Component Production in Stressed Human Primary Retinal Pigment Epithelium Cells

et al. 2020

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The retinal pigment epithelium (RPE) maintains visual function and preserves structural integrity of the retina. Chronic dysfunction of the RPE is associated with retinal degeneration, including age-related macular degeneration (AMD). The AMD pathogenesis includes both increased oxidative stress and complement dysregulation. Physiological sources of oxidative stress in the retina are well known, while complement sources and regulation are still under debate. Using human primary RPE (hpRPE) cells, we have established a model to investigate complement component expression on transcript and protein level in AMD-risk and non-risk hpRPE cells. We evaluated the effect of properdin, a complement stabilizer, on the hpRPE cell-dependent complement profile exposed to oxidative stress. hpRPE cells expressed complement components, receptors and regulators. Complement proteins were also stored and secreted by hpRPE cells. We associated AMD-risk single nucleotide polymorphisms with an increased secretion of complement factors D (CFD) and I (CFI). Furthermore, we detected hpRPE cell-associated complement activation products (C3a, C5a) independent of any extracellularly added complement system. Exogenous properdin increased the mRNA expression of CFI and CFD, but decreased levels of complement components (C1Q, C3), receptors (C3AR, C5AR1, CD11B) and inflammation-associated transcripts (NLRP3, IL1B) in hpRPE cells exposed to oxidative stress. This properdin effect was time-dependently counter regulated. In conclusion, our data unveiled a local, genotype-associated complement component production in hpRPE cells, regulated by exogenous properdin. The local complement production and activation via blood-independent mechanisms can be a new therapeutic target for AMD.

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“…7KC is cytotoxic [20], but nontoxic effects involve pathways of inflammation, oxidation [27], and angiogenesis including through VEGF [28]. 7KC is also the predominant oxysterol in the blood of patients with cardiovascular disease [29], an associated risk of AMD [20].…”

Section: Introductionmentioning

confidence: 99%

7-ketocholesterol induces endothelial-mesenchymal transition and promotes fibrosis: implications in neovascular age-related macular degeneration and treatment

et al. 2021

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Oxidized cholesterols and lipids accumulate in Bruch's membrane in age-related macular degeneration (AMD). It remains unknown what causal relationship exists between these substances and AMD pathophysiology. We addressed the hypothesis that a prevalent form, 7-ketocholesterol (7KC), promotes choroidal endothelial cell (CEC) migration and macular neovascularization in AMD. Compared to control, 7KC injection caused 40% larger lectin-stained lesions, but 70% larger lesions measured by optical coherence tomography one week after laser-injury. At two weeks, 7KC-injected eyes had 86% larger alpha smooth muscle actin (αSMA)-labeled lesions and more collagen-labeling than control. There was no difference in cell death. 7KC-treated RPE/choroids had increased αSMA but decreased VE-cadherin. Compared to control-treated CECs, 7KC unexpectedly reduced endothelial VE-cadherin, CD31 and VEGFR2 and increased αSMA, fibroblast activation protein (FAP) and transforming growth factor beta (TGFβ). Inhibition of TGFβ receptor-mediated signaling by SB431542 abrogated 7KC-induced loss of endothelial and increase in mesenchymal proteins in association with decreased transcription factor, SMAD3. Knockdown of SMAD3 partially inhibited 7KC-mediated loss of endothelial proteins and increase in αSMA and FAP. Compared to control, 7KC-treatment of CECs increased Rac1GTP and migration, and both were inhibited by the Rac1 inhibitor; however, CECs treated with 7KC had reduced tube formation. These findings suggest that 7KC, which increases in AMD and with age, induces mesenchymal transition in CECs making them invasive and migratory, and causing fibrosis in macular neovascularization. Further studies to interfere with this process may reduce fibrosis and improve responsiveness to anti-VEGF treatment in non-responsive macular neovascularization in AMD.

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Progression from Early/Intermediate to Advanced Forms of Age-Related Macular Degeneration in a Large UK Cohort: Rates and Risk Factors

Cited by 49 publications

References 35 publications

Increased Systemic C-Reactive Protein Is Associated With Choroidal Thinning in Intermediate Age-Related Macular Degeneration

Increased Systemic C-Reactive Protein Is Associated With Choroidal Thinning in Intermediate Age-Related Macular Degeneration

Properdin Modulates Complement Component Production in Stressed Human Primary Retinal Pigment Epithelium Cells

7-ketocholesterol induces endothelial-mesenchymal transition and promotes fibrosis: implications in neovascular age-related macular degeneration and treatment

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