Major Predictive Factors for Progression of Early to Late Age-Related Macular Degeneration

Abstract

Introduction: We present a prediction model for progression from early/intermediate to advanced age-related macular degeneration (AMD) within 5.9 years. Objectives: To evaluate the combined role of genetic, nongenetic, and phenotypic risk factors for conversion from early to late AMD over ≥5 years. Methods: Baseline phenotypic characteristics were evaluated based on color fundus photography, spectral-domain optical coherence tomography, and infrared images. Genotyping for 36 single-nucleotide polymorphisms as well as systemic lipid and complement measurements were performed. Multivariable backward logistic regression resulted in a final prediction model. Results and Conclusions: During a mean of 5.9 years of follow-up, 22.4% (n = 52) of the patients (n = 232) showed progression to late AMD. The multivariable prediction model included age, CFH variant rs1061170, pigment abnormalities, drusenoid pigment epithelial detachment (DPED), and hyperreflective foci (HRF). The model showed an area under the curve of 0.969 (95% confidence interval 0.948–0.990) and adequate calibration (Hosmer-Lemeshow test, p = 0.797). In addition to advanced age and carrying a CFH variant, pigment abnormalities, DPED, and HRF are relevant imaging biomarkers for conversion to late AMD. In clinical routine, an intensified monitoring of patients with a high-risk phenotypic profile may be suitable for the early detection of conversion to late AMD.

The Relevance of Oxidative Stress in the Pathogenesis and Therapy of Retinal Dystrophies

“…RPE-damaged cells release cytokines and chemokines that recruit and activate choroid dendritic cells, which amplify the inflammatory process due to cell-cell contact, overall triggering a chronic inflammation that has been reported to play a key role in the AMD pathogenicity [81]. Indeed, genetic risk variants may exacerbate the inflammatory response due to OS in the retina, and several polymorphic variants in genes encoding or regulating key complement proteins have been associated to AMD [82]. The major genetic risk factor to develop AMD is the Y402H polymorphism of complement factor H (CFH), which reduces CFH's ability to neutralize the effect of oxidized photoreceptor phospholipids from photoreceptors, which are incorporated into the RPE membrane and trigger RPE cell apoptosis [83,84].…”

Association of imaging biomarkers and local activation of complement in aqueous humor of patients with early forms of age-related macular degeneration

“…Interestingly, in this study, RPD showed only slight correlation with CFB and none of the other complement factors. Like DV and HRF, RPD have been also recognized as a risk factor for progression to advanced AMD [23,24,47,48].…”

“…The findings also correspond to genetic studies, which showed an association between greater DV and drusen area with higher number of AMD risk alleles in complement genes [ 34 – 36 ]. Several clinical studies suggested using DV as a quantitative tool to assess the risk for AMD progression [ 23 , 37 – 39 ].…”

“…Interestingly, in this study, RPD showed only slight correlation with CFB and none of the other complement factors. Like DV and HRF, RPD have been also recognized as a risk factor for progression to advanced AMD [ 23 , 24 , 47 , 48 ]. Furthermore, the presence of RPD has been associated with major AMD risk polymorphisms in ARMS2/HTRA1 genes [ 24 , 49 , 50 ].…”

“…Their detection can be important for future therapeutic intervention and risk estimation. With the wide use of non-invasive spectral-domain optical coherence tomography (SD-OCT), distinctive morphological features such as drusen volume (DV), hyperreflective foci (HRF), and reticular pseudodrusen (RPD) were identified as imaging biomarkers for AMD progression [21][22][23][24][25]. It is still unknown whether those imaging biomarkers reflect the level of local complement activation in the eye.…”