Macular Degeneration: Charbel Issa P

Finger RP, Krohne TU, Charbel Issa P, Fleckenstein M, Scholl HP, Holz FG. · No affiliation provided · Retina. · Pubmed #19430277 No free full text.

This publication has no abstract.

Scholl HP, Fleckenstein M, Charbel Issa P, Keilhauer C, Holz FG, Weber BH. · Department of Ophthalmology, University of Bonn, Bonn, Germany. <> · Mol Vis. · Pubmed #17327825 links to  free full text

Abstract: Age-related macular degeneration (AMD) is a genetically complex disorder of the photoreceptor-RPE-Bruch's membrane-choriocapillaris complex. Family and twin studies have shown that the susceptibility for this disease is genetically influenced. The heritability has been estimated to be up to 71%. Linkage and association studies have identified several chromosomal regions that are likely to contain susceptibility loci with strongest evidence found on chromosome 1q31 and 10q26. Variants in the complement factor H (CFH) gene have been shown by several independent studies to be associated with an increased risk for AMD in Caucasian populations. These findings imply that the innate immune system may play a significant role in AMD pathogenesis. The LOC387715/HTRA1 locus within 10q26 has been identified as a second major locus contributing to AMD pathogenesis. The two late forms of AMD, choroidal neovascularization and geographic atrophy, have not been found to be different in risk allele distribution. Variants within CFH and LOC387715/HTRA1 may contribute to the increased risk of late AMD largely through their impact on precursors, such as drusen and/or other RPE/Bruch's membrane changes. Considering variants at CFH, LOC387715/HTRA1 and complement component 2-complement factor B (C2-FB), high-risk homozygotes at all three loci may have a 250-fold increased risk compared to baseline. However, the identification of genetic factors has not resulted in therapeutic strategies to modify the disease so far and additional genetic and environmental factors are yet to be discovered in order to influence the onset and the progression of AMD.

Charbel Issa P, Scholl HP, Holz FG, Knolle P, Kurts C. · Augenklinik, Universität, Bonn. · Ophthalmologe. · Pubmed #16215754 No free full text.

Abstract: The discovery of the complement factor H (CFH) polymorphism in age-related macular degeneration (AMD) strongly suggests a causative role of the complement system in the pathogenesis of this disease. The complement system is part of the innate immune system and is closely associated with the cellular response and the adaptive immune system. This article provides an overview of the complement system and, taking the new data into account, of possible immunopathogenetic processes in AMD.

Fleckenstein M, Charbel Issa P, Helb HM, Schmitz-Valckenberg S, Scholl HP, Holz FG. · Department of Ophthalmology, University of Bonn, Bonn, Germany. · Arch Ophthalmol. · Pubmed #18852430 No free full text.

This publication has no abstract.

Scholl HP, Charbel Issa P, Walier M, Janzer S, Pollok-Kopp B, Börncke F, Fritsche LG, Chong NV, Fimmers R, Wienker T, Holz FG, Weber BH, Oppermann M. · Department of Ophthalmology, University of Bonn, Bonn, Germany. · PLoS One. · Pubmed #18596911 links to  free full text

Abstract: Dysregulation of the alternative pathway (AP) of complement cascade has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. To further test the hypothesis that defective control of complement activation underlies AMD, parameters of complement activation in blood plasma were determined together with disease-associated genetic markers in AMD patients. Plasma concentrations of activation products C3d, Ba, C3a, C5a, SC5b-9, substrate proteins C3, C4, factor B and regulators factor H and factor D were quantified in patients (n = 112) and controls (n = 67). Subjects were analyzed for single nucleotide polymorphisms in factor H (CFH), factor B-C2 (BF-C2) and complement C3 (C3) genes which were previously found to be associated with AMD. All activation products, especially markers of chronic complement activation Ba and C3d (p<0.001), were significantly elevated in AMD patients compared to controls. Similar alterations were observed in factor D, but not in C3, C4 or factor H. Logistic regression analysis revealed better discriminative accuracy of a model that is based only on complement activation markers Ba, C3d and factor D compared to a model based on genetic markers of the complement system within our study population. In both the controls' and AMD patients' group, the protein markers of complement activation were correlated with CFH haplotypes.This study is the first to show systemic complement activation in AMD patients. This suggests that AMD is a systemic disease with local disease manifestation at the ageing macula. Furthermore, the data provide evidence for an association of systemic activation of the alternative complement pathway with genetic variants of CFH that were previously linked to AMD susceptibility.

Fleckenstein M, Charbel Issa P, Helb HM, Schmitz-Valckenberg S, Finger RP, Scholl HP, Loeffler KU, Holz FG. · Department of Ophthalmology, University of Bonn, Bonn, Germany. · Invest Ophthalmol Vis Sci. · Pubmed #18487363 No free full text.

Abstract: PURPOSE: To describe morphologic variations in outer retinal layers in eyes with atrophic age-related macular degeneration (AMD) using high-resolution, spectral-domain optical coherence tomography (SD-OCT). METHODS: SD-OCT scans were obtained with a combined confocal scanning laser ophthalmoscope (cSLO) and SD-OCT for simultaneous tomographic and topographic in vivo imaging. A total of 81 eyes of 56 patients (mean age, 77.8 +/- 7.4 years) with geographic atrophy (GA) were examined. Morphologic alterations were analyzed and classified in the perilesional zone, at the junction between GA and nonatrophic retina, and in the atrophic area itself. RESULTS: In the perilesional zone, distinct morphologic alterations included elevations of the outer retinal layers, thickening, and spikes of the outer hyperreflective band as well as clumps at different neurosensory retinal levels. At the junction, highly variable transitions of the outer retinal layers were present with different degrees of loss of the normal hyperreflective bands. Within the actual GA, hyperreflective clumps at different retinal levels, segmented plaques of the outer band and elevations with variable reflectivity were visualized. CONCLUSIONS: SD-OCT imaging in eyes with GA revealed a wide spectrum of morphologic alterations, both in the surrounding retinal tissue and in the atrophic area. These alterations may reflect different disease stages or, alternatively, heterogeneity on a cellular and molecular level. Longitudinal studies using in vivo SD-OCT imaging may allow evaluation of the relevance of these phenotypic changes as potential predictive markers for the progression of disease (i.e., enlargement rates of GA over time) and may be used for monitoring of future therapeutic interventions.