Anatomical, psychophysical and quality of life measures in patients with age related macular degeneration with and without cataract surgery

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Age‐related macular degeneration and recent developments: new hope for old eyes?

Age‐related macular degeneration (AMD) is the commonest cause of blindness in the population over 60 years of age and accounts for over 50% of those registered blind in the UK. The incidence is increasing and as older generations live longer a growing number of patients will be affected in the future. Affected patients lose central vision, important in all aspects of everyday life. This review outlines risk factors for AMD, clinical features, treatment and management strategies for patients, families and physicians caring for those with AMD. Recent trials are included along with practical clinical advice. While there is no curative treatment at present, intervention can reduce the risk of developing AMD and limit disease progression if it occurs. These modalities are discussed here. As new discoveries in the field of genetics and novel therapies emerge, a brighter future seems certain for the ageing population

The amyloid peptide precursor in Alzheimer's disease

beta A4, an hydrophobic peptide containing from 39 to 43 amino acids, is the major constituent of the amyloid core of characteristic lesions of Alzheimer's disease (AD) known as senile plaques. By cDNA cloning, it was demonstrated that beta A4 is derived from a much larger precursor named the amyloid peptide precursor or APP The isolation of cDNA clones and the characterization of their nucleotide sequence has shown that several APP proteins containing from 365 to 770 amino acids are produced by alternative splicing of a single primary transcript. The major APP isoforms contain a large extracellular N-terminal domain and a short intracellular C-terminal end. The beta A4 sequence itself is contained for 15 amino acids in the transmembrane domain while 28 amino acids are protruding into the extracellular space. The gene encoding APP is located on human chromosome 21, which is involved in the autosomal dominant inheritance of some early onset of familial AD (FAD). In a few families, mutations of the APP gene have been described. Although they can explain less than 3% of all FAD cases, these mutations clearly demonstrate that APP metabolism is involved in the development of AD. The overexpression of APP in several cultured cells allowed to characterize two catabolic pathways of the protein. A non amyloidogenic pathway precludes formation of beta A4, because APP is cleaved by an alpha-secretase within the beta A4 sequence, leading to the extracellular release of a C-terminal truncated protein. The amyloidogenic pathway produces soluble extracellular beta A4, by cleavage of APP by beta- and gamma-secretases after endocytosis of the transmembrane protein. Although soluble beta A4 is non toxic, it becomes very neurotoxic as soon as it makes fibrils. It is therefore essential to characterize the different factors which favor the organization of beta A4 into fibrils. They have to be considered as risk factors for AD, as well as targets for new therapies. Another therapeutic approach could consist in developing molecules able to inhibit beta A4 production by stimulating the non amyloidogenic pathway of APP

Complement factor h autoantibodies and age-related macular degeneration

PURPOSE. In this case-control study, the hypothesis that factor H autoantibodies are associated with age-related macular degeneration (AMD) was examined. METHODS. One hundred AMD patients (median age, 78 years), 98 age-matched control subjects (median age, 78 years) known not to have AMD, and 100 healthy blood donors (median age, 43 years) were enrolled. An enzyme-linked immunosorbent assay (ELISA) was used to screen for complement factor H autoantibodies and either quantitative polymerase chain reaction (qPCR) or multiplex ligation-dependent probe amplification (MLPA) were performed to measure the copy number of the gene encoding complement factor H-related protein 3 (CFHR3). RESULTS. There was a significant difference in the median complement factor H autoantibody titer between the three groups (AMD patients, 196 reference units [RU]]; age-match control subjects, 316 RU; and blood donor control subjects, 121 RU; Kruskal-Wallis test, P Ͻ 0.001). Pair-wise comparison (MannWhitney test) showed that all three groups were significantly different from each other. Two different thresholds were used in the healthy blood donors to identify individuals with complement factor H autoantibodies. Both suggested that the prevalence of factor H autoantibodies was decreased in AMD patients. The CFHR3 copy number was measured as a surrogate for the deletion of the genes encoding complement factor H-related proteins 3 and 1 (CFHR3/1). The allele frequency of the deletion was significantly higher in the age-matched control subjects than in the AMD patients (22.2% vs. 8.2%). CONCLUSIONS. The level of factor H autoantibodies is lower in AMD patients than in age-matched control subjects. (Invest Ophthalmol Vis Sci

Complement Factor H Autoantibodies and Age-Related Macular Degeneration

PURPOSE. In this case-control study, the hypothesis that factor H autoantibodies are associated with age-related macular degeneration (AMD) was examined. METHODS. One hundred AMD patients (median age, 78 years), 98 age-matched control subjects (median age, 78 years) known not to have AMD, and 100 healthy blood donors (median age, 43 years) were enrolled. An enzyme-linked immunosorbent assay (ELISA) was used to screen for complement factor H autoantibodies and either quantitative polymerase chain reaction (qPCR) or multiplex ligation-dependent probe amplification (MLPA) were performed to measure the copy number of the gene encoding complement factor H-related protein 3 (CFHR3). RESULTS. There was a significant difference in the median complement factor H autoantibody titer between the three groups (AMD patients, 196 reference units [RU]]; age-match control subjects, 316 RU; and blood donor control subjects, 121 RU; Kruskal-Wallis test, P Ͻ 0.001). Pair-wise comparison (MannWhitney test) showed that all three groups were significantly different from each other. Two different thresholds were used in the healthy blood donors to identify individuals with complement factor H autoantibodies. Both suggested that the prevalence of factor H autoantibodies was decreased in AMD patients. The CFHR3 copy number was measured as a surrogate for the deletion of the genes encoding complement factor H-related proteins 3 and 1 (CFHR3/1). The allele frequency of the deletion was significantly higher in the age-matched control subjects than in the AMD patients (22.2% vs. 8.2%). CONCLUSIONS. The level of factor H autoantibodies is lower in AMD patients than in age-matched control subjects. (Invest Ophthalmol Vis Sci

Genome-wide association study of age-related macular degeneration identifies associated variants in the TNXB–FKBPL–NOTCH4 region of chromosome 6p21.3

Age-related macular degeneration (AMD) is a leading cause of visual loss in Western populations. Susceptibility is influenced by age, environmental and genetic factors. Known genetic risk loci do not account for all the heritability. We therefore carried out a genome-wide association study of AMD in the UK population with 893 cases of advanced AMD and 2199 controls. This showed an association with the well-established AMD risk loci ARMS2 (age-related maculopathy susceptibility 2)-HTRA1 (HtrA serine peptidase 1) (P =2.7 × 10(-72)), CFH (complement factor H) (P =2.3 × 10(-47)), C2 (complement component 2)-CFB (complement factor B) (P =5.2 × 10(-9)), C3 (complement component 3) (P =2.2 × 10(-3)) and CFI (P =3.6 × 10(-3)) and with more recently reported risk loci at VEGFA (P =1.2 × 10(-3)) and LIPC (hepatic lipase) (P =0.04). Using a replication sample of 1411 advanced AMD cases and 1431 examined controls, we confirmed a novel association between AMD and single-nucleotide polymorphisms on chromosome 6p21.3 at TNXB (tenascin XB)-FKBPL (FK506 binding protein like) [rs12153855/rs9391734; discovery P =4.3 × 10(-7), replication P =3.0 × 10(-4), combined P =1.3 × 10(-9), odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.3-1.6] and the neighbouring gene NOTCH4 (Notch 4) (rs2071277; discovery P =3.2 × 10(-8), replication P =3.8 × 10(-5), combined P =2.0 × 10(-11), OR = 1.3, 95% CI = 1.2-1.4). These associations remained significant in conditional analyses which included the adjacent C2-CFB locus. TNXB, FKBPL and NOTCH4 are all plausible AMD susceptibility genes, but further research will be needed to identify the causal variants and determine whether any of these genes are involved in the pathogenesis of AMD