Genetic Polymorphisms and the Phenotypic Characterization of Individuals with Early Age-Related Macular Degeneration.

PURPOSE: While the importance of risk polymorphisms for the pathogenesis of age-related macular degeneration (AMD) is well established, their impact on morphological and functional phenotypes is largely unclear. We aimed to characterize individual phenotypes in patients who were either homozygous for a risk allele in the CFH gene, ARMS2 gene, or both as compared to non-carriers. METHODS: Patients with early AMD (n = 85) were assessed during a follow-up examination of a prospective study (MARS) with multimodal diagnostics including SD-OCT and microperimetry. RESULTS: Compared to non-carriers, OCT scans revealed lower retinal thickness in patients homozygous for CFH or ARMS2, which was caused by a significantly reduced photoreceptor layer. The number and ultrastructure of drusen were also significantly different. CONCLUSIONS: These findings indicate that patients with risk alleles demonstrate distinct phenotypic differences of morphology and function as compared to non-carriers. In particular in the CFH group, a loss of photoreceptors occurred concomitantly with reduced retinal sensitivity. Further studies might help to better understand the pathophysiology.

Changes of macular pigment optical density in elderly eyes: a longitudinal analysis from the MARS study.

BACKGROUND: Macular pigment (MP) has been related to the occurrence of age related macular degeneration (AMD). We investigated prospectively in eyes of elderly individuals how magnitude and spatial distribution of MP had changed after 4 years. METHODS: The study included 380 eyes from 237 participants of the Münster Ageing and Retina Study cohort which were free of advanced stages of AMD. MP optical density (MPOD) was measured in density units (D.U.) at eccentricities of 0.25°, 0.5°, 1.0° and 2.0° from the fovea using dual-wavelength autofluorescence; ring-like MP distributions were identified from MP density profiles. Changes were assessed with mixed linear models. RESULTS: The study participants' mean age at baseline was 70.5 years. Early AMD was present in 150 study eyes (39.5 %) and a ring-like distribution of MPOD was found in 87 study eyes (22.9 %). After a median follow-up time of 3.96 years, the MPOD averaged over all eyes was slightly raised at the central fovea (from 0.658 to 0.670 D.U. (relative change +1.8 %), p = 0.08) and most markedly at 2.0° (from 0.157 to 0.172 D.U. (+9.5 %), p < 0.001). Multivariate analyses, adjusting for sex, body mass and carotenoid supplement intake, revealed that MPOD increments, at any distance from the fovea, were slightly less pronounced in older eyes. Serum concentrations of lutein at follow-up, presumably reflecting recent intake of antioxidant supplements, raised MPOD levels significantly at 1.0° and 2.0° (both p < 0.01) but not in the central fovea. Early AMD at baseline and ring-like MPOD distribution did not significantly impact on MPOD changes over time. A ring-like spatial distribution of MPOD persisted in over 80 % of the affected eyes. CONCLUSIONS: Overall, the magnitude and spatial arrangement of MPOD was remarkably stable over time in elderly eyes. Significant MPOD rises in perifoveal regions probably indicate effects of lutein containing supplements. The persistence of ring-like MPOD distributions over time seems to suggest their determination by anatomical structures.

The contribution of genetic factors to phenotype and progression of drusen in early age-related macular degeneration.

PURPOSE: Genetic factors contribute to the development and progression of age-related macular degeneration (AMD). We aimed to assess the association of drusen as phenotypic characteristics of early AMD and their progression with polymorphisms in the CFH, ABCA1, and ARMS2 genes. METHODS: In the Münster Aging and Retina Study (MARS), drusen were detected in 406 patients with early AMD and 170 healthy controls according to the International Classification using fundus photographs, with a follow-up examination after 2.6 years (median). Six drusen features were assessed: drusen number (

Correlation between disease severity and presence of ocular autoantibodies in juvenile idiopathic arthritis-associated uveitis.

PURPOSE: The pathogenesis of juvenile idiopathic arthritis-associated uveitis (JIAU) is undefined. This study intended to analyze the presence of antiocular autoantibodies in serum and their correlation with disease course. METHODS: Serum samples from children with JIAU (n = 47); JIA without uveitis (n = 67); idiopathic anterior uveitis (IAU; n = 12); and healthy controls (n = 52) were collected. The binding patterns of serum antibodies to ocular cryosections from swine eyes were analyzed by indirect immunohistochemistry, and were correlated to epidemiological, clinical, and laboratory test results. RESULTS: The patient groups differed with respect to their presence of antibody binding to the sections: JIAU (94%), JIA (75%), IAU (75%), and healthy controls (29%) to uveal and/or retinal structures. Serum antibodies of JIAU patients predominantly bound at iris (74%), and ciliary body (79%). Iris/ciliary body positive staining correlated with the presence of uveitis complications (P < 0.005) in JIAU patients, but not with positivity of serum antinuclear antibodies (ANA), rheumatoid factor (RF), or HLA-B27, and was independent from uveitis activity or type of anti-inflammatory therapy. CONCLUSIONS: In JIAU patients, antiocular serum antibodies can be detected more frequently than in control groups. Binding patterns to ocular tissue correlate with complicated uveitis course but not with uveitis activity and anti-inflammatory treatment. Antibody binding is not specific for this uveitis entity, and does not correlate with ANA positivity.

The association of retinal structure and macular pigment distribution.

PURPOSE: Macular pigment optical density (MPOD) and age-related macular degeneration (AMD) are thought to be associated; however, the details are not yet understood clearly. This study aimed at investigating how retinal anatomic structures relate with the spatial MPOD distribution in single eyes. METHODS: In a subgroup of the third follow-up examination of the Münster Aging and Retina Study (MARS) cohort (mean age, 78.4 years), 124 single eyes of 79 participants with early AMD were examined. The MPOD was assessed using 2-wavelength autofluorescence (AF). Retinal thickness (RT) and fovea pit profile slopes were measured using optical coherence tomography (OCT). The results were analyzed for interocular correlation in 58 pairs of eyes, and for the association of MPOD distribution patterns with RT using uni- and multivariate statistical methods. RESULTS: The interocular correlations for several measures of RT and RT layers were high (P < 0.001). The RT was inversely and significantly related to MPOD at 1.0° and at 2.0° from the foveal center, but not to central MPOD. After controlling for sex, age, smoking, and spherical equivalent, RT was significantly thinner (-39.7 µm, P < 0.001) in eyes with ring-like compared to normal MPOD distribution. In particular, a thinner layer between internal and external limiting membrane showed strong associations with ring-like structures. CONCLUSIONS: Higher values of MPOD at 1° and 2°, as well as a ring-like distribution of MPOD were associated significantly with thinner maculae, due to thinner inner retinal layers. The MPOD distribution was unrelated to the slope of the foveal pit or the choroidal thickness. Our results suggest that the retinal section between the internal and external limiting membrane is involved in the spatial distribution of MPOD.

Profiles of macular pigment optical density and their changes following supplemental lutein and zeaxanthin: new results from the LUNA study.

PURPOSE: Based on latest analyses disclosing an inverse association between ring-like structures in macular pigment (MP) spatial profile and age-related macular degeneration, we performed additional analyses of MP measurements obtained in participants of our earlier lutein nutrition effects measured by autoflourescence (LUNA) study to disclose if oral lutein (L) and zeaxanthin (Z) can attenuate, amplify, or generate a ring structure. METHODS: A total of 97 subjects attended the last follow-up visit 3 months after discontinuation of a 6-month trial of 12 mg L and 1 mg Z supplementation. Of the subjects, 11 eyes had a secondary peak (ring-like structure) and 8 had an implied pericentral plateau/shoulder on the slope of MP density profile (intermediate distribution). RESULTS: L and Z intake led to a general shift toward higher MP values in eyes without ring structure. The difference between mean optical density of retinal MP (Diff MPOD) at last follow-up and baseline was +0.16 density units (D.U.) at 0° eccentricity. Increments at 0.25°, 0.5°, 1°, and 2° (all P < 0.0001) decayed exponentially with higher eccentricity. MPOD showed comparatively slight central changes in eyes with ring and intermediate distribution (diff_MPOD at 0° +0.03 and +0.09), and increased at minimum (+0.06, P = 0.01) and maximum (+0.07, P = 0.02) of the ring, and at inner (+0.07, P = 0.04) and outer (+0.09, P = 0.01) radius of the pericentral "shoulder." CONCLUSIONS: Ring structures were neither attenuated nor generated de novo following supplementation. Individuals with second peak/implied plateau in the slope of the profile appear to have the most effective retinal stabilization of L and Z located at a pericentral rather than the central location.

The ringlike structure of macular pigment in age-related maculopathy: results from the Muenster Aging and Retina Study (MARS).

PURPOSE: The role of macular pigment (MP) in age-related maculopathy (ARM) is still not clearly understood. Recent studies have reported on variations in the spatial distribution of MP optical density (MPOD) including a secondary peak ("ring") in the slope of the MPOD profile. The authors investigated in a cross-sectional manner the presence of ringlike structures, their determinants, and their relationship with ARM. METHODS: In all, 369 participants of the Muenster Aging and Retina Study were examined using dual-wavelength analysis of autofluorescence images. ARM was graded using digital fundus photographs according to the International Classification System. RESULTS: A ringlike structure was observed in 73 (19.8%) study participants. The MP maximum of the ring was located on average at 0.85° and the minimum at 0.48° from the center of the fovea. Their concordance between pairs of eyes was highly significant. MPOD measured at eccentricities of 0°, 0.25°, and 0.5° from the fovea was significantly lower in eyes with ringlike structure, whereas it was significantly higher at 1.0° and 2.0° than that in eyes without the ring. Ringlike structures were significantly more common in females and never smokers and were found significantly less often in eyes with ARM than in healthy eyes, even after adjustment for influential factors (adjusted odds ratio, 0.347; 95% confidence interval, 0.196-0.617). CONCLUSIONS: Ringlike structures in the MP spatial profile are fairly common, show a high degree of bilaterality, and appeared inversely related with ARM.

Determinants of macular pigment optical density and its relation to age-related maculopathy: results from the Muenster Aging and Retina Study (MARS).

PURPOSE: The controversial protective effect of macular pigment (MP), consisting of lutein (L) and zeaxantin (Z), in age-related maculopathy (ARM) and its late-stage, age-related macular degeneration (AMD) is discussed. Determinants of MP optical density (MPOD) and its relation to ARM were investigated. METHODS: MPOD was accessed at eccentricities of 0.5° and 2.0° from the fovea in 369 participants in the 2.6-year follow-up examination of the prospective Muenster Aging and Retina Study using dual-wavelength analysis of autofluorescence images. ARM was graded from standardized fundus photographs according to the International Classification System. RESULTS: MPOD at 0.5° and 2.0° between pairs and within single eyes was strongly correlated (P < 0.001). Smoking and body mass index showed moderately inverse associations with MPOD at 2.0°, and age was positively related to MPOD at both eccentricities. Serum L, measured at the baseline examination, was significantly associated with MPOD measured at follow-up. Likewise, use of L/Z-containing supplements raised MPOD. Crude mean MPOD increased with ascending stage of ARM. However, adjustment for influential factors and exclusion of L supplement users removed differences of mean MPOD between ARM stages. Considering further the accompanying eye, study eyes with ARM had significantly higher MPOD when the contralateral eye had AMD. CONCLUSIONS: MPOD levels showed a high degree of intraindividual concordance and interindividual variability. Long-standing serum L levels, and in particular L supplementation, were the strongest determinants of MPOD. The hypothetical inverse association between MPOD and ARM stage was not confirmed.

Long-term visual course after anti-VEGF therapy for exudative AMD in clinical practice evaluation of the German reinjection scheme.

BACKGROUND: In phase III trials, the therapeutic efficacy of anti-VEGF therapy with ranibizumab (Lucentis) in patients with choroidal neovascularization due to AMD was demonstrated in a 24-month period with monthly injections. Other studies and models suggested that flexible reinjection regimens can provide similar visual results. The aim of the present study was to evaluate the flexible, predominantly visual acuity-driven ranibizumab retreatment regimen in clinical practice in Germany. PATIENTS AND METHODS: Best-corrected visual acuity (VA, logMAR) and central retinal thickness (CRT) were recorded initially and every 4-6 weeks during follow-up (mean follow-up 75.5 weeks) from 152 eyes. All eyes were treated initially 3 times with ranibizumab at 4-weekly intervals, and retreated with another three injections if visual acuity decreased and/or CRT increased (>100 µm), and/or if new angiographic leakage and/or new retinal hemorrhages developed. Visual acuity development was analyzed in the whole group. A quartile analysis was also performed, and visual course was correlated with CRT. In all groups, numbers and times of reinjections within the first year were registered and analyzed. RESULTS: An increase in mean VA of 0.14 (SD 0.22) logMAR could be observed after 3 months, but during follow-up from months 3 to 12 the mean visual acuity decreased again by 0.14 (SD 0.24) logMAR, and was similar to the initial VA despite several reinjections (mean five injections). Stratification of patients according to the visual effect after 3 months (quartile analysis) demonstrated a differentiation of the visual course. Quartile 1, with the largest increase in VA after 3 months and reduction of the retinal edema, lost this positive effect during follow-up (100% of eyes received further injections). In contrast, quartile 2, with a minor increase, and quartile 3 demonstrated a stabilized response during follow-up (80% reinjections), while quartile 4 demonstrated a further loss in VA despite reinjections initially and during follow-up (60% reinjections). CONCLUSIONS: The flexible, predominantly visual acuity-driven ranibizumab retreatment regimen employed in clinical practice in Germany generally resulted in a loss of initially gained VA during 12 months of follow-up. Subgroup analysis showed that this negative effect was especially present in patients with relatively bad VA at treatment entry as well as the highest visual gain. Because this result demonstratse that a visual acuity-related retreatment regimen can not preserve the initial positive treatment effects with ranibizumab in exudative AMD, a revision of this schematic retreatment regimen used in Germany and adaptation to more sensitive retreatment parameters is recommended.

Fundus autofluorescence and spectral domain optical coherence tomography in uveitic macular edema.

BACKGROUND: Cystoid macular edema (CME) is a common vision-limiting complication of uveitis. This study correlated fundus autofluorescence (FAF) and optical coherence tomography (OCT) with visual acuity (VA). PATIENTS AND METHODS: Prospective, observational, cross-sectional study with 31 patients (53 eyes) with endogenous uveitis and fluorescein angiographically (FA) confirmed CME. Foveal thickness, epiretinal membrane formation, and altered (increased or decreased) foveal FAF were analyzed with a combined spectral domain OCT/FA device (Spectralis/HRA Heidelberg Retina Angiograph 2). Primary outcome measures were an association between central FAF with foveal thickness and VA (t-test, each). Secondary outcome measures included the association of FAF and epiretinal membrane formation, the presence of cystoid spaces in the outer plexiform and inner nuclear layers, and integrity of the third highly reflective band as detected by OCT (Fisher s exact test, each). RESULTS: Of the 24 eyes (59%) with altered FAF in the central 500 microm, all had increased foveal FAF, and 10% also had increased perifoveal petaloid FAF. In eyes with altered FAF, the VA was frequently worse (p = 0.019) and foveal thickness increased (p = 0.015). Foveal thickness (mean 369.4 mum) correlated with VA (p < 0.01). FAF alterations correlated with the presence of cystoid spaces in the outer plexiform and inner nuclear layer in OCT (p < 0.001). Epiretinal membrane formation (70%) was associated with increased foveal thickness (p = 0.003) and poor VA (p = 0.08). Irregularity or loss of the third HRB (51%) correlated with poor VA (p < 0.01) and altered central FAF (p = 0.031). CONCLUSIONS: FAF and OCT are useful diagnostic tools for the evaluation of uveitic CME. Increased central FAF, presence of cystoid retinal changes and disrupted third highly reflective band in OCT, and epiretinal membrane formation are associated with poor vision.

Smoking history and the incidence of age-related macular degeneration--results from the Muenster Aging and Retina Study (MARS) cohort and systematic review and meta-analysis of observational longitudinal studies.

To compare the association of smoking with age-related macular degeneration (AMD) in the Muenster Aging and Retina Study (MARS) cohort with current evidence. Adjusted risk ratios for incident AMD in MARS were compared with findings of a systematic review and meta-analysis of observational prospective studies. 9.6% of MARS participants progressed to AMD over a median of 30.9 months. In MARS the adjusted risk ratio in current versus never smokers was 3.25 (95% confidence interval [1.50-7.06]), and 1.28 [0.70-2.33] in former smokers versus never smokers. The meta-analysis of previous studies showed a pooled adjusted risk ratio of 2.51 [1.09-5.76] in current versus never smokers. Inclusion of the MARS findings removed between-study heterogeneity and accentuated the pooled adjusted risk ratio for current smokers to 2.75 [1.52-4.98]. Specific analyses in MARS revealed a protective effect for time since smoking cessation in former smokers with an adjusted risk ratio=0.50 [0.29-0.89] per log(year). Current smoking nearly triples AMD incidence, while smoking cessation lowers AMD incidence in a non-linear fashion even in the elderly.

LOC387715, smoking and their prognostic impact on visual functional status in age-related macular degeneration-The Muenster Aging and Retina Study (MARS) cohort.

PURPOSE: To prospectively evaluate the impact of homozygosity in the A69S-SNP of the LOC387715-gene, smoking history, and their interaction on visual functional status (v-FS) in age-related macular degeneration (AMD). METHODS: The Muenster Aging and Retina Study (MARS) cohort (n = 656; 58.8% women, mean age 70.2 years) was followed over a mean of 2.5 years. AMD-status, genotype and smoking history were assessed at baseline. V-FS [from 0 (low) to 100 (unimpaired) points in general-, near- and far-vision], were AMD-status assessed at baseline and at follow-up. Linear models with stepwise adjustments for covariates were used to analyze decline of v-FS over time. RESULTS: In initial models, homozygosity for the A69S-variant was negatively associated with all three dimensions of the v-FS. After including smoking history, ever smoking was negatively associated with declines in near and far vision (-4.82 and -5.12 points, respectively; each p < 0.05). In smokers homozygous for the A69S-variant the number of cigarettes smoked per day (smoking intensity) was negatively associated with all three dimensions of the v-FS (interaction term each p < 0.05). Time since smoking cessation in former smokers protected against declines in near and far vision. These effects were independent of the AMD-status at baseline. CONCLUSIONS: The interaction of homozygosity for the A69S-variant and smoking intensity had a negative impact on general-, near-, and far visual functional status independent of AMD-status. Quitting smoking seemed to have a time-dependent protective effect on near and far vision.

Modeling smoking history: a comparison of different approaches in the MARS study on age-related maculopathy.

PURPOSE: Smoking is an established risk factor for the development of age-related maculopathy (ARM), and its end stage, age-related macular degeneration (AMD). We evaluated the benefit of various smoking-related variables in modeling the association of smoking with ARM and AMD in a mixed sample of current, former, and never smokers. METHODS: This was a cross-sectional study in participants of the Muensteraner Altern- und Retina-Studie (MARS). Participants were classified according to the Rotterdam classification system as healthy, or having ARM or AMD. Using multinomial logistic regression techniques, the association with number of cigarettes, years of smoking, pack-years and time since cessation in former smokers were evaluated. RESULTS: Mean age of the 982 participants (58.6% females) was 70.9 +/- 5.5 years. ARM was present in 483 (49.2%) and AMD in 285 (29.0%) individuals. The adjusted prevalence odds ratio (OR) in current smokers versus never smokers was 2.61 (95% confidence interval [CI] 1.34-5.09) for ARM and 3.94 (95% CI 1.91-8.14) for AMD. This effect decreased in former smokers with an OR = 0.55 (95% CI 0.33-0.99) per log-transformed time since smoking cessation for ARM and an OR = 0.52 (95% CI 0.30-0.90) for AMD. CONCLUSIONS: By including a variable for time since smoking cessation, we were able to handle current, former, and never smokers in one model that estimates the association of smoking with ARM or AMD. Logarithmical transformation of the time since smoking cessation seemed to increase the model fit and to reflect a non-linear protective effect of smoking cessation on the onset of ARM and AMD in former smokers.