Johanna Maria Colijn

Five-year progression of unilateral age-related macular degeneration to bilateral involvement: the Three Continent AMD Consortium report

Purpose To assess the 5-year progression from unilateral to bilateral age-related macular degeneration (AMD) and associated risk factors. Design Pooled data analyses of three prospective population-based cohorts, the Blue Mountains Eye Study, Beaver Dam Eye Study and Rotterdam Study. Methods Retinal photography and interview with comprehensive questionnaires were conducted at each visit of three studies. AMD was assessed following the modified Wisconsin AMD grading protocol. Progression to bilateral any (early and late) or late AMD was assessed among participants with unilateral involvement only. Factors associated with the progression were assessed using logistic regression models while simultaneously adjusting for other significant risk factors. Results In any 5-year duration, 19–28% of unilateral any AMD cases became bilateral and 27–68% of unilateral late AMD became bilateral. Factors associated with the progression to bilateral involvement of any AMD were age (per year increase, adjusted OR 1.07), carrying risk alleles of the complement factor H and age-related maculopathy susceptibility 2 genes (compared with none, OR 1.76 for 1 risk allele and OR 3.34 for 2+ risk alleles), smoking (compared with non-smokers, OR 1.64 for past and OR 1.67 for current smokers), and the presence of large drusen area or retinal pigmentary abnormalities in the first eye. Conclusion One in four to one in five unilateral any AMD cases, and up to one in two unilateral late AMD cases, progressed to bilateral in 5 years. Known AMD risk factors, including smoking, are significantly associated with the progression to bilateral involvement.

A new perspective on lipid research in age-related macular degeneration

&NA; There is an urgency to find new treatment strategies that could prevent or delay the onset or progression of AMD. Different classes of lipids and lipoproteins metabolism genes have been associated with AMD in a multiple ways, but despite the ever‐increasing knowledge base, we still do not understand fully how circulating lipids or local lipid metabolism contribute to AMD. It is essential to clarify whether dietary lipids, systemic or local lipoprotein metabolismtrafficking of lipids in the retina should be targeted in the disease. In this article, we critically evaluate what has been reported in the literature and identify new directions needed to bring about a significant advance in our understanding of the role for lipids in AMD. This may help to develop potential new treatment strategies through targeting the lipid homeostasis. HighlightsHigh dietary intake of omega‐3 is consistently associated with decreased risk of AMD.HDL‐C levels are elevated and triglycerides are decreased in AMD patients.Composition and activity of HDL particles might be relevant for AMD.Genes involved in cholesterol transport associate with both AMD and lipid levels.AMD pathogenesis may be related to circulating lipids, local lipid transport, or both.

Whole-Exome Sequencing in Age-Related Macular Degeneration Identifies Rare Variants in COL8A1, a Component of Bruch's Membrane

Purpose Genome-wide association studies and targeted sequencing studies of candidate genes have identified common and rare variants that are associated with age-related macular degeneration (AMD). Whole-exome sequencing (WES) studies allow a more comprehensive analysis of rare coding variants across all genes of the genome and will contribute to a better understanding of the underlying disease mechanisms. To date, the number of WES studies in AMD case-control cohorts remains scarce and sample sizes are limited. To scrutinize the role of rare protein-altering variants in AMD cause, we performed the largest WES study in AMD to date in a large European cohort consisting of 1125 AMD patients and 1361 control participants. Design Genome-wide case-control association study of WES data. Participants One thousand one hundred twenty-five AMD patients and 1361 control participants. Methods A single variant association test of WES data was performed to detect variants that are associated individually with AMD. The cumulative effect of multiple rare variants with 1 gene was analyzed using a gene-based CMC burden test. Immunohistochemistry was performed to determine the localization of the Col8a1 protein in mouse eyes. Main Outcome Measures Genetic variants associated with AMD. Results We detected significantly more rare protein-altering variants in the COL8A1 gene in patients (22/2250 alleles [1.0%]) than in control participants (11/2722 alleles [0.4%]; P = 7.07×10–5). The association of rare variants in the COL8A1 gene is independent of the common intergenic variant (rs140647181) near the COL8A1 gene previously associated with AMD. We demonstrated that the Col8a1 protein localizes at Bruch’s membrane. Conclusions This study supported a role for protein-altering variants in the COL8A1 gene in AMD pathogenesis. We demonstrated the presence of Col8a1 in Bruch’s membrane, further supporting the role of COL8A1 variants in AMD pathogenesis. Protein-altering variants in COL8A1 may alter the integrity of Bruch’s membrane, contributing to the accumulation of drusen and the development of AMD.

Association of Retinal Neurodegeneration on Optical Coherence Tomography With Dementia: A Population-Based Study

Importance Retinal structures may serve as a biomarker for dementia, but longitudinal studies examining this link are lacking. Objective To investigate the association of inner retinal layer thickness with prevalent and incident dementia in a general population of Dutch adults. Design, Setting, and Participants From September 2007 to June 2012, participants from the prospective population-based Rotterdam Study who were 45 years and older and had gradable retinal optical coherence tomography images and at baseline were free from stroke, Parkinson disease, multiple sclerosis, glaucoma, macular degeneration, retinopathy, myopia, hyperopia, and optic disc pathology were included. They were followed up until January 1, 2015, for the onset of dementia. Exposures Inner retinal layer thicknesses (ie, retinal nerve fiber layer [RNFL]) and ganglion cell–inner plexiform layer (GC-IPL) thicknesses measured on optical coherence tomography images. Main Outcomes and Measures Odds ratios and hazard ratios for incident dementia per SD decrease in retinal layer thickness adjusted for age, sex, education, and cardiovascular risk factors. Results Of 5065 individuals eligible for optical coherence tomography scanning, 3289 (64.9%) (mean [SD] age 68.9 [9.9] years, 1879 [57%] women) were included in the analysis. Of these 3289 individuals, 41 (1.2%) already had dementia. Thinner GC-IPL was associated with prevalent dementia (odds ratio per SD decrease in GC-IPL, 1.37 [95% CI, 0.99-1.90]). No association was found of RNFL with prevalent dementia. During 14 674 person-years of follow-up (mean [SD], 4.5 [1.6] years), 86 individuals (2.6%) developed dementia of whom 68 (2.1%) had Alzheimer disease. Thinner RNFL at baseline was associated with an increased risk of developing dementia (hazard ratio per SD decrease in RNFL, 1.44 [95% CI, 1.19-1.75]), which was similar for Alzheimer disease (hazard ratio, 1.43 [95% CI, 1.15-1.78]). No association was found between GC-IPL thickness and incident dementia (hazard ratio, 1.13 [95% CI, 0.90-1.43]). Conclusions and Relevance Thinner RNFL is associated with an increased risk of dementia, including Alzheimer disease, suggesting that retinal neurodegeneration may serve as a preclinical biomarker for dementia.

Intake of vegetables, fruit, and fish is beneficial for Age-related Macular Degeneration

PURPOSE What patients should eat to reduce their risk of age-related macular degeneration (AMD) is still unclear. We investigated the effect of a diet recommended by Health Councils on AMD. DESIGN Prospective population-based cohort study. METHODS Four thousand two hundred and two participants from the Rotterdam Study ≥55 years of age who were free of AMD at baseline were included and followed up for 9.1 ± 5.8 years. Incident AMD was graded on fundus photographs. Dietary data were collected using a validated 170-item food frequency questionnaire, and food intakes were categorized into food patterns based on guidelines from Health Councils. Associations with incident AMD were analyzed using Cox proportional hazards models that were adjusted for age, sex, total energy intake, smoking, body mass index, hypertension, education, and income. RESULTS Seven hundred fifty-four people developed incident AMD. Intake of the recommended amounts of vegetables (≥200 g/day), fruit (2×/day), and fish (2×/week) were 30.6%, 54.9%, and 12.5%, respectively. In particular, the intake of fish (2×/week) decreased the risk of incident AMD (hazard ratio 0.76 [95% confidence interval 0.60-0.97]). Intake of the recommended amounts of all 3 food groups was only 3.7%, but adherence to this pattern showed a further reduction of the risk of incident AMD (hazard ratio 0.58 [95% confidence interval 0.36-0.93]). Younger age, higher income, and not smoking were associated with this food pattern, but the risk-lowering effects remained significant after additional adjustment for these factors. CONCLUSION A diet of 200 grams per day of vegetables, fruit two times per day, and fish two times per week is associated with a significantly reduced risk of AMD.

RETINAL NEURODEGENERATION ON OPTICAL COHERENCE TOMOGRAPHY AND RISK OF DEMENTIA AND STROKE

APL1b28 peptide in plasma. The concentration of APL1b28 is w0.4pM, which is much less than that in CSF (w500pM). Currently, we are analyzing the APL1b28 ratio in CSF and plasma paired samples. We are also investigating correlation between plasma APL1b28 ratio and CSF Ab42 ratio. Conclusions:We have tried to develop an Ab42 surrogate marker in peripheral blood. We intend to show how and to what degree the plasma APL1b28 ratio correlates with CSF Ab42 ratio.