Unal Mutlu

Retinal Microvasculature Is Associated With Long-Term Survival in the General Adult Dutch Population

Retinal vascular diameters are associated with (sub)clinical cardiovascular disease and short-term cardiovascular mortality, but their association with long-term mortality is uncertain. We studied the association of retinal vascular diameters with cause-specific mortality in the general adult Dutch population during 25 years of follow-up. From 1990 to 1993, arteriolar and venular diameters were measured semiautomatically on digitized images in 5674 persons (mean age 68.0 years, 59% women) from the population-based Rotterdam study. Follow-up for mortality was complete till March 2015. Associations between vascular diameters and mortality were examined using Cox proportional hazards models, adjusting for age, sex, cardiovascular risk factors, and the fellow vessel diameter. During 85 770 person-years (mean±SD: 15.1±6.67), 3794 (66.8%) persons died, of whom 1034 due to cardiovascular causes. We found that narrower arterioles and wider venules were associated with higher risk of mortality (adjusted hazard ratio [95% confidence interval] per SD decrease 1.04 [1.00–1.08] and increase 1.07 [1.03–1.12], respectively). For arterioles, these associations were strongest for cardiovascular mortality, whereas venules showed consistent associations for cardiovascular and noncardiovascular mortality. Importantly, these associations remained unchanged after excluding the first 10 years of follow-up as immortal person-time. We found evidence for effect modification with stronger associations in persons <70 years (venules only) and smokers (P value for interaction<0.01). We replicated our findings in another independent cohort from the Rotterdam Study of 3106 persons with 19 880 person-years of follow-up and 144 deaths (hazard ratio for venules 1.22 [1.00–1.49]). Markers of retinal microvasculature are associated with long-term mortality in the general adult Dutch population.

Retinal microvasculature and white matter microstructure: The Rotterdam Study

Objective: To investigate whether retinal microvascular damage is related to normal-appearing white matter microstructure on diffusion tensor MRI. Methods: We included 2,436 participants (age ≥45 years) from the population-based Rotterdam Study (2005–2009) who had gradable retinal images and brain MRI scans. Retinal arteriolar and venular calibers were measured semiautomatically on fundus photographs. White matter microstructure was assessed using diffusion tensor MRI. We used linear regression models to investigate the associations of retinal vascular calibers with markers of normal-appearing white matter microstructure, adjusting for age, sex, the fellow vascular caliber, and additionally for structural MRI markers and cardiovascular risk factors. Results: Narrower arterioles and wider venules were associated with poor white matter microstructure: adjusted difference in fractional anisotropy per SD decrease in arteriolar caliber −0.061 (95% confidence interval −0.106 to −0.016), increase in venular caliber −0.054 (−0.096 to −0.011), adjusted difference in mean diffusivity per SD decrease in arteriolar caliber 0.048 (0.007–0.088), and increase in venular caliber 0.047 (0.008–0.085). The associations for venules were more prominent in women. Conclusions: Retinal vascular calibers are related to normal-appearing white matter microstructure. This suggests that microvascular damage in the white matter is more widespread than visually detectable as white matter lesions.

Retinal Microvascular Calibers Are Associated With Enlarged Perivascular Spaces in the Brain

Background and Purpose— Perivascular enlargement in the brain is a putative imaging marker for microvascular brain damage, but this link has not yet been confirmed using direct in vivo visualization of small vessels. We investigated the relation between microvascular calibers on retinal imaging and enlarged perivascular spaces (ePVSs) on brain magnetic resonance imaging. Methods— We included 704 participants from the Rotterdam study. Retinal arteriolar and venular calibers were measured semiautomatically on fundus photographs. ePVSs were counted in the centrum semiovale, basal ganglia, hippocampus, and mesencephalon, using a standardized rating method. We determined the association between retinal microvascular calibers and ePVSs with negative binomial regression models, adjusting for age, sex, the other vascular caliber, structural brain magnetic resonance imaging markers, and cardiovascular risk factors. Results— Both narrower arteriolar and wider venular calibers were associated with more ePVSs in the centrum semiovale and hippocampal region. Rate ratios (95% confidence interval) for arterioles in the centrum semiovale and hippocampus were 1.07 (1.01–1.14) and 1.13 (1.04–1.22), respectively, and for venules 1.08 (1.01–1.16) and 1.09 (1.00–1.18), respectively. These associations were independent from other brain magnetic resonance imaging markers and cardiovascular risk factors. Conclusions— Retinal microvascular calibers are related to ePVSs, confirming the putative link between microvascular damage and ePVSs.

Novel Genetic Loci Associated With Retinal Microvascular Diameter.

Background—There is increasing evidence that retinal microvascular diameters are associated with cardiovascular and cerebrovascular conditions. The shared genetic effects of these associations are currently unknown. The aim of this study was to increase our understanding of the genetic factors that mediate retinal vessel size. Methods and Results—This study extends previous genome-wide association study results using 24 000+ multiethnic participants from 7 discovery cohorts and 5000+ subjects of European ancestry from 2 replication cohorts. Using the Illumina HumanExome BeadChip, we investigate the association of single-nucleotide polymorphisms and variants collectively across genes with summary measures of retinal vessel diameters, referred to as the central retinal venule equivalent and the central retinal arteriole equivalent. We report 4 new loci associated with central retinal venule equivalent, one of which is also associated with central retinal arteriole equivalent. The 4 single-nucleotide polymorphisms are rs7926971 in TEAD1 (P=3.1×10−11; minor allele frequency=0.43), rs201259422 in TSPAN10 (P=4.4×10−9; minor allele frequency=0.27), rs5442 in GNB3 (P=7.0×10−10; minor allele frequency=0.05), and rs1800407 in OCA2 (P=3.4×10−8; minor allele frequency=0.05). The latter single-nucleotide polymorphism, rs1800407, was also associated with central retinal arteriole equivalent (P=6.5×10−12). Results from the gene-based burden tests were null. In phenotype look-ups, single-nucleotide polymorphism rs201255422 was associated with both systolic (P=0.001) and diastolic blood pressures (P=8.3×10−04). Conclusions—Our study expands the understanding of genetic factors influencing the size of the retinal microvasculature. These findings may also provide insight into the relationship between retinal and systemic microvascular disease.

Aortic Valve Calcification and Risk of Stroke: The Rotterdam Study

Background and Purpose— It remains uncertain whether aortic valve calcification (AVC) is a risk factor for stroke. Methods— From the population-based Rotterdam Study, 2471 participants (mean age: 69.6 years; 51.8% women) underwent computed tomography to quantify AVC. We assessed prevalent stroke and continuously monitored the remaining participants for the incidence of stroke. Logistic and Cox regression models were used to investigate associations of AVC with prevalent stroke and risk of incident stroke. Results— AVC was present in 33.1% of people. At baseline, 97 participants had ever suffered a stroke. During 18 665 person-years of follow-up (mean: 7.9 years), 135 people experienced a first-ever stroke. The presence of AVC was not associated with prevalent stroke (fully adjusted odds ratio: 0.97 (95% confidence interval, 0.61–1.53]) or with an increased risk of stroke (fully adjusted hazard ratio: 0.99 (95% confidence interval, 0.69–1.44]). Conclusions— Although AVC is a common finding in middle-aged and elderly community-dwelling people, our results suggest that AVC is not associated with an increased risk of stroke.

N-Terminal Pro-B–Type Natriuretic Peptide Is Related to Retinal Microvascular Damage: The Rotterdam Study

Objective—N-terminal pro-B–type natriuretic peptide (NT-proBNP) is a marker of cardiac dysfunction and has been linked to various indices of large vessel disease. However, it remains unclear whether NT-proBNP also relates to microvascular damage. In a community-dwelling population, we studied the association between NT-proBNP and retinal microvascular damage. Approach and Results—From the population-based Rotterdam Study, we included 8437 participants (mean age 64.1 years and 59% women) without a history of cardiovascular disease, with NT-proBNP data and gradable retinal images. NT-proBNP serum levels were measured using an immunoassay. Retinopathy signs, that is, exudates, microaneurysms, cotton wool spots, and dot/blot hemorrhages, present on fundus photographs were graded in the total study population; retinal vascular calibers, that is, arteriolar and venular calibers, were semiautomatically measured in a subsample (n=2763) of the study population. We conducted cross-sectional analyses on the association between NT-proBNP and retinal microvascular damage using logistic and linear regression models, adjusting for age, sex, and cardiovascular risk factors. We found that NT-proBNP was associated with the presence of retinopathy (adjusted odds ratio [95% confidence interval] per SD increase in natural log-transformed NT-proBNP: 1.14 [1.03–1.27]). We also found that higher NT-proBNP was associated with narrower arteriolar calibers (adjusted mean difference in arteriolar caliber per SD increase in natural log-transformed NT-proBNP: −0.89 µm [−1.54 to −0.24]). This association remained unchanged after excluding participants with retinopathy signs. Conclusions—In participants free of clinical cardiovascular disease, higher levels of NT-proBNP are associated with retinal microvascular damage, suggesting a potential role for NT-proBNP as marker for small vessel disease.

Vitamin D and retinal microvascular damage : The Rotterdam Study

Abstract Vitamin D has been linked to various cardiovascular risk factors including indices of large-vessel disease. However, it remains unclear whether vitamin D is also associated with microvascular damage. In a community-dwelling population, we studied associations between vitamin D serum levels and retinal microvascular damage defined as retinopathy signs, narrower arterioles, and wider venules. From the population-based Rotterdam Study, we included 5675 participants (age ≥45 years) with vitamin D data and gradable retinal photographs. Serum levels of vitamin D were measured using an antibody-based assay. Retinal exudates, microaneurysms, cotton wool spots, and dot/blot hemorrhages were graded on fundus photographs by experienced graders in the whole sample; retinal vascular calibers, that is, arteriolar and venular diameters, were semiautomatically measured in a subsample (n = 2973). We examined the cross-sectional association between vitamin D and retinal microvascular damage using logistic and linear regression models, adjusting for age, sex, and cardiovascular risk factors. We found that persons with lower vitamin D levels were more likely to have retinopathy (adjusted odds ratio per standard deviation (SD) decrease of vitamin D = 1.30; 95% confidence interval (CI): = 1.12–1.49). Furthermore, lower vitamin D levels were associated with wider venular calibers (adjusted mean difference per SD decrease in vitamin D = 1.35; 95% CI = 0.64–2.06). This association was strongest among men (P for interaction = 0.023). Lower levels of vitamin D are associated with retinal microvascular damage, suggesting that the link with cardiovascular risk may partly run through changes in the microvasculature.

N-Terminal Pro-B–Type Natriuretic Peptide Is Related to Retinal Microvascular Damage

Objective—N-terminal pro-B–type natriuretic peptide (NT-proBNP) is a marker of cardiac dysfunction and has been linked to various indices of large vessel disease. However, it remains unclear whether NT-proBNP also relates to microvascular damage. In a community-dwelling population, we studied the association between NT-proBNP and retinal microvascular damage. Approach and Results—From the population-based Rotterdam Study, we included 8437 participants (mean age 64.1 years and 59% women) without a history of cardiovascular disease, with NT-proBNP data and gradable retinal images. NT-proBNP serum levels were measured using an immunoassay. Retinopathy signs, that is, exudates, microaneurysms, cotton wool spots, and dot/blot hemorrhages, present on fundus photographs were graded in the total study population; retinal vascular calibers, that is, arteriolar and venular calibers, were semiautomatically measured in a subsample (n=2763) of the study population. We conducted cross-sectional analyses on the association between NT-proBNP and retinal microvascular damage using logistic and linear regression models, adjusting for age, sex, and cardiovascular risk factors. We found that NT-proBNP was associated with the presence of retinopathy (adjusted odds ratio [95% confidence interval] per SD increase in natural log-transformed NT-proBNP: 1.14 [1.03–1.27]). We also found that higher NT-proBNP was associated with narrower arteriolar calibers (adjusted mean difference in arteriolar caliber per SD increase in natural log-transformed NT-proBNP: −0.89 µm [−1.54 to −0.24]). This association remained unchanged after excluding participants with retinopathy signs. Conclusions—In participants free of clinical cardiovascular disease, higher levels of NT-proBNP are associated with retinal microvascular damage, suggesting a potential role for NT-proBNP as marker for small vessel disease.

Psoriasis is not associated with cognition, brain imaging markers and risk of dementia: the Rotterdam Study

BACKGROUND Based on increased cardio-metabolic comorbidities, inflammation and an overlap in genetics with Alzheimers disease, psoriasis patients may be at risk for cognitive dysfunction and dementia. OBJECTIVE To compare cognition, magnetic resonance imaging (MRI)-markers and dementia risk in psoriasis and non-psoriasis participants in the population-based Rotterdam Study. METHODS We identified 318 psoriatic and 9678 non-psoriatic participants (mean age: 66.1 years, 58% women). The association of psoriasis with cognitive function, mild cognitive impairment (MCI) and MRI-markers of brain damage was examined by linear and logistic regression. Dementia risk was calculated using Cox regression. Models were adjusted for age, gender, education and cardio-vascular risk factors. RESULTS Cognitive test scores and volumetric, microstructural, focal measures on brain MRI did not differ between psoriasis (28% systemic/UV treatment) and non-psoriasis participants and psoriasis was not associated with MCI (adjusted odd ratio 0.87, (95% Confidence Interval (CI): 0.53-1.43)). During 115.000 person-years of follow-up, 810 incident dementia cases (15 among psoriasis patients) occurred. After adjusting for confounders, psoriasis was associated with a lower risk of developing dementia (adjusted hazard ratio 0.50, (95% CI: 0.28-0.91)). LIMITATIONS Limited dementia cases among psoriasis patients. CONCLUSIONS In this population-based study, psoriasis was not associated with preclinical markers or higher dementia risk.

Thinner retinal layers are associated with changes in the visual pathway: A population-based study

Increasing evidence shows that thinner retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL), assessed on optical coherence tomography (OCT), are reflecting global brain atrophy. Yet, little is known on the relation of these layers with specific brain regions. Using voxel‐based analysis, we aimed to unravel specific brain regions associated with these retinal layers. We included 2,235 persons (mean age: 67.3 years, 55% women) from the Rotterdam Study (2007–2012) who had gradable retinal OCT images and brain magnetic resonance imaging (MRI) scans, including diffusion tensor (DT) imaging. Thicknesses of peripapillary RNFL and perimacular GCL were measured using an automated segmentation algorithm. Voxel‐based morphometry protocols were applied to process DT‐MRI data. We investigated the association between retinal layer thickness with voxel‐wise gray matter density and white matter microstructure by performing linear regression models. We found that thinner RNFL and GCL were associated with lower gray matter density in the visual cortex, and with lower fractional anisotropy and higher mean diffusivity in white matter tracts that are part of the optic radiation. Furthermore, thinner GCL was associated with lower gray matter density of the thalamus. Thinner RNFL and GCL are associated with gray and white matter changes in the visual pathway suggesting that retinal thinning on OCT may be specifically associated with changes in the visual pathway rather than with changes in the global brain. These findings may serve as a basis for understanding visual symptoms in elderly patients, patients with Alzheimers disease, or patients with posterior cortical atrophy.