The Retina as a Biomarker for Vascular and Neurodegenerative Brain Diseases

Over the years, the research field investigating the eye-brain connection has increased steeply, and researchers have begun to recognize the potential to use retinal structures as biomarkers for brain diseases. Given that retinal structures such as vessels and neurons share many similarities in anatomy and physiology to the brain, it has been thought that these structures provide a direct measure for the vascular and neuronal status of the brain. The main objective of this thesis is to expand our current knowledge on retinal microvascular damage and retinal neurodegeneration as biomarker of vascular and neurodegenerative brain diseases. My main conclusion is firstly that retinal imaging can serve as a source of biomarkers to study small vessel disease and atrophy of the brain. Secondly, microvascular abnormalities may be intermediates in pathways of vascular brain diseases, or may interact with other mechanisms to cause vascular brain diseases. Finally, applying interaction and mediation analysis can provide new insight into the pathophysiology of brain diseases

Cognitive and physical impairment and the risk of stroke - A prospective cohort study

The manifestation of cognitive and physical impairment in stroke patients before the acute event suggests accumulating subclinical vascular pathology in the brain. We investigated whether impairments in cognitive and physical functioning were associated with an increased stroke risk. Between 2002 and 2008, 8,519 stroke-free non-demented participants from the population-based Rotterdam Study underwent cognition and physical assessments including Mini-Mental State Examination, 15-word learning test, Stroop test, letter-digit substitution test, verbal fluency test, Purdue pegboard test and questionnaires on basic and instrumental activities of daily living (BADL; IADL). Principal component analysis was used to derive global cognition (G-factor). Incident stroke was assessed through continuous monitoring of medical records until 2016. Among 8,519 persons (mean age 66.0 years; 57.8% wome

The retinal microcirculation in migraine: The Rotterdam Study

Background: To explore the role of microvascular pathology in migraine, we investigated the association between migraine and retinal microvascular damage. Methods: We included 3270 participants (age ≥ 45 years, 63% women) from the population-based Rotterdam Study (2006–2009). Participants with migraine were identified using a validated questionnaire based on ICHD-II criteria (n = 562). Retinopathy signs were graded on fundus photographs. Retinal arteriolar and venular caliber were measured by semi-automatic assessment of fundus photographs. Associations of migraine with retinopathy and retinal microvascular calibers were examined using logistic and linear regression models, respectively, adjusting for age, sex, and cardiovascular risk factors. Results: Migraine was not associated with the presence of retinopathy (odds ratio (OR): 1.09, 95% confidence interval (CI) 0.62; 1.92). In the fully adjusted model, adjusting for the companion vessel, persons with migraine did not differ in retina

Unspecified Strokes: Time Trends, Determinants, and Long-Term Prognosis in the General Population

Introduction: In the absence of neuroimaging, a stroke is typically labelled as unspecified. While the majority of clinic-based stroke research focuses on hemorrhagic or ischemic stroke, in the general population, a substantial proportion of strokes remains unspecified. Objective: To investigate time trends in the occurrence and determinants of unspecified strokes and differences in patient characteristics and survival compared to ischemic or hemorrhagic stroke. Methods: We included 1,546 participants from the population-based Rotterdam Study who suffered a first-ever stroke during follow-up (1990-2016). We calculated the proportion of unspecified strokes per year and compared their characteristics between 3 time periods (1990-1999, 2000-2009, and 2010-2016) using a chi-square test, and furthermore investigated differences between unspecified, ischemic, and hemorrhagic stroke in patient characteristics and survival using age- and sex-adjusted survival curves. Results: The occurrence of unspecified stroke among all strokes decreased from 75% in 1990 to 16% in 2016. Compared to the first time period (1991-1999), diagnosis of unspecified strokes was more often done by nursing home physicians (13 vs. 40%) and unspecified stroke patients had more often dementia (30 vs. 43%) in the last time period (2010-2016). Compared to patients with ischemic or hemorrhagic stroke, patients with unspecified stroke were on average older (84.3 vs. 78.5 years) and had more often physical impairments and dementia. Furthermore, patients with unspecified stroke had a lower survival probability up to 10 years after stroke than those with ischemic stroke. Conclusions: The proportion of unspecified strokes decreased drastically from 75 to 16% in the last decades. Patients who do not undergo neuroimaging and therefore are classified as unspecified stroke represent an older, more frail patient group that suffers more often from multimorbidities and poor long-term prognosis than those who do undergo neuroimaging and are thus classified as ischemic or hemorrhagic stroke

The mediating role of the venules between smoking and ischemic stroke

A potential mechanism by which smoking affects ischemic stroke is through wider venules, but this mediating role of wider venules has never been quantified. Here, we aimed to estimate to what extent the effect of smoking on ischemic stroke is possibly mediated by the venules via the recently developed four-way effect decomposition. This study was part of a population-based study including 9109 stroke-free persons participated in the study in 1990, 2004, or 2006 (mean age: 63.7 years; 58% women). Smoking behavior (smoking versus non-smoking) was identified by interview. Retinal venular calibers were measured semi-automatically on retinal photographs. Incident strokes were assessed until January 2016. A regression-based approach was used with venular calibers as mediator to decompose the total effect of smoking compared to non-smoking into four components: controlled direct effect (neither mediation nor interaction), pure indirect effect (mediation only), reference interaction effect (interaction only) and mediated interaction effect (both mediation and interaction). During a mean follow-up of 12.5 years, 665 persons suffered an ischemic stroke. Smoking increased the risk of developing ischemic stroke compared to non-smoking with an excess risk of 0.41 (95% confidence interval 0.10; 0.67). With retinal venules as a potential mediator, the excess relative risk could be decomposed into 77% controlled direct effect, 4% mediation only, 4% interaction only, and 15% mediated interaction. To conclude, in the pathophysiology of ischemic stroke, the effect of smoking on ischemic stroke may partly explained by changes in the venules, where there is both pure mediation and mediated interaction

Fabrication of halloysite nanotubes embedded thin film nanocomposite membranes for dye removal

Environmental friendly Halloysite nanotubes (HNTs) are used to fabricate novel nanofiltration membranes by in situ interfacial polymerization of piperazine and trimesoyl chloride. The removal of excess amine solution from the porous support membrane surface is a critical step to obtain defect free active layer. Hereby, two main removal tools for the excess aqueous amine solution; a rubber roll or air knife are compared to fabricate a defect free thin film nanocomposite (TFN) nanofiltration (NF) membrane. Removal by the rubber roll is eventuated more favorable than air knife in terms of the reproducibility of NF membranes by comparing salt rejections. By determining the removal step of excess amines, various HNTs concentrations are used to fabricate NF membranes and, these membranes are tested with salt and dye solutions at various pH and temperature ranges. R2 membrane (containing 0.02% [w/v] HNTs) performs the best flux results beside higher rejections of MgSO4 (93.0%) and dye (99.5%). To evaluate the extreme conditionals, further performance tests such as pH and temperature resistance are also performed for R2 membrane. Considering the performances of R2 membrane, HNTs can be demonstrated for tailoring the balance between flux and separation performance of NF membranes

Fabrication of halloysite nanotubes embedded thin film nanocomposite membranes for dye removal

Environmental friendly Halloysite nanotubes (HNTs) are used to fabricate novel nanofiltration membranes by in situ interfacial polymerization of piperazine and trimesoyl chloride. The removal of excess amine solution from the porous support membrane surface is a critical step to obtain defect free active layer. Hereby, two main removal tools for the excess aqueous amine solution; a rubber roll or air knife are compared to fabricate a defect free thin film nanocomposite (TFN) nanofiltration (NF) membrane. Removal by the rubber roll is eventuated more favorable than air knife in terms of the reproducibility of NF membranes by comparing salt rejections. By determining the removal step of excess amines, various HNTs concentrations are used to fabricate NF membranes and, these membranes are tested with salt and dye solutions at various pH and temperature ranges. R2 membrane (containing 0.02% [w/v] HNTs) performs the best flux results beside higher rejections of MgSO4 (93.0%) and dye (99.5%). To evaluate the extreme conditionals, further performance tests such as pH and temperature resistance are also performed for R2 membrane. Considering the performances of R2 membrane, HNTs can be demonstrated for tailoring the balance between flux and separation performance of NF membranes

Fabrication and characterization of temperature and pH resistant thin film nanocomposite membranes embedded with halloysite nanotubes for dye rejection

In this study, nanofiltration (NF) membranes with high pH and temperature resistance were fabricated by introducing halloysite nanotubes (HNTs) into the organic phase during the interfacial polymerization step. HNTs were dispersed in cyclohexane with the concentration 0% (TFNO), 0.02% (TFN0.02), 0.04% (TFN0.04) and 0.06% (TFN0.06) as w/v (%). Fabricated membranes were characterized by FT-IR spectroscopy, SEM and AFM analyses, optical profilometry, contact angle and zeta potential measurements. Filtration performance tests were conducted with 2000 ppm MgSO4 and NaCl solutions and 100 ppm of synthetic dye solutions (Setazol Red Reactive and Reactive Orange dyes), respectively. For pH -resistance tests, synthetic dyes were filtrated in acidic, neutral and base conditions (pH = 4-7-11) to measure changes in flux and rejection. The effect of the temperature of the feed stream on membranes were determined by the filtration of pure water and dye solutions at 15 degrees C, 25 degrees C and 40 degrees C. Among different membranes fabricated with varying HNTs content, TFN0.04 membrane showed increased water flux without considerable salt and dye rejection loss

Geochemical characterization of geothermal systems in western Anatolia (Turkey): implications for CO 2

Geological storage of CO2 is currently regarded as one of the major strategies to mitigate the increasing CO2 concentrations in the atmosphere due to anthropogenic emissions from large-scale point sources. Enhanced geothermal systems (EGS) are a novel concept in which CO2 is used as a working fluid to increase energy recovery, combined with its subsurface storage. In this study, the geothermal systems of western Anatolia are considered as potential sites for EGS, and the published hydrogeochemical data relevant to these systems are compiled and evaluated in terms of potential water/CO2/rock interaction processes. The evaluation is performed with geochemical approaches including speciation-solubility calculations, and inverse and dedolomitization modelling. The results lead to the recognition of two different groups with respect to the effective processes: carbonate precipitation, and carbonate precipitation plus dissolution. In high-enthalpy fields, carbonate precipitation seems to be the major mechanism, while others show the effects of both precipitation and dissolution; dedolomitization is also identified as a potential mechanism for one of the fields. These processes are examined with regard to CO2-fixation; carbonate precipitation may lead to mineral trapping while carbonate dissolution provides additional cations to the system to react with CO2. Being relevant to CO2 storage in geothermal fields, the conclusions from this study point to the importance of temperature control for CO2 stabilization, as high temperatures seem to promote mineral trapping. The success of a CO2-EGS project depends on complete geochemical characterization of reservoir processes with further kinetic modelling accompanying the thermodynamic modelling exemplified by this study. (c) 2017 Society of Chemical Industry and John Wiley & Sons, Ltd

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