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 Effect of the Pairing Interaction on the Energies of Isobar Analog Resonances in 112−124^{112-124}Sb and Isospin Admixture in 100−124^{100-124}Sn Isotopes

In the present study, the effect of the pairing interaction and the isovector correlation between nucleons on the properties of the isobar analog resonances (IAR) in $^{112-124}$Sb isotopes and the isospin admixture in $^{100-124}$Sn isotopes is investigated within the framework of the quasiparticle random phase approximation (QRPA). The form of the interaction strength parameter is related to the shell model potential by restoring the isotopic invariance of the nuclear part of the total Hamiltonian. In this respect, the isospin admixtures in the $^{100-124}$Sn isotopes are calculated, and the dependence of the differential cross section and the volume integral $J_{F}$ for the Sn($^{3}$He,t)Sb reactions at E($^{3}$He)$=200$ MeV occurring by the excitation of IAR on mass number A is examined. Our results show that the calculated value for the isospin mixing in the $^{100}$Sn isotope is in good agreement with Colo et al.'s estimates $(4-5$, and the obtained values for the volume integral change within the error range of the value reported by Fujiwara et al. (53$\pm$5 MeV fm$^{3}$). Moreover, it is concluded that although the differential cross section of the isobar analog resonance for the ($^{3}$He,t) reactions is not sensitive to pairing correlations between nucleons, a considerable effect on the isospin admixtures in $N\approx Z$ isotopes can be seen with the presence of these correlations.Comment: 16 pages, 5 EPS figures and 2 tables, Late

LES-based Study of the Roughness Effects on the Wake of a Circular Cylinder from Subcritical to Transcritical Reynolds Numbers

This paper investigates the effects of surface roughness on the flow past a circular cylinder at subcritical to transcritical Reynolds numbers. Large eddy simulations of the flow for sand grain roughness of size k/D = 0.02 are performed (D is the cylinder diameter). Results show that surface roughness triggers the transition to turbulence in the boundary layer at all Reynolds numbers, thus leading to an early separation caused by the increased momentum deficit, especially at transcritical Reynolds numbers. Even at subcritical Reynolds numbers, boundary layer instabilities are triggered in the roughness sublayer and eventually lead to the transition to turbulence. The early separation at transcritical Reynolds numbers leads to a wake topology similar to that of the subcritical regime, resulting in an increased drag coefficient and lower Strouhal number. Turbulent statistics in the wake are also affected by roughness; the Reynolds stresses are larger due to the increased turbulent kinetic energy production in the boundary layer and separated shear layers close to the cylinder shoulders.We acknowledge “Red Española de Surpercomputación” (RES) for awarding us access to the MareNostrum III machine based in Barcelona, Spain (Ref. FI-2015-2-0026 and FI-2015-3-0011). We also acknowledge PRACE for awarding us access to Fermi and Marconi Supercomputers at Cineca, Italy (Ref. 2015133120). Oriol Lehmkuhl acknowledges a PDJ 2014 Grant by AGAUR (Generalitat de Catalunya). Ugo Piomelli acknowledges the support of the Natural Sciences and Engineering Research Council (NSERC) of Canada under the Discovery Grant Programme (Grant No. RGPIN-2016-04391). Ricard Borrell acknowledges a Juan de la Cierva postdoctoral grant (IJCI-2014-21034). Ivette Rodriguez, Oriol Lehmkuhl, Ricard Borrell and Assensi Oliva acknowledge Ministerio de Economía y Competitividad, Secretaría de Estado de Investigación, Desarrollo e Innovación, Spain (ref. ENE2014-60577-R).Peer ReviewedPostprint (author's final draft

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

Occupational Noise, Smoking, and a High Body Mass Index are Risk Factors for Age-related Hearing Impairment and Moderate Alcohol Consumption is Protective: A European Population-based Multicenter Study

A multicenter study was set up to elucidate the environmental and medical risk factors contributing to age-related hearing impairment (ARHI). Nine subsamples, collected by nine audiological centers across Europe, added up to a total of 4,083 subjects between 53 and 67 years. Audiometric data (pure-tone average [PTA]) were collected and the participants filled out a questionnaire on environmental risk factors and medical history. People with a history of disease that could affect hearing were excluded. PTAs were adjusted for age and sex and tested for association with exposure to risk factors. Noise exposure was associated with a significant loss of hearing at high sound frequencies (>1 kHz). Smoking significantly increased high-frequency hearing loss, and the effect was dose-dependent. The effect of smoking remained significant when accounting for cardiovascular disease events. Taller people had better hearing on average with a more pronounced effect at low sound frequencies (<2 kHz). A high body mass index (BMI) correlated with hearing loss across the frequency range tested. Moderate alcohol consumption was inversely correlated with hearing loss. Significant associations were found in the high as well as in the low frequencies. The results suggest that a healthy lifestyle can protect against age-related hearing impairment