Thesis (Ph. D. (Medical Sciences)) -- University of Limpopo, 2016 / Refer to document / The Belgium Development Co-operation through VLIR-UOS, The University of Limpopo,and The Flemish Universities

abstract: This research is an anthology of a series of papers intended to describe the health state, healthcare experiences, healthcare preventive practice, healthcare barriers, and cardiovascular disease (CVD) risk factors of Asian Americans (AA) residing in Arizona (AZ). Asian Americans are known to be vulnerable populations and there is paucity of data on interventions to reduce CVD risk factors. An extensive literature review showed no available disaggregated health data of AA in AZ. The Neuman Systems Model guided this study. Chapter 1 elucidates the importance of conducting the research. It provides an overview of the literature, theory, and methodology of the study. Chapters 2 and 3 describe the results of a cross-sectional descriptive secondary analysis using the 2013, 2015, and 2017 Behavior Risk Factor Surveillance System (BRFSS) datasets. The outcomes demonstrate the disaggregated epidemiological phenomenon of AA. There were variations in their social determinants of health, healthcare barriers, healthcare preventive practice, CVD risk factors, and healthcare experiences based on perceived racism. It highlighted modifiable and non-modifiable predictors of hypertension (HTN) and diabetes. Chapter 4 is an integrative review of interventions implemented to reduce CVD risks tailored for Filipino Americans. Chapter 5 summarizes the research findings. The results may provide the community of practicing nurses, researchers, and clinicians the evidence to plan, prioritize, and implement comprehensive, theoretically guided, and culturally tailored community-led primary and secondary prevention programs to improve their health outcomes. The data may serve as a tool for stakeholders and policy makers to advocate for public health policies that will elevate population health of AA or communities of color in AZ to be in line with non-Hispanic White counterparts. / Dissertation/Thesis / Doctoral Dissertation Nursing 2020

3. Summary Dissertation zur Erlangung des akademischen Grades Dr. rer. med. Cardiovascular risk factors in ageing brains: Functional and structural correlates of modifiable risk factors of brain ageing and Alzheimer’s disease among older individuals Eingereicht von: Shahrzad Kharabian Masouleh Angefertigt am: Max-Planck-Institut für Kognitions- und Neurowissenschaften, Abteilung für Neurologie, Leipzig Betreut von: Prof. Dr. med. Arno Villringer Dr. A. Veronica Witte March 2018 Due to a world-wide demographic change ageing-associated complications including cognitive impairments and neurodegenerative diseases such as dementia are becoming increasingly prevalent. In 2015, almost 47 million people worldwide were estimated to be affected by dementia, and the numbers are expected to reach 75 million by 2030, and 131 million by 2050, with the greatest increase expected in low-income and middle-income countries (Prince, M.; Wimo, A.; Guerchet, M.; Ali, G.; Wu, Y.; Prina, 2015). As no cure or substantial symptom-relieving treatment is yet available for these ever growing pathologic conditions, identifying modifiable factors that causally impact the risk of these diseases has become an important mission (Barnes and Yaffe, 2011). Although age is known to be the most important risk factor for these conditions, not all older individuals develop these pathologic states and pathologic neurodegenerative changes are not considered as part of a normal aging process. However, observations show that almost all aged brains show characteristic changes that are linked to neurodegeneration (Wyss-Coray, 2016). These observations raise the possibility that fundamental mechanisms of ageing may display early disease changes or contribute to the pathogenesis of neurodegenerative disorders (Bartzokis, 2011; Bishop et al., 2010; Raz, 2005). A better understanding of possible modulators of function and structure of brain in regions that are known to be vulnerable in aging would thus open a novel window towards targets for intervention of disease progression. Epidemiological studies have begun to identify many environmental and genetic risk factors that influence prevalence of neurodegenerative diseases in older ages. Importantly, with respect to Alzheimer’s disease (AD), conditions such as depression, obesity and hypertension, specifically in midlife and diabetes are shown to independently affect increased prevalence of AD worldwide. In 2010, fifteen thousand AD-cases world-wide were attributed to cigarette smoking and low physical or mental activity (Norton et al., 2014). Moreover, disadvantageous metabolic profiles such as higher blood glucose levels or lower high-density lipoprotein (HDL) levels have also been associated with worse cognition, brain alterations in AD-vulnerable regions and ultimately increased likelihood of developing AD in older ages (Crane et al., 2013; Villeneuve et al., 2014). In the first study of this thesis, we reviewed the epidemiological evidence regarding the impact of a “Mediterranean style diet” (MeDi) on brain health in aging (Huhn et al., 2015). MeDi, which is based on high consumption of fruits, vegetables, grains as well as sea-fish and low intake of sweets, convenient food, meat and dairy products, is shown to reduce cardio-vascular risk factors and benefit lipid and glucose metabolism while reducing risk of AD and cognitive dysfunction in aging. Despite extensive epidemiological evidence, little is known about neurobiological mechanisms, linking these life-style and health related factors to alterations in cognitive performance and incidence of AD. In the recent years whole brain magnetic resonance (MR) measurements have immensely increased our knowledge about the brain in health and disease. Novel MR protocols and analysis routines have been invented to assess different aspects of structure of the brain regions and their function within the living individuals. Studies in elderly AD patients have linked deposition of amyloid plaques, assessed using positron emission tomography (PET), in vulnerable structures such as frontal lobe, medial temporal structures and posterior cingulate area to atrophy and lower metabolic rate of glucose within these brain regions in association with accelerated cognitive decline (Buckner et al., 2005). Also, within healthy ageing population it has been shown that these AD-prone structures create a network, in which grey matter (GM) volume follow a different ageing trajectory compared to the rest of the brain, with a late development during adolescence and accelerated decline in older ages (Douaud et al., 2014; Fjell et al., 2014). Such coordinated change, specifically in older ages, might be a result of shared susceptibility of regions within this network to selective pathologies or a network-based spread of toxic agents (Zhou et al., 2012). Consequently, the above-mentioned AD-risk factors could through similar mechanisms impact brain structures within vulnerable regions, resulting in accelerated ageing, possibly reducing resilience of these regions towards AD-related pathology and thus increasing risk of developing AD in older ages. Based on this working hypothesis, in the rest of this doctoral research we investigate cerebral correlates of these risk factors and their impact on cognitive performance in healthy older adults. We initially focused on obesity as a major epidemic of the twentieth century, a major component of metabolic syndrome and an important AD-risk factor. Here we used conventional techniques to identify effects of Body-mass index (BMI) on regional GM volume (n = 617) as well as resting-state network connectivity (n = 712) and relations to cognitive performance in well-characterized samples of community-dwelled older adults (60-80 years) from Leipzig Research Centre for Civilization Diseases (LIFE) adult-study. The LIFE-Adult-Study is a population-based cohort study, which has already completed the baseline examination of 10,000 randomly selected participants from Leipzig, out of which ~2600 underwent a 3Tesla MRI brain scan, structured interviews, neuropsychological tests, and an extensive set of medical assessments (Loeffler et al., 2015). Our results showed that independent of age and a wide range of other confounding factors such as diabetes, hypertension, smoking status and APOE-genotype, there is a robust linear association between a higher BMI and lower GM volume in multiple brain regions, including (pre)frontal, temporal, insular and occipital cortex, thalamus, putamen, amygdala and cerebellum, which partially mediated negative effects of higher BMI on memory performance in our sample of older adults (Kharabian Masouleh et al., 2016). Furthermore, in the follow-up study, we found reproducible association between higher BMI and lower functional connectivity of the posterior cingulate cortex with other nodes of the default mode network (Beyer et al., 2017). This network that consists of AD-prone regions within frontal, temporal and parietal lobes, exhibits similar alterations in normal ageing and among patients with AD (Damoiseaux et al., 2012; Tomasi and Volkow, 2012). Inspired by our results on network-based functional connectivity alterations and in-line with the hypothesis of network-based spread of toxic agents in neurodegenerative diseases, in our third MRI-study, we extended the number of risk factors to cover major “modifiable” risk factors of AD and identified the potential impact of these factors on morphological properties of large-scale structural covariance networks (Kharabian Masouleh et al., 2017). We therefore systematically assessed independent effects of obesity, smoking, blood pressure, as well as markers of glucose and lipid metabolism and physical activity on major GM networks in the same cohort as our first MR study. Furthermore, we detailed our analysis by adding both BMI as well as waist-to-hip ratio as measures of obesity and identified the structural networks based on information on area, thickness and volume of cortical structures. The spatial extent and composition of the co-varying GM measures within the different networks indicated that smoking and, to a lesser degree, higher blood pressure affected GM throughout the brain, which might be attributed to direct and indirect damage of neuronal tissue. Higher glycosylated hemoglobin, as a long-term marker of glucose metabolism, was found to predominantly affect areas that are known to have high glucose metabolism and early A-beta deposition. In addition, we detected negative effects of visceral obesity on a structural network consisting of multimodal regions, covering areas rich in intracortical myelinated fibres. This network spatially recapitulated the pattern of brain atrophy observed in Alzheimer’s disease and has been previously shown to develop relatively slowly during adolescence but present “accelerated” age-related degeneration at an old age. Accordingly, our findings possibly point towards detrimental effects of visceral fat-induced low-grade inflammation on myelin. This is a hypothesis that we are going to test in our future studies in LIFE (by direct assessment of visceral fat (VAT) on abdominal MRI and inflammatory markers). Future longitudinal studies that incorporate more detailed microstructural assessments are now needed to prove our proposed neurobiological hypotheses on the underlying mechanisms of the observed effects and to test if improving cardiovascular risk, specifically visceral obesity, would help to maintain the integrity of GM networks throughout old age and reduce the risk of AD.:List of Abbreviations 3 List of Figures 4 List of Tables 5 1. Introduction: 6 1.1: “Normal” cognitive ageing: 9 1.1.1. Ageing-associated changes in brain structure and function: 9 1.2. Modifiers of brain ageing and AD: 11 1.3. Methods: 18 1.3.1. Imaging protocols: 18 1.3.2. Network Identification: 19 1.3.2.1. Resting-state fMRI network extraction 19 1.3.2.2. Grey matter structural network extraction 20 1.4. Rationale of the work: 23 2. Publications: 25 2.1. Publication1: Review: Huhn et al, 2015 25 2.2. Publication2: Original article: Kharabian et al, 2016 36 2.3. Publication3: Original article: Beyer et al, 2017 47 2.4. Publication4: Original article: Kharabian et al, 2017 62 3. Summary: 76 References: 83 A. Supplemental Materials 93 Publication2- Kharabian Masouleh et. al., 2016 93 Supplementary Tables for Publication2 97 Supplementary Figures for Publication 2 101 Supplementary Figures for Publication4 105 B. Declaration of Authenticity 106 C. Author contributions to the publications 107 D. Curriculum Vitae 114 E. List of Publications: 117 F. Acknowledgements 119

Background: Annually, over 150,000 cardiovascular events occur among individuals ,65 years old in the United States, including asymptomatic ones. Coronary artery calcium (CAC), a subclinical marker of coronary artery disease (CAD), enhances risk stratification among asymptomatic individuals. This study assessed the prevalence of CAC in a rural population and determined relationships between traditional risk factors for CAD and CAC scores. Methods: During January 2011 to December 2012, asymptomatic individuals from central Appalachia were screened for CAC in the largest tertiary cardiovascular institute. Based on Agatston scale, participants were grouped into 4 CAC scores: zero (CAC 5 0), mild (CAC 5 1-99), moderate (CAC 5 100-399) and severe (CAC $ 400). Multinomial logistic regression was used to examine associations between potential risk factors of CAD and CAC score. Results: Of 1,674 participants, 55.4% had positive CAC score (CAC . 0). Increasing age and being male were positively associated with higher CAC scores. Although there was significant association between mild CAC and hypertension and family history of CAD, moderate CAC was positively associated with smoking status. Except hypercholesterolemia and sedentary lifestyle, severe CAC was significantly associated with major health conditions (obesity, diabetes and hypertension), lifestyle (smoking) and family history of CAD. Conclusions: More than half of participants in the CAC screening had subclinical CAD (CAC score . 0). The association between CAC score and CAD risk factors suggests that education about subclinical atherosclerosis among asymptomatic individuals in this region with high cardiovascular disease prevalence is needed because CAC improves CAD risk stratification, and the knowledge of CAC enhances medication adherence and motivates individuals towards beneficial behavioral/lifestyle modification.

Purpose of Review: To review the landmark studies in predicting obstructive coronary artery disease (CAD) in symptomatic patients with stable chest pain and identify better prediction tools and propose a simplified algorithm to guide the health care providers in identifying low risk patients to defer further testing. Recent Findings: There are a few risk prediction models described for stable chest pain patients including Diamond-Forrester (DF), Duke Clinical Score (DCS), CAD Consortium Basic, Clinical, and Extended models. The CAD Consortium models demonstrated that DF and DCS models overestimate the probability of CAD. All CAD Consortium models performed well in the contemporary population. PROMISE trial secondary data results showed that a clinical tool using readily available ten very low-risk pre-test variables could discriminate low-risk patients to defer further testing safely. Summary: In the contemporary population, CAD Consortium Basic or Clinical model could be used with more confidence. Our proposed simple algorithm would guide the physicians in selecting low risk patients who can be managed conservatively with deferred testing strategy. Future research is needed to validate our proposed algorithm to identify the low-risk patients with stable chest pain for whom further testing may not be warranted.

Accumulating evidence suggests that measures of abdominal obesity outperform BMI in predicting diabetes and cardiovascular risk. However, it is debated which measure of obesity should be used. Currently, waist circumference (WC) is most commonly used and codefines the metabolic syndrome.

No description available.

No description available.

Retinale Venenverschlüsse sind eine der häufigsten vaskulären Netzhauterkrankungen. Bei der Entstehung und dem Verlauf von venösen Gefäßverschlüssen im Auge spielen kardiovaskuläre Risikofaktoren eine entscheidende Rolle. Patienten mit einem retinalen Venenverschluss weisen vermehrt vaskuläre Risikofaktoren für arterielle Gefäßkrankheiten auf, weswegen es von hoher klinischer Relevanz ist, diese frühzeitig zu erkennen und zu behandeln. Bisher gibt es kein einheitliches Untersuchungsschema zur Ursachenabklärung eines retinalen Venenverschlusses. Ziel ist es, Empfehlungen einer zukünftigen Routinediagnostik für venöse Gefäßverschlüsse im Auge auszusprechen. In der FIND-AF-EYE-Studie wurde erstmals durch eine umfangreiche Diagnostik an insgesamt 101 Patienten mit retinalen Gefäßverschlüssen eine systematische Abklärung kardiovaskulärer Risikofaktoren kontrolliert durchgeführt. Die Diagnostik umfasste eine duplexsonographische Untersuchung der A. carotis, eine Echokardiographie, eine 24 h-Blutdruckmessung, ein 7 d-LZ-EKG und eine laborchemische Erhebung des Lipid- und Glukosestatus. Bei der Auswertung der 41 Patienten mit venösen Gefäßverschlüssen im Auge konnte wie auch in vergleichbaren Studien gezeigt werden, dass vor allem die arterielle Hypertonie, der Nikotinkonsum, die Hyperlipidämie und der Diabetes mellitus die wichtigsten kardiovaskulären Risikofaktoren darstellen. Zudem wurde durch die verlängerte elektrokardiographische Aufzeichnungsdauer über sieben Tage mehr als ein Drittel aller Patienten mit Herzrhythmusstörungen identifiziert. Anhand der Ergebnisse der vorliegenden Studie sind apparative Untersuchungen wie eine 24 h-Blutdruckmessung, eine Echokardiographie und ein 7-Tage-Langzeit-EKG unverzichtbar. Laborchemisch sollten ein Lipidstatus und ein Blutzuckerprofil routinemäßig erhoben werden. Zur Einschätzung des kardiovaskulären Risikos des Patienten erscheint eine Untersuchung der A. carotis sinnvoll. Um die Morbidität und die Mortalität zu senken bedarf es einer interdisziplinären Ursachenabklärung, welches die enge Zusammenarbeit zwischen Ophthalmologen und Internisten erfordert. Vergleicht man die FIND-AF-EYE-Studie mit der bereits publizierten FIND-AF-Studie litten die Patienten der FIND-AF-Studie signifikant häufiger an einer Karotisstenose. Zusammenfassend lässt sich sagen, dass akuten arteriellen Verschlüssen, wie beispielsweise einer zerebralen Ischämie, in den meisten Fällen thromboembolische Ereignisse zugrunde liegen. Kardiovaskuläre Risikofaktoren spielen aber auch bei venösen Gefäßverschlüssen im Auge eine wichtige Rolle. Hierbei führen sie zu arteriosklerotischen Veränderungen der eng benachbarten Zentralarterie. Durch die Kompression kommt es somit zur Thrombenbildung in der Zentralvene.

In recent times the potential impact of preeclampsia on the cardiovascular health of offspring has been identified. This thesis explores the relationship between preeclampsia and offspring cardiovascular phenotype during the first three decades of life. A systematic review and meta-analysis provided evidence that there was increased blood pressure and BMI in the offspring of preeclamptic pregnancies (n = 45,249). There was however limited data on metabolic features and inadequate characterisation of the degree of prematurity or growth restriction in existing literature. I therefore studied data on two birth cohorts with up to 28 years of detailed prospective follow up (n = 2868 and n = 926). Those born very preterm to preeclamptic pregnancies had transient perinatal reductions in insulin and cholesterol, although extreme prematurity was the only determinant of variation in cardiovascular risk in later life, with changes in both metabolism and blood pressure. In those born closer to, or at term, gestation was no longer relevant and an independent impact of preeclampsia on blood pressure was evident, so that by age 20, those born at term to preeclamptic pregnancies were four and a half times more likely to demonstrate clinically-apparent hypertension. I then investigated whether there were changes in other features of cardiovascular phenotype, independent of blood pressure, in preterm neonates born following preeclampsia (n = 46). At 3 months of age preterm infants born to hypertensive pregnancies had subclinical alterations in cardiac strain, independent of gestation or birth weight but not differences in blood pressure, or microvascular structure. These findings highlight preeclampsia and prematurity as key, independent perinatal factors, important in determining cardiovascular phenotype and risk during early life. Preeclampsia is associated with a specific lean, hypertensive phenotype, associated with cardiac functional alterations; these findings begin to define a distinct at risk population who may require targeted preventative interventions.