Introdução: A morbi-mortalidade por DCV representa relevante problema de saúde pública da atualidade. Os mecanismos envolvidos na aterogênese envolvem a inflamação e resistência à insulina. Diante das evidências de que hábitos saudáveis são capazes reduzir eventos cardiovasculares e da baixa adesão à dieta saudável, foi elaborada a Dieta Cardioprotetora Brasileira DICA-Br, utilizando conceitos de densidade energética e de nutrientes para auxiliar a orientação dietética. Objetivo: Comparar os efeitos da DICA-Br com a orientação alimentar habitual do sistema de saúde pública quanto a fatores de risco tradicionais, biomarcadores circulantes de aterogênese e índice de resistência à insulina em sub-amostra do estudo matriz. A amostra incluiu 212 adultos que apresentaram prévio evento cardiovascular, alocados aleatoriamente para o grupo DICA-Br ou Controle (orientações alimentares habitualmente usadas no SUS). A DICA-Br diferencia-se pelo fato de incluir alimentos brasileiros e pela estratégia educacional. No basal e após 6 meses das intervenções foram obtidos dados clínicos e as concentrações de glicose de jejum, insulina, perfil lipídico, PCR, MCP-1,VCAM-1, ICAM-1 e selectina-E, comparados por testes t de Student ou equivalentes não paramétricos.Resultados: Os grupos DICA-Br e Controle apresentaram resultados similares após as intervenção, respectivamente quanto às reduções de peso (76,6±13,9 para 75,1±14,0 e75,5±13,1 para 74,4±13,2 kg; p<0,001), circunferência da cintura (100,0±11,1 para 98,1±12,0 e 99,3±10,4 para 98,2±10,2 cm; p<0,05), pressão arterial sistólica (132±22 para 125±17 e 133±21 para 124±18 mmHg; p<0,05) e diastólica (79±10 para 73±10 e 77±13 para 71±11 mmHg; p<0,05). As ingestões de energia total, gordura total e saturada também reduziram significantemente, porém sem correlação com medidas antropométricas. As intervenções não induziram mudanças em variáveis bioquímicas, de adesão celular e inflamação e HOMA-IR e tiveram comportamentos semelhantes quanto a estas variáveis. Conclusões: DICA-Br e orientação alimentar habitual induzem efeitos similares sobre fatores de risco cardiovasculares tradicionais, biomarcadores de aterogênese e resistência à insulina. Desconhece-se se a DICA-Br poderá ser estratégia de educação alimentar alternativa às orientações dietéticas padrão a ser empregada no sistema público de saúde, capaz de reduzir a adiposidade corporal de indivíduos de alto risco. / Background: Nowadays, morbidity and mortality due to CVD represent relevant public health problem. The mechanisms of atherogenesis involve inflammation and insulin resistance. Considering that healthy habits are able to reduce cardiovascular events and the low compliance to healthy diet, the Brazilian Cardioprotective Diet DICA-Br was proposed using concept of energy and nutrients density to help dietary guidance. Objective: To compare the effects of DICA-Br with the usual food orientation delivered by the public health system to traditional risk factors, circulating biomarkers of atherogenesis and insulin resistance index, in sub-study sample of the main study. The sample consisted of 212 adults with overt atherosclerosis, randomly allocated to the DICA-Br or Control group (usual dietary guidelines used in SUS). The differential of DICA-Br is that it includes Brazilian foods and the innovative educational strategy. At baseline and after 6 months of interventions, clinical data and fasting glucose, insulin, lipids, CRP, MCP-1, VCAM-1, ICAM-1 and E-selectin concentrations were obtained and compared by Student t test or the non-parametric correspondent ones. Results: DICA-Br and Control group showed similar results after 6 months of intervention concerning respectively, weight loss(76.6±13.9 to 75.1±14.0 and 75.5±13.1 to 74.4±13.2 kg; p<0.001), waist circumference (100.0±11.1 to 98.1±12.0 and 99.3±10.4 and 98.2±10.2 cm; p<0.05), systolic (132±22 to 125±17 and 133±21 to 124±18 mmHg, p<0.05) and diastolic blood pressure (79±10 to 73±10 and ± 77±13 to 71±11 mmHg, p<0.05). Total energy, total fat and saturated fat intakes also reduced significantly, but no correlation was found with anthropometric measurements. The interventions did not induce changes in metabolic variables, cell adhesion molecules and inflammation biomarkers and HOMA-IR and both showed similar results regarding these variables. Conclusion: The DICA-Br and usual food counseling induce similar effects on traditional cardiovascular risk factors, biomarkers of atherogenesis and insulin resistance. It is unknown whether the DICA-Br will be an alternative approach for dietary education to the standard strategy to be employed in the public health system, able to reduce the body fat in high-risk individuals.

Introdução: Existe crescente interesse em identificar marcadores de risco para eventos cardiovasculares em pacientes com HIV/aids. Atualmente observa-se alteração do perfil epidemiológico desses pacientes, com diminuição da mortalidade por infecção e comorbidades e aumento por eventos cardiovasculares. A elasticidade arterial, principalmente dos pequenos vasos, tem sido investigada como alteração precoce de evento cardiovascular. Objetivo: Avaliar a relação entre elasticidade arterial e outros indicadores de risco cardiovascular como fatores demográficos e socioeconômicos, hábitos de vida, estado nutricional e marcadores inflamatórios. Métodos: Foram selecionados aleatoriamente 132 indivíduos voluntários em tratamento regular com antirretrovirais em ambulatório especializado em HIV/aids, com idade entre 19 e 59 de ambos os sexos. A elasticidade arterial dos grandes vasos (LAEI) e pequenos vasos (SAEI) foi investigada pelo equipamento HDI/ PulseWaveTM CR-2000 Cardio Vascular Profiling System®. Foram determinados colesterol total e frações, triglicérides, proteína C-reativa, fibrinogênio, medidas antropométricas e de avaliação de composição corporal, fumo, consumo de bebidas alcoólicas, uso de drogas, prática de atividade física, além de avaliação de fatores demográficos e socioeconômicos e imunológicos (carga viral, T-CD4, T-CD8). Para investigar a associação entre LAEI e SAEI e outros fatores de risco cardiovascular utilizou-se análise de regressão linear múltipla. Resultados: Em relação à elasticidade dos grandes e pequenos vasos, 71,97 por cento e 32,58 por cento , respectivamente, dos participantes foram classificados com elasticidade normal. Observou-se associação positiva entre LAEI e peso (p<0,001) e associações negativas entre LAEI e prega cutânea subescapular (p<0,001) e linfócitos T-CD4 (p<0,02). Verificou-se associação negativa de LAEI com sexo (p<0,02), mostrando que o sexo feminino está relacionado com menor elasticidade. Houve associação positiva entre SAEI e peso (p<0,001) e associações negativas entre SAEI e prega cutânea subescapular (p<0,001), idade (p<0,01) e linfócitos totais (p<0.01). Conclusão: As alterações de elasticidade arterial em pacientes HIV/aids apresentaram relação com outros fatores de risco cardiovascular. SAEI mostrou-se diminuído na maioria dos participantes, sendo uma alteração que pode identificar a disfunção endotelial antes que a doença se torne clinicamente aparente. A monitoração constante da elasticidade arterial através de método não invasivo pode se tornar uma importante ferramenta na predição e prevenção de eventos cardiovasculares em pacientes HIV/aids / Introduction: There is a growing interest in identifying markers of risk for cardiovascular events in patients with HIV / AIDS. Currently there is a change in the epidemiological profile of patients with reduced mortality from infections and comorbidities and increased cardiovascular events. The arterial elasticity, mainly of small vessels, has been investigated as early alteration of cardiovascular events. Objective: To evaluate the relationship between arterial elasticity and other cardiovascular risk factors such as demographic and socioeconomic factors, lifestyle habits, nutritional status and inflammatory markers. Methods: We randomly selected 132 individuals volunteers, ages between 19 and 59, of both sexes, regularly treated with antiretrovirals in specialized clinics on HIV / AIDS. Arterial elasticity of the large (LAEI) and small (SAEI) vessels were investigated by the equipment HDI/ PulseWaveTM CR-2000 Cardio Vascular Profiling System®. We determined total cholesterol, HDL, triglycerides, C-reactive protein, fibrinogen, and anthropometric assessment of body composition, smoking, alcohol consumption, drug use, physical activity, and evaluation of demographic, socio-economic and immunological (viral load, T-CD4, T-CD8) factors. The association between LAEI and SAEI and other cardiovascular risk factors were assessed by multiple linear regression. Results: Regarding the elasticity of large and small vessels, 71.97 per cent and 32.58 per cent , respectively, of the participants were classified as having normal elasticity. We observed a positive association between LAEI and weight (p <0.001) and negative associations between LAEI and subscapular skinfold (p <0.001) and CD4 counts (p <0.02). There was a negative association of LAEI with gender (p <0.02), showing that female gender is associated with lower elasticity. There was a positive association between SAEI and weight (p <0.001) and negative associations between SAEI and subscapular skinfold (p <0.001), age (p <0.01) and total lymphocytes (p <0.01). Conclusion: Changes in arterial elasticity in patients with HIV / AIDS correlate with other cardiovascular risk factors. SAEI was altered in most participants, a change that can identify endothelial dysfunction before the disease becomes clinically apparent. The constant monitoring of arterial elasticity through noninvasive method may become an important tool in the prediction and prevention of cardiovascular events in HIV / aids patients

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-07-22T13:08:31Z No. of bitstreams: 1 fabianaalmeidadasilva.pdf: 1594039 bytes, checksum: 77b77016a1e251abcae4fd0a6aa49147 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-07-22T15:42:20Z (GMT) No. of bitstreams: 1 fabianaalmeidadasilva.pdf: 1594039 bytes, checksum: 77b77016a1e251abcae4fd0a6aa49147 (MD5) / Made available in DSpace on 2016-07-22T15:42:20Z (GMT). No. of bitstreams: 1 fabianaalmeidadasilva.pdf: 1594039 bytes, checksum: 77b77016a1e251abcae4fd0a6aa49147 (MD5) Previous issue date: 2016-03-18 / Introdução: As doenças cardiovasculares representam a principal causa de morbidade e mortalidade mundial e seu desenvolvimento se associa a comportamentos alimentares. Objetivos: Investigar a relação entre a frequência de refeições diárias e o hábito de consumo do café da manhã (CM) com fatores de risco para doenças cardiovasculares (FRC) em crianças e adolescentes. Métodos: Realizou-se estudo transversal com uma amostra de 708 escolares (7 a 14 anos) residentes na cidade de Juiz de Fora, MG. Um questionário semiestruturado foi aplicado para coleta de variáveis demográficas, socioeconômicas e comportamentais. Para a obtenção do consumo diário de energia foram utilizados recordatórios alimentares de 24 horas e registros alimentares de três dias. Medidas de peso, altura, gordura corporal, perímetro da cintura e pressão arterial também foram realizadas. Por fim, coletaram-se amostras de sangue para análises de colesterol total (CT), lipoproteína de baixa (LDL) e de alta densidade (HDL), triglicerídeos e glicemia. A normalidade dos dados foi verificada pelo teste Kolmogorov-Smirnov e o teste de Mann-Whitney foi utilizado para verificar diferenças significativas nos valores de medidas de tendência central. Além disso, modelos de regressão de Poisson foram construídos para avaliar o quanto os comportamentos alimentares foram associados aos FRC. Resultados: Realizar ≥ 4 refeições diárias foi mais prevalente entre as crianças que entre os adolescentes (80,1% vs. 68,8%, p= 0,003) e mais prevalente entre o sexo masculino em comparação ao sexo feminino (77,9% vs. 66,6%, p= 0,001). Frequência de refeições < 4 se associaram, em crianças, a renda familiar < 3 salários (p= 0,021) e em adolescentes, ao número de filhos na família > 2 (p= 0,010). Ainda na faixa etária de 10 a 14 anos, < 4 refeições se relacionou a maior prevalência de excesso de peso (p= 0,032) e LDL (p= 0,030) elevados, após ajustes. Omitir o CM foi mais comum entre os adolescentes em comparação com as crianças (30,0% vs. 22,0%; p = 0,035) e entre as meninas em comparação com os meninos (33,1% vs. 22,1%; p = 0,001). Após ajustes, a omissão do CM se associou, em crianças, a valores aumentados de pressão arterial diastólica (p= 0,003), CT (p= 0,001) e LDL (p< 0,001) e em adolescentes, não foram encontradas associações. Conclusão: Comportamentos alimentares como maiores frequências de refeições diárias e consumo do CM estão relacionados à FRC, em crianças e adolescentes e devem ser considerados em discussões e ações de promoção à saúde. / Introduction: Cardiovascular diseases are the leading cause of morbidity and mortality worldwide and its development is associated with eating habits. Objectives: Investigate the relationship between the frequency of meals and breakfast consumption habit (CM) with risk factors for cardiovascular disease (CRF) in children and adolescents. Methods: A crosssectional study with a sample of 708 schoolchildren (7-14 years) living in the city of Juiz de Fora, MG. A semi-structured questionnaire was used to collect sociodemographic, behavioral and relating to eating habits variables. To obtain the daily energy intake were used food 24hour recalls and food records three days. Weight, height, body fat, waist circumference and blood pressure were also performed. Finally, they collected blood samples for analysis of total cholesterol (TC), low lipoprotein (LDL) and high density (HDL) cholesterol, triglycerides and glucose levels. Data normality was verified by the Kolmogorov-Smirnov test and the MannWhitney test was used to identify significant differences in the values of central tendency. Moreover, Poisson regression models were constructed to evaluate how dietary habits were associated with the CRF. Results: Perform ≥ 4 meals was more prevalent among children than among adolescents (80.1% vs. 68.8%, p = 0.003) and more prevalent among males compared to females (77.9% vs. 66.6%, p = 0.001). Meal frequency < 4 were associated in children, family income < 3 minimum wages (p = 0.021) and in adolescents, the number of children in the family > 2 (p = 0.010). Even in the age group 10-14 years < 4 meals was related to associated with increased prevalence of overweight (p = 0.032) and LDL (p = 0.030) higher, after adjustments. Omit the CM was more common among adolescents compared to children (30.0% vs. 22.0%; p = 0.035) and among girls compared to boys (33.1% vs. 22.1%; p = 0.001). After adjustments, the omission of breakfast was associated in children, increased levels of diastolic blood pressure (DBP) (p = 0.003), CT (p = 0.001) and LDL (p <0.001) and in adolescents, associations were not found. Conclusion: Dietary habits as higher frequency of daily meals and CM consumption are related to the CRF, in children and adolescents and should be considered in discussions and health promotion actions.

Abstract It has been proposed that in addition to oral glucose tolerance test, detected by impaired fasting glucose (IFG), impaired glucose tolerance (IGT), glycosylated hemoglobin (HbA1c 5.7–6.4%) can be used for screening individuals at high risk of developing type 2 diabetes and CVD. The aim of the present study was to assess whether the use of ADA 2010 prediabetes definition, especially the use of HbA1c 5.7–6.4% may detect different individuals with prediabetes as compared to the use of IFG or IGT, and whether the traditional CVD-risk factors differed between these definitions. Furthermore, the aim was to study if the inflammatory mediators associated with cardiovascular disease are increased in prediabetes and to assess the power of HbA1c 5.7–6.4%, 2-h glucose, and fasting glucose predicting type 2 diabetes and CVD. The present study consisted of the Oulu 35 population. This prospective population-based study was conducted in 1990–2008 to assess the prevalence of type 2 diabetes and glucose abnormalities. All inhabitants of the City of Oulu, Finland, born in 1935 and living in Oulu on 1st October 1990 (n=1,008), were invited to participate 1990–1992 (831 enrolled). At the baseline of the present study 1996–1998, 815 were invited and 593 (73%) of them enrolled. Prediabetes was classified as IFG (fasting blood glucose, FBG 5.6–6.0 mmol/L), IGT (2-hour BG &#8805;7.8 and &#60;11.1 mmol/L) and/or HbA1c 5.7–6.4%. Inflammation was measured with IL-1Ra, IL-8 and RANTES. Prevalence of isolated prediabetes in this population was common with limited overlap between the three different definitions. Differences in CVD risk factors were observed between the three hyperglycemia groups. Isolated HbA1c was associated with overweight and more adverse lipid profile. Low-grade inflammation (measured by IL-1Ra, IL-8 and RANTES) was associated with prediabetes with levels comparable to those with diabetes. The association was independent of visceral adiposity. Finally, HbA1c and 2-h glucose, but not fasting glucose, predicted CVD in 10 years follow-up in women, but not in men. In conclusion, this study demonstrates that HbA1c 5.7–6.4% detects partly different individuals with prediabetes as compared to IFG and IGT. Using only fasting glucose and HbA1c for screening, many subjects at high risk for diabetes and CVD would be missed. However, HbA1c 5.7-6.4% diagnose individuals with high traditional cardiovascular risk factors. Prediabetes is associated with inflammation measured with IL-1Ra, IL-8 and RANTES. Finally, 2-h glucose value is important in screening subjects in high risk for diabetes and CVD. / Tiivistelmä Vuonna 2010 Amerikan diabetesyhdistys (ADA) esitti sokerihemoglobiinin HbA1c 5.7-6.4&#160;% -arvoa diabeteksen esiasteeksi kohonneen paastosokerin (IFG) ja heikentyneen sokerinsiedon (IGT) lisäksi. Tämän tutkimuksen tarkoituksena oli selvittää, miten ADA 2010 -määritelmä diabeteksen esiasteista löytää riskihenkilöitä ja mitkä ovat perinteiset sydän- ja verisuonisairauksien riskitekijät eri ryhmillä (IFG, IGT ja HbA1c 5.7–6.4%). Tulehdusmarkkereita ja näiden eroja määritettiin verrattuna diabeetikoihin ja terveisiin henkilöihin. Lisäksi selvitettiin, kuinka nämä eri diabeteksen esiasteet ennustavat sydän- ja verisuonisairauksien syntyä. Tutkimusaineistona oli Oulu 35 aineisto, jota on tutkittu v. 1990–2008 tyypin 2 diabeteksen ja sokerihäiriöiden esiintyvyyden selvittämiseksi. Ensimmäinen seurantatutkimus tässä ikäkohortissa, joka on nykyisen tutkimuksen alkuvaihe, tehtiin 1996–1998. Osallistujia oli tällöin 593. Seuraava seurantatutkimus tehtiin 2007–2008. Diabeteksen esiasteeksi määritettiin IFG (kohonnut paastoverensokeri, FBG 5.6–6.0 mmol/L), IGT (2-tunnin verensokeri BG &#8805;7.8 ja &#60;11.1 mmol/L) ja HbA1c 5.7–6.4%. Diabeteksen esiasteiden esiintyvyys tässä aineistossa oli huomattava ja määritelmät löysivät vain vähän samoja ihmisiä. Perinteisissä sydän- ja verisuonisairauksien riskitekijöissä oli selkeitä eroja: henkilöt, joilla oli HbA1c 5.7–6.4%, olivat selkeästi enemmän ylipainoisia ja vyötärölihavia, sekä heillä oli huonommat rasva-arvot (HDL ja triglyseridit). HbA1c ja IGT ennustivat sydän- ja verisuonitautien ilmaantumista naisilla, mutta eivät miehillä. Kaikki nämä määritelmät ennustivat diabeteksen syntyä, mutta ei-diabeetikoilla vain 2 tunnin sokeri ennusti sydän- ja verisuonitautia. Sen sijaan matala-asteinen tulehdusreaktio mitattuna IL-1Ra, IL-8 and RANTES- tulehdusmarkkereilla liittyi jo diabeteksen esiasteeseen (ADA 2010) yhtä paljon kuin diabeetikoilla, eikä tämä selittynyt vyötärölihavuudella. Tutkimus osoitti, että diabeteksen eri esiasteet diagnosoivat eri ihmisiä. Jos 2- tunnin sokerirasitusta ei käytettäisi, jäisi runsaasti todellisessa sydän- ja verisuonisairauksien riskissä olevia henkilöitä löytymättä. Toisaalta sokerihemoglobiini HbA1c 5.7–6.4% löytää eri ihmisiä, joilla perinteiset riskitekijät sydän- verisuonisairauksille ovat yleisemmät, joten senkin käyttö voi diabeteksen seulonnassa olla parempi kuin paastosokerin, joka löysi selkeästi huonommin riskihenkilöitä. Sokerirasituskoe on edelleen tärkeä riskihenkilöiden seulonnassa.

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.

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