Stroke is the leading cause of adult neurological disability. Novel markers of vascular disease progression, such as arterial stiffness and endothelial function, may provide early and sensitive stroke risk detection. However, measurement properties of these novel vascular risk markers have not yet been established in the post-stroke population, nor has the association between these risk markers and measures of physical function. Moreover, given that subclinical vascular disease may initially manifest as a decline in cognitive function, understanding vascular disease progression in older adults with and without cognitive impairment may provide information regarding early stroke risk. This study aimed to investigate 1) test-retest reliability and between-side differences in novel vascular risk markers in individuals with stroke, 2) differences in arterial stiffness and endothelial function between older adults without cognitive impairment, with cognitive impairment, and with stroke, and 3) relationships between novel vascular risk markers and physical function in individuals with and without stroke. Participants were 50-80 years of age, able to ambulate ≥10 meters, and for those with stroke, ≥1 year post-stroke. Carotid-femoral, carotid-radial, and femoral-foot pulse wave velocity (cfPWV, crPWV, and ffPWV, respectively) were used to quantify systemic arterial stiffness, and compliance and distensibility were used to quantify local carotid arterial stiffness. Flow-mediated dilation (FMD) was used to quantify endothelial function. Findings revealed almost perfect test-retest reliability of cfPWV (ICC>0.91, P<0.0001) and substantial test-retest reliability of FMD in individuals with stroke (ICC>0.70, P<0.01). There were no between-side differences in novel vascular measures, no differences in these measures across subgroups of increasing vascular risk, and a positive correlation between cfPWV and walking speed. Findings suggest that in the post-stroke population, cfPWV and FMD may be the most appropriate measures of vascular risk progression, that it may be more clinically feasibly to assess these measures on the unaffected side. / Thesis / Master of Science (MSc) / Novel measures of arterial health, such as arterial stiffness and endothelial function, may provide early stroke risk detection. This study aimed to assess the day-to-day reliability and between-side differences of these new arterial measures in people with stroke, and to also investigate relationships between these measures and cognitive function in older adults with and without stroke. Arterial stiffness was assessed using pressure sensors that measure the speed of the pulse waves, and endothelial function was assessed using ultrasound to measure the capacity of the arteries to expand following an increase in blood flow. Results found that the most well-established measures of arterial health were reliable and there were no between-side differences in any measures. No relationships were observed between arterial measures and cognitive function. Overall, this study increases knowledge surrounding novel measures of arterial health in older adults with and without stroke.

Thesis (M.S.M.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Endothelial dysfunction is a key modulator of the development of cardiovascular disease. Prior studies in selected samples have suggested that the association of age and vascular function may vary between men and women. To investigate the sex-specific patterns of this association, we utilized non-invasive vascular function testing in the Framingham Heart Study. We measured brachial artery flow-mediated vasodilation, a measure of conduit artery function, and hyperemic flow velocity, a measure of small vessel function, in 6790 participants (49±14 years, 53% women) in the Offspring and Third Generation cohorts. We found evidence of effect modification by sex on the relation of age and flow-mediated dilation (P=0.0001) and the relation of age and hyperemic flow velocity (P<0.0001). Using restricted cubic spine analysis, we observed that the relation of age and flow-mediated dilation was linear in men but nonlinear in women. To further characterize the patterns of vascular aging, we divided the cohort by the median age of 47 years old. In multivariable regression models adjusting for cardiovascular risk factors, there was a greater decline in flow-mediated dilation with increasing age in older as compared to younger women (β=-0.113 95% CI -0.129,-0.098 vs β=-0.046 95%CI -0.064,-0.029, p<0.0001 for difference). Whereas in men the association of age and flow-mediated dilation was similar in old and young men (β=-0.038 95%CI-0.054,-0.021 vs β=-0.038 95%CI-0.061,-0.023, p=0.199 for difference). For reactive hyperemia, we found a greater decline in older participants for both men and women (for young men, β=-0.087 95%CI-0.200,0.027 compared to older men β=-0.776 95%CI-0.883,-0.669 p<0.0001 for difference, for young women β=0.141 95%CI 0.033,0.249 compared to older women, β=-1.054 95%CI-1.156,-0.952, p<0.0001 for difference). In a large, community-based cohort the patterns of association between age and conduit vessel vasodilation differed in men and women with an accelerated decline in women after age 47. Small vessel function declined more rapidly in older participants in both men and women, however the decline was more pronounced in women. Our findings suggest that the process of vascular aging differs based on sex and between conduit vessels and the microcirculation. Further studies are needed to evaluate the longitudinal patterns of vascular aging in men and women. / 2031-01-01

No description available.

This study was designed to test the hypothesis that 60 days continuous head down bed rest (HDBR), an Earth-based analogue of the effects of space flight, would elevate factors that increase vasoconstriction and would increase markers of vascular inflammation. The study incorporated countermeasures consisting of treadmill running within lower-body negative pressure and resistive "flywheel" exercise (exercise countermeasure, EX) or an increased protein intake of 0. 6 g/kg body weight/day (dietary countermeasures, DIET) to determine whether these interventions might prevent the vasoconstrictor and inflammatory responses when compared to a control (CON) group. Markers of vascular health measured in the study include the vasoactive molecules angiotensin II (Ang II), endothelin-1 (ET-1), and nitric oxide metabolites (NO_met); and markers of inflammation including C-reactive protein (CRP), and the adhesion molecules E-selectin (E-sel), intracellular adhesion molecule-1 (ICAM), and vascular cell adhesion molecule-1 (VCAM). Twenty four women were housed at the MEDES clinic in Toulouse, France, as part of a large international study (Women International Space Simulation for Exploration, WISE) in which various experimental protocols and countermeasures were integrated into a single experimental design completed during two campaigns. Each 100 day campaign included 20 days of pre-testing (pre-HDBR), 60 days of bed rest (HDBR), and 20 days of post-testing (post-HDBR). The experimental countermeasures were applied only during the 60-day HDBR period. Following 60 days of HDBR, many changes occurred in the concentrations of the measured molecules. Specifically, the concentration of Ang II significantly increased in the CON and DIET groups (52. 9%, p = 0. 014; and 124. 4%, p <0. 0001 respectively), but not in the EX group. Also, NO_met decreased in all groups, with reductions in the EX and DIET groups (p = 0. 013, and p = 0. 056 respectively). Markers used to assess vascular inflammation increased following the HDBR. The increase in CRP in the CON and DIET groups and the decrease in the EX group from pre- to post-HDBR were not significant; however, the directional changes resulted in an interaction between group and HDBR (p = 0. 052). The adhesion molecule E-sel was significantly increased in the DIET group (p = 0. 003), and VCAM was significantly increased in the CON group (p = 0. 016) with a smaller increase in the DIET group (p = 0. 08). No changes in adhesion molecules were observed in the EX group. This study demonstrated that 60 days of HDBR by young, healthy, women caused changes in several different molecules that are beginning to emerge as risk factors for the development of cardiovascular diseases. Further, it was observed that regular, vigorous exercise during HDBR prevented these changes. These results suggest that future studies of this kind should directly monitor the effects of simulated space flight on vascular health in men and women to obtain a greater understanding of the adaptations that might occur during long term space exploration missions. HDBR can be considered an extreme model of physical inactivity and could be used to provide insight into mechanisms of disease processes associated with the sedentary lifestyle that is prevalent in Western society.

O diabetes mellitus do tipo 2 (DM2) é uma doença crônico-degenerativa em que o risco de morte por complicações vasculares é elevado. Em grande parte esse risco se deve à inflamação crônica de baixo grau, aceleração do processo de formação da placa aterosclerótica e diminuição da função vascular. O treinamento de força se mostra uma opção interessante de tratamento para esses pacientes, uma vez que o mesmo é capaz de alterar positivamente uma série de fatores associados a saúde do paciente com diabetes. Sendo assim, o objetivo desse estudo foi verificar os efeitos de um programa de treinamento de força de 12 semanas sobre a saúde vascular e sinalizadores inflamatórios circulantes de indivíduos idosos com DM2. Trinta e nove indivíduos (17 mulheres e 22 homens) idosos com DM2 que se enquadravam nos critérios de inclusão foram selecionados para participar do estudo e, a partir de uma randomização, foram alocados em grupo intervenção(GI, n=18) e grupo controle ativo (GCA, n=21). O primeiro realizou três sessões semanais de treinamento de força durante o período de 12 semanas, enquanto o segundo realizou uma sessão semanal de alongamento de baixa intensidade. Foi avaliada a dilatação mediada por fluxo (DMF) e o diâmetro arterial basal (DAB) por ultrassonografia. Além disso, o perfil lipídico, glicemia, hemoglobina glicada e perfil inflamatório (TNF-α, interleucina 6, interleucina 1β, interleucina 10, proteína C reativa) dos pacientes foram verificados, antes e após o processo de intervenção. As comparações de médias foram realizadas a partir do princípio de intenção de tratar (ITT). Tais comparações foram obtidas a partir da equação de estimativa generalizada (GEE). Os efeitos principais foram avaliados através do pós hoc LSD.O grupo intervenção apresentou uma diminuição significativa no DAB ao final do estudo. O grupo controle apresentou reduções significativas de TNF-α. Ambos os grupos apresentaram reduções significativas na IL-1β e na razão TNF-α/IL-10, sem diferenças significativas entre os grupos. Não houve diferenças significativas para as variáveis de perfil lipídico e de controle glicêmico nos pacientes de ambos os grupos. O treinamento de força não foi capaz de promover adaptações significativas na função vascular de indivíduos idosos com DM2, porém parece modificar o DAB. Algumas importantes adaptações inflamatórias foram observadas no GCA, que pode ser devido ao grau de sedentarismo dos participantes. Sugere-se estudos de maior duração envolvendo semelhante intervenção, bem como um estudo aprimorado e aprofundado das variáveis de saúde vascular. / Type 2 diabetes mellitus (DM2) is a chronic-degenerative disease in which the risk of death from vascular complications is high. To a large extent, this risk is due to chronic low-grade inflammation, acceleration of the atherosclerotic plaque formation process, and decreased vascular function. Strength training is an interesting treatment option for these patients, since it is able to positively alter a number of factors associated with the health of patients with diabetes. Therefore, the objective of this study was to verify the effects of a 12-week strength training program on vascular health and circulatory inflammatory markers of elderly individuals with T2DM. Thirty-nine elderly individuals with DM2 who met the inclusion criteria were selected to participate in the study and, from one randomization, were allocated to the intervention group (GI, n = 18) and the active control group (GCA, n = 21). The first performed three weekly sessions of strength training during the 12-week period, while the second performed a weekly session of low-intensity stretching. Flow-mediated dilation (DMF) and basal arterial diameter (ABD) were evaluated by ultrasonography. In addition, the lipid profile, glycemia, glycated hemoglobin and inflammatory profile (TNF-α, interleukin 6, interleukin 1β, interleukin 10, C-reactive protein) were verified before and after the intervention process. Mean comparisons were performed using the intention to treat (ITT) principle. Such comparisons were obtained from the generalized estimation equation (GEE). The main effects were evaluated through the hoc LSD post. The intervention group showed a significant decrease in ABD at the end of the study. The control group showed significant reductions of TNF-α. Both groups showed significant reductions in IL-1β and in the TNF-α / IL-10 ratio, without significant differences between groups. There were no significant differences for the variables of lipid profile and glycemic control in the patients of both groups. Strength training was not able to promote significant adaptations in the vascular function of elderly individuals with T2DM, but it seems to modify DAB. Some important inflammatory adaptations were observed in GCA, which may be due to the degree of sedentarism of the participants. Longer-term studies involving such intervention are suggested, as well as an improved and in-depth study of vascular health variables.

This study was designed to test the hypothesis that 60 days continuous head down bed rest (HDBR), an Earth-based analogue of the effects of space flight, would elevate factors that increase vasoconstriction and would increase markers of vascular inflammation. The study incorporated countermeasures consisting of treadmill running within lower-body negative pressure and resistive "flywheel" exercise (exercise countermeasure, EX) or an increased protein intake of 0. 6 g/kg body weight/day (dietary countermeasures, DIET) to determine whether these interventions might prevent the vasoconstrictor and inflammatory responses when compared to a control (CON) group. Markers of vascular health measured in the study include the vasoactive molecules angiotensin II (Ang II), endothelin-1 (ET-1), and nitric oxide metabolites (NO_met); and markers of inflammation including C-reactive protein (CRP), and the adhesion molecules E-selectin (E-sel), intracellular adhesion molecule-1 (ICAM), and vascular cell adhesion molecule-1 (VCAM). Twenty four women were housed at the MEDES clinic in Toulouse, France, as part of a large international study (Women International Space Simulation for Exploration, WISE) in which various experimental protocols and countermeasures were integrated into a single experimental design completed during two campaigns. Each 100 day campaign included 20 days of pre-testing (pre-HDBR), 60 days of bed rest (HDBR), and 20 days of post-testing (post-HDBR). The experimental countermeasures were applied only during the 60-day HDBR period. Following 60 days of HDBR, many changes occurred in the concentrations of the measured molecules. Specifically, the concentration of Ang II significantly increased in the CON and DIET groups (52. 9%, p = 0. 014; and 124. 4%, p <0. 0001 respectively), but not in the EX group. Also, NO_met decreased in all groups, with reductions in the EX and DIET groups (p = 0. 013, and p = 0. 056 respectively). Markers used to assess vascular inflammation increased following the HDBR. The increase in CRP in the CON and DIET groups and the decrease in the EX group from pre- to post-HDBR were not significant; however, the directional changes resulted in an interaction between group and HDBR (p = 0. 052). The adhesion molecule E-sel was significantly increased in the DIET group (p = 0. 003), and VCAM was significantly increased in the CON group (p = 0. 016) with a smaller increase in the DIET group (p = 0. 08). No changes in adhesion molecules were observed in the EX group. This study demonstrated that 60 days of HDBR by young, healthy, women caused changes in several different molecules that are beginning to emerge as risk factors for the development of cardiovascular diseases. Further, it was observed that regular, vigorous exercise during HDBR prevented these changes. These results suggest that future studies of this kind should directly monitor the effects of simulated space flight on vascular health in men and women to obtain a greater understanding of the adaptations that might occur during long term space exploration missions. HDBR can be considered an extreme model of physical inactivity and could be used to provide insight into mechanisms of disease processes associated with the sedentary lifestyle that is prevalent in Western society.

O diabetes mellitus do tipo 2 (DM2) é uma doença crônico-degenerativa em que o risco de morte por complicações vasculares é elevado. Em grande parte esse risco se deve à inflamação crônica de baixo grau, aceleração do processo de formação da placa aterosclerótica e diminuição da função vascular. O treinamento de força se mostra uma opção interessante de tratamento para esses pacientes, uma vez que o mesmo é capaz de alterar positivamente uma série de fatores associados a saúde do paciente com diabetes. Sendo assim, o objetivo desse estudo foi verificar os efeitos de um programa de treinamento de força de 12 semanas sobre a saúde vascular e sinalizadores inflamatórios circulantes de indivíduos idosos com DM2. Trinta e nove indivíduos (17 mulheres e 22 homens) idosos com DM2 que se enquadravam nos critérios de inclusão foram selecionados para participar do estudo e, a partir de uma randomização, foram alocados em grupo intervenção(GI, n=18) e grupo controle ativo (GCA, n=21). O primeiro realizou três sessões semanais de treinamento de força durante o período de 12 semanas, enquanto o segundo realizou uma sessão semanal de alongamento de baixa intensidade. Foi avaliada a dilatação mediada por fluxo (DMF) e o diâmetro arterial basal (DAB) por ultrassonografia. Além disso, o perfil lipídico, glicemia, hemoglobina glicada e perfil inflamatório (TNF-α, interleucina 6, interleucina 1β, interleucina 10, proteína C reativa) dos pacientes foram verificados, antes e após o processo de intervenção. As comparações de médias foram realizadas a partir do princípio de intenção de tratar (ITT). Tais comparações foram obtidas a partir da equação de estimativa generalizada (GEE). Os efeitos principais foram avaliados através do pós hoc LSD.O grupo intervenção apresentou uma diminuição significativa no DAB ao final do estudo. O grupo controle apresentou reduções significativas de TNF-α. Ambos os grupos apresentaram reduções significativas na IL-1β e na razão TNF-α/IL-10, sem diferenças significativas entre os grupos. Não houve diferenças significativas para as variáveis de perfil lipídico e de controle glicêmico nos pacientes de ambos os grupos. O treinamento de força não foi capaz de promover adaptações significativas na função vascular de indivíduos idosos com DM2, porém parece modificar o DAB. Algumas importantes adaptações inflamatórias foram observadas no GCA, que pode ser devido ao grau de sedentarismo dos participantes. Sugere-se estudos de maior duração envolvendo semelhante intervenção, bem como um estudo aprimorado e aprofundado das variáveis de saúde vascular. / Type 2 diabetes mellitus (DM2) is a chronic-degenerative disease in which the risk of death from vascular complications is high. To a large extent, this risk is due to chronic low-grade inflammation, acceleration of the atherosclerotic plaque formation process, and decreased vascular function. Strength training is an interesting treatment option for these patients, since it is able to positively alter a number of factors associated with the health of patients with diabetes. Therefore, the objective of this study was to verify the effects of a 12-week strength training program on vascular health and circulatory inflammatory markers of elderly individuals with T2DM. Thirty-nine elderly individuals with DM2 who met the inclusion criteria were selected to participate in the study and, from one randomization, were allocated to the intervention group (GI, n = 18) and the active control group (GCA, n = 21). The first performed three weekly sessions of strength training during the 12-week period, while the second performed a weekly session of low-intensity stretching. Flow-mediated dilation (DMF) and basal arterial diameter (ABD) were evaluated by ultrasonography. In addition, the lipid profile, glycemia, glycated hemoglobin and inflammatory profile (TNF-α, interleukin 6, interleukin 1β, interleukin 10, C-reactive protein) were verified before and after the intervention process. Mean comparisons were performed using the intention to treat (ITT) principle. Such comparisons were obtained from the generalized estimation equation (GEE). The main effects were evaluated through the hoc LSD post. The intervention group showed a significant decrease in ABD at the end of the study. The control group showed significant reductions of TNF-α. Both groups showed significant reductions in IL-1β and in the TNF-α / IL-10 ratio, without significant differences between groups. There were no significant differences for the variables of lipid profile and glycemic control in the patients of both groups. Strength training was not able to promote significant adaptations in the vascular function of elderly individuals with T2DM, but it seems to modify DAB. Some important inflammatory adaptations were observed in GCA, which may be due to the degree of sedentarism of the participants. Longer-term studies involving such intervention are suggested, as well as an improved and in-depth study of vascular health variables.

O diabetes mellitus do tipo 2 (DM2) é uma doença crônico-degenerativa em que o risco de morte por complicações vasculares é elevado. Em grande parte esse risco se deve à inflamação crônica de baixo grau, aceleração do processo de formação da placa aterosclerótica e diminuição da função vascular. O treinamento de força se mostra uma opção interessante de tratamento para esses pacientes, uma vez que o mesmo é capaz de alterar positivamente uma série de fatores associados a saúde do paciente com diabetes. Sendo assim, o objetivo desse estudo foi verificar os efeitos de um programa de treinamento de força de 12 semanas sobre a saúde vascular e sinalizadores inflamatórios circulantes de indivíduos idosos com DM2. Trinta e nove indivíduos (17 mulheres e 22 homens) idosos com DM2 que se enquadravam nos critérios de inclusão foram selecionados para participar do estudo e, a partir de uma randomização, foram alocados em grupo intervenção(GI, n=18) e grupo controle ativo (GCA, n=21). O primeiro realizou três sessões semanais de treinamento de força durante o período de 12 semanas, enquanto o segundo realizou uma sessão semanal de alongamento de baixa intensidade. Foi avaliada a dilatação mediada por fluxo (DMF) e o diâmetro arterial basal (DAB) por ultrassonografia. Além disso, o perfil lipídico, glicemia, hemoglobina glicada e perfil inflamatório (TNF-α, interleucina 6, interleucina 1β, interleucina 10, proteína C reativa) dos pacientes foram verificados, antes e após o processo de intervenção. As comparações de médias foram realizadas a partir do princípio de intenção de tratar (ITT). Tais comparações foram obtidas a partir da equação de estimativa generalizada (GEE). Os efeitos principais foram avaliados através do pós hoc LSD.O grupo intervenção apresentou uma diminuição significativa no DAB ao final do estudo. O grupo controle apresentou reduções significativas de TNF-α. Ambos os grupos apresentaram reduções significativas na IL-1β e na razão TNF-α/IL-10, sem diferenças significativas entre os grupos. Não houve diferenças significativas para as variáveis de perfil lipídico e de controle glicêmico nos pacientes de ambos os grupos. O treinamento de força não foi capaz de promover adaptações significativas na função vascular de indivíduos idosos com DM2, porém parece modificar o DAB. Algumas importantes adaptações inflamatórias foram observadas no GCA, que pode ser devido ao grau de sedentarismo dos participantes. Sugere-se estudos de maior duração envolvendo semelhante intervenção, bem como um estudo aprimorado e aprofundado das variáveis de saúde vascular. / Type 2 diabetes mellitus (DM2) is a chronic-degenerative disease in which the risk of death from vascular complications is high. To a large extent, this risk is due to chronic low-grade inflammation, acceleration of the atherosclerotic plaque formation process, and decreased vascular function. Strength training is an interesting treatment option for these patients, since it is able to positively alter a number of factors associated with the health of patients with diabetes. Therefore, the objective of this study was to verify the effects of a 12-week strength training program on vascular health and circulatory inflammatory markers of elderly individuals with T2DM. Thirty-nine elderly individuals with DM2 who met the inclusion criteria were selected to participate in the study and, from one randomization, were allocated to the intervention group (GI, n = 18) and the active control group (GCA, n = 21). The first performed three weekly sessions of strength training during the 12-week period, while the second performed a weekly session of low-intensity stretching. Flow-mediated dilation (DMF) and basal arterial diameter (ABD) were evaluated by ultrasonography. In addition, the lipid profile, glycemia, glycated hemoglobin and inflammatory profile (TNF-α, interleukin 6, interleukin 1β, interleukin 10, C-reactive protein) were verified before and after the intervention process. Mean comparisons were performed using the intention to treat (ITT) principle. Such comparisons were obtained from the generalized estimation equation (GEE). The main effects were evaluated through the hoc LSD post. The intervention group showed a significant decrease in ABD at the end of the study. The control group showed significant reductions of TNF-α. Both groups showed significant reductions in IL-1β and in the TNF-α / IL-10 ratio, without significant differences between groups. There were no significant differences for the variables of lipid profile and glycemic control in the patients of both groups. Strength training was not able to promote significant adaptations in the vascular function of elderly individuals with T2DM, but it seems to modify DAB. Some important inflammatory adaptations were observed in GCA, which may be due to the degree of sedentarism of the participants. Longer-term studies involving such intervention are suggested, as well as an improved and in-depth study of vascular health variables.

Cardiovascular disease (CVD) is the leading cause of death in the United States. Age is a primary risk factor for the development of CVD and middle-age is a vulnerable period where risk factors for the disease begin to exceed diagnostic thresholds. Interest has increased for the use of low carbohydrate high fat (LCHF) ketogenic diets due to their reported improvements for cardiometabolic health. Supplementation with exogenous ketone esters (KE) has been shown to increase plasma β-hydroxybutyrate (BHB) and mimic the metabolic effects of LCHF ketogenic diets. Evidence suggests elevated concentrations of plasma BHB may lower blood pressure, improve vascular function, attenuate hyperglycemic responses, and enhance cognitive function. The majority of research has been conducted in preclinical models, and whether exogenous KE supplementation has similar improvements in humans of any ages remains relatively unanswered. To address this we conducted a randomized, placebo controlled, crossover design study in healthy, sedentary, middle to older aged adults who received the exogenous KE (or placebo), and consumed the supplement for 2-weeks (3x/day, 15 minutes prior to each meal; breakfast, lunch, and dinner). Our first hypothesis was to test that KE supplementation would improve vascular function by increasing flow-mediated dilation, reducing arterial stiffness, and lowering blood pressure. Secondly, we hypothesized that KE supplementation would attenuate the glycemic response to an oral glucose tolerance test, improve glycemic variability, and show reductions in postprandial glucose levels. Thirdly, we tested the hypothesis that KE supplementation would improve cognitive performance by showing improvements in processing speed, memory, attention control, and executive functions. In support of our first hypotheses, KE supplementation increased flow-mediated dilation (8.1 ± 1.3 vs. 7.7 ± 1.2%, p = 0.023), but it did not show any difference in arterial stiffness or blood pressure. In contrast to our second hypotheses, following the KE supplementation intervention there were no significant difference from the placebo in terms of glycemic response, variability or mean 2-hour post-meal glucose. In support of our third hypotheses, we found a significant improvement in measures of working memory (7.55 ± 0.93 vs. 7.27 ± 0.29, p = 0.026) and inhibitory control (80 ± 38 vs. 87 ± 32ms, p = 0.035) following the 14-day KE supplementation. More research is needed to elucidate the effects of KE on cardiometabolic health and cognition. / Doctor of Philosophy / Recently there has been an increase in the popularity of low carbohydrate high fat (LCHF) ketogenic diets, with advocates for the diet claiming increased benefits in weight loss and blood glucose control, therefore leading to an increased interest for its use in the treatment for cardiovascular disease, obesity, and diabetes. As more evidence has accumulated much of the impact LCHF ketogenic diets are said to have, has been attributed to a state known as nutritional ketosis, which occurs in response to the restriction of carbohydrates from the diet. Ketone esters (KE) have been shown to effectively elevate ketone bodies (alternative energy produced by the body during times when glucose stores are low) without the need of altering one's own diet, however, this method of inducing ketosis is still lacking evidence for its impact on cardiometabolic health in humans. The purpose of these studies is to determine the effect of having sustained elevations of ketone bodies on our health and cognition in humans. Study 1 included healthy, sedentary middle to older aged adults who consumed a KE for 2-weeks (3x/day, prior to each meal) and a placebo. Following supplementation participants completed test to assess our vascular health and blood sugar control. Study 2 included healthy, sedentary middle to older aged adults who consumed a KE for the same 2-weeks (3x/day, prior to each meal) and a placebo. Participants underwent a series of tests to assess cognitive performance. Overall, after a 2-week supplementation period we found significant improvements in our blood vessel function and with cognitive performance where we saw improvements in working memory, and inhibitory control.

While evidence suggests there is indeed a relationship between arterial stiffness and changes in brain structure and function cross-sectionally, the longitudinal relationship between arterial stiffness and changes in brain structure and function is unclear. Also unclear is whether a regional effect of arterial stiffness on brain structure exists, or if the effect is homogenous across brain regions. Using a healthy cohort of the UK Biobank study (N = 1858, meanSD: 61  7 years), we investigated the longitudinal association between changes in arterial stiffness index (ASI) and brain structure (grey matter cortical thickness, whole brain grey matter volume, white matter hyperintensity volume) and function (cognitive performance in 6 tests) over 2.5  1 years. We also examined the association between baseline ASI and all structural and functional brain outcomes 8-11 years post-baseline (N = 630). Prior to post-hoc correction, we observed a significant effect of changes in ASI over 2.5  1 years on grey matter cortical thickness in 11 brain regions contributing to reductions between 0.0004-0.0024mm annually, but none of the 11 regions remained significant post-correction. Following correction there was also no effect of changes in ASI on whole brain grey matter volume (p = 0.76), white matter hyperintensity volume (p = 0.84), or cognitive performance in the domains of interest. Baseline ASI was not associated with regional grey matter cortical thickness, white matter hyperintensity volume, or cognitive function, but did have a significant negative association with whole brain grey matter volume 8.5  1.05 (p = 0.015) years later and 11  1.02 (p = 0.03) years later. Our findings suggest that taken with the effect of age, elevations in ASI may have an additive effect to accelerate changes in brain structure beyond the range that is to be expected as a part of normal aging. Our findings also suggest the relationship between ASI and reductions in whole brain grey matter volume may require long-term exposure to elevations in arterial stiffness in otherwise healthy older adults. / Thesis / Master of Science in Kinesiology / Arterial stiffening both accompanies the normal aging process and can progress due to acquired health conditions. As arteries begin to stiffen the ability to buffer high pressure blood flow is impaired and can put microvasculature at risk of damage. Microvascular damage in the brain can disrupt blood and subsequent oxygen delivery to the brain. When delivery to the brain does not meet the metabolic demand, changes in brain structure brain can occur. Changes in brain structure are associated with impaired brain function, as well as potentially accelerating the progression of neurological diseases. What remains unclear is whether arterial stiffness impacts brain structure differently across regions or all regions homogenously. The purpose of this thesis was to examine the relationship between arterial stiffness and structural and functional changes in the brain over time (objective 1: 2-5 years; objective 2: 8-11 years). Our observations suggest that the progression of arterial stiffness had an effect that was equivalent to approximately 30% of the rate of grey matter tissue loss associated with normal healthy aging (~0.25% reduction in grey matter per year). We found no effect of changes in arterial stiffness on the progression of total grey matter volume, white matter lesions or brain function. We did observe a significant negative relationship between arterial stiffness at baseline and total grey matter volume 8-11 years later. We found no relationship between baseline arterial stiffness and brain structure or function 8–11-years post-baseline. Taken with the effects of normal aging, the loss of tissue in select brain regions associated with changes in arterial stiffness may result in grey matter reductions beyond the range associated with what is considered healthy or normal aging. The association of arterial stiffness and total grey matter volume 8-11 years later suggests that changes in whole brain structure are the product of long-term exposure to arterial stiffness.