Impacts of systemic hemodynamic factors on cerebral and peripheral perfusion

Changes in physiological factors involving modulation of hemodynamics such as baroreflex sensitivity (BRS), heart rate, and/or blood pressure influence blood flow to downstream tissues leading to changes in response and/or function of tissues. For example, a sufficient increase in heart rate elicits greater accumulative shear stimuli on a per minute basis leading to a greater vasodilatory response of endothelial cells and providing greater perfusion to skeletal muscle. The high-flow and low-impedance nature of the cerebral circulation leads to increased susceptibility to damage from considerable blood pressure fluctuations. For this reason, the cerebrovasculature holds a very narrow range of operation of cerebral autoregulation in response to changes in perfusion pressure. In a nondemented elderly population and patients with Alzheimer’s disease, impaired BRS has been linked with poor cognitive function and a link between high pulsatile components of blood pressure (i.e., pulse pressure) and impaired cognitive function has also been reported. Three research investigations were included in this dissertation study. The first study was to determine the association between heart rate at rest and endothelium-dependent vasodilation as assessed by flow-mediated dilation (FMD) of the brachial artery. The primary findings from study 1 revealed an indirect association between heart rate and FMD through shear stimuli. The studies 2 and 3 sought to determine the association of regional cerebral perfusion with cardiovagal BRS and blood pressure components. A link between cardiovagal BRS and regional cerebral perfusion of the hippocampus was demonstrated in the study 2. This finding may add mechanistic insight to the relationship between impaired BRS and cognitive dysfunction. The primary finding from the study 3 revealed a significant relationship between peripheral pulsatile blood pressure components and regional cerebral perfusion of the hippocampus as well as anterior white matter. This finding highlights the importance of pulsatile pressure on cerebral vascular beds. Taken together, the overall findings from this dissertation study indicate the potential impacts of systemic hemodynamic factors on cerebral and peripheral perfusion. Future longitudinal studies in nondemented elderly and individuals with Alzheimer’s disease are warranted to reveal the causality of these associations.Kinesiology and Health Educatio

Impact of arterial stiffness on white matter microstructure in the elderly

La rigidité artérielle fait référence à la perte d'élasticité principalement dans les grandes artères telles que l'aorte et les carotides. On sait que la rigidité artérielle chroniquement élevée contribue à des modifications vasculaires cérébrales telles que des lésions parenchymateuses de la substance blanche cérébrale via une modification du flux sanguin cérébral. En particulier, parmi les structures perfusées par les artérioles fournies par les artères cérébrales antérieure et moyenne, le corps calleux, la capsule interne, la corona radiata et le faisceau longitudinal supérieur sont les plus vulnérables à l’hypoperfusion. Des études antérieures ont montré que l'augmentation de la rigidité artérielle évaluée par la vitesse de l'onde de pouls carotide-fémorale (cfPWV) est associée à une diminution de l'anisotropie fractionnelle (FA) et à une augmentation de la diffusivité radiale (RD). On a émis l'hypothèse que les altérations au niveau des régions vulnérables de la substance blanche (par exemple, le corps calleux, la capsule interne) seraient probablement liées à la démyélinisation axonale. Cependant, bien que la RD a auparavant été corrélée avec la démyélinisation axonale, l'imagerie de diffusion est principalement aveugle à la myéline. En revanche, l'imagerie par transfert de magnétisation (MT) est une métrique adaptée pour estimer la fraction volumique de myéline. De plus, malgré leur sensibilité à l'organisation des fibres axonales, les métriques de tenseur de diffusion (DTI) telles que les FA et RD manquent de spécificité pour la microstructure tissulaire individuelle. Des modèles microstructuraux plus avancés tels que l’imagerie dispersion et de l'orientation des neurites (NODDI) fournissent des outils pour disséquer les changements microstructuraux derrière les mesures DTI. Dans l'article 1, nous avons utilisé les métriques de DTI et basé sur le MT pour examiner de plus près l'interaction entre la rigidité artérielle et la microstructure de la substance blanche chez les personnes âgées de plus de 65 ans. Nous avons constaté que la mesure de référence absolue de la rigidité artérielle, la mesure de la vitesse de l'onde de pouls entre l’artère fémorale et carotidienne (cfPWV) était associée à l'organisation axonale des fibres telle que reflétée par FA et RD plutôt qu'à la démyélinisation dans les régions de la substance blanche qui ont été précédemment désignées comme vulnérables à rigidité artérielle. Dans notre deuxième article, nous avons utilisé le modèle NODDI pour approfondir la relation entre le cfPWV et l'organisation axonale. Nos résultats ont montré que la cfPWV est positivement associée à la diffusion extracellulaire de l'eau (ISOVF), ce qui signifie que la rigidité artérielle peut entraîner une dispersion axonale, diminuant la contrainte de directionnalité de l'eau le long des axones. En outre, nous avons constaté que la rigidité artérielle est associée à une augmentation de la densité des fibres dans le corps calleux tel que mesuré par l’ICVF, ce qui pourrait suggérer que les personnes à risque plus élevé de déclin cognitif présentent des mécanismes compensatoires précoces avant l'apparition de signes cliniques de déclin cognitif. Compte tenu de la forte interaction entre la rigidité artérielle et le déclin à la fois de la structure du cerveau et des fonctions cérébrales, on peut envisager un avenir meilleur où la rigidité artérielle sera mesurée dans la pratique clinique de routine afin d'identifier les personnes à risque plus élevé d’altérations de la substance blanche et de déclin cognitif. Ces personnes pourraient bénéficier de programmes multi-interventionnels visant à préserver la structure et la fonction cérébrale. Un seuil de rigidité artérielle est donc nécessaire pour identifier ces individus. L'article 3 présente la première estimation d'une valeur seuil de cfPWV à laquelle la rigidité artérielle affecte la microstructure de la substance blanche chez les personnes âgées. Nos résultats suggèrent que le seuil actuel de 10 m / s de cfPWV adopté par la Société européenne d'hypertension n'est peut-être pas le seuil optimal pour diviser les individus en groupes à risque neurovasculaire élevé et faible. Au lieu de cela, nos résultats suggèrent que le seuil de cfPWV est plus susceptible d’être autour de 8,5 m / s. Bien que le cfPWV offre une excellente valeur pronostique chez les adultes, il reste malheureusement principalement utilisé dans la recherche en raison du besoin d'experts formés pour cette mesure. À l'inverse, la mesure de l'indice de rigidité artérielle (ASI) à l'aide de la pléthysmographie suscite un intérêt croissant ces dernières années en raison de son approche simple à utiliser. Dans l'article 4, nous avons étudié la relation entre l'ASI et la pression pulsée (PP) qui est une mesure indirecte de la rigidité artérielle, avec la FA et les lésions de la substance blanche chez les participants du UK Biobank. Nous avons constaté que la PP prédit mieux l'intégrité de la substance blanche que l'ASI chez les participants de moins de 75 ans. Cette constatation implique que l'ASI de la pléthysmographie ne semble pas être une mesure fiable de la rigidité artérielle chez les personnes âgées. Des études futures sont évidemment nécessaires pour valider nos résultats, en particulier notre seuil de cfPWV. Une fois ce seuil validé, nous envisageons un avenir radieux où la mesure du cfPWV sera non seulement utilisée pour aider à sélectionner les personnes qui bénéficieraient le plus d'un programme multi-interventionnel visant à préserver l'intégrité cérébrale, mais pourrait également être utilisée pour surveiller l’effet d’une telle intervention.Arterial stiffness refers to the loss of elasticity mainly in large arteries such as the aorta and carotids. Chronically elevated arterial stiffness contributes to cerebrovascular changes such as cerebral white matter parenchymal damage via an alteration of cerebral blood flow. In particular, among the areas perfused by arterioles supplied by the anterior and middle cerebral arteries, the corpus callosum, the internal capsule, the corona radiata, and the superior longitudinal fasciculus are more vulnerable to cerebral hypoperfusion. Previous studies have shown that increased arterial stiffness as assessed by carotid-femoral pulse wave velocity (cfPWV) is associated with a decrease in fractional anisotropy (FA) and increase in radial diffusivity (RD). It was hypothesized that alterations in vulnerable white matter tracts (e.g. corpus callosum, internal capsule) are likely to be related to axonal demyelination. However, while RD was previously correlated with axonal demyelination, diffusion imaging is mostly blind to myelin. In contrast magnetization transfer (MT) imaging is a tailored metric to estimate myelin volume fraction. Moreover, despite their sensitivity to axon fiber organization, diffusion tensor metrics (DTI) such as FA and RD lack specificity for individual tissue microstructure. More advanced microstructural model such as neurite orientation dispersion and density imaging (NODDI) give tools to disecate the microstructural changes behind DTI metrics. In Article 1 we used DTI and MT based metric to look more closely at the interplay between arterial stiffness and white matter microstructure in older adults > 65 years old. We found that the gold standard measure of arterial stiffness, the measure of carotid femoral pulse wave velocity (cfPWV) was associated with axonal fiber organization as reflected by FA and RD rather than demyelination in the white matter regions that have been previously denoted as vulnerable to arterial stiffness. In our second Article, we used the NODDI model to take a further look at the relationship between cfPWV and axonal organization. Our results showed that cfPWV is positively associated with the extracellular water diffusion (ISOVF) which means that arterial stiffness may result in axonal dispersion, lessening the constraint of water directionality along axons. In addition, we found that arterial stiffness is associated with increased fibers density in the corpus callosum as measured by ICVF which could suggest that individuals at higher risk for cognitive decline demonstrate early compensatory mechanisms before the appearance of clinical signs of cognitive decline. Considering the strong interplay between arterial stiffness and decline both in brain structure and function, one can envision a bright future where arterial stiffness would be measured in routine clinical practice in order to identify individuals at higher risk for white matter changes and cognitive decline. Such individuals could benefit from multi-interventions programs aiming to preserve brain structure and function. A cut-off arterial stiffness is thus needed to identify these individuals. Article 3 presents the first estimation of an cfPWV cut-off value at which arterial stiffness impacts the white matter microstructure in older adults. Our results suggested that the current 10 m/s cfPWV cut-off adopted by the European Society of Hypertension may not be the optimal threshold to split individuals into high and low neurovascular risk groups. Instead, our findings suggest that the cfPWV cut-off is more likely to fall around 8.5 m/s. While cfPWV provides excellent prognostic value in adults, it remains unfortunately mainly used in research due to the need of trained experts. Conversely, measure of arterial stiffness index (ASI) using plethysmography is getting increased interest in the last few years due to its simple-to-use approach. In article 4, we investigated the relationship between ASI and pulse pressure (PP), an indirect measure of arterial stiffness, with FA and white matter lesions in participants of the UK Biobank. We found that PP better predicts white matter integrity compared to ASI in participants younger than 75 years old. This finding implies that ASI from plethysmography may not be a reliable measure of arterial stiffness in older adults. Future studies are obviously needed to validate our results, in particular our cfPWV cut-off. Once such cut-off will be validated, the present author envision a bright future where measure of cfPWV will not only be used to help selecting individuals that would most benefit from a multi intervention program aiming to preserve brain integrity, but could also be used to monitor the effect of such intervention

Investigation of the association between central arterial stiffness and aggregate g-ratio in cognitively unimpaired adults

Stiffness of the large arteries has been shown to impact cerebral white matter (WM) microstructure in both younger and older adults. However, no study has yet demonstrated an association between arterial stiffness and aggregate g-ratio, a specific magnetic resonance imaging (MRI) measure of axonal myelination that is highly correlated with neuronal signal conduction speed. In a cohort of 38 well-documented cognitively unimpaired adults spanning a wide age range, we investigated the association between central arterial stiffness, measured using pulse wave velocity (PWV), and aggregate g-ratio, measured using our recent advanced quantitative MRI methodology, in several cerebral WM structures. After adjusting for age, sex, smoking status, and systolic blood pressure, our results indicate that higher PWV values, that is, elevated arterial stiffness, were associated with lower aggregate g-ratio values, that is, lower microstructural integrity of WM. Compared to other brain regions, these associations were stronger and highly significant in the splenium of the corpus callosum and the internal capsules, which have been consistently documented as very sensitive to elevated arterial stiffness. Moreover, our detailed analysis indicates that these associations were mainly driven by differences in myelination, measured using myelin volume fraction, rather than axonal density, measured using axonal volume fraction. Our findings suggest that arterial stiffness is associated with myelin degeneration, and encourages further longitudinal studies in larger study cohorts. Controlling arterial stiffness may represent a therapeutic target in maintaining the health of WM tissue in cerebral normative aging

Neuroprotective Effects of Long-term Endurance Training on the Cortical Autonomic Network in the Aging Brain

This study tested whether long-term endurance training in older adults (ET; n = 15, 55 ± 4 years, relative VO2max = 50 ± 8 ml/kg/min) would alter cardiovagal control and preserve the cortical autonomic network compared to age-matched controls (CON; n = 15, 56 ± 4 years, relative VO2max = 37 ± 9 ml/kg/min). The hypothesis predicts 1) altered deactivation patterns of the ventral medial prefrontal cortex (vMPFC) in response to isometric hand grip (IHG) and 2) greater indices of cardiovagal control; a) increased baroreflex sensitivity at rest, b) greater heart rate change (ΔHR) and c) reductions in high frequency heart rate variability (ΔHF HRV) in the ET group. Functional magnetic resonance imaging was utilized to observe BOLD signal changes. There was no difference in measured indices of cardiovagal control between groups and both exhibited vMPFC deactivation with IHG. Overall, ET does not preserve cortical functional patterns in the older brain or enhance cardiovagal control compared to age-matched controls

Arterial stiffness and brain health : investigating the impact of sex-related differences

Introduction: Il est bien établi que les maladies vasculaires, cérébrovasculaires et cardiovasculaires se manifestent différemment chez les hommes que chez les femmes. La rigidité artérielle (RA), un prédicteur indépendant de la maladie cardiovasculaire (MCV), a été associée à des changements de la réactivité cérébrovasculaire (RCV) et à un déclin cognitif lors du vieillissement. Plus précisément, les personnes âgées ayant une RA plus élevée présentent un déclin plus marqué au niveau des tâches exécutives. Une diminution des fonctions exécutives (FE) est également liée à une réduction de la RCV chez les personnes âgées. Cependant, il est important de noter que la relation entre la RA et la RCV est plus complexe. Certaines études montrent une diminution de la RCV associée avec une RA plus élevée, tandis que d’autres rapportent une RCV préservée avec une RA élevée. De plus, des travaux récents suggèrent que les différences de concentration en hématocrit (HCT) pourraient avoir une incidence sur les mesures de RA. Ici, nous avons étudié le rôle possible du sexe et de l'HCT sur ces relations hémodynamiques. Méthodes: Des acquisitions ont été effectuées chez 48 adultes âgés en bonne santé (31 femmes, 63 ± 5 ans) dans un scanneur d’imagerie par résonance magnétique (IRM) 3T. Des données de marquage de spin artériel pseudo-continu utilisant des lectures à double écho ont été collectées pendant un défi d'hypercapnie (changement de CO2 de 5mmHg, pendant deux blocs de 2 minutes). La RCV a été calculée comme étant le % de changement du signal de débit sanguin cérébral (% ∆CBF) par changement de mmHg dans le CO2 à la fin de l’expiration. Les données de vitesse d’onde de pouls (VOP) aortique ont été acquises à l’aide d’une série de contraste de phase cine encodée par la vitesse durant 60 phases cardiaques avec un encodage en vélocité de 180cm/s dans le plan. La VOP dans l'arcade aortique a été calculée entre l'aorte ascendante et descendante. Les analyses statistiques ont été effectuées à l'aide de SPSS. Résultats: Un test de modération contrôlant pour l’âge et le volume des hyperintensités de la matière blanche a révélé un effet direct significatif de la VOP sur la RCV (β = 1,630, IC à 95% [.654, 2,607), ainsi que de la VOP sur la FE (β = -. 998, IC 95% [-1,697, -,299]). Le sexe a modéré la relation entre VOP et RCV (β = -1,013, IC 95% [-1,610, -,4169]), et VOP et FE (β = .447, IC 95% [.020, .875]). En outre, il existait un effet significatif de l’HCT sur les différences de sexe observées dans l’effet de modération (VOP * SEXE) sur la FE (β = -0,7680, SE = 0,3639, IC 95% [-1,5047, -0,0314], p = 0,0414). Conclusion: Nos résultats indiquent que les relations entre la VOP, la RCV et la FE sont complexes et que le sexe et l’HCT modulentces relations. L’influence des variations hormonales (p. ex. la ménopause) sur ces relations devrait être étudiée dans le futur et pourrait permettre de personnaliser les stratégies de prévention des MCV.Introduction: It is well established that sex differences exist in the manifestation of vascular, cerebrovascular and cardiovascular disease. Arterial stiffness (AS), an independent predictor of cardiovascular disease (CVD), has been associated with changes in cerebrovascular reactivity (CVR) and cognitive decline in aging. Specifically, older adults with increased AS show a steeper decline on executive function (EF) tasks. Decreased EF is also linked with reduction in CVR among older adults. Interestingly, the relationship between AS and CVR is more complex, where some works show decreased CVR with increased AS, and others demonstrate preserved CVR with higher AS. In addition, recent work suggests that measurements of AS may be affected by differences in the concentration of hematocrit (HCT). Here, we investigated the possible role of sex and HCT on these hemodynamic relationships. Methods: Acquisitions were completed in 48 healthy older adults (31 females, 63 ± 5 years) on a 3T MRI. Pseudo-continuous arterial spin labeling using dual-echo readouts were collected during a hypercapnia challenge (5mmHg CO2 change, during two, 2 min blocks). CVR was calculated as the %∆CBF signal per mmHg change in end-tidal CO2. Aortic PWV data was acquired using a cine phase contrast velocity encoded series during 60 cardiac phases with a velocity encoding of 180cm/s through plane. PWV in the aortic arch was computed between ascending and descending aorta. Statistical analyses were done using SPSS. Results: A moderation model test controlling for age and white matter hyperintensity volume revealed a significant direct effect of PWV on CVR (β=1.630, 95% CI [.654, 2.607), as well as PWV on EF (β=-.998, 95% CI [-1.697, -.299]). Sex moderated the relationship between PWV and CVR (β=-1.013, 95% CI [-1.610, -.4169]), and PWV and EF (β=.447, 95% CI [.020, .875]). In addition, there was a significant effect of HCT on the sex differences observed in the moderation effect (PWV*SEX) on EF (β=-0.7680, SE = 0.3639 ,95% CI [-1.5047, -0.0314], p=0.0414). Conclusion: Together, our results indicate that the relationships between PWV, CVR and EF is complex and in part mediated by sex and HCT. Future work should investigate the role of hormone variations (e.g., menopause) on these relationships to better personalize CVD prevention strategies

Midlife cardiovascular indicators of cerebral white matter health and cognitive function

Recent evidence suggests that modifiable cardiovascular risk factors additionally play a causal role in the development of dementia and cognitive dysfunction. Currently, no cure for dementia exists making identification of early relationships in dementia pathophysiology critical for the purpose of primary prevention or remediation. As approximately 70% of adults in the United States are clinically overweight, the aim of Study 1 was to determine the anthropometric measures most strongly associated with early white matter disease and cognitive function at midlife. In this cross-sectional investigation of 126 middle-aged adults, waist circumference, body fat percentage, and visceral adiposity all significantly predicted white matter hyperintensities, indicating that midlife abdominal obesity is associated with the early development of white mater disease. Midlife visceral adiposity is also associated with increased arterial stiffening. The aim of Study 2 was to determine if subclinical carotid artery stiffening is associated with lower cerebral white matter integrity at midlife in a priori regions of interest susceptible to vascular and cognitive aging. This study employed diffusion tensor imaging to gauge cerebral white matter integrity. In a middle-aged cohort of 143 adults, we determined that arterial stiffening was associated with reduced integrity of multiple white matter regions independent of age, sex, and waist circumference. Arterial stiffness indirectly affected processing speed. These data suggest that arterial stiffening may negatively affect CWMI prior to clinically overt cognitive decline. Individuals with metabolic syndrome are at increased risk of arterial stiffening and dementia. The purpose of Study 3 was to determine the role of physical activity on mitigating the adverse influence of metabolic syndrome on arterial stiffness and cerebral white matter integrity. In this cross-sectional investigation of 66 middle-aged adults, individuals with MetS who were physically active demonstrated lower arterial stiffness and more favorable CWM integrity than their sedentary peers, indicating that PA may be effective in mitigating the adverse effects of MetS on the vasculature and brain at midlife. Taken together, these findings indicate that cardiometabolic risk factors negatively affect the vasculature, cerebral white matter health, and cognitive function at middle-ageKinesiology and Health Educatio

Effects of Aerobic Exercise on Cognitive and Cerebrovascular Function in Hypertensive Adults

The presence of hypertension in middle-age is a major risk factor for later-life development of cognitive and cardiovascular disease. Exercise is widely recommended to combat vascular and brain aging in hypertension. We sought to compare the effects of a single bout of aerobic exercise on 1) arterial stiffness and cerebral hemodynamics and 2) cognitive function in middle-aged adults with controlled-hypertension and without hypertension. Vascular and cognitive measures were assessed pre and post 30-min of aerobic exercise at ≈55% maximal oxygen consumption. Arterial stiffness and cerebral hemodynamics were measured non-invasively. Cognitive function was measured using a computerized testing battery that included executive function and memory tasks. Acute aerobic exercise resulted in similar 1) increases in arterial stiffness and cerebral hemodynamic pulsatility, and 2) accelerated executive function and memory reaction time post-exercise in adults with and without hypertension. Based on these results, we investigated if adults with hypertension had differential vascular contributions to cognitive activity. We measured cerebrovascular hemodynamics non-invasively during cognitive activity as a measure of neurovascular coupling. Adults with and without hypertension exhibit similar increases in large artery stiffness and decreases in extracranial hemodynamic pulsatility during cognitive activity, indicating similar neurovascular coupling between groups. In conclusion, these data indicate that middle-aged adults with controlled-hypertension experience similar 1) vascular responses to acute exercise and cognitive activity, and 2) beneficial changes in cognitive function following acute exercise as their counterparts without hypertension. Our results will be interpreted and explored in the context of hypertension severity and underscore the importance of optimal blood pressure control

ACUTE DOSE RESPONSE EFFECTS OF AEROBIC EXERCISE ON CEREBROVASCULAR HEMODYNAMICS AND ARTERIAL STIFFNESS

Accumulating evidence suggests that aerobic exercise benefits cerebrovascular hemodynamics and arterial stiffness. Few studies have evaluated acute effects of aerobic exercise on cerebral blood flow and even fewer on cerebral pulsatile flow. Furthermore, it has been proposed that cerebral blood flow is more pulsatile with higher arterial stiffness, though little is known about this relationship, particularly in response to exercise. PURPOSE: To evaluate acute effects of aerobic exercise on cerebrovascular hemodynamics and arterial stiffness. METHODS: Fifteen middle-aged adults were recruited for this randomized crossover study comprised of three experimental visits: 30 minutes of sitting (SIT), 20 minutes of sitting followed by a 10-minute exercise bout (EX10), and a 30-minute exercise bout (EX30). Cerebrovascular hemodynamics and arterial stiffness were measured before the experimental session and at 30- and 60-minute post-session. Cerebrovascular hemodynamics were measured using Transcranial Doppler ultrasonography at the middle cerebral artery (MCA). Arterial stiffness was measured by pulse wave velocity (cfPWV and crPWV) and pulse pressure. RESULTS: Pulsatility index was marginally higher in EX30 versus SIT (4.7%, P=0.08) at the 30-minute post-session assessment. Cerebrovascular blood flow velocity was not different across conditions (P>0.10). Pulse pressure was lower in EX10 (β =-2.79 mmHg, P=0.01) and in EX30 (β=-3.85 mmHg, P=0.001) versus SIT at the 60-minute post-session assessment. Neither cfPWV nor crPWV were different from SIT following EX30 (P>0.05). However, compared to SIT, cfPWV was higher in EX10 at the 30-minute post-session assessment (β =0.30 m/s, P=0.02) and crPWV was lower in EX10 at the 60-minute post-session assessment (β =-0.88 m/s, P=0.004). Neither changes in cfPWV nor crPWV were associated with changes in cerebral pulsatile flow (P>0.05). Higher pulse pressure was associated with higher cerebral pulsatile flow (β =0.004, P=0.02) at the 30- but not the 60-minute post-session assessment. CONCLUSIONS: Based on our results, aerobic exercise does not improve cerebrovascular hemodynamics in the MCA within an hour of aerobic exercise. Future research should include more frequent and longer post-exercise observation periods, different cerebral regions and vessels, and relationships with arterial stiffness. Additionally, our results suggest 10- and 30-minute exercise bouts have differential effects on PWV which also warrants further research