O processo de envelhecimento é acompanhado por um declínio nas funções cognitivas, principalmente, de funções fluidas ou de processamento. Essas diminuições são pelo menos, em parte, devido a alterações estruturais e funcionais do sistema nervoso central. Uma abordagem para estudar as mudanças funcionais é a medição da utilização metabólica regional da glicose, ou, alternativamente, um parâmetro físico correlacionado ao metabolismo cerebral e à atividade funcional local, como o fluxo sanguíneo cerebral (CBF). Neste contexto, em Imagens por Ressonância Magnética (IRM), a técnica de Marcação dos Spins Arteriais (ASL) surge como uma importante ferramenta não invasiva para análises perfusionais. Seu uso não só permite avaliar a perfusão sanguínea cerebral, gerando mapas quantitativos de CBF, mas também fornecer uma alternativa para estudar a conectividade funcional (FC), um parâmetro importante para descrição da topologia e funcionalidade cerebral. Sessenta e três indivíduos saudáveis, na faixa etária entre dezoito à setenta e dois anos, foram recrutados para participar deste estudo. Análises estatísticas mostram uma diminuição de CBF em várias regiões cerebrais, especialmente nos lobos frontal e temporal, que acompanham o processo de envelhecimento. As medidas de FC foram obtidas em análises por regiões de interesse e teoria de grafos; estas também demostraram uma diminuição, com o avanço da idade, em regiões presentes nos lobos frontal e temporal, mas também relataram um maior número de regiões prejudicadas no lobo parietal. Portanto, usando uma técnica de imagem não invasiva, foi possível observar déficits de CBF além de alterações de aspectos da organização funcional, oferecendo valores quantitativos que podem ajudar na melhor descrição dos efeitos do envelhecimento na hemodinâmica cerebral. / Aging process is accompanied by a decline in cognitive functions foremost comprise fluid or processing-based functions. These decreases are at least partly due to structural and functional deteriorating changes of the central nervous system. One approach to study these functional changes is the measurement of the regional metabolic utilization of glucose, or, alternatively, a physical quantity correlated to cerebral metabolism and local functional activity, such as the cerebral blood flow (CBF). In this context, Arterial spin labeling (ASL) emerges as a noninvasive Magnetic Resonance Imaging (MRI) perfusion technique. Its use not only allows assessing cerebral perfusion, by generating CBF values, but also can provide an alternative to study functional connectivity (FC), which is an important parameter that describes the brain topology and functionality. Sixty-three healthy subjects, from age eighteen to seventy-two years, were recruited to participate in this study. ASL-CBF maps showed a decrease in several brain regions, especially in frontal and temporal lobes that follows aging process. FC measures were assessed with regions of interest (ROI-to-ROI) and graph theory analysis, also showing a decrease in regions present in frontal and temporal lobes, and also more impaired regions in the parietal lobe. Therefore, using a noninvasive imaging technique it was possible to observe CBF deficits besides alteration in aspects on functional organization, offering quantitative values that can help to describe better the aging effects on cerebral hemodynamics.

Blood oxygen level-dependent (BOLD) magnetic resonance (MR) imaging enables non-invasive spatial mapping of changes in cerebral blood flow (CBF). By applying a vasodilatory stimulus (such as inhaled CO2) during BOLD MR imaging, one can measure cerebral vasodilatory capacity. "Cerebrovascular reactivity" (CVR) is defined as the change in CBF per unit of vasodilatory stimulus. Vasodilatory capacity is clinically important as vasodilatation is a mechanism by which the brain maintains constant CBF despite reductions in cerebral perfusion pressure.ii Patients with arterial narrowing commonly demonstrate a paradoxical response: vasodilatory stimulus-induced reduction of BOLD MR signal. BOLD MR depends on CBF but on other factors too. Does a reduction of BOLD MR signal indicate a decrease in flow? Does BOLD MR CVR correlate with CVR measured using arterial spin labeling (ASL) MR? I studied thirty-eight patients with stenosis of brain-supplying arteries and found that the BOLD CVR and ASL CVR results correlate strongly (R=0.83, P<0.0001 for cerebral hemispheric gray matter). The second study aimed to determine whether preoperative CVR predicts the hemodynamic effect of extracranial-intracranial bypass surgery. Whereas prior studies relied on right-left interhemispheric CVR asymmetry indices, this study used “absolute” CVR from each hemisphere. I studied twenty-five patients with intracranial arterial stenosis. I found that the group with normal pre-operative CVR showed no change in CVR following bypass surgery (0.22% ± 0.05% to 0.22% ± 0.01% (mean ± SD)(P=0.881)), the group with reduced pre-operative CVR demonstrated an improvement (0.08% ± 0.05% to 0.21 ± 0.08% (mean ± SD)(P<0.001)), and the group with paradoxical pre-operative CVR demonstrated the greatest improvement (-0.04% ± 0.03% to 0.27% ± 0.03% (P=0.028)). ii Patients with arterial narrowing commonly demonstrate a paradoxical response: vasodilatory stimulus-induced reduction of BOLD MR signal. BOLD MR depends on CBF but on other factors too. Does a reduction of BOLD MR signal indicate a decrease in flow? Does BOLD MR CVR correlate with CVR measured using arterial spin labeling (ASL) MR? I studied thirty-eight patients with stenosis of brain-supplying arteries and found that the BOLD CVR and ASL CVR results correlate strongly (R=0.83, P<0.0001 for cerebral hemispheric gray matter). The second study aimed to determine whether preoperative CVR predicts the hemodynamic effect of extracranial-intracranial bypass surgery. Whereas prior studies relied on right-left interhemispheric CVR asymmetry indices, this study used “absolute” CVR from each hemisphere. I studied twenty-five patients with intracranial arterial stenosis. I found that the group with normal pre-operative CVR showed no change in CVR following bypass surgery (0.22% ± 0.05% to 0.22% ± 0.01% (mean ± SD)(P=0.881)), the group with reduced pre-operative CVR demonstrated an improvement (0.08% ± 0.05% to 0.21 ± 0.08% (mean ± SD)(P<0.001)), and the group with paradoxical pre-operative CVR demonstrated the greatest improvement (-0.04% ± 0.03% to 0.27% ± 0.03% (P=0.028)). The third study arose from an unexpected observation: paradoxical reactivity in the white matter of young healthy subjects. I evaluated healthy subjects using BOLD CVR and ASL CVR, transformed all CVR maps into a common brain space, and generated composite maps of CVR. Composite maps confirmed regions of significant paradoxical iii reactivity in the white matter. These regions may represent the physiological correlate of previously anatomically defined border-zones (watershed zones). The regions match the locations where elderly patients develop white matter rarefaction, so-called leukoaraiosis.

Blood oxygen level-dependent (BOLD) magnetic resonance (MR) imaging enables non-invasive spatial mapping of changes in cerebral blood flow (CBF). By applying a vasodilatory stimulus (such as inhaled CO2) during BOLD MR imaging, one can measure cerebral vasodilatory capacity. "Cerebrovascular reactivity" (CVR) is defined as the change in CBF per unit of vasodilatory stimulus. Vasodilatory capacity is clinically important as vasodilatation is a mechanism by which the brain maintains constant CBF despite reductions in cerebral perfusion pressure.ii Patients with arterial narrowing commonly demonstrate a paradoxical response: vasodilatory stimulus-induced reduction of BOLD MR signal. BOLD MR depends on CBF but on other factors too. Does a reduction of BOLD MR signal indicate a decrease in flow? Does BOLD MR CVR correlate with CVR measured using arterial spin labeling (ASL) MR? I studied thirty-eight patients with stenosis of brain-supplying arteries and found that the BOLD CVR and ASL CVR results correlate strongly (R=0.83, P<0.0001 for cerebral hemispheric gray matter). The second study aimed to determine whether preoperative CVR predicts the hemodynamic effect of extracranial-intracranial bypass surgery. Whereas prior studies relied on right-left interhemispheric CVR asymmetry indices, this study used “absolute” CVR from each hemisphere. I studied twenty-five patients with intracranial arterial stenosis. I found that the group with normal pre-operative CVR showed no change in CVR following bypass surgery (0.22% ± 0.05% to 0.22% ± 0.01% (mean ± SD)(P=0.881)), the group with reduced pre-operative CVR demonstrated an improvement (0.08% ± 0.05% to 0.21 ± 0.08% (mean ± SD)(P<0.001)), and the group with paradoxical pre-operative CVR demonstrated the greatest improvement (-0.04% ± 0.03% to 0.27% ± 0.03% (P=0.028)). ii Patients with arterial narrowing commonly demonstrate a paradoxical response: vasodilatory stimulus-induced reduction of BOLD MR signal. BOLD MR depends on CBF but on other factors too. Does a reduction of BOLD MR signal indicate a decrease in flow? Does BOLD MR CVR correlate with CVR measured using arterial spin labeling (ASL) MR? I studied thirty-eight patients with stenosis of brain-supplying arteries and found that the BOLD CVR and ASL CVR results correlate strongly (R=0.83, P<0.0001 for cerebral hemispheric gray matter). The second study aimed to determine whether preoperative CVR predicts the hemodynamic effect of extracranial-intracranial bypass surgery. Whereas prior studies relied on right-left interhemispheric CVR asymmetry indices, this study used “absolute” CVR from each hemisphere. I studied twenty-five patients with intracranial arterial stenosis. I found that the group with normal pre-operative CVR showed no change in CVR following bypass surgery (0.22% ± 0.05% to 0.22% ± 0.01% (mean ± SD)(P=0.881)), the group with reduced pre-operative CVR demonstrated an improvement (0.08% ± 0.05% to 0.21 ± 0.08% (mean ± SD)(P<0.001)), and the group with paradoxical pre-operative CVR demonstrated the greatest improvement (-0.04% ± 0.03% to 0.27% ± 0.03% (P=0.028)). The third study arose from an unexpected observation: paradoxical reactivity in the white matter of young healthy subjects. I evaluated healthy subjects using BOLD CVR and ASL CVR, transformed all CVR maps into a common brain space, and generated composite maps of CVR. Composite maps confirmed regions of significant paradoxical iii reactivity in the white matter. These regions may represent the physiological correlate of previously anatomically defined border-zones (watershed zones). The regions match the locations where elderly patients develop white matter rarefaction, so-called leukoaraiosis.

L'encéphalopathie associée au sepsis (EAS) est définie comme un dysfonctionnement cérébral diffus induit par une réponse systémique à une infection. Chez les patients septiques, l'imagerie par résonance magnétique (IRM) a indiqué à la fois des anomalies de la substance grise (SG) et blanche (SB) associées à des troubles cognitifs graves, y compris le delirium. Pour améliorer notre compréhension des changements hémodynamiques, métaboliques et structuraux associés au sepsis, différentes séquences d'IRM ont été réalisées chez des rats ayant subi une injection ip de solution saline ou de lipopolysaccharide bactérien (LPS) 2,5h plus tôt ou une ligature et ponction caecale 24h plus tôt. Après ip LPS, l'IRM de contraste de phase a été réalisée pour étudier le flux des artères cérébrales antérieures et moyennes et le marquage des spins artériels (ASL) pour étudier la perfusion des structures cérébrales de la SB et SG. Des séquences d'imagerie par diffusion pondérée (DWI) ont été utilisées pour évaluer les changements structurels. Après la chirurgie CLP, ASL a été utilisé pour étudier les changements de la microcirculation. L'imagerie pondérée en T2, l'imagerie du tenseur de diffusion (DTI) et les statistiques spatiales basées sur les faisceaux (TBSS) ont été réalisées pour caractériser les événements structurels dans différentes structures cérébrales. Après imagerie, les animaux ont été sacrifiés et leur cerveau a été traité pour l'histologie afin de détecter l'enzyme synthétisant les prostaglandines vasoactives cyclooxygénase-2 (COX-2) et le canal hydrique astrocytaire aquaporin-4 (AQP4) dont l'expression peut être régulée à la hausse, évaluer la présence d'immunoglobulines périvasculaires (Ig) indiquant une rupture de la barrière hémato-encéphalique (BHE) et étudier la morphologie des glies puisque la microglie et l’astroglie changent de morphologie lors des conditions inflammatoires. L'IRM n'a indiqué aucun changement hémodynamique dans la substance grise après l'administration de ip LPS, alors qu'une perfusion cérébrale accrue a été montrée au niveau du corps calleux comme indiqué par l'ASL. DTI a indiqué une augmentation de la diffusion des molécules d’eau parallèlement aux fibres du corps calleux. Ces changements étaient accompagnés d'une dégradation de BHE dans la SB ainsi que la substance grise corticale et striatale adjacente tel est indiqué par la présence périvasculaire d'IgG, sans aucun changement majeur de COX-2 vasculaire ou de morphologie des glies du coprs calleux. Le dysfonctionnement du SNC induit par le sepsis a résulté en une augmentation du contraste pondéré en T2 dans le cortex, le striatum et la base du cerveau, une diminution de la perfusion sanguine dans le cortex et une augmentation de la diffusion hydrique du corps calleux et du striatum ventral. Ces changements ont été associés dans la SB à des modifications de la morphologie des glies et dans la substance grise à une expression constitutive de COX-2 et AQP4 plus faible dans le cortex cérébral. La comparaison entre CLP ayant subit ou non une IRM sous anesthésie à l'isoflurane a montré une réponse inflammatoire réduite tel est indiqué par l'expression de COX- 2, une activation réduite des glies ainsi qu’une lésion réduite de la BHE dans le CLP subissant une IRM sous anesthésie. Collectivement, nos résultats suggèrent que des changements hémodynamiques peuvent survenir en l'absence de flux altéré dans les artères irriguant le cerveau antérieur. Ensuite, l'altération de la structure de la SB est une étape précoce de la pathogenèse de l’EAS qui peut résulter soit de la dégradation de la BHE, soit de l'activation des glies. Cette étude sous-tend l'effet délétère d'une seule exposition à l'anesthésie à l'isoflurane qui peut être atténuée par une seconde exposition chez les rats ayant subi une laparotomie ainsi que les effets de l'inflammation systémique induite par le CLP sur les glies pouvant être atténués par imagerie sous anesthésie à l'isoflurane. / Sepsis-associated encephalopathy (SAE) refers to central nervous system dysfunction during the systemic inflammatory response to infection. In septic patients with encephalopathy MRI has indicated both gray and white matter abnormalities that were associated with worse cognitive outcome including delirium. To improve our understanding of sepsis-associated hemodynamic, metabolic, and structural changes, different MRI sequences were performed in rats that either underwent an i.p injection of saline or bacterial lipopolysaccharide (LPS) 2.5h earlier or cecal ligation and puncture (CLP) 24h earlier. After ip LPS, phase contrast MRI was performed to study anterior and middle cerebral arteries flow and Arterial Spin Labeling (ASL) to study perfusion of white and grey matter brain structures. Diffusion Weighted Imaging (DWI) sequences was used to assess structural changes. After CLP surgery, ASL was used to study microcirculation changes. T2-Weighted Imaging, Diffusion Tensor Imaging (DTI) and tract-based spatial statistics (TBSS) were performed to characterize structural events in different brain structures. After imaging, animals were sacrificed and their brains processed for histology to detect the vasoactive prostaglandin-synthesizing enzyme cyclooxygenase-2 (COX-2) and the astrocytic aquaporin-4 water channel (AQP4) the expression of which can be upregulated during inflammation, to assess the presence of perivascular immunoglobulins (Ig) indicating blood-brain barrier (BBB) leakage and to study glia cell morphology as both microglia and astrocytes are known to change their morphology in inflammatory conditions. Magnetic resonance rat brain imaging indicated no hemodynamic changes in the grey matter after ip LPS administration while an increased CBF was shown in corpus callosum white matter as indicated by ASL. DTI indicated increased water diffusion parallel to fibers of the corpus callosum white matter. These changes were accompanied by BBB breakdown in the white matter and adjacent cortical and striatal grey matter as indicated by the perivascular presence of IgG, but no major changes in vascular COX-2 or white matter glia cell morphology. CLP induced sepsis-associated CNS dysfunction resulted in higher T2-weighted contrast intensities in the cortex, striatum and base of the brain, decreased blood perfusion distribution to the cortex and increased water diffusion in the corpus callosum and ventral striatum compared to sham surgery. These changes were associated in the white matter with modifications in glia cells morphology and in the grey matter with lower expression of constitutive COX-2 expression and AQP4 in the cerebral cortex. The comparison between CLP that underwent or not MRI under isoflurane anesthesia indicated reduced inflammatory response as indicated by COX-2 expression, reduced glia activation and reduced BBB damage in CLP that underwent MRI under isoflurane anesthesia. Collectively, our results suggest that hemodynamic changes may occur in the absence of altered flow in forebrain irrigating arteries. Then, altered white matter structure is an early step in SAE pathogenesis that may result either from BBB breakdown or glial cells activation. This study underlies the deleterious effects of a single exposure to isoflurane anesthesia that may be mitigated by a second exposure in sham-operated rats and the effects of CLP-induced systemic inflammation on glial cells that can be attenuated by imaging under isoflurane anesthesia.

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.

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