Imagerie multimodale des corrélats vasculaires du vieillissement cérébral

RÉSUMÉ Plusieurs décennies de recherche ont permis de démontrer que le vieillissement a des effets sur une multitudes de composantes du cerveau. En particulier, des preuves s'accumulent à l'effet qu'il existe un lien entre le fonctionnement du cerveau au niveau cognitif et la santé du système vasculaire, notamment le débit sanguin cérébral (DSC) qui diminue avec l'âge, ainsi que la santé cardiorespiratoire qui pourrait corréler à la performance cognitive selon certaines études. Plusieurs techniques d'imagerie cérébrale couramment utilisées en recherche, telles que le signal dépendant du niveau d'oxygénation du sang en imagerie par résonance magnétique (BOLDIRM), se basent sur les corrélats vasculaires de l'activité des neurones. Cela en fait des outils propices pour l'étude des effets vasculaires du vieillissement, qui influencent directement les signaux mesurés. Cette thèse a utilisé plusieurs techniques d'imagerie cérébrale basées sur l'hémodynamique pour étudier les effets du vieillissement sur le cerveau à différentes échelles spatiales, chez l'humain et dans un modèle animal chez le rat. Dans un premier temps, la microscopie biphotonique a été utilisée pour mesurer la vitesse des globules rouges, le diamètre et la densité des capillaires ainsi que l'hématocrite local dans près de 1000 capillaires chez 12 rats Long-Evans jeunes (3 mois) et 12 rats âgés (24 mois) anesthésiés. Il a été mesuré que la vitesse des globules rouges et le diamètre étaient plus élevés dans les capillaires de rats âgés (par 48 et 7% respectivement), tandis que l'hématocrite et la densité volumiques des capillaires étaient plus faibles (par 32 et 20%). Ces résultats suggèrent que la diminution du DSC avec l'âge serait surtout attribuable à une baisse de densité vasculaire. En second lieu, l'IRM et la spectroscopie résolue en temps de vol ont permis de mesurer le débit, l'oxygénation (sO2) et la concentration totale d'hémoglobine (HbT) dans les cerveaux d'humains jeunes (18-30 ans) et âgés (62-72 ans), en plus de la réponse à une tâche cognitive de Stroop en termes de BOLD et de DSC. La capacité cardiorespiratoire des sujets et été mesurée par un test de VO2max. Nous avons mesuré, dans le cortex préfrontal gauche sollicité par la tâche de Stroop, des valeurs plus faibles de DSC (par 19%), sO2 (par 6%) et HbT (par 21%) chez les sujets âgés. Dans le groupe âgé, les mesures de sO2 étaient corrélées à la performance cognitive dans la tâche Stroop ainsi qu'au VO2max, mais pas celles de DSC ni de HbT. Ces résultats suggèrent un effet protecteur de l'exercice physique sur la santé cognitive dans le vieillissement, dont les mécanismes seraient liés à une amélioration de l'oxygénation cérébrale. Enfin, les mêmes groupes de rats jeune et âgé ont été soumis à un stimulus vasodilatateur, l'hypercapnie, afin de mesurer la réponse hémodynamique à l'aide de----------ABSTRACT Several decades of research have demonstrated that aging affects a multitude of components in the brain. In particular, evidence is accumulating on the relation between brain function and vascular health, including cerebral blood flow (CBF), which decreases with age, and cardiopulmonary health which could correlate with cognitive performance according to some studies. Several brain imaging techniques commonly used in research, such as the blood oxygenation level dependent signal in magnetic resonance imaging (BOLD-MRI), are based on the vascular correlates of neural activity. This makes them suitable tools for the study of the vascular effects of aging, which directly influence the measured signals. This thesis used several imaging modalities based on hemodynamics to study the effects of aging on the brain at different spatial scales, in humans and in an animal model, the rat. Initially, two-photon microscopy was used to measure the velocity of red blood cells (RBCs), the diameter and the density of capillaries and the local hematocrit in nearly 1000 capillaries in 12 young (3 months-old) and 12 aged anesthetized Long-Evans rats (24 months-old). We measured higher RBCs velocity and diameter in the capillaries of aged rats (by 48 and 7 % respectively), while the hematocrit and volumetric capillary density were lower (by 32 and 20 %). These results suggest that the decrease in CBF with age is due primarily to a decrease in vascular density. Second, MRI and time-resolved spectroscopy were used to measure the CBF, oxygenation (sO2) and total hemoglobin concentration (HbT) in the brains of young (18-30 years-old) and elderly (62-72 years-old) humans, in addition to the response to a cognitive Stroop task in terms of BOLD and CBF. Cardiorespiratory fitness was measured by a VO2max test. In the left prefrontal cortex activated by the Stroop task, we measured lower values of CBF (by 19%), sO2 (by 6%) and HbT (by 21%) in the elderly. In the older group, measures of sO2 were correlated with Stroop task cognitive performance and with VO2max, while CBF and HbT were not. These results suggest a protective effect of physical activity on cognitive health in aging, mediated by an improvement in cerebral oxygenation. Finally, the same groups of young and old rats were subjected to a vasodilating stimulus, hypercapnia, for measuring the hemodynamic response with several imaging modalities. The data demonstrated a decrease in the hemodynamic response to hypercapnia in terms of CBF, HbT and HbO (oxygenated hemoglobin) in aged rats, suggesting decreased vascular reactivity. The vessels' compliance could also be reduced with age, as the ratio o

An exploration of the effect of hemodynamic changes due to normal aging on the fNIRS response to semantic processing of words

Like other neuroimaging techniques assessing cerebral blood oxygenation, near-infrared spectroscopy (NIRS) has been applied in many neurocognitive studies. With NIRS, neural activation can be explored indirectly via hemodynamic changes in the imaged region. In studies of aging, changes in baseline physiology and brain anatomy confound NIRS measures seeking to investigate age-related changes in neuronal activity. The field is thus hampered by the complexity of the aging process itself, and statistical inferences from functional data acquired by optical imaging techniques must be interpreted with care. Multimodal integration of NIRS with both structural and baseline physiological assessments is crucial to avoid misinterpreting neuroimaging signals. In this study, a combination of two different optical techniques, anatomical MRI and Arterial Spin Labeling (ASL), was used to investigate age-related changes in activation during a lexical-semantic processing task. Quantitative analysis revealed decreased baseline oxyhemoglobin and cerebral blood flow in the older adults. Using baseline physiology measures as regressors in the investigation of functional concentration changes when doing analyses of variance, we found significant changes in task-induced areas of activity. In the right hemisphere, more significant age-related activity was observed around the junction of the inferior frontal gyrus and inferior precentral sulcus, along with engagement of Wernicke's area. In the left hemisphere, the degree and extent of frontal activation, including the dorsolateral prefrontal cortex and inferior frontal gyrus, differed between age groups. Measuring background physiological differences and using their values as regressors in statistical analyses allowed a more appropriate, age-corrected understanding of the functional differentiations between age groups. Age-corrected baselines are thus essential to investigate which components of the NIRS signal are altered by aging

Chronic cranial windows for long term multimodal neurovascular imaging in mice

Chronic cranial windows allow for longitudinal brain imaging experiments in awake, behaving mice. Different imaging technologies have their unique advantages and combining multiple imaging modalities offers measurements of a wide spectrum of neuronal, glial, vascular, and metabolic parameters needed for comprehensive investigation of physiological and pathophysiological mechanisms. Here, we detail a suite of surgical techniques for installation of different cranial windows targeted for specific imaging technologies and their combination. Following these techniques and practices will yield higher experimental success and reproducibility of results.R21 EY030727 - NEI NIH HHS; R01 NS108472 - NINDS NIH HHS; R01 NS057198 - NINDS NIH HHS; K99 AG063762 - NIA NIH HHS; R01 DA050159 - NIDA NIH HHS; R01 EB021018 - NIBIB NIH HHS; R01 MH111359 - NIMH NIH HHSPublished versio

Baseline oxygen consumption decreases with cortical depth

The cerebral cortex is organized in cortical layers that differ in their cellular density, composition, and wiring. Cortical laminar architecture is also readily revealed by staining for cytochrome oxidase—the last enzyme in the respiratory electron transport chain located in the inner mitochondrial membrane. It has been hypothesized that a high-density band of cytochrome oxidase in cortical layer IV reflects higher oxygen consumption under baseline (unstimulated) conditions. Here, we tested the above hypothesis using direct measurements of the partial pressure of O2 (pO2) in cortical tissue by means of 2-photon phosphorescence lifetime microscopy (2PLM). We revisited our previously developed method for extraction of the cerebral metabolic rate of O2 (CMRO2) based on 2-photon pO2 measurements around diving arterioles and applied this method to estimate baseline CMRO2 in awake mice across cortical layers. To our surprise, our results revealed a decrease in baseline CMRO2 from layer I to layer IV. This decrease of CMRO2 with cortical depth was paralleled by an increase in tissue oxygenation. Higher baseline oxygenation and cytochrome density in layer IV may serve as an O2 reserve during surges of neuronal activity or certain metabolically active brain states rather than reflecting baseline energy needs. Our study provides to our knowledge the first quantification of microscopically resolved CMRO2 across cortical layers as a step towards better understanding of brain energy metabolism.publishedVersio

Critical food guidance from the slow food movement: The relationship barometer

The Slow Food movement embeds food guidance that encourages interaction with local food production and appreciation of local cuisine. It advocates critical thinking and actions that support the preservation of traditional food practices, as well as environmental considerations around food harvesting and processing. We begin by contextually situating Slow Food as a movement and a change agent. We then introduce a critical guidance tool called the Slow Food Relationship Barometer, developed by Fader and Mesmain from their experience in southern Vancouver Island, British Columbia. This tool is meant for use by advocacy groups and policy makers rather than individuals. It is based on the view that identifying and assessing the multiple relationships intrinsic to a local food product—from origins to the table—can reveal pathways toward its improved sustainability. We illustrate how the Relationship Barometer can be applied to the case of wild and farmed salmon, which also underlies the Slow Fish movement