Gray matter hypertrophy and thickening with obstructive sleep apnea in middle-aged and older adults

Rationale: Obstructive sleep apnea causes intermittent hypoxemia, hemodynamic fluctuations, and sleep fragmentation, all of which could damage cerebral gray matter that can be indirectly assessed with neuroimaging. Objectives: To investigate whether markers of obstructive sleep apnea severity are associated with gray matter changes among middle-aged and older individuals. Methods: Seventy-one subjects (ages: 55 to 76; apnea–hypopnea index: 0.2 to 96.6 events/h) were evaluated with magnetic resonance imaging. Two techniques were used: 1) voxel-based morphometry, which measures gray matter volume and concentration; 2) FreeSurfer automated segmentation, which estimates the volume of predefined cortical/subcortical regions and cortical thickness. Regression analyses were performed between gray matter characteristics and markers of obstructive sleep apnea severity (hypoxemia, respiratory disturbances, sleep fragmentation). Measurements and Main Results: Subjects had few symptoms, i.e. sleepiness, depression, anxiety and cognitive deficits. While no association was found with voxel-based morphometry, FreeSurfer revealed increased gray matter with obstructive sleep apnea. Higher levels of hypoxemia correlated with increased volume and thickness of the left lateral prefrontal cortex as well as increased thickness of the right frontal pole, the right lateral parietal lobules, and the left posterior cingulate cortex. Respiratory disturbances positively correlated with right amygdala volume while more severe sleep fragmentation was associated with increased thickness of the inferior frontal gyrus. Conclusions: Gray matter hypertrophy and thickening were associated with hypoxemia, respiratory disturbances, and sleep fragmentation. These structural changes in a group of middle-aged and older individuals may represent adaptive/reactive brain mechanisms attributed to a presymptomatic stage of obstructive sleep apnea

Brainstem changes associated with increased muscle sympathetic drive in obstructive sleep apnoea

Obstructive sleep apnoea (OSA) is associated with significantly increased bursts of muscle sympathetic nerve activity (MSNA), leading to hypertension and increased cardiovascular morbidity. The underlying mechanism responsible for this sympathoexcitation is unknown. The aim of this investigation was to determine brainstem sites that contribute to this increased on-going muscle vasoconstrictor drive. We measured regional grey matter volume using voxel-based morphometry of T1-weighted anatomical images in 20 subjects with OSA and 19 healthy age-matched controls. We also performed concurrent recordings of MSNA and Blood Oxygen Level Dependent (BOLD) signal intensity of the brainstem, using high-resolution functional magnetic resonance imaging, in 15 subjects with OSA and 15 controls. OSA subjects had significantly elevated MSNA, which was correlated to altered BOLD signal intensity changes in the dorsolateral pons, rostral ventrolateral medulla, medullary raphe and midbrain. The medullary raphe, rostroventrolateral medulla and dorsolateral pons also had significantly increased grey matter volumes in subjects with obstructive sleep apnoea compared with controls. Furthermore, we also found that obstructive sleep apnoea was associated with increases in grey matter volume in the region of the hypoglossal nucleus. These data suggest that the elevated muscle vasoconstrictor drive in obstructive sleep apnoea may result from functional and anatomical changes within the dorsolateral pons, rostroventrolateral medulla and medullary raphe. These brainstem regions are known to modulate sympathetic output either directly or indirectly via sympathetic preganglionic neurons within the spinal cord. In addition, the known increase in genioglossus muscle activity in OSA may reflect the increase in grey matter volume of the hypoglossal nucleus

Effet du traitement par pression positive continue sur les changements de flot sanguin cérébral dans l’apnée obstructive du sommeil

L'apnée obstructive du sommeil (AOS) est un problème de santé important, affectant jusqu’à 38% de la population générale et augmentant en prévalence avec l’âge. L'AOS mène à une hypoxémie intermittente, une fragmentation du sommeil et des changements de flot sanguin qui peuvent provoquer des dommages vasculaires et neuronaux. Récemment, des anomalies de flot sanguin cérébral (FSC) mesurées à l’éveil ont été observées chez les adultes présentant de l’AOS sévère. On ne sait toutefois pas si ces anomalies s’accentuent avec le temps et si le traitement de l'AOS (généralement la pression positive continue - PPC) peut diminuer ces anomalies chez les personnes âgées. Ainsi, ce projet de maîtrise vise à déterminer si le traitement par PPC d’une durée de 18 mois chez les personnes apnéiques de plus de 55 ans normalise le FSC mesuré en tomographie d'émission monophotonique. De plus, ce projet vise à investiguer les effets à moyen-terme de l'AOS non traitée relativement à un groupe contrôle. Nous avons émis l’hypothèse que les sujets avec de l'AOS traitée par PPC auront des augmentations de FSC dans des régions précédemment hypoperfusées alors que les individus avec l'AOS non traitée auront des diminutions de FSC à travers le temps dans des régions sensibles à l’AOS. Nous avons évalué 12 participants contrôles et 23 participants nouvellement diagnostiqués avec de l’AOS. Ces-derniers ont été référés à une clinique d’AOS et 13 d’entre eux ont suivi un traitement par PPC. Pour l’analyse de l’imagerie par émission monophotonique, nous avons utilisé une méthode basée sur le voxel ainsi qu’une méthode d’extraction pour mesurer les changements à travers le temps dans chacun des groupes. Nous avons observé une augmentation du FSC chez le groupe traité au niveau du gyrus temporal inférieur gauche. De plus, nous avons observé des diminutions de FSC chez le groupe non traité au niveau de l’hippocampe gauche, du gyrus parahippocampal droit et du pôle temporal supérieur gauche. Aucun changement n’a été observé chez le groupe contrôle. Les diminutions de FSC observées dans le groupe non traité pourraient être causées par les conséquences de l’AOS, notamment par une combinaison de diminution du calibre vasculaire et une perte cellulaire. En éliminant ces mécanismes pathologiques, le traitement par PPC permettrait une revascularisation et une prolifération cellulaire. Puisque les régions cérébrales affectées par l’AOS dans ce projet sont associées au déclin cognitif, d’autres études sont nécessaires pour clarifier le lien entre l’AOS, son traitement et la démence.Obstructive sleep apnea (OSA) is an important health problem, affecting up to 38% of the general population and increasing in prevalence with age. OSA causes blood flow changes leading to vascular and neuronal damage. Indeed, decreases in regional cerebral blood flow (rCBF) have been observed in OSA. The treatment of OSA is continuous positive airway pressure (CPAP). CPAP treatment has been associated with increases in rCBF. However, studies evaluating rCBF in OSA were predominantly composed of middle-aged people. Therefore, we don’t know if these results could be generalized to the aging population. Thus, this master's project aims to determine whether an 18-month CPAP treatment for apneic individuals older than 55 years normalizes the rCBF measured in single-photon emission computed tomography. In addition, this project aims to investigate the longitudinal effects of untreated OSA relative to a control group. We hypothesized that treated subjects will have rCBF increases in previously hypoperfused regions while individuals with untreated OSA will have decreased rCBF over time in OSA-sensible regions. We evaluated 12 control participants and 23 newly diagnosed participants with OSA. The latter were referred to an OSA clinic and 13 of them followed a CPAP treatment. For the analysis of single photon emission imaging, we used a voxel-based method and an extraction method to measure changes over time in each of the groups. We observed an increased rCBF in the treated group in the left inferior temporal gyrus. In addition, we observed decreased rCBF in the untreated group in the left hippocampus, the right parahippocampal gyrus, and left superior temporal pole. No change was observed in the control group. The decreased rCBF seen in the untreated group could be caused by the consequences of OSA, including a combination of decreased blood vessels caliber and cell loss. By eliminating these pathological mechanisms, CPAP treatment would allow revascularization and cell proliferation. Since brain regions affected by OSA in this project are associated with cognitive decline, further studies are needed to clarify the link between OSA, its treatment, and dementia

Značajke neuroinflamacije tijekom kronične intermitentne hipoksije na mišjem modelu opstruktivne apneje spavanja [Characteristics of neuroinflammation during chronic intermittent hypoxia, a mouse model of obstructive sleep apnea]

Obstructive sleep apnea (OSA) is a chronic, underdiagnosed, multi-system disease characterized by intermittent hypoxia (IH) and sleep fragmentation that occurs due to periodic upper airway obstruction during sleep. OSA often presents with multiple comorbidities, the most important of which are cardiovascular diseases, stroke and Alzheimer's dementia (AD). Detailed research is needed to confirm the hypothesis that neuroinflammation is the common ethiopathogenic background for both OSA and AD. The study focused on establishing the properties of neuroinflammation in animals exposed to IH, the mouse model of OSA. To optimize the IH model a fast and precise system was developed. Transgenic TLR2-luc-GFP mice underwent 21 days of IH (N=20) and their TLR2 expression was followed using in vivo bioluminescenc imaging (BLI), while the controls (N=6) were imaged in the same way without IH exposure. Groups of mice with and without Tlr2 gene exposed to IH (N(TLR2 IH)= 15, N(TLR2-/- IH)= 15) and their controls (N(TLR2 CTRL)= 11, N(TLR2-/- CTRL)= 8) were tested using the tail suspension test (TST), open field and Y maze. The brains were subsequently isolated and imaged ex vivo using MRI. Immunohistochemical staining for microglia (Iba1), astrocytes (GFAP) and c-Fos positive neurons was quantified. BLI showed an acute upregulation of TLR2 after IH exposure that remained elevated throughout the 21-day protocol. Bilateral hypertrophy of the hippocampal, and left motor and cingulate cortex as well as hypotrophy of the thalamus and piriform cortex were found in the TLR2 IH group. Structural changes were less pronounced in the TLR2-/- IH group in the cerebrum, while significant hypotrophic changes were found in the midbrain, pons and medulla as well as hypertrophy of the cerebellum. Behavioral and histological testing found limited effects that warrant further investigation. IH exposure caused an acute and chronic upregulation of TLR2 expression in the brain and induced structural changes that were more pronounced in animals with the functional TLR2 gene. IH caused limited functional and histological changes in the brain

Interactions between sympathetic baroreflex sensitivity and vascular transduction in males and females

The control of muscle sympathetic nerve activity (MSNA) via the baroreflex is an important mechanism of blood pressure control. Spontaneous sympathetic baroreflex sensitivity (BRS) is a tool used to examine how well the baroreflex buffers beat-to-beat changes in arterial pressure. Due to the lack of research around the baroreflex control of MSNA, it is unknown if an individual's sympathetic BRS reflects the end organ response and thus is indicative of how effective they are at regulating their blood pressure. It was hypothesised that poor baroreflex sensitivity was compensated for by enhanced vascular transduction, and vice versa. Given that sex differences are known to exist in regulatory mechanisms involved in cardiovascular control, these interactions were explored and contrasted in young males and females. In order to further our understanding of the regulatory mechanism of the sympathetic baroreflex, MSNA, blood pressure and superficial femoral artery (SFA) blood flow were measured to i) examine the stability and repeatability of measures of spontaneous sympathetic BRS, ii) examine whether vascular transduction, quantified on a beat-to-beat basis using two different approaches, were different between males and females, iii) examine the relationship between sympathetic BRS and vascular transduction, and iv) examine sympathetic BRS and vascular transduction during physiological stressors that drive increases in MSNA. Here I present evidence of sex differences in sympathetic baroreflex function in healthy young adults. Spontaneous sympathetic BRS was moderately stable in the same recording period and also when examined on different days. Recording periods of at least 5 min should be used when quantifying BRS as shorter durations can overestimate BRS values. Using the Fairfax method, sympathetic vascular transduction was significantly lower in males when compared with females. In contrast, the Briant method did not reveal sex differences in vascular transduction between males and females. Sympathetic BRS and vascular transduction was negatively correlated under resting conditions. This means that individuals with high sympathetic BRS have less effective vascular transduction during spontaneous changes in blood pressure. However, this was only apparent in young males; there was no relationship observed in females. Furthermore, resting MSNA did not predict sympathetic BRS or vascular transduction in either males or females. Finally, vascular transduction was significantly greater in males when quantified as the relationship between MSNA and leg vascular conductance during isometric handgrip and the cold pressor test. Sympathetic BRS was not different between males and females during the cold pressor test but was reset to a higher blood pressure range. Collectively, the studies conducted in this thesis provide insight into the dynamic nature of the baroreflex control of arterial pressure at rest, and during increases in muscle vasoconstrictor drive. Whilst this thesis provides evidence of sex differences in sympathetic BRS and vascular transduction, it also highlights the differences between the various approaches available for quantifying vascular transduction. The method chosen can have a profound effect on the findings regarding sex differences and the interaction vascular transduction has with sympathetic BRS

Dysfonctions cérébrales et changements neuroanatomiques dans l’apnée obstructive du sommeil chez les personnes âgées

L’apnée obstructive du sommeil (AOS) est un trouble du sommeil particulièrement prévalent dans la population âgée, qui peut se présenter par différents niveaux de sévérité. Des études épidémiologiques récentes ont montré une association entre l’AOS et l’incidence de la démence. De plus, l’AOS a été identifiée de façon répétée comme un facteur de risque d’accident vasculaire cérébral. Ces conséquences potentielles de l’AOS sur le cerveau pourraient être dues à l’hypoxémie intermittente et à la fragmentation du sommeil causées par les obstructions respiratoires répétées. Bien que l’AOS soit impliquée dans l’incidence de conséquences graves sur le cerveau, son impact sur la fonction et la structure du cerveau vieillissant reste sous-évalué. Ainsi, l’objectif de cette thèse est d’évaluer l’association entre l’AOS et sa sévérité sur le fonctionnement cérébral et la structure neuroanatomique chez des personnes âgées de plus de 55 ans. Nous avons émis l’hypothèse que les changements cérébraux chez les personnes avec AOS pourraient s’apparenter aux profils observés dans les stades précurseurs de déclin cognitif. Pour ce faire, diverses méthodes de neuroimagerie ont été utilisées pour caractériser l’ensemble du cerveau des personnes avec AOS. Le fonctionnement cérébral au repos éveillé a été évalué par le biais de la tomographie par émission monophotonique en mesurant le flot sanguin cérébral régional. La structure anatomique de la matière grise et de la matière blanche a été évaluée en imagerie par résonance magnétique. La structure de la matière grise a été évaluée grâce à diverses techniques structurelles, mesurant le volume de la matière grise et l’épaisseur corticale. La structure de la matière blanche a été évaluée avec des méthodes d’imagerie de diffusion, mesurant la diffusivité des molécules d’eau dans la matière blanche. Dans notre premier article, nous observons que l’AOS sévère, ainsi que plusieurs marqueurs de sévérité de l’AOS sont associés avec des régions d’hypoperfusion au repos éveillé. Ces réductions régionales de la perfusion cérébrales pourraient être dues à un moins bon fonctionnement des neurones et cellules gliales. Dans notre deuxième article, nous montrons que le profil régional d’hypoperfusion cérébrale diurne diffère selon que l’AOS soit observée en sommeil paradoxal ou en sommeil lent. Chez des personnes avec une sévérité plus faible d’AOS, la présence d’évènements respiratoires en sommeil paradoxal était tout de même associée avec une réduction de la perfusion cérébrale. Ceci suggère que les évènements respiratoires en sommeil paradoxal pourraient être plus dommageables pour le cerveau que ceux en sommeil lent. Nos résultats suggèrent que l’AOS entraine une réduction du fonctionnement cérébral mesuré par une réduction régionale de la perfusion cérébrale. De plus, ces articles suggèrent également que plusieurs facteurs dans l’AOS contribuent différemment aux dysfonctions cérébrales. Dans notre troisième article, nous observons que les perturbations respiratoires, la fragmentation du sommeil, mais surtout l’hypoxémie contribuent à l’hypertrophie de la matière grise. Nous suggérons qu’un processus d’œdème, ou d’autres processus réactifs et aigus pourraient être en cause dans l’augmentation de la taille de la matière grise. Ce processus pourrait également expliquer nos résultats du dernier article. Dans notre quatrième et dernier article, nous montrons que l’AOS est associée avec une réduction de la diffusivité des molécules d’eau dans la matière blanche, surtout dans les cas légers d’AOS. Un processus d’œdème intracellulaire pourrait restreindre la diffusivité des molécules d’eau dans les cellules de la matière blanche. Les résultats de cette thèse clarifient les changements cérébraux observés dans la population vieillissante avec l’AOS. Ainsi, malgré des réductions de la perfusion cérébrale suggérant un dysfonctionnement cérébral, l’AOS est également associée avec des changements de structure de la matière grise et de la matière blanche suggérant des processus réactifs et aigus. Puisque ce profil a été rapporté dans les stades précurseurs de déclin cognitif et de démence, nos résultats soulèvent l’importance d’identifier les facteurs dans l’AOS qui sont associés avec les changements cérébraux, afin d’identifier les individus à risque de conséquences cérébrales négatives. De plus, nos résultats soulèvent également l’importance d’évaluer les effets du traitement de l’AOS pour éviter ou ralentir les conséquences de celle-ci sur la santé cérébrale et cognitive.Obstructive sleep apnea (OSA) is a sleep disorder especially common in the older population, which can present itself at different levels of severity. Recent epidemiological studies showed an association between OSA and incident dementia. In addition, AOS was repeatedly identified as a risk factor for stroke. These potential consequences of OSA on the brain could be caused by intermittent hypoxemia and sleep fragmentation, which is observed following repeated respiratory obstructions. Although OSA has been implicated in the incidence of serious consequences on brain health, its impact on the function and structure of the aging brain remains unclear. Thus, the objective of this thesis was to evaluate the association between OSA as well as its severity with cerebral functioning and structure in adults aged 55 years old and over. We hypothesized that cerebral changes in individuals with OSA would be similar to profiles observed in preclinical stages of cognitive decline. In order to achieve this goal, various neuroimaging methods were used to characterize the brain of individuals with OSA as a whole. Cerebral functioning during wakeful rest was evaluated with single-photon emission computed tomography by measuring regional cerebral blood flow. Grey matter and white matter structure were evaluated with magnetic resonance imaging. Grey matter structure was assessed with structural techniques that measure grey matter volume and cortical thickness. White matter was assessed with diffusion tensor imaging that measures water molecules diffusion. In our first study, we observed that severe OSA as well as many markers associated with OSA severity were correlated with hypoperfused regions during wakeful rest. These regions of reduced cerebral perfusion could present altered neuronal and glial functioning. In our second study, we showed that the daytime regional pattern of cerebral hypoperfusion was different whether apneas and hypopneas were observed during rapid eye movement sleep or non-rapid eye movement sleep. In individuals with a milder OSA severity, respiratory events during rapid eye movement sleep were still associated with regions of hypoperfusion. This suggests that respiratory events during rapid eye movement sleep may be more detrimental to brain health than those in non-rapid eye movement sleep. Overall, these results suggest that OSA leads to an altered cerebral functioning as evidenced by decreased regional cerebral perfusion. In addition, these studies also suggest that many factors contribute differently to cerebral dysfunction in OSA. In our third study, we observed that respiratory disturbances, sleep fragmentation, and mostly hypoxemia all contributed to grey matter hypertrophy. We suggest that oedema or other reactive or acute processes could cause these increased in grey matter structure. These processes may also explain our results observed in our last study. In that fourth study, we showed that OSA is associated with reduced white matter diffusivities, especially in milder OSA cases. An intracellular oedema process may restrict the diffusion of water molecules inside cells. The results of this thesis clarify the cerebral changes observed in the aging population with OSA. Although reduced regional brain perfusion suggests cerebral dysfunctions, OSA was also associated with grey and white matter structural changes that suggest reactive and acute processes. Because this pattern was reported previously in preclinical stages of cognitive decline and dementia, our results highlight the importance of identifying individuals at higher risk of negative outcomes to brain health. In addition, our results also emphasize the importance of understanding the efficiency of treating OSA in order to prevent or slow its impact on cerebral functioning and structure

Development and application of functional MRI methods to investigate brainstem haemodynamics in the context of systemic hypertension

The selfish brain mechanism proposes that in some cases hypertension could develop as a compensatory mechanism that aims to maintain cerebral blood flow (CBF) by increasing systemic blood pressure through an increase in cardiovascular sympathetic tone. The mechanism that might trigger this hypothesised initial reduction in CBF is uncertain, but the brainstem is an important component of the central autonomic nervous system and may therefore play an important role in the development of hypertension via the selfish brain mechanism. Various techniques have been used to investigate the selfish brain mechanism in humans, including magnetic resonance imaging (MRI) methods to measure CBF and cerebrovascular reactivity (CVR). CVR quantifies the change in CBF in response to a vascular stimulus, and is related to the responsiveness, tone and functional reserve of the cerebrovascular system. This thesis aims to validate, optimise and apply a variety of MRI-based methods of quantifying human cerebrovascular function, which may then be used in future studies to further investigate the selfish brain mechanism. Firstly, methods of measuring CBF and CVR using MRI are tailored towards their application in the brainstem and the feasibility of measuring regional brainstem CBF and CVR is demonstrated. Next, existing data is explored to study the association between vertebral artery hypoplasia (VAH) and brainstem CBF in hypertensives but no statistically significant association between regional CBF, VAH and hypertension is found. Brainstem co-registration is then optimised using machine learning. The UK biobank dataset is explored to study the amplitude of low-frequency fluctuations (ALFF) in the BOLD signal, a potential surrogate index of CVR, in hypertensives. There is no statistically significant difference in the regional variation in ALFF between hypertensives and normotensives. Following this, the relationship between ALFF and CVR is investigated to validate ALFF as a surrogate marker of CVR, but no evidence to support the use of ALFF as a specific metric of CVR is demonstrated. Finally, a pilot study of functional MRI in the locus coeruleus, an important noradrenergic brainstem nucleus that is integral to the central autonomic network, is undertaken. The feasibility of mapping functional connectivity of the LC using an anatomical localiser tailored to each participant is demonstrated