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Thesis (M.Eng.). / Written for the Dept. of Biomedical Engineering & Montreal Neurological Institute. Title from title page of PDF (viewed 2008.05/13). Includes bibliographical references.

Thesis (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2005. / Not Embargoed. Vita. Bibliography: 182-204.

La tomographie par émission de positons au 18F-Fluorodésoxyglucose (TEP au 18F-FDG) est une technique d’imagerie permettant de quantifier le métabolisme glycolytique cérébral. L’objectif de nos travaux de thèse était d’essayer de caractériser au mieux les modifications cérébrales liées au vieillissement, y compris la partie possiblement liée à des dysfonctions vasculaires, grâce à une analyse quantitative tridimensionnelle voxel-à-voxel des images de TEP au 18F-FDG. Nos travaux montrent, tout d’abord, qu’il existe un intérêt pratique à utiliser un logiciel de normalisation spatial particulier (BM : Block Matching) pour l’analyse quantitative cérébrale, au moins pour la fabrication de modèles anatomiques (« template ») adaptés à chaque population étudiée. Cet intérêt a été tout d’abord montré pour localiser des foyers épileptiques temporaux, puis pour quantifier l’impact de l’âge sur le métabolisme cérébral (détermination plus précise des aires cérébrales affectées). Avec cette méthode, il est possible d’observer une diminution du métabolisme cérébral tout au long de la vie, en particulier dans certaines aires frontales. Nous avons essayé de déterminer la composante du vieillissement cérébral qui est possiblement liée à une dysfonction vasculaire et qui serait donc susceptible d’être traitée ou prévenue par des thérapeutiques vasculaires appropriées. Dans ce domaine de recherche, nous avons pu montrer que les anomalies micro-vasculaires de la substance blanche, appelées leucoaraïose, étaient associées à une diminution du métabolisme de la substance grise, en particulier au niveau frontal. Cet effet était indépendant de l’effet spécifique de l’âge et du phénomène d’atrophie corticale. Enfin, dans une population de patients âgés et à forte prévalence d’hypertension artérielle, nous avons montré que la pression artérielle était étroitement corrélée au remodelage métabolique cérébral, en particulier lorsque cette pression est mesurée au niveau central et lorsque l’on tient compte de la pression différentielle, avec alors une valeur seuil de 50 mmHg. Le vieillissement cérébral global et l’accélération qui peut être liée à des facteurs vasculaires sont des données qui peuvent être estimées en TEP au 18F-FDG, avec une méthode d’analyse quantitative voxel-à-voxel adaptée. Cette identification pourrait peut-être guider la prescription de traitements vasculaires appropriés et aussi, aider à différencier ces atteintes liées à l’âge ou d’origine vasculaire des autres maladies cérébrales. / 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) is a brain-imaging technique allowing brain glycolytic metabolism to be quantified. The aim of this doctoral thesis work was to try to better characterize the aging-related changes in brain metabolism, including the part with a possible vascular origin, thanks to a three-dimensional voxel-based quantitative analysis of 18F-FDG PET images. Our work shows firstly that there is a clear advantage to use a particular spatial normalization software (BM: Block Matching) for the brain quantitative analysis, at least for the providing of templates adapted to each study population. This advantage was shown, initially, for the localization of temporal epileptic foci and thereafter, for quantifying the age-related changes in brain metabolism (enhanced determination of the involved brain areas). With this method, a decrease in brain metabolism could be documented throughout the life especially within certain frontal areas. In addition, we tried to determine the component of cerebral aging, which might be of a vascular origin and thus, susceptible to be treated or prevented by vascular treatments. In this research field, we have shown that microvascular abnormalities, setting within white-matter and called leukoaraiosis, were associated with a decrease in the grey-matter metabolism, in particular within certain frontal areas. This effect was independent of the inherent effect of age and of cortical atrophy. Finally, in a population of older patients with a high prevalence of hypertension, we showed that the blood pressure level was correlated to a brain metabolic remodeling, especially when this pressure was measured at central level and when considering the pulse pressure and a threshold value of 50 mmHg. The global cerebral aging and its acceleration in relation to vascular factors may be assessed by 18F-FDG PET when using an adapted voxel-based quantitative method. This assessment could potentially be useful for the monitoring of vascular treatments and for differentiating the aging- and vascular-related metabolic changes to those corresponding to brain diseases of other origins.

Yes / Venous abnormalities contribute to the pathophysiology of several neurological conditions. This paper reviews the literature regarding venous abnormalities in multiple sclerosis (MS), leukoaraiosis, and normal-pressure hydrocephalus (NPH). The review is supplemented with hydrodynamic analysis to assess the effects on cerebrospinal fluid (CSF) dynamics and cerebral blood flow (CBF) of venous hypertension in general, and chronic cerebrospinal venous insufficiency (CCSVI) in particular.CCSVI-like venous anomalies seem unlikely to account for reduced CBF in patients with MS, thus other mechanisms must be at work, which increase the hydraulic resistance of the cerebral vascular bed in MS. Similarly, hydrodynamic changes appear to be responsible for reduced CBF in leukoaraiosis. The hydrodynamic properties of the periventricular veins make these vessels particularly vulnerable to ischemia and plaque formation.Venous hypertension in the dural sinuses can alter intracranial compliance. Consequently, venous hypertension may change the CSF dynamics, affecting the intracranial windkessel mechanism. MS and NPH appear to share some similar characteristics, with both conditions exhibiting increased CSF pulsatility in the aqueduct of Sylvius.CCSVI appears to be a real phenomenon associated with MS, which causes venous hypertension in the dural sinuses. However, the role of CCSVI in the pathophysiology of MS remains unclear.

yes / BACKGROUND AND PURPOSE Aging of the healthy brain is characterized by focal or nonfocal white matter (WM) signal abnormality (SA) changes, which are typically detected as leukoaraiosis (LA). Hypertension is a risk factor for WM lesion formation. This study investigated whether LA might be associated with increased cerebrospinal fluid (CSF) pulsatility linked to arterial hypertension. METHODS A total of 101 individuals without neurologic diseases (53 females and 48 males) aged between 18 and 75 years underwent 3T brain MRI with cine phase contrast imaging for CSF flow estimation, after providing their informed consent. LA was defined as the presence of focal T2 WM SA changes and/or nonfocal uniform areas of signal increase termed dirty appearing white matter (DAWM). Relevant information relating to cardiovascular risk factors was also collected. RESULTS When controlled for age and hypertension, significant partial correlations were observed between: DAWM volume and: net negative flow (r = –.294, P = .014); net positive flow (NPF) (r = .406, P = .001); and peak positive velocity (r = .342, P = .004). Multiple linear regression analysis revealed DAWM volume to be significantly correlated with CSF NPF (P = .019) and hypertension (P = .007), whereas T2 WM SA volume was only significantly correlated with age (P = .002). Combined DAWM and T2 WM SA volumes were significantly related with age (P = .001) and CSF peak negative velocity (P = .041). CONCLUSIONS Rarefaction of WM leading to LA is a multifactorial process, in which formation of DAWM induced by hypertension and increased aqueductal CSF pulsatility, may play a contributory role. These two factors appear to act independently of each other in a process that is independent of age.

White matter changes (WMC) seen on CT and MRI brain scans of healthy subjects and of vascular or dementia patients are strongly associated with age. Their pathogenesis is still under debate, and associations with vascular risk factors have varied according to studies. Their prognostic meaning, both in the general population and in stroke patients, is also not completely established. I systematically reviewed the literature on prevalence and associations of WMC and then evaluated CT and MRI scans of the first 8 years of a population-based study of all strokes and TIA in Oxfordshire (OXVASC). In this population I researched sex and age-specific associations between WMC and different types of strokes (TOAST), different components of blood pressure, and possible vascular risk factors. I also looked into their prognostic meaning for stroke recurrence and outcome, cognitive performance and mortality. 1840 patients were assessed by MRI (520) and/or CT (1717). White matter changes were independently associated with the lacunar type of stroke. The association with hypertension was confirmed (using 10 years of pre-morbid blood pressure readings), and it was particularly strong in the younger patients, mainly for diastolic hypertension. There was no association with blood pressure variability and peripheral pulse pressure. Hypercholesterolaemia, diabetes, smoking, ischaemic heart disease, carotid stenosis and atrial fibrillation were not associated with white matter changes. There was also no association with gender. Severe WMC posed a higher risk of disability and cognitive impairment at one year from the stroke, and of death in the following 10 years. This is the first study on white matter changes associations and on their prognostic meaning, to be set in a large population-based cohort of stroke and TIA. I confirmed the association between white matter changes and higher blood pressure, in particular diastolic hypertension. I also showed the association with lacunar type of stroke to be independent from vascular risk factors, and WMC to reduce life expectancy and functional and cognitive outcome of patients with stroke.

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.

yes / To determine whether jugular venous reflux (JVR) is associated with cerebral white matter changes (WMCs) in individuals with Alzheimer's disease (AD), we studied 12 AD patients 24 mild cognitive impairment (MCI) patients, and 17 elderly age- and gender-matched controls. Duplex ultrasonography and 1.5T MRI scanning was applied to quantify cerebral WMCs [T2 white matter (WM) lesion and dirty-appearing-white-matter (DAWM)]. Subjects with severe JVR had more frequently hypertension (p = 0.044), more severe WMC, including increased total (p = 0.047) and periventricular DAWM volumes (p = 0.008), and a trend for increased cerebrospinal fluid volumes (p = 0.067) compared with the other groups. A significantly decreased (65.8%) periventricular DAWM volume (p = 0.01) in the JVR-positive AD individuals compared with their JVR-negative counterparts was detected. There was a trend for increased periventricular and subcortical T2 WMC lesion volumes in the JVR-positive AD individuals compared with their JVR-negative counterparts (p = 0.073). This phenomenon was not observed in either the control or MCI groups. In multiple regression analysis, the increased periventricular WMC lesion volume and decreased DAWM volume resulted in 85.7% sensitivity and 80% specificity for distinguishing between JVR-positive and JVR-negative AD patients. These JVR-WMC association patterns were not seen in the control and MCI groups. Therefore, this pilot study suggests that there may be an association between JVR and WMCs in AD patients, implying that cerebral venous outflow impairment might play a role in the dynamics of WMCs formation in AD patients, particularly in the periventricular regions. Further longitudinal studies are needed to confirm and validate our findings.