Alzheimer’s disease (AD) is the most common form of dementia and is characterized by a gradual deterioration of the patients’ ability to independently perform day to day activities. Researchers have discovered significant changes in neuroanatomy, cognition and behavior that are related to the disease process of AD and researchers continue to uncover new variables, such as the presence of vascular risk factors, which may further increase our ability to understand and characterize the disease. The purpose of this study is to identify the neuroanatomical, cognitive and behavioral variables that best predict impairment of instrumental activities of daily living in individuals with probable AD. Reduced white matter integrity in the dorsolateral prefrontal cortex as well as the presence of vascular risk factors significantly predicted impairments in activities of daily living (ADLs). Executive functioning skills, typically described as frontal lobe system behaviors, were positively associated with ADLs. Further, executive functions fully mediated the relationship between frontal lobe white matter integrity and ADLs. A better understanding of the variables responsible for diminished ADLs in AD will allow researchers and clinicians to better target prevention and intervention strategies and ultimately help individuals with AD to maintain their independence for a longer duration.

A number of chronic disease and behavioural factors are recognised to increase the risk of cardiovascular and cerebrovascular diseases. These putative ???vascular??? risk factors have increasingly been recognised to increase the risk of cognitive impairment in the absence of clinically manifest ischemic events. Their relationship to structural brain changes has received limited attention. In this dissertation, I used high resolution magnetic resonance image (MRI) to examine two structural features of the brain, regional gray matter (GM) volumes and silent lacunar infarcts, and determined their association with vascular risk factors. I related these to cognitive function in both cross-sectional and longitudinal studies. The work was based on the data of three waves in two healthy cohorts drawn from the PATH Through Life Study, which is a population-based longitudinal study of ageing comprising 3 cohorts aged 20-24, 40-44, and 60-64 years, with about 2500 participants in each cohort. Random subsamples of Wave 1 of the cohort aged 60-64 years (N = 478) and Wave 2 of the 40+ cohort (aged 44-48 years) (N = 411) were examined cross-sectionally for the MRI sub-study. The MRI cohort aged 60-64 years was re-examined 4 years later in Wave 2. These studies showed that vascular risk factors are associated with lower regional GM volumes and this association varies at different ages. In adults aged 44-48 years, individual risk factors did not show a significant relationship with GM volumes, but the Framingham risk score was associated with less GM volumes in a number of brain regions, suggesting an additive effect of the risk factors. In the 60+ cohort, hypertension was independently associated with less regional GM volumes in bilateral medial frontal, right superior frontal, left superior temporal and precentral gyri. The same cohort, when examined in Wave 2, showed the negative association of hypertension with gray matter volumes to be more widespread. These associations were observed in men but not in women in either wave. Sex dimorphism was observed in the younger cohort as well, with greater GM volumes in temporal and occipital cortices, midbrain and cerebellum in men, while less GM volumes in cingulate and parietal cortices in comparison with women. Lacunar infarcts were present in 7.8 % of the 60+ cohort, and asymptomatic new lacunar lesions developed in 0.4 % per year in this group. The prevalence of lacunar infarcts was correlated with hypertension and a steeper decline in mental speed. These series of studies indicate the relationship of vascular risk factors with changes in brain structure and cognitive function in healthy middle-aged adults. It is suggested that modifying these vascular risk factors may protect the brain from silent lesions and cognitive impairment, and that intervention should begin early in life to have a major impact.

Identification of modifiable risk factors for Alzheimer’s disease (AD) is crucial in order to diminish suffering from this devastating disease. The aim of this thesis was to investigate if different aspects of glucose metabolism, insulin, fatty-acid composition or other vascular risk factors predict the future development of AD and dementia. This thesis is based on the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort, which started in 1970. A total of 2322 men at age 50 were examined with focus on vascular risk factors. The cohort was re-examined at ages 60, 71, 77, 82 and 88. Incident diagnoses of AD, vascular dementia, other dementias and cognitive impairment were assessed in 2005–2010. The risk of AD was increased in subjects with lower early insulin response measured with both an intravenous glucose tolerance test at 50 years and an oral glucose tolerance test at 71 years of age. The presence of vascular risk factors such as hypertension, obesity, hypercholesterolemia and smoking increased the risk of future vascular dementia but not of AD. Furthermore, saturated fatty acids at midlife were inversely associated with risk of AD. No evidence of a protective effect of omega-3 fatty acids against dementia was found. The susceptibility allele, APOE ε4, was the strongest individual risk factor. APOE ε4 carriers with vascular risk factors had the greatest risk of developing dementia. Low insulin response was a risk factor for AD mainly in APOE ε4 non-carriers. Disturbances in insulin and glucose metabolism, vascular risk factors and fatty acids are linked differentially to the pathogenesis of AD and vascular dementia. These observations should be considered when future clinical approaches are planned to prevent and postpone the onset of dementia. / ULSAM

A number of chronic disease and behavioural factors are recognised to increase the risk of cardiovascular and cerebrovascular diseases. These putative ???vascular??? risk factors have increasingly been recognised to increase the risk of cognitive impairment in the absence of clinically manifest ischemic events. Their relationship to structural brain changes has received limited attention. In this dissertation, I used high resolution magnetic resonance image (MRI) to examine two structural features of the brain, regional gray matter (GM) volumes and silent lacunar infarcts, and determined their association with vascular risk factors. I related these to cognitive function in both cross-sectional and longitudinal studies. The work was based on the data of three waves in two healthy cohorts drawn from the PATH Through Life Study, which is a population-based longitudinal study of ageing comprising 3 cohorts aged 20-24, 40-44, and 60-64 years, with about 2500 participants in each cohort. Random subsamples of Wave 1 of the cohort aged 60-64 years (N = 478) and Wave 2 of the 40+ cohort (aged 44-48 years) (N = 411) were examined cross-sectionally for the MRI sub-study. The MRI cohort aged 60-64 years was re-examined 4 years later in Wave 2. These studies showed that vascular risk factors are associated with lower regional GM volumes and this association varies at different ages. In adults aged 44-48 years, individual risk factors did not show a significant relationship with GM volumes, but the Framingham risk score was associated with less GM volumes in a number of brain regions, suggesting an additive effect of the risk factors. In the 60+ cohort, hypertension was independently associated with less regional GM volumes in bilateral medial frontal, right superior frontal, left superior temporal and precentral gyri. The same cohort, when examined in Wave 2, showed the negative association of hypertension with gray matter volumes to be more widespread. These associations were observed in men but not in women in either wave. Sex dimorphism was observed in the younger cohort as well, with greater GM volumes in temporal and occipital cortices, midbrain and cerebellum in men, while less GM volumes in cingulate and parietal cortices in comparison with women. Lacunar infarcts were present in 7.8 % of the 60+ cohort, and asymptomatic new lacunar lesions developed in 0.4 % per year in this group. The prevalence of lacunar infarcts was correlated with hypertension and a steeper decline in mental speed. These series of studies indicate the relationship of vascular risk factors with changes in brain structure and cognitive function in healthy middle-aged adults. It is suggested that modifying these vascular risk factors may protect the brain from silent lesions and cognitive impairment, and that intervention should begin early in life to have a major impact.

Idiopathic normal pressure hydrocephalus (INPH) is a dementia treatable by insertion of a cerebrospinal fluid shunt. It has been suggested that INPH has similar pathophysiological mechanisms as cerebrovascular disease, but the vascular risk factor (VRF) profile of INPH patients has not been assessed using a modern epidemiological approach. The cognitive symptoms of INPH resemble the symptoms of depression, but the prevalence of depression among INPH patients is unknown. In addition, few studies investigate the impact of shunting on the quality of life (QoL), and no study has investigated the impact of comorbidity on QoL in INPH patients. The objective of this dissertation was to present the VRF profile of INPH and to investigate the hypothesis that INPH may be a subgroup of vascular dementia. Additional objectives were to assess the prevalence of depression in INPH patients and to investigate the impact of shunting and comorbidities on QoL in INPH. In the first cohort, the prevalence of possible INPH was assessed through clinical and radiological examinations in patients with a transient ischemic attack (TIA), consecutively admitted to the same hospital during 2006-2008. In the second cohort, VRFs, vascular disease and QoL were analysed in INPH patients consecutively shunted 2008-2010 in five out of six neurosurgical centres in Sweden. Patients remaining after inclusion (n=176, within the age-span 60-85 years and not having dementia) were compared to population-based age- and gender-matched controls (n=368, same inclusion criteria as for the INPH patients). Assessed VRFs were: hypertension, diabetes, obesity, hyperlipidemia, psychosocial factors (stress and depression), smoking, alcohol intake, physical activity and, dietary pattern. Cardiovascular, cerebrovascular and peripheral vascular disease as well as QoL were also assessed. Parameters were assessed through questionnaires, clinical examinations, measurements, ECG and, blood samples. In the first cohort, 4% of the TIA patients had clinically and radiologically verified INPH. In the second cohort, VRFs were overrepresented among the INPH patients compared with the controls. The VRFs independently associated with INPH were: hyperlipidemia (Odds ratio (OR): 2.4, 95%CI: 1.4-4.0), diabetes (OR: 2.2, 95%CI: 1.2-3.9), obesity (OR: 5.4, 95%CI: 2.5-11.8) and, psychosocial factors (OR: 5.3, 95%CI: 3.2-8.9). When adding the VRFs that were overrepresented in INPH, although not independently (physical inactivity and hypertension), these six VRFs accounted for 24% of the INPH cases in the elderly population (population attributable risk %: 24). Depression was overrepresented in shunted INPH patients compared to the controls (46% vs. 13%, p<0.001) and the main predictor for low QoL was a coexisting depression (p<0.001). In conclusion, the results of the INPH-CRasH study are consistent with a vascular pathophysiological component of INPH and indicate that INPH may be subgroup of vascular dementia. In clinical care and research, a complete risk factor analysis as well as screening for depression and a measurement for quality of life should be included in the work-up of INPH patients. The effect of targeted interventions against modifiable VRFs and anti-depressant treatment in INPH patients should be evaluated. / Idiopatisk normaltryckshydrocefalus (INPH, från engelskans ”idiopathic normal pressure hydrocephalus”) är en neurokirurgiskt behandlingsbar demens. Behandlingen är att operera in en shunt som dränerar cerebrospinalvätska från ventriklarna. Det har föreslagits att INPH skulle kunna orsakas av liknande patofysiologiska mekanismer som vid cerebrovaskulär sjukdom, men den vaskulära riskfaktorprofilen hos INPH-patienter har aldrig undersökts i en modern epidemiologisk studie. De kognitiva symtomen vid INPH påminner om symtomen vid depression, men prevalensen av depression hos INPH-patienter är okänd. Få studier undersöker hur shuntning påverkar livskvalitet och ingen studie har undersökt hur komorbiditet påverkar livskvaliteten vid INPH. Syftet med den här avhandlingen var att undersöka den vaskulära riskfaktorprofilen hos INPH-patienter samt att utforska hypotesen att INPH skulle kunna vara en undergrupp till vaskulär demens. Ytterligare ett syfte med avhandlingen var att undersöka hur många INPH-patienter som har depression samt undersöka hur shunting och komorbiditet påverkar livskvalitet vid INPH. I den första kohorten undersöktes kliniska och radiologiska fynd som tydde på INPH hos de patienter som blivit diagnostiserade med en TIA (från engelskans: transient ischemic attack) 2006-2008 på Norrlands Universitetssjukhus i Umeå. I den andra kohorten undersöktes konsekutivt shuntade INPH-patienter 2008-2010 från fem av sex neurokirurgiska kliniker i Sverige. De patienter som inkluderades i studien (n=176, ålder: 60-85 år, ej dementa) jämfördes med köns- och åldersmatchade kontroller från normalpopulationen (n=368, samma inklusionskriterier som för INPH-patienterna). De riskfaktorer som undersöktes var: hypertension, hyperlipidemi, diabetes, fetma, psykosociala faktorer (stress och depression), rökning, alkohol, fysisk aktivitet och diet. Även kardiovaskulära och cerebrovaskulära sjukdomar undersöktes, liksom perifer vaskulär sjukdom samt livskvalitet. Datainsamling skedde genom frågeformulär, kliniska undersökningar, mätningar, EKG och blodprov. I den första kohorten hade 4% av TIA-patienterna kliniskt och radiologiskt verifierad INPH. I den andra kohorten var vaskulära riskfaktorer överrepresenterade hos INPH-patienterna jämfört med iv normalpopulationen. Hyperlipidemi (OR: 2.4, 95%CI: 1.4-4.0), diabetes (OR: 2.2, 95%CI: 1.2-3.9), fetma (OR: 5.4, 95%CI: 2.5-11.8) och psykosociala faktorer (OR: 5.3, 95%CI: 3.2-8.9) var associerade med INPH oberoende av kön, ålder och de andra riskfaktorerna. Hypertension och fysisk inaktivitet var också associerade med INPH, dock inte oberoende av övriga riskfaktorer. Sammanlagd PAR% (från engelskans: population attributable risk %) för de här sex riskfaktorerna var 24%. INPH-patienterna hade depression i högre utsträckning än kontrollerna (46% vs. 13%, p<0.001), och depression var den viktigaste prediktorn för låg livskvalitet. Resultaten tyder på att vaskulär sjukdom och vaskulära riskfaktorer är involverade i den patofysiologiska mekanismen vid INPH. INPH kan vara en undergrupp till vaskulär demens. En fullständig riskfaktoranalys och screening för depression bör ingå i den preoperativa utvärderingen såväl som i forskning på INPH-patienter, och ett mått på livskvalitet bör införas. Effekten av riktade insatser mot såväl vaskulära riskfaktorer som depression vid INPH bör utvärderas.

Les néoplasies myéloprolifératives (NMP) sont des hémopathies myéloïdes clonales, chroniques et prolifératives. Les plus fréquentes sont la polyglobulie de Vaquez et la thrombocytémie essentielle. Elles s’accompagnent de risques importants de thrombose (artérielles et veineuses) et de transformation en pathologies plus agressives (myélofibrose secondaire et leucémie aigüe). Les thromboses peuvent être la situation diagnostique de ces maladies, ou survenir au cours de la prise en charge. Le sujet de cette thèse est d’étudier la relation clinique entre NMP et thrombose. Dans un contexte de survenue de thrombose veineuse idiopathique, sans antécédent NMP, nous nous sommes intéressés à la recherche de mutation clonale chez les patients comme moyen diagnostique d’une NMP. Nous avons ainsi exploité la cohorte EDITH du CIC en prenant les patients ayant expérimentés un puis une récurrence thrombotique. A l’inverse, nous avons constitué une base de données (OBENE) des patients pris en charge pour une NMP au CHRU de Brest.Nous avons ensuite exploité cette base, en analysant la fréquence et l’impact des arythmies cardiaques auriculaires, la balance bénéfice-risque à l’utilisation des NACO, l’impact des statines sur la réduction du risque de thrombose ainsi que la fréquence et l’impact de la nonadhérence aux traitements dans les PV et TE.NMP et thromboses sont liées, il est donc nécessaire d’approfondir les connaissances de leur physiopathologie spécifique pour améliorer la prévention et le traitement des épisodes. Cette thèse amène quelques réponses àcertaines questions mais elle est surtout le point de départ de réflexion commune entre les praticiens et biologistes intéressés par ces domaines. / The myeloproliferative neoplasms (MPN) are clonal myeloid, chronic and proliferative disorders. The most frequent are polycythemia vera and essential thrombocythemia. The more frequent complications are thromboses (arterial and venous) and phenotypic evolutions (secondary myelofibrosis and acute leukemia). Thromboses can be a situation of diagnosis or observed during the followup of a MPN. This thesis is focused on the clinical link between MPN and thromboses.In a context of idiopathic venous thromboses (first event or recurrence), without medical history of MPN, we have tested patients for the most frequent MPN clonal mutations. So, we have used the informations and patients of the dedicated EDITH cohort.On the other hand, we have constituted a MPN database (OBENE) of the patients diagnosed for MPN in our Hospitalcentre. By this way, we have analysed the frequency and impact of atrial arrhythmias, the benefit-risk balance of the use of DOAC, the impact of statins to reduce the thrombotic risk and the frequency and impact of the treatment nonadherence in this population.MPN and thromboses are linked, so it is necessary to increase our knowledge of their physiopathology to improve prevention and treatment of the events. This thesis brings some answers to some questions but, she is almost the starting point of common reflexion between clinicians and biologists interested in these domains.

Au cours du vieillissement, la rigidification des artères élastiques entraine une augmentation de l'amplitude de la pression pulsée centrale, qui se propage dans la microcirculation cérébrale. De façon chronique, l’élévation anormale de la pression pulsée endommage les fonctions vasculaires et cérébrales, pouvant être impliquée dans le développement d’une déficience cognitive d’origine vasculaire. Ceci est supporté par l’observation d’anomalies cérébrovasculaires chez les individus atteints de démence vasculaire et de la maladie d’Alzheimer. De plus, les individus exposés aux facteurs de risque vasculaires (hypertension, obésité, diabète, athérosclérose), démontrent une vascularisation fragilisée, une augmentation de la pression pulsée centrale et présentent un déclin cognitif. Il est donc probable qu’en association avec l’âge, les facteurs de risque vasculaires favorisent de façon mécanistique la propagation de la pression pulsée dans la circulation cérébrale et révèlent de façon prématurée le déclin cognitif. Le lien mécanistique entre l’augmentation de la pression pulsée cérébrale, les facteurs de risque vasculaires, les dommages cérébrovasculaires et l’incidence de la démence reste à être plus clairement investigué. La présente thèse vise ainsi à étudier l’hypothèse biomécanique du rôle délétère de la pression pulsée dans la détérioration des fonctions cérébrovasculaires et cognitives, avec l’âge et en association avec les facteurs de risque vasculaires, en élucidant la cascade des événements pathologiques depuis l’élévation de la pression pulsée centrale jusqu’à l’incidence de la démence. Afin de vérifier notre hypothèse, nous avons entrepris dans une première étude d’étudier chez la souris WT, l’impact de l’augmentation in vivo d’un stress mécanique pulsatile central (par chirurgie TAC) sur la vasculature cérébrale, le tissu cérébral et les fonctions cognitives. Ce stress a été induit en parallèle dans le modèle de souris transgénique APP/PS1 de la maladie d’Alzheimer. Nous avons pu démontrer que les vaisseaux cérébraux des souris WT et APP/PS1 sont vulnérables au stress mécanique de la pression pulsée, caractérisé par une diminution de la réponse vasodilatatrice des artères piales, une raréfaction des capillaires due à une apoptose, l’incidence de micro-hémorragies, une rupture de la barrière hémato-encéphalique et une hypoperfusion cérébrale. Ces dommages cumulatifs à la microcirculation cérébrale sont associés à une inflammation cérébrale et à une diminution des performances d’apprentissage et de mémoire de travail et spatiale des souris. De plus, le phénotype Alzheimer des souris APP/PS1 est exacerbé en présence du stress vasculaire, exprimé par l’augmentation des dépôts béta-amyloïdes, ainsi que la dysfonction endothéliale cérébrale et l’inflammation cérébrale déjà présentes dans ce modèle. Dans une deuxième étude, nous avons caractérisé les fonctions cérébrovasculaires et cognitives des souris transgéniques LDLR-/-;hApoB100+/+ avec l’ajout ou non d’un stress mécanique pulsatile central in vivo (par chirurgie TAC). Ces souris présentent des facteurs de risques des maladies cardiovasculaires (hypertension et dyslipidémie) menant au développement d’athérosclérose et miment un vieillissement artériel central accéléré (rigidité aortique et des carotides, dysfonction endothéliale, augmentation de la pression pulsée). Nous avons démontré que les souris LDLR-/-;hApoB100+/+ exhibent des anomalies cérébrovasculaires structurelles et fonctionnelles, dont une atrophie cérébrale, une dysfonction endothéliale cérébrale, une hypoperfusion cérébrale, une augmentation de la perméabilité de la barrière hémato-encéphalique, des micro-hémorragies corticales, la présence d’inflammation, de sénescence et de stress oxydant au niveau vasculaire et parenchymateux. L’ensemble de ces altérations majoritairement vasculaires, sont associées à une diminution des performances cognitives et sont exacerbées en présence d’un stress vasculaire additif. Nos deux études chez la souris démontrent qu’en présence d’une pression pulsée élevée, les dommages à la microvasculature cérébrale conduisent à une perte fonctionnelle de l’homéostasie cérébrale et à un déclin cognitif, dont l’incidence est accélérée soit dans un modèle de démence ou soit de vieillissement artériel central et en présence de facteurs de risque des maladies cardiovasculaires. Nos études fournissent la démonstration mécanistique d’un continuum entre une augmentation de pression pulsée et un déclin cognitif vasculaire. / With advancing age, the large elastic arteries undergo significant stiffening, resulting in increased central pulse pressure waves that penetrates deeper the cerebral microcirculation and may result in cerebrovascular and neuronal tissue damages, likely contributing to the development of cognitive impairment from vascular injury origin. This is compatible with strong evidence between impaired cerebrovascular structure and function in the brain of patients with vascular dementia or Alzheimer’s disease. In addition, elderly individuals are subjected in their lifetime to multiple vascular risk factors (hypertension, obesity, diabetes, atherosclerosis), all of which are known to be deleterious to the vascular function, are associated with an increase in central pulse pressure and with cognitive decline. Therefore, it is likely that with age, risk factors for vascular diseases may mechanistically promote the propagation of pulse pressure into the cerebrovascular system and reveal prematurely the brain susceptibility to cognitive decline. The present thesis was conducted to study the biomechanical hypothesis of the deleterious role of the pulse pressure in the deterioration of cerebrovascular and cognitive functions, with age and in association with vascular risk factors, by elucidating the cascade of pathological events linking the increase in central pulse pressure to the expression of dementia. To validate our hypothesis, we first studied in mice the impact of the in vivo increase of central pulsatile mechanical stress (achieved by trans-aortic constriction surgery) on the cerebral vasculature, brain tissue and cognitive functions. This stress was also induced in the APP/PS1 transgenic mouse model of Alzheimer's disease. We have shown that cerebral vessels of WT and APP/PS1 mice are vulnerable to the mechanical stress of the increased pulse pressure, which is characterized by a decrease in the vasodilatory response of the pial arteries, a rarefaction of the capillaries due to apoptosis, the incidence of micro-hemorrhages, a rupture of the blood-brain barrier and cerebral hypoperfusion. These cumulative damages to the cerebral microcirculation are associated with brain inflammation and poorer learning and working and spatial memory performances in mice. The Alzheimer's phenotype of APP/PS1 mice was exacerbated in the presence of elevated pulse pressure, as shown by the increase in beta-amyloid deposits, the decreased in endothelial cerebral vasodilatory responses and brain inflammation, which are already present in this model. In a second study, we sought to characterize the cerebrovascular and cognitive functions in the transgenic mouse model LDLR-/-;hApoB100+/+, subjected or not in vivo to a central pulsatile mechanical stress (by trans-aortic constriction surgery). These mice exhibit risk factors for cardiovascular diseases (hypertension and dyslipidemia), develop atherosclerosis and mimic premature central arterial aging (aortic and carotid stiffness, endothelial dysfunction, increased pulse pressure). We reported that LDLR-/-;hApoB100+/+ mice were characterized by structural and functional brain vascular abnormalities, including cerebral hypoperfusion, increased permeability of the blood-brain barrier, endothelial cerebral dysfunction, microhemorrhages, but also cerebral atrophy and the presence of inflammation, senescence and high oxidative stress at the vascular and parenchymal level. In addition, all these alterations, which are mainly vascular, were associated with a decrease in the cognitive performance of mice. Also, these vascular, parenchymal and cognitive changes were exacerbated in the presence of the vascular stress induced by transverse aortic constriction. Altogether, our two studies in mice demonstrated that, in the presence of an increase in pulse pressure, the damages to the micro-cerebrovascular system lead to loss of cerebral homeostasis and to cognitive decline, which are accelerated in a model of dementia or a model of central vascular aging and in presence or vascular risk factors. Our studies highlight the mechanistic demonstration of a continuum between an increase in pulse pressure and vascular cognitive decline.