O transtorno bipolar (TB) é uma das doenças psiquiátricas mais comuns e com altas taxas de morbimortalidade. Existe uma busca de um modelo neurofisiológico que poderia fornecer medidas objetivas para o diagnóstico desta doença, bem como fornecer parâmetros fisiológicos para monitorar a progressão, quantificar o dano causado pela mesma e prever a resposta ao tratamento na tentativa de direcionar a terapêutica adequada a cada estágio e evitar sua progressão. Kapczinski et al (2014) propôs um modelo de estadiamento do TB baseado em sintomas interepisódio, biomarcadores (inflamatórios e neuroplásticos) e dano cognitivo. Na última década, técnicas de neuroimagem e de genética proliferaram e vem se tornando promissoras ferramentas para se estabelecer a base de modelos neurofisiológicos do TB. Embora o prejuízo cognitivo já esteja bem descrito na literatura, o conhecimento sobre as alterações de conectividade em estudos de neuroimagem associadas a esta condição ainda é escasso. A atual pesquisa se propos a investigar os mecanismos fisiopatológicos do transtorno do humor bipolar com enfoque na substância branca (SB) cerebral. Primeiramente foi feita uma revisão sistemática da literatura internacional de estudos que correlacionaram o TB e estudo de tensor de difusão (DTI) por ressonância magnética (RM). Foram incluidos 18 trabalhos que fechavam com os critérios da pesquisa. Os trabalhos mostraram nas análises de DTI alterações na integridade da SB entre o os pacientes com TB em comparação com os controles normais. Essas alterações foram encontradas especialmente nos tratos de SB implicados em conectar uma ampla gama de redes neurais, incluindo as regiões estriatais ventrais e fronto-temporais. A maioria dos estudos mostrou valores de anisotropia fracionada (FA) reduzidos em tratos comissurais inter-hemisféricos e de associação frontolímbicos, com destaque para o corpo caloso que foi a estrutura mais acometida nos diferentes estudos. Estes achados são concordantes com a "síndrome de desconexão" que é encontrada em pacientes com TB. O segundo propósito desta tese foi fazer uma comparação dos volumes de substância branca total, do volume do corpo caloso e do volume total de substância cinzenta entre pacientes com TB em estagio inicial e avançado em relação aos seus respectivos controles normais pareados para sexo, idade, hemisfério dominante e nível de escolaridade. A análise de volumetria das estruturas corticais e subcorticais foi feita por meio de método de segmentação automatizada pelo software Freesurfer. Foram avaliados 55 sujeitos, sendo 29 pacientes com TB e 26 controles normais. A análise volumétrica encontrou redução da SB total e do volume do corpo caloso tanto em pacientes com TB no estagio inicial quanto tardio da doença. O volume de susbtância cinzenta (SC) total estava reduzido somente nos pacientes com TB em estágio tardio. Estes achados são inéditos na literatura e podem explicar a síndrome desconectiva dos pacientes com TB desde os estágios iniciais e o declínio cognitivo acentuado dos pacientes em estágios mais avançados da doença. Podem propor uma pista para achados de biomarcadores em populações em risco para desenvolver TB. / Bipolar disorder (BD) is one of the most common psychiatric disorders and with high morbidity and mortality rates. There is a search for a neurophysiological model that could provide objective measurements for diagnosis of this disease, as well as providing physiological parameters to monitor the progression, quantify the damage caused by it and predict response to treatment in an attempt to direct the appropriate therapy for each stage and prevent its progression. Kapczinski et al. (2014) proposed a staging BD model based on interepisode symptoms, biomarkers (inflammatory and neuroplastic) and cognitive impairment. In the last decade, techniques of neuroimaging and genetic proliferated and are becoming promising tools to settle the basis of neurophysiological models of BD. Although cognitive impairment is already well described in the literature, knowledge of the connectivity changes in neuroimaging studies associated with this condition is still scarce. Current research is proposed to investigate the pathophysiological mechanisms of bipolar disorder focusing on white matter (WM) brain. It was first made a systematic review of the literature studies that correlated the BD and diffusion tensor imaging (DTI). We found 18 published DTI studies that identified WM changes in subjects with bipolar disorder. The studies showed changes in the integrity of DTI WM between BD patients compared with normal controls. These changes were found especially in the treatment of WM connecting implicated in a wide range of neural networks, including ventral striatal regions and frontotemporal. Most studies showed reduced FA values in commissural inter-hemispheric and fronto-limbic association tracts, especially the corpus callosum which was the most affected structure in different studies. These findings are consistent with the "disconnection syndrome" which is found in patients with TB. The second purpose of this thesis was to compare the total white matter volume, the corpus callosum volume and total volume of gray matter in patients with BD in early and advanced stage in relation to their normal controls matched for sex, age, dominant hemisphere and education level. The volumetric analysis of cortical and subcortical structures was performed by automated segmentation method by FreeSurfer software. We evaluated 55 subjects, 29 BD patients and 26 normal controls. Volumetric analysis found reduced total WM and the corpus callosum volume both in BD patients at the early stage and late disease. The volume of total gray matter (GM) was reduced only in patients with late-stage BD. These findings are unprecedented in the literature and may explain the disconnection syndrome that is present in patients from the early stages and the marked cognitive decline of patients in more advanced stages of the disease. These findings may offer a clue to biomarker findings in populations at risk to develop BD.

Myelinated axons are crucial for rapid information transmission within the central nervous system (CNS). Myelin injury is a common feature of white matter (WM) pathology in a number of disease states, including ischemic stroke. Myelin disruption can lead to a complete failure in saltatory action potential conduction, resulting in devastating neurological deficits. However, the fundamental mechanism of ischemic myelin injury is controversial. Glutamate-mediated excitotoxicity is now recognised as a crucial event in the development of ischemic WM pathology. This thesis investigates the potential mechanisms of glutamate release in central WM and examines the hypothesis that NMDA receptor over-activation mediates ischemic myelin damage. Using glutamate biosensor microelectrodes and FM-dye imaging, I show that axonal depolarisation in the adult corpus callosum evokes rapid vesicular docking in axons, capable of elevating extracellular glutamate concentration. My findings show that vesicular fusion occurs under the myelin sheath in myelinated axons, which supports the existence of a novel synapse between the axon and overlaying myelin. Simulation of ischemia triggered an early and robust rise in optic nerve extracellular glutamate levels. Unexpectedly, a significant component of ischemic glutamate release also originated from axonal vesicular fusion. Together, these findings show that the axon-myelin synapse represents a significant site of excitotoxic injury during ischemia. Resolving prior conflicting results, I show that NMDA receptor antagonists prevent myelin degradation and improve functional recovery when applied for sufficient time to penetrate the sheath. Finally, I identify a fluorescent myelin stain (QNZ-46) which is a negative allosteric modulator of NR2C/D-containing NMDA receptors. QNZ-46 selectively accumulates in myelinated WM regions of the CNS following systemic administration, and is retained following wash-out. As a result, QNZ-46 provides persistent protection during ischemia by preserving myelin structure and improving functional recovery.

O transtorno bipolar (TB) é uma das doenças psiquiátricas mais comuns e com altas taxas de morbimortalidade. Existe uma busca de um modelo neurofisiológico que poderia fornecer medidas objetivas para o diagnóstico desta doença, bem como fornecer parâmetros fisiológicos para monitorar a progressão, quantificar o dano causado pela mesma e prever a resposta ao tratamento na tentativa de direcionar a terapêutica adequada a cada estágio e evitar sua progressão. Kapczinski et al (2014) propôs um modelo de estadiamento do TB baseado em sintomas interepisódio, biomarcadores (inflamatórios e neuroplásticos) e dano cognitivo. Na última década, técnicas de neuroimagem e de genética proliferaram e vem se tornando promissoras ferramentas para se estabelecer a base de modelos neurofisiológicos do TB. Embora o prejuízo cognitivo já esteja bem descrito na literatura, o conhecimento sobre as alterações de conectividade em estudos de neuroimagem associadas a esta condição ainda é escasso. A atual pesquisa se propos a investigar os mecanismos fisiopatológicos do transtorno do humor bipolar com enfoque na substância branca (SB) cerebral. Primeiramente foi feita uma revisão sistemática da literatura internacional de estudos que correlacionaram o TB e estudo de tensor de difusão (DTI) por ressonância magnética (RM). Foram incluidos 18 trabalhos que fechavam com os critérios da pesquisa. Os trabalhos mostraram nas análises de DTI alterações na integridade da SB entre o os pacientes com TB em comparação com os controles normais. Essas alterações foram encontradas especialmente nos tratos de SB implicados em conectar uma ampla gama de redes neurais, incluindo as regiões estriatais ventrais e fronto-temporais. A maioria dos estudos mostrou valores de anisotropia fracionada (FA) reduzidos em tratos comissurais inter-hemisféricos e de associação frontolímbicos, com destaque para o corpo caloso que foi a estrutura mais acometida nos diferentes estudos. Estes achados são concordantes com a "síndrome de desconexão" que é encontrada em pacientes com TB. O segundo propósito desta tese foi fazer uma comparação dos volumes de substância branca total, do volume do corpo caloso e do volume total de substância cinzenta entre pacientes com TB em estagio inicial e avançado em relação aos seus respectivos controles normais pareados para sexo, idade, hemisfério dominante e nível de escolaridade. A análise de volumetria das estruturas corticais e subcorticais foi feita por meio de método de segmentação automatizada pelo software Freesurfer. Foram avaliados 55 sujeitos, sendo 29 pacientes com TB e 26 controles normais. A análise volumétrica encontrou redução da SB total e do volume do corpo caloso tanto em pacientes com TB no estagio inicial quanto tardio da doença. O volume de susbtância cinzenta (SC) total estava reduzido somente nos pacientes com TB em estágio tardio. Estes achados são inéditos na literatura e podem explicar a síndrome desconectiva dos pacientes com TB desde os estágios iniciais e o declínio cognitivo acentuado dos pacientes em estágios mais avançados da doença. Podem propor uma pista para achados de biomarcadores em populações em risco para desenvolver TB. / Bipolar disorder (BD) is one of the most common psychiatric disorders and with high morbidity and mortality rates. There is a search for a neurophysiological model that could provide objective measurements for diagnosis of this disease, as well as providing physiological parameters to monitor the progression, quantify the damage caused by it and predict response to treatment in an attempt to direct the appropriate therapy for each stage and prevent its progression. Kapczinski et al. (2014) proposed a staging BD model based on interepisode symptoms, biomarkers (inflammatory and neuroplastic) and cognitive impairment. In the last decade, techniques of neuroimaging and genetic proliferated and are becoming promising tools to settle the basis of neurophysiological models of BD. Although cognitive impairment is already well described in the literature, knowledge of the connectivity changes in neuroimaging studies associated with this condition is still scarce. Current research is proposed to investigate the pathophysiological mechanisms of bipolar disorder focusing on white matter (WM) brain. It was first made a systematic review of the literature studies that correlated the BD and diffusion tensor imaging (DTI). We found 18 published DTI studies that identified WM changes in subjects with bipolar disorder. The studies showed changes in the integrity of DTI WM between BD patients compared with normal controls. These changes were found especially in the treatment of WM connecting implicated in a wide range of neural networks, including ventral striatal regions and frontotemporal. Most studies showed reduced FA values in commissural inter-hemispheric and fronto-limbic association tracts, especially the corpus callosum which was the most affected structure in different studies. These findings are consistent with the "disconnection syndrome" which is found in patients with TB. The second purpose of this thesis was to compare the total white matter volume, the corpus callosum volume and total volume of gray matter in patients with BD in early and advanced stage in relation to their normal controls matched for sex, age, dominant hemisphere and education level. The volumetric analysis of cortical and subcortical structures was performed by automated segmentation method by FreeSurfer software. We evaluated 55 subjects, 29 BD patients and 26 normal controls. Volumetric analysis found reduced total WM and the corpus callosum volume both in BD patients at the early stage and late disease. The volume of total gray matter (GM) was reduced only in patients with late-stage BD. These findings are unprecedented in the literature and may explain the disconnection syndrome that is present in patients from the early stages and the marked cognitive decline of patients in more advanced stages of the disease. These findings may offer a clue to biomarker findings in populations at risk to develop BD.

Memory structure, memory assessment, Grober-Buschke paradigm, Alzheimer disease, and vascular dementia were discussed in the first part of the present thesis. Present study aims to examine the relationship between white matter changes, hippocampal atrophy and the performance in Enhanced Cued Recall test in nondemented geriatric population (n = 104). Partial neparametric correlations were used while controlling for age and Fazekas score. Medium correlations were found between left/right hippocampal volumes and free and total recall. No correlations were found between Fazekas score and ECR scores while controlling for age and left and right hippocampal volumes. Keywords: hippocampal atrophy, white matter changes, cued recall, ECR

La connaissance de la morphologie des faisceaux de fibres blanches, qui connectent des régions cérébrales distantes, est indispensable à la compréhension du fonctionnement cérébral. La tractographie par IRM de diffusion reconstruit indirectement cette anatomie à partir d'algorithmes mathématiques complexes. Après une revue des méthodes proposées pour la validation de la tractographie, nous proposons une méthode originale basée sur la reconstruction 3D de faisceaux disséqués. Notre méthode, FIBRASCAN, utilise des acquisitions itératives de surface en cours de dissection. Les faisceaux étaient segmentés sur chaque surface puis reconstruits par empilement. Un support rigide permettait le recalage entre surfaces puis vers l'IRM. Nous avons démontré la précision de chaque étape de reconstruction, et sa faisabilité sur plusieurs faisceaux. Dans la dernière partie de ce travail, la structure des fibres blanches et les modifications induites par la préparation et la dissection sont explorées en microscopie électronique. Nous avons montré que la dissection préservait la structure des axones et peut ainsi être considérée comme un outil de validation de la tractographie. / The knowledge of the morphology of white matter fiber tracts, which connect distant cerebral areas, is essential to better understand brain functions. Diffusion MR tractography indirectly reconstructs this anatomy using complex mathematical algorithms. After a review of the existing methods for tractography validation, we propose an original method based on 3D reconstruction of dissected tracts. Our method, FIBRASCAN, used iterative surface acquisitions during dissection. The tracts were segmented on each surface and then reconstructed by stacking these surfaces. A rigid support allowed registration between surfaces and then registration to MRI. We demonstrated the accuracy of each reconstructing step, and the feasibility of our method on several tracts. In the last part of this work, the structure of white matter fibers and the changes induced by preparation and dissection were investigated using electron microscopy. We showed that dissection preserves the structure of axons and can thus be considered as a validation tool for tractography.

L’imagerie par résonance magnétique pondérée en diffusion est une modalité unique sensible aux mouvements microscopiques des molécules d’eau dans les tissus biologiques. Il est possible d’utiliser les caractéristiques de ce mouvement pour inférer la structure macroscopique des faisceaux de la matière blanche du cerveau. La technique, appelée tractographie, est devenue l’outil de choix pour étudier cette structure de façon non invasive. Par exemple, la tractographie est utilisée en planification neurochirurgicale et pour le suivi du développement de maladies neurodégénératives.Dans cette thèse, nous exposons certains des biais introduits lors de reconstructions par tractographie, et des méthodes sont proposées pour les réduire. D’abord, nous utilisons des connaissances anatomiques a priori pour orienter la reconstruction. Ainsi, nous montrons que l’information anatomique sur la nature des tissus permet d'estimer des faisceaux anatomiquement plausibles et de réduire les biais dans l’estimation de structures complexes de la matière blanche. Ensuite, nous utilisons des connnaissances microstructurelles a priori dans la reconstruction, afin de permettre à la tractographie de suivre le mouvement des molécules d’eau non seulement le long des faisceaux, mais aussi dans des milieux microstructurels spécifiques. La tractographie peut ainsi distinguer différents faisceaux, réduire les erreurs de reconstruction et permettre l’étude de la microstructure le long de la matière blanche. Somme toute, nous montrons que l’utilisation de connaissances anatomiques et microstructurelles a priori, en tractographie, augmente l’exactitude des reconstructions de la matière blanche du cerveau. / Diffusion-weighted magnetic resonance imaging is a unique imaging modality sensitive to the microscopic movement of water molecules in biological tissues. By characterizing the movement of water molecules, it is possible to infer the macroscopic neuronal pathways of the brain. The technique, so-called tractography, had become the tool of choice to study non-invasively the human brain's white matter in vivo. For instance, it has been used in neurosurgical intervention planning and in neurodegenerative diseases monitoring. In this thesis, we report biases from current tractography reconstruction and suggest methods to reduce them. We first use anatomical priors, derived from a high resolution T1-weighted image, to guide tractography. We show that knowledge of the nature of biological tissue helps tractography to reconstruct anatomically valid neuronal pathways, and reduces biases in the estimation of complex white matter regions. We then use microstructural priors, derived from the state-of-the-art diffusionweighted magnetic resonance imaging protocol, in the tractography reconstruction process. This allows tractography to follow the movement of water molecules not only along neuronal pathways, but also in a microstructurally specific environment. Thus, the tractography distinguishes more accurately neuronal pathways and reduces reconstruction errors. Moreover, it provides the mean to study white matter microstructure characteristics along neuronal pathways. Altogether, we show that anatomical and microstructural priors used during the tractography process improve brain’s white matter reconstruction.

Background: Given that brain pathology precedes clinical symptoms in Alzheimer’s disease (AD), identifying pre-symptomatic biomarkers is critical in order to implement symptom-delaying strategies as early as possible. Magnetic resonance imaging (MRI) is an ideal method for detecting early brain changes in Alzheimer's disease, as it is non-invasive, easily repeatable, and widely available. To date, MRI biomarker research has largely focused on neuronal loss in grey matter, but there is a lack of research on white matter and its relationship with cognitive performance. Diffusion tensor imaging (DTI) is a MRI-based technique that is particularly sensitive to microstructural white matter characteristics, making it an ideal method to study white matter changes. Methods: Longitudinal DTI and clinical data from the Alzheimer’s Disease Neuroimaging Initiative 2 database were used to examine the 1) within-group microstructural white matter changes in individuals with AD and healthy aging controls at baseline and year one; 2) the between-group microstructural differences in individuals with AD and controls at both time points; and 3) the relationship between white matter and cognitive performance at both time points. Results: 1) Within-group: Tract-based Spatial Statistics reveal that individuals with AD have reduced fractional anisotropy (FA) and increased mean diffusivity (MD) in the corpus callosum; internal and external capsule; corona radiata; posterior thalamic radiations; superior and inferior longitudinal fasciculus; fronto-occipital fasciculus; cingulate gyri; fornix; uncinate fasciculus; tapetum; medial lemniscus; cerebellar and cerebral peduncle; and hippocampal cingulum at year one compared to baseline. Controls also had reduced FA and increased MD at year one compared to baseline, but such changes were less extensive and did not include the hippocampal cingulum. 2) Between-group: Relative to controls, individuals with AD had lower FA and higher MD in the corpus callosum, internal and external capsule; corona radiata; posterior thalamic radiation; superior and inferior longitudinal fasciculus and fronto-occipital fasciculus; cingulate gyri; fornix; uncinate fasciculus; tapetum and hippocampal cingulum. 3) There was a positive relationship between FA and an ADNI- derived memory composite score in individuals with AD. Conclusion: The results revealed that DTI holds potential as an AD biomarker given its sensitivity to detect microstructural white matter characteristics. Longitudinal tracking of brain imaging and AD clinical signs in large cohorts are necessary to further evaluate potential clinical utility. / Graduate

Older age is a primary risk factor for the development of cardiovascular disease in part through the stiffening of the large cardiothoracic elastic arteries (e.g., aorta, carotid arteries). Aging is also associated with reduced cognitive function, cerebrovascular reactivity and brain white matter integrity, but whether these changes in brain structure and function are associated with age-related large artery stiffness remains unclear. In contrast, older adults who have high aerobic fitness demonstrate attenuated large artery stiffness and better cognitive performance compared to their sedentary counterparts, but the effects of aerobic fitness on white matter integrity and cerebrovascular reactivity with aging are conflicting and limited. Moreover, whether high aerobic fitness-associated lower large artery stiffness in older adults is associated with, and perhaps mediates, the beneficial changes in cognitive function and white matter structure remains unknown. The purpose of this study was to investigate the extent to which high aerobic fitness is associated with preserved white matter structure, cerebrovascular reactivity, and cognitive performance in aged individuals, and if these changes in brain structure and function are associated with attenuated large artery stiffness. In young (n=19, 23.6 ± 2.5 years) and old (n=22, 64.4 ± 4.2 years) healthy adults, large elastic artery stiffness was measured by carotid-femoral pulse wave velocity (cfPWV, aortic stiffness) via non-invasive applanation tonometry of carotid and femoral pulse waveforms and carotid artery beta-stiffness index (β-stiffness index) and compliance using high-resolution ultrasound and carotid blood pressure via applanation tonometry. Aerobic fitness was measured as maximal exercise oxygen uptake (VO2max) using respiratory gas analysis on an upright cycle ergometer. Older subjects were stratified as high or low fit based on gender and age VO2max classification. Letter, pattern and N-Back cognitive tests were used to assess processing speed and working memory respectively. Fractional anisotropy (FA) from diffusion tensor images and Blood Oxygenation Level Dependent (BOLD) imaging was used to assess cerebrovascular reactivity (CVR) response to a breath hold and brain activation during a working memory task. The association between large artery stiffness and FA was then assessed using a voxel-wise general linear model approach and a region-of-interest analysis. Our results confirmed age-related increases in cfPWV, carotid β-stiffness index and central (carotid) but not brachial systolic blood pressure, and expected reductions in carotid compliance, VO2max, working memory and processing speed, and in white matter integrity in select brain regions (bilateral cingulate, frontal, occipital, temporal). In contrast, we found no age-associated differences in CVR to breath hold stimulus or change in BOLD response to the N-Back. In our cohort of health adults, we found that the age-related changes in large artery stiffness were not attenuated by high compared with low VO2max. Among older adults, large elastic artery stiffness was not associated with regional white matter integrity or cerebrovascular reactivity in any regions-of-interest. Greater carotid artery compliance and lower β-stiffness index was associated with higher processing speed, while compliance was related to higher d'Prime scores and lower reaction time on the 2-Back task among the older adults. CVR to a breath hold stimulus was not related to any measure of cognitive performance. VO2max was not associated with any measures of vascular function, brain structure, function or cognition, indicating relations between large artery stiffness and cognition were independent of aerobic fitness capacity. Taken together, these data suggest that select measures of cognitive performance, but not white matter structure or CVR, may be susceptible to age-related changes in carotid stiffness/compliance and that are unaffected by aerobic fitness. More work is needed to understand the mechanisms by which age-related declines in carotid artery compliance and increased carotid stiffness are associated with reductions in cognitive function in older adults.

Eine häufige Komplikation diverser Malignome ist die Hirnmetastasierung. Im Verlauf einer Krebserkrankung kommt es bei mehr als einem Drittel aller Patienten mit einem soliden Tumor zur Absiedelung von Tochterzellen ins Gehirn. Therapeutisch einzuleitenden Maßnahmen hängen maßgeblich davon ab, wie zahlreich und wie groß die vorhandenen Hirnmetastasen sind. Zumeist wird so zwischen eine lokalen Therapie oder Ganzhirnbestrahlung entschieden. Nichtsdestotrotz bleibt die Prognose oft mit einer medianen Überlebenszeit von maximal 12 Montane sehr schlecht. Faktoren, die die Anzahl und Größe von Hirnmetastasen beeinflussen, sind bis heute nur wenig definiert. Die Metastasierung eines Primärtumors in das zentrale Nervensystem (ZNS) scheint von hämatogener Tumorzellaussaat und einer Affinität zum ZNS abhängig zu sein. Eine gesicherte Blutversorgung ist unerlässlich für das Wachstum von Metastasen im ZNS. Ob Neoangiogenese oder die Anpassung an vorhandene Gefäße durch Patienten-abhängige Faktoren beeinflusst werden, ist nicht detailliert untersucht. Ziel dieser Studie war die retrospektive Beurteilung des Einflusses von Alter und zerebraler Mikroangiopathie auf die Anzahl und Große von Hirnmetastasen diverser Tumortypen. Initial wurden alle Patienten, bei denen von Oktober 2004 bis Januar 2016 am Universitätsklinikum Leipzig die Diagnose „Hirnmetastase oder Hirnmetastasierung“ gestellt wurde, gesammelt. Basierend auf zwei Hauptkriterien wurden diese anschließend selektiert. Voraussetzungen für die Aufnahme in diese Studie waren eine vollständige Krankenakte mit allen biologischen Daten, als auch ein 3D-T1 gewichtete MRT-Aufnahme vor und nach Kontrastmittelgabe, und eine T2/FLAIR Aufnahme vor begonnener Behandlung. Ein 3-Tesla MRT wurde hierzu verwendet; die Schichtdicke betrug 1 bis 1.5 mm. Die MRT-Aufnahmen wurden hinsichtlich der Anzahl und Größe der Hirnmetastasen, sowie des Grades der Läsionen der weißen Hirnsubstanz (White Matter Lesions, WML) analysiert. Die Patienten wurden anschließend basierend auf Altersgruppen- und WML-Grad Zugehörigkeit univariat und multivariat betrachtet. Zur Untersuchung des Alters, im Rahmen des WML Grades, erfolgten zwei Untergruppierung: 1) Patienten  65 vs. Patienten >65 Jahre; 2) Einteilung nach Dekaden, beginnend bei 30 und endend bei 100 Jahren. Der Grad der Läsionen der weißen Hirnsubstanz – als Marker der zerebralen Mikroangiopahie – wurde basierend auf der vierstufigen Fazekas-Skala (0-3) (Fazekas et al. 1987) ermittelt. Patienten ohne hyperintense Läsionen der weißen Substanz wurden dem WML Grad 0, mit punktförmigen Läsionen dem Grad 1, mit beginnend konfluierenden punktförmigen Läsionen dem WML Grad 2 und großen konfluierenden Läsionen dem WML Grad 3 zugeordnet. Innerhalb dieser Untergruppen wurden durchschnittliche Metastasenzahl und der mittlere Durchmesser der Raumforderungen berechnet. Zur statistischen Analyse wurde die Software SPSS V22.0 von IBM eingesetzt. Zu Beginn wurden alle Daten mittels Kolmogorov-Smirnov Test auf Normalverteilung überprüft. Da die gemessenen Daten höchst signifikant (p=0.001) keiner Normalverteilung folgten, wurden alle weiteren Analysen mittels nicht-parametrischer statistischer Tests (Mann-Whitney U-Test bei N=2, Independent Samples Kruskal-Wallis-Test bei N>2) durchgeführt. Univariate und multivariate Analysen wurden zur Beurteilung individueller und kumulativer Effekte verwendet. Die statistische Signifikanz wurde bei einem p-Wert < 0.05 akzeptiert. Diese wurde mit zusätzlichen Korrelationsanalysen verschiedener Parameter mittels Pearson’s Chi-Square Test of Independence (pχ2) ergänzt. Die Patienten dieser Studie waren überwiegend männlich (60.5 %, n=121) und - in einem Bereich von 32 bis 91 Jahren - im Median 64,5 Jahre alt. Die Kohorte bestand aus Patienten mit nicht-kleinzelligem Bronchialkarzinom (NSCLC, n=89), kleinzelligem Bronchialkarzinom (SCLC, n=14), Mammakarzinom (BC, n=20), malignen Melanom (MM, n=30), Nierenzellkarzinom (RCC, n=17), kolorektalen Karzinom (CRC, n=10) und anderen Tumorarten (OT, n=20). Ein Anteil von 31 der 200 Patienten (15.5 %) hatte eine Hirnmetastase, 42 Patienten (21 %) zeigten zwei und 91 (45.5 %) 3–9 Metastasen. 36 Patienten hatten über 9 Metastasen. Die Analyse des cMRT ergab, dass insgesamt 88 Patienten (44%) keine WML zeigten, wohingegen 74 (37%) dem WML Grad 1, 37 (18.5%) Grad 2 und nur 1 Fall (0.5%) Grad 3 zugeordnet werden konnte. Die Veränderungen der weißen Substanz waren wesentlich häufiger und gravierender in Patienten mit NSCLC, RCC und CRC (Median: WML1) anzutreffen, als im Vergleich zu Patienten mit MM, BC oder SCLC (WML0). Die durchschnittliche Anzahl (pNoM=0.832) und der mittlere Durchmesser (pmDM=0.662) der Hirnmetastasen waren nicht signifikant verschieden zwischen Patienten 65 und >65 Jahren oder bei einer Einteilung nach Dekaden. In monovariater Analyse zeigten Patienten mit einem WML Grad 1 (NoM: 5.595.68; p=0.009) und Grad 2 (NoM: 3.683.81; p = 0.002) signifikant weniger Hirnmetastasen als Patienten ohne WML (NoM: 6.996.04; pNoM= 0.013). Mit zunehmendem Alter war der WML-Grad signifikant höher (p=0.001, r=0.422). Innerhalb der Patienten mit NSCLC (p=0.048) und bei Patienten mit anderen Tumorarten (SCLC, MM, BC, RCC, CRC, OT, n=111, p=0.05) war mit zunehmendem WML-Grad die Anzahl von Hirnmetastasen signifikant geringer. Im Gegensatz zur Anzahl, war der Durchmesser der Hirnmetastasen zwischen WML-Graden nicht unterschiedlich (p=0.0806). Weiterhin konnte kein Zusammenhang zwischen WML-Grad und Metastasierung in die weiße Hirnsubstanz festgestellt werden. Zusammenfassend kann gesagt werden, dass sich ein hoher Grad an WML bei verschiedenen Tumorarten reduzierend auf die Anzahl von Hirnmetastasen auswirkt, während das Patientenalter keinen Einfluss hat. Veränderungen der Hirngefäße im Rahmen zerebraler Mikroangiopathie, können somit die Absiedelung von Tumorzellen in das zentrale Nervensystem erschweren. Dieser Sachverhalt könnte auch für die Therapie von Hirnmetastasen mit Ganzhirnbestrahlung relevant sein. So hat die Ganzhirnbestrahlung von Hirnmetastasen neben einem lokaltherapeutischen Effekt auf die sichtbaren Hirnmetastasen auch einen prophylaktischen Einfluss auf makroskopisch nicht-befallene Hirnbereiche. Dieser prophylaktische Effekt ist nach unseren Daten bei Patienten mit Mikroangiopathie mutmaßlich weniger relevant, was eher für die Anwendung lokaler Therapien (stereotaktische Bestrahlung, Resektion) statt Ganzhirnbestrahlung bei diesen Patienten spricht.:INHALTSVERZEICHNIS VORWORT 4 ABKÜRZUNGSVERZEICHNIS 7 ABBILDUNGSVERZEICHNIS 9 TABELLENVERZEICHNIS 9 1 EINFÜHRUNG 10 1.1 Anatomie der Blutversorgung des Gehirns 10 1.1.1 Arterielle zerebrale Gefäßversorgung 10 1.1.1.1 Karotisstromgebiet (KSG) 10 1.1.1.2 Vertebrobasilläres Stromgebiet (VBS) 12 1.1.2 Venöse zerebrale Gefäßversorgung 12 1.1.3 Kleinkalibrige Gefäßversorgung des Gehirns 13 1.2 Die zerebrale Mikroangiopathie 14 1.2.1 Definition 14 1.2.2 Inzidenz, Pathologie und Pathogenese 15 1.2.3 Zusammenfassende Epikrise zerebraler Mikroangiopathie 20 1.2.4 Hirnschäden durch Mikroangiopathien 22 1.3 Zerebrale Mikroangiopathie in der Magnetresozanztomographie 24 1.4 Zerebrale Metastasierung 30 1.5 Zielsetzung und Rationale der Untersuchung 33 2 VORBEMERKUNG ZU VERÖFFENTLICHUNG 35 3 PUBLIKATION 37 4 ZUSAMMENFASSUNG 44 5 LITERATURVERZEICHNIS 48 6 ANLAGEN 68 DARSTELLUNG DES EIGENEN BEITRAGS 68 SELBSTÄNDIGKEITSERKLÄRUNG 69 CURRICULUM VITAE 70 PUBLIKATIONSLISTE DES PROMOVENDEN 73 DANKSAGUNG 75

While the association between blood pressure (BP) and brain health is increasingly strengthened by various clinical and epidemiologic research findings, less is known about the relationship between longitudinal patterns of BP across midlife and their impact on cognitive aging. Therefore, the current project used a large-scale, prospective longitudinal dataset of the Framingham Heart Study to model various long-term BP patterns using traditional methods and a novel machine-learning approach and investigated their impact on the development of dementia, as well as cognitive performance and brain volumes in late life. Study 1 examined intra-individual BP variability (BPV) across midlife and assessed its association with neuropsychological test performance, brain volumetric measures, and the development of dementia in late life. Contrary to previous findings in the elderly population, increased BP variability across midlife was not significantly associated with any brain aging measures. However, greater mean BP across midlife significantly predicted a greater risk of dementia. This finding led to the hypothesis that elevated BP in midlife, rather than BPV, may predict poorer brain and cognitive outcomes in late life. Study 2 investigated a long-term pattern of elevated BP using a cumulative exposure model, which has been well-recognized as a summary measure of longitudinal variation and cumulative burden associated with elevated cardiovascular risk. Consistent with the hypothesis driven from Study 1, elevated values of cumulative BP were associated with increased risk of dementia, along with poorer performance in most cognitive domains and reduced brain volume in areas including frontal, occipital, and temporal regions. Finally, Study 3 capitalized on a machine-learning approach, and namely, the dynamic time warping algorithm, to analyze BP data over the course of midlife using various pattern clusters. Although preliminary in nature, analyses using this novel approach detected various shapes of BP patterns across midlife. Clinical utility of these shapes and advantages of the machine-learning tool in BP research are discussed. Together, the results from these three studies suggest that BP pattern over the course of midlife, especially regarding long-term elevation of BP, is significantly associated with brain aging outcomes in late life.