Early Effects of Castration Therapy in Non-malignant and Malignant Prostate Tissue BACKGROUND. Androgen ablation, the standard treatment for advanced prostate cancer, results in increased apoptosis, decreased cell proliferation and subsequent involution of the prostate gland. The mechanisms behind these responses are largely unknown, but effects in the prostatic epithelium are believed to be mediated by primary changes in the stroma. The purpose of this thesis was to investigate short-term cellular effects of castration-induced prostate tissue involution in mice and humans. METHODS. Prostate tissue factors affected by castration were investigated using cDNA-arrays, micro-dissection, RT-PCR, immunohistochemistry and Western blot analysis. The effects of local insulin-like growth factor-1 (IGF-1) administration were investigated in intact and castrated mice. Non-malignant and malignant epithelial and stromal cells were micro-dissected from human prostate biopsies taken before and within two weeks after castration treatment from patients with advanced prostate cancer. These tissue compartments were analyzed by RT-PCR and/or immunohistochemistry for IGF-1, IGF-1 receptor, androgen receptor (AR) and prostate specific antigen (PSA) expression. Treatment-induced changes in these factors were related to apoptosis and proliferation as well as to clinical data and cancer specific survival. RESULTS. Similar to our observations in mouse ventral prostate (VP), non-malignant and malignant human prostate tissues responded with increased epithelial cell apoptosis and decreased proliferation after androgen withdrawal. Also, the PSA mRNA levels were reduced within the first days after therapy both in non-malignant and malignant human prostate epithelial cells. However, neither of these changes was related to subsequent nadir serum PSA or to survival. Locally injected IGF-1 increased epithelial cell proliferation and vascular volume in intact but not in castrated mice. IGF-1 was found to be mostly, but not exclusively, expressed in the stroma, and it decreased rapidly after castration in both humans and mice. This decrease was, however, largely absent in prostate tumor stroma, and tumor stroma cells showed lower pre-treatment levels of AR than stroma surrounding normal epithelial glands. Furthermore, decreased levels of IGF-1 mRNA in the non-malignant and tumor stroma cells, and in tumor epithelial cells in response to castration, were associated with high levels of apoptosis in epithelial cells after therapy. CONCLUSIONS. In the prostate, IGF-1 may be an important mediator of stroma-epithelial cell interaction that is involved in castration-induced epithelial and vascular involution. Moreover, reduced AR in the tumor stroma may play an important role in prostate cancer progression towards androgen-independency, resulting in inadequate IGF-1 reduction and apoptosis induction in response to castration. Most primary tumors initially respond to castration with markedly decreased PSA synthesis and cell proliferation, and moderately increased apoptosis. Death due to metastatic disease is, however, still common, despite primary tumor regression. This may suggest that tumor cells in metastases respond differently to treatment than primary tumor cells, probably influenced by a different and possibly androgen-independent stroma. Further studies should test the hypothesis that the effect of castration therapy can be enhanced by simultaneous blocking of IGF-1 signaling.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-07-25T23:07:30Z No. of bitstreams: 1 PatriciaIngridMacedoDeCastro_DISSERT.pdf: 960843 bytes, checksum: 3369f0056a2e2ab1f071631a2015066a (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-08-04T20:48:06Z (GMT) No. of bitstreams: 1 PatriciaIngridMacedoDeCastro_DISSERT.pdf: 960843 bytes, checksum: 3369f0056a2e2ab1f071631a2015066a (MD5) / Made available in DSpace on 2016-08-04T20:48:06Z (GMT). No. of bitstreams: 1 PatriciaIngridMacedoDeCastro_DISSERT.pdf: 960843 bytes, checksum: 3369f0056a2e2ab1f071631a2015066a (MD5) Previous issue date: 2015-11-30 / A pr?-ecl?mpsia ? uma doen?a que afeta 3-8% das mulheres gr?vidas. Os fatores de risco para essa doen?a n?o s?o completamente compreendidos, mas incluem desregula??o da resposta imune oriundos de defeitos na placenta??o, fatores ambientais e gen?ticos. O presente estudo teve como objetivo investigar associa??o varia??o na quantidade de receptores de citocinas pr?-inflamat?rias (IL-1R, IL-6R e TNF-?R) estariam envolvidos com a pr?-ecl?mpsia. Receptores de citocinas (IL-1R2, TNF-?R1 e IL-6R) foram avaliados em c?lulas mononucleares das gr?vidas normotensas (controle n=11) e gr?vidas com pr?-ecl?mpsia (PE, n=24). Mulheres com pr?-eclampsia tinham peso mais elevado no in?cio da gravidez (p=0.0171). Foi observado uma diminui??o de mon?citos cl?ssicos, mas n?o de mon?citos intermedi?rios e n?o-cl?ssicos na pr?-ecl?mpsia. A frequ?ncia dos receptores de citocinas proinflamat?rias IL-1R2, TNF-?R IL-6R aderidos a membrana das subpopula??es de mon?citos (cl?ssicos, intermedi?rios e n?o cl?ssicos) e linf?citos (CD3+CD4+ e CD3+CD8+) estavam diminu?das em pacientes com pr?-ecl?mpsia, quando comparados com gr?vidas normais. A redu??o na quantidade de receptores de citocinas IL-1R2, TNF-?R1 e IL-6R em mon?ciots e linf?citos pode ser um fator mantenedor do estado inflamat?rio na pr?-eclampsia. / Preeclampsia is a disease specific of human pregnancy that affects 3-8% of pregnant women, and it is one of the three leading causes of maternal mortality and morbidity. The disease is characterized by hypertension and proteinuria after the 20th week of gestation. The risk factors for this disease are not completely understood but appear to include dysregulation of the immune response arising from defects in placentation, environmental and genetic factors. This study aimed to determine whether the variation in the amount of proinflammatory cytokine receptors IL-1R2, IL-6R and TNF-?R1 would be involved in preeclampsia. They were recruited women with preeclampsia (n=24) and women who evolved during pregnancy without changes in blood pressure (n=12) were recruited. Clinical and laboratory data were collected. The cytokine receptors (IL-1R2, TNF-?R1 and IL-6R) were assessed in mononuclear cells isolated from peripheral blood using flow cytometry (Control = 8; PE = 24). C-reactive protein (CRP) was determined by CRP ultrasensitive method (Control = 7; PE = 18) was performed using sera pregnant women. Women with preeclampsia had higher weight at the beginning of the pregnancy (p=0.0171) and lower gestational age at delivery (0.0008). Classical monocytes were decreased in preeclampsia but not intermediate or non-classical monocytes. The frequency of IL-1R2 pro inflammatory cytokine receptors is decreased in women with PE only in the subpopulation of non-classical monocytes (p = 0.0011). TNF-?R1 receptor and IL-6R, had a decreased frequency in the three subpopulations of monocyte (classic, intermediate and non-classical) when compared to women with normal pregnancy. An increase in IL-1R2 receptor in TCD4+ lymphocytes, but a decrease in TNF-receptor and IL-6R in women with preeclampsia were found. No differences in the frequency of those receptors in CD3+/CD8+ in preeclampsia. There was no difference in C-reactive protein in preeclampsia. The reduction in the amount of IL-1R2, TNF- ?R1 and IL-6R monocytes and lymphocytes can be involved in the regulation of inflammation observed in preeclampsia, contributing to disease.

Der Gleason-Score ist ein wichtiges Kriterium für die prognostische Einteilung des Prostatakarzinoms und sollte auch am positiven Resektionsrand bestimmt werden. Es wurden 1 836 Prostatakarzinomfälle aus den Jahren 2006-2010 analysiert. Dabei wurden Anzahl sowie Lokalisation der R1-Resektionen; der Gleason-Score und die Länge (mm) des positiven Resektionsrand bestimmt. Danach wurden Unterschiede zwischen R0- und R1-resezierten Patienten; Unterschiede innerhalb der R1-Kohorte und die Länge des positiven Resektionsrands ausgewertet. Es erfolgte eine statistisch-explorative Analyse der Überlebenszeit der R1-Kohorte und der Einfluss der klinisch-pathologischen Variablen (Alter, PSA, pT-, pN-Kategorie, EPE, Gleason-Score im Tumor, Gleason-Score am Resektionsrand, Länge des Resektionsrand, Operationsmodus) auf die Prognose des Prostatakarzinoms. Alle Einteilungen wurden anhand der TNM-Klassifikation 7. Auflage, (UICC), Gleason-Grading-System Revision 2015 (ISUP) und dem prognostischen Gruppierungssystem der ISUP 2015 vorgenommen. Nach radikaler Prostatektomie zeigten 242 (13,2 %) Patienten eine R1-Resektion und 166 (9 %) ein biochemisches Rezidiv. Es zeigte sich, dass in der R1-Kohorte gegenüber der R0-Kohorte mehr pT3-/pT3b-/pT4-Kategorien, mehr positive Lymphknoten, Infiltrationen der Perineuralscheiden und Venen, EPE und Samenblaseninfiltrationen auftraten ( p <0,001). In der R0-Kohorte häuften sich die Gleason-Scores 6 und 7a (25,4 % | 47,5 %), in der R1-Kohorte dagegen die Werte 8 und 9-10 (28,5 % | 17,8 %). Von 242 positiven Resektionsrändern unterschieden sich 147 (60,74 %) in ihrem Gleason-Score vom Gleason-Score des Tumors, 103 (42,56 %) hatten einen niedrigeren und 44 (18,18 %) einen höheren Gleason-Score am Resektionsrand. Die Analyse der R1-Kohorte mittels der ISUP-Grade zeigte, dass in Präparaten mit Gleason-Score von 6 und 7a mehr pT2c- und pT3a-Kategorien vorhanden waren, dagegen in solchen mit Gleason-Score 7b, 8 und 9-10 ein Anstieg von pT3b- und pT4-Kategorien zu verzeichnen war. Mit steigendem ISUP-Grad kam es zum Anstieg der pN-Kategorie, der EPE und der Infiltrationen der Samenblase sowie der Anzahl und medianen Länge der positiven Resektionsränder. Nach Kaplan-Meier wurde der Einfluss der o.g. Variablen auf die Überlebenszeit bis zum biochemischen Rezidiv überprüft. Die roboterassistierten Prostatektomien zeigten mit (82 Mon. | CI 70-96) im Vergleich mit den retropubischen (72 Mon. | CI 68–76) und laparoskopischen (53 Mon. | CI 39–67) die höchste Überlebensrate. Nach 85 Mon. hatten 70 % der R1-Resezierten ein Rezidiv vs. 30 % R0-Resezierter. Überraschend ergab sich innerhalb der R1-Kohorte eine prognostisch „gute“ Gruppe aus Gleason-Score 6 und 7a mit Überlebenszeiten von (72 Mon. | (CI 50–95) || 49 Mon.|(CI 30–69)). Die prognostisch „schlechte“ Gruppe bildeten Gleason-Score 7b, 8, 9-10 (27 Mon. | (CI 16–38), 25 Mon. | (CI 14–36) & 24 Mon. | (CI 11–36)). Patienten mit Gleason-Score ≤6 und 7a am Resektionsrand zeigten (53 bzw. 51 Mon. | CI 50–95) im Vergleich zu Gleason-Score 7b, 8 und 9-10 (25; 24 bzw. 26 Mon.|CI 15–36) rezidivfreies Überleben. Patienten mit Gleason-Score 6 zeigten bei R0- (82 Mon. | CI 78–98) und R1-Resektion (72 Mon | CI 51–94) nur einen geringen Unterschied. Positive Resektionsränder ≤3mm vs. ≥3mm zeigten wie nur ein positiver Resektionsrand vs. multiple positive Resektionsränder ein längeres Überleben. Mittels Cox-Regression wurden die o.g. Variablen auf ihr Risiko für die Entstehung eines biochemischen Rezidivs überprüft. In der univariaten Analyse ergaben sich hohe Risiken für die Gleason-Scores 7b, 8 & 9-10 am positiven Resektionsrand (HR 2,5 bis HR 2,3) und für multiple positive Resektionsränder (HR 2,1). Die multivariate Cox-Regression mit Basis pT-Kategorie ergab eine Steigerung des Risikos für ein Rezidiv durch die Gleason-Scores am Resektionsrand 7b und 8 (HR 1,8) sowie für den positiven Resektionsrand ≥3mm (HR 1,4). Wurde der Gleason-Score des Tumors als Basis genutzt, so erhöhte sich das Risiko für ein Rezidiv durch den Gleason-Score des Resektionsrands 9-10 (HR 1,8), den positiven Resektionsrand ≥3mm (HR 1,4) und multiple positive Resektionsränder (HR 1,4). Auf Basis dieser Ergebnisse ist die Bestimmung des Gleason-Scores am Resektionsrand sowie der Länge und Anzahl der positiven Resektionsränder nach R1-Resektionen erforderlich, um eine bessere Risikostratifizierung durchführen und so die angemessene Therapie auswählen zu können.:Inhaltsverzeichnis Abkürzungsverzeichnis Tabellenverzeichnis Abbildungsverzeichnis 1. Einführung 1.1 Klassifikation 1.1.1 TNM-Klassifikation 1.1.2 Gleason-Score 1.2 Forschungsstand zu positiven Resektionsrändern 1.2.1 Forschungsstand zum Gleason-Score am Resektionsrand 1.2.2 Forschungsstand zur Länge des positiven Resektionsrand 2. Ziele der Arbeit 3. Materialien und Methoden 3.1 Studienpopulation 3.2 Vorgehen der Erhebung 3.2.1 Bestimmung des Gleason-Scores am Resektionsrand 3.2.2 Bestimmung der Länge des positiven Resektionsrands 3.3 Pathologische Klassifikationen 3.4 Geräte 3.5 Statistische Methoden 4. Ergebnisse 4.1 Analyse der klinisch-pathologischen Kriterien für Grundgesamtheit, R1- und R0-Kohorte 4.1.1 Subgruppenanalyse der R1-Kohorte nach ISUP-Graden 4.2 Korrelationsanalyse von Gleason-Score und Länge des positiven Resektionsrandes 4.3 Überlebenszeitanalyse der Grundgesamtheit 4.3.1 Überlebenszeitanalyse der R1-Kohorte unter Gruppierung klinisch-pathologischer Variable 4.4 Hazard Ratios der klinisch-pathologischen Variablen 5. Diskussion 5.1 Limitationen 6. Zusammenfassung 7. Literaturverzeichnis Anhang Lebenslauf Danksagung Eigenständigkeitserklärung

Au niveau clinique, il a été observé que de 15 à 30 % des patients qui ont subi un infarctus du myocarde développent une dépression majeure. De plus, la population atteinte de dépression post-infarctus présente un risque de mortalité de trois à quatre fois plus élevé, et ce, en comparaison avec la population non dépressive post-infarctus. Dans un modèle de rat développé pour étudier la dépression post-infarctus, des cellules apoptotiques ont été retrouvées au niveau du système limbique. Il apparaît que les cytokines seraient en partie responsables de cette mort cellulaire qui relie le cœur en ischémie et le système nerveux central. Donc, les objectifs de cette thèse sont : 1) de caractériser spatialement et temporellement la survenue de la mort cellulaire par apoptose dans les structures du système limbique du rat, à la suite d’un infarctus du myocarde ; 2) de déterminer l’effet de l’anti-inflammatoire celecoxib sur cette apoptose observée au niveau de l’amygdale et de déterminer l’implication de l’enzyme COX-2 ; 3) de déterminer l’implication de la cytokine pro-inflammatoire TNF-α dans l’apoptose observée au niveau des structures du système limbique du rat, à la suite d’un infarctus du myocarde. Afin d’atteindre ces objectifs, les rats ont subi une ischémie de 40 minutes, suivi d’une période de reperfusion qui varie d’un protocole à l’autre (15 minutes, 24, 48, 72 heures ou 7 jours). De plus, en fonction du protocole, ces rats ont été traités avec soit du célécoxib (inhibiteur sélectif de la COX-2), soit avec du PEG sTNF-R1 (inhibiteur du TNF-α). À la suite de ces protocoles, les rats ont été sacrifiés, la taille de l’infarctus a été déterminée et les différentes structures cérébrales du système limbique prélevées. Des tests biochimiques propres à chaque protocole ont été réalisés afin de documenter l'apoptose. Il a alors été observé qu’aucun des deux traitements ne présentait d’effet sur la taille de l’infarctus. L’étude de l’apoptose dans le système limbique a révélé que : 1) le processus apoptotique se mettait en place dans l’hippocampe dès les 15 premières minutes de reperfusion suivant l’infarctus du myocarde et que ce processus était spatialement dynamique dans le système limbique jusqu’au septième jour postreperfusion ; 2) il est apparu que la COX-2 était impliquée dans l'apoptose du système limbique ; 3) il a été observé que le TNF-α périphérique était impliqué dans ce processus apoptotique après 72 heures de reperfusion en activant la voie extrinsèque de l'apoptose. Ces résultats ont permis de caractériser la survenue de l’apoptose au niveau du système limbique chez le rat à la suite d’un infarctus du myocarde et de documenter l'implication de la COX-2 et du TNF-α dans ce processus. Bien que ces résultats n’apportent pas de schémas thérapeutiques clairs ou de mécanismes physiopathologiques globaux ces derniers permettent une meilleure compréhension de la relation existante entre le cœur et le système nerveux central dans le cadre de l’infarctus du myocarde. De manière moins spécifique ils précisent la relation entre le système inflammatoire et le système nerveux central. / About 15 to 30% of clinical patients with myocardial infarction develop major depression. This population is three to four times more vulnerable to fatalities such as death when compared to the non depressed post-myocardial population. In a rat model, developed in order to study post myocardial infarct depression, apoptotic cells within the limbic system have been found. It has been shown that cytokines could be responsible for the cell death linking the ischemic heart to the central nervous system. Thus, the aims of this thesis are: 1) to characterize the spatial time course of the apoptotic cell death within the limbic system, following a myocardial infarct, in a rat model; 2) to determine the effect of the anti-inflammatory celecoxib on this apoptosis in the amygdala and determine the COX-2 enzyme’s implication; 3) to determine the implication of the pro-inflammatory cytokine TNF-α in the apoptosis observed within the limbic system, following a myocardial infarct, in a rat model. In order to achieve these goals, rats were submitted to 40 minutes of myocardial ischemia followed by a variable reperfusion period (15 minutes, 24, 48, 72 hours or 7 days). Moreover, depending on the protocol, rats were treated with celecoxib (COX-2 selective inhibitor), or with PEG sTNF-R1 (TNF-α inhibitor). At the end of each respective reperfusion period, rats were sacrificed, infarct size was determined and the different structures of the limbic system were dissected for further analysis. Biochemical tests, specific to each protocol were performed in order to characterize this apoptosis. With respect to obtained results, we observed that the infarct size was impacted by none of the two treatments. Apoptosis study within the limbic system revealed that: 1) the apoptotic process was activated in the hippocampus area within the first 15 minutes of reperfusion and this process was spatially dynamic in the limbic system until the seventh day of reperfusion; 2) it appeared that COX-2 was implicated in the apoptosis in the limbic system; 3) peripheral TNF-α was implicated in the apoptotic process after 72 hours of reperfusion by activating the extrinsic and intrinsic pathways of apoptosis. These results allowed characterization of apoptosis within the limbic system, in a rat model, following a myocardial infarct and the establishment of the implication of COX-2 and TNF-α in this process. Although these results do not provide any clear therapeutic schemas or global physiopathological mechanisms, they allow a better comprehension of the existing relationship between the heart and the central nervous system within the myocardial infarct context. To a less specific extent these results bring more information on the relationship between the inflammatory system and the central nervous system.

Younger People with Dementia (YPwD) are those who receive a diagnosis of dementia under the age of 65. In Scotland the number of people with dementia who meet this definition is approximately 3200 (Alzheimer Scotland, 2017). The purpose of this study was to explore the human experience of living with dementia at a younger age and to consider interpretations of well-being as defined by the subjective experience of the participants. At the start of this study there was limited quality research available which explored the lives and experiences of YPwD. At that time there was some recognition within professional groups and practitioners that YPwD would benefit from age appropriate services. This study used an Interpretive Phenomenological design to explore the experiences of YPwD and used in-depth qualitative interviews with eight people who were diagnosed with dementia under the age of 65, to capture their journey through pre-diagnosis, diagnosis and beyond. Interpretive Phenomenological Analysis was utilised for the primary analysis. A secondary analysis was then conducted with the initial findings using Self-determination Theory, Basic Psychological Needs Theory, autonomy, competence and relatedness to identify areas of well-being. The study identified four superordinate themes situated within a four phase transition pathway, which identified how a diagnosis of dementia impacted on the person and the process they underwent following diagnosis. These are:pre-diagnosis phase, living in a changing world, awareness of the changing self, discombobulation; diagnostic phase, anger and relief, the fragmented self, consideration; post diagnostic phase, the challenge of learning to livewith dementia as a younger person, the evolving self, assimilation; and the phase living well beyond dementia, consolidated self, consolidation. The study highlighted that while having a diagnosis of dementia at a younger age is a challenging and devastating experience, it is possible to live a good and productive life beyond the diagnosis of dementia. The secondary analysis using Self-determination Theory, Basic Psychological Needs Theory identified that where the basic psychological needs were supported, this enabled participants to embrace their lives living with and beyond dementia with improved wellbeing. The findings suggest that the basic psychological needs were thwarted in the pre-diagnostic phase and during and immediately after diagnosis, creating feelings of ill-being. The study acknowledges the strong sense of identity around the younger person with dementia and suggests that this group perceive their dementia, and the support they need to live with the condition to be a different experience to that of older people. The ability of a number of the participants to live an active life within a supported community cannot be underestimated, and suggests that this area of care and support needs to be evaluated in light of the changing needs of people living with dementia, particularly those who are diagnosed at such an early part of their lifecycle.

Diese Dissertation befaßt sich mit kinetischen und dynamischen Analysen an spinmarkierten Proteinen mittels Elektronenspinresonanz-Spektroskopie (ESR-S) in Kombination mit weiteren biophysikalischen Methoden. Die Spinmarkierung der hier untersuchten Proteine (z.B. Bakteriorhodopsin (EF-loop) bzw. Reverse Transkriptase) erfolgt durch spezifische Substitution ausgewählter Aminosäure-Seitenketten durch eine radikalische Seitenkette ("R1", MTS-Spinlabel an Cystein gebunden). Der Schwerpunkt dieser Arbeit liegt in der Methodenentwicklung eines neuen Simulationsverfahrens für ESR-Spektren basierend auf einer speziellen Molekulardynamik-Simulation (MD-S). Das Verfahren nutzt den von Robinson et al. (J.Chem.Phys.96:2609-2616) vorgeschlagenen Trajektorien-basierten Berechnungsalgorithmus für ESR-Spektren. Hierfür sind zahlreiche Trajektorien der umgebungsabhängigen Umorientierungsdynamik von R1 mit Längen von jeweils über 700 ns erforderlich. Diese Trajektorien werden im hier präsentierten Simulationsverfahren mit minimalem Zeitaufwand in drei Stufen generiert: i) statistisch korrekte Erfassung des gesamten verfügbaren Konformationsraums von R1 in positionsspezifischer Proteinumgebung mittels einer kurzen (ca. 10 ns) speziellen MD-S (in-vacuo, 600 Kelvin); ii) Berechnung eines Potentials im Eulerwinkelraum welches das spezifische Umorientierungsverhalten der radikalischen R1-Kopfgruppe widerspiegelt; iii) Trajektorienberechnung mittels Simulation der potentialabhängigen Brownschen Umorientierungsdynamik eines virtuellen Teilchens bei 300 Kelvin (Einteilchen-Simulation). Die Statistiken wichtiger dynamischer Prozesse während der speziellen MD-S werden analysiert und mit Langzeit-Dynamiken aus herkömmlichen MD-S unter physiologischen Bedingungen verglichen. Zusätzlich wird ein Simulationsverfahren zur Identifikation von Wasserstoff-Brücken vorgestellt. In einem weiteren Kapitel dieser Arbeit werden Konzeption, Aufbau und Test einer Temperatursprung-ESR-Anlage beschrieben.

No description available.

Multi-site MRI studies collect large amounts of data in a short time frame. Large sample sizes are desirable to address power and replicability issues that have been problematic for scientists in the past. Although multi-site MRI solves the sample size problem, it brings with it a new set of challenges. Scanning the same person at different sites might result in differences in MRI derived measurements. In this thesis we compared three approaches to facilitate the analysis of multi-site MRI data: quantitative R1 mapping, adding site as a covariate in a linear model, and using the ComBat method. We also investigated the relationship between two common MRI measurements: signal and volume. We collected data from 64 healthy participants across 3 GE scanners and 1 Siemens scanner at 3T. We found that signal intensity was different between vendors whereas volume was not. Our R1 method resulted in values that were different across vendor and significantly lower than those reported in the literature. B1+ maps used to calculate R1 were different across sites. Using a scale factor, we were able to compensate for mistakes in R1 mapping. We also found that adding site as a covariate corrected mean differences in signal intensity across sites, but not differences in variance. The ComBat method gave best similarity between sites. However, since different people were scanned at each site, we couldn’t evaluate the effectiveness of each method as variation in the data could have been due to site effects or heterogeneity in participants. White matter volume and signal intensity in the white matter were correlated in males but not in females. We found that this low correlation was caused by outliers in our female sample. The correlation between white matter volume and signal in males suggests that both metrics are measuring myelin and can be used as converging evidence to detect changes in brain myelination. / Thesis / Master of Science (MSc)

<p dir="ltr">Manganese (Mn) is an essential trace element for humans that functions primarily as a coenzyme in several biological processes such as nerve and brain development, energy metabolism, bone growth and development, as well as cognitive functioning. However, overexposure to environmental Mn via occupational settings or contaminated drinking water can lead to toxic effects on the central nervous systems and cause a Parkinsonian disorder that features symptoms such as fine motor control deficits, dystonia rigidity, speech and mood disturbances, and cognitive deficits summarized under the term “manganism”. Over time, Mn exposure has shifted from acute, high-level instances leading to manganism, to low-level chronic exposure. Considering that Mn exposure is significantly lower than in the past, it is unlikely to expect manganism from chronic Mn exposure under current working conditions. Therefore, there is a need to develop sensitive methods to aid in updating the clinical diagnostic standards for manganism and Mn neurotoxicity as chronic exposure to Mn leads to more subtle symptoms.</p><p><br></p><p dir="ltr">Historically, magnetic resonance imaging (MRI) has been used as a non-invasive tool for detecting excess brain Mn accumulation. Specifically, T1-weighted images show bilateral hyperintensities of the globus pallidus (GP) due to the paramagnetic properties of Mn which increases the MR relaxation rate R1. Although the GP is considered the hallmark of excess brain Mn, this brain area is not necessarily associated with symptoms, exposure, or neuropsychological outcomes. Thus, the focus should not be on the GP only but on the entire brain. With recent advances in quantitative MRI (qMRI), whole brain mapping techniques allow for the direct measurement of relaxation rate changes due to Mn accumulation. The work in this dissertation uses such quantitative techniques and network science to establish novel computational in vivo imaging methods to a) visualize and quantify excess Mn deposition at the group and individual level, and b) characterize the toxicokinetics of excess brain Mn accumulation and the role of different brain regions in the development of neurotoxicity effects.</p><p><br></p><p dir="ltr">First, we developed a novel method for depicting excess Mn accumulation at the group level using high-resolution R1 relaxation maps to identify regional differences using voxel-based quantification (VBQ) and statistical parametric mapping. Second, we departed from a group analysis and developed subject-specific maps of excess brain Mn to gain a better understanding of the relationship between the spatial distribution of Mn and exposure settings. Third, we developed a novel method that combines network science with MRI relaxometry to characterize the storage and propagation of Mn and Fe in the human brain and the role of different brain regions in the development of neurotoxic effects. Lastly, we explore the application of ultra-short echo (UTE) imaging to map Fe content in the brain and compare it against R2* and quantitative susceptibility mapping (QSM).</p><p><br></p><p dir="ltr">Overall, this dissertation is a successful step towards establishing sensitive neuroimaging screening methods to study the effects of occupational Mn exposure. The individual Mn maps offer great potential for evaluating personal risk assessment for Mn neurotoxicity and allow monitoring of temporal changes in an individual, offering valuable information about the toxicokinetics of Mn. The integration of network science provides a holistic analysis to identify subtle changes in the brain’s mediation mechanisms of excess metal depositions and their associations with health outcomes.</p>

Desenvolveu-se uma metodologia para integração de dois modelos matemáticos, um de quantidade de água, em rede de fluxo, denominado ACQUANET com outro de qualidade de água, de uma dimensão, aplicado a represas, denominado CE-QUAL-R1. Para tanto, foi elaborada uma INTERFACE em linguagem de programação possibilitando que as vazões resultantes, simuladas pelo ACQUANET, servissem como dados de entrada ao CE-QUAL-R1 para simular a distribuição vertical das variáveis de qualidade de água em uma represa. Essa metodologia foi aplicada à Represa Jaguari-Jacareí no Sistema Cantareira em São Paulo, Brasil, como alternativa de gerenciamento quali-quantitativo, além de possibilitar o uso de retirada de água em diferentes profundidades, através da operação de tomadas d’água seletivas existentes. / A methodology was developed for the integration of two mathematical models, one of water quantity in network named ACQUANET with other of water quality, in one dimension, applied in revervoirs, named CE-QUAL-R1. In order to achieve this goal, an INTERFACE was developed to link the CE-QUAL-R1 with ACQUANET outflow results. It should be highlighted that ACQUANET has been used for beginning values of CE-QUAL-R1 and to simulate the vertical distribution of water quality variables in a reservoir. This methodology was applied to Jaguari-Jacarei Reservoir, of Cantareira System in Sao Paulo, Brazil, as a management quality and quantity tool of the system and it showed the use possibility of withdrawal of outflowing waters from different depths, through existing selective withdrawals ports operation.