A relação entre as alterações estruturais cerebrais e a resposta ao tratamento da depressão em idosos continua a ser uma área intrigante de pesquisa. Neste estudo, foram investigadas diferenças quanto ao volume total e regionalizado de substância cinzenta e branca em exames de ressonância magnética (RM) de idosos com depressão (de acordo com os critérios do DSMIV-TR) e de controles. Além disso, para melhor compreender a fisiopatologia da depressão no idoso, o volume total das hiperintensidades em substância branca foi quantificado e comparado entre os grupos. A amostra foi composta por 30 idosos com depressão e 22 controles. Os idosos com depressão foram divididos em grupos de acordo com o uso prévio de antidepressivos, a resposta ao tratamento farmacológico, assim como de acordo com a idade de início da depressão. As imagens de RM foram processadas utilizando o programa Statistical Parametric Mapping e a morfometria baseada em voxel (DARTEL). A quantificação do volume total das hiperintensidades em substância branca foi realizada através de uma variação do método automático conhecido como Expectation Maximization Segmentation (EMS). Na análise do cérebro inteiro, encontramos uma redução volumétrica significativa no giro reto e no córtex orbitofrontal bilateralmente em pacientes em comparação com os controles.Além disso, os pacientes que não estavam em uso de antidepressivos no momento da aquisição da RM apresentaram uma redução volumétrica ainda maior no giro reto e no córtex orbitofrontal bilateralmente. Pacientes com uso prévio de antidepressivos mostraram uma redução volumétrica no giro reto e córtex orbitofrontal bilateralmente em comparação com os controles e pacientes sem uso prévio de antidepressivos apresentaram uma redução ainda maior no giro reto e no córtex orbitofrontal bilateralmente em comparação com os controles. De acordo com seu estado de remissão após o uso de um algoritmo de tratamento farmacológico da depressão em idosos, os pacientes foram classificados nos grupos remissão e não remissão. O grupo remissão apresentou uma redução volumétrica no giro reto e no córtex orbitofrontal bilateralmente e no pólo temporal médio direito, em comparação com o grupo controle. O grupo não remissão mostrou uma redução volumétrica ainda maior no giro reto e no córtex orbitofrontal bilateralmente em comparação com o grupo controle. Para investigar fatores preditores de remissão, foi utilizada uma regressão logística. A pontuação inicial do Mini Exame do Estado Mental e o volume corrigido (para o volume total de substância branca) inicial do córtex orbitofrontal superior lateral esquerdo classificaram os pacientes de acordo com a resposta ao tratamento farmacológico. As mesmas análises estatísticas foram realizadas em relação ao volume de substância branca. Pacientes sem uso prévio de antidepressivos mostraram uma redução volumétrica no giro frontal superior direito em comparação com os controles. Além disso, o grupo com depressão de início tardio apresentou um aumento volumétrico no lóbulo posterior esquerdo do cerebelo em comparação com o grupo controle. Em relação ao volume total das hiperintensidades de substância branca, a amostra final processada com o EMS foi constituída por 22 pacientes e 19 controles. As mesmas comparações entre grupos descritas anteriormente foram realizadas e não foi encontrada diferença estatisticamente significante entre os grupos. Foi realizada uma nova regressão logística para investigar fatores preditores de remissão nessa amostra menor, incluindo o volume total de hiperintensidades de substância branca e não foi encontrado resultado estatisticamente significante. Em conclusão, os idosos com depressão apresentam redução volumétrica no giro reto e no córtex orbitofrontal bilateralmente e isso pode ser uma característica da depressão em idosos e um potencial biomarcador dessa condição. O uso de antidepressivos pode proteger contra a redução volumétrica de substância cinzenta e branca e parece ter um efeito neurotrófico nesses pacientes. Além disso, déficit cognitivo e redução de substância cinzenta no córtex orbitofrontal superior lateral esquerdo no início do estudo podem ser preditores de pior resposta ao tratamento farmacológico da depressão no idoso. Estudos longitudinais, com amostras maiores e com pacientes com depressão mais grave poderão contribuir para uma melhor compreensão da fisiopatologia da depressão em idosos / The association between structural brain changes and treatment response in patients with late-life depression (LLD) remains an intriguing area of research. This magnetic resonance imaging (MRI) study investigated the baseline gray and white matter volume of elderly with and without major depression (according to the DSM-IV-TR criteria). Moreover, to better understand the pathophysiology of LLD, white matter hyperintensities total volume was quantified and compared among groups. The sample consisted of 30 elderly patients with depression and 22 elderly healthy controls. Depressed patients were classified according to their previous use of antidepressants, to their response to pharmacological treatment, and to their age of depression onset. Brain MRI scans were processed using statistical parametric mapping and voxel-based morphometry (DARTEL). White matter hyperintensities total volume was conducted with a variation of an automatic method known as Expectation Maximization Segmentation (EMS). In the whole-brain analysis, we found a significant volumetric reduction in the gyrus rectus and in the orbitofrontal cortex (OFC) bilaterally in patients in comparison with controls. Additionally, patients who were not taking antidepressants at the time of the MRI had an even greater volumetric decrease in the gyrus rectus and in the orbitofrontal cortex bilaterally. Besides, we classified patients according to their previous antidepressant use (with or without) and compared them with controls. Patients with previous antidepressant use had a volumetric reduction in the gyrus rectus and in the OFC bilaterally in comparison with controls and patients without previous antidepressant use had an even greater reduction in the gyrus rectus and in the OFC bilaterally in comparison with controls. According to their remission status after the use of a pharmacologic algorithm treatment, patients were classified in remitted or not remitted. In comparison with controls, remitted patients showed a volumetric reduction in a cluster that included the gyrus rectus and in the OFC bilaterally and in another cluster that included the right middle temporal pole. Non-remitted patients showed an even greater volumetric reduction in the gyrus rectus and in the OFC bilaterally compared with controls. A logistic regression was used to investigate baseline predictive factors of remission. Baseline Mini Mental State Examination scores and the left superior lateral OFC standardized (to the total gray matter volume) volume classified patients with respect to their remission status. Regarding white matter volume, the same statistical analyses were conducted. Patients without previous antidepressant use showed a volumetric reduction in the right superior frontal gyrus in comparison with controls. In addition, late onset depression group had a volumetric increase in the left posterior cerebellum lobe in comparison with controls. In relation to the white matter hyperintensities total volume, 22 patients and 19 controls were processed with EMS. The same comparisons among groups were conducted and no statistical significant difference was found. A logistic regression was conducted to investigate baseline predictive factors of remission in this smaller sample, including the white matter hyperintensities total volume and no statistically significant result was found. In conclusion elderly with depression have volumetric reduction in the gyrus rectus and in the OFC bilaterally and this may be characteristic of late life depression and a potential biomarker of this condition. Antidepressant use seems to protect against gray matter reduction and to have a neurotrophic effect. In addition, cognitive deficits and regional gray matter abnormalities at baseline seem to be predictors of worse response to antidepressant treatment. Further longitudinal studies with larger sample size and more severe depression intensity may contribute to a better understanding of the pathophysiology of depression in the elderly

A percepção de esforço (PSE) e a fadiga tem grande participação do cérebro durante o exercício físico, no entanto, pouco se sabe quanto às áreas associadas a essas respostas. Dessa forma, o presente estudo teve como objetivo identificar e comparar as áreas cerebrais associadas à percepção de esforço durante exercício de ciclismo em diferentes intensidades e níveis de treinamento. Participaram do estudo 24 sujeitos adultos; 12 ciclistas (75,6 ± 8,4 kg; 175 ± 5,3 cm; 24,4 ± 7,1 anos; atividade física 5,4 ± 1,5 vezes por semana) e 12 não ciclistas (treinados) (79,7 ± 10,5 kg; 177 ± 9,1 cm; 27,4 ± 4,8 anos; atividade física 2,3 ± 1,3 vezes por semana). Os sujeitos foram posicionados ao ergômetro de ciclismo acoplado a ressonância magnética e realizaram um teste intervalado de carga incremental constituído por blocos de 30 s intervalados por 30 s de repouso. Ao término de cada bloco a percepção de esforço foi reportada. As análises comparativas das imagens foram todas geradas no Matlab através dos softwares SPM e NCA. Foi considerado para análise das imagens o período de 4 s imediatamente ao final de cada bloco de exercício com o objetivo de verificar as áreas relacionadas com o processamento da PSE. As seguintes áreas relacionadas à percepção de esforço foram ativadas: giro cingulado, giro pré-central, giro pós-central, giro frontal superior, giro frontal superior, lóbulo superior parietal, giro lingual, giro temporal médio, giro frontal médio, precuneus, cuneus e cerebelo. De forma complementar, as áreas inibidas foram: giro angular, giro temporal superior, giro temporal médio, giro pré-central, giro temporal superior, giro frontal médio, giro occipital médio, giro lingual, lóbulo paracentral, precuneus e tálamo. Essas áreas ativadas e inibidas estão associadas a uma resposta cognitiva, ou seja, o momento que o indivíduo reportava a percepção de esforço diante de um protocolo de exercício incremental, considerando todas as intensidades. Em intensidades baixas houve ativação do cerebelo e giro pós-central, e inibição do giro frontal médio e giro temporal superior. Em intensidades altas, houve uma ativação do giro cingulado e inibição do giro angular e precuneus. Na comparação entre as intensidades podemos destacar que em intensidades baixas houve maior ativação do lóbulo parietal superior. Por outro lado, em intensidades altas houve maior inibição do giro angular, cingulado posterior, lóbulo parietal inferior e precuneus. Quando comparados indivíduos ciclistas e saudáveis houve uma maior ativação do giro pré-central e maior inibição do giro pré-central, giro temporal inferior e cerebelo nos ciclistas considerando todas as intensidades. Por fim, na comparação entre ciclistas e treinados, nas intensidades altas houve maior inibição do giro temporal médio (giro fusiforme) nos ciclistas. As áreas cerebrais, ativadas e inibidas, associadas à percepção de esforço estão relacionadas à área motora, pré-motora, motor suplementar somatossensoriais, controle emocional, processamento de atenção, linguagem, auditivas, integração de informação, gerenciamento de memória, planejamento e resolução de problemas e cognitiva. Em intensidades baixas, áreas motoras e somatossensorias foram ativadas e houve inibição de área pré-frontal e auditiva. Por outro lado, em intensidades altas, foram ativadas áreas relacionadas com o controle de emoções e foram inibidas áreas relacionadas ao processamento de linguagem e memória episódica. Entre ciclistas e não ciclistas, houve maior ativação de área motora e maior inibição de área somatossensorial, processamento de atenção e motora / Perception of effort and fatigue are widely represented in the brain during exercise, however, the information is not clear about the areas associated with these responses. Thus, this study aimed to identify and compare the brain areas associated with perception of effort during cycling exercise at different intensities and levels of training. This study included 24 adult subjects; 12 cyclists (75.6 ± 8.4 kg, height 175 cm ± 5.3, 24.4 ± 7.1 years; physical activity 5.4 ± 1.5 times per week) and 12 non-cyclists (trained) (79.7 ± 10.5 kg; 177 cm ± 9.1, 27.4 ± 4.8 years; physical activity 2.3 ± 1.3 times per week). Subjects were positioned to cycling ergometer coupled to magnetic resonance equipment and performed an incremental load interval test comprising blocks 30 s intervals for 30 s rest. At the end of each block, the perception of effort was reported. Comparative analysis of the images was all generated in Matlab using the SPM and NCA software. The following areas related to perceived exertion were activated: cingulate gyrus, precentral gyrus, post-central gyrus, superior frontal gyrus, superior frontal gyrus, parietal upper lobe, gyrus lingual, middle temporal gyrus, middle frontal gyrus, precuneus, cuneus and cerebellum. Complementarily, these were inhibited areas: angular gyrus, superior temporal gyrus, middle temporal gyrus, precentral gyrus, superior temporal gyrus, middle frontal gyrus, middle occipital gyrus, gyrus lingual, paracentral lobule, precuneus and thalamus. These activated and inhibited areas are related to cognitive response, when the individual reported the perceived exertion on an incremental exercise protocol, considering all intensities. At low intensities, there was activation of the cerebellum and post-central gyrus, and inhibition of the middle frontal gyrus and superior temporal gyrus. At high intensities, there was an activation of the cingulate gyrus and inhibition of angular and precuneus spin. Comparing the intensities, there was greater activation in the superior parietal lobe at low intensities. On the other hand, high intensity demonstrated greater inhibition of the angular gyrus, posterior cingulate, inferior parietal lobule and precuneus. Compared trained and healthy individuals there was a greater activation of the precentral gyrus and greater inhibition of pre-central gyrus, inferior temporal gyrus and cerebellum in trained subjects considering all intensities. Finally, comparing trained healthy subjects at high intensities there was greater inhibition of medial temporal gyrus (fusiform gyrus) in trained individuals. The brain areas, activated and inhibited, associated with the perception of effort are related to motor, pre-motor, somatosensory supplemental motor, emotional control, attention processing, language, auditory, information integration, memory management, planning and resolution problems and cognitive. At low intensities, motor and somatosensory areas were activated and there was inhibition of the prefrontal and auditory area. On the other hand, at high intensities, areas related to the control of emotions were activated and areas related to language processing and episodic memory were inhibited. Between cyclists and non-cyclists, there was greater activation of motor area and greater inhibition of somatosensory area, attention and motor processing

<p>Manganese (Mn) is an essential element and, at high doses, a neurotoxin that many workers are exposed to daily. Increased Mn body burden due to occupational exposures leads to a parkinsonian disorder that features symptoms such as mood disturbances, cognition deficits, and motor dysfunction. To understand exposed workers’ risk, biomarkers of exposure have been developed using blood, hair, bone, and toenails. None of these biomarkers take into account how much Mn is in the brain and instead rely on the assumption that Mn uptake in these materials is proportional and related to the levels in the brain. One way to measure Mn in the brain is through neuroimaging modalities, such as magnetic resonance imaging and positron emission tomography, however there remains a need to establish reliable neuroimaging biomarkers for Mn exposure and its toxicological effects. This thesis addresses this need.</p><p>First, we hypothesized that changes in Mn exposure would be reflected by changes in the MRI relaxation rate R1 and thalamic γ-aminobutyric acid (GABA). As part of a prospective cohort study, 17 welders were recruited and imaged on two separate occasions approximately two years apart. MRI relaxometry was used to assess changes of Mn accumulation in the brain. Additionally, GABA was measured using magnetic resonance spectroscopy (MRS) in the thalamic and striatal regions of the brain. Air Mn exposure ([Mn]air) and cumulative exposure indexes of Mn (Mn-CEI) for the past three months (Mn-CEI3M), past year (Mn-CEI12M), and lifetime (Mn-CEILife) were calculated using personal air sampling and a comprehensive work history, while toenails were collected for analysis of internal Mn body burden. Finally, welders’ motor function was examined using the Unified Parkinson’s Disease Rating Scale (UPDRS). Mn-CEI12M decreased significantly between the first and second scan (Wilcoxon Signed Rank, p = 0.02). ΔMn-CEI3M were correlated with R1 in the substantia nigra (spearman partial correlation, ρ = 0.50, p = 0.036) and thalamic GABA (ρ = 0.66, p = 0.001), but only GABA significantly decreased linearly with Mn-CEI3M (quantile regression, β = 15.22, p = 0.02). Finally, Mn-CEILife influences the change in R1 in the substantia nigra with Δ[Mn]Air, where higher Mn-CEILife lessened the ΔR1 per Δ[Mn]Air (F-test, p = 0.005). While R1 and GABA changed with Mn exposure, UPDRS was unaffected.</p><p>Secondly, we hypothesized that occupational exposure to Mn would lead to disturbances in dopamine release (DA), as measured with PET. Excess exposure to manganese (Mn) can lead to symptoms similar to Parkinson’s disease (PD). While symptoms of PD are due to loss of nigrostriatal dopaminergic neurons, there is no DA neuron loss with Mn toxicity. To assess how DA release may be affected by Mn exposure, 6 subjects (3 welders, 3 controls) were scanned with positron emission tomography and [11C]raclopride (a DA D2/D3 receptor antagonist displaceable by endogenous DA) at baseline and during an amphetamine challenge. There were no apparent differences in amphetamine-induced striatal DA release between groups. However, UPDRS motor scores were positively linearly related to [11C]raclopride binding potential (BPND) in the putamen, whereas Mn-CEILife was negatively related to baseline pre-commissural caudate and ventral striatum BPND. The pilot results suggest that [11C]raclopride PET might delineate the cause of mood and motor dysfunction in subjects exposed to Mn.</p><p>Third, we hypothesized that advanced data analysis techniques, such as machine learning, would increase our power in finding differences between groups of welders and controls based on exposure and biological outcomes. This study used data from previous studies in occupationally exposed welders and controls. Whole brain relaxometry using MRI measuring the relaxation rate R1 was acquired in 52 welders and 37 controls. Because measures of R1 in selected regions of the brain have been previously found to be proportional to Mn, we hypothesized that an advanced model taking into account the whole brain might be more predictive for Mn exposure. Additionally, because R1 is proportional to Mn in the region, we used a biokinetic model to estimate the amount of excess Mn in the brain from occupational exposures. Support vector machines (SVM) with a linear kernel were trained using leave-one-out cross-validation. Results indicated that models had recall and accuracy better than chance targeting air Mn exposure, years welding, age, and thalamic GABA. In comparison to all models, R1 appears to reliably predict thalamic GABA across all thresholds, which was previously shown to change with increased Mn exposure. This suggests that while R1 may be proportional to Mn, some Mn may not be free to contribute to signal, and instead thalamic GABA might better reflect the overall amount of free Mn in the brain. </p><p>Collectively, this thesis is a successful step towards establishing neuroimaging biomarkers of effect from occupational Mn exposure. The MRI relaxation rate R1, with adequate modeling, could eventually be used to measure total Mn brain burden while thalamic GABA might represent a better metric for measuring the neurochemical effects from recent exposures. However, future research should incorporate more endpoints, such as motor tests, mood assessments, and behavior assessments. </p><div><br></div><p><br></p>

Os métodos minimamente invasivos têm sido cada vez mais utilizados para o tratamento do leiomioma e, a embolização da artéria uterina, tem se destacado como método seguro e efetivo. O objetivo deste estudo foi avaliar, pela ressonância magnética da pelve, os fatores preditores da diminuição dos leiomiomas de pacientes submetidos a embolização da artéria uterina. Métodos: Estudaram-se 50 mulheres sintomáticas com leiomioma uterino, na menacme, que foram submetidas a embolização da artéria uterina. Acompanhou-se, por meio da ressonância magnética o volume do útero e dos leiomiomas. Foram examinados 179 leiomiomas nestas pacientes, um mês antes e seis meses depois do procedimento. Resultados: Seis meses após o tratamento, a redução média do volume uterino foi de 38,91%, enquanto os leiomiomas tiveram redução de 55,23%. Nos leiomiomas submucosos e/ou com a relação nódulo/músculo em T2 mais elevada, a redução do volume foi ainda maior (maior que 50,00%). Conclusões: As pacientes portadoras de leiomiomas e submetidas à embolização da artéria uterina apresentaram redução de volume dos nódulos superior a 50,00%, à ressonância magnética, quando eram submucosos e/ou tinham uma relação nódulo/músculo em T2 mais elevada / Objective : Minimally invasive methods are being an alternative to treat leiomyomas, including the uterine artery embolization that has emerged as a safe and effective method. The aim of this study was to evaluate the magnetic resonance imaging predictors of decrease in leiomyomas of patients who underwent uterine artery embolization. Methods: This study followed 50 symptomatic premenopausal women with uterine leiomyoma who underwent uterine artery embolization. Treatment was accompanied by magnetic resonance imaging of both the volume of the uterus and the leiomyomas. We examined 179 leiomyomas in that 50 patients, one month before and six months after of the procedure. Results: Six months after treatment, the mean reduction in uterine was 38.91%, while leiomyomas decreased by 55.23%. In submucosal leiomyomas and/or with a higher node/muscle ratio in T2, the volume reduction was even higher (greater than 50.00%). Conclusions: The patients with leiomyomas and underwent uterine artery embolization, showed reductions in the volume of nodes greater than 50,00%, on the magnetic resonance imaging, when they were submucosal and / or had a higher node-to-muscle ratio in T2

This thesis combines phenomenological and neuroscientific research to elucidate the effects of psychedelic agents on the human brain, mind and psychological well-being. Psychoactive plants have been used for thousands of years for ceremonial and ritual purposes. Psychedelics are psychoactive substances that affect cognitive processes and alter perception, thoughts, and mood. Illegalization of psychedelics in the 1960s rendered them impossible to study empirically but in the last couple of decades, relaxed legal restrictions regarding research purposes, renewed interest in the effects of psychedelic drugs and new brain imaging techniques have started to reveal the possibilities of these mind-altering substances. Psychedelics mainly affect the serotonin receptor 5-HT2A which in turn affect the functioning of largescale cortical areas by changing cerebral blood flow, alpha oscillations, and functional connectivity. These cortical changes not only induce immediate alterations in perception and cognition but have been shown to have positive effects in therapeutic interventions for depression, anxiety, and addiction, and also positively affect well-being in general. Although the pharmacology and neurobiology of psychedelics are still poorly understood, the potential benefits justify empirical research on psychedelics in humans.

Manual analysis of medical images such as magnetic resonance imaging (MRI) requires a trained professional, is time-consuming and results may vary between experts. We propose an automated method for kidney segmentation using a convolutional Neural Network (CNN) model based on the U-Net architecture. Investigations are done to compare segmentations between trained experts, inexperienced operators and the Neural Network model, showing near human expert level performance from the Neural Network. Stratified sampling is performed when selecting which subject volumes to perform manual segmentations on to create training data. Experiments are run to test the effectiveness of transfer learning and data augmentation and we show that one of the most important components of a successful machine learning pipeline is larger quantities of carefully annotated data for training.

Dynamic contrast enhanced (DCE) cardiac magnetic resonance imaging (MRI) is well-established as a non-invasive method for qualitatively detecting obstructive coronary artery disease (CAD) which can impair myocardial blood flow and may result in myocardial infarction. Mathematical modelling of cardiac DCE-MRI data can provide quantitative assessment of myocardial blood flow. Quantitative assessment of myocardial blood flow may have merit in further stratification of patients with obstructive CAD and to improve the diagnosis and prognostication of the disease in the clinical setting. This thesis investigates the development of a quantitative analysis protocol for cardiac DCE-MRI data. In the first study presented in this thesis, Fermi and distributed parameter (DP) modelling are compared in single bolus versus dual bolus analysis. For model-based myocardial blood flow quantification, the convolution of a model with the arterial input function (i.e. contrast agent concentration-time curve extracted from the left ventricular cavity) is fitted to the tissue contrast agent concentration-time curve. In contrast to dual bolus DCE-MRI protocols, single bolus protocols reduce patient discomfort and acquisition protocol duration/complexity but, are prone to arterial input function saturation caused in the left ventricular cavity by the high concentration of contrast agent during bolus passage. Saturation effects can degrade the accuracy of quantification using Fermi modelling. The analysis presented in this study showed that DP modelling is less dependent on arterial input function saturation than Fermi modelling in eight healthy volunteers. In a pilot cohort of five patients, DP modelling detected for the first time reduced myocardial blood flow in all stenotic vessels versus standard clinical assessments. In the second study, it was investigated whether first-pass DP modelling can give accurate myocardial blood flow, against ideal values generated by numerical simulations. Unlike Fermi modelling which is convolved with only the first-pass range of the arterial input function, DP modelling is convolved with the entire contrast agent concentration-time course. In noisy and/or dual bolus data, it can be particularly challenging to identify the end point of the first-pass in the arterial input function. This study demonstrated that contrary to Fermi modelling, myocardial blood flow analysis using DP modelling does not depend on the number of time points used for fitting. Furthermore, this data suggests that DP modelling can reduce the quantitative variability caused by subjectivity in selection of the first-pass range in cardiac MR data. This in turn may help to facilitate the development of more automated software algorithms for myocardial blood flow quantification. In the third study, Fermi and DP modelling were compared against invasive clinical assessments and visual MR estimates, to assess their diagnostic ability in detecting obstructive CAD. A single bolus DCE-MRI protocol was implemented in twentyfour patients. In per vessel analysis, DP modelling reached superior sensitivity and negative predictive value in detecting obstructive CAD compared to Fermi modelling and visual estimates. In per patient analysis, DP modelling reached the highest sensitivity and negative predictive value in detecting obstructive CAD. These studies show that DP modelling analysis of cardiac single bolus DCE-MRI data can provide important functional information and can establish haemodynamic biomarkers to non-invasively improve the diagnosis and prognostication of obstructive CAD.

Cerebral small vessel disease (SVD) is a common cause of strokes and dementia. The pathogenesis of SVD is poorly understood, but imaging and biochemical investigations suggest that subtle blood-brain barrier (BBB) leakage may contribute to tissue damage. The most widely-used imaging method for assessing BBB integrity and other microvascular properties is dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). DCE-MRI has primarily been applied in situations where contrast uptake in tissue is typically large and rapid (e.g. neuro-oncology); the optimal approach for quantifying BBB integrity in diseases where the BBB remains largely intact and the reliability of resulting measurements is unclear. The main purpose of this thesis was to assess and improve the reliability of quantitative assessment of subtle BBB disruption, in order to illuminate its potential role in cerebral SVD. Firstly, a systematic literature review was performed in order to provide an overview of DCE-MRI methods in the brain. This review found large variations in MRI procedures and data analysis methods, resulting in widely varying estimates of tracer kinetic parameters. Secondly, this thesis focused on the analysis of DCE-MRI data acquired in an on-site clinical study of mild stroke patients. After performing basic DCE-MRI processing (e.g. selection of a vascular input function), this work aimed to determine the tracer kinetic modelling approach most suitable for assessing subtle BBB disruption in this cohort. Using data-driven model selection and computer simulations, the Patlak model was found to provide accurate estimates of blood plasma volume and low-level BBB leakage. Thirdly, this thesis aimed to investigate two potential pitfalls in the quantification of subtle BBB disruption. Contrast-free measurements in healthy volunteers revealed that a signal drift of approximately 0.1 %/min occurs during the DCE-MRI acquisition; computer simulations showed that this drift introduces significant systematic errors when estimating low-level tracer kinetic parameters. Furthermore, tracer kinetic analysis was performed in an external patient cohort in order to investigate the inter-study comparability of DCE-MRI measurements. Due to the nature of the acquisition protocol it proved difficult to obtain reliable estimates of BBB leakage, highlighting the importance of study design. Lastly, this thesis examined the relationship between quantitative MRI parameters and clinical measurements in cerebral SVD, with a focus on the estimates of blood volume and BBB leakage obtained in the internal SVD patient cohort. This work did not provide evidence that BBB leakage in normal-appearing tissue increases with SVD burden or predicts disease progression; however, increased BBB leakage was found in white matter hyperintensities. Furthermore, this work raises the possibility of a role for blood plasma volume and dietary salt intake in cerebral SVD. The work described in this thesis has demonstrated that it is possible to estimate subtle BBB disruption using DCE-MRI, provided that the measurement and data analysis strategies are carefully optimised. However, absolute values of tracer kinetic parameters should be interpreted with caution, particularly when making comparisons between studies, and sources of error and their influence should be estimated where possible. The exact roles of BBB breakdown and other microvascular changes in SVD pathology remain to be defined; however, the work presented in this thesis contributes further insights and, together with technical advances, will facilitate improved study design in the future.

Considerando que a batata é o terceiro produto alimentar mais importante no mundo é necessária sua preservação e adaptação para as diferentes comunidades e condições ambientais do planeta, pois a consequência da redução da produção desse alimento pode ser a fome em todo o mundo. Um potecial causador desse problema é o aquecimento global, que é cada vez mais aceito pela ciência e as mudanças climáticas que vêm acontecendo no planeta. Alguns estudos sobre o efeito do aquecimento global e também mais especificamente do estresse hídrico sobre a cultura da batata estão sendo realizados, e são analisados os efeitos sobre cada parte da planta, como folhas, brotos, raízes, etc, porém o estudo sobre a raiz da batata é realizado de forma invasiva, ou seja, é necessário remover a planta do substrato. Nesse trabalho, apresentamos uma técnica para o estudo dos efeitos do estresse hídrico sobre a raiz da batata de forma não invasiva, portanto, os estudos serão realizados sem a remoção da planta do substrato. Dessa forma, poderão ser acompanhados os efeitos do estresse hídrico na planta em todos os estádios do desenvolvimento. Além disso, pode-se acompanhar o crescimento natural da raiz, diferentemente de outros modelos de estudo. A análise foi realizada com amostras da cultivar Ágata, plantadas em substrato sem substâncias paramagnéticas, e para isso foi utilizada a cultura hidropônica. Foram realizadas Imagens de Ressonância Magnética e em seguida um processamento e quantificação das imagens através da ferramenta matemática Multifractal. A técnica mostrou-se promissora para esse estudo, pois parâmetros multifractais mostraram-se sensíveis ao estresse hídrico, portanto, poderão ser realizados futuros estudos em outras cultivares de batata sob efeito do estresse hídrico. / Considering that potato is the third most important food product in the world, it is necessary its preservation and adaptation to different communities and environmental conditions on the planet, because the consequence of reducing the production of that crop may be the hunger of people around the world. With global warming, which is increasingly more accepted by science, and the climate changes that are happening on the planet it is necessary to generate new genotypes more resistant to these changes, as well as the generation of varieties suitable for tropical climates. Some studies on the effect of global warming and also more specifically on water stress on potato crops are being conducted. In these studies, one analyze the effects on every part of the plant, such as leaves, shoots, roots, etc., but the study on potato root is conducted invasively, i.e., to observe the result is necessary to remove the plant from the substrate. In this work, we present a technique for studying the effects of water stress on the potato root in a noninvasively way, therefore, various studies may be performed without requiring the removal of the plant from the substrate. Thus, the studies may accompany the effects of water stress on the plant at all stages of development. In addition, this tool allows the observation and monitoring of the natural growth of the root, unlike the other study designs. The analysis was performed with samples of cultivar Agata, planted in cups with substrate containing no paramagnetic substances, and to make this possible hydroponic culture was used. Magnetic Resonance Imaging studies were performed followed by processing and quantification of the images obtained through the mathematical tool Multifractal . The technique has shown promising for this study because multifractal parameters were sensitive to water stress, so future studies can be conducted in other potato cultivars under effect of water stress.

Proposta: O objetivo do presente estudo foi a análise da associação entre a vascularização das metástases hepáticas, detectadas através de exames de ressonância magnética, e a progressão da doença em pacientes com câncer de mama. Casuística e Métodos: Partiu-se do rastreamento de pacientes com câncer de mama dentre todos os pacientes atendidos para exames de ressonância magnética, entre 1995 e 2002, no Hospital da Universidade da Carolina do Norte em Chapel Hill, USA. Foram identificadas 16 pacientes com câncer primário de mama e com metástases hepáticas, com 99 exames de ressonância magnética antes e após a terapia sistêmica. Comparando-se cada exame de ressonância magnética com o seu anterior, a doença das pacientes foi classificada em quatro diferentes status: Resposta Completa, Resposta Parcial, Doença Estável e Doença em Progressão. As metástases hepáticas foram caracterizadas como hipervasculares ou hipovasculares, de acordo com a intensidade do realce durante a fase arterial do exame de ressonância magnética. Estatisticamente, o teste exato de Fisher e o modelo de regressão logística ordinal foram usados para estimar o não ajustamento e o risco de ajustamento entre a presença de metástases hepáticas hipervasculares e a progressão da doença. Resultados: Todas as pacientes eram do sexo feminino, com uma média de idade de 51.5 anos. Na análise não ajustada, a associação entre a presença de hipervascularização nas metástases hepáticas e a progressão da doença foi, de um ponto de vista estatístico, altamente significativa (p< 0,0001). Na análise de regressão logística múltipla, a hipervascularidade de metástases hepáticas foi caracterizada como um fator preditivo independente de progressão da doença. Pacientes com lesões hepáticas hipervasculares apresentaram uma incidência 20,5 vezes maior de progressão da doença, comparadas com pacientes sem hipervascularidade (relação das probabilidades= 20,5; 95% de intervalo de confiança [5,1; 83,5], p < 0,0001). Conclusão: Os resultados de nossa análise mostram evidências de que a progressão da doença pode ser predita através da avaliação da vascularidade das metástases hepáticas pelo exame de ressonância magnética, em pacientes com metástases hepáticas de câncer de mama / Purpose: The aim of the present investigation was to evaluate the association of liver metastases vascularity, as characterized by MR imaging, and disease progression in breast cancer patients. Materials and Methods: Breast cancer patients undergoing liver MR from 1995 through 2002 were extracted from University of North Carolina at Chapel Hill\'s database. Sixteen patients with liver metastases were identified who had 99 MR imaging studies prior and after receiving systemic therapy. Based on comparison of MR imaging with the previous MR examination, disease status of patients were classified as Complete Response, Partial Response, Stable Disease, and Progressive Disease. Liver metastases were characterized as hypervascular or hypovascular based on the degree of enhancement in arterial, portal and interstitial phase after administration of contrast agent. Fisher\'s exact test and ordinal logistic regression models were used to estimate the unadjusted and risk adjusted association between the presence of hypervascular liver metastases and disease progression. Results: All patients were female, and had a median age of 51.5 years old. In unadjusted analyses the association between the presence of hypervascularity of liver metastases and disease progression was highly statistically significant (p < 0.0001). In multiple logistic regression analyses, hypervascularity of liver metastases was found to be an independent predictor of disease progression. Patients with hypervascular liver lesions were 20.5 times more likely to experience disease progression compared with patients without hypervascularity (odds ratio: 20.5; 95% confidence interval [5.1, 83.5], p<0.0001). Conclusion: Our analysis provides suggestive evidence that disease progression can be predicted through MR imaging assessment of the vascularity of liver metastases in breast cancer patients