Development and application of novel algorithms for quantitative analysis of magnetic resonance imaging in multiple sclerosis.

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Characterization of vascular heterogeneity of astrocytomas grade 4 for supporting patient prognosis estimation, and treatment response assessment

[ES] Los tumores cerebrales son una de las enfermedades más devastadoras en la actualidad por el importante deterioro cognitivo que sufren los pacientes, la elevada tasa de mortalidad y el mal pronóstico. Los astrocitomas de grado 4 conllevan una supervivencia de cinco años en aproximadamente el 5% de los pacientes diagnosticados, siendo los tumores más agresivos y letales del Sistema Nervioso Central (SNC). Los astrocitomas de grado 4 siguen siendo un problema médico complejo aún sin resolver. A pesar de representar más del 60% de los tumores cerebrales malignos en adultos, estos tumores tienen una baja prevalencia relativa y se consideran una enfermedad huérfana, lo que dificulta el desarrollo de nuevos fármacos o tratamientos que puedan beneficiar a los pacientes. La agresividad de estos tumores se debe a diferentes características, como la fuerte angiogénesis, la necrosis, la microproliferación vascular, la capacidad de invasión e infiltración de las células tumorales y un microambiente inmunológico particular. Además, debido a la rápida progresión de los astrocitomas de grado 4, en la zona de la lesión coexisten diferentes regiones específicas que cambian con el tiempo. Esta naturaleza compleja, junto con la marcada heterogeneidad interpaciente, intratumoral y longitudinal, complica el éxito de un único tratamiento eficaz para todos los pacientes. La imagen de resonancia magnética (MRI) supone una técnica útil para caracterizar la morfología y la vascularidad del tumor. El uso de métodos avanzados y robustos para analizar las imágenes de MR recogidas en las fases iniciales del tratamiento de los pacientes permite la delimitación de las diferentes regiones de los astrocitomas de grado 4, convirtiéndose en herramientas útiles para investigadores, radiólogos y neurocirujanos. Además, el cálculo de biomarcadores vasculares de imagen, como los propuestos en esta tesis, facilitaría la caracterización del tumor, la estimación del pronóstico y los enfoques de tratamiento más personalizados. Esta tesis propone cuatro pilares fundamentales para avanzar en el manejo de los astrocitomas de grado 4. Estos incluyen I) la caracterización multinivel del tumor para mejorar las clasificaciones de los gliomas de alto grado del SNC; II) la búsqueda y desarrollo de biomarcadores robustos para estimar el pronóstico de los pacientes desde el momento prequirúrgico; III) así como para evaluar la respuesta a los tratamientos y la selección de los pacientes que pueden beneficiarse de terapias específicas; y IV) el diseño e implementación de estudios clínicos y protocolos para la recogida de datos a largo plazo de cohortes de pacientes notables a nivel internacional. Para abordar estos cuatro pilares, se ha utilizado un enfoque interdisciplinario que combina el análisis de imágenes médicas, técnicas avanzadas de inteligencia artificial y variables moleculares, histopatológicas y clínicas. En conclusión, hemos abordado la influencia de la heterogeneidad interpaciente e intratumoral del astrocitoma de grado 4 para la caracterización y clasificación del tumor, la estimación del pronóstico del paciente y la predicción de las respuestas al tratamiento. Además, se han diseñado e implementado diferentes estudios clínicos que permiten la recogida de datos multinivel de cohortes internacionales de pacientes con astrocitoma de grado 4.[CA] Els tumors cerebrals són una de les malalties més devastadores en l'actualitat per la important deterioració cognitiva que pateixen els pacients, l'elevada taxa de mortalitat i el mal pronòstic. Els astrocitomes de grau 4 comporten una supervivència de cinc anys en aproximadament el 5% dels pacients diagnosticats, sent els tumors més agressius i letals del Sistema Nerviós Central (SNC). Els astrocitomes de grau 4 continuen sent un problema mèdic complex encara sense resoldre. Malgrat representar més del 60% dels tumors cerebrals malignes en adults, aquests tumors tenen una baixa prevalença relativa i es consideren una malaltia òrfena, la qual cosa dificulta el desenvolupament de nous fàrmacs o tractaments que puguen beneficiar als pacients. L'agressivitat d'aquests tumors es deu a diferents característiques, com la forta angiogènesis, la necrosi, la microproliferació vascular, la capacitat d'invasió i infiltració de les cèl·lules tumorals i un microambient immunològic particular. A més, a causa de la ràpida progressió dels astrocitomes de grau 4, en la zona de la lesió coexisteixen diferents regions específiques que canvien amb el temps. Aquesta naturalesa complexa, juntament amb la marcada heterogeneïtat interpacient, intratumoral i longitudinal fa que es complique l'èxit d'un únic tractament eficaç per a tots els pacients. L'imatge de ressonància magnètica (MRI) suposa una tècnica útil per a caracteritzar la morfologia i la vascularitat del tumor. L'ús de mètodes avançats i robustos per a analitzar les imatges de MR recollides en les fases inicials del tractament dels pacients permet la delimitació de les diferents regions dels astrocitomes de grau 4, convertint-se en eines útils per a investigadors, radiòlegs i neurocirugians. A més, el càlcul de biomarcadors vasculars d'imatge, com els proposats en aquesta tesi, facilitaria la caracterització del tumor, l'estimació del pronòstic i els enfocaments de tractament més personalitzats. Aquesta tesi proposa quatre pilars fonamentals per a avançar en el maneig dels astrocitomes de grau 4. Aquests inclouen I) la caracterització multinivell del tumor per a millorar les classificacions dels gliomes d'alt grau del SNC; II) la cerca i desenvolupament de biomarcadors robustos per a estimar el pronòstic dels pacients des del moment prequirúrgic; III) així com per a avaluar la resposta als tractaments i la selecció dels pacients que poden beneficiar-se de teràpies específiques; i IV) el disseny i implementació d'estudis clínics i protocols per a la recollida de dades a llarg termini de cohorts de pacients notables a nivell internacional. Per a abordar aquests quatre pilars, s'ha utilitzat un enfocament interdisciplinari que combina l'anàlisi d'imatges mèdiques, tècniques avançades d'intel·ligència artificial i variables moleculars, histopatològiques i clíniques. En conclusió, hem abordat la influència de l'heterogeneïtat interpacient i intratumoral del astrocitoma de grau 4 per a la caracterització i classificació del tumor, l'estimació del pronòstic del pacient i la predicció de les respostes al tractament. A més, s'han dissenyat i implementat diferents estudis clínics que permeten la recollida de dades multinivell de cohorts internacionals de pacients amb astrocitoma de grau 4.[EN] Brain tumors are one of the most devastating diseases today because of the significant cognitive impairment suffered by patients, high mortality rates, and poor prognosis. Astrocytomas grade 4 bring five-year survival in approximately 5% of diagnosed patients, being the most aggressive and lethal tumors of the Central Nervous System (CNS). Astrocytomas grade 4 continue to be an unresolved complex medical problem. Despite accounting for more than 60% of malignant brain tumors in adults, these tumors have a low relative prevalence and are considered an orphan disease, making difficult developing new drugs or treatments that might benefit patients. The aggressiveness of these tumors is due to different characteristics, such as strong angiogenesis, necrosis, vascular microproliferation, the capacity of the tumor cells to invade and infiltrate, and a particular immune microenvironment. In addition, due to the rapid progression of astrocytomas grade 4, different specific regions coexist in the lesion area which change over time. This complex nature, along with the marked interpatient, intratumor, and longitudinal heterogeneity, makes complicate the success of a single efficient treatment for all patients. Magnetic Resonance Imaging (MRI) represents a useful technique to characterize tumor morphology and vascularity. Using advanced and robust methods to analyze MR images collected from initial stages of patient management allows the delineation of different regions of astrocytomas grade 4, becoming useful tools for researchers, radiologists and neurosurgeons. In addition, the calculation of imaging vascular biomarkers, such as those proposed in this thesis, would facilitate tumor characterization, prognosis estimation and more personalized treatment approaches. This thesis proposes four fundamental pillars to advance the management of astrocytomas grade 4. These include I) the multilevel characterization of the tumor to improve classifications of high-grade CNS gliomas; II) the search and development of robust biomarkers for estimating patient prognosis from the presurgical moment; III) as well as for evaluating the response to treatments and the selection of patients who may benefit from specific therapies; and IV) the design and implementation of clinical studies and protocols for long-term collecting data from internationally remarkable cohorts of patients. To address these four pillars, an interdisciplinary approach has been used that combines medical imaging analysis, advanced artificial intelligence techniques, and molecular, histopathological, and clinical variables. Concluding, we have addressed the influence of both interpatient and intratumor heterogeneity of astrocytoma grade 4 for tumor characterization and classification, patient prognosis estimation and predicting treatment responses. In addition, different clinical studies have been designed and implemented allowing the collection of multilevel data from international cohorts of patients with astrocytoma grade 4.Álvarez Torres, MDM. (2022). Characterization of vascular heterogeneity of astrocytomas grade 4 for supporting patient prognosis estimation, and treatment response assessment [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/18895

Quantifying age-related differences in diffusion tensor imaging biomarkers for the male urethral sphincter of prostate cancer patients

Tese de mestrado integrado, Engenharia Biomédica e Biofísica (Sinais e Imagens Médicas) Universidade de Lisboa, Faculdade de Ciências, 2019For the past years, radical prostatectomy (RP) has been the treatment of choice for locally advanced prostate cancer (PC) because of its high accuracy in tumor removal. However, the surgical techniques performed tend to be invasive, with a complete removal of the proximal lisso-sphincter and partial removal of the distal rhabdosphincter. Whereas the former has been related with maintenance of continence at rest, the latter is related with active continence. Between 4 to 69 % [1] of patients undergoing RP develop urinary incontinence, with a reported decrease in quality of life. This can be a consequence, not only from the surgical technique used, but from other factors including the competence of the sphincter function, that it is expected to decrease with age [2]. It is important to find preoperative imaging biomarkers that can help predict the risk of the patient developing postoperative urinary incontinence. The TransDouglas project, approved by the Ethics Committee of Champalimaud Foundation since July 2018, aims at validating the implementation of a new surgical procedure for RP, which is an improved version of the robotic-assisted laparoscopic radical prostatectomy (RALRP) procedure. Preoperative anatomical parameters are extracted from the T2-weighted magnetic resonance imaging (MRI) that can be related with urinary incontinence after the new surgical technique, and to construct a model that can help predict the likely time until urinary continence recovery. Diffusion tensor imaging (DTI) is a MRI-based technique that allows the quantification of anisotropic movement of water molecules. It has been proven [3] that this technique can be used to visualize the microarchitecture of the urethral sphincters, and to extract relevant diffusion metrics. DTI metrics can be incorporated in the model to predict urinary incontinence recovery after RP. Considering this, an addendum to the TransDouglas project that requests the acquisition of an additional DTI sequence to the standard multiparametric (mpMRI) of the prostate has been approved this January, enabling the use of DTI to study the microarchitecture of the urethral sphincters in vivo and non-invasively. However, since parameters of sphincter function significantly change with age [2], it is important to study the influence of patient age at scan on these parameters prior to predicting the likely chance of continence recovery after RP. Therefore, the main goal of this thesis was to investigate age-related differences in DTI metrics of the male urethral sphincter complex. Furthermore, the influence of a prostate condition, including PC and benign prostatic hyperplasia (BPH), was studied. The proximal and distal sphincters, as well as the membranous urethra, were reconstructed for 95 subjects by using the deterministic tractography algorithm in DSIStudio software [4]. DTI metrics were extracted including tract length and density, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) and additional histogram parameters for each DTI metric, namely standard deviation, median, trimmed mean, median absolute deviation, minimum, maximum, range, skewness, kurtosis, standard error and the 5th, 25th, 75th and 95th percentiles. The influence of subject motion and eddy currents corrections on the extracted DTI metrics was investigated. Linear regressions and Pearson or Spearman correlations were performed between age and each of the DTI metrics. Additionally, analysis of variance (ANOVA), or the non-parametric Kruskal-Wallis test, were used to compare DTI metrics between four age groups (from 50 to 59, 60 to 69, 70 to 79 and 80 to 89 years old). For a subset of the 69 subjects with a confirmed diagnosis for PC, BPH and the absence of any of both, ANOVA testing was used to compare between disease groups, and t-tests, or the nonparametric Wilcoxon test, to compare between cancer status. For statistically significant ANOVA test results, post-hoc t-tests were used to investigate the groups between which the difference lied. No statistically significant differences were found on DTI metrics with and without motion and eddy currents corrections, so the non-corrected DTI data was used for the subsequent analysis. In this study, it was found that MD and RD distributions statistical significantly changed with age. In particular, older subjects evidenced lower RD kurtosis in the proximal sphincter, lower MD maximum in the distal sphincter and higher MD median absolute deviation in the membranous urethra. On the other hand, further investigations are needed to understand if the presence of a prostate condition affects the DTI metrics of the sphincters and membranous urethra. This project was the first to examine age related differences in the urethral sphincter complex using DTI, as well as, the first time a DTI sequence for the prostate was implemented at Champalimaud Centre for the Unknown (CCU). It was concluded that age should be used as a covariate in a model that makes use of DTI biomarkers representative of the male urethral complex microstructure to predict the likely time of post-surgical continence recovery. Ultimately, this investigation should be a starting point for helping clinicians in the prediction of the risk of complications for each patient before undergoing RP, and balance the advantages and disadvantages comparing with other available treatment options for PC.Segundo dados de 2016, no sexo masculino e em paises desenvolvidos, o cancro da prostata foi o cancro que registou maior incidencia [5]. Apos uma detecao atraves do aumento da evolucao dos niveis do antigenio especifico da prostata (PSA) no sangue e/ou de realizacao do teste do toque retal, o método de diagnostico mais comum e a biopsia, que pode ser auxiliada por ultrassons ou por ressonância magnetica multiparametrica. A escolha do tratamento adequado para cada paciente depende do estadio da doenca e das suas preferencias individuais, que geralmente pretendem equiponderar a esperanca de vida para o paciente e a qualidade de vida apos tratamento. Geralmente, as opcoes de tratamento mais adequadas para um paciente com PSA > 10 ng/mL e nodulos palpaveis sao: acompanhamento e tratamento dos sintomas a medida que estes surgem, radioterapia ou braquiterapia, e cirurgia [6]. A ultima opcao, em particular a prostatectomia radical, tem demonstrado maior precisao na remocao de tecido maligno e no aumento da esperanca media de vida para os pacientes operados [7]. Mais recentemente, tecnicas laparoscopicas convencionais tem vindo a ser substituidas por tecnicas robóticas que oferecem maiores vantagens no pos-operatorio. No entanto, a incontinencia urinaria e a disfunção eretil continuam a ser complicacoes reportadas por uma percentagem significativa de pacientes submetidos a cirurgia. Relativamente ao primeiro, afeta cerca de 4 a 69 % dos pacientes [1], e a sua ocorrencia esta intimamente ligada a remocao do esfincter proximal ou liso, que ocorre aquando da remocao da prostata, e consequente dano no esfincter distal ou rabdoesfincter. A construcao de um modelo preditivo da recuperacao da continencia pos-cirurgica com base na utilizacao de biomarcadores do esfincter, pode permitir aos prospetivos pacientes uma escolha ponderada do tipo de tratamento. No entanto, e sabido que a microestrutura do esfincter varia com a idade [2], logo e necessario conhecer o padrao de variacao dos biomarcadores do esfincter com a idade, no sentido de avaliar a recuperacao pos-cirurgica da continencia. Para estudar a microestrutura do esfincter tem sido utilizadas diversas tecnicas in vivo [8]–[13] que, no entanto, nao fornecem informacao tridimensional da estrutura e orientacao das fibras que o compoem. Contrariamente, imagem por tensor de difusao (DTI) e uma tecnica nao invasiva baseada em ressonância magnetica que permite quantificar o movimento das moleculas de agua nos tecidos, atraves da aplicação de gradientes em varias direcoes nao colineares [14]. Relacionando o gradiente aplicado com o sinal medido, obtem-se em cada voxel informacao sobre a magnitude e direcao da difusao. A partir da diagonalizacao do tensor de difusao e possivel calcular eigenvalues e eigenvectors. Enquanto que os ultimos refletem a direccionalidade, os primeiros quantificam a magnitude da difusao e combinados entre si permitem obter um conjunto de metricas – que inclui a anisotropia fracional (FA), difusibilidade axial (AD), difusibilidade media (MD) e difusibilidade radial (RD) – que permitem estudar a organizacao estrutural das fibras. Apesar das aplicacoes de DTI se focarem essencialmente em estudos de conectividade da substancia branca do cerebro, tem progressivamente sido alargadas ao estudo de outros orgaos, como o rim [15], o coracao [16] e a prostata. Relativamente ao uso de DTI para o estudo da prostata, esta tecnica tem sido utilizada para estudar este orgao em condicoes normais [17] e para definir metricas que permitam distinguir tecido saudavel de tumoral [18]. Ademais, estudos tem avaliado os feixes neuro-vasculares da prostata antes e apos a cirurgia e correlacionado com a disfunção eretil pos-prostatectomia radical [7]. Para alem de um estudo que investigou o esfincter uretral feminino usando DTI [19], que se tenha conhecimento, existe apenas um estudo que conseguiu utilizar DTI para estudo da microarquitectura do esfincter masculino em sujeitos jovens e sem patologia [3]. Assim, o principal objetivo da presente tese de mestrado e investigar variacoes derivadas da idade no complexo do esfincter uretral, que compreende os esfincteres proximais e distais e a uretra membranosa – correspondente ao segmento da uretra que se estende desde o apice da prostata ate ao bulbo peniano. No sentido de estudar o efeito da presenca de uma condicao da prostata, incluindo cancro da prostata e hiperplasia benigna da prostata (HBP), a variacao das metricas de DTI do esfincter para o grupo de pacientes diagnosticados foi tambem avaliada. Como objetivo secundario, que teve importancia na etapa de processamento dos dados de DTI, foi investigado se a correcao de movimento durante a aquisicao e correcao de correntes de Foucault afetava significativamente as metricas de DTI em estudo, para cada uma das estruturas. Para tal, os esfincteres proximal e distal, bem como a uretra membranosa, foram reconstruidos para 95 individuos usando o algoritmo deterministico de tractografia no software DSIStudio [4]. Previamente foram definidas manualmente um conjunto de regioes de interesse nos mapas coloridos de FA para os esfincteres proximal e distal, e na imagem anatomica em T2 para a uretra membranosa. Para a tractografia, foram otimizados alguns parametros segundo uma abordagem de tentativa e erro, que acabou por estabelecer um valor limite de anisotropia fracional de 0.15, e um limite angular de 75o e 45o, respetivamente para os esfincteres e para a uretra. As metricas de DTI foram extraidas para cada uma das estruturas reconstruidas, incluindo o comprimento e densidade das fibras, FA, AD, MD e RD e parametros adicionais do histograma para cada metrica de DTI, ou seja, desvio padrao, mediana, media aparada, desvio absoluto mediano, minimo, maximo, amplitude, assimetria, curtose, erro padrao e os percentis 5, 25, 75 e 95. A influencia do movimento e da presenca de correntes de Foucault nas métricas de DTI extraidas foram investigadas. Regressoes lineares e correlacoes de Pearson ou Spearman foram realizadas entre a idade e cada uma das metricas de DTI. Alem disso, uma analise de variância (ANOVA) – ou o equivalente teste nao parametrico de Kruskal-Wallis –, foram realizados para comparar metricas de DTI entre quatro faixas etarias (de 50 a 59, 60 a 69, 70 a 79 e 80 a 89 anos). Para um subconjunto dos 69 individuos com diagnostico confirmado de cancro de prostata, HBP ou da ausencia de qualquer um dos dois, o teste ANOVA foi usado para comparar entre grupos de doenca. Adicionalmente, testes t-student – ou o teste nao parametrico de Wilcoxon – foram utilizados para comparar a presenca vs. ausencia de cancro. Para resultados estatisticamente significativos do teste ANOVA, foram posteriormente empregues testes t-student para investigar entre que grupos se encontrava a diferenca. Nao foram encontradas diferencas estatisticamente significativas nas metricas de DTI com e sem correcao de movimento e correntes de Foucault, logo, os dados de DTI sem correcao foram utilizados para a analise subsequente. Neste estudo, verificou-se que as distribuicoes de MD e RD variaram significativamente com a idade. Em particular, individuos mais velhos evidenciaram menor curtose da RD no esfincter proximal, menor valor maximo de MD no esfincter distal e maior desvio absoluto mediano de MD na uretra membranosa. Por outro lado, sao necessarias investigacoes adicionais para entender se a presenca de uma condicao da prostata pode afetar as metricas de DTI dos esfincteres e da uretra membranosa. Tal acontece, pois os resultados obtidos neste estudo para a presenca de doença estao limitados pela heterogeneidade da amostra em termos das diferentes condicoes que cada individuo pode apresentar. Julga-se que este estudo foi o primeiro a identificar variacoes com a idade nas metricas de DTI do esfincter. Alem disso, definiu a inclusao de uma sequencia de DTI a ressonancia magnética multiparametrica da pratica clinica da Fundacao Champalimaud. Por se tratar de um estudo prospetivo, foi possivel definir os parametros de aquisicao – nomeadamente o valor de b (em s/mm2), o numero de direcoes da aplicacao do gradiente, o numero de cortes adquiridos e a extensao da aquisicao - otimospara a visualizacao das estruturas do complexo uretral masculino, com o melhor compromisso entre duracao da aquisicao (em minutos) e a resolucao espacial (em milimetros). Esta nova sequencia so comecou a ser incluida na clinica desde Janeiro 2019, o que representa cerca de 14 pacientes operados, dos 45 diagnosticados com cancro da prostata. Assim que for possivel aumentar a amostra de pacientes operados com um intervalo de tempo pos-cirurgico de 3 a 6 meses, sera possivel utilizar os resultados dos testes de incontinencia, os dados de DTI do esfincter corrigidos da idade e as medidas do comprimento da uretra em T2, para prever o tempo de recuperacao de continencia pos-cirurgica. No futuro, esperamos poder extrair os biomarcadores de DTI para o complexo do esfincter uretral de cada paciente e usa-los como um preditor da taxa de incontinencia pos-cirurgica. No entanto, e importante que este modelo tenha em conta alteracoes nas metricas de DTI do complexo uretral masculino que são influenciadas pelo envelhecimento. Esse modelo preditivo pode orientar os pacientes na escolha informada da melhor opcao de tratamento personalizado para tratar o tumor da prostata e, simultaneamente, proporcionar uma qualidade de vida satisfatoria

Magnetic resonance imaging of brain tissue abnormalities: transverse relaxation time in autism and Tourette syndrome and development of a novel whole-brain myelin mapping technique

The transverse relaxation time (T2) is a fundamental parameter of magnetic resonance imaging sensitive to tissue microstructure and water content, thus offering a non-invasive approach to evaluate abnormalities of brain tissue in-vivo. Prevailing hypotheses of two childhood psychiatric disorders were tested using quantitative T2 imaging and automated region of interest (ROI) analyses. In autism, the under-connectivity theory, which proposes aberrant connectivity within white matter (WM) was assessed, finding T2 to be eleveted in the frontal and parietal lobes, while dividing whole brain data into neurodevelopmentally relevant WM ROIs found increased T2 in bridging and radiate WM. In Tourette syndrome, tissue abnormalities of deep gray matter structures implicated in the symptomology of this disorder were evaluated and increased T2 of the caudate was found. Despite the sensitivity of quantitative T2 measurements to underlying pathophysiology, interpretation remain difficult. However, in WM, the compartmentalization of distinct water environments may lead to the detection of multi-exponential T2 decay. The metric of interest is principally the myelin water fraction (MWF), which is the proportion of the MRI signal arising from water trapped within layers of the myelin sheath. As a proof of concept study, the ability to measure the MWF based on T2* decay was evaluated and compared to a MWF measurements obtained from T2 decay. Data were analysed using both non-negative least squares and a two-pool model. Signal losses near sources of magnetic field inhomogeneity, such as the sinuses, rendered T2* components inseparable, invalidating this approach for whole brain MWF measurements. However, this study demonstrated the suitability of a two-pool model to calculate the MWF in WM. A novel approach, based on the multi-component gradient echo sampling of spin echoes (mcGESSE) and a two-pool model of WM, is proposed and its feasibility demonstrated using simulations. The in-vivo implementation of mcGESSE followed, with reproducibility of MWF measurements being assessed and the potential of an accelerated protocol using parallel imaging being investigated. While further work is needed to assess data quality, this approach shows great potential to obtain whole brain MWF data within a clinically relevant scan time

Urological Cancer 2020

This Urological Cancer 2020 collection contains a set of multidisciplinary contributions to the extraordinary heterogeneity of tumor mechanisms, diagnostic approaches, and therapies of the renal, urinary tract, and prostate cancers, with the intention of offering to interested readers a representative snapshot of the status of urological research

Characterisation and segmentation of basal ganglia mineralization in normal ageing with multimodal structural MRI

Iron is the most abundant trace metal in the brain and is essential for many biological processes, such as neurotransmitter synthesis and myelin formation. This thesis investigates small, multifocal hypointensities that are apparent on T2*- weighted (T2*w) MRI in the basal ganglia, where presumably most iron enters the brain via the blood-brain-barrier along the penetrating arteries. These basal ganglia T2*w hypointensities are believed to arise from iron-rich microvascular mineral deposits, which are frequently found in community-dwelling elderly subjects and are associated with age-related cognitive decline. This thesis documents the characteristic spatial distribution and morphology of basal ganglia T2*w hypointensities of 98 community-dwelling, elderly subjects in their seventies, as well as their imaging signatures on T1-weighted (T1w) and T2- weighted (T2w) MRI. A fully automated, novel method is introduced for the segmentation of basal ganglia T2*w hypointensities, which was developed to reduce the high intra- and inter-rater variability associated with current semi-automated segmentation methods and to facilitate the segmentation of these features in other single- and multi-centre studies. This thesis also presents a multi parametric quantitative MRI relaxometry methodology for conventional clinical MRI scanners that was developed and validated to improve the characterisation of brain iron. Lastly, this thesis describes the application of the developed methods in the segmentation of basal ganglia T2*w hypointensities of 243 community-dwelling participants of the Austrian Stroke Prevention Study Family (ASPS-Fam) and their analysis on R2* (=1/T2*) relaxation rate and Larmor frequency shift maps. This work confirms that basal ganglia T2*w hypointensities, especially in the globus pallidus, are potentially MRI markers of microvascular mineralization. Furthermore, the ASPS-Fam results show that basal ganglia mineral deposits mainly consist of paramagnetic particles, which presumably arise from an imbalance in the brain iron homeostasis. Hence, basal ganglia T2*w hypointensities are possibly an indicator of age-related microvascular dysfunction with iron accumulation, which might help to explain the variability of cognitive decline in normal ageing