Biomarker for tracking progression of Alzheimer's disease in clinical trials

Currently, there are no treatments available for mitigating the neurological effects of Alzheimer's disease. All clinical trials of disease-modifying treatments, which showed promise in animal models, have failed to show a significant treatment effect in human trials. The lack of a sensitive outcome measure and the focus on the dementia stage for investigating treatments are believed to be the primary reasons behind the failure of all clinical trials till date. The currently used outcome measure, the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), suffers from low sensitivity in tracking progression of cognitive impairment in clinical trials. A shift in the focus to the prodromal mild cognitive impairment (MCI) stage may help improve the efficiency of clinical trials. However, even lower sensitivity of the ADAS-Cog and an inability to specifically select progressive MCI patients limit the efficiency of clinical trials in the MCI stage. Cerebral atrophy measured on structural magnetic resonance (MR) imaging is highly promising for tracking disease progression in clinical trials. However, cerebral atrophy has not been yet approved as a valid biomarker due to the lack of an understanding behind its relationship with cognitive impairment. The focus of this dissertation spans across the two research areas of (i) developing automatic algorithms for analysis of patients' brain MR volumes, and (ii) improving the efficiency of clinical trials of disease-modifying treatments. This dissertation presents a novel knowledge-driven decision theory approach for automatic tissue segmentation of brain MR volumes, which shows better segmentation performance than the existing approaches. The remaining dissertation contributions focus at improving the efficiency of clinical trials of disease-modifying treatments. An improved scoring methodology is presented for the ADAS-Cog outcome measure, which measures cognitive impairment with better accuracy and significantly improves the sensitivity of the ADAS-Cog in the mild-to-moderate Alzheimer's disease stage. However, the ADAS-Cog continues to suffers from low sensitivity in the MCI stage due to inherent limitations of its items. For improving the efficiency of clinical trials in the MCI stage, a biomarker has been developed that combines the ADAS-Cog with cerebral atrophy for more accurate tracking of Alzheimer's progression and facilitating selection of MCI patients in clinical trials.Biomedical Engineerin

Brain lesion segmentation from diffusion weighted MRI based on adaptive thresholding and gray level co-occurrence matrix

This project presents brain lesion segmentation of diffusion-weighted magnetic resonance images (DWI) based on thresholding technique and gray level co-occurrence matrix (GLCM). The lesions are hyperintense lesion from tumour, acute infarction, haemorrhage and abscess, and hypointense lesion from chronic infarction and haemorrhage. Pre-processing is applied to the DWI for intensity normalization, background removal and intensity enhancement. Then, the lesions are segmented by using two different methods which are thresholding technique and GLCM. For the thresholding technique, image histogram is calculated at each region to find the maximum number of pixels for each intensity level. The optimal threshold is determined by comparing normal and lesion regions. Conversely, GLCM is computed to segment the lesions. Different peaks from the GLCM crosssection indicate the present of normal brain region, cerebral spinal fluid (CSF), hyperintense or hypointense lesions. Minimum and maximum threshold values are computed from the GLCM cross-section. Region and boundary information from the GLCM are introduced as the statistical features for segmentation of hyperintense and hypointense lesions. The proposed technique has been validated by using area overlap (AO), false positive rate (FPR), false negative rate (FNR), misclassified area (MA), mean absolute percentage error (MAPE) and pixels absolute error ratio (rerr). The results are demonstrated in three indexes MA, MAPE and rerr, where 0.3167, 0.1440 and 0.0205 for GLCM, while 0.3211, 0.1524 and 0.0377 for thresholding technique. Overall, GLCM provides better segmentation performance compared to thresholding technique

Brain Lesion Segmentation from Diffusion-Weighted MRI Based on Adaptive Thresholding and Gray Level Co-Occurence Matrix

This project presents brain lesion segmentation of diffusion-weighted magnetic resonance images (DWI) based on thresholding technique and gray level co-occurrence matrix (GLCM). The lesions are hyperintense lesion from tumour, acute infarction, haemorrhage and abscess, and hypointense lesion from chronic infarction and haemorrhage. Pre-processing is applied to the DWI for intensity normalization, background removal and intensity enhancement. Then, the lesions are segmented by using two different methods which are thresholding technique and GLCM. For the thresholding technique, image histogram is calculated at each region to find the maximum number of pixels for each intensity level. The optimal threshold is determined by comparing normal and lesion regions. Conversely, GLCM is computed to segment the lesions. Different peaks from the GLCM crosssection indicate the present of normal brain region, cerebral spinal fluid (CSF), hyperintense or hypointense lesions. Minimum and maximum threshold values are computed from the GLCM cross-section. Region and boundary information from the GLCM are introduced as the statistical features for segmentation of hyperintense and hypointense lesions. The proposed technique has been validated by using area overlap (AO), false positive rate (FPR), false negative rate (FNR), misclassified area (MA), mean absolute percentage error (MAPE) and pixels absolute error ratio (r err) . The results are demonstrated in three indexes MA, MAPE and r err , where 0.3167, 0.1440 and 0.0205 for GLCM, while 0.3211, 0.1524 and 0.0377 for thresholding technique. Overall, GLCM provides better segmentation performance compared to thresholding techniqu

Probabilistic partial volume modelling of biomedical tomographic image data

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Visual attention models and arse representations for morphometrical image analysis

Abstract. Medical diagnosis, treatment, follow-up and research activities are nowadays strongly supported on different types of diagnostic images, whose main goal is to provide an useful exchange of medical knowledge. This multi-modal information needs to be processed in order to extract information exploitable within the context of a particular medical task. In despite of the relevance of these complementary sources of medical knowledge, medical images are rarely further processed in actual clinical practice, so the specialists take decisions only based in the raw data. A new trend in the development of medical image processing and analysis tools follows the idea of biologically-inspired methods, which resemble the performance of the human vision system. Visual attention models and sparse representations are examples of this tendency. Based on this, the aim of this thesis was the development of a set of computational methods for automatic morph metrical analysis, combining the relevant region extraction power of visual attention models with the incorporation of a priori information capabilities of sparse representations. The combination of these biologically inspired tools with common machine learning techniques allowed the identification of visual patterns relevant for pathology discrimination, improving the accuracy and interpretability of morph metric measures and comparisons. After extensive validations with different image data sets, the computational methods proposed in this thesis seems to be promising tools for the definition of anatomical biomarkers, based on visual pattern analysis, and suitable for patient's diagnosis, prognosis and follow-up.Las actividades de diagnóstico, tratamiento, seguimiento e investigación en medicina están actualmente soportadas en diferentes clases de imágenes diagnósticas, cuyo objetivo principal es el de proveer un intercambio efectivo de conocimiento médico. Esta información multimodal necesita ser procesada con el objetivo de extraer información aprovechable en el contexto de una tarea médica particular. A pesar de la relevancia de estas fuentes complementarias de información clínica, las imágenes médicas son raramente procesadas en la práctica clínica actual, de forma que los especialistas sólo toman decisiones basados en los datos crudos. Una nueva tendencia en el desarrollo de herramientas de análisis y procesamiento de imágenes médicas persigue la idea de métodos biológicamente inspirados, que se asemejan al sistema de visión humana. Son ejemplos de esta tendencia los modelos de atención visual y las representaciones escasas (sparse representations). Con base en esto, el objetivo de esta tesis fue el desarrollo de un conjunto de métodos computacionales para soportar automáticamente los análisis morfo métricos, combinando el poder de extracción de regiones relevantes de los modelos de atención visual junto con la capacidad de incorporación de información a priori de las representaciones escasas. La combinación de estos métodos biológicamente inspirados con técnicas de aprendizaje de maquina facilito la identificación de patrones visuales relevantes para discriminar patologías cerebrales, mejorando la precisión e interpretabilidad de las medidas y comparaciones morfo métricas. Después de extensivas validaciones con diferentes conjuntos de imágenes, los métodos computacionales propuestos en esta tesis se perfilan como herramientas prometedoras para la definición de biomarcadores anatómicos, basados en el análisis visual de patrones, y convenientes para el diagnóstico, pronóstico y seguimiento del paciente.Doctorad

Hidden Markov models-based 3D MRI brain segmentation

This paper introduces a 3D MRI segmentation algorithm based on Hidden Markov Models (HMMs). The mathematical models for the HMM that forms the basis of the segmentation algorithm for both the continuous and discrete cases are developed and contrasted with Hidden Markov Random Field in terms of complexity and extensibility to larger fields. The presented algorithm clearly demonstrates the capacity of HMM to tackle multi-dimensional classification problems. The HMM-based segmentation algorithm was evaluated through application to simulated brain images from the McConnell Brain Imaging Centre, Montréal Neurological Institute, McGill University as well as real brain images from the Internet Brain Segmentation Repository (IBSR), Harvard University. The HMM model exhibited high accuracy in segmenting the simulated brain data and an even higher accuracy when compared to other techniques applied to the IBSR 3D MRI data sets. The achieved accuracy of the segmentation results is attributed to the HMM foundation and the utilization of the 3D model of the data. The IBSR 3D MRI data sets encompass various levels of difficulty and artifacts that were chosen to pose a wide range of challenges, which required handling of sudden intensity variations and the need for global intensity level correction and 3D anisotropic filtering. During segmentation, each class of MR tissue was assigned to a separate HMM and all of the models were trained using the discriminative MCE training algorithm. The results were numerically assessed and compared to those reported using other techniques applied to the same data sets, including manual segmentations establishing the ground truth for real MR brain data. The results obtained using the HMM-based algorithm were the closest to the manual segmentation ground truth in terms of an objective measure of overlap compared to other methods

Construction d'un modèle per-opératoire 3D du rachis pour la navigation en thoracoscopie.

RÉSUMÉ: Lors de discectomie par thoracoscopie, les outils de visualisation procurent peu d’information de profondeur et le champ de visualisation de la caméra miniature insérée dans le patient est relativement restreint. Aussi, le mouvement simultané de la caméra et des instruments chirurgicaux peut provoquer une désorientation. Ainsi, la courbe d’apprentissage pour l’utilisation de cette technologie est très abrupte et un nombre restreint de chirurgiens choisissent l’intervention minimalement invasive malgré les avantages qu’elle peut procurer aux patients. En effet la discectomie par thoracoscopie réduit les pertes sanguines, le traumatisme des tissus entourant le disque afin d’accéder à la zone d’intérêt et le temps d’hospitalisation. Les discectomies sont prescrites à certains patients scoliotiques afin de redonner de la flexibilité à la colonne avant l’instrumentation (pose de vis et tige pour corriger la déformation). La résection du disque intervertébral est faite partiellement et la quantité du disque réséqué dépend du degré de flexibilité que le chirurgien désire redonner au patient. En effectuant la discectomie par thoracoscopie, il est impossible pour le chirurgien de visualiser rapidement la quantité de disque restant en plus d’avoir les désavantages de désorientation et de petit champ de vision de la caméra miniature insérée dans le patient. Il est donc pertinent de tenter de réduire les problèmes de visualisation rencontrés lors des thoracoscopies en procurant au chirurgien la possibilité d’examiner en 3D les structures anatomiques du patient pendant la chirurgie sans ajouter de radiations supplémentaires au patient. Ce système d’assistance permettrait également d’accroître la sécurité du patient et la qualité de la chirurgie en donnant aux chirurgiens la possibilité de localiser en 3D la moelle épinière et en leur donnant également la possibilité de visualiser la quantité de disque restant. Ainsi, l’intérêt de fusionner les images vidéo avec un modèle pré-opératoire 3D est alors tout indiqué.---------- ABSTRACT: Visualization tools available while doing thoracoscopic diskectomy do not show depth information and the field of view of the miniaturized camera inserted into the patient is small. Also, simultaneous movement of the camera and surgical tools may result in disorientation. The learning curve for the use of this technology is very steep and numbers of surgeons choose not to use minimally invasive surgery despite important advantages for the patients. Indeed, thoracoscopic diskectomy reduce blood loss, trauma of surrounding soft tissues to access intervertebral disks and hospitalization time. Diskectomy are prescribed to specific scoliotic patients to gain flexibility of the spine before instrumentation surgery (fixation of screws and rod to correct the deformation). The intervertebral disk is partly resected depending on the level of flexibility the patient has to gain according to the surgeon. During thoracoscopic diskectomy, it is impossible for the surgeon to rapidly visualize the remaining disk tissue and this further increase the disadvantages for the surgeons. Hence, it is relevant to try to reduce visualization problems encountered during thoracoscopic diskectomy by providing to the surgeons a 3D view of the whole spine during the surgery, without adding supplementary radiation to the patient. The computer assisted surgery system would also increase the security of the patient by allowing the surgeons to localize rapidly in 3D the spinal canal as well as the remaining disk. The fusion of the video images with 3D spine of the patient is of great interest for the surgeons

Mathematical approaches for the clinical translation of hyperpolarised 13C imaging in oncology

Dissolution dynamic nuclear polarisation is an emerging clinical technique which enables the metabolism of hyperpolarised 13C-labelled molecules to be dynamically and non- invasively imaged in tissue. The first molecule to gain clinical approval is [1-13C]pyruvate, the conversion of which to [1-13C]lactate has been shown to detect early treatment re- sponse in cancers and correlate with tumour grade. As the technique has recently been translated into humans, accurate and reliable quantitative methods are required in order to detect, analyse and compare regions of altered metabolism in patients. Furthermore, there is a requirement to understand the biological processes which govern lactate pro- duction in tumours in order to draw reliable conclusions from this data. This work begins with a comprehensive analysis of the quantitative methods which have previously been applied to hyperpolarised 13C data and compares these to some novel approaches. The most appropriate kinetic model to apply to hyperpolarised data is determined and some simple, robust quantitative metrics are identified which are suitable for clinical use. A means of automatically segmenting 5D hyperpolarised imaging data using a fuzzy Markov random field approach is presented in order to reliably identify regions of abnormal metabolic activity. The utility of the algorithm is demonstrated on both in silico and animal data. To gain insight into the processes driving lactate metabolism, a mathematical model is developed which is capable of simulating tumour growth and treatment response under a range of metabolic and tissue conditions, focusing on the interaction between tumour and stroma. Finally, hyperpolarised 13C-pyruvate imaging data from the first human subjects to be imaged in Cambridge is analysed. The ability to detect and quantify lactate production in patients is demonstrated through application of the methods derived in earlier chapters. The mathematical approaches presented in this work have the potential to inform both the analysis and interpretation of clinical hyperpolarised 13C imaging data and to aid in the clinical translation of this technique.Joint funded by GlaxoSmithKline and the Cambridge Biomedical Research Centre