Multi-Modal Magnetic Resonance Imaging Predicts Regional Amyloid Burden in the Brain

Alzheimer’s disease (AD) is the most common cause of dementia and identifying early markers of this disease is important for prevention and treatment strategies. Amyloid- β (Aβ) protein deposition is one of the earliest detectable pathological changes in AD. But in-vivo detection of Aβ using positron emission tomography (PET) is hampered by high cost and limited geographical accessibility. These factors can become limiting when PET is used to screen large numbers of subjects into prevention trials when only a minority are expected to be amyloid-positive. Structural MRI is advantageous; as it is non-invasive, relatively inexpensive and more accessible. Thus it could be widely used in large studies, even when frequent or repetitive imaging is necessary. We used a machine learning, pattern recognition, approach using intensity-based features from individual and combination of MR modalities (T1 weighted, T2 weighted, T2 fluid attenuated inversion recovery [FLAIR], susceptibility weighted imaging) to predict voxel-level amyloid in the brain. The MR- Aβ relation was learned within each subject and generalized across subjects using subject–specific features (demographic, clinical, and summary MR features). When compared to other modalities, combination of T1-weighted, T2-weighted FLAIR, and SWI performed best in predicting the amyloid status as positive or negative. A combination of T2-weighted and SWI imaging performed the best in predicting change in amyloid over two timepoints. Overall, our results show feasibility of amyloid prediction by MRI and its potential use as an amyloid-screening tool

Improved brain PET quantification using partial volume correction techniques

Positron emission tomography (PET) suffers from a degradation in quantitative accuracy due to a phenomenon known as the partial volume effect (PVE). The effects are due to the limited spatial resolution of the scanner. Methods that correct for PVEs are known as partial volume correction (PVC) techniques and are either data-driven or make use of anatomical information from other modalities such as magnetic resonance (MR) imaging. This thesis reports investigations into PVC techniques for improving the quantification of brain amyloid PET tracers. These tracers image amyloid plaque aggregation in-vivo, which is a pathological hallmark of Alzheimer’s disease. An extension to existing anatomy-based PVC methods is reported. Region-based voxelwise (RBV) correction has been shown to reduce PVE-induced regional bias and variance when compared to commonly applied PVC techniques. This has been proven in phantom studies and observed in clinical data. In addition, RBV has been used to demonstrate that white matter variability exists in two different amyloid tracers. This finding has implications for the application of PVC in amyloid imaging and also how scans should be normalised. Alternative reference regions were investigated in two amyloid PET tracers. The brain stem, in combination with PVC, was found to result in the strongest agreement between tracers. Anatomy-based PVC techniques rely on parcellations of structural images. These parcellations are not necessarily representative of the PET data. A further extension to RBV is proposed which iteratively modifies the parcellations to find an optimal PVC in terms of the observed PET data. This novel technique reduces quantification errors due to PET-MR mismatch and has the potential to provide an additional parameter of ‘functional volume change’ in longitudinal studies

Efficient dense non-rigid registration using the free-form deformation framework

Medical image registration consists of finding spatial correspondences between two images or more. It is a powerful tool which is commonly used in various medical image processing tasks. Even though medical image registration has been an active topic of research for the last two decades, significant challenges in the field remain to be solved. This thesis addresses some of these challenges through extensions to the Free-Form Deformation (FFD) registration framework, which is one of the most widely used and well-established non-rigid registration algorithm. Medical image registration is a computationally expensive task because of the high degrees of freedom of the non-rigid transformations. In this work, the FFD algorithm has been re-factored to enable fast processing, while maintaining the accuracy of the results. In addition, parallel computing paradigms have been employed to provide near real-time image registration capabilities. Further modifications have been performed to improve the registration robustness to artifacts such as tissues non-uniformity. The plausibility of the generated deformation field has been improved through the use of bio-mechanical models based regularization. Additionally, diffeomorphic extensions to the algorithm were also developed. The work presented in this thesis has been extensively validated using brain magnetic resonance imaging of patients diagnosed with dementia or patients undergoing brain resection. It has also been applied to lung X-ray computed tomography and imaging of small animals. Alongside with this thesis an open-source package, NiftyReg, has been developed to release the presented work to the medical imaging community

Machine learning for image-based classification of Alzheimer's disease

Imaging biomarkers for Alzheimer's disease are important for improved diagnosis and monitoring, as well as drug discovery. Automated image-based classification of individual patients could provide valuable support for clinicians. This work investigates machine learning methods aimed at the early identification of Alzheimer's disease, and prediction of progression in mild cognitive impairment. Data are obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL). Multi-region analyses of cross-sectional and longitudinal FDG-PET images from ADNI are performed. Information extracted from FDG-PET images acquired at a single timepoint is used to achieve classification results comparable with those obtained using data from research-quality MRI, or cerebrospinal fluid biomarkers. The incorporation of longitudinal information results in improved classification performance. Changes in multiple biomarkers may provide complementary information for the diagnosis and prognosis of Alzheimer's disease. A multi-modality classification framework based on random forest-derived similarities is applied to imaging and biological data from ADNI. Random forests provide consistent similarities for multiple modalities, facilitating the combination of different types of features. Classification based on the combination of MRI volumes, FDG-PET intensities, cerebrospinal fluid biomarkers, and genetics out-performs classification based on any individual modality. Multi-region analysis of MRI acquired at a single timepoint is used to show volumetric differences in cognitively normal individuals differing in amyloid-based risk status for the development of Alzheimer's disease. Reduced volumes in temporo-parietal and orbito-frontal regions in high-risk individuals from both ADNI and AIBL could be indicative of early signs of neurodegeneration. This suggests that volumetric MRI can reveal structural brain changes preceding the onset of clinical symptoms. Taken together, these results suggest that image-based classification can support diagnosis in Alzheimer's disease and preceding stages. Future work may lead to more finely meshed prognostic data that may be useful clinically and for research

Data harmonization in PET imaging

Medical imaging physics has advanced a lot in recent years, providing clinicians and researchers with increasingly detailed images that are well suited to be analyzed with a quantitative approach typical of hard sciences, based on measurements and analysis of clinical interest quantities extracted from images themselves. Such an approach is placed in the context of quantitative imaging. The possibility of sharing data quickly, the development of machine learning and data mining techniques, the increasing availability of computational power and digital data storage which characterize this age constitute a great opportunity for quantitative imaging studies. The interest in large multicentric databases that gather images from single research centers is growing year after year. Big datasets offer very interesting research perspectives, primarily because they allow to increase statistical power of studies. At the same time, they raised a compatibility issue between data themselves. Indeed images acquired with different scanners and protocols could be very different about quality and measures extracted from images with different quality might be not compatible with each other. Harmonization techniques have been developed to circumvent this problem. Harmonization refers to all efforts to combine data from different sources and provide users with a comparable view of data from different studies. Harmonization can be done before acquiring data, by choosing a-priori appropriate acquisition protocols through a preliminary joint effort between research centers, or it can be done a-posteriori i.e. images are grouped into a single dataset and then any effects on measures caused by technical acquisition factors are removed. Although the a-priori harmonization guarantees best results, it is not often used for practical and/or technical reasons. In this thesis I will focus on a-posteriori harmonization. It is important to note that when we consider multicentric studies, in addition to the technical variability related to scanners and acquisition protocols, there may be a demographic variability that makes single centers samples not statistically equivalent to each other. The wide individual variability that characterize human beings, even more pronounced when patients are enrolled from very different geographical areas, can certainly exacerbate this issue. In addition, we must consider that biological processes are complex phenomena: quantitative imaging measures can be affected by numerous confounding demographic variables even apparently unrelated to measures themselves. A good harmonization method should be able to preserve inter-individual variability and remove at the same time all the effects due acquisition technical factors. Heterogene ity in acquisition together with a great inter-individual variability make harmonization very hard to achieve. Harmonization methods currently used in literature are able to preserve only the inter-subjects variability described by a set of known confounding variables, while all the unknown confounding variables are wrongly removed. This might lead to incorrect harmonization, especially if the unknown confounders play an important role. This issue is emphasized in practice, as sometimes happens that demographic variables that are known to play a major role are unknown. The final goal of my thesis is a proposal for an harmonization method developed in the context of amyloid Positron Emission Tomography (PET) which aim to remove the effects of variability induced by technical factors and at the same time are able to keep all the inter-individual differences. Since knowing all the demographic confounders is almost impossible, both practically and a theoretically, my proposal does not require the knowledge of these variables. The main point is to characterize image quality through a set of quality measures evaluated in regions of interest (ROIs) which are required to be as independent as possible from anatomical and clinical variability in order to exclusively highlight the effect of technical factors on images texture. Ideally, this allows to decouple the between-subjects variability from the technical ones: the latter can be directly removed while the former is automatically preserved. Specifically, I defined and validated 3 quality measures based on images texture properties. In addition I used a quality metric already existing, and I considered the reconstruction matrix dimension to take into account image resolution. My work has been performed using a multicentric dataset consisting of 1001 amyloid PET images. Before dealing specifically with harmonization, I handled some important issues: I built a relational database to organize and manage data and then I developed an automated algorithm for images pre-processing to achieve registration and quantification. This work might also be used in other imaging contexts: in particular I believe it could be applied in fluorodeoxyglucose (FDG) PET and tau PET. The consequences of harmonization I developed have been explored at a preliminary level. My proposal should be considered as a starting point as I mainly dealt with the issues of quality measures, while the harmonization of the variables in itself was done with a linear regression model. Although harmonization through linear models is often used, more sophisticated techniques are present in literature. It would be interesting to combine them with my work. Further investigations would be desirable in future

Optimization of the diffusion-weighted MRI processing pipeline for the longitudinal assessment of the brain microstructure in a rat model of Alzheimer’s disease

Tese de mestrado integrado, Engenharia Biomédica e Biofísica (Radiações em Diagnóstico e Terapia) Universidade de Lisboa, Faculdade de Ciências, 2019The mechanism that triggers Alzheimer’s disease (AD) is not well-established, with amyloid plaques, neurofibrillary tangles of tau protein, microgliosis and glucose hypometabolism all likely involved in the early cascade. One main advantage of animal models is the possibility to tease out the impact of each insult on the neurodegeneration. Following an intracerebroventricular (icv) injection of streptozotocin (STZ), rats and monkeys develop impaired brain glucose metabolism, i.e. “diabetes of the brain”. Nu-merous studies have reported AD-like features in icv-STZ animals, but this model has never been char-acterized in terms of Magnetic Resonance Imaging (MRI)-derived biomarkers beyond structural brain atrophy. White matter degeneration has been proposed as a promising biomarker for AD that well pre-cedes cortical atrophy and correlates strongly with disease severity. Therefore, this project proposes a longitudinal study of white matter degeneration in icv-STZ rats using diffusion MRI. An existing image processing pipeline was primarily used to obtain preliminary results and propose an optimization strat-egy to improve it in terms of data quality and reliability. These strategies were tested and implemented in the pipeline when confirmed to be valuable, in order to achieve results as reproducible as possible and find the spatio-temporal pattern of brain degeneration in this animal model. All experiments were approved by the local Service for Veterinary Affairs. Male Wistar rats (N=18) (236±11 g) underwent a bilateral icv-injection of either streptozotocin (3 mg/kg, STZ group, N=10) or buffer (control group, CTL, N=8). Rats were scanned at four timepoints following surgery on a 14 T Varian system. Diffusion data were acquired using a semi-adiabatic SE-EPI PGSE sequence as follows: 4 (b=0 ms/μm2), 12 (b=0.8 ms/μm2), 16 (b=1.3 ms/μm2) and 30 (b=2 ms/μm2) directions; TE/TR=48/2500 ms, 9 coronal 1 mm slices, δ/Δ=4/27 ms, FOV=23x17 mm2, matrix=128x64 and 4 shots. The existing image processing pipeline included image denoising and eddy-correction. Moreover, diffusion and kurtosis tensors were calculated for each voxel, producing parametric maps of fractional anisotropy (FA), mean, axial and radial diffusivity (MD, AxD and RD) and mean, axial and radial kur-tosis (MK, AK and RK). Additionally, the two-compartment WMTI-Watson model was further esti-mated to provide specificity to the microstructure assessment. The following metrics were derived from the model: volume water fraction , parallel intra-axonal diffusivity , parallel ,║ and perpendicular extra-axonal diffusivities ,ꓕ and dispersion of fiber orientations 2. Since the model allows for two mathematical solutions, the >,║ solution was retained based on recent evidence. Considering pre-vious findings, the corpus callosum, cingulum, fornix and fimbria were chosen as white matter regions of interest (ROIs) and automatically segmented using anatomical atlas-based registration. Mean diffu-sion metrics were calculated in each ROI for each dataset. CTL and STZ groups were compared using two-sided t-tests at each timepoint. Within-group longitudinal changes were assessed using one-way ANOVA. Because of the small cohort, statistical analysis excluded the last time point. In the course of this project, strategies to optimize the existing pipeline were developed and tested. The existing brain atlas template was supplemented with white matter labels, rat brain extraction was semi-automated, and bias field correction of anatomical data was added before registration. Ventricle enlargement is typically reported in icv-STZ animals and normally constitutes an issue of misalignment in registration. In order to better match the label ROIs with the respective underlying tissue, several registration procedures were tested with different FA and color-coded FA template images. Color-coded FA-based registration dramatically improved the segmentation of the corpus callosum and the fimbria and reliability of diffusion metrics extracted from these regions. Moreover, additional fiber metrics were extracted from a newly developed tractography pipeline to compare with tensors metrics and finally, tensors metrics were evaluated in the gray matter for a more comprehensive spatio-temporal character-ization of brain degeneration. Results from statistical analysis were obtained after implementing the successful optimization strat-egies into the pipeline. There were few significant differences within groups over time. However, be-tween-group differences at each time point were more pronounced. White matter microstructure altera-tions were consistent with previous studies of histology and cognitive performance of the icv-STZ model. Changes in tensors metrics indicate early axonal injury in the fimbria and fornix at 2 weeks after injection, a period of potential recovery at 6 weeks after injection and late axonal injury at 13 weeks in all ROIs. The WMTI-Watson biophysical model provided specificity to the underlying microstructure, by showing intra-axonal damage in the fimbria and corpus callosum as early as 2 weeks, followed by a recover period and definite axonal loss at 13 weeks after injection. Results from tensors metrics and the WMTI-Watson model are not only complementary, they are consistent with each other and with previously-established trends for structural thickness, memory per-formance, amyloid deposition and inflammation. The icv-STZ model displays white matter changes in tracts reportedly affected by AD, while the degeneration is induced primarily by impaired brain glucose metabolism. The icv-STZ constitutes an excellent model to reproduce sporadic AD and should allow to further explore the hypothesis of AD being “type III diabetes”. The combination of diffusion information extracted from tensor imaging and biophysical modelling is a promising set of tools to assess white matter in the AD brain and might be the upcoming strategy to assess the human brain. Regarding future work, it will focus on estimating the correlation between microstructural alterations and functional con-nectivity (from resting-state functional MRI), glucose hypometabolism (from FDG-PET), and patholog-ical features (from histological stainings) – all currently under processing at CIBM. Tractography is a cutting-edge methodology to assess brain connectivity and the pipeline created could be further devel-oped to improve understanding and support diffusion metrics. The relationship between white and gray matter will also improve the understanding of spatio-temporal degeneration and the progression nature of the disease.O mecanismo que desencadeia a doença de Alzheimer (DA) não é bem conhecido, contudo sabe-se que a presença de placas amilóides e de emaranhados neurofibrilares da proteína tau, microgliose e ainda hipometabolismo de glucose estão envolvidos na fase inicial da cascata de desenvolvimento da doença. A principal vantagem dos modelos animais é justamente a possibilidade de estudar individualmente o impacto de cada um destes mecanismos no processo de neurodegeneração. Após uma injeção intracere-broventricular (icv) de estreptozotocina (STZ), várias espécies de animais mostraram um metabolismo anormal de glucose no cérebro, processo que foi referido como “diabetes do cérebro”. Vários estudos demonstraram que animais icv-STZ são portadores de características típicas de DA, mas este modelo animal nunca foi estudado em termos de biomarcadores derivados de técnicas de imagem por ressonân-cia magnética (IRM), exceto atrofia estrutural do cérebro. Um biomarcador promissor de DA que se acredita preceder a atrofia do córtex cerebral é a degeneração da matéria branca do cérebro, uma vez que foi fortemente correlacionado com a progressão e gravidade da doença. Logo, este projeto propõe um estudo longitudinal da degeneração da matéria branca em ratazanas icv-STZ utilizando IRM de di-fusão. O plano de processamento de imagem existente foi utilizado primeiramente para obter resultados preliminares e viabilizar a proposta de estratégias de otimização da mesma, em termos de melhoramento da qualidade de imagem e credibilidade das variáveis extraídas das imagens resultantes. Estas estratégias foram testadas e implementadas no plano de processamento quando a sua performance confirmou ser de valor, para que os resultados fossem o mais reproduzíveis possível em caracterizar a distribuição espácio-temporal da degeneração do cérebro neste modelo animal. Todos os procedimentos aqui descritos foram aprovados pelo serviço local dos assuntos veterinários. Ratazanas macho Wistar (N=18, 236±11 g) foram submetidas a uma injeção icv de STZ (3 mg/kg) no caso do grupo infetado (N=10) ou de um buffer no caso do grupo de controlo (N=8). As ratazanas foram examinadas no scanner de IRM do tipo Varian de 14 T em quatro momentos no tempo: 2, 6, 13 e 21 semanas após a injeção. As imagens por difusão foram adquiridas com uma sequência semi-adiabática spin-echo EPI PGSE com os seguintes parâmetros: 4 (b=0), 12 (b=0.8 ms/μm2), 16 (b=1.3 ms/μm2) and 30 (b=2 ms/μm2) direções; TE/TR=48/2500 ms, 9 secções coronais de 1 mm, δ/Δ=4/27 ms, FOV=23x17 mm2, matriz=128x64 e 4 shots. O plano existente de processamento de imagem incluía a correção das imagens ao nível de ruído e correntes-eddy. Posteriormente, os tensores de difusão e curtose foram estimados para cada voxel e os mapas paramétricos de anisotropia fracional (FA), difusão média, axial e radial (MD, AD e RD) e cur-tose média, axial e radial (MK, AK e RK) foram calculados. Adicionalmente, um modelo de difusão de água nas fibras da matéria branca foi utilizado para providenciar maior especificidade ao estudo da microestrutura do cérebro. Como tal, o modelo de dois compartimentos denominado WMTI-Watson foi também estimado e as seguintes variáveis foram derivadas do mesmo: a fração do volume de água , a difusividade paralela intra-axonal , as difusividades paralela ,║ e perpendicular ,ꓕ extra-axonais e, finalmente, a orientação da dispersão axonal 2. Este modelo matemático tem duas soluções possíveis dada a sua natureza quadrática, pelo que a solução >,║ foi imposta com base em evidências re-centes. Considerando estudos anteriores, as regiões de interesse (RDIs) da matéria branca escolhidas para analisar a microestrutura cerebral foram o corpo caloso, o cíngulo, a fimbria e a fórnix. Estes foram automaticamente segmentados através de registo de imagem de um atlas das regiões do cérebro da rata-zana e as médias das medidas extraídas dos tensores de difusão e curtose e ainda do modelo biofísico neuronal foram calculadas em cada RDI para cada conjunto de imagens obtidas. Os dois grupos de teste e controlo foram comparados usando testes t de Student bilaterais em cada momento do tempo, e a comparação das alterações longitudinais em cada grupo foi feita usando uma ANOVA. Devido ao baixo número de amostras, o último momento no tempo às 21 semanas foi excluído da análise. No decorrer deste projeto, várias estratégias para otimizar o processamento de imagem ou comple-mentar a análise da informação disponível foram testadas. Nomeadamente, o atlas cerebral da ratazana foi aperfeiçoado relativamente às regiões de matéria branca, a segmentação do cérebro foi testada com algoritmos automáticos e a correção do bias field em imagens estruturais de IRM foi adicionada ao plano antes do registo de imagem. O aumento dos ventrículos cerebrais é uma característica frequente em animais icv-STZ, constituindo um problema de alinhamento nos métodos de registo de imagem. No sentido de otimizar a correspondência entre as regiões do atlas e as respetivas regiões na imagem estru-tural e por difusão, vários procedimentos de registo de imagem foram testados. O co-registo de imagem convencional utiliza imagens estruturais para normalizar o espaço das imagens por difusão, no entanto os mapas paramétricos de FA têm vindo a substituir este conceito dado o excelente contraste que provi-denciam entre a matéria branca e cinzenta do cérebro. Mapas de FA com diferentes direções predomi-nantes mostraram uma melhoria significante da segmentação do corpo caloso e da fimbria e também do poder estatístico das variáveis extraídas destas RDIs. Adicionalmente, um novo plano de processamento de tratografia foi construído de raiz no âmbito deste projeto para extrair variáveis adicionais das fibras de interesse e compará-las com as variáveis de difusão obtidas por análise voxel-a-voxel. Por último, as variáveis calculadas através dos tensores de difusão e curtose foram avaliadas na matéria cinzenta do cérebro para uma caracterização espácio-temporal da degeneração cerebral na DA. Os resultados da análise estatística foram obtidos após integrar no plano de processamento as estra-tégias que mostraram valorizar o projeto em termos de qualidade de imagem ou credibilidade das vari-áveis. Houve poucas diferenças significativas ao longo do tempo em cada grupo, no entanto as diferen-ças entre grupos foram bastante acentuadas. As alterações ao nível da microestrutura da matéria branca foram consistentes com estudos prévios em animais icv-STZ usando métodos histológicos e avaliações das suas capacidades cognitivas. Alterações nas variáveis extraídas dos tensores indicaram deficiência axonal inicial na fimbria e no fórnix 2 semanas após injeção no grupo de teste, um potencial período de recuperação às 6 semanas e novamente deficiência axonal às 13 semanas, sendo que neste período tardio todas as RDIs foram afetadas. O modelo biofísico WMTI-Watson confirmou aumentar especificidade ao estudo da microestrutura, visto que demostrou danos intra-axonais na fimbria e no corpo caloso 2 semanas após injeção, seguidos de um período de recuperação e de perda de estrutura axonal definitiva às 13 semanas em todas as RDIs. Não só estes dois métodos de análise de IRM de difusão se complementam, como são também con-sistentes entre eles e com as tendências de alterações ao longo do tempo descritas noutros estudos. Além disso, o animal icv-STZ mostrou alterações características da DA, mesmo tendo a degeneração cerebral sido induzida pela disrupção do metabolismo de glucose no cérebro. Como tal, este modelo animal é excelente para reproduzir a doença e deverá continuar a ser avaliado nas diferentes áreas multidiscipli-nares para explorar a hipótese de a DA ser desencadeada pela falha do sistema insulina/glucose. A com-binação da informação de difusão obtida dos tensores e da modelação da difusão neuronal provou ser uma ferramenta promissora no estudo das fibras da matéria branca do cérebro e poderá vir a ser o desafio futuro no que toca a investigação clínica da DA. Este estudo focar-se-á em correlacionar as alterações microestruturais aqui descritas com dados de conectividade funcional (obtida por IRM funcional em repouso), hipometabolismo de glucose (por FDG-PET) e outras características patológicas (por colora-ção histológica) – todos já em curso no CIBM. Tratografia é a metodologia topo de gama para aceder à conetividade cerebral e o plano de processamento gerado neste projeto poderá continuar a ser desenvol-vido no futuro para informação adicional, assim como a relação entre a matéria branca e cinzenta poderá suplementar a compreensão da progressão da doença no espaço e no tempo

Perspectives on Nuclear Medicine for Molecular Diagnosis and Integrated Therapy

nuclear medicine; diagnostic radiolog

Méthodes mathématiques d’analyse d’image pour les études de population transversales et longitudinales

In medicine, large scale population analysis aim to obtain statistical information in order to understand better diseases, identify their risk factors, develop preventive and curative treatments and improve the quality of life of the patients.In this thesis, we first introduce the medical context of Alzheimer’s disease, recall some concepts of statistical learning and the challenges that typically occurwhen applied in medical imaging. The second part focus on cross-sectional studies,i.e. at a single time point. We present an efficient method to classify white matter lesions based on support vector machines. Then we discuss the use of manifoldlearning techniques for image and shape analysis. Finally, we present extensions ofLaplacian eigenmaps to improve the low-dimension representations of patients usingthe combination of imaging and clinical data. The third part focus on longitudinalstudies, i.e. between several time points. We quantify the hippocampus deformations of patients via the large deformation diffeomorphic metric mapping frameworkto build disease progression classifiers. We introduce novel strategies and spatialregularizations for the classification and identification of biomarkers.En médecine, les analyses de population à grande échelle ont pour but d’obtenir des informations statistiques pour mieux comprendre des maladies, identifier leurs facteurs de risque, développer des traitements préventifs et curatifs et améliorer la qualité de vie des patients.Dans cette thèse, nous présentons d’abord le contexte médical de la maladie d’Alzheimer, rappelons certains concepts d’apprentissage statistique et difficultés rencontrées lors de l’application en imagerie médicale. Dans la deuxième partie,nous nous intéressons aux analyses transversales, c-a-d ayant un seul point temporel.Nous présentons une méthode efficace basée sur les séparateurs à vaste marge (SVM)permettant de classifier des lésions dans la matière blanche. Ensuite, nous étudions les techniques d’apprentissage de variétés pour l’analyse de formes et d’images, et présentons deux extensions des Laplacian eigenmaps améliorant la représentation de patients en faible dimension grâce à la combinaison de données d’imagerie et cliniques. Dans la troisième partie, nous nous intéressons aux analyses longitudinales, c-a-d entre plusieurs points temporels. Nous quantifions les déformations des hippocampus de patients via le modèle des larges déformations par difféomorphismes pour classifier les évolutions de la maladie. Nous introduisons de nouvelles stratégies et des régularisations spatiales pour la classification et l’identification de marqueurs biologiques

Optimising the quantitative analysis in functional pet brain imaging

Patlak analysis techniques based on linear regression are often applied to positron emission tomography (PET) images to estimate a number of physiological parameters. The Patlak equation forms the basis for most extension works regarding graphical analysis of many tracers in quantitative PET measurements. Patlak analysis is primarily used to obtain the rate constant Ki, which represents the tracer transfer rate from plasma to the targeted tissue. One of the most common issues associated with Patlak analysis is the introduction of statistical noise, adopted originally from the images, that affects the slope of the graphical plot, leading to bias, and causes errors in the calculation of the rate constant Ki i. In this thesis, several statistical and noise reduction methods for 2 and 3 dimensional data are proposed and applied to simulated 18F-FDOPA brain images generated from a PET imaging simulator. The methods were applied to investigate whether their utilisation could reduce the bias and error caused by noisy images and improve the accuracy of quantitative measurements. Then, validation step extended to 18F-FDOPA PET images obtained from a clinical trial for Parkinson’s disease. The minimum averaged SE, SSE and the highest averaged reduction of noisy Ki values were found with the feasible generalised least squares (FGLS) model. Battle-Lemarie wavelet (BLW) showed significant change in data for the 3D PET images. Savitzky-Golay filtering (SGF) demonstrated significant change for most of the noise levels applied to 2D data. In clinical 18F-FDOPA images, the mean and standard deviation of standard error (SE) and sum-squared error (SSE) were significantly reduced in both baseline and after therapy groups. This work has the potential to be extended to other graphical analysis in quantitative PET data measurements