Thesis (Ph.D.) OGI School of Science & Engineering at OHSU, July 2007. / Includes bibliographical references (leaves 202-216).

Alzheimer's Disease (AD) is a neurodegenerative disorder affecting over 35 million people. Early diagnosis and intervention are crucial for improving outcomes. Digital Cognitive Biomarkers (DCBs) offer a promising approach for early detection and disease management, quantifying cognitive processes of encoding and retrieval through a hierarchical Bayesian cognitive processing model using wordlist memory tests. We hypothesize that DCBs will correlate with classic AD cerebrospinal fluid (CSF) biomarkers (Aβ42, T-tau, p-tau) in patients with varying cognitive decline levels compared to healthy elderly controls. Using Alzheimer's Disease Neuroimaging Initiative (ADNI) data and paired Pearson correlation coefficient analysis, our results support the hypothesis, indicating that DCBs correlate with CSF biomarkers and demonstrating their potential as a noninvasive diagnostic tool for AD. Furthermore, DCBs exhibited improved diagnostic accuracy compared to classic AD CSF biomarkers, as indicated by the area under the Receiver Operating Characteristic curve analysis. DCBs hold promise for monitoring disease progression, response to therapeutics, and identifying patients at earlier disease stages. Future research should validate these findings in diverse populations and conduct longitudinal studies to assess DCBs' potential in tracking disease progression and treatment response. Integrating DCBs with other diagnostic approaches, such as neuroimaging, could enhance overall AD diagnosis accuracy and provide a comprehensive understanding of an individual's cognitive health. In conclusion, DCBs may offer a valuable, noninvasive tool for early diagnosis and management of Alzheimer's Disease, supporting the initial hypothesis.

Les maladies chroniques du foie constituent un problème majeur de santé publique. L’évaluation précise du degré de fibrose hépatique apporte au clinicien une estimation du pronostic dès la prise en charge initiale de ces patients, mais permet également la réalisation d’une surveillance évolutive, et intervient dans la décision et le choix d’un traitement. L’évaluation noninvasive de la fibrose hépatique par élastographie a permis de révolutionner la prise en charge des malades atteints d’une maladie chronique du foie. L’objectif de notre travail est d’évaluer les performances diagnostiques d’une nouvelle technique d’élastographie hépatique, appelée « Supersonic ShearImaging » (SSI), et d’analyser sa plus-value dans l’évaluation non-invasive des maladies chroniques du foie.Dans une première étude, nous avons prospectivement analysé et comparé les performances diagnostiques de l’élastographie SSI par rapport au FibroScan et l’ARFI pour le staging de la fibrose hépatique sur une série de 349 patients avec une maladie chronique du foie diagnostiquée et gradée par ponction-biopsiehépatique.Dans une seconde étude, nous avons prospectivement étudié l’impact diagnostique de l’élastographie SSIsur le foie et la rate chez une population de 401 patients avec cirrhose pour l’évaluation de la gravité de la maladie cirrhotique.Dans une troisième étude, nous avons réalisé une analyse prospective bicentrique (Angers et Bordeaux)de la performance diagnostique de l’élastographie SSI par rapport au FibroScan et l’ARFI dans l’évaluation non invasive de la fibrose hépatique sur une série de 291 patients avec stéatopathie non-alcoolique et ponction-biopsiehépatique. / Abstract :The management and the prognosis for chronic liver diseases are widely based on the presence and the development of a liver fibrosis. The progressive worsening of liver fibrosis leads in a certain number of patients to the development of cirrhosis and its complications. Thus, the development of non-invasive diagnostic tools for the diagnosis and the monitoring of the liver fibrosis is of crucial interest. Liver elastography is one of the most promising techniques that have recently emerged in the field of chronic liver diseases. In this study, we aim to assess the diagnostic accuracy of a new elastography technique, named “Supersonic Shear Imaging” (SSI), and toanalyse its added value in the non invasive diagnosis of chronic liver diseases.In a first study, we prospectively analysed and compared the diagnostic performances of SSI elastography versus FibroScan and ARFI for the staging of liver fibrosis in a cohort of 349 patients with chronic liver diseases that consecutively underwent a liver biopsy. In a second study, we prospectively analysed the impact of liver and spleen SSI elastography in a cohortof 401 cirrhotic patients for the non invasive diagnosis of cirrhosis severity and oesophageal varices.In a third study, we assessed the clinical use of liver stiffness measurement evaluated by SSI, FibroScan,and ARFI in a cohort of nonalcoholic fatty liver disease patients who underwent liver biopsy. A total of 291 NAFLD patients were prospectively enrolled at 2 French university hospitals (Angers and Bordeaux).

INTRODUÇÃO: A ecocardiografia tridimensional em tempo real (E3DTR) vem provando sua acurácia para quantificar os volumes do ventrículo esquerdo (VE), fração de ejeção (FEVE) e massa em pacientes com cardiomiopatia. Na cardiomiopatia hipertrófica (CMH), onde a morfologia ventricular pode estar muito alterada, a análise das estruturas cardíacas é fundamental para indicação da terapêutica ideal. A ressonância magnética cardiovascular (RMC) é um método superior na análise segmentar do VE em comparação a ecocardiografia bidimensional (E2D), mas com alta complexidade e existente em poucos centros diagnósticos, com contraindicações e limitações para a sua realização. MÉTODOS: Estudo transversal, comparativo, duplo cego, em 20 portadores de CMH, com E2D, E3DTR e RMC realizados com intervalo máximo de 06 meses e armazenados em formato digital. A espessura das paredes, volumes, função sistólica e massa ventricular esquerda foram analisados pelos métodos ecocardiográficos e pela RMC, assim como o movimento anterior sistólico da valva mitral, o índice geométrico do VE e o índice sistólico de dissincronia do VE. ANÁLISE ESTATÍSTICA: Análise estatística pelo coeficiente de concordância de Lin, correlação linear de Pearson e modelo de Bland-Altman. RESULTADOS: Foi obtida exeqüibilidade elevada acima de 94%, dependente do parâmetro avaliado. Concordância satisfatória e forte correlação linear evidenciada para a análise segmentar (Rc>0.84 e r>0.85; p<0.0001) observada para os métodos ecocardiográficos comparados à RMC, com concordância excelente entre os métodos ecocardiográficos (Rc=0,92 e r=0,92, p<0,0001). Concordância satisfatória e forte correlação linear para a fração de ejeção do VE (Rc=0.83 e r=0.93; p<0.0001) pela E3DTR comparada à RMC. Concordância excelente e forte correlação linear para o VDFVE e VSFVE pela E3DTR comparada à RMC e pela E2D comparada à E3DTR (Rc>0.90 and r>0.95; p<0.0001), assim como para a massa do VE, para os métodos E3DTR e RMC (Rc=0.96 e r=0.97; p<0.0001). Evidenciada maior exeqüibilidade da análise do MAS pela E3DTR. O índice geométrico do VE foi >0,15mmxm²xml-1 para todos os métodos. Observada correlação negativa entre o índice de dissincronia do VE e o percentual de fibrose miocárdica, sem significância estatística. CONCLUSÕES: A E3DTR é precisa e superior à E2D na avaliação da distribuição da hipertrofia miocárdica, quantificação dos volumes, função e massa ventricular esquerda em pacientes com CMH quando comparada à RMC, e parece ser superior na análise do MAS, pela melhor visão espacial da valva mitral.Todas as medidas do índice geométrico do ventrículo esquerdo estavam acima de 0,15mmxm²xml-1, compatível com CMH. Não foi identificada correlação entre o índice sistólico de dissincronia ventricular esquerda e a fibrose miocárdica. / INTRODUCTION: Real-time three-dimensional echocardiography (RT3D) has been demonstrated an accurate technique for the quantification of left ventricular (LV) volumes, ejection fraction (LVEF), and mass. In patients with hypertrophic cardiomyopathy (HCM), in which alterations of ventricular morphology are common, cardiac structural analysis is of utmost importance for guiding adequate therapy. Although magnetic resonance imaging (MRI) seems to have better definition for segmental analysis than two-dimensional echocardiography, (2D-E), it is considered a complex test with low availability and some limitations for use. METHODS: Comparative and double-blinded study in 20 patients with HCM. All patients underwent 2DE, RT3D and MRI within maximal interval of 6 months. Parameters analyzed by echocardiography and MRI included: wall thickness, LV volumes, systolic function, LV mass, systolic anterior motion of mitral valve, LV geometric index and LV dyssynchrony index. Statistical analysis was performed by Lin agreement coefficient, Pearson linear correlation and Bland-Altman model. RESULTS: Feasibility for measurements by MRI and echocardiography was 94%. There was good agreement and linear correlation between segmental analysis by echocardiography and MRI (Rc>0.84 and r>0.85; p<0.0001) and excellent correlation between 2DE and RT3DE (Rc=0.92 and r=0.92; p<0.0001). We also observed good agreement and linear correlation between RT3DE and MRI for ejection fraction (Rc=0.83 and r=0.93; p<0.0001) and excellent agreement and linear correlation between RT3DE and MRI for LV end diastolic volume and LV end systolic volume determinations (Rc>0.90 and r>0.95; p<0.0001) and mass (Rc=0.96 and r=0.97; p<0.0001). The feasibility for systolic anterior motion of mitral valve was higher by RT3DE (91%) than 2DE (64%). LV geometric index was >0.15 mmxm²xml-1 for all techniques. There was no correlation between LV dyssynchrony index and the percentage of myocardial fibrosis. CONCLUSIONS: RT3D is an accurate technique with superior performance than 2DE for the evaluation of myocardial hypertrophy localization, LV volume and functional determination as well as for LV mass assessment in patients with HCM in comparison with MRI. In addition, it seems to be superior for the analysis of systolic anterior motion due to its better spatial view of mitral valve. All measurements of LV geometric index were above the value of 0.15 mmxm²xml-1, and such findings are compatible with HCM. No correlation between LV dyssynchrony index by RT3D and the percentage of myocardial fibrosis determined by MRI was identified.

Die im Rahmen dieser Arbeit vorgestellten Studien führen zu einer Erweiterung der Indikationen der kardiovaskulären Magnetresonanztomographie bei der Diagnostik der koronaren Herzerkrankung. Die Methoden zur schnellen Erfassung der Myokardbewegung bis hin zu Echtzeittechniken, zur Bestimmung der Myokardperfusion, zur Quantifizierung von hibernating Myokard und zur Unterdrückung von Atemartefakten bei der Koronararteriendarstellung oder Koronarflussmessung wurden optimiert und in klinischen Studien evaluiert. Die Magnetresonanztomographie ist der Echokardiographie bei Dobutamin-Stress-Untersuchungen zur Erkennung einer koronaren Herzerkrankung signifikant überlegen, was sich insbesondere durch die bessere Bildqualität erklärt. Dabei kann zur Überwachung der Patienten während der Stressuntersuchung auf Echtzeitverfahren zurückgegriffen werden, die sowohl für eine quantitative Analyse der linksventrikulären Funktion, als auch für die Erkennung von stressinduzierten Wandbewegungsstörungen geeignet ist. Für die Beurteilung der Myokardperfusion ist die Magnetresonanztomographie mit herkömmlichen Techniken wie SPECT oder PET vergleichbar. Dabei ist insbesondere die Analyse der Einwaschgeschwindigkeit eines Kontrastmittelbolus in Ruhe und unter Vasodilatation geeignet, ischämische und normal perfundierte Myokardabschnitten zu differenzieren. Für die Abbildung der Koronararterien haben sich insbesondere Navigatortechniken als sinnvoll erwiesen. Dabei kann die Anwendung optimierter Korrekturverfahren der Zwerchfellposition zu einer Verringerung von ateminduzierten Bewegungsartefakten führen. Mit Hilfe diese Navigatortechnik können auch Koronarflussmessungen optimiert und ihre Genauigkeit im Vergleich zur intravaskulären Doppler-Sonographie durch Verbesserung der räumlichen und zeitlichen Auflösung gesteigert werden. Damit steht die kardiovaskuläre Magnetresonanztomographie an der Schwelle zum breiten Einsatz in der klinischen Routine. Das derzeitige Indikationsspektrum ist für eine integrative und genaue Untersuchung geeignet und kann in den nächsten Jahren durch weitere Aspekte (z.B. Darstellung von Gefäßplaques, Anwendung spezifischer Kontrastmittel) noch erweitert werden. / The studies compiled in the following manuscript lead to a broadening of indications for cardiovascular magnetic resonance imaging for the diagnosis of coronary artery disease Methods for rapid assessment of myocardial motion including real-time techniques, for the determination of myocardial perfusion, for the quantification of hibernating myocardium, and for the reduction of artefacts from breathing motion for the visualization of the coronary arteries and coronary flow measurements were optimised and evaluated in clinical studies. Dobutamin stress magnetic resonance imaging is superior to dobutamine stress echocardiography for the detection of coronary artery disease, which is mainly due to the superior image quality. For patient monitoring real-time techniques can be used which allow quantitative assessment of left ventricular function and detection of stressinduced wall motion abnormalities. The accuracy of perfusion measurements with magnetic resonance imaging is comparable to conventional techniques such as SPECT of PET. Especially the analysis of the wash-in of a contrast agent bolus at rest and during vasodilation allows a differentiation of ischemic and normal myocardium. For coronary artery imaging especially navigator techniques have been shown to be useful. The application of optimised correction techniques for the position of the diaphragm can lead to a reduction of breathing induced artefacts. Thus, cardiovascular magnetic resonance is on its way towards broad clinical application. The current spectrum of indications allows an integrative and accurate examination and can be expanded with additional aspects (e.g. plaque imaging, use of specific contrast agents) in the next years

INTRODUÇÃO: A ecocardiografia tridimensional em tempo real (E3DTR) vem provando sua acurácia para quantificar os volumes do ventrículo esquerdo (VE), fração de ejeção (FEVE) e massa em pacientes com cardiomiopatia. Na cardiomiopatia hipertrófica (CMH), onde a morfologia ventricular pode estar muito alterada, a análise das estruturas cardíacas é fundamental para indicação da terapêutica ideal. A ressonância magnética cardiovascular (RMC) é um método superior na análise segmentar do VE em comparação a ecocardiografia bidimensional (E2D), mas com alta complexidade e existente em poucos centros diagnósticos, com contraindicações e limitações para a sua realização. MÉTODOS: Estudo transversal, comparativo, duplo cego, em 20 portadores de CMH, com E2D, E3DTR e RMC realizados com intervalo máximo de 06 meses e armazenados em formato digital. A espessura das paredes, volumes, função sistólica e massa ventricular esquerda foram analisados pelos métodos ecocardiográficos e pela RMC, assim como o movimento anterior sistólico da valva mitral, o índice geométrico do VE e o índice sistólico de dissincronia do VE. ANÁLISE ESTATÍSTICA: Análise estatística pelo coeficiente de concordância de Lin, correlação linear de Pearson e modelo de Bland-Altman. RESULTADOS: Foi obtida exeqüibilidade elevada acima de 94%, dependente do parâmetro avaliado. Concordância satisfatória e forte correlação linear evidenciada para a análise segmentar (Rc>0.84 e r>0.85; p<0.0001) observada para os métodos ecocardiográficos comparados à RMC, com concordância excelente entre os métodos ecocardiográficos (Rc=0,92 e r=0,92, p<0,0001). Concordância satisfatória e forte correlação linear para a fração de ejeção do VE (Rc=0.83 e r=0.93; p<0.0001) pela E3DTR comparada à RMC. Concordância excelente e forte correlação linear para o VDFVE e VSFVE pela E3DTR comparada à RMC e pela E2D comparada à E3DTR (Rc>0.90 and r>0.95; p<0.0001), assim como para a massa do VE, para os métodos E3DTR e RMC (Rc=0.96 e r=0.97; p<0.0001). Evidenciada maior exeqüibilidade da análise do MAS pela E3DTR. O índice geométrico do VE foi >0,15mmxm²xml-1 para todos os métodos. Observada correlação negativa entre o índice de dissincronia do VE e o percentual de fibrose miocárdica, sem significância estatística. CONCLUSÕES: A E3DTR é precisa e superior à E2D na avaliação da distribuição da hipertrofia miocárdica, quantificação dos volumes, função e massa ventricular esquerda em pacientes com CMH quando comparada à RMC, e parece ser superior na análise do MAS, pela melhor visão espacial da valva mitral.Todas as medidas do índice geométrico do ventrículo esquerdo estavam acima de 0,15mmxm²xml-1, compatível com CMH. Não foi identificada correlação entre o índice sistólico de dissincronia ventricular esquerda e a fibrose miocárdica. / INTRODUCTION: Real-time three-dimensional echocardiography (RT3D) has been demonstrated an accurate technique for the quantification of left ventricular (LV) volumes, ejection fraction (LVEF), and mass. In patients with hypertrophic cardiomyopathy (HCM), in which alterations of ventricular morphology are common, cardiac structural analysis is of utmost importance for guiding adequate therapy. Although magnetic resonance imaging (MRI) seems to have better definition for segmental analysis than two-dimensional echocardiography, (2D-E), it is considered a complex test with low availability and some limitations for use. METHODS: Comparative and double-blinded study in 20 patients with HCM. All patients underwent 2DE, RT3D and MRI within maximal interval of 6 months. Parameters analyzed by echocardiography and MRI included: wall thickness, LV volumes, systolic function, LV mass, systolic anterior motion of mitral valve, LV geometric index and LV dyssynchrony index. Statistical analysis was performed by Lin agreement coefficient, Pearson linear correlation and Bland-Altman model. RESULTS: Feasibility for measurements by MRI and echocardiography was 94%. There was good agreement and linear correlation between segmental analysis by echocardiography and MRI (Rc>0.84 and r>0.85; p<0.0001) and excellent correlation between 2DE and RT3DE (Rc=0.92 and r=0.92; p<0.0001). We also observed good agreement and linear correlation between RT3DE and MRI for ejection fraction (Rc=0.83 and r=0.93; p<0.0001) and excellent agreement and linear correlation between RT3DE and MRI for LV end diastolic volume and LV end systolic volume determinations (Rc>0.90 and r>0.95; p<0.0001) and mass (Rc=0.96 and r=0.97; p<0.0001). The feasibility for systolic anterior motion of mitral valve was higher by RT3DE (91%) than 2DE (64%). LV geometric index was >0.15 mmxm²xml-1 for all techniques. There was no correlation between LV dyssynchrony index and the percentage of myocardial fibrosis. CONCLUSIONS: RT3D is an accurate technique with superior performance than 2DE for the evaluation of myocardial hypertrophy localization, LV volume and functional determination as well as for LV mass assessment in patients with HCM in comparison with MRI. In addition, it seems to be superior for the analysis of systolic anterior motion due to its better spatial view of mitral valve. All measurements of LV geometric index were above the value of 0.15 mmxm²xml-1, and such findings are compatible with HCM. No correlation between LV dyssynchrony index by RT3D and the percentage of myocardial fibrosis determined by MRI was identified.

Résumé de l'étude in vitro. L'objectif de cette étude in vitro était de créer un fantôme avec la même architecture musculaire (fibre, aponévrose ...) et les mêmes propriétés mécaniques que le muscle en condition passive et active. Deux fantômes homogènes ont été fabriqués avec différentes concentrations de plastisol pour simuler les propriétés élastiques du muscle en condition passive (50% plastisol) et active (70% de plastisol). Pour cela, des fils en Téflon (d = 0,9 mm) ont été insérés dans la partie supérieure du fantôme (50%) pour représenter les fibres musculaires. De plus, une feuille en matière plastique (8 x 15 cm) a également été placée au milieu du fantôme pour imiter la structure de l'aponévrose. Ensuite, des tests ERM ont été effectués à 90 Hz avec deux stimulateurs pneumatiques de différentes formes (tube en silicone, membrane circulaire) pour analyser l'effet du type du stimulateur sur la propagation des ondes. La longueur d'onde a été mesurée à partir des images phase et les propriétés élastiques (module de cisaillement) ont été calculées. Les deux fantômes (50% et 70%) ont montré des propriétés élastiques similaires à celles du muscle à l’état passif (2,40 ± 0,18 kPa) et actif (6,24 ± 0,21 kPa). Le stimulateur en forme de tube a donné des valeurs plus élevées (environ 1,2 kPa à 1,53 kPa). L'analyse du comportement des ondes a révélé un glissement le long de la feuille plastique. Ce phénomène a aussi été observé in vivo le long de l’aponévrose. L'onde a également été sensible à la présence des fils en téflon car des coupures, des trous, ont été identifiés au cours de la propagation de l’onde. Une nouvelle méthode de post-traitement a été créée pour mesurer les paramètres G' et G" à partir de tests ERM réalisés à plusieurs fréquences (60, 80, 100 Hz) et en utilisant des modèles rhéologiques. Cette méthode a été testée sur un fantôme (50%) qui n’avait pas d’inclusion. Les résultats des mesures viscoélastiques (G', G") ont été validés avec la technique HFVS (Hyper-Fréquence viscoélastique Spectroscopy). Des valeurs similaires, G' et G’’, ont été obtenues avec les deux techniques. Ce dernier résultat valide la nouvelle méthode de post-traitement pour mesurer les propriétés viscoélastiques. Résumé de l'étude in vivo. L'objectif de cette étude in vivo a été de développer des protocoles ERM pour caractériser les propriétés élastiques (module de cisaillement) des neuf muscles de la cuisse. Ces tests ont été effectués à une seule fréquence (90 Hz). Différents modules de cisaillement ont été trouvés entre les muscles. Le gracilis a révélé des propriétés élastiques plus élevées que les autres muscles. Ces différentes élasticités peuvent être dues à différentes compositions physiologiques et architecturales entre les tissus. Ensuite, les propriétés viscoélastiques des muscles ischio (ST, SM, et la BC) et du muscle Gr ont été déterminées en appliquant la nouvelle méthode de post-traitement des données (précédemment validée sur le fantôme 50%) avec des tests ERM multi fréquences (70, 90 et 120 Hz) et en utilisant des modèles rhéologiques. Les résultats ont montré que deux modèles rhéologiques, Zener et springpot, peuvent être utilisés pour mesurer les propriétés viscoélastiques des muscles à l’état passif. De plus, des résultats similaires ont été trouvés entre G "/ G ', obtenus expérimentalement à 90 Hz, et la valeur α du modèle de springpot. / Summary of the vitro studies. The objective of this in vitro study was to create a phantom witch the same muscle architecture (fiber, aponeurosis …) and mechanical properties of muscle in passive and active states. Two homogeneous phantoms were manufactured with different concentrations of plastisol to simulate the muscle elastic properties in passive (50% of plastisol) and active (70% of plastisol) muscle conditions. Moreover, teflon tubing pipes (D = 0.9 mm) were thread in the upper part of the phantom (50%) to represent the muscle fibers and a plastic sheet (8 x 15 cm) was also included in the middle of the phantom to mimic the aponeurosis structure. Subsequently, MRE tests were performed at 90Hz with two different pneumatic drivers, tube and round shapes, to analyze the effect of the type of driver on the wave propagation. The wavelength was measured from the phase images and the elastic properties (shear modulus) were calculated. Both phantoms revealed elastic properties which were in the same range as in vivo muscle in passive (2.40 ± 0.18 kPa) and active (6.24 ± 0.21 kPa) states. The impact of the type of driver showed higher values with the tube (range: 1.2 kPa to 1.53 kPa). The analysis of the wave behavior revealed a sliding along the plastic sheet as it was observed for in vivo muscle study. The wave was also sensitive to the presence of the fibers where gaps were identified. A new post processing method was established to measure G’ and G” from experimental multi frequencies (60, 80, 100 Hz) MRE (MMRE) tests and rheological models. This method was tested on the phantom (50%) made without fiber. Cross validation of the viscoelastic (G’, G”) results was made with Hyper-Frequency Viscoelastic Spectroscopy (HFVS). Both techniques showed similar range of values for G’ and G” at the same frequencies. This last result validated our new data processing for the viscoelastic measurement. Summary of the in vivo studies. The objective of this in vivo study was to develop MRE protocols to characterize the elastic properties (shear modulus) of the nine thigh muscles. These tests were performed at a single frequency (90Hz). Different shear moduli were found between the muscles. The gracilis revealed the highest elastic properties compared to all the other muscles. These different elasticities may be due to different physiological and architectural compositions between the tissues. Then the viscoelastic properties of the ischio (ST, SM, and BC) and Gr muscles were determined based on our new data-processing method (validated on the phantom 50%) using MMRE tests (70, 90 and 120Hz) and rheological models. The results revealed that two rheological models, zener and springpot, can be used to measure the viscoelastic properties in passive state. A similar trend was found between the experimental ratios G”/G’ obtained at 90 Hz and the α value of the springpot model. The present MRE muscle protocol, and the viscoelastic data base, could be used as non-invasive diagnostic tools to evaluate tissue alterations, the progression of diseases, and the effect of treatments, such as the ongoing therapeutic trials for Duchenne muscular dystrophy.