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Approximately 23% of Canadians over the age of 65 are considered frail, with that number predicted to increase up to 40% for the population over the age of 85. Frailty is a geriatric syndrome defined by the natural decline in muscle mass and function caused by the natural aging process. When developing to an excessive degree, frailty may present as a disease state, which is recognized as sarcopenia. The exact definition of sarcopenia relies on the presence of low muscle mass, strength, and/or function, but quantitative cut-off values are still a topic of debate. Understanding how biomarkers measured via diagnostic imaging such as magnetic resonance imaging (MRI) and dual-energy x-ray absorptiometry (DXA) describe skeletal muscle can allow doctors to develop a profile of sarcopenia and define predictors to aide in preventative therapy. 4 male and 9 female (mean age = 78 ± 6.5 years) participants from a frailty study underwent full-body DXA and had their dominant thigh scanned using a 3.0T MRI. DXA-derived appendicular lean mass (ALM) and MRI-derived cross-sectional area (CSA), fat fraction (FF), T2 relaxation (T2), magnetization transfer ratio (MTR), fractional anisotropy (FA) and mean diffusivity (MD) from 4 muscle groups at the mid-thigh were defined as muscle biomarkers. Pearson's correlation was calculated to identify relationships between biomarkers and a Wilcoxon rank-sum test was performed to assess the agreement of low-muscle mass characterization between ALM normalized by height (ALMI), ALM normalized by BMI (ALM/BMI), and the gold standard MRI cross-sectional area. Strong positive correlations between muscle quantity biomarkers such as ALMI and CSA were recognized within the quadriceps (p=0.0095), adductors (p=0.035), and sartorius (p=0.00065) muscles while muscle quality biomarkers such as FF and T2 showed significant positive correlation within the quadriceps (p=3.58*10^-5) and the hamstring (p=0.0042) muscles. Finally, ALM/BMI displayed a much stronger agreement in muscle mass quantification with the gold-standard of MRI-CSA over the more commonly researched ALMI from DXA. The main purpose of this study was to collate a vast array of skeletal muscle biomarkers obtained using DXA and MRI on a frail population, and show that significant correlations can be recognized from a single MRI-slice located at the mid-thigh. Additionally, this study recognized the potential of ALM/BMI as the DXA-derived biomarker of choice in muscle mass assessment of frailty. / Thesis / Master of Applied Science (MASc) / A person is diagnosed with sarcopenia when they present symptoms of low muscle mass, strength, and/or function. Defining these three criteria with objective measures has been long debated by researchers and clinicians alike. By understanding how different properties, or biomarkers, of skeletal muscle relate to one another and change as a person becomes more frail, we hope to better understand sarcopenia and identify the best measures to classify someone as sarcopenic. Being able to accurately diagnose someone as sarcopenic early allows for more effective treatment of this muscle disease. In this study, non-invasive magnetic resonance imaging (MRI) and dual energy x-ray absorptiometry (DXA) were used to measure many different biomarkers of skeletal muscle at the mid-thigh. Through characterizing these measures of muscle quality and quantity between different imaging techniques this study aimed to recognize which imaging techniques, and more specifically biomarkers, can best distinguish between a person who is sarcopenic and one who is non-sarcopenic.

No description available.

Current quantitative nuclear magnetic resonance (NMR) technics offer biomarkers that allow performing non-invasive longitudinal studies for the follow up of therapeutic trials in neuromuscular disorders (NMD). In contrast to fat degeneration, the mechanisms of inflammation/oedema/necrosis and fibrosis are characteristic signs of disease activity, which makes their quantification a promising source of crucial biomarkers for longitudinal studies. This thesis work consisted on the implementation of more precise quantitative NMR methods adapted to the clinical study of skeletal muscle (SKM) for : (i) detection and quantification of sites of disease activity by T2-mapping of muscle water ; (ii) investigation of the different pathophysiological mechanisms underlying T2 alterations ; and (iii) Detection and quantification of muscle fibrosis. We implemented two methods for T2 mapping of muscle water. The first one is based on a multi-spin-echo sequence du type CPMG. In this method the 1H-NMR signals from water and lipids are acquired simultaneously. The acquired data are fitted to a tri-exponential model, in which water and fat signals are separated by exploring the T2 difference between water and fat. This method allows extraction of muscle water T2-value in the presence of fat infiltration. The second method is based on a " partially spoiled steady state free precession " (pSSFP) sequence. In contrast to the first method, which demands a sophisticated post-treatment of images acquired at 17 different echo-times, with the pSSFP a T2-mapping is extracted from two 3D data sets. 3D acquisition is compatible with spectrally selective water excitation, which eliminates signal contribution from lipids. Both methods were validated experimentally on patients and healthy subjects. The results demonstrated their capacity to detect and quantify disease activity sites. This 2 works have been published in two international journals : Azzabou, de Sousa, Araujo, & Carlier, 2014. Journal of Magnetic Resonance Imaging. DOI 10.1002/jmri.24613 (in press); et de Sousa, Vignaud, Araujo, & Carlier . 2012. Magnetic Resonance in Medicine. 67:1379-1390. Although it was shown to reveal disease activity, mono-exponential T2 of muscle water is non-specific to what concerns the mechanisms underlying its alterations. It has been long known that T2 relaxation in SKM tissue is multi-exponential. This is currently accepted to reveal anatomical compartmentation of myowater. We implemented a method for localized spectroscopic CPMG acquisition. CPMG data respect echo-time sampling and signal to noise ration limits for allowing robust multiexponential analysis. This work allowed us to establish a compartmentation model that perfectly explains the multi-exponential T2 relaxation observed in SKM tissue. This work was published in the " Biophysical Journal " (Araujo, Fromes & Carlier 2014. New Insights on skeletal muscle tissue compartments revealed by T2 NMR relaxometry. (In press)). Pilot studies performed in patients show promising results and suggest potential application of the method in clinical studies. Fibrosis starts with an excessive accumulation of intramuscular connective tissue (IMCT). We have explored the " Ultrashort time to echo " (UTE) method with the aim to detect and characterize the signal from IMCT. In a first study we characterized in vivo a short T2 component (~500 µs) in SKM, and we collected evidences suggesting that this component might reflect IMCT. Then we implemented a methodology that allowed imaging this short component in SKM tissue for the first time.

Magnetic resonance imaging (MRI) is one of the most important diagnostic tools of modern healthcare. The signal in medical MRI predominantly originates from water and fat molecules. Separation of the two components into water-only and fat-only images can improve diagnosis, and is the premier non-invasive method for measuring the amount and distribution of fatty tissue. Fat-water imaging (FWI) enables fast fat/water separation by model-based estimation from chemical shift encoded data, such as multi-echo acquisitions. Qualitative FWI is sufficient for visual separation of the components, while quantitative FWI also offers reliable estimates of the fat percentage in each pixel. The major problems of current FWI methods are long acquisition times, long reconstruction times, and reconstruction errors that degrade image quality. In this thesis, existing FWI methods were reviewed, and novel fully automatic methods were developed and evaluated, with a focus on fast 3D image reconstruction. All MRI data was acquired on standard clinical scanners. A triple-echo qualitative FWI method was developed for the specific application of 3D whole-body imaging. The method was compared with two reference methods, and demonstrated superior image quality when evaluated in 39 volunteers. The problem of qualitative FWI by dual-echo data with unconstrained echo times was solved, allowing faster and more flexible image acquisition than conventional FWI. Feasibility of the method was demonstrated in three volunteers and the noise performance was evaluated. Further, a quantitative multi-echo FWI method was developed. The signal separation was based on discrete whole-image optimization. Fast 3D image reconstruction with few reconstruction errors was demonstrated by abdominal imaging of ten volunteers. Lastly, a method was proposed for quantitative mapping of average fatty acid chain length and degree of saturation. The method was validated by imaging different oils, using gas-liquid chromatography (GLC) as the reference. The degree of saturation agreed well with GLC, and feasibility of the method was demonstrated in the thigh of a volunteer. The developed methods have applications in clinical settings, and are already being used in several research projects, including studies of obesity, dietary intervention, and the metabolic syndrome.

Quantitative cardiac magnetic resonance imaging (CMR) has gained traction within both the clinical and research field due to high prevalence of cardiovascular diseases. Cardiac magnetic resonance fingerprinting (cMRF) is a novel approach introduced to address the limitation associated with evaluation of multiparametric quantitative CMR. cMRF enables simultaneous and co-registered estimation of tissue relaxation times, T1 and T2, in a single acquisition, making it a more time-efficient approach to multiparametric quantitative CMR. Nevertheless, cMRF has not gained widespread adaption due to insufficient evidence regarding its performance in accurately quantifying tissue characteristics. This study aims to evaluate the accuracy and reproducibility of a single cMRF sequence described by Hamilton et. al. using self-constructed phantoms to validate the sequence performance for cardiac imaging. The objective was to construct in-vitro phantoms with physiological combinations of T1 and T2 markers. The phantoms were then imaged using gold standard and conventional mapping sequences to establish reference values for comparison. The measurements obtained from the two distinct cMRF reconstruction approaches were then compared to these reference values and to each other to evaluate the accuracy. The statistical assessments did not find a statistically significant difference between neither the cMRF sequence and conventional mapping techniques, nor cMRF and the gold-standard method, when compared in in-vitro phantoms with physiological combinations of T1 and T2. / Kvantitativ kardiovaskulär magnetresonans (CMR) har fått ökad uppmärksamhet inom både den kliniska- och forskningsfältet på grund av hög förekomst av hjärt- och kärlsjukdomar. För att åtgärda begränsningarna vid utvärdering av multiparametrisk kvantitativ CMR, introducerades cardiac magnetic resonance fingerprinting (cMRF) som en ny metod. cMRF möjliggör simultan och samregistrerad uppskattning av vävnadens relaxationstider, T1 och T2, i samma insamling, vilket gör det till en mer tidseffektiv metod för multiparametrisk kvantitativ CMR. Trots detta är kliniska implementeringen av cMRF inte utbredd på grund av otillräckligt bevis för dess utförande vid exakt kvantifiering av vävnadsegenskaper. Syftet med denna studie är att bedöma noggrannheten hos en cMRF-sekvens som utvecklats av Hamilton et al. genom att använda egentillverkade fantomer för att verifiera hur effektiv sekvensen är för avbildning av hjärtat. Målet är att konstruera in vitro-fantom med fysiologiska kombinationer av  T1- och T2-markörer. Dessa fantomer avbildades med hjälp av referensmetoder och konventionell karaktärisering för att etablera jämförelsevärden. Mätningarna som erhölls från de två distinkta cMRF-rekonstruktionsmetoderna jämfördes sedan statistiskt med jämförelsevärdena och med varandra för att utvärdera mätnoggrannheten. De statistiska bedömningarna kunde inte påvisa en skillnad mellan varken cMRF-sekvensen och konventionella metoder, eller referensmetod, vid jämförelse i in vitro-fantom med fysiologiska kombinationer av T1- och T2-värden.

Actuellement, des méthodes quantitatives de résonance magnétique nucléaire (RMN) offrent des biomarqueurs qui permettent la réalisation d’études longitudinales pour le suivi de l’évolution des maladies neuromusculaires et des essais thérapeutiques de manière non-invasive. A la différence de la dégénérescence graisseuse, les processus d’inflammation/œdème/nécrose et fibrose sont des signes d’activité des maladies et leurs quantifications constitueraient ainsi de biomarqueurs parfaitement adaptés pour le suivi thérapeutique. Ce travail de thèse a consisté à mettre en place des méthodologies quantitatives plus précises et adaptées à l’étude clinique du muscle pour : (i) détecter et quantifier des sites d’activité de maladies par la cartographie T2 de l’eau ; (ii) identifier les différents processus pathophysiologiques qui sont à l’origine des altérations du T2 ; et (iii) détecter et quantifier la fibrose musculaire. Nous avons implémenté deux méthodes pour la quantification du T2 de l’eau dans le muscle. La première est basée sur une séquence d’écho de spin du type CPMG, où les signaux provenant des protons des lipides et de l’eau sont acquis simultanément et séparés à postériori par un traitement tri-exponentiel qui exploite la différence entre les T2 qui caractérisent les signaux de l’eau et de la graisse. La deuxième technique est basée sur une séquence de « partially spoiled steady state free precession (pSSFP) ». Différemment de la première technique qui nécessite un traitement assez élaboré sur des images acquises à 17 temps d’écho différents, dans la pSSFP la cartographie T2 est extraite à partir de deux séries de données 3D. L’acquisition 3D est compatible avec des techniques de sélection spectrale de l’eau, ce qui évite la contamination par les signaux des lipides. Les deux méthodes ont été validées expérimentalement chez des malades et des sujets sains et ont démontré leur capacité à détecter et quantifier des sites d’activité de maladies. Ces deux travaux font l’objet de deux publications dans des journaux scientifiques internationaux : Azzabou, de Sousa, Araujo, & Carlier, 2014. Journal of Magnetic Resonance Imaging. DOI 10.1002/jmri.24613 (in press); et de Sousa, Vignaud, Araujo, & Carlier . 2012. Magnetic Resonance in Medicine. 67:1379-1390. Malgré le fait de permettre la détection des sites d’activité de maladies, la mesure mono-exponentielle du T2 de l’eau par imagerie reste non-spécifique vis-à-vis des processus physiologiques à l’origine de l’augmentation du T2. Il est connu que la relaxation T2 du muscle squelettique n’est pas mono-exponentielle. Cela est interprété comme une conséquence de la compartimentation anatomique de l’eau tissulaire. Nous avons mis au point une méthode pour l’acquisition localisée de données CPMG. Cette technique permet l’acquisition des données dans des conditions nécessaires pour la réalisation de traitements multi-exponentiels précis. Ce travail nous a permis d’établir un modèle de compartimentation qui explique parfaitement la relaxation T2 dans le muscle. Il a fait l’objet d’un article publié dans le « Biophysical Journal » (Araujo, Fromes & Carlier 2014. New Insights on skeletal muscle tissue compartments revealed by T2 NMR relaxometry. (In press)). Les essais réalisés chez des sujets malades suggèrent un grand potentiel pour l’application de la méthode dans des études cliniques. La formation de la fibrose commence avec une accumulation excessive de tissu conjonctif intramusculaire (TCIM). Nous avons exploité la technique « Ultrashort Time-to-Echo » (UTE) pour essayer de détecter et caractériser le signal du TCIM. Dans une première étude, nous avons caractérisé in vivo une composante à T2 court (~500 µs) dans le muscle, et nous avons trouvé des indices qui suggèrent qu’elle représente le TCIM. Dans une deuxième étude, nous avons mis au point une méthodologie qui a permis d’imager cette composante à T2 court dans le muscle pour la première fois. / Current quantitative nuclear magnetic resonance (NMR) technics offer biomarkers that allow performing non-invasive longitudinal studies for the follow up of therapeutic trials in neuromuscular disorders (NMD). In contrast to fat degeneration, the mechanisms of inflammation/oedema/necrosis and fibrosis are characteristic signs of disease activity, which makes their quantification a promising source of crucial biomarkers for longitudinal studies. This thesis work consisted on the implementation of more precise quantitative NMR methods adapted to the clinical study of skeletal muscle (SKM) for : (i) detection and quantification of sites of disease activity by T2-mapping of muscle water ; (ii) investigation of the different pathophysiological mechanisms underlying T2 alterations ; and (iii) Detection and quantification of muscle fibrosis. We implemented two methods for T2 mapping of muscle water. The first one is based on a multi-spin-echo sequence du type CPMG. In this method the 1H-NMR signals from water and lipids are acquired simultaneously. The acquired data are fitted to a tri-exponential model, in which water and fat signals are separated by exploring the T2 difference between water and fat. This method allows extraction of muscle water T2-value in the presence of fat infiltration. The second method is based on a « partially spoiled steady state free precession » (pSSFP) sequence. In contrast to the first method, which demands a sophisticated post-treatment of images acquired at 17 different echo-times, with the pSSFP a T2-mapping is extracted from two 3D data sets. 3D acquisition is compatible with spectrally selective water excitation, which eliminates signal contribution from lipids. Both methods were validated experimentally on patients and healthy subjects. The results demonstrated their capacity to detect and quantify disease activity sites. This 2 works have been published in two international journals : Azzabou, de Sousa, Araujo, & Carlier, 2014. Journal of Magnetic Resonance Imaging. DOI 10.1002/jmri.24613 (in press); et de Sousa, Vignaud, Araujo, & Carlier . 2012. Magnetic Resonance in Medicine. 67:1379-1390. Although it was shown to reveal disease activity, mono-exponential T2 of muscle water is non-specific to what concerns the mechanisms underlying its alterations. It has been long known that T2 relaxation in SKM tissue is multi-exponential. This is currently accepted to reveal anatomical compartmentation of myowater. We implemented a method for localized spectroscopic CPMG acquisition. CPMG data respect echo-time sampling and signal to noise ration limits for allowing robust multiexponential analysis. This work allowed us to establish a compartmentation model that perfectly explains the multi-exponential T2 relaxation observed in SKM tissue. This work was published in the « Biophysical Journal » (Araujo, Fromes & Carlier 2014. New Insights on skeletal muscle tissue compartments revealed by T2 NMR relaxometry. (In press)). Pilot studies performed in patients show promising results and suggest potential application of the method in clinical studies. Fibrosis starts with an excessive accumulation of intramuscular connective tissue (IMCT). We have explored the « Ultrashort time to echo » (UTE) method with the aim to detect and characterize the signal from IMCT. In a first study we characterized in vivo a short T2 component (~500 µs) in SKM, and we collected evidences suggesting that this component might reflect IMCT. Then we implemented a methodology that allowed imaging this short component in SKM tissue for the first time.