Yes / The purpose of this paper is to identify current UK screening practices prior to contrast-enhanced CT. To determine the patient management strategies to minimize the risk of contrast-induced acute kidney injury (CI-AKI) risk in outpatients. An invitation to complete an electronic survey was distributed to the CT managers of 174 UK adult National Health Service hospital trusts. The survey included questions related to local protocols and national guidance on which these are based. Details of the assessment of renal function prior to imaging and thresholds for contrast contraindication and patient management were also sought. A response rate of 47.1% was received. Almost all sites had a policy in place for contrast administration (n = 80/82; 97.6%). The majority of sites require a blood test on outpatients undergoing a contrast-enhanced CT scan (n = 75/82; 91.5%); however, some (15/75; 20.0%) sites only check the result in patients at high risk and a small number (7/82; 8.5%) of sites indicated that it was a referrer responsibility. The estimated glomerular filtration rate (eGFR) or serum creatinine (SCr) result threshold at which i.v. contrast was contraindicated varied and 19 different threshold levels of eGFR or SCr were identified, each leading to different prophylactic strategies. Inconsistency was noted in the provision of follow-up blood tests after contrast administration. The wide variation in practice reflects inconsistencies in published guidance. Evidence-based consensuses of which patients to test and subsequent risk thresholds will aid clinicians identify those patients in which the risk of CI-AKI is clinically significant but manageable. There is also a need to determine the value of the various prophylactic strategies, follow-up regimen and efficient service delivery pathways. This survey has identified that further work is required to define which patients are high risk, confirm those which require renal function testing prior to contrast administration and how best to manage patients at risk of CI-AKI. The role of new technologies within this service delivery pathway requires further investigation.

The global objectives of this research are to develop a liver-specific magnetic resonance (MR) image registration and segmentation algorithms and to find highly correlated MR imaging features that help automatically score the severity of chronic liver disease (CLD). For a concise analysis of liver disease, time sequences of 3-D MR images should be preprocessed through an image registration to compensate for the patient motion, respiration, or tissue motion. To register contrast-enhanced MR image volume sequences, we propose a novel version of the demons algorithm that is based on a bi-directional local correlation coefficient (Bi-LCC) scheme. This scheme improves the speed at which a convergent sequence approaches to the optimum state and achieves the higher accuracy. Furthermore, the simple and parallelizable hierarchy of the Bi-LCC demons can be implemented on a graphics processing unit (GPU) using OpenCL. To automate segmentation of the liver parenchyma regions, an edge function-scaled region-based active contour (ESRAC), which hybridizes gradient and regional statistical information, with approximate partitions of the liver was proposed. Next, a significant purpose in grading liver disease is to assess the level of remaining liver function and to estimate regional liver function. On motion-corrected and segmented liver parenchyma regions, for quantitative analysis of the hepatic extraction of liver-specific MRI contrast agent, liver signal intensity change is evaluated from hepatobiliary phases (3-20 minutes), and parenchymal texture features are deduced from the equilibrium (3 minutes) phase. To build a classifier using texture features, a set of training input and output values, which is estimated by experts as a score of malignancy, trains the supervised learning algorithm using a multivariate normal distribution model and a maximum a posterior (MAP) decision rule. We validate the classifier by assessing the prediction accuracy with a set of testing data.

Cerebral small vessel disease (SVD) is a common cause of strokes and dementia. The pathogenesis of SVD is poorly understood, but imaging and biochemical investigations suggest that subtle blood-brain barrier (BBB) leakage may contribute to tissue damage. The most widely-used imaging method for assessing BBB integrity and other microvascular properties is dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). DCE-MRI has primarily been applied in situations where contrast uptake in tissue is typically large and rapid (e.g. neuro-oncology); the optimal approach for quantifying BBB integrity in diseases where the BBB remains largely intact and the reliability of resulting measurements is unclear. The main purpose of this thesis was to assess and improve the reliability of quantitative assessment of subtle BBB disruption, in order to illuminate its potential role in cerebral SVD. Firstly, a systematic literature review was performed in order to provide an overview of DCE-MRI methods in the brain. This review found large variations in MRI procedures and data analysis methods, resulting in widely varying estimates of tracer kinetic parameters. Secondly, this thesis focused on the analysis of DCE-MRI data acquired in an on-site clinical study of mild stroke patients. After performing basic DCE-MRI processing (e.g. selection of a vascular input function), this work aimed to determine the tracer kinetic modelling approach most suitable for assessing subtle BBB disruption in this cohort. Using data-driven model selection and computer simulations, the Patlak model was found to provide accurate estimates of blood plasma volume and low-level BBB leakage. Thirdly, this thesis aimed to investigate two potential pitfalls in the quantification of subtle BBB disruption. Contrast-free measurements in healthy volunteers revealed that a signal drift of approximately 0.1 %/min occurs during the DCE-MRI acquisition; computer simulations showed that this drift introduces significant systematic errors when estimating low-level tracer kinetic parameters. Furthermore, tracer kinetic analysis was performed in an external patient cohort in order to investigate the inter-study comparability of DCE-MRI measurements. Due to the nature of the acquisition protocol it proved difficult to obtain reliable estimates of BBB leakage, highlighting the importance of study design. Lastly, this thesis examined the relationship between quantitative MRI parameters and clinical measurements in cerebral SVD, with a focus on the estimates of blood volume and BBB leakage obtained in the internal SVD patient cohort. This work did not provide evidence that BBB leakage in normal-appearing tissue increases with SVD burden or predicts disease progression; however, increased BBB leakage was found in white matter hyperintensities. Furthermore, this work raises the possibility of a role for blood plasma volume and dietary salt intake in cerebral SVD. The work described in this thesis has demonstrated that it is possible to estimate subtle BBB disruption using DCE-MRI, provided that the measurement and data analysis strategies are carefully optimised. However, absolute values of tracer kinetic parameters should be interpreted with caution, particularly when making comparisons between studies, and sources of error and their influence should be estimated where possible. The exact roles of BBB breakdown and other microvascular changes in SVD pathology remain to be defined; however, the work presented in this thesis contributes further insights and, together with technical advances, will facilitate improved study design in the future.

Les propriétés microvasculaires de la moëlle osseuse (MO) sont mal connues chez l’être humain. L’IRM de perfusion en permet une évaluation quantitative non invasive. La hanche a été choisie, car elle est la cible de pathologies fréquentes et handicapantes, qu’il est nécessaire de diagnostiquer plus précocement telle la coxarthrose. Nous avons d’abord implémenté une séquence IRM volumique à voxels isotropiques, avec une couverture large et une résolution spatiale élevée. Celle-ci a ensuite permis l’étude d’une série de 60 patients âgés de 18 à 60 ans, sans antécédent de pathologie osseuse et présentant une MO d’aspect normal en IRM. Les paramètres de perfusion semi-quantitatifs et pharmacocinétiques ont été mesurés dans 15 régions d’intérêt chez chaque patient. Tous les paramètres de perfusion diffèrent entre les zones de MO rouge et de MO jaune. La perfusion est différente entre les MO acétabulaire (squelette axial) et fémorale intertrochantérienne (squelette appendiculaire). Plusieurs paramètres sont corrélés de manière négative à l’âge. Plusieurs paramètres sont différents entre les hommes et les femmes. La perfusion de la tête fémorale est hétérogène, probablement en raison de l’exposition aux contraintes mécaniques. Les paramètres Ktrans, Kep et TTP sont corrélés à l’indice de masse corporelle, ce qui suggère que l’obésité influence le métabolisme de la MO. Enfin, le tabagisme et l’hypercholestérolémie ont une incidence sur ces mêmes paramètres dans certaines zones. Ils pourraient donc être le reflet d’altérations de la microvascularisation osseuse. Ces travaux ouvrent de nouvelles perspectives de recherche sur la physiologie et la pathologie de la MO. / Bone Marrow (BM) microvascular properties are insufficently known in humans. Dynamic-Contrast Enhanced (DCE) MRI allows its non-invasive quantitative assessment. We concentrated on the hip because this joint is frequently affected by debilitating pathologies such as osteoarthritis. Their early diagnosis is a current medical challenge. We implemented a 3D DCE-MRI sequence with isotropic voxels, high spatial resolution and a large coverage. It was used in a study of 60 patients aged 18 to 60, with no previous history of bone disease and with normal-appearing BM on MR images. Semi-quantitative and pharmacokinetic parameters were measured in 15 regions of interest in each patient. All the parameters were different between red and yellow BM. Perfusion was different between acetabular (axial skeleton) and femoral intertrochanteric (appendicular skeleton) BMs. Several parameters were negatively correlated with age. Perfusion was different in men and women. The femoral head perfusion was heterogeneous, likely because of mechanical load exposure. Ktrans, Kep and TTP were correlated with body mass index. This suggests that obesity influences BM metabolism. Smoking and hypercholesterolemia influenced these same parameters in several zones. We hypothesized that these parameters might reflect BM microvascular aletrations. Our results open new research perspectives both in the physiology and pathology of BM.

In an effort to develop an optical-acoustical understanding of ultrasound contrast agent microbubble dynamics in a micro-environment that resembles blood vessels, this thesis presents experimental work on optical trapping and acoustical probing of ultrasound contrast agent microbubbles confined in regenerated cellulose capillaries. First, we showed by acoustical means that the pressure threshold of an individual microbubble shell rupture increases significantly when confined in regenerated cellulose capillaries. We report that the shell rupture threshold in regenerated cellulose capillaries increased by at least 0.3 MPa from 0.8 MPa for unconfined microbubbles. Second, we achieved optical trapping and manipulation of ultrasound contrast agent microbubbles confined in capillaries using Hermite-Gaussian laser beams. / Graduation date: 2012

Purpose: To compare hemodynamic of malignant and benign SRMs on CT and CEUS. Method: Seventy biopsy proven SRM underwent CEUS. Sixty-three had CT. After injection of 0.2 ml of Definity, 3min and after 0.9 ml infusion, 30 sec of data were acquires. Lesion hemodynamics relative to the cortex was evaluated both qualitatively and quantitatively. Results: Considering 15 and 20 HU as enhancement threshold, 10% to 13% of patients did not enhance on CT, while all lesions enhanced on CEUS. Papillary RCCs showed hypovascularity with 100% specificity. In other RCCs, PI, WI slope 5 to45%, 50 to100%, 10 to 90%, WO slope 100 to 50%, 100 to 10%, WO intensity at peak+30 seconds were statistically higher than benign SRMs. Conclusion: All solid SRMs enhance on CEUS, while CT does not show vascularity in 10-13% of solid SRMs. CEUS can differentiate malignant from benign SRMs by evaluating their hemodynamics.

Microvascular permeability is a pharmacologic indicator of tumor response to therapy, and it is expected that this biomarker will evolve into a clinical surrogate endpoint and be integrated into protocols for determining patient response to antiangiogenic or antivascular therapies. The goal of this research is to develop a method by which microvascular permeability (Ktrans) and vascular volume (vp) as measured by DCE-MRI were directly compared to the same parameters measured by intravital fluorescence microscopy in an MRI-compatible window chamber model. Dynamic contrast enhanced-MRI (DCE-MRI) is a non-invasive, clinically useful imaging approach that has been used extensively to measure active changes in tumor microvascular hemodynamics. However, uncertainties exist in DCE-MRI as it does not interrogate the contrast reagent (CR) itself, but the effect of the CR on tissue water relaxivity. Thus, direct comparison of DCE-MRI with a more quantitative measure would help better define the derived parameters. The combined imaging system was able to obtain both dynamic contrast-enhanced MRI data high spatio-termporal resolution fluorescence data following injection of fluorescent and gadolinium co-labeled albumin. This approach allowed for the cross-validation of vascular permeability data, in relation tumor growth, angiogenesis and response to therapy in both imaging systems.

Background: Parameters of carotid atherosclerosis dynamic contrast-enhanced MRI (DCE-MRI) are associated with stroke risk indices, but studies have only evaluated symptomatic arteries. I hypothesized that DCE-MRI parameters are different between carotid atherosclerotic plaques at high and low risk for precipitating ischemic stroke. Methods: High and low risk carotid plaques undergoing nonmodel-based DCE-MRI (n=18) were compared using two independent schema: 1) clinical standard (high risk defined as ipsilateral stroke/TIA <1 week old or stenosis >70%); 2) MRI standard (high risk defined as presence of intraplaque hemorrhage [IPH]). Results: IPH-positive plaques (n=9) exhibited greater area under the curve, early and late enhancement rate, and peak enhancement than IPH-negative plaques (n=9) (p<0.05 for all). High (n=8) and low (n=7) risk plaques defined by clinical criteria were not differentiated by any DCE-MRI parameters. Conclusions: Nonmodel-based DCE-MRI discriminates high versus low risk carotid plaque based on the presence of IPH, but not by clinical criteria.

Background: Parameters of carotid atherosclerosis dynamic contrast-enhanced MRI (DCE-MRI) are associated with stroke risk indices, but studies have only evaluated symptomatic arteries. I hypothesized that DCE-MRI parameters are different between carotid atherosclerotic plaques at high and low risk for precipitating ischemic stroke. Methods: High and low risk carotid plaques undergoing nonmodel-based DCE-MRI (n=18) were compared using two independent schema: 1) clinical standard (high risk defined as ipsilateral stroke/TIA <1 week old or stenosis >70%); 2) MRI standard (high risk defined as presence of intraplaque hemorrhage [IPH]). Results: IPH-positive plaques (n=9) exhibited greater area under the curve, early and late enhancement rate, and peak enhancement than IPH-negative plaques (n=9) (p<0.05 for all). High (n=8) and low (n=7) risk plaques defined by clinical criteria were not differentiated by any DCE-MRI parameters. Conclusions: Nonmodel-based DCE-MRI discriminates high versus low risk carotid plaque based on the presence of IPH, but not by clinical criteria.

Purpose: To compare hemodynamic of malignant and benign SRMs on CT and CEUS. Method: Seventy biopsy proven SRM underwent CEUS. Sixty-three had CT. After injection of 0.2 ml of Definity, 3min and after 0.9 ml infusion, 30 sec of data were acquires. Lesion hemodynamics relative to the cortex was evaluated both qualitatively and quantitatively. Results: Considering 15 and 20 HU as enhancement threshold, 10% to 13% of patients did not enhance on CT, while all lesions enhanced on CEUS. Papillary RCCs showed hypovascularity with 100% specificity. In other RCCs, PI, WI slope 5 to45%, 50 to100%, 10 to 90%, WO slope 100 to 50%, 100 to 10%, WO intensity at peak+30 seconds were statistically higher than benign SRMs. Conclusion: All solid SRMs enhance on CEUS, while CT does not show vascularity in 10-13% of solid SRMs. CEUS can differentiate malignant from benign SRMs by evaluating their hemodynamics.