Analysis of first pass myocardial perfusion imaging with magnetic resonance

Early diagnosis and localisation of myocardial perfusion defects is an important step in the treatment of coronary artery disease. Thus far, coronary angiography is the conventional standard investigation for patients with known or suspected coronary artery disease and it provides information about the presence and location of coronary stenoses. In recent years, the development of myocardial perfusion CMR has extended the role of MR in the evaluation of ischaemic heart disease beyond the situations where there have already been gross myocardial changes such as acute infarction or scarring. The ability to non-invasively evaluate cardiac perfusion abnormalities before pathologic effects occur, or as follow-up to therapy, is important to the management of patients with coronary artery disease. Whilst limited multi-slice 2D CMR perfusion studies are gaining increased clinical usage for quantifying gross ischaemic burden, research is now directed towards complete 3D coverage of the myocardium for accurate localisation of the extent of possible defects. In 3D myocardial perfusion imaging, a complete volumetric data set has to be acquired for each cardiac cycle in order to study the first pass of the contrast bolus. This normally requires a relatively large acquisition window within each cardiac cycle to ensure a comprehensive coverage of the myocardium and reasonably high resolution of the images. With multi-slice imaging, long axis cardiac motion during this large acquisition window can cause the myocardium imaged in different cross- sections to be mis-registered, i.e., some part of the myocardium may be imaged more than twice whereas other parts may be missed out completely. This type of mis-registration is difficult to correct for by using post-processing techniques. The purpose of this thesis is to investigate techniques for tracking through plane motion during 3D myocardial perfusion imaging, and a novel technique for extracting intrinsic relationships between 3D cardiac deformation due to respiration and multiple ID real-time measurable surface intensity traces is developed. Despite the fact that these surface intensity traces can be strongly coupled with each other but poorly correlated with respiratory induced cardiac deformation, we demonstrate how they can be used to accurately predict cardiac motion through the extraction of latent variables of both the input and output of the model. The proposed method allows cross-modality reconstruction of patient specific models for dense motion field prediction, which after initial modelling can be use in real-time prospective motion tracking or correction. In CMR, new imaging sequences have significantly reduced the acquisition window whilst maintaining the desired spatial resolution. Further improvements in perfusion imaging will require the application of parallel imaging techniques or making full use of the information content of the ¿-space data. With this thesis, we have proposed RR-UNFOLD and RR-RIGR for significantly reducing the amount of data that is required to reconstruct the perfusion image series. The methods use prospective diaphragmatic navigator echoes to ensure UNFOLD and RIGR are carried out on a series of images that are spatially registered. An adaptive real-time re-binning algorithm is developed for the creation of static image sub-series related to different levels of respiratory motion. Issues concerning temporal smoothing of tracer kinetic signals and residual motion artefact are discussed, and we have provided a critical comparison of the relative merit and potential pitfalls of the two techniques. In addition to the technical and theoretical descriptions of the new methods developed, we have also provided in this thesis a detailed literature review of the current state-of-the-art in myocardial perfusion imaging and some of the key technical challenges involved. Issues concerning the basic background of myocardial ischaemia and its functional significance are discussed. Practical solutions to motion tracking during imaging, predictive motion modelling, tracer kinetic modelling, RR-UNFOLD and RR-RIGR are discussed, all with validation using patient and normal subject data to demonstrate both the strength and potential clinical value of the proposed techniques.Open acces

Kinetic Modelling in Human Brain Imaging

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Advanced Imaging Techniques for Cardiovascular Research

Objectives: In this thesis we addressed some of those difficulties by exploring new applications of a 68Galabeled radiotracer (68Ga-DOTA). 68Ga can be obtained from a 68Ge/68Ga generator and has a half-life of 68 minutes, which makes it a convenient candidate for its widespread clinical use. We proposed and validated the use of 68Ga-DOTA as a radiotracer for assessment of myocardial blood flow (MBF), myocardial viability and pulmonary blood flow (PBF). Additionally, we introduced a new methodology to perform a PET scan in which this tracer could be coinjected simultaneously with some other radiotracers such as 18FDG (multi-tracer PET). Lastly, we developed an automatic detector able to perform blood spectroscopy analysis, which offered the possibility to perform multi-tracer PET with minimal human intervention. Methods To test the capability of 68Ga-DOTA to measure MBF, viability and PBF, different groups of Large White pigs underwent PET/CT scans using 68Ga-DOTA as the injected radiotracer. For PBF studies, a group of healthy pigs (n = 4) were scanned under rest conditions. For MBF studies, a group of 8 pigs were scanned under rest and pharmacologically-induced stress in order to perform rest/stress tests, as it is done for humans in clinical routine. Additionally, a group of 5 pigs were scanned 7 days after the induction of a myocardial infarction (MI) to assess viability and MBF in a MI model. MBF, extracellular volume fraction (ECV, for viability assessment) and PBF maps were obtained after fitting the dynamic PET images to the corresponding pharmacokinetic model followed by 68Ga-DOTA in each tissue under study. Global and regional perfusion maps for the myocardial tissue (MBF) and lungs (PBF) were obtained. For validation purposes, the “goldstandard” technique used in tissue perfusion quantification (fluorescent-labeled microspheres (MS)) was simultaneosly performed along with the PET/CT scans. The blood sampling spectroscopic methodology was evaluated and calibrated in vitro using different 68Ga/18F mixtures. Then, it was tested in pigs (n = 3) injected with 68Ga-DOTA and 18FDG in the same acquisition. The activity concentration of each radiotracer in myocardial tissue was subsequently measured ex vivo. The automatic blood sampling detector was built from scratch and characterized using a catheter filled with different 68Ga/18F mixtures. Finally, it was additionally evaluated in vivo in n = 3 pigs under conditions resembling to those encountered in clinical routine. Results Regarding MBF quantification and validation with 68Ga-DOTA-PET, a strong correlation (r = 0.91) between MBF measured with PET and MS was obtained (slope = 0.96 ± 0.10, y-intercept = 0.11 ± 0.19 ml·min−1·g−1). For the myocardial infarction model, MBF values obtained with 68Ga-DOTA-PET in the infarcted area (LAD, left anterior descendant) were significantly reduced in comparison to remote ones LCX (left circumflex artery, p < 0.0001) and RCA (right coronary artery, p < 0.0001). In addition, 68Ga-DOTA-PET detected a significant ECV increase in the infarcted area (p < 0.0001). The correlation evaluation between 68Ga-DOTA-PET and MS as a PBF radiotracer also showed a good and significant correlation (r = 0.74, p < 0.0001). The gamma spectroscopic analysis on blood samples proposed for multi-tracer PET imaging was also succesfully validated, showing a correlation of r = 0.95 (p < 0.0001) for 18FDG concentration in myocardium measured with multi-tracer PET and by ex vivo validation. The blood sampling detector was able to measure the arterial input function in pigs in an experimental setup under realistic conditions. Discussion and conclusions 68Ga-DOTA-PET allowed accurate non-invasive assessment of MBF and ECV in pigs with myocardial infarction and under rest-stress conditions. This technique could provide wide access to quantitative measurement of both MBF and ECV with PET imaging. 68Ga-DOTA-PET was also demonstrated to be a potential inexpensive method for measuring PBF in clinical settings. As for multi-tracer PET imaging, the proposed methodology allowed explicit measurement of separate arterial input functions, offering very similar results to those obtained as a reference from the ex vivo analysis of the tissue under evaluation. Finally, a novel blood sampling device was developed and characterized, showing performance parameters similar to other devices in the literature. Noteworthy, this detector has the additional and unique feature of allowing us to perform multi-tracer PET by means of a gamma spectroscopic analysis of the blood flowing between its detection blocks. All the results summarized in this abstract may contribute to spread the use of PET in clinical routine, either by the clinical use of 68Ga-DOTA as an inexpensive but accurate radiotracer for MBF, PBF or viability assessment, or by the implementation of multi-tracer PET, which could lead to cost reduction of PET examinations by shortening the scanning time and eliminating misalignment inaccuracies. This multi-tracer PET methodology could also be safely implemented using our proposed automated device that permits to perform the gamma spectroscopic analysis on blood samples with minimal human intervention

Advanced imaging techniques for cardiovascular research

According to the World Health Organization, cardiovascular diseases (CVDs) are the first cause of death globally. CVDs are a cluster of disorders that involve heart and blood vessels. Among them, coronary artery disease (CAD) is the most important disease in terms of mortality, causing more than 50% of the annual deaths. Over the last decades, many recognized international organisms, such as the World Health Organization and the American College of Cardiology have done great efforts to reduce the mortality and morbidity of CAD. In this line, accurate diagnosis and cost-effective management of CAD have revealed to be of utmost importance. Several imaging techniques are currently used in the clinical practice to provide a diagnosis and clinical assessment of the disease. Among them, Positron Emission Tomography (PET) is considered to be the “gold standard” for non invasive assessment of myocardial perfusion and viability, the two most relevant physiological parameters used to diagnose and manage patients with known or suspected CAD..

Quantification of the novel N-methyl-D-aspartate receptor ligand [11C]GMOM in man

[11C]GMOM (carbon-11 labeled N-(2-chloro-5-thiomethylphenyl)-N0-(3-[11C]methoxy-phenyl)-N0-methylguanidine) is a PET ligand that binds to the N-methyl-D-aspartate receptor with high specificity and affinity. The purpose of this first in human study was to evaluate kinetics of [11C]GMOM in the healthy human brain and to identify the optimal pharmacokinetic model for quantifying these kinetics, both before and after a pharmacological dose of S-ketamine. Dynamic 90 min [11C]GMOM PET scans were obtained from 10 subjects. In six of the 10 subjects, a second PET scan was performed following an S-ketamine challenge. Metabolite corrected plasma input functions were obtained for all scans. Regional time activity curves were fitted to various single- and two-tissue compartment models. Best fits were obtained using a two-tissue irreversible model with blood volume parameter. The highest net influx rate (Ki) of [11C]GMOM was observed in regions with high N-methyl-D-aspartate receptor density, such as hippocampus and thalamus. A significant reduction in the Ki was observed for the entire brain after administration of ketamine, suggesting specific binding to the N-methyl-D-aspartate receptors. This initial study suggests that the [11C]GMOM could be used for quantification of N-methyl-D-aspartate receptors

Development of novel radiotracers as tools for imaging the human brain

Introduction: Brain imaging using single photon emission computed tomography (SPECT) or positron emission tomography (PET) can be used to study the processes underlying neurological and psychiatric disorders. In addition, in vivo brain imaging using SPECT or PET may provide new approaches for drug target identification, pre-clinical testing and occupancy studies, and therefore improve drug discovery. The utility of in vivo brain imaging using SPECT or PET relies on the ability of different radiotracers (typically organic compounds labelled with radionuclides) to bind to a wide variety of targets, including receptors, transporters and enzymes. Therefore the development of novel radiotracers for in vivo brain imaging using SPECT of PET is of vital importance. This thesis is focused on the process of developing novel radiotracers as tools for imaging the human brain, where the radiotracer discovery and development pipeline is discussed and each step prior to clinical trials investigated. Radiotracer discovery: Previously, discovery of novel brain radiotracers has largely relied on simplistic screening tools. Improved selection methods at the early stages of radiotracer discovery and an increased understanding of the relationships between in vitro physicochemical and in vivo radiotracer properties are needed. This thesis investigated if high performance liquid chromatography (HPLC) methodologies could provide criteria for lead candidate selection by comparing HPLC measurements with radiotracer properties in humans. In this study, ten molecules, previously used as radiotracers in humans, were analysed to obtain the following measures: partition coefficient (Log P); permeability (Pm); percentage of plasma protein binding (%PPB); and membrane partition coefficient (Km). Relationships between brain entry measurements (Log P, Pm and %PPB) and in vivo brain percentage injected dose (%ID); and Km and specific binding in vivo (BPND) were investigated. Results showed that HPLC measurements of Pm, %PPB and Km were potentially useful in predicting in vivo performance and hence allow evaluation and ranking of compound libraries for the selection of lead radiotracer candidates at early stages of radiotracer discovery. The HPLC tool developed provides information on in vivo non-specific binding and binding potential that is not possible using conventional screening methods. Another important finding reported in this thesis is that Log P should not be relied on as a predictor of brain entry. The HPLC tool developed, together with competition binding assays, was used to characterise a newly synthesised library of compounds for imaging of the translocator protein (TSPO) in brain using SPECT. Results showed that compound LS 1 was the most likely to succeed within the library investigated, but the high %PPB observed for LS 1 suggested novel compounds with improved %PPB were needed. Thus, a novel library of compounds for imaging of TSPO in brain using SPECT is currently been developed for future testing using the HPLC tool developed here and competition binding assays. Pre-clinical research: radiotracers for imaging the noradrenaline transporter (NAT) in brain using SPECT. In this thesis, NKJ64, a novel iodinated analogue of reboxetine, was successfully radiolabelled via electrophilic iododestannylation and evaluated as a potential SPECT radiotracer for imaging the NAT in brain using rodents and non-human primates. Biological evaluation of the novel radiotracer, 123/125I-NKJ64, in rodents included: in vitro ligand binding assays; in vitro and ex vivo autoradiography; in vivo biodistribution studies and ex vivo pharmacological blocking studies. In rats, 123/125I-NKJ64 displayed saturable binding with nanomolar affinity for the NAT in cortical homogenates, regional distribution consistent with the known density of NAT in the rodent brain and high maximum brain uptake of around 2.93 % of the injected dose. The specific: non-specific ratio (locus coeruleus:caudate putamen) of 123I-NKJ64 uptake was 2.8 at 30 minutes post intravenous injection and prior administration of reboxetine significantly reduced the accumulation of 123I-NKJ64 in the locus coeruleus (> 50% reduction). Data obtained using rodents indicated that further evaluation of 123I-NKJ64 in non-human primates was needed to determine its utility as a SPECT radiotracer for imaging of NAT in brain. Consequently, in vivo kinetic modelling studies using SPECT imaging with 123I-NKJ64 and two baboons were carried out to determine 123I-NKJ64 brain binding kinetics, brain distribution and plasma metabolism in non-human primates. Even though a high brain uptake of around 3.0% of the injected dose was determined, the high non-specific binding observed throughout the brain, a low binding potential (BPND<2) in NAT rich regions and a brain distribution that was inconsistent with the known NAT distribution in non-human primate brain precludes the translation of 123I-NKJ64 into humans. Another NAT radiotracer, 123I-INER, developed by Tamagnan and colleagues at Yale University and Institute for Degenerative Disorders, New Haven, USA, was also investigated as part of this thesis. Kinetic modelling analysis of 123I-INER in baboon brain was investigated for different models, namely invasive and reference tissue models. Bolus plus constant infusion experiments with displacement at equilibrium using six different doses of atomoxetine and four different doses of reboxetine were carried out in several baboons to obtain occupancy measurements as a function of injected dose (mg/kg) for the two NAT selective drugs. Results showed that reference tissue models were able to determine BPND values of 123I-INER in different brain regions. In addition the volume of distribution could be determined by dividing concentration in tissue by the concentration in venous blood at 3 hours post-injection. After administration of atomoxetine or reboxetine, dose-dependent occupancy was observed in brain regions known to contain high densities of NATs. Results supported the translation of 123I-INER into humans studies, despite the slow kinetics determined over the imaging period. Pharmacokinetic properties of 123I-INER described in this thesis may be used to simplify future data acquisition and image processing. Conclusion In conclusion, this thesis reported: (1) the development of novel radiotracers for brain imaging, namely NAT and TSPO; and (2) the development of a new methodology for aiding lead molecule identification at early stages of radiotracer discovery (i.e. prior to radiolabelling). In addition, an overview of radiotracer discovery and development process is provided in a single document, with a focus on brain radiotracers

Exploiting MRI information for improved kinetic modelling of dynamic PET data

Kinetic analysis of dynamic PET data requires an accurate estimation of the concen- tration of the available tracer in blood plasma, also known as the arterial input function (AIF). The gold standard method to determine the AIF involves serial blood sampling and is avoided in practice due to its invasiveness. An image derived input function (IDIF) can be a blood-free alternative but its accuracy is limited due to partial volume (PV) effects caused by the restricted spatial resolution of PET scanners. Furthermore, IDIFs are not accurate when metabolite products are present in the blood. Magnetic resonance imaging (MRI) can provide complementary information to PET with high spatial resolution and excellent soft tissue contrast. Furthermore, dynamic MRI techniques can be reliably used to measure the AIF, the concentration of contrast agent in plasma, due to their high temporal resolution. The underlying aim of this research is to improve IDIF estimation in PET, utilising spatial and temporal information from MRI. An IDIF measurement method was developed which involves segmentation of carotid arteries from MR angiography images and uses a practical PVC method to correct for PV effects. It was demonstrated that the IDIFs can be used to compute the cerebral metabolic rate of glucose in the brain with no significant difference compared to arterial sampling. The simultaneous estimation method (SIME) is an alternative technique used to estimate the AIF by fitting time activity curves derived from multiple regions. Due to its computational complexity, SIME is usually complemented with blood samples. In this work, we observed that the early part of an image derived blood curve or an MRI derived AIF could provide prior knowledge regarding the AIF. This was incorporated into SIME to make more accurate kinetic parameter estimations and to perform blood-free analysis of tracers with metabolites

Advanced perfusion quantification methods for dynamic PET and MRI data modelling

The functionality of tissues is guaranteed by the capillaries, which supply the microvascular network providing a considerable surface area for exchanges between blood and tissues. Microcirculation is affected by any pathological condition and any change in the blood supply can be used as a biomarker for the diagnosis of lesions and the optimization of the treatment. Nowadays, a number of techniques for the study of perfusion in vivo and in vitro are available. Among the several imaging modalities developed for the study of microcirculation, the analysis of the tissue kinetics of intravenously injected contrast agents or tracers is the most widely used technique. Tissue kinetics can be studied using different modalities: the positive enhancement of the signal in the computed tomography and in the ultrasound dynamic contrast enhancement imaging; T1-weighted MRI or the negative enhancement of T2* weighted MRI signal for the dynamic susceptibility contrast imaging or, finally, the uptake of radiolabelled tracers in dynamic PET imaging. Here we will focus on the perfusion quantification of dynamic PET and MRI data. The kinetics of the contrast agent (or the tracer) can be analysed visually, to define qualitative criteria but, traditionally, quantitative physiological parameters are extracted with the implementation of mathematical models. Serial measurements of the concentration of the tracer (or of the contrast agent) in the tissue of interest, together with the knowledge of an arterial input function, are necessary for the calculation of blood flow or perfusion rates from the wash-in and/or wash-out kinetic rate constants. The results depend on the acquisition conditions (type of imaging device, imaging mode, frequency and total duration of the acquisition), the type of contrast agent or tracer used, the data pre-processing (motion correction, attenuation correction, correction of the signal into concentration) and the data analysis method. As for the MRI, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a non-invasive imaging technique that can be used to measure properties of tissue microvasculature. It is sensitive to differences in blood volume and vascular permeability that can be associated with tumour angiogenesis. DCE-MRI has been investigated for a range of clinical oncologic applications (breast, prostate, cervix, liver, lung, and rectum) including cancer detection, diagnosis, staging, and assessment of treatment response. Tumour microvascular measurements by DCE-MRI have been found to correlate with prognostic factors (such as tumour grade, microvessel density, and vascular endothelial growth factor expression) and with recurrence and survival outcomes. Furthermore, DCE-MRI changes measured during treatment have been shown to correlate with outcome, suggesting a role as a predictive marker. The accuracy of DCE-MRI relies on the ability to model the pharmacokinetics of an injected contrast agent using the signal intensity changes on sequential magnetic resonance images. DCE-MRI data are usually quantified with the application of the pharmacokinetic two-compartment Tofts model (also known as the standard model), which represents the system with the plasma and tissue (extravascular extracellular space) compartments and with the contrast reagent exchange rates between them. This model assumes a negligible contribution from the vascular space and considers the system in, what-is-known as, the fast exchange limit, assuming infinitely fast transcytolemmal water exchange kinetics. In general, the number, as well as any assumption about the compartments, depends on the properties of the contrast agent used (mainly gadolinium) together with the tissue physiology or pathology studied. For this reason, the choice of the model is crucial in the analysis of DCE-MRI data. The value of PET in clinical oncology has been demonstrated with studies in a variety of cancers including colorectal carcinomas, lung tumours, head and neck tumours, primary and metastatic brain tumours, breast carcinoma, lymphoma, melanoma, bone cancers, and other soft-tissue cancers. PET studies of tumours can be performed for several reasons including the quantification of tumour perfusion, the evaluation of tumour metabolism, the tracing of radiolabelled cytostatic agents. In particular, the kinetic analysis of PET imaging has showed, in the past few years, an increasing value in tumour diagnosis, as well as in tumour therapy, through providing additional indicative parameters. Many authors have showed the benefit of kinetic analysis of anticancer drugs after labelling with radionuclide in measuring the specific therapeutic effect bringing to light the feasibility of applying the kinetic analysis to the dynamic acquisition. Quantification methods can involve visual analysis together with compartmental modelling and can be applied to a wide range of different tracers. The increased glycolysis in the most malignancies makes 18F-FDG-PET the most common diagnostic method used in tumour imaging. But, PET metabolic alteration in the target tissue can depend by many other factors. For example, most types of cancer are characterized by increased choline transport and by the overexpression of choline kinase in highly proliferating cells in response to enhanced demand of phosphatidylcholine (prostate, breast, lung, ovarian and colon cancers). This effect can be diagnosed with choline-based tracers as the 18Ffluoromethylcholine (18F-FCH), or the even more stable 18F-D4-Choline. Cellular proliferation is also imaged with 18F-fluorothymidine (FLT), which is trapped within the cytosol after being mono phosphorylated by thymidine kinase-1 (TK1), a principal enzyme in the salvage pathway of DNA synthesis. 18F-FLT has been found to be useful for noninvasive assessment of the proliferation rate of several types of cancer and showed high reproducibility and accuracy in breast and lung cancer tumours. The aim of this thesis is the perfusion quantification of dynamic PET and MRI data of patients with lung, brain, liver, prostate and breast lesions with the application of advanced models. This study covers a wide range of imaging methods and applications, presenting a novel combination of MRI-based perfusion measures with PET kinetic modelling parameters in oncology. It assesses the applicability and stability of perfusion quantification methods, which are not currently used in the routine clinical practice. The main achievements of this work include: 1) the assessment of the stability of perfusion quantification of D4-Choline and 18F-FLT dynamic PET data in lung and liver lesions, respectively (first applications in the literature); 2) the development of a model selection in the analysis of DCE-MRI data of primary brain tumours (first application of the extended shutter speed model); 3) the multiparametric analysis of PET and MRI derived perfusion measurements of primary brain tumour and breast cancer together with the integration of immuohistochemical markers in the prediction of breast cancer subtype (analysis of data acquired on the hybrid PET/MRI scanner). The thesis is structured as follows: - Chapter 1 is an introductive chapter on cancer biology. Basic concepts, including the causes of cancer, cancer hallmarks, available cancer treatments, are described in this first chapter. Furthermore, there are basic concepts of brain, breast, prostate and lung cancers (which are the lesions that have been analysed in this work). - Chapter 2 is about Positron Emission Tomography. After a brief introduction on the basics of PET imaging, together with data acquisition and reconstruction methods, the chapter focuses on PET in the clinical settings. In particular, it shows the quantification techniques of static and dynamic PET data and my results of the application of graphical methods, spectral analysis and compartmental models on dynamic 18F-FDG, 18F-FLT and 18F-D4- Choline PET data of patients with breast, lung cancer and hepatocellular carcinoma. - Chapter 3 is about Magnetic Resonance Imaging. After a brief introduction on the basics of MRI, the chapter focuses on the quantification of perfusion weighted MRI data. In particular, it shows the pharmacokinetic models for the quantification of dynamic contrast enhanced MRI data and my results of the application of the Tofts, the extended Tofts, the shutter speed and the extended shutter speed models on a dataset of patients with brain glioma. - Chapter 4 introduces the multiparametric imaging techniques, in particular the combined PET/CT and the hybrid PET/MRI systems. The last part of the chapter shows the applications of perfusion quantification techniques on a multiparametric study of breast tumour patients, who simultaneously underwent DCE-MRI and 18F-FDG PET on a hybrid PET/MRI scanner. Then the results of a predictive study on the same dataset of breast tumour patients integrated with immunohistochemical markers. Furthermore, the results of a multiparametric study on DCE-MRI and 18F-FCM brain data acquired both on a PET/CT scanner and on an MR scanner, separately. Finally, it will show the application of kinetic analysis in a radiomic study of patients with prostate cancer

Algorithmic Analysis Techniques for Molecular Imaging

This study addresses image processing techniques for two medical imaging modalities: Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI), which can be used in studies of human body functions and anatomy in a non-invasive manner. In PET, the so-called Partial Volume Effect (PVE) is caused by low spatial resolution of the modality. The efficiency of a set of PVE-correction methods is evaluated in the present study. These methods use information about tissue borders which have been acquired with the MRI technique. As another technique, a novel method is proposed for MRI brain image segmen- tation. A standard way of brain MRI is to use spatial prior information in image segmentation. While this works for adults and healthy neonates, the large variations in premature infants preclude its direct application. The proposed technique can be applied to both healthy and non-healthy premature infant brain MR images. Diffusion Weighted Imaging (DWI) is a MRI-based technique that can be used to create images for measuring physiological properties of cells on the structural level. We optimise the scanning parameters of DWI so that the required acquisition time can be reduced while still maintaining good image quality. In the present work, PVE correction methods, and physiological DWI models are evaluated in terms of repeatabilityof the results. This gives in- formation on the reliability of the measures given by the methods. The evaluations are done using physical phantom objects, correlation measure- ments against expert segmentations, computer simulations with realistic noise modelling, and with repeated measurements conducted on real pa- tients. In PET, the applicability and selection of a suitable partial volume correction method was found to depend on the target application. For MRI, the data-driven segmentation offers an alternative when using spatial prior is not feasible. For DWI, the distribution of b-values turns out to be a central factor affecting the time-quality ratio of the DWI acquisition. An optimal b-value distribution was determined. This helps to shorten the imaging time without hampering the diagnostic accuracy.Siirretty Doriast