Sammanfattning Inledning: Den årliga incidensen för pankreascancer är 9 per 100 000 invånare. En tidig diagnos ger förbättrad 5-årsöverlevnad men botar fortfarande få patienter. De senaste åren har den dåliga prognosen förbättras tack vare utvecklingen inom bilddiagnostiken. Författaren i denna litteraturstudie har valt att jämföra multidetektor datortomografi (MDCT) och magnetisk resonans (MR) med kontrastmedel för diagnostik av pankreastumör vid misstänkt pankreascancer. Syfte: Syftet med denna litteraturstudie är att undersöka vilken radiologisk undersökningsmetod som är att föredra vid diagnostisering av pankreascancer, MDCT eller MR. Frågeställning: Är det MDCT eller MR som är bäst vid diagnostisering av pankreascancer? Metod: En litteraturstudie baserad på 12 antal artiklar som är funna i databasen PubMed. Resultat: MDCT och MR har likvärdig diagnostisk säkerhet att upptäcka pankreastumör samt påvisa kärlinväxt och förutse operabilitet. Båda metoderna har en jämförbar hög noggrannhet för karakterisering av förändringens aggressivitet. Slutsats: Såväl MDCT och MR är likvärdiga två mycket bra radiologiska metoder för att diagnostisera pankreascancer. MDCT har fortfarande en större tillgänglighet är MR men dess nackdel är man utsätter patienterna för joniserande strålning. MR är därför en metod att föredra och med stor sannolikhet kommer dess tillgänglighet att öka kraftigt i framtiden.

<p>Mouse models of cancer are an invaluable tool for studying the mechanism of the disease and the effect of new therapies. Recent years have seen an explosive growth in the development of such models and consequently there is an increased need for better imaging techniques to study them. The goal of this work was to develop a technique that satisfied the requirements for preclinical cancer imaging: high spatial resolution, good soft tissue differentiation, excellent motion immunity, fast and non-invasive imaging to enable high-throughput, longitudinal studies. </p> <p>T₂-weighted and diffusion-weighted magnetic resonance imaging (MRI) has been shown to be effective for tumor characterization clinically. But translation of these techniques to the mouse is challenging. The higher spatial resolution and faster physiologic motion make conventional approaches very susceptible to phase artifacts. Additionally, at higher magnetic fields required for these studies, T<super>*</super>₂ and T₂ are significantly shorter and T₁ is longer, making in vivo imaging even harder.</p> <p>A rigorous cancer imaging protocol was developed by optimizing and integrating various components of the system, including MR hardware, animal handling, and pulse sequence design to achieve reliable, repeatable and rapid imaging. The technique presented here relies heavily on the non-Cartesian sampling strategy of PROPELLER (Periodically Rotated Overlapping ParallEL Lines with Enhanced Reconstruction) MRI. The novel data acquisition and reconstruction overcomes the adverse effects of physiological motion, allows for rapid setup and acquisition and provides excellent tissue contrast. The sequence was optimized to enable T₂-weighted and diffusion-weighted imaging in tumor-bearing mice with in-plane resolution of 117&mu;m and slice thickness of 1mm. Multi-slice datasets covering the entire thorax and abdomen were acquired in &sim;30 minutes.</p> <p>The imaging protocol developed here was applied to a high-throughput, longitudinal study in a mouse model of liver metastases. The liver is a common site of distal metastases in colon and rectal cancer, and if detected early has an improved prognosis. Unfortunately, severe respiratory motion make it hard to image. The relative merits of the proposed PROPELLER technique were analyzed with respect to the accepted gold-standard for abdominal cancer imaging, computed tomography (CT).</p> <p>The non-Cartesian MR microscopy technique proposed here is a valuable tool in the &ldquo;Cancer analysis toolkit&rdquo;. It allows for high-throughput, longitudinal experiments in free-breathing mice generating both structural and functional information with minimal artifacts and excellent spatial resolution. This work should find broad applications in various mouse models of cancer for studying the pathology of the disease, its progression as well as its response to treatment.</p> / Dissertation

<p>Liposomes are excellent chemotherapy drug delivery agents, on the cutting edge of cancer treatment technology. Since liposomes are already used to deploy cancer drugs in patients, imaging capacity would make them dual-purpose "theranostic" vesicles. Intermolecular double quantum coherence (iDQC) MRI is uniquely suited to this application, as its contrast does not require any additional chemicals. Adding contrast agents to liposomes can be time-consuming, add to toxicity, interfere with membrane function, or adversely affect drug loading. Furthermore, iDQC contrast measures diffusion and thus directly depends on membrane permeability and related properties. In this set of experiments, it has been shown that iDQC signal from intra-liposomal water can be distinguished from that of bulk water, and that the T2 dynamics of intra-liposomal water are predictable and dependent on the percent of water encapsulated. These techniques to distinguish between water molecules based on their current physical circumstances lead to many novel possibilities in MRI, as nearly all the signal in conventional MRI is from water protons. Based on the signal to noise ratio in the aforementioned iDQC experiments, we predict that iDQC contrast from liposomes will be visible in vivo, and propose to prove this in a murine model. By examining intra-liposomal water, iDQC can be used to improve chemotherapy delivery via real time monitoring of liposome location and drug release.</p> / Thesis

Magnetic resonance imaging (MRI) is one of the most powerful imaging techniques for research and clinical diagnosis. To expand upon the intrinsic capabilities of MRI, new contrast agents that can detect the presence of biomarkers in vivo are being developed. My Masters thesis research focuses on the design and synthesis of a new MRI contrast agent that can detect glutathione (GSH), a biomarker that has been implicated in a number of oxidative stress diseases. This new MRI contrast agent is based on chelated dysprosium (Dy), an inorganic metal, which provides negative contrast to surrounding tissue. Preliminary data has shown that attaching a poly(ethylene glycol) (PEG) chain to the Dy chelate, effectively increasing its molecular weight, enhances the contrast ability of Dy. Using this new information, the contrast agent was designed to have a large molecular weight PEG chain attached to the Dy chelate through a disulfide, creating a thiol-sensitive linkage. In the presence of a thiol-containing molecule such as GSH, the Dy will be dePEGylated through a disulfide exchange reaction, removing the molecular weight effect of the PEG, and allowing for the detection of GSH by MRI. This new MRI contrast agent could provide insight into the progression and diagnosis of oxidative stress pathologies associated with GSH.

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The development of a child can be monitored by studying the changes in physical appearance or the development of capabilities e.g. walking and talking. But is it possible to find a quantitative measure for brain development? The aim of this thesis work is to investigate that possibility using quantitative magnetic resonance imaging (qMRI) images by answering the following questions: Can brain development be determined using qMRI? If so, what properties of the brain can be used? Can the age of a child be automatically detected with an algorithm? If so, how can this algorithm function? With what accuracy? Previous studies have shown that it is possible to detect properties in the brain changing with age, based on MRI images. These properties have e.g. been changes in T1 and T2 relaxation time, i.e. properties in water signal behavior that can be measured using multiple MR acquisitions. In the literature this was linked to a rapid myelination process that occurs after birth. Furthermore the organization and growth of the brain is a property that can be measured and monitored. This thesis have investigated several different properties in the brain based on qMRI images in order to identify those who have a strong correlation with age in the range 0-20 years. The properties that were found to have a high correlation were: Position of the first histogram peak in T1 weighted qMRI images, Fraction of white matter in the brain, Mean pixel value of PD weighted qMRI images, Volume of white matter in the brain, Curves on the form f(x) = ae^(-bx) +c are fitted to the data sets and confidence intervals are calculated to frame the statistical insecurity of the curve. The mean error in percent for the different properties can be seen in the list below: Property, Mean error [%] 0-20 years, Mean error [%] 0-3 years Peak position: 53.84, 98.17 Fraction of WM: 118.97, 71.67 Mean pixel value: 200.89, 126.28 Volume of WM: 241.72, 72.58 The conclusions drawn based on the presented results are that there are properties in the brain that correlates well to aging, but the error is too large for making a valid prediction of age over the entire range of 0-20 years. When decreasing the age range to 0-3 years the mean error becomes smaller, but it is still too large. More data is needed to evaluate and improve this result.

Tumor acidosis is an important biomarker in cancer. We have developed a noninvasive imaging method, termed acidosis Chemical Exchange Saturation Transfer (acidoCEST) MRI to measure extracellular pH (pHe) in the tumor microenvironment. Chapter 1 introduces the importance of measuring tumor acidosis and presents various imaging modalities and their shortcoming to measure pHe. Chapter 2 describes the optimization of acidoCEST MRI for in vivo pHe measurement. The acidoCEST MRI protocol consists of a CEST-FISP acquisition and Lorentzian line shape fittings. We determined the optimal saturation time, saturation power and bandwidth, 5 sec, 2.8 µT and 90 Hz respectively. We also tried various routes of administration to increase contrast agent uptake in the tumor. We decided upon 200 µL bolus followed by 150 µL/hr infusion. The optimized acidoCEST MRI protocol was tested on a mammary carcinoma mouse model of MDA- MB-231. Our method can detect an increase in pHe in the bladder and tumor of the mice treated with bicarbonate. We used this optimized acidoCEST MRI method to measure pHe in lymphoma tumor model of Raji, Ramos and Granta 519 as described in Chapter 3. Pixel-wise pHe maps showed tumor heterogeneity. The pHe of Raji, Ramos and Granta 519 were determined to be mildly acidic with no significant difference. Chapter 4 describes the evolution of pixel-wise analysis in more detail. Besides the pHe map and spatial heterogeneity, we were able to determine the % contrast agent uptake. We monitored these biomarkers in two different mammary carcinoma mouse models, MDA- MB-231 and MCF-7 longitudinally and made comparisons between the different tumor models: MCF-7 were more acidic, more heterogeneous and faster growing than MDA- MB-231.

Enzymes are important biomarkers for determining tumor growth and progression. We have developed two molecules to image enzyme response by catalyCEST MRI. This technology allows for non-invasive detection of enzymes. A background of importance of measuring enzyme activity and MRI agents developed for this purpose have been covered in Chapter 1. We have synthesized a responsive paramagnetic Chemical Exchange Saturation Transfer (CEST) agent, called Tm-DO3A-cadaverine. This contrast agents has been successfully cross-linked to the protein albumin by the enzyme transglutaminase leading to the appearance of CEST at -9.2 ppm. The enzyme catalysis has been validated by measuring chemical exchange rates. We have shown that the position of the CEST peak is influenced by the conformation of the molecule depending on the neighboring amino acids to glutamine. This is the first example to show the appearance of CEST due to formation of a covalent bond. We have also synthesized a diamagnetic CEST agent with a large chemical shift dispersion to detect cathespin B activity. Upon enzyme mediated cleavage of PheArgSal, the aryl amide CEST peak at 5.3 ppm disappears. Taking a ratio of the CEST effects from salicylic acid at 9.5 ppm and aryl amide at 5.3 ppm we can detect enzyme activity. The salicylic acid moiety also undergoes some slow response due to enzyme action, as evident by the disappearance of CEST at 9.5 ppm. However, this proof of concept study is the first example of a DIACEST agent designed to measure enzyme activity using a ratio of two CEST effects from the same substrate. The last chapter highlights suggests improvements to the catalyCEST research. The appendix shows the use of bulk magnetic susceptibility measurements by NMR to determine bio-distribution of lanthanides in ex-vivo tissue.

A number of studies have indicated that individuals with arthritis have a decreased risk for Alzheimer's disease (AD). Inflammatory processes are implicated in the neurodegeneration associated with AD and the reduced risk associated with arthritis may be due to the anti-inflammatory (AI) drugs used by these individuals. The present project used magnetic resonance imaging (MRI) to assess the integrity of gray and white brain matter in AI users compared to controls not taking AIs. Thirty six female AI users were compared to thirty three controls. All participants underwent extensive neuropsychological testing. MRI scans included diffusion-weighted imaging, sensitive to the microstructural integrity of brain matter, high resolution anatomical imaging for the determination of brain volume, and T2 fluid attenuated inversion recovery (FLAIR) imaging, sensitive to white matter damage that is seen as hyperintense regions on this type of image. AI users showed increased brain integrity in the frontal lobes and in the corpus callosum, compared to controls indicated by diffusion imaging. Volumetric analysis indicated that AI users and controls have different relationships between brain volume and age. AI users showed greater brain volume than controls at higher ages, particularly in frontal and parietal brain regions, and in the cingulate. White matter hyperintensity volume did not differ between AI users and controls. Finally, the data indicated that non-steroidal anti-inflammatory drug (NSAID) use, but not methotrexate use, had a beneficial effect on cognitive function, particularly in the domain of memory function.