Dynamic glucose enhanced chemical exchange saturation transfer MRI : Optimization of methodology and characterization of cerebral transport kinetics

Dynamic glucose enhanced (DGE) chemical exchange saturation transfer (CEST) MRI is an emerging imaging technique that provides a molecular-specific type of image contrast, based on magnetic labelling of exchangeable protons. The technique enables the use of biodegradable sugars as contrast agents, and such compounds are believed to have less side effects than conventional MRI contrast agents. However, as with most novel techniques, DGE MRI is associated with technical challenges, including small contrast enhancement compared to conventional techniques, sensitivity to motion and long scan durations. Therefore, DGE MRI is not yet ready for clinical implementation, and further evaluation and methodological development are required. The focus of the work presented in this thesis has been on the optimization and development of DGE MRI in humans. We first implemented the DGE MRI technique at 7 T for evaluation in healthy volunteers, and subsequently optimized and applied the DGE imaging protocol at 3 T. We demonstrated that it is possible to measure arterial input functions using DGE MRI data, and that the arterial DGE MRI signal is correlated to the venous blood glucose level. Our experiments also showed that the glucose infusion duration should preferably be prolonged to minimize the sensory side effects of the injection. We also evaluated and compared DGE MRI tissue response curves in healthy tissue and in brain tumours and confirmed that DGE MRI enables differentiation of tumour from normal tissue, but that motion-related artefacts may complicate the interpretation. We developed a post-processing method for DGE MRI based on visualization of tissue response curve types with different characteristic temporal enhancement patterns. Finally, we developed a model for kinetic analysis of DGE MRI, accounting for the different signal origin and uptake kinetics of normal D-glucose. In summary, DGE MRI has potential for tumour detection in humans and can provide information on glucose delivery, transport, and metabolism. However, further optimization of imaging and post-processing techniques is necessary, especially at lower field strengths

Natural sugar as an MRI contrast agent for brain cancer detection using chemical exchange saturation transfer (CEST) imaging at 3T

Hjärntumörer utgör cirka 2,5% av alla cancerdiagnoser i Sverige (2013) och femårsöverlevnaden är cirka 50%. Hjärntumörer diagnostiseras med bildtagningstekniker såsom datortomografi (CT), positronemissionstomografi (PET) och magnetkamera (MR). En MR-bild byggs upp av signaler från protoner i vatten, som är en av människokroppens vanligaste beståndsdelar. För att möjliggöra diagnostisering och klassificering av tumörer används ett kontrastmedel som sprutas in i blodet, och på så vis kan information om blodflödet i hjärnan och framförallt i tumören erhållas. De MR-kontrastmedel som används är i regel väldigt säkra men kan påverka vissa patientgrupper negativt och på senare år har det påvisats att de kan ansamlas i vissa vävnader efter upprepade undersökningar (6-9). Metoden begränsas även av att inte alla tumörer tar upp kontrastmedlet. Nackdelarna med den nuvarande metoden skapar ett behov av en ny typ av kontrastmedel. CEST (Chemical Exchange Saturation Transfer) är en teknik som innebär att små mängder av ett ämne kan detekteras med magnetkamera. CEST-tekniken öppnar upp för användning av andra typer av kontrastmedel, exempelvis kan kroppsegna ämnen, såsom vissa proteiner som är vanliga i tumörer, detekteras. Dessutom kan vanligt socker (glukos) injiceras och användas som kontrastmedel, en teknik som kallas för glucoCEST. Socker är väl lämpat för användning som kontrastmedel, dels eftersom det är en naturlig del av vår kost, men också för att tumörer ofta har ett ökat energibehov. GlucoCEST-tekniken bygger på att protoner i sockret märks magnetiskt med en radiofrekvent puls. Därefter sker ett utbyte mellan de märkta protonerna och omärkta protoner i fritt vatten vilket leder till att MR-signalen ändras där glukos är närvarande. Genom att injicera glukos intravenöst samtidigt som patienten ligger i kameran kan en bild som ger information om blodflödet i hjärnan skapas. I det här projektet implementeras glucoCEST-tekniken på en magnetkamera i kliniskt bruk, vilket inte har gjorts tidigare i Sverige. Både friska frivilliga och patienter med hjärntumör deltog i studien. Genom att analysera blodprover som tas kontinuerligt under undersökningen kan blodsockervärdet jämföras med den ändring i MR-signalen som fås då sockret sprutas in och når hjärnan. Resultaten jämförs med data från ett forskningsprojekt utfört vid en magnetkamera med högre magnetfält. En ändring av MR-signalen, som generellt sett följde ändringen av blodglukosnivån, kunde ses i alla deltagare (framförallt i blodkärl), men det är ännu inte helt klart vilka fysiologiska parametrar som kan extraheras ur glucoCEST-bilderna. Resultatet av studien indikerar att glucoCEST har potential att bli ett alternativ eller komplement till konventionella kontrastmedel, även om mycket arbete kvarstår. Sammanfattningsvis har det här projektet tagit ett första steg mot klinisk implementering av glucoCEST-tekniken.Background and Purpose: Dynamic glucose-enhanced (DGE) imaging is a novel technique that can be used to assess information about microvasculature by using natural sugar (D-glucose) as a biodegradable contrast agent. The method relies on chemical exchange saturation transfer (CEST). The hydroxyl protons in glucose are saturated using a selective radio-frequent pulse and will subsequently exchange with non-saturated water protons. This approach, called glucoCEST, will lower the water signal so that the presence of glucose can be studied through its saturation effect on the water signal. DGE is an approach in which glucoCEST is applied dynamically to track glucose response over time. Earlier studies (1-4) have successfully shown that glucoCEST and DGE can be used for tumor imaging at higher field strengths and the translation to clinical field strengths (3 T) is ongoing. The aim of this master thesis project was to implement glucoCEST at 3 T and to compare dynamic response curves in arteries, so called arterial input functions (AIFs), to blood glucose levels sampled over the same time period. A secondary goal was to compare DGE images from this study with DGE images from a 7 T-study. Materials and Methods: 3 healthy volunteers and 2 patients were scanned on a 3 T scanner (Siemens Prisma) and 50 mL D-glucose (50% dextrose) were manually administered intravenously after 3 minutes of imaging. The infusion duration was approximately 1 minute and the total scan time was 15 minutes. To acquire glucoCEST images, RF-pulses were applied at a saturation offset of 2 ppm. A single axial slice of the brain was imaged dynamically using a single-shot turbo gradient echo. Blood samples were collected at predefined time points to enable monitoring of blood glucose levels as a function of time following the glucose infusion. DGE images were created by calculating the signal difference between each dynamic image and the averaged pre-infusion image. Dynamic response curves were calculated in chosen regions of interest (ROIs) in an artery and in white matter, and were compared to blood glucose curves. Results and Discussion: The DGE images acquired at 3 T showed a change in the water signal after glucose infusion in all subjects. The signal change in a cerebral artery, which was attributed to the altered glucose concentration, did generally correspond to the change in blood glucose level in a peripheral vein. Enhancement of the tumor region was seen in one patient. Each subject showed an individual response to the glucose infusion, addressed to the variance in metabolism and insulin response between subjects. GlucoCEST at 7 T had a higher specificity, but the results indicate that the method works well also at 3 T.Conclusion: The results showed that glucoCEST and DGE are feasible at 3 T. The study indicates that tumor enhancement is possible, but due to the low number of participants (3 healthy volunteers, 2 patients) the project should be continued by scanning more patients and optimizing the method further. Possible improvements to the method could be to improve the CEST-sequence, by for example extend the saturation duration and include CSF suppression, and to implement a kinetic model for calculation of perfusion parameters

Tissue response curve shape analysis of dynamic glucose enhanced (DGE) and dynamic contrast enhanced (DCE) MRI in patients with brain tumor

Dynamic glucose enhanced (DGE) MRI is used to study the signal intensity time course (tissue response curve) after D-glucose injection. D-glucose has potential as a biodegradable alternative or complement to gadolinium-based contrast agents, with DGE being comparable to dynamic contrast enhanced (DCE) MRI. However, the tissue uptake kinetics as well as the detection methods of DGE differ from DCE, and it is relevant to compare these techniques in terms of spatiotemporal enhancement patterns. This study aims to develop a DGE analysis method based on tissue response curve shapes, and to investigate whether DGE MRI provides similar or complementary information to DCE MRI. Eleven patients with suspected gliomas were studied. Tissue response curves were measured for DGE and DCE MRI at 7 tesla and the area under curve (AUC) was assessed. Seven types of response curve shapes were postulated and subsequently identified by deep learning to create color-coded “curve maps” showing the spatial distribution of different curve types. DGE AUC values were significantly higher in lesions than in normal tissue (

Towards robust glucose chemical exchange saturation transfer imaging in humans at 3 T: Arterial input function measurements and the effects of infusion time

Dynamic glucose-enhanced (DGE) magnetic resonance imaging (MRI) has shown potential for tumor imaging using D-glucose as a biodegradable contrast agent. The DGE signal change is small at 3 T (around 1 and accurate detection is hampered by motion. The intravenous D-glucose injection is associated with transient side effects that can indirectly generate subject movements. In this study, the aim was to study DGE arterial input functions (AIFs) in healthy volunteers at 3 T for different scanning protocols, as a step towards making the glucose chemical exchange saturation transfer (glucoCEST) protocol more robust. Two different infusion durations (1.5 and 4.0 min) and saturation frequency offsets (1.2 and 2.0 ppm) were used. The effect of subject motion on the DGE signal was studied by using motion estimates retrieved from standard retrospective motion correction to create pseudo-DGE maps, where the apparent DGE signal changes were entirely caused by motion. Furthermore, the DGE AIFs were compared with venous blood glucose levels. A significant difference (p = 0.03) between arterial baseline and postinfusion DGE signal was found after D-glucose infusion. The results indicate that the measured DGE AIF signal change depends on both motion and blood glucose concentration change, emphasizing the need for sufficient motion correction in glucoCEST imaging. Finally, we conclude that a longer infusion duration (e.g. 3–4 min) should preferably be used in glucoCEST experiments, because it can minimize the glucose infusion side effects without negatively affecting the DGE signal change

A numerical human brain phantom for dynamic glucose-enhanced (DGE) MRI : On the influence of head motion at 3T

PURPOSE: Dynamic glucose-enhanced (DGE) MRI relates to a group of exchange-based MRI techniques where the uptake of glucose analogues is studied dynamically. However, motion artifacts can be mistaken for true DGE effects, while motion correction may alter true signal effects. The aim was to design a numerical human brain phantom to simulate a realistic DGE MRI protocol at 3T that can be used to assess the influence of head movement on the signal before and after retrospective motion correction.METHODS: MPRAGE data from a tumor patient were used to simulate dynamic Z-spectra under the influence of motion. The DGE responses for different tissue types were simulated, creating a ground truth. Rigid head movement patterns were applied as well as physiological dilatation and pulsation of the lateral ventricles and head-motion-induced B 0 -changes in presence of first-order shimming. The effect of retrospective motion correction was evaluated. RESULTS: Motion artifacts similar to those previously reported for in vivo DGE data could be reproduced. Head movement of 1 mm translation and 1.5 degrees rotation led to a pseudo-DGE effect on the order of 1% signal change. B 0 effects due to head motion altered DGE changes due to a shift in the water saturation spectrum. Pseudo DGE effects were partly reduced or enhanced by rigid motion correction depending on tissue location. CONCLUSION: DGE MRI studies can be corrupted by motion artifacts. Designing post-processing methods using retrospective motion correction including B 0 correction will be crucial for clinical implementation. The proposed phantom should be useful for evaluation and optimization of such techniques

Arterial Input Functions and Tissue Response Curves in Dynamic Glucose-Enhanced (DGE) Imaging: Comparison Between glucoCEST and Blood Glucose Sampling in Humans

Dynamic glucose-enhanced (DGE) imaging uses chemical exchange saturation transfer magnetic resonance imaging to retrieve information about the microcirculation using infusion of a natural sugar (D-glucose). However, this new approach is not yet well understood with respect to the dynamic tissue response. DGE time curves for arteries, normal brain tissue, and cerebrospinal fluid (CSF) were analyzed in healthy volunteers and compared with the time dependence of sampled venous plasma blood glucose levels. The arterial response curves (arterial input function [AIF]) compared reasonably well in shape with the time curves of the sampled glucose levels but could also differ substantially. The brain tissue response curves showed mainly negative responses with a peak intensity that was of the order of 10 times smaller than the AIF peak and a shape that was susceptible to both noise and partial volume effects with CSF, attributed to the low contrast-to-noise ratio. The CSF response curves showed a rather large and steady increase of the glucose uptake during the scan, due to the rapid uptake of D-glucose in CSF. Importantly, and contrary to gadolinium studies, the curves differed substantially among volunteers, which was interpreted to be caused by variations in insulin response. In conclusion, while AIFs and tissue response curves can be measured in DGE experiments,partial volume effects, low concentration of D-glucose in tissue, and osmolality effects between tissue and blood may prohibit quantification of normal tissue perfusion parameters. However, separation of tumor responses from normal tissue responses would most likely be feasible

d-glucose weighted chemical exchange saturation transfer (glucoCEST)-based dynamic glucose enhanced (DGE) MRI at 3T : early experience in healthy volunteers and brain tumor patients

PURPOSE: Dynamic glucose enhanced (DGE) MRI has shown potential for imaging glucose delivery and blood-brain barrier permeability at fields of 7T and higher. Here, we evaluated issues involved with translating d-glucose weighted chemical exchange saturation transfer (glucoCEST) experiments to the clinical field strength of 3T.METHODS: Exchange rates of the different hydroxyl proton pools and the field-dependent T2 relaxivity of water in d-glucose solution were used to simulate the water saturation spectra (Z-spectra) and DGE signal differences as a function of static field strength B0 , radiofrequency field strength B1 , and saturation time tsat . Multislice DGE experiments were performed at 3T on 5 healthy volunteers and 3 glioma patients.RESULTS: Simulations showed that DGE signal decreases with B0 , because of decreased contributions of glucoCEST and transverse relaxivity, as well as coalescence of the hydroxyl and water proton signals in the Z-spectrum. At 3T, because of this coalescence and increased interference of direct water saturation and magnetization transfer contrast, the DGE effect can be assessed over a broad range of saturation frequencies. Multislice DGE experiments were performed in vivo using a B1 of 1.6 µT and a tsat of 1 second, leading to a small glucoCEST DGE effect at an offset frequency of 2 ppm from the water resonance. Motion correction was essential to detect DGE effects reliably.CONCLUSION: Multislice glucoCEST-based DGE experiments can be performed at 3T with sufficient temporal resolution. However, the effects are small and prone to motion influence. Therefore, motion correction should be used when performing DGE experiments at clinical field strengths