Background: Osteoarthritis (OA) is characterized by progressive loss of cartilage in joints, and is a major cause of pain and disability, and imposes significant health care expense. New therapies are being developed to treat the sympto- matic effect of OA, one of which is intra-articular injection of viscosupplementations of different forms of hyaluronic acid (HA). The current study evaluates the chemical exchange saturation transfer (CEST) effect from two popular viscosupplementations [Hylan gf-20 (Synvisc) and hyaluronan (Orthovisc)] by targeting the exchangeable hydroxyl protons present on these molecules (ViscoCEST).
The cellular environment in humans contains several different proton exchanging systems including the amide and amine protons of intracellular proteins and peptides, the hydroxyl (-OH) protons present in sugar, cellulose and glycogen, and free water protons. The rate of chemical exchange of these protons is pH dependent; exchange increases with higher pH. Recently, Zhou and coworkers used CEST contrast arising from intracellular proteins and peptides to acquire pH-weighted images of rat brain with ischemic regions and tumors. The CEST contrast was named amide proton transfer (APT) . Our laboratory has also recently developed a ratiometric CEST contrast technique called Amine and Amide Concentration Independent (AACID) detection. AACID is a ratio of CEST effects arising from amide protons resonating at 3.5 ppm (parts per million) and amine protons resonating at 2.75 ppm downfield from the bulk water protons. This technique was successfully applied to measure pH changes in glioblastoma tumors after the selective acidification of the tumor environment with a drug called lonidamine . However lonidamine is not currently approved for use in humans. Therefore the goal of this thesis was to apply the AACID technique to measure pH changes induced by a single dose of the drug Topiramate, which is a well-established and approved anticonvulsant. 126.96.36.199 Chemical Exchange Saturation Transfer (CEST) measurements
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No previous studies had demonstrated the ability of CEST to image endogenous hydroxyl protons of lactate in vivo. Recent work from Zhang et al. has shown that lactate can be imaged in vitro and in vivo by means of a paramagnetic shift agent, but this requires the injection of the contrast agent (Zhang, Martins et al. 2017). In this chapter, we will describe the method based on endogenous lactate chemical exchange saturation transfer (CEST) to image lactate as LATEST (DeBrosse, Nanga et al. 2016). First, we identified the chemical shift of lactate hydroxyl protons through high-resolution NMR, and then demonstrated the CEST effect from those protons in lactate phantoms. We determined optimal CEST saturation parameters for lactate imaging. Then, we examined the pH and concentration dependence of the LATEST contrast in phantoms. The feasibility of measuring LATEST in vivo was demonstrated in a lymphoma tumor model and in human skeletal muscle. Dynamic changes in LATEST were observed in tumors pre- and post- infusion of pyruvate and in exercising human skeletal muscle. LATEST measurements were compared to lactate measured with multiple quantum filtered proton magnetic resonance spectroscopy (SEL-MQC 1 H-MRS) (He, Shungu et al. 1995).
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15. van Zijl PC, Jones CK, Ren J, Malloy CR, Sherry AD. MRI detection of glycogen in vivo by using chemical exchange saturation transfer imaging (glycoCEST). Proc Natl Acad Sci U S A 2007;104:4359–4364. 16. Terreno E, Stancanello J, Longo D, Castelli DD, Milone L, Sanders HM, Kok MB, Uggeri F, Aime S. Methods for an improved detection of the MRI-CEST effect. Contrast Media Mol Imaging 2009;4:237–247. 17. Gunther H. NMR spectroscopy. New York: John Wiley; 1980. 18. Pfau A, Perlberg S, Shapira A. The pH of the prostatic fluid in health
Chemical exchange saturation transfer magnetic resonance imaging (CEST-MRI) exploits the direct chemical exchange of metabolite protons with the bulk tissue water, enabling the detection of specific tissue metabolites at concentrations that are otherwise below the detection limit of conventional 1 H MRI . Recently, CEST MRI has been successfully utilized to acquire high temporal and spatial resolution images of glutamate (Glu) in the human brain, where the neurotransmitter is present at mM concentration . Glutamate demonstrates fast amine exchange rates, giving rise to a strong CEST effect at a resonance offset of +3 ppm from the water frequency (GluCEST), which is dependent on glutamate concentration and pH.
All DSC-MR imaging acquisitions completely covered the spa- tial extent of contrast-enhancing and nonenhancing tumors. Cal- culation of CBV was performed by first motion-correcting the dynamic time-series using FSL (MCFLIRT). Next, CBV maps were calculated using a bidirectional contrast agent leakage-cor- rection algorithm to model contrast flux into and out of the vas- culature. Last, normalized CBV was computed by dividing the CBV map by the average CBV value within a 5-mm sphere in contralateral, normal-appearing white matter. Last, final CBV maps were aligned to the corresponding postcontrast T1- weighted images for subsequent analyses.
There are several limitations to the current work that should be considered when interpreting the results. First, cariporide at the dose studied (6 mg/kg) cannot be dissolved in distilled water or PBS. Therefore, it was dissolved in DMSO. DMSO alone caused a small increase in AACID value suggesting a decrease in intracellular pH. However, this could be an advantage for studies aimed at lowering intracellular pH, as long as the concentration of DMSO is sufficiently small to limit any toxic effects. Second, in the current study, only one dose of cariporide was examined. Future studies should determine whether higher doses of cariporide could increase tumor acidification, and whether the effect is repeatable after multiple exposures. Third, the number of animals included in the current study was small. However due to the large change induced by the drug, more animals were not needed in this proof of principle study. It should also be noted that the use of AACID CEST to measure absolute intracellular pH requires further calibration. In the current study, an estimate of the change in pH induced by cariporide was made using a previously published calibration performed in the brain under normoxic and ischemic conditions (60).
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ing capillary blood vessels. And in order to monitor the blood flows in brain tissues, a series of images must be acquired in less than 2 s intervals. Medical imaging seeks to answer multiple questions once a tumor is identified, including whether the tu- mor is malignant, where the tumor is located, the size of the tumor, whether cancer has begun to metastasize, and whether surgical resection would impact any critical anatomical structures. Medical imaging technologies have experienced tremendous growth over the past few decades, and now play a central role in almost every med- ical specialty. However, the truly revolutionary techniques that empower effective early-stage disease diagnosis and treatment still lie in the future, when imaging will be achieved at the molecular level.
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MR imaging was performed on a 3T clinical scanner (Achieva 3.0TX; Philips Healthcare, Best, the Netherlands) equipped with a second-order shim, using the posterior part of a 32-channel car- diac coil for signal reception and 2-channel parallel transmission via the body coil for radiofrequency transmission. The acquisition software was modified to alternate the operation of the 2 trans- mission channels during the radiofrequency saturation pulse. The alternate activation of the 2 transmission channels enables long quasicontinuous radiofrequency saturation up to 5 seconds be- yond the 50% duty cycle of a single radiofrequency amplifier. 23
I would also like to thank Dr. Alex Li for his extensive help throughout my entire PhD. Alex taught me a great deal about CEST theory and trained me to use the MRI. Alex was always willing to discuss different aspects of my project and other CEST topics in the literature. The Imaging lab at Robarts Research Institute has offered me a world-class setting to complete my PhD. I must offer a special thank you to Miranda Bellyou for teaching me how to care for the animals and complete my experiments independently. Miranda brought her comforting presence and great sense of humor to the lab, which I always appreciated. Without Miranda’s technical expertise, my in vivo experiments would not have been possible. Also, thank you to Ashley Kirley for your never-ending help throughout the last few months of my PhD. I am so grateful that you are a quick learner! Thanks for putting in the extra time to ensure that my experiments were complete before my departure to Vancouver. Technical support was always nearby with significant help from Martyn Klassen, Dr. Mark Milne, Dr. Mojmir Suchy, Joe Gati, Igor Solovey, and Dr. Kyle Gilbert. The collaborations at Robarts with Dr. Robert Hudson, Dr. Susan Meakin and Dr. Marco Prado enabled me to move my projects forward with novel applications using different PARACEST agents and small animal brain cancer and stroke models.
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There is indeed a large variation in accuracy from center to center, varying from 64% to 94%. 18 Differences in accuracy could also result from differences in scanning protocol. Multiple radiologists were included in this study. Using a single radiologist would have improved the consistency of radiographic diagnoses (1). MRI accuracy may improve as radiologists gain more experience and use more effective protocol. There are several reports indicating that the level of diagnostic accuracy in meniscal and cruciate ligament tears of the knee is comparable for low- and high-field-strength MR imagers (17,11)
Today the practice of most medical disciplines is almost unrecognizable without modern radiology since the outcome of any treatment largely depends upon how appropriately the particular medical condition has been diagnosed. Imaging technology is fascinating, is developing rapidly, and is without doubt beneficial in medical and veterinary practices. Over the last decade, the quality of diagnostic imaging equipment and the habit of using it for diagnosis in veterinary practice has greatly improved. There are number of imaging techniques like ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), nuclear medicine and scintegraphy that are currently available for clinical diagnosis leading to greater demands and expectations from veterinary clients. The modern imaging diagnosis though well established in medical science is still in its infancy in veterinary practice due to heavy initial investment and maintenance costs, lack of expert interpretation, requirement of specialized technical staff and need of adjustable machines to accommodate the different range of animal sizes. The present review briefly gives an update of the development and present status of imaging techniques in veterinary medical diagnosis.
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In addition to continuing to improve early can- cer diagnosis, some clinical researchers have recently tried using DWI combined with other imaging techniques for preoperative assess- ment of rectal cancer. For example, some stud- ies found that combining DWI with MRI subtrac- tion techniques in preoperative TN staging of rectal cancer is convenient, fast, and highly accurate . Other studies have analyzed the effect of DWI and MRI in evaluating invasion, metastasis, recurrence, and prognosis of rectal cancer and found that DWI is highly valuable for diagnosis of lymph node metastasis in colorec- tal cancer; that ADC values can provide accu- rate quantitative information; and that stan- dard T2WI has higher accuracy in estimating postoperative local recurrence of rectal cancer. That study also concluded that combining DWI and T2WI can improve diagnostic performance and is also an effective way to evaluate mesen- tery infiltration, invasion, and prognosis of rec- tal cancer .
Abstract: Magnetic particle imaging (MPI) is a novel imaging method that was first proposed by Gleich and Weizenecker in 2005. Applying static and dynamic magnetic fields, MPI exploits the unique characteristics of superparamagnetic iron oxide nanoparticles (SPIONs). The SPIONs’ response allows a three-dimensional visualization of their distribution in space with a superb contrast, a very high temporal and good spatial resolution. Essentially, it is the SPIONs’ superparamagnetic characteristics, the fact that they are magnetically saturable, and the harmonic composition of the SPIONs’ response that make MPI possible at all. As SPIONs are the essential element of MPI, the development of customized nanoparticles is pursued with the greatest effort by many groups. Their objective is the creation of a SPION or a conglomerate of particles that will feature a much higher MPI performance than nanoparticles currently avail- able commercially. A particle’s MPI performance and suitability is characterized by parameters such as the strength of its MPI signal, its biocompatibility, or its pharmacokinetics. Some of the most important adjuster bolts to tune them are the particles’ iron core and hydrodynamic diameter, their anisotropy, the composition of the particles’ suspension, and their coating. As a three-dimensional, real-time imaging modality that is free of ionizing radiation, MPI appears ideally suited for applications such as vascular imaging and interventions as well as cellular and targeted imaging. A number of different theories and technical approaches on the way to the actual implementation of the basic concept of MPI have been seen in the last few years. Research groups around the world are working on different scanner geometries, from closed bore systems to single-sided scanners, and use reconstruction methods that are either based on actual calibration measurements or on theoretical models. This review aims at giving an overview of current developments and future directions in MPI about a decade after its first appearance. Keywords: magnetic particle imaging, superparamagnetic iron oxide nanoparticles, magnetic particle spectrometer, peripheral nerve stimulation, cardiovascular interventions
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forms, including particular proteins or peptides (ovarian- specific antigen as an indicator of increased risk for ovarian cancer), antibodies (anti–citrullinated protein antibodies for rheumatoid arthritis), cell types (white blood cell counts in infection or cancer), metabolites (phenylalanine in urine of newborns with phenylketonuria), lipids (cholesterol and other lipid levels in cardiovascular disease), hormones (thyroid stimulating hormone in Hashimoto's disease), enzyme levels (various hepatic enzymes for liver cancer), physiological states such as blood pressure or fever, or imaging studies of particular organs or organ systems (neural degeneration in Parkinson's disease). A biomarker can also be a substance introduced into a patient to assess how internal organ systems are functioning, such as radioactive iodine used to measure thyroid function. Ultimately, biomarkers can be used to detect a change in the physiological state of a patient that correlates with the risk or progression of a disease.
MRI uses magnetic fields and radio waves to view the structure of the brain. It produces two or three dimensional images of the brain. It is one of the safest imaging techniques because it uses magnetic field for diagnosis. There are different types of MRI. A contrast medium is injected into the patient‟s body. It gives detailed pixels of the image .It can point the exact position and function of the brain. Diagnosis Of Brain Tumor Using Magnetic Resonance Imaging (MRI)
For diagnosing a soft tissue cyst, ultrasound has been the traditional method used for diagnosis. Some periarticular cysts, such as Baker ’ s cysts, can be characterized by the presence of ﬂuid in a characteristic location (between the tendons of the semimembranous and medial gastrocnemius). Otherwise, with MRI, intravenous contrast is typically needed, and a thin rim-enhancing soft tissue mass by MRI without internal enhancement is the criterion used to rule out a tumor and diagnose a cystic lesion; the latter may represent a simple cyst, an abscess, or a lymphatic malformation, depending on the clinical context. A cystic lesion with clinical features of infection is consistent with an abscess. A mass containing
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Blood was collected prior to MRI scans (total volumes per draw of 2–4 ml) in heparin blood collection tubes for quantification of liver enzymes (U/l) and lipids (mg/ dl). The biomarker analysis included measurements of the liver enzymes: aspartate aminotransferase (ALT), alanine aminotransferase (AST), and gamma-glutamyl transferase (GGT). The ratio of AST and ALT, also known as the De Ritis ratio , was used to assess liver damage in NASH . Other biomarkers meas- ured included: total plasma triglycerides, plasma free CHOL, and total protein (g/dl) concentrations. Blood lipoproteins (mg/dl) were measured and compared to normal diet fed rabbits, including high density lipopro- tein (HDL), low density lipoprotein (LDL), and very- low density lipoprotein (VLDL). All blood biomarkers were measured by the Abbott Piccolo Xpress Analyzer (Abbott, Chicago, IL).
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Due to the small sample size, the power of the study was limited and no power calculation was performed. Another limitation is the lack of detection of small bowel lesions with either MRI protocol. Furthermore, the lack of oral contrast medium in the colon with MRFT renders the two MRI protocols identical for the colon. To enable a better comparison of MRFT and MRI-NOC, an alteration of this study is needed. Limiting the selection of patients to either CD or UC, thereby restricting the prevalence of lesions to either the small bowel or the co- lon, enables contrast delivery to be targeted. The small bowel of CD patients would be examined with oral con- trast, whereas the colon of UC patients would be examined with contrast delivered by enema. Limitation is also that endoscopy and CE in some cases are done one month before or after the MRI. The disease activity could have changed within this time gap. However, the strength of this study is that we use endoscopy and CE as the reference standard. We also did the MRFT two days after the MRI-NOC, therefore avoiding the alteration of the lesions between the scans. The FC was also sent to the laboratory one day after the MRI-NOC. The HBI and SCCAI were done on the same day as MRI-NOC.
A previous report was made regarding the study of DOTAM-tetraanilide PARACEST agents which were varied with regards to their para-substituents. 1 This was done with the aim of exploring the adjustment of the amide exchange rate by the presence of electron- withdrawing groups (EWGs) and electron-donating groups (EDGs). The adjustment of the amide exchange rate in turn would affect the CEST due to amide protons. Unfortunately, with the exception of the Dy 3+ and Tm 3+ -p-H and -p-OMe complexes (Figure 6.1), the other complexes were insoluble and could not be further analyzed after synthesis. 1 The solid state structure of the Tm 3+ -p-OMe complex revealed that the angle between the N-Ln-N and O-Ln-O planes (α) was 27 o , thus indicating a twisted square antiprismatic (TSAP) geometry. It was also noted that the complex lacked a metal bound water molecule and was more accurately termed as the TSAP' isomer. Additionally, the Tm 3+ -p-OMe complex had an interesting feature of two CEST signals of moderate
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