Quantitative tissue pH measurement during cerebral ischemia using amine and amide concentration-independent detection (AACID) with MRI

Tissue pH is an indicator of altered cellular metabolism in diseases including stroke and cancer. Ischemic tissue often becomes acidic due to increased anaerobic respiration leading to irreversible cellular damage. Chemical exchange saturation transfer (CEST) effects can be used to generate pH-weighted magnetic resonance imaging (MRI) contrast, which has been used to delineate the ischemic penumbra after ischemic stroke. In the current study, a novel MRI ratiometric technique is presented to measure absolute pH using the ratio of CEST-mediated contrast from amine and amide protons: amine/amide concentration-independent detection (AACID). Effects of CEST were observed at 2.75 parts per million (p.p.m.) for amine protons and at 3.50 p.p.m. for amide protons downfield (i.e., higher frequency) from bulk water. Using numerical simulations and in vitro MRI experiments, we showed that pH measured using AACID was independent of tissue relaxation time constants, macromolecular magnetization transfer effects, protein concentration, and temperature within the physiologic range. After in vivo pH calibration using phosphorus ( 31P) magnetic resonance spectroscopy (31P-MRS), local acidosis is detected in mouse brain after focal permanent middle cerebral artery occlusion. In summary, our results suggest that AACID represents a noninvasive method to directly measure the spatial distribution of absolute pH in vivo using CEST MRI. © 2014 ISCBFM All rights reserved

Magnetization Transfer Prepared Gradient Echo MRI for CEST Imaging

Chemical exchange saturation transfer (CEST) is an emerging MRI contrast mechanism that is capable of noninvasively imaging dilute CEST agents and local properties such as pH and temperature, augmenting the routine MRI methods. However, the routine CEST MRI includes a long RF saturation pulse followed by fast image readout, which is associated with high specific absorption rate and limited spatial resolution. In addition, echo planar imaging (EPI)-based fast image readout is prone to image distortion, particularly severe at high field. To address these limitations, we evaluated magnetization transfer (MT) prepared gradient echo (GRE) MRI for CEST imaging. We proved the feasibility using numerical simulations and experiments in vitro and in vivo. Then we optimized the sequence by serially evaluating the effects of the number of saturation steps, MT saturation power (B1), GRE readout flip angle (FA), and repetition time (TR) upon the CEST MRI, and further demonstrated the endogenous amide proton CEST imaging in rats brains (n = 5) that underwent permanent middle cerebral artery occlusion. The CEST images can identify ischemic lesions in the first 3 hours after occlusion. In summary, our study demonstrated that the readily available MT-prepared GRE MRI, if optimized, is CEST-sensitive and remains promising for translational CEST imaging

Temperature and pH Imaging using Chemical Exchange Saturation Transfer (CEST) MRI Contrast

Chemical exchange saturation transfer (CEST) is a novel mechanism used to generate contrast in magnetic resonance imaging (MRI). Recently, CEST contrast was proposed to noninvasively measure physiological parameters including temperature and pH. Tissue temperature and pH are known markers of pathological processes in many diseases including stroke and cancer. CEST contrast can be generated using endogenous proteins and peptides (endogenous CEST) or using exogenous paramagnetic lanthanide agents (PARACEST). The general problem of optimizing applications of endogenous CEST and PARACEST contrast to measure temperature and pH is addressed in this thesis. Highlights of the thesis include a novel application of PARACEST contrast to measure extracellular pH and temperature in-vivo and a novel ratiometric approach that uses endogenous CEST contrast to measure intracellular pH in-vivo. Using a Tm3+-based PARACEST agent (Tm3+-DOTAM-Gly-Lys), the PARACEST amide peak chemical shift and linewidth were shown to depend on pH and temperature in a deterministic manner. Quantitative temperature and pH maps were simultaneously measured in a normal mouse leg following agent injection using empirical relations derived in-vitro. A ratio of endogenous amide and amine proton CEST effects was developed to measure absolute tissue pH that is heavily weighted to the intracellular compartment. The technique called amine and amide concentration-independent detection (AACID) was developed using in-vitro phantoms and numerical simulations. Following in-vivo pH-calibration using 31P-magnetic resonance spectroscopy (MRS), tissue pH measurement was demonstrated in mice following focal cerebral ischemia. Local acidosis was measured in ischemic regions and found to correlate with regions of tissue damage. Finally, two endogenous CEST metrics including the AACID ratio were used to monitor cancer treatment using an anticancer drug called lonidamine. Lonidamine selectively acidifies cancer cells. In-vivo experiments demonstrate that endogenous CEST imaging is sensitive to intracellular acidification by lonidamine in a glioblastoma brain tumor mouse model. Overall, the results presented in this thesis demonstrate quantitative measurement of pH and temperature using CEST and/or PARACEST contrast in-vivo. Some of the novel techniques developed in this thesis were demonstrated in stroke and cancer mouse models. Future work should focus on 1) development of PARACEST agents with higher sensitivity in-vivo to improve accuracy of temperature and pH maps; 2) application of AACID for absolute pH measurement to differentiate high- and low-grade tumors in-vivo; and 3) application of endogenous CEST measurement to monitor tumor response to different clinically approved chemotherapy treatments

Research of chemical exchange saturation transfer in brain

化学交换饱和转移(chemical exchange saturation transfer,CEST)成像是在磁化传递及化学交换理论基础上发展起来的一种磁共振成像新方法,其扩展了磁共振分子影像新领域,但还处于研究阶段。其以细胞内物质为内源性对比剂,通过水信号间接检测代谢物信息,进行组织的酸碱度成像及其各种代谢物成像。本文主要探讨MRI领域中与水相关的化学交换饱和转移现象,阐述其原理、研究现状及其在不同场强磁共振仪上脑部疾病的应用。Chemical exchange saturation transfer(CEST) imaging is a new method for magnetic resonance imaging theory of exchange in the magnetization transfer and chemical, the expansion of the new field of molecular magnetic resonance imaging,but it's still in the research stage. The intracellular substances as an endogenous contrast agent, through the indirect detection of metabolite water signal information for tissue p H imaging and imaging of various metabolites. This paper mainly discusses the chemical and water exchange in the field of MRI saturation transfer phenomenon,expounds the principle, research status and the application in brain diseases used the different field strength clinical MRI scanner.2014年厦门市科技局科技惠民计划项目(编号:3502Z20144052)~

Tumor pH and Protein Concentration Contribute to the Signal of Amide Proton Transfer Magnetic Resonance Imaging

Abnormal pH is a common feature of malignant tumors and has been associated clinically with suboptimal outcomes. Amide proton transfer magnetic resonance imaging (APT MRI) holds promise as a means to noninvasively measure tumor pH, yet multiple factors collectively make quantification of tumor pH from APT MRI data challenging. The purpose of this study was to improve our understanding of the biophysical sources of altered APT MRI signals in tumors. Combining in vivo APT MRI measurements with ex vivo histological measurements of protein concentration in a rat model of brain metastasis, we determined that the proportion of APT MRI signal originating from changes in protein concentration was approximately 66%, with the remaining 34% originating from changes in tumor pH. In a mouse model of hypopharyngeal squamous cell carcinoma (FaDu), APT MRI showed that a reduction in tumor hypoxia was associated with a shift in tumor pH. The results of this study extend our understanding of APT MRI data and may enable the use of APT MRI to infer the pH of individual patients' tumors as either a biomarker for therapy stratification or as a measure of therapeutic response in clinical settings.Significance: These findings advance our understanding of amide proton transfer magnetic resonance imaging (APT MRI) of tumors and may improve the interpretation of APT MRI in clinical settings

Investigation of Endogenous Chemical Exchange Saturation Transfer Effects with Magnetic Resonance Imaging in Various Animal Models of Neurological Disorders

Chemical Exchange Saturation Transfer (CEST), is an emerging Magnetic Resonance Imaging (MRI) technique. CEST indirectly measures exchangeable protons contained in either endogenous or exogenous compounds by measuring the water signal reduction due to magnetisation exchange between these compounds and the surrounding water. CEST offers sensitivity enhancement compared to any method which directly measures these compounds. The complexity of the CEST signal in-vivo limits direct quantitative interpretation. However, the technique is inherently sensitive to a range of physiological parameters, such as temperature, pH and metabolite concentration. In order to investigate the relative importance of these different contributing factors, the work described in this thesis used the Bloch-McConnell equation system to model the CEST effect, for CEST sequence optimisation and data interpretation. Bovine Serum Albumin (BSA) phantoms were scanned with a CEST sequence and the results were compared to standard contrast methods (T1, T2). The CEST effects were correlated with changes in environmental pH, temperature and metabolite concentration. Next, a spectroscopic CEST sequence was implemented for spinal cord CEST and two models of neurodegenerative diseases were investigated. First, a model of Amyotrophic Lateral Sclerosis (ALS), revealed no changes in the CEST signal over the time course of the disease; the finding matched post-mortem soluble protein concentration analysis. Second, a model of Spinal and Bulbar Muscular Atrophy (SBMA), revealed no changes in the CEST signal of affected mice scanned at 10 and 12 months of age. However, changes in the CEST signal were observed in control mice and this again agreed with post-mortem protein concentration analysis. Finally, the potential for CEST to measure regional pH changes in a piglet model of Hypoxic Ischemia (HI) was investigated. CEST data were compared and found to agree with 31P MRS, measuring intracellular pH (pHi) and 1H MRS, measuring cerebral lactate levels

Investigation of brain tumour metabolism using naturally occurring chemical exchange saturation transfer agents with magnetic resonance imaging

This thesis presents a thorough study on the newly developed glucoCEST magnetic resonance imaging (MRI) technique and its application for the assessment of malignant brain tumours. The key asset of glucoCEST is that it allows the detection of small concentration of glucose with standard MRI scanners and has the potential to provide a novel imaging tool to investigate diseases in which glucose metabolism is affected, in particular cancer. The physical principles and the rationale behind the glucoCEST technique are described in detail and factors influencing the measurements (both physiological and hardware related) are analysed using computer simulations and evaluated with in vitro experiments. Special attention is given to the analysis of the first four sugars along the glycolytic pathway i.e. glucose, glucose 6-phosphate, fructose 6-phosphate and fructose 1,6-biphosphate as contributors to the overall observed signal. The results of this analysis give grounds for the argument of the intracellular origin of the glucoCEST signal, which opens the possibility of characterising tumours based on their metabolism with MRI. A preclinical glucoCEST study on mice bearing human xenograft glioblastoma is also presented in which cancers with diverse phenotype are scanned longitudinally throughout the different stages of tumour development. While not conclusive, the results suggest that the glucoCEST technique is able to identify the presence of cancer at an earlier stage than standard MRI methods