Chemical exchange saturation transfer magnetic resonance imaging and its main and potential applications in pre-clinical and clinical studies

Abstract

Chemical exchange saturation transfer (CEST) imaging is a novel contrast mechanism, relying on the exchange between mobile protons in amide (-NH), amine (-NH 2 ) and hydroxyl (-OH) groups and bulk water. Due to the targeted protons present in endogenous molecules or exogenous compounds applied externally, CEST imaging can respectively, generate endogenous or exogenous contrast. Nowadays, CEST imaging for endogenous contrast has been explored in pre-clinical and clinical studies. Amide CEST, also called amide proton transfer weighted (APT) imaging, generates CEST effect at 3.5 ppm away from the water signal and has been widely investigated. Given the sensitivity to amide proton concentration and pH level, APT imaging has shown robust performance in the assessment of ischemia, brain tumors, breast and prostate cancer as well as neurodegenerative diseases. With advanced methods proposed, pure APT and Nuclear Overhauser Effect (NOE) mediated CEST effects were separately fitted from original APT signal. Using both effects, early but promising results were obtained for glioma patients in the evaluation of tumor response to therapy and patient survival. Compared to amide CEST, amine CEST is also mobile proton concentration and pH dependent, but has a faster exchange rate between amine protons and water.The resultant CEST effect is usually introduced at 1.8-3 ppm. Glutamate and creatine, as two main metabolites with amine groups for CEST imaging, have been applied to quantitatively assess diseases in the central nervous system and muscle system, respectively. Glycosaminoglycan (Gag) as a representative metabolite with hydroxyl groups has also been measured to evaluate the cartilage of knee or intervertebral discs in CEST MRI. Due to limited frequency difference between hydroxyl protons and water, 7T for better spectral separation is preferred over 3T for GagCEST measurement. The applications of CEST MRI with exogenous contrast agents are still quite limited in clinic. While certain diamagnetic CEST agents, such as dynamic-glucose, have been tried in human for brain tumor or neck cancer assessment, most exogenous agents, i.e., paramagnetic CEST agents, are still tested in the pre-clinical stage, mainly due to potential toxicity. Engineered tissues for tissue regeneration and drug delivery have also shown a great potential in CEST imaging, as many of them, such as hydrogel and polyamide materials, contain mobile protons or can be incorporated with CEST specific chemical compounds. These engineered tissues can thus generate CEST effect in vivo, allowing a possibility to understand the fate of them in vivo longitudinally. Although the CEST MRI with engineered tissues has only been established in early stage, the obtained first evidence is crucial for further optimizing these biomaterials and finally accomplishing the translation into clinical use. 1748 Dou et al. CEST imaging and its pre-clinical and clinical applications

Advanced imaging techniques for neuro-oncologic tumor diagnosis, with an emphasis on PET-MRI imaging of malignant brain tumors

“…MR CEST is a non-contrast technique which detects and amplifies metabolic substrates in the tumor tissue not found with other MRI sequences [ 72 – 75 ]. Imaging relies on the exchange between targeted chemical compounds and bulk water [ 76 ]. The most frequent CEST utilized for brain tumor imaging is amide proton transfer (APT) also called amide-CEST MRI, which detects and amplifies an exchange between the intrinsic hydrogen protons located on amide groups and water molecules within tissue [ 77 ].…”

“…In addition to amide groups, hydroxyl and amine groups are also mobile protons that can be used to generate detectable CEST signals (i.e., amine-CEST and hydroxyl-CEST). In comparison to metallic contrast agents (i.e., gadolinium or iron oxide), CEST does not negatively impact the intrinsic MRI properties of tissues nor induces a tissue toxicity potential [ 76 ]. Although an advantage of CEST is the reliance on intrinsic contrast within the tissue, exogenous application of solutes such as glucose [ 79 ] and glucose derivatives [ 80 ] can also be utilized.…”

Advanced Magnetic Resonance Imaging in Osteoarthritis

“…To generate technically adequate scans, GAG CEST typically requires higher field strengths, such as 7 T, and long scan times; therefore, clinical application of this technique is currently limited. [11][12][13][14] Diffusion imaging provides a measurement of the mobility of water protons in various tissues. Various diffusion parameters have been correlated with changes in the cartilage matrix.…”

Editorial for “Comparative Analysis of Amide Proton Transfer MRI and Diffusion‐Weighted Imaging in Assessing p53 and Ki‐67 Expression of Rectal Adenocarcinoma”

“…APT MRI has been successfully applied in the characterization of brain tumor, demonstrating superior capacity in differentiating high‐ from low‐grade gliomas; in the evaluation of treatment response; in differentiating malignant brain tumors (including metastasis) from glioblastoma; and in the selection of tumor sampling in the biopsy of infiltrating gliomas 3 . APT imaging was also proposed as a possible biomarker in the diagnosis of breast and prostate cancer 4 . In breast cancer APT was indicated as a possible biomarker in the early response to neoadjuvant chemotherapy 5 …”

“…Studies on the correlation of APT signal intensity with oncogenic protein markers are few and contradictory. APT imaging identified mutations such as isocitrate dehydrogenase (IDH) status and O6‐methylguanine‐DNA‐methyltransferase (MGMT) promotor methylation status in glioma patients, suggesting APT MRI as a noninvasive approach for identifying prognostic genetic markers 4 . Moreover, APT signal intensity was positively correlated with the Ki‐67 labeling index in meningioma and gliomas 9 .…”