A comparison of exogenous and endogenous <scp>CEST</scp><scp>MRI</scp> methods for evaluating in vivo p<scp>H</scp>

Lindeman, Leila R.; Randtke, Edward A.; High, Rachel; Jones, Kyle M.; Howison, Christine M.; Pagel, Mark

doi:10.1002/mrm.26924

Cited by 53 publications

(44 citation statements)

References 43 publications

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“…14 In this respect, it is worth mentioning that there was no correlation between the amide proton exchange rate and extracellular pH measured in an exogenous contrast agent-based CEST experiment (acidoCEST). 75 As shown recently, 14,76 the increased protein content in the tumor is the most likely explanation, because only a small intracellular pH increase (<0.1 unit) is often detected. The results are consistent with increasing protein concentrations in malignant tumors, as revealed by MRI-guided proteomics 77,78 and in vivo MR spectroscopy.…”

Section: Current Applicationsmentioning

confidence: 84%

“…Theoretically, the APTw hyperintensity in glioma can be caused by increased cytosolic protein content or increased intracellular pH . In this respect, it is worth mentioning that there was no correlation between the amide proton exchange rate and extracellular pH measured in an exogenous contrast agent‐based CEST experiment (acidoCEST) . As shown recently, the increased protein content in the tumor is the most likely explanation, because only a small intracellular pH increase (<0.1 unit) is often detected.…”

Section: Current Applicationsmentioning

confidence: 93%

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APT‐weighted MRI: Techniques, current neuro applications, and challenging issues

Zhou

Heo

Knutsson

et al. 2019

Magnetic Resonance Imaging

259

329

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Amide proton transfer‐weighted (APTw) imaging is a molecular MRI technique that generates image contrast based predominantly on the amide protons in mobile cellular proteins and peptides that are endogenous in tissue. This technique, the most studied type of chemical exchange saturation transfer imaging, has been used successfully for imaging of protein content and pH, the latter being possible due to the strong dependence of the amide proton exchange rate on pH. In this article we briefly review the basic principles and recent technical advances of APTw imaging, which is showing promise clinically, especially for characterizing brain tumors and distinguishing recurrent tumor from treatment effects. Early applications of this approach to stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and traumatic brain injury are also illustrated. Finally, we outline the technical challenges for clinical APT‐based imaging and discuss several controversies regarding the origin of APTw imaging signals in vivo. Level of Evidence: 3 Technical Efficacy Stage: 3 J. Magn. Reson. Imaging 2019;50:347–364.

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Section: Current Applicationsmentioning

confidence: 84%

Section: Current Applicationsmentioning

confidence: 93%

APT‐weighted MRI: Techniques, current neuro applications, and challenging issues

Zhou

Heo

Knutsson

et al. 2019

Magnetic Resonance Imaging

259

329

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“…Recent reports have indicated that the concentration dependence dominates the pH dependence of endogenous APT CEST MRI . Also, endogenous CEST measures a combination of intracellular and extracellular pH, while tumor acidosis predominately affects only extracellular pH, reducing the sensitivity of endogenous CEST MRI for tumor acidosis . Therefore, the pH dependence of endogenous CEST MRI may contribute to localizing acidic tumors, but current endogenous CEST MRI methods are insufficient to quantitatively measure tumor pH.…”

Section: Acidocest Mrimentioning

confidence: 99%

Assessments of tumor metabolism with CEST MRI

Goldenberg

Pagel

2018

NMR in Biomedicine

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Chemical exchange saturation transfer (CEST) is a relatively new contrast mechanism for MRI. CEST MRI exploits a specific MR frequency (chemical shift) of a molecule while generating an image with good spatial resolution using standard MRI techniques, combining the specificity of MRS with the spatial resolution of MRI. Many CEST MRI acquisition methods have been developed to improve analyses of tumor metabolism. GluCEST, CrCEST, and LATEST can map glutamate, creatine, and lactate, which are important metabolites involved in tumor metabolism. GlucoCEST MRI tracks the pharmacokinetics of glucose transport and cell internalization within tumors. CatalyCEST MRI detects enzyme catalysis that changes a substrate CEST agent. AcidoCEST MRI measures extracellular pH of the tumor microenvironment by exploiting a ratio of two pH-dependent CEST signals. This review describes each technique, the technical issues involved with CEST MRI and each specific technique, and the merits and challenges associated with applying each CEST MRI technique to study tumor metabolism.

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“…The MRI contrast of these probes can be analyzed by using a ratiometric approach, thanks to which pHe can be assessed independently of knowing the actual probe concentration . Both diamagnetic and paramagnetic CEST molecules have been reported for such applications …”

Section: Introductionmentioning

confidence: 99%

“…29 Both diamagnetic and paramagnetic CEST molecules have been reported for such applications. [30][31][32][33][34][35][36] Recently, YbHPDO3A (ytterbium 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane) has been investigated for this purpose. 37 This chemical compound is analogous to a clinically approved molecule (GdHPDO3A, gadolinium 1,4,7-triscarboxymethyl-1,4,7,10tetraazacyclododecane, ProHance from Bracco Imaging) in which gadolinium (Gd) is replaced by ytterbium (Yb).…”

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confidence: 99%

CEST‐MRI for glioma pH quantification in mouse model: Validation by immunohistochemistry

et al. 2018

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In glioma, the acidification of the extracellular tumor microenvironment drives proliferation, angiogenesis, immunosuppression, invasion and chemoresistance. Therefore, quantification of glioma extracellular pH (pHe) is of crucial importance. This study is focused on the application of the YbHPDO3A (ytterbium 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane) probe for in vivo glioma pHe quantification using chemical exchange saturation transfer (CEST)-MRI and its correlation with tumor metabolism assessed by immunohistochemistry. The U87 glioma mouse model was used (n = 18) and MRI performed at 4.7 T. CEST-MRI of YbHPDO3A solutions at different pH values showed two resolved CEST spectra at 71 ppm and 99 ppm, both sensitive to pH variations, allowing therefore calculation of the ratiometric curve for in vivo pH quantification. In vivo MRI sequences consisted of T for tumor localization, T * to assess YbHPDO3A biodistribution by exploiting its magnetic susceptibility effect and CEST for glioma pHe mapping. T * images show that YbHPDO3A extravasates in tumor in regions with damaged blood-brain barrier. The pHe is calculated only in these regions. Hematoxylin/eosin histology and Ki-67, CA-IX (carbonic anhydrase 9) and NHE-1 immunohistochemical staining were performed; their expression rates were compared with the in vivo pHe values. On the basis of the cell proliferation marker Ki-67, two groups were defined: one group with a lower mitotic index (MI% < 20% = mean value) and a mean pHe value of 7.00 (low-proliferation/high-pH group) and the other with MI% > 20% and an acidic pHe of 6.6 (high-proliferation/low-pH group). CA-IX and NHE-1 were over-expressed in the high-proliferation/low-pH group (CA-IX, 92 ± 7% versus 30 ± 13%; NHE-1, 84 ± 8% versus 35 ± 11%), indicating an acidic/hypoxic microenvironment. These immunohistochemical results are consistent with our pHe mapping (Pearson correlation coefficient > 0.70) and provide evidence for the feasibility of the CEST-MRI method with the YbHPDO3A probe for glioma pHe quantification at 4.7 T. Importantly, the YbHPDO3A probe has similar chemical and biological properties to the clinically approved MRI contrast agent GdHPDO3A. This makes the method promising for a clinical translation.

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A comparison of exogenous and endogenous CESTMRI methods for evaluating in vivo pH

Cited by 53 publications

References 43 publications

APT‐weighted MRI: Techniques, current neuro applications, and challenging issues

APT‐weighted MRI: Techniques, current neuro applications, and challenging issues

Assessments of tumor metabolism with CEST MRI

CEST‐MRI for glioma pH quantification in mouse model: Validation by immunohistochemistry

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