Detection of tissue pH with quantitative chemical exchange saturation transfer magnetic resonance imaging

Abstract

Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) has emerged as a novel means for sensitive detection of dilute labile protons and chemical exchange rates. By sensitizing to pH-dependent chemical exchange, CEST MRI has shown promising results in monitoring tissue statuses such as pH changes in disorders like acute stroke, tumor, and acute kidney injury. This article briefly reviews the basic principles for CEST imaging and quantitative measures, from the simplistic asymmetry analysis to multipool Lorentzian decoupling and quasi-steady-state reconstruction. In particular, the advantages and limitations of commonly used quantitative approaches for CEST applications are discussed.acute stroke, amide proton transfer, chemical exchange saturation transfer, pH, pH-weighted, tumor | INTRODUCTIONpH is a physiological index tightly regulated in healthy tissue. 1,2 A notable pH change often signals altered tissue states, such as those following acute ischemia [3][4][5][6][7][8] and the development of cancer. 9-15 For example, tissue acidosis is associated with anaerobic glycolysis following acute stroke. [16][17][18][19] The pH drop compromises essential adenosine triphosphate (ATP)-dependent functions, often leading to cell death and ultimately tissue infarction. [20][21][22][23][24] In the case of cancers, excessive amounts of lactate are produced, disrupting pH homeostasis, a hallmark of the Warburg effect. [25][26][27] It has been recognized that pH change profoundly affects tumor growth and metastasis. 28 As such, pH measurement may provide novel insights into tissue microenvironment and response to therapy, and potentially facilitate the development of new therapeutics. pH measurement in vivo, however, is not straightforward because common strategies such as pH immunohistology, fluorescence microscopy, or phosphorus magnetic resonance approaches are either invasive, [29][30][31][32][33] of limited penetration depth, 34,35 or insensitive. [36][37][38] To address such an unmet biomedical need, Balaban and coworkers introduced chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) as a new sensitive means of imaging pH and dilute labile protons, [39][40][41][42] laying the groundwork for CEST MRI research over the following Abbreviations used: APT, amide proton transfer; CEST, chemical exchange saturation transfer; CESTR, CEST ratio; CNR, contrast-to-noise ratio; MMTR, mean magnetization transfer ratio; MRAPT, MT and relaxation normalized APT; MT, magnetization transfer; MTR, magnetization transfer ratio; MTR asym , MTR asymmetry; NOE, nuclear Overhauser enhancement; pHw, pHweighted; QUASS, quasi-steady-state; rCESTR, ratiometric CESTR; rCNR, relative CNR; ΔMRAPTR, delta MRAPT ratio.

Demonstration of pH imaging in acute stroke with endogenous ratiometric chemical exchange saturation transfer magnetic resonance imaging at 2 ppm

“…Therefore, it will be helpful to optimize RF levels for ratiometric pH imaging to balance the labeling efficiency versus the DWS, which is critical to optimizing the ratiometric analysis at different field strengths. 31 Nevertheless, our study demonstrated that the RF amplitude-based CEST@2 ppm ratio is highly correlated with ischemic tissue acidosis at 4.7 T, which provides a potential alternative to the commonly used APTw MRI. This study evaluated RF amplitude-based endogenous CEST@2 ppm imaging in vivo and demonstrated it as a novel means of tissue pH imaging following acute stroke.…”

Guanidinium and amide CEST mapping of human brain by high spectral resolution CEST at 3 T

“…For the same reason, the amide or GuanCEST signal cannot be directly correlated to the protein concentration. Extracting protein concentration from the CEST signal can be achieved by the quantitative CEST (qCEST) MRI, 73,74 which can correct the scaling introduced by the MTC or T 1 contrasts with the Bloch–McConnell equations or R 1ρ theory 75–78 …”

“…For the same reason, the amide or GuanCEST signal cannot be directly correlated to the protein concentration. Extracting protein concentration from the CEST signal can be achieved by the quantitative CEST (qCEST) MRI, 73,74 which can correct the scaling introduced by the MTC or T 1 contrasts with the Bloch-McConnell equations or R 1ρ theory. [75][76][77][78] In the current study, the PLOF background function was assumed with a simple linear function with a Lorentzian function, which was validated with the CrossBSA.…”

Quasi–steady‐state amide proton transfer (QUASS APT) MRI enhances pH‐weighted imaging of acute stroke

“…The QUASS calculation models the impacts of experimental parameters on the CEST signal. The equilibrium CEST effect can be calculated from the experimental measurements by solving the QUASS spin‐lock relaxation rate, despite not insufficiently long Ts and Td 56 …”