Quantitative Guanidinium CEST-Based pH Mapping at 3 T in Healthy and Pathological Muscle

Intramuscular pH has been shown to be a valuable biomarker in muscle diseases. Both ¹H and ³¹P MRS approaches are commonly used to determine pH in vivo. MRS-based pH measurements are highly sensitive and reproducible but come with limitations: single-voxel approaches and MRS imaging applications suffer from long acquisition times. High spatial resolution pH mapping can be achieved using chemical exchange saturation transfer (CEST), which is intrinsically sensitive to pH. The chemical exchange phenomenon allows for the indirect, noninvasive detection of metabolites by measuring the water signal after a saturation at a given frequency offset. Several metabolites, such as creatine (Cr) and phosphocreatine (PCr), which are abundant in skeletal muscle, were reported to be detectable using CEST in vivo. Moreover, pH changes alter the exchange rate (k_ex,guan2.0) between guanidinium protons (of Cr and PCr) and bulk water, thereby modifying the CEST effect. In this study at 3 T, we estimate k_ex,guan2.0 based on a three-pool model, verifying the Bloch-McConnell (BM) analytical solution. The method's sensitivity was assessed in a phantom within the physiological pH range. CEST-based pH correlated strongly with the true pH measured with an analytical pH meter (R² = 0.97, p < 0.001). The method demonstrated sensitivity to subtle in vivo pH changes on the order of 0.02 pH units in leg muscles of healthy controls at rest and postexercise and in subjects with a neuromuscular disease. The CEST-based pH was significantly decreased in exercised muscle (p < 0.001) and significantly increased in pathological muscles (p < 0.05). This work demonstrates sensitive, high-resolution pH mapping of skeletal leg muscle with an ability to separate healthy from pathological tissue, highlighting its potential as a biomarker for muscle diseases.