Sensitivity and Source of Amine‐Proton Exchange and Amide‐Proton Transfer Magnetic Resonance Imaging in Cerebral Ischemia

Abstract

Purpose Amide proton transfer (APT) and amine-water proton exchange (APEX) can be viable to map pH-decreasing ischemic regions. However, their exact contributions are unclear. Methods We measured APEX- and APT-weighted magnetization transfer ratio asymmetry (denoted as APEXw and APTw), ADC, T2 and T1 images, and localized proton spectra in rats with permanent middle cerebral artery occlusion at 9.4 T. Phantoms and theoretical studies were also performed. Results Within one hour post-occlusion, APEXw and APTw maps showed hyperintensity (3.1% of M0) and hypointensity (−1.8%), respectively, in regions with decreased ADC. Ischemia increased lactate and gamma aminobutyric acid (GABA) concentrations, but decreased glutamate and taurine concentrations. Over time, the APEXw contrast decreased with glutamate, taurine and creatine, while the APTw contrast and lactate level were similar. Phantom and theoretical studies suggest that the source of APEXw signal is mainly from proteins at normal pH, while at decreased pH, GABA and glutamate contributions increase, inducing the positive APEXw contrast in ischemic regions. The APTw contrast is sensitive to lactate concentration and pH, but contaminated from contributions of the faster amine-water proton exchange processes. Conclusion Positive APEXw contrast is more sensitive to ischemia than negative APTw contrast. They may provide complementary tissue metabolic information.

Physical Modeling of Chemical Exchange Saturation Transfer Imaging

“…Usually, the amide group has a slow exchange rate, 34) and the CEST effect for the amide protons increases as pH increases because the exchange rate increases in a low pH. 26,27) We showed the pseudo-exchange rates of Glu and Gly were decreased with increasing the acidity.…”

“…Previous research has demonstrated that the CEST effect of amide and amine groups has a complex relationship with the chemical exchange rate and acidity. 26,27) We previously showed that the CEST asymmetry of the molecules was decreased with increasing pH at 9.4T MRI. 9) The CEST asymmetry values for GABA, Glu, and Gly which contain amine groups were lowest with the highest pH which was consistent with the previous amine group studies, 9,28) which showed the decreased CEST asymmetry values with increasing pH for the amine protons.…”

Amide Proton Transfer Imaging in Clinics: Basic Concepts and Current and Future Use in Brain Tumors and Stroke

“…The water longitudinal relaxation time (T1w) and water proton concentration can affect the APT signal (2,7,8). With respect to (12,13).…”

“…Third, CEST sensitivity is low according to pH changes in amide protons. Although the CEST effect is shown to be sensitive to changes in pH, the sensitivity of an amide proton was found to be lower than that of an amine proton, a faster-exchanging molecule in the physiologic range (i.e., pH 6.0-8.5) (3,8,38,59). Finally, the interpretation of APT imaging in the subacute phase is not straightforward, and several factors can significantly increase APT asymmetry (i.e., proteolysis and inflammation are likely to increase the amount of mobile proteins) (22).…”

“…For the amine proton, which has a peak centered around 3 ppm, the CEST effects appear to increase as pH decreases in the physiologic range (3,8,38,60).…”