Quantitative Tissue Ph Measurement during Cerebral Ischemia Using Amine and Amide Concentration-Independent Detection (AACID) with MRI

Abstract

Tissue pH is an indicator of altered cellular metabolism in diseases including stroke and cancer. Ischemic tissue often becomes acidic due to increased anaerobic respiration leading to irreversible cellular damage. Chemical exchange saturation transfer (CEST) effects can be used to generate pH-weighted magnetic resonance imaging (MRI) contrast, which has been used to delineate the ischemic penumbra after ischemic stroke. In the current study, a novel MRI ratiometric technique is presented to measure absolute pH using the ratio of CEST-mediated contrast from amine and amide protons: amine/amide concentration-independent detection (AACID). Effects of CEST were observed at 2.75 parts per million (p.p.m.) for amine protons and at 3.50 p.p.m. for amide protons downfield (i.e., higher frequency) from bulk water. Using numerical simulations and in vitro MRI experiments, we showed that pH measured using AACID was independent of tissue relaxation time constants, macromolecular magnetization transfer effects, protein concentration, and temperature within the physiologic range. After in vivo pH calibration using phosphorus ((31)P) magnetic resonance spectroscopy ((31)P-MRS), local acidosis is detected in mouse brain after focal permanent middle cerebral artery occlusion. In summary, our results suggest that AACID represents a noninvasive method to directly measure the spatial distribution of absolute pH in vivo using CEST MRI.

Amide proton transfer imaging to discriminate between low- and high-grade gliomas: added value to apparent diffusion coefficient and relative cerebral blood volume

“…Thus, the conflicting results may be partially attributed to the different phantoms and to the mobile proton sources for the APT signal, resulting in mixed effects of the amide, amine and other factors on the APT signal changes according to the pH. Our results are supported by other studies using BSA phantoms, in which the correlation between the APT signal and pH was not consistent with numerical simulations [24, 25]. Although the mechanisms underlying the APT signal change according to the pH change remain unclear, our phantom experiment confirmed that protein and peptide concentrations are major contributors to the APT signal.…”

pH-dependent structural modulation is conserved in the human small heat shock protein HSBP1

“…We have reported pHdependent properties of HSPB5 that include destabilization of its ACD dimer and, paradoxically, expansion of the number of subunits in its oligomeric species as a function of decreasing pH over a range of pH 7.5-6.5 (Rajagopal et al 2015b). A decrease in pH within this range is consistent with pH measurements in ischemic tissue in mouse brains (McVicar et al 2014) and may destabilize some cellular proteins, particularly those whose pI values fall within this pH range. Additionally, HSPB1 was found to be phosphorylated in response to low pH incubation of cultured AGS gastric cancer cells (Singh et al 2011).…”

Reciprocal regulation of two G protein-coupled receptors sensing extracellular concentrations of Ca 2+ and H +

“…Moreover, it has been implicated in brain pathologies, such as ischemia, neurodegenerative disease, and brain tumors (32). Intriguingly, these conditions are accompanied by extracellular acidosis (8,(33)(34)(35)(36). OGR1 is functionally expressed in brain tumor cells (15) ] o (37).…”