Quantitative tissue pH measurement during cerebral ischemia using amine and amide concentration-independent detection (AACID) with MRI.
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.
Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada.
Nevin
N
McVicar
Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
Alex X
AX
Li
1] Robarts Research Institute, University of Western Ontario, London, Ontario, Canada [2] Department of Physiology and Biophysics, Neuroscience Centre, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Daniela F
DF
Gonçalves
Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
Miranda
M
Bellyou
1] Robarts Research Institute, University of Western Ontario, London, Ontario, Canada [2] Department of Biochemistry, University of Western Ontario, Western University, London, Ontario, Canada.
Susan O
SO
Meakin
1] Robarts Research Institute, University of Western Ontario, London, Ontario, Canada [2] Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada [3] Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada.
Marco Am
MA
Prado
1] Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada [2] Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
Robert
R
Bartha
D000140:Acidosis, Lactic / Q000175:diagnosis / Q000378:metabolism; D000577:Amides / Q000032:analysis*; D000588:Amines / Q000032:analysis*; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002545:Brain Ischemia / Q000378:metabolism*; D002138:Calibration; D003198:Computer Simulation; D004195:Disease Models, Animal; D006863:Hydrogen-Ion Concentration; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008956:Models, Chemical
D000577:Amides; D000588:Amines; D015415:Biomarkers