Determination of an optimally sensitive and specific chemical exchange saturation transfer MRI quantification metric in relevant biological phantoms

• Published in: NMR in biomedicine Vol. 29; no. 11; pp. 1624 - 1633
• Main Authors: Ray, Kevin J., Larkin, James R., Tee, Yee K., Khrapitchev, Alexandre A., Karunanithy, Gogulan, Barber, Michael, Baldwin, Andrew J., Chappell, Michael A., Sibson, Nicola R.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.11.2016; Wiley Subscription Services, Inc; John Wiley and Sons Inc
• Subjects: Algorithms; Animals; brain; CEST; Equipment Design; Hydrogen-Ion Concentration; Image Enhancement - methods; Image Interpretation, Computer-Assisted - methods; Magnetic Resonance Imaging - instrumentation; Magnetic Resonance Imaging - methods; metastases; Mice; Molecular Imaging - instrumentation; Molecular Imaging - methods; MRI; Neoplasms, Experimental - chemistry; Neoplasms, Experimental - diagnostic imaging; Neoplasms, Experimental - pathology; Phantoms, Imaging; Proton Magnetic Resonance Spectroscopy - methods; Reproducibility of Results; Sensitivity and Specificity; Signal Processing, Computer-Assisted; pH; metastases; CEST; brain; MRI
• ISSN: 0952-3480; 1099-1492; 1099-1492
• DOI: 10.1002/nbm.3614

The purpose of this study was to develop realistic phantom models of the intracellular environment of metastatic breast tumour and naïve brain, and using these models determine an analysis metric for quantification of CEST MRI data that is sensitive to only labile proton exchange rate and concentration. The ability of the optimal metric to quantify pH differences in the phantoms was also evaluated. Novel phantom models were produced, by adding perchloric acid extracts of either metastatic mouse breast carcinoma cells or healthy mouse brain to bovine serum albumin. The phantom model was validated using 1H NMR spectroscopy, then utilized to determine the sensitivity of CEST MRI to changes in pH, labile proton concentration, T1 time and T2 time; six different CEST MRI analysis metrics (MTRasym, APT*, MTRRex, AREX and CESTR* with and without T1/T2 compensation) were compared. The new phantom models were highly representative of the in vivo intracellular environment of both tumour and brain tissue. Of the analysis methods compared, CESTR* with T1 and T2 time compensation was optimally specific to changes in the CEST effect (i.e. minimal contamination from T1 or T2 variation). In phantoms with identical protein concentrations, pH differences between phantoms could be quantified with a mean accuracy of 0.6 pH units. We propose that CESTR* with T1 and T2 time compensation is the optimal analysis method for these phantoms. Analysis of CEST MRI data with T1/T2 time compensated CESTR* is reproducible between phantoms, and its application in vivo may resolve the intracellular alkalosis associated with breast cancer brain metastases without the need for exogenous contrast agents. Novel biologically relevant phantom models of the intracellular environment of metastatic breast tumour and naïve brain were produced, and used to determine an optimally sensitive and specific analysis metric for quantification of pH from CEST MRI data. Of the analysis methods compared, CESTR* with T1 and T2 time compensation was optimally specific to changes in the CEST effect (i.e. minimal contamination from T1 or T2 variation), with the ability to measure quantitative differences in pH with an accuracy of 0.6 pH units.