Abnormal pH is a common feature of malignant tumours and has been associated clinically with sub-optimal outcomes. Amide proton transfer magnetic resonance imaging (APT MRI) holds promise as a means to non-invasively measure tumour pH, yet multiple factors collectively make quantification of tumour pH from APT MRI data challenging. The purpose of this study was to improve our understanding of the biophysical sources of altered APT MRI signals in tumours. Combining in vivo APT MRI measurements with ex vivo histological measurements of protein concentration in a rat model of brain metastasis, we determined that the proportion of APT MRI signal originating from changes in protein concentration was approximately 66%, with the remaining 34% originating from changes in tumour pH. In a mouse model of hypopharyngeal squamous cell carcinoma (FaDu), APT MRI showed that a reduction in tumour hypoxia was associated with a shift in tumour pH. The results of this study extend our understanding of APT MRI data and may enable the use of APT MRI to infer the pH of individual patients' tumours as either a biomarker for therapy stratification or as a measure of therapeutic response in clinical settings.
Cerebral blood flow is an important parameter in many diseases and functional studies that can be accurately measured in humans using arterial spin labelling (ASL) MRI. However, although rat models are frequently used for preclinical studies of both human disease and brain function, rat CBF measurements show poor consistency between studies. This lack of reproducibility is due, partly, to the smaller size and differing head geometry of rats compared to humans, as well as the differing analysis methodologies employed and higher field strengths used for preclinical MRI. To address these issues, we have implemented, optimised and validated a multiphase pseudo-continuous ASL technique, which overcomes many of the limitations of rat CBF measurement. Three rat strains (Wistar, Sprague Dawley and Berlin Druckrey IX) were used, and CBF values validated against gold-standard autoradiography measurements. Label positioning was found to be optimal at 45°, while post-label delay was optimised to 0.55 s. Whole brain CBF measures were 109 ± 22, 111 ± 18 and 100 ± 15 mL/100 g/min by multiphase pCASL, and 108 ± 12, 116 ± 14 and 122 ± 16 mL/100 g/min by autoradiography in Wistar, SD and BDIX cohorts, respectively. Tumour model analysis shows that the developed methods also apply in disease states. Thus, optimised multiphase pCASL provides robust, reproducible and non-invasive measurement of CBF in rats.
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