BBB permeability as a magnetic resonance imaging biomarker for low glioblastoma infiltration

Abstract

Detecting and measuring invasion of the normal brain is crucial for the successful treatment of glioblastoma (GBM) as it allows increasing the accuracy of target volume delineation for radiotherapy planning. Probing the integrity of the peritumoral Blood-Brain Barrier (BBB) could substantially facilitate drug delivery planning. While magnetic resonance imaging (MRI) is a valuable tool for clinicians treating GBM, standard imaging techniques fail to detect regions of low tumour cell density and provide poor information about subtle BBB permeability changes caused by GBM invasion. However, invading tumour cells often progress along blood vessels and recent results indicate that even individual cells can disrupt the normal BBB function, providing an opportunity to detect tumour invasion at its earliest stages. Our research focuses on the development of MRI techniques probing brain perfusion and BBB permeability, and their assessment as biomarkers for detecting low tumour infiltration regions in mouse GBM models presenting highly invasive tumour margins. A high SNR multiple boli Arterial Spin Labelling (mbASL) technique was optimised for rodent brain perfusion imaging and a diffusion-weighted ASL (DWASL) method was implemented for probing the molecular mobility of perfused blood water. Introducing diffusion gradients into the ASL sequence allows minimising the signal contribution of the fast motion “vascular component” providing with perfusion images dominated by the slower motion “tissue component”. The ratio of the “tissue component” perfusion images to the overall perfusion ones obtained by ASL was expected to produce BBB permeability-weighed maps. The resulting maps were compared with histological sections stained (FITC)-dextrans to assess BBB disruption. The ability of perfusion and BBB permeability techniques to characterise tumour invasion was evaluated by comparison with standard MRI techniques (T2W and DW) and immunohistochemistry sections cut in the MRI plane. Both techniques were shown to detect low tumour regions not detected by standard MRI techniques.