Characterization of the C6 Glioma Microenvironment using 9.4T MRI: Evaluation of Diffusion and Chemical Exchange Weighted Contrasts
Abstract
The most malignant form of diffuse infiltrative gliomas, glioblastoma multiforme (GBM), is the most common primary brain tumor in adults. Diffuse gliomas are characterized by extensive, diffuse infiltration of tumor cells into neighboring tissues. Due to the diffuse glioma growth pattern, curative treatment is not possible.
Conventional MRI has failed to accurately define the extent of brain tumor invasion, grade the tumor preoperatively, and predict treatment effects, making biopsy the gold standard. Histological analysis of brain tissue is currently the most accurate and reliable means of assessing brain pathology. However, developing noninvasive biomarkers that could provide information about tissue pathology \textit{in vivo} in humans would be invaluable, as it would enable a dynamic view of pathological processes and their impact on function in health and disease. In fact, the heterogeneous nature of glioma tumors and the existence of necrosis and inflammatory regions make biopsy challenging and increase the incidence of unsuccessful biopsies and the underestimation of the tumor grade. Diffusion tensor imaging (DTI), a standard diffusion magnetic resonance imaging (dMRI) technique, can non-invasively probe the brain microstructure and provide indicators of cell morphology and organization. More recently, the development of the neurite orientation dispersion and density imaging (NODDI) technique has allowed the estimation of the density and orientation dispersion of neurites using dMRI. Additionally, chemical exchange saturation transfer (CEST) is an advanced MRI technique that offers unique insights into the molecular composition and physiological properties of tissues by detecting the exchange of magnetization between protons in water and those on mobile proteins and other metabolites. The overreaching goal of this thesis was to characterize the tumor microenvironment using advanced diffusion MRI and tumor pH using chemical exchange saturation transfer MRI following treatment. This work is vital to determine whether these quantitative MRI methods could provide future benefits for clinical assessments. The C6 glioma rat model, a reproducible GBM model replicating many human glioma features, was used throughout the thesis to study glioma microstructure and microenvironment.
The comparison of dMRI contrasts demonstrated that the NODDI contrasts complemented the DTI contrasts and provided potentially greater contrast between the tumor and surrounding tissue than that produced by anatomical images or DTI. Specifically, the elevated isotropic volume fraction (IsoVF) value in the tumor tissue better-discriminated tumor tissue compared to other contrasts and did not provide the same information as that provided by conventional T2 weighted imaging. The feasibility of DTI and NODDI to characterize the properties of water diffusion within \textit{ex vivo} brain tumor and surrounding tissue was also confirmed. Observed diffusion changes within tumors were consistent with the structural changes visible in conventional histology. The chemical exchange saturation transfer method of monitoring tissue pH was also successfully able to detect pH changes in the C6 tumor after pharmacologically inhibiting the NHE1 transporter using Cariporide.
The NODDI dMRI and CEST pH-weighted imaging methods were both sensitive to variations in the tumor microenvironment. As these techniques continue to evolve and improve, they could contribute to advances in personalized medicine, where visualization of tumor microenvironment is determined non-invasively and used to guide treatment planning and monitoring.