Quantitative cross-relaxation imaging for the in vivo assessment of glioma cell invasion in the rat brain at 3.0 Tesla

Gliomas are the most common primary brain tumor and the most malignant form, the glioblastoma multiforme, is associated with an overall median survival of less than 12 months. The medical intractability and lethality of both high- and low-grade gliomas has been largely attributed to their extensive infiltration into normal healthy brain tissue. Understanding the tumor biology that governs glioma invasion has been limited by an inability to non-invasively study in vivo gliomas in an animal model.Cross-relaxation imaging (CRI) is a quantitative magnetic resonance imaging technique that measures the kinetic parameters of magnetization transfer. CRI may afford the opportunity to image cellular invasion since the destruction and alteration of the extracellular matrix by migratory glioma cells alters the normal balance between the protons bound to water and protons bound to macromolecules --- a ratio measured directly by CRI (i.e. the bound pool fraction).In this dissertation, CRI is proposed as a non-invasive technique for detecting the in vivo growth and invasion of gliomas in an animal model. CRI is first established as an imaging tool that yields unique information to diffusion-based imaging in the in vivo human brain at 3.0 T. Second, to enable CRI in the in vivo rat brain a novel coil specific for whole-brain rat imaging at 3.0 T that substantially improves signal-to-noise ratio (SNR) over conventional coils is developed. Third, in vivo CRI of the normal rat brain at 3.0 T was directly compared to histology to determine the dominant tissue property in the rat brain that CRI parameters are measuring. Subsequently, a time-efficient approach for capturing the key parameter of CRI was validated with histology enabling rapid, whole-brain production of in vivo myelin maps. Whole-brain rat bound pool fraction maps and myelin maps were then produced to identify changes in both gray matter and white matter in response to tumor infiltration, which were confirmed with histology. Finally, initial in vivo data are presented that indicate alteration to a specific protein known to govern cell motility may alter in vivo tumor behavior and drive invasion in glioblastoma. These successive experiments establish CRI as a viable technique for imaging bulk tumor and cellular invasion of glioblastoma in the in vivo rat brain at 3.0 T.