PROJECT SUMMARY / ABSTRACT Glioblastoma (GBM) is the most aggressive and inevitably recurrent brain tumor with a dismal prognosis and highly heterogeneous profiles. While front-line chemoradiotherapy (CRT) improves survival, it also complicates the assessment of early tumor progression (TP). Pseudoprogression (PsP), presenting as increased enhancement indistinguishable from TP by conventional MRI, occurs in about 36% of GBM patients. The current RANO criteria require longitudinal follow-up imaging exams and occasionally biopsy to make the ultimate distinction, often 6 or more months after the completion of CRT, precluding the possibility of timely and potentially more effective interventions. Despite advances in sophisticated physiological and metabolic MRI techniques, response assessment remains a prevailing challenge in the clinical management of GBM. Encouraged by recent findings in murine GBM xenografts that are corroborated further by a patient case, this proposal aims to validate the underlying histopathological basis and assess the ability of MR elastography (MRE) in the early differentiation of TP by spatially mapping the heterogenous response in GBM patients. MRE is an MRI technique that provides noninvasive, quantitative, and direct 3D maps of tissue viscoelastic properties in vivo. These biomechanical factors of tumors have been increasingly recognized to have profound implications for malignant progression, tumor heterogeneity, and treatment resistance. The central hypothesis of this project is that MRE can accurately differentiate between early TP and PsP by mapping the spatial distribution of active tumor and treatment-related changes (TRCs) within the known heterogeneous tumor response. Two independent specific aims are outlined to test this hypothesis. MRE features distinctive of active tumors and TRCs will be validated in Aim 1 in a pre-operative cohort with gold-standard tissue confirmation. The approach takes advantage of high-precision sampling during neuro-navigational surgeries to obtain co- localized tissue and imaging volumes for quantitative correlation analysis. This much-needed but never studied correlation in human GBM is crucial to help elucidate the pathophysiologic basis of the heterogenous MRE contrast. The ability of viscoelastic imaging markers to differentiate early TP from PsP will be determined in a longitudinal post-CRT imaging study in Aim 2. The approach leverages a robust high-sensitivity MRE methodology developed by the study team originally for mapping rapid functional changes in human brains to provide a high-resolution mapping of tissue viscoelastic properties. This enables full utilization of the diagnostic features in the heterogeneous biomechanical response of tumors for more accurate distinction. This innovative project will establish the first evidence on the role of MRE in the clinical evaluation of the treatment response of GBM. It is significant as the accurate and early understanding of the tr...