NMR Characterization of Pathological Disease States: Monitoring Response to Single-Dose Radiotherapy in a RIF-1 Tumor Model and the Role of Spreading Depression in the Evolution of Ischemic Stroke

Henning, Erica C.

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NMR Characterization of Pathological Disease States: Monitoring Response to Single-Dose Radiotherapy in a RIF-1 Tumor Model and the Role of Spreading Depression in the Evolution of Ischemic Stroke

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The research presented within this dissertation focused on two major areas of research: monitoring the response to single-dose radiotherapy in a RIF-1 tumor model and the role of cortical spreading depression in the evolution of ischemic stroke.For the research in the first half of this dissertation, quantitative MRI was performed to investigate the spatial correlation between the apparent diffusion coefficient (ADC), spin-spin relaxation times (T2), and proton density (M0) in murine radiation-induced fibrosarcoma (RIF-1) tumors following single-dose (1000cGy) radiotherapy using the k-means (KM) algorithm. An in-depth comparison between KM-derived volume estimates and conventional histology via the hematoxylin-eosin (H&E) staining procedure (for identification of viable tumor versus necrosis), as well as via hypoxic-inducible factor-1alpha (HIF-1alpha) immunohistochemistry (for identification of regions of hypoxia versus well-oxygenated tissue) was performed. The results of this study demonstrated that multispectral (MS) analysis provides: (1) an improved tissue segmentation method over results obtained from conventional single-parameter approaches, (2) subdivision based on the degree of necrosis, as well as delineation between well-oxygenated and hypoxic viable tissue, (3) good correlation with both H&E staining and HIF-1alpha immunohistochemistry, and (4) a method for monitoring the range of tissue viability as a function of time post-treatment, with the potential for predicting therapeutic efficacy.For the research in the second half of this dissertation, manganese-enhanced MRI (MEMRI) was employed for the characterization of both experimental and pathological cortical spreading depression (CSD). In order to determine the utility of manganese ions (Mn2+) as a marker for spreading depression (SD), experimental SD was elicited by chemical stimulation (KCl application to exposed rat cortex) and compared with control conditions. This study demonstrated that (1) Mn2+ is a more accurate marker for SD than DWI or T2* methods, (2) cortical restriction of MEMRI enhancement supports the contention that apical dendrites are necessary for SD propagation. (3) subcortical enhancement was a result of cortical-subcortical neuronal connectivity. Based on these results, preliminary experiments involving the study of SD in ischemia using Mn2+ were performed. Initial results indicate: (1) MEMRI may provide a method for estimating the likelihood of progression to infarction at acute timepoints post onset of stroke. These studies provide a foundation for further investigation into the role of SD in stroke, and the application of Mn2+ towards the design of therapeutic strategies targeting SD inhibition.

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