Browsing by Author "Butch, Elizabeth R."

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    Estimating the synaptic density deficit in Alzheimer’s disease using multi-contrast CEST imaging
    (Public Library of Science, 2024-03-14) Shahid, Syed Salman; Dzemidzic, Mario; Butch, Elizabeth R.; Jarvis, Erin E.; Snyder, Scott E.; Wu, Yu-Chien; Radiology and Imaging Sciences, School of Medicine
    In vivo noninvasive imaging of neurometabolites is crucial to improve our understanding of the underlying pathophysiological mechanism in neurodegenerative diseases. Abnormal changes in synaptic organization leading to synaptic degradation and neuronal loss is considered as one of the primary factors driving Alzheimer's disease pathology. Magnetic resonance based molecular imaging techniques such as chemical exchange saturation transfer (CEST) and magnetic resonance spectroscopy (MRS) can provide neurometabolite specific information which may relate to underlying pathological and compensatory mechanisms. In this study, CEST and short echo time single voxel MRS was performed to evaluate the sensitivity of cerebral metabolites to beta-amyloid (Aβ) induced synaptic deficit in the hippocampus of a mouse model of Alzheimer's disease. The CEST based spectra (Z-spectra) were acquired on a 9.4 Tesla small animal MR imaging system with two radiofrequency (RF) saturation amplitudes (1.47 μT and 5.9 μT) to obtain creatine-weighted and glutamate-weighted CEST contrasts, respectively. Multi-pool Lorentzian fitting and quantitative T1 longitudinal relaxation maps were used to obtain metabolic specific apparent exchange-dependent relaxation (AREX) maps. Short echo time (TE = 12 ms) single voxel MRS was acquired to quantify multiple neurometabolites from the right hippocampus region. AREX contrasts and MRS based metabolite concentration levels were examined in the ARTE10 animal model for Alzheimer's disease and their wild type (WT) littermate counterparts (age = 10 months). Using MRS voxel as a region of interest, group-wise analysis showed significant reduction in Glu-AREX and Cr-AREX in ARTE10, compared to WT animals. The MRS based results in the ARTE10 mice showed significant decrease in glutamate (Glu) and glutamate-total creatine (Glu/tCr) ratio, compared to WT animals. The MRS results also showed significant increase in total creatine (tCr), phosphocreatine (PCr) and glutathione (GSH) concentration levels in ARTE10, compared to WT animals. In the same ROI, Glu-AREX and Cr-AREX demonstrated positive associations with Glu/tCr ratio. These results indicate the involvement of neurotransmitter metabolites and energy metabolism in Aβ-mediated synaptic degradation in the hippocampus region. The study also highlights the feasibility of CEST and MRS to identify and track multiple competing and compensatory mechanisms involved in heterogeneous pathophysiology of Alzheimer's disease in vivo.
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    Use of multimodality imaging, histology, and treatment feasibility to characterize a transgenic Rag2-null rat model of glioblastoma
    (Frontiers, 2022-11-22) Jackson, Luke R.; Masi, Megan R.; Selman, Bryce M.; Sandusky, George E.; Zarrinmayeh, Hamideh; Das, Sudip K.; Maharjan, Surendra; Wang, Nian; Zheng, Qi-Huang; Pollok, Karen E.; Snyder, Scott E.; Sun, Phillip Zhe; Hutchins, Gary D.; Butch, Elizabeth R.; Veronesi, Michael C.; Pediatrics, School of Medicine
    Many drugs that show potential in animal models of glioblastoma (GBM) fail to translate to the clinic, contributing to a paucity of new therapeutic options. In addition, animal model development often includes histologic assessment, but multiparametric/multimodality imaging is rarely included despite increasing utilization in patient cancer management. This study developed an intracranial recurrent, drug-resistant, human-derived glioblastoma tumor in Sprague–Dawley Rag2-Rag2 tm1Hera knockout rat and was characterized both histologically and using multiparametric/multimodality neuroimaging. Hybrid 18F-fluoroethyltyrosine positron emission tomography and magnetic resonance imaging, including chemical exchange saturation transfer (18F-FET PET/CEST MRI), was performed for full tumor viability determination and characterization. Histological analysis demonstrated human-like GBM features of the intracranially implanted tumor, with rapid tumor cell proliferation (Ki67 positivity: 30.5 ± 7.8%) and neovascular heterogeneity (von Willebrand factor VIII:1.8 to 5.0% positivity). Early serial MRI followed by simultaneous 18F-FET PET/CEST MRI demonstrated consistent, predictable tumor growth, with exponential tumor growth most evident between days 35 and 49 post-implantation. In a second, larger cohort of rats, 18F-FET PET/CEST MRI was performed in mature tumors (day 49 post-implantation) for biomarker determination, followed by evaluation of single and combination therapy as part of the model development and validation. The mean percentage of the injected dose per mL of 18F-FET PET correlated with the mean %CEST (r = 0.67, P < 0.05), but there was also a qualitative difference in hot spot location within the tumor, indicating complementary information regarding the tumor cell demand for amino acids and tumor intracellular mobile phase protein levels. Finally, the use of this glioblastoma animal model for therapy assessment was validated by its increased overall survival after treatment with combination therapy (temozolomide and idasanutlin) (P < 0.001). Our findings hold promise for a more accurate tumor viability determination and novel therapy assessment in vivo in a recently developed, reproducible, intracranial, PDX GBM.