Minori Tanoue1, Shigeyoshi Saito2, Yusuke Takahashi3, Rikita Araki4, Takashi Hashido5, Hidetaka Kioka3, Yasushi Sakata3, Yoshichika Yoshioka1. 1. Laboratory of Biofunctional Imaging, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 560-0871, Japan; Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka 560-0871, Japan. 2. Department of Medical Physics and Engineering, Division of Health Sciences, Osaka University Graduate School of Medicine, Suita, Osaka 560-0871, Japan. Electronic address: saito@sahs.med.osaka-u.ac.jp. 3. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan. 4. BioSpin Division, Bruker Japan K.K., Yokohama, Kanagawa 221-0022, Japan. 5. Department of Medical Physics and Engineering, Division of Health Sciences, Osaka University Graduate School of Medicine, Suita, Osaka 560-0871, Japan.
Abstract
PURPOSE: The purpose of this study was (i) to determine the optimal magnetization transfer (MT) pulse parameter for amide proton transfer (APT) chemical exchange saturation transfer (CEST) imaging on an ultra-high-field magnetic resonance imaging (MRI) system and (ii) to use APT CEST imaging to noninvasively assess brain orthotopic and ectopic tumor cells transplanted into the mouse brain. METHODS: To evaluate APT without the influence of other metabolites, we prepared egg white phantoms. Next, we used 7-11-week-old nude female mice and the following cell lines to establish tumors after injection into the left striatum of mice: C6 (rat glioma, n = 8) as primary tumors and Neuro-2A (mouse neuroblastoma, n = 11) and MDA-MB231 (human breast cancer, n = 8) as metastatic tumors. All MRI experiments were performed on an 11.7 T vertical-bore scanner. CEST imaging was performed at 1 week after injection of Neuro-2A cells and at 2 weeks after injection of C6 and MDA-MB231 cells. The MT pulse amplitude was set at 2.2 μT or 4.4 μT. We calculated and compared the magnetization transfer ratio (MTR) and difference of MTR asymmetry between normal tissue and tumor (ΔMTR asymmetry) on APT CEST images between mouse models of brain tumors. Then, we performed hematoxylin and eosin (HE) staining and Ki-67 immunohistochemical staining to compare the APT CEST effect on tumor tissues and the pathological findings. RESULTS: Phantom study of the amide proton phantom containing chicken egg white, z-spectra obtained at a pulse length of 500 ms showed smaller peaks, whereas those obtained at a pulse length of 2000 ms showed slightly higher peaks. The APT CEST effect on tumor tissues was clearer at a pulse amplitude of 2.2 μT than at 4.4 μT. For all mouse models of brain tumors, ΔMTR asymmetry was higher at 2.2 μT than at 4.4 μT. ΔMTR asymmetry was significantly higher for the Neuro-2A model than for the MDA-MB231 model. HE staining revealed light bleeding in Neuro-2A tumors. Immunohistochemical staining revealed that the density of Ki-67-positive cells was higher in Neuro-2A tumors than in C6 or MDA-MB231 tumors. CONCLUSION: The MTR was higher at 4.4 μT than at 2.2 μT for each concentration of egg white at a pulse length of 500 ms or 2000 ms. High-resolution APT CEST imaging on an ultra-high-field MRI system was able to provide tumor information such as proliferative potential and intratumoral bleeding, noninvasively.
PURPOSE: The purpose of this study was (i) to determine the optimal magnetization transfer (MT) pulse parameter for amide proton transfer (APT) chemical exchange saturation transfer (CEST) imaging on an ultra-high-field magnetic resonance imaging (MRI) system and (ii) to use APT CEST imaging to noninvasively assess brain orthotopic and ectopic tumor cells transplanted into the mouse brain. METHODS: To evaluate APT without the influence of other metabolites, we prepared egg white phantoms. Next, we used 7-11-week-old nude female mice and the following cell lines to establish tumors after injection into the left striatum of mice: C6 (ratglioma, n = 8) as primary tumors and Neuro-2A (mouseneuroblastoma, n = 11) and MDA-MB231 (humanbreast cancer, n = 8) as metastatic tumors. All MRI experiments were performed on an 11.7 T vertical-bore scanner. CEST imaging was performed at 1 week after injection of Neuro-2A cells and at 2 weeks after injection of C6 and MDA-MB231 cells. The MT pulse amplitude was set at 2.2 μT or 4.4 μT. We calculated and compared the magnetization transfer ratio (MTR) and difference of MTR asymmetry between normal tissue and tumor (ΔMTR asymmetry) on APT CEST images between mouse models of brain tumors. Then, we performed hematoxylin and eosin (HE) staining and Ki-67 immunohistochemical staining to compare the APT CEST effect on tumor tissues and the pathological findings. RESULTS: Phantom study of the amide proton phantom containing chicken egg white, z-spectra obtained at a pulse length of 500 ms showed smaller peaks, whereas those obtained at a pulse length of 2000 ms showed slightly higher peaks. The APT CEST effect on tumor tissues was clearer at a pulse amplitude of 2.2 μT than at 4.4 μT. For all mouse models of brain tumors, ΔMTR asymmetry was higher at 2.2 μT than at 4.4 μT. ΔMTR asymmetry was significantly higher for the Neuro-2A model than for the MDA-MB231 model. HE staining revealed light bleeding in Neuro-2A tumors. Immunohistochemical staining revealed that the density of Ki-67-positive cells was higher in Neuro-2A tumors than in C6 or MDA-MB231 tumors. CONCLUSION: The MTR was higher at 4.4 μT than at 2.2 μT for each concentration of egg white at a pulse length of 500 ms or 2000 ms. High-resolution APT CEST imaging on an ultra-high-field MRI system was able to provide tumor information such as proliferative potential and intratumoral bleeding, noninvasively.
Authors: Annabelle Shaffer; Susanna S Kwok; Anant Naik; Aaron T Anderson; Fan Lam; Tracey Wszalek; Paul M Arnold; Wael Hassaneen Journal: Front Neurol Date: 2022-04-05 Impact factor: 4.003