Mapping Radiation Injury and Recovery in Bone Marrow Using ¹⁸F-FLT PET/CT and USPIO MRI in a Rat Model

Abstract

We present and test the use of multimodality imaging as a topological tool to map the amount of the body exposed to ionizing radiation and the location of exposure, which are important indicators of survival and recovery. To achieve our goal, PET/CT imaging with 3′-deoxy-3′-18 Ffluorothymidine ( 18 F-FLT) was used to measure cellular proliferation in bone marrow (BM), whereas MRI using ultra-small superparamagnetic iron oxide (USPIO) particles provided noninvasive information on radiationinduced vascular damage. Methods: Animals were x-ray-irradiated at a dose of 7.5 Gy with 1 of 3 radiation schemes-whole-body irradiation, half-body shielding (HBS), or 1-leg shielding (1LS)-and imaged repeatedly. The spatial information from the CT scan was used to segment the region corresponding to BM from the PET scan using algorithms developed in-house, allowing for quantification of proliferating cells, and BM blood volume was estimated by measuring the changes in the T 2 relaxation rates (DR 2 ) collected from MR scans. Results: 18 F-FLT PET/CT imaging differentiated irradiated from unirradiated BM regions. Two days after irradiation, proliferation of 1LS animals was significantly lower than sham (P 5 0.0001, femurs; P , 0.0001, tibias) and returned to sham levels by day 10 (P 5 0.6344, femurs; P 5 0.3962, tibias). The degree of shielding affected proliferation recovery, showing an increase in the irradiated BM of the femurs, but not the tibias, of HBS animals when compared with 1LS (P 5 0.0310, femurs; P 5 0.5832, tibias). MRI of irradiated spines detected radiation-induced BM vascular damage, measured by the significant increase in DR 2 2 d after wholebody irradiation (P 5 0.0022) and HBS (P 5 0.0003) with a decreasing trend of values, returning to levels close to baseline over 10 d. Our data were corroborated using γ-counting and histopathology. Conclusion: We demonstrated that 18 F-FLT PET/CT and USPIO MRI are valuable tools in mapping regional radiation exposure and the effects of radiation on BM. Analysis of the 18 F-FLT signal allowed for a clear demarcation of exposed BM regions and elucidated the kinetics of BM recovery, whereas USPIO MRI was used to assess vascular damage and recovery.

Radioprotective Effects of Heat-Killed Mycobacterium Tuberculosis in Cultured Cells and Radiosensitive Tissues

“…IR induces a huge decrease of nucleated cells in bone marrow and repression of hematopoiesis [25,26]. We found that HKMT protected bone marrow structure and restored the number of nucleated cells.…”

Imaging Radiation-Induced Gastrointestinal, Bone Marrow Injury and Recovery Kinetics Using 18F-FDG PET

“…Preservation of bone marrow has been shown to increase survival rates after radiation exposure at doses that are within the range of the gastrointestinal syndrome (7.5 Gy in rats) [12, 25, 43] and the role of bone marrow in the recovery of the gastrointestinal syndrome have been studied and established through many studies [12, 43]. By affecting survival, partial shielding can mask the effect of the gastrointestinal syndrome, which renders our imaging observations of both bone marrow and gastrointestinal signals ever more important.…”

“…Tissue uptake is measured using standardized uptake value normalized to body weight (SUV) or radioactivity activity concentration over amount injected normalized by body weight of the animal. Bone marrow ROIs were selected using the spatial information from the CT scan and an algorithm developed in-house, the details of our method has been previously published [25]. Briefly, a mask was generated corresponding to the bone structures from the CT scan and applied to the PET data.…”

“…The localization of activated immune cells and therefore local increase in glucose consumption can be characterized using 18 F-FDG imaging. Furthermore, radiation-induced bone marrow injury has been shown to damage highly proliferative progenitor cell populations and its vascular network [25, 26]. These functional and structural effects result in a reduction in the metabolic activity of the bone marrow [27].…”

CpG-Oligodeoxynucleotides Improved Irradiation-Induced Injuries by G-CSF and IL-6 Up-Regulation

“…IR induced severe injuries in hematopoietic tissue which may lead to death [15, 16]. G-CSF and IL-6 are critical in hematopoiesis [17-20].…”