Systematic evaluation of 99mTc-tetrofosmin versus 99mTc-sestamibi to study murine myocardial perfusion in small animal SPECT/CT

Background: The “back-translation” of clinically available protocols to measure myocardial perfusion to preclinical imaging in mouse models of human disease is attractive for basic biomedical research. With respect to singlephoton emission computed tomography (SPECT) approaches, clinical myocardial perfusion imaging protocols are established with different 99mTc-labeled perfusion tracers; however, studies evaluating and optimizing protocols for these tracers in high-resolution pinhole SPECT in mice are lacking. This study aims at evaluating two clinically available 99mTc-labeled myocardial perfusion tracers (99mTc-sestamibi vs. 99mTc-Tetrofosmin) in mice using four different imaging protocols. Methods: Adult C57BL/6 male mice were injected with 99mTc-sestamibi (MIBI) or 99mTc-Tetrofosmin (TETRO) (4 MBq/g body weight) either intravenously through the tail vein (n = 5) or retroorbitally (n = 5) or intraperitoneally (i. p.) under anesthesia (n = 3) or i.p. in an awake state (n = 3) at rest. Immediately after injection, a multi-frame singlephoton emission computed tomography/computed tomography (SPECT/CT) acquisition was initiated with six subsequent time frames of 10 min each. Reconstructed images of the different protocols were assessed and compared by visual analysis by experts and by time-activity-curves generated from regions-of-interest for various organs (normalized uptake values). Results: Visually assessing overall image quality, the best image quality was found for MIBI for both intravenous injection protocols, whereas TETRO only had comparable image quality after retroorbital injections. These results were confirmed by quantitative analysis where left ventricular (LV) uptake of MIBI after tail vein injections was found significantly higher for all time points accompanied with a significantly slower washout of 16% for MIBI vs. 33% for TETRO (p = 0.009) from 10 to 60 min post injection (PI). Interestingly, LV washout from 10 to 60 min PI was significantly higher for TETRO when applied by tail vein injections when compared to retroorbital injections (22%, p = 0.008). However, liver uptake was significant and comparable for both tracers at all time points. Radioactivity concentration in the lungs was negligible for all time points and both tracers. Conclusion: Intravenous MIBI injection (both tail vein and retroorbital) results in the best image quality for assessing myocardial perfusion of the murine heart by SPECT/CT. TETRO has a comparable image quality only for the retroorbital injection route

Demonstration of Metabolic and Cellular Effects of Portal Vein Ligation Using Multi-Modal PET/MRI Measurements in Healthy Rat Liver.

OBJECTIVES: In the early recognition of portal vein ligation (PVL) induced tumor progression, positron emission tomography and magnetic resonance imaging (PET/MRI) could improve diagnostic accuracy of conventionally used methods. It is unknown how PVL affects metabolic patterns of tumor free hepatic tissues. The aim of this preliminary study is to evaluate the effect of PVL on glucose metabolism, using PET/MRI imaging in healthy rat liver. MATERIALS AND METHODS: Male Wistar rats (n = 30) underwent PVL. 2-deoxy-2-(18F)fluoro-D-glucose (FDG) PET/MRI imaging (nanoScan PET/MRI) and morphological/histological examination were performed before (Day 0) and 1, 2, 3, and 7 days after PVL. Dynamic PET data were collected and the standardized uptake values (SUV) for ligated and non-ligated liver lobes were calculated in relation to cardiac left ventricle (SUVVOI/SUVCLV) and mean liver SUV (SUVVOI/SUVLiver). RESULTS: PVL induced atrophy of ligated lobes, while non-ligated liver tissue showed compensatory hypertrophy. Dynamic PET scan revealed altered FDG kinetics in both ligated and non-ligated liver lobes. SUVVOI/SUVCLV significantly increased in both groups of lobes, with a maximal value at the 2nd postoperative day and returned near to the baseline 7 days after the ligation. After PVL, ligated liver lobes showed significantly higher tracer uptake compared to the non-ligated lobes (significantly higher SUVVOI/SUVLiver values were observed at postoperative day 1, 2 and 3). The homogenous tracer biodistribution observed before PVL reappeared by 7th postoperative day. CONCLUSION: The observed alterations in FDG uptake dynamics should be taken into account during the assessment of PET data until the PVL induced atrophic and regenerative processes are completed

Radiomics-based differentiation of lung disease models generated by polluted air based on X-ray computed tomography data

BACKGROUND: Lung diseases (resulting from air pollution) require a widely accessible method for risk estimation and early diagnosis to ensure proper and responsive treatment. Radiomics-based fractal dimension analysis of X-ray computed tomography attenuation patterns in chest voxels of mice exposed to different air polluting agents was performed to model early stages of disease and establish differential diagnosis. METHODS: To model different types of air pollution, BALBc/ByJ mouse groups were exposed to cigarette smoke combined with ozone, sulphur dioxide gas and a control group was established. Two weeks after exposure, the frequency distributions of image voxel attenuation data were evaluated. Specific cut-off ranges were defined to group voxels by attenuation. Cut-off ranges were binarized and their spatial pattern was associated with calculated fractal dimension, then abstracted by the fractal dimension -- cut-off range mathematical function. Nonparametric Kruskal-Wallis (KW) and Mann-Whitney post hoc (MWph) tests were used. RESULTS: Each cut-off range versus fractal dimension function plot was found to contain two distinctive Gaussian curves. The ratios of the Gaussian curve parameters are considerably significant and are statistically distinguishable within the three exposure groups. CONCLUSIONS: A new radiomics evaluation method was established based on analysis of the fractal dimension of chest X-ray computed tomography data segments. The specific attenuation patterns calculated utilizing our method may diagnose and monitor certain lung diseases, such as chronic obstructive pulmonary disease (COPD), asthma, tuberculosis or lung carcinomas

Evaluation of Brain Nuclear Medicine Imaging Tracers in a Murine Model of Sepsis-Associated Encephalopathy

PURPOSE: The purpose of this study was to evaluate a set of widely used nuclear medicine imaging agents as possible methods to study the early effects of systemic inflammation on the living brain in a mouse model of sepsis-associated encephalopathy (SAE). The lipopolysaccharide (LPS)-induced murine systemic inflammation model was selected as a model of SAE. PROCEDURES: C57BL/6 mice were used. A multimodal imaging protocol was carried out on each animal 4 h following the intravenous administration of LPS using the following tracers: [(99m)Tc][2,2-dimethyl-3-[(3E)-3-oxidoiminobutan-2-yl]azanidylpropyl]-[(3E)-3-hyd roxyiminobutan-2-yl]azanide ([(99m)Tc]HMPAO) and ethyl-7-[(125)I]iodo-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbox ylate ([(125)I]iomazenil) to measure brain perfusion and neuronal damage, respectively; 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) to measure cerebral glucose uptake. We assessed microglia activity on another group of mice using 2-[6-chloro-2-(4-[(125)I]iodophenyl)-imidazo[1,2-a]pyridin-3-yl]-N-ethyl-N-methyl -acetamide ([(125)I]CLINME). Radiotracer uptakes were measured in different brain regions and correlated. Microglia activity was also assessed using immunohistochemistry. Brain glutathione levels were measured to investigate oxidative stress. RESULTS: Significantly reduced perfusion values and significantly enhanced [(18)F]FDG and [(125)I]CLINME uptake was measured in the LPS-treated group. Following perfusion compensation, enhanced [(125)I]iomazenil uptake was measured in the LPS-treated group's hippocampus and cerebellum. In this group, both [(18)F]FDG and [(125)I]iomazenil uptake showed highly negative correlation to perfusion measured with ([(99m)Tc]HMPAO uptake in all brain regions. No significant differences were detected in brain glutathione levels between the groups. The CD45 and P2Y12 double-labeling immunohistochemistry showed widespread microglia activation in the LPS-treated group. CONCLUSIONS: Our results suggest that [(125)I]CLINME and [(99m)Tc]HMPAO SPECT can be used to detect microglia activation and brain hypoperfusion, respectively, in the early phase (4 h post injection) of systemic inflammation. We suspect that the enhancement of [(18)F]FDG and [(125)I]iomazenil uptake in the LPS-treated group does not necessarily reflect neural hypermetabolism and the lack of neuronal damage. They are most likely caused by processes emerging during neuroinflammation, e.g., microglia activation and/or immune cell infiltration

Diastolic dysfunction in prediabetic male rats: role of mitochondrial oxidative stress

Although incidence and prevalence of prediabetes are increasing, little is known on its cardiac effects. Therefore, our aim was to investigate the effect of prediabetes on cardiac function and to characterize parameters and pathways associated with deteriorated cardiac performance. Long-Evans rats were fed with either control or high-fat chow for 21 weeks and treated with a single low dose (20 mg/kg) streptozotocin at week 4. High-fat and streptozotocin treatment induced prediabetes as characterized by slightly elevated fasting blood glucose, impaired glucose- and insulin tolerance, increased visceral adipose tissue and plasma leptin levels, as well as sensory neuropathy. In prediabetic animals a mild diastolic dysfunction was observed, the number of myocardial lipid droplets increased, and left ventricular mass and wall thickness were elevated, however, no molecular sign of fibrosis or cardiac hypertrophy was evidenced. In prediabetes, production of reactive oxygen species was elevated in subsarcolemmal mitochondria. Expression of mitofusin-2 was increased while the phosphorylation of phospholamban and expression of Bcl-2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3, a marker of mitophagy) decreased. However, expression of other markers of cardiac auto- and mitophagy, mitochondrial dynamics, inflammation, heat shock proteins, Ca2+/calmodulin-dependent protein kinase II, mTOR or apoptotic pathways were unchanged in prediabetes. This is the first comprehensive analysis of cardiac effects of prediabetes indicating that mild diastolic dysfunction and cardiac hypertrophy are multifactorial phenomena which is associated with early changes in mitophagy, cardiac lipid accumulation and elevated oxidative stress, and that prediabetes-induced oxidative stress originates from the subsarcolemmal mitochondria