Reduced 18F-FDG Uptake Research Articles

Reduced 18F-FDG uptake in the basal interventricular septum as a predictor of fatal ventricular arrhythmic events in patients with cardiac sarcoidosis

BackgroundPatients with cardiac sarcoidosis (CS) are at an increased risk of fatal ventricular arrhythmic events (FVAE). However, the predictive value of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in assessing the risk of FVAE in patients with CS remains uncertain. MethodsWe included data from 121 patients with CS (39 men and 82 women; mean age: 59.5 years) who underwent FDG-PET imaging between March 2008 and November 2020, with follow-ups completed in July 2023. Of these, 82 patients had available cardiac magnetic resonance imaging data, including late gadolinium enhancement (LGE). FDG-PET images were analysed using a polar-map model to determine the regional mean percentage uptake relative to the maximal cardiac 18F-FDG uptake in each of the 17 segments defined by the American Heart Association. ResultsPatients experiencing FVAE after FDG-PET (n = 43) showed lower percent uptake in the basal inferoseptal segment compared to those who did not (n = 78) (41.8 ± 15.2 % vs. 54.4 ± 13.8 %, P < 0.001). Patients with a basal inferoseptal percent uptake below the median had a lower FVAE-free survival rate than those with a higher percent uptake (58.1 % vs. 78 % at 5 years, P = 0.007), which was consistent in patients with LGE in the same regions with reduced 18F-FDG uptake. A Cox hazard model indicated that the FVAE risk decreased with a hazard ratio of 0.862 (95 % CI 0.770–0.964) for every 5 % increase in basal inferoseptal percent uptake (P = 0.009). ConclusionReduced 18F-FDG uptake in the basal interventricular septum, including the inferoseptal segment, may be a valuable predictor of future FVAE in patients with CS.

Cortical cerebrovascular and metabolic perturbations in the 5xFAD mouse model of Alzheimer's disease.

The 5xFAD mouse is a popular model of familial Alzheimer's disease (AD) that is characterized by early beta-amyloid (Aβ) deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic perturbations over its lifespan. Male and female 5xFAD and wild type (WT) littermates underwent in vivo 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging at 4, 6, and 12 months of age to assess regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent "vessel painting" which labels all cerebral vessels and were analyzed for vascular characteristics such as vessel density, junction density, vessel length, network complexity, number of collaterals, and vessel diameter. With increasing age, vessels on the cortical surface in both 5xFAD and WT mice showed increased vessel length, vessel and junction densities. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but collateral diameters were significantly increased only in 5xFAD mice. MCA total vessel length and junction density were decreased in 5xFAD mice compared to WT at 4 months. Analysis of 18F-FDG cortical uptake revealed significant differences between WT and 5xFAD mice spanning 4-12 months. Broadly, 5xFAD males had significantly increased 18F-FDG uptake at 12 months compared to WT mice. In most cortical regions, female 5xFAD mice had reduced 18F-FDG uptake compared to WT across their lifespan. While the 5xFAD mouse exhibits AD-like cognitive deficits as early as 4 months of age that are associated with increasing Aβ deposition, we only found significant differences in cortical vascular features in males, not in females. Interestingly, 5xFAD male and female mice exhibited opposite effects in 18F-FDG uptake. The MCA supplies blood to large portions of the somatosensory cortex and portions of motor and visual cortex and increased vessel length alongside decreased collaterals which coincided with higher metabolic rates in 5xFAD mice. Thus, a potential mismatch between metabolic demand and vascular delivery of nutrients in the face of increasing Aβ deposition could contribute to the progressive cognitive deficits seen in the 5xFAD mouse model.

Abstract 13560: System Gene Regulatory Network-Based Drug Repurposing Combined With Preclinical Molecular Imaging Identifies Anti-Atherosclerotic Properties of Auranofin

Introduction: The identification of new treatments for atherosclerosis (ACVD), a common complex disease, is a daunting task because sets of genes, rather than individual genes, control cell functions. Using systems genetics, our team identified gene regulatory network (GRN42) that is active in the human atherosclerotic arterial wall and is involved in the regulation of foam cell formation. Hypothesis: A network-driven drug repurposing approach combined with rigorous preclinical validation will identify new uses for existing drugs to treat ACVD. Methods: We developed a GRN42-based computational drug repurposing pipeline to infer new uses for existing drugs. Selected compounds were screened by measuring their ability to inhibit foam cell formation in vitro using THP-1-derived macrophages. The in vivo efficacy was validated in ApoE-/- mice fed a western diet by histology and in atherosclerotic rabbits using histology and non-invasive 18 F-FDG PET-MR imaging. Results: 30 candidate compounds were predicted to influence the function of GRN42 and 5 were selected for in vitro screening based on their prediction scores (Figure 1A). As expected, vitamin D reduced cholesteryl esters accumulation in foam cells. Auranofin, and FDA-approved drug for rheumatoid arthritis reduced foam cell formation. As predicted methyl-fasudil had no effect, while nicardipine and flutamide increased foam cell formation (Figure 1B). Auranofin reduced plaque burden in ApoE-/- mice (Figure 1C) and in rabbits reduced lipid accumulation (Figure 1D) and inflammation shown as reduced 18 F-FDG uptake in the arterial wall (Figure 1E). Conclusions: Our results provide robust evidence that a GRN-based computational drug repurposing approach, when combined with robust preclinical validation using translational molecular imaging, can successfully identify new uses of existing drugs for the treatment of ACVD.

Relationship between astrocyte reactivity, using novel 11C-BU99008 PET, and glucose metabolism, grey matter volume and amyloid load in cognitively impaired individuals

Post mortem neuropathology suggests that astrocyte reactivity may play a significant role in neurodegeneration in Alzheimer’s disease. We explored this in vivo using multimodal PET and MRI imaging. Twenty subjects (11 older, cognitively impaired patients and 9 age-matched healthy controls) underwent brain scanning using the novel reactive astrocyte PET tracer 11C-BU99008, 18F-FDG and 18F-florbetaben PET, and T1-weighted MRI. Differences between cognitively impaired patients and healthy controls in regional and voxel-wise levels of astrocyte reactivity, glucose metabolism, grey matter volume and amyloid load were explored, and their relationship to each other was assessed using Biological Parametric Mapping (BPM). Amyloid beta (Aβ)-positive patients showed greater 11C-BU99008 uptake compared to controls, except in the temporal lobe, whilst further increased 11C-BU99008 uptake was observed in Mild Cognitive Impairment subjects compared to those with Alzheimer’s disease in the frontal, temporal and cingulate cortices. BPM correlations revealed that regions which showed reduced 11C-BU99008 uptake in Aβ-positive patients compared to controls, such as the temporal lobe, also showed reduced 18F-FDG uptake and grey matter volume, although the correlations with 18F-FDG uptake were not replicated in the ROI analysis. BPM analysis also revealed a regionally-dynamic relationship between astrocyte reactivity and amyloid uptake: increased amyloid load in cortical association areas of the temporal lobe and cingulate cortices was associated with reduced11C-BU99008 uptake, whilst increased amyloid uptake in primary motor and sensory areas (in which amyloid deposition occurs later) was associated with increased11C-BU99008 uptake. These novel observations add to the hypothesis that while astrocyte reactivity may be triggered by early Aβ-deposition, sustained pro-inflammatory astrocyte reactivity with greater amyloid deposition may lead to astrocyte dystrophy and amyloid-associated neuropathology such as grey matter atrophy and glucose hypometabolism, although the evidence for glucose hypometabolism here is less strong.

Synergistic Effect of Phloretin Combined With Radiotherapy on Lung Cancer

The purpose of this study was to investigate the synergistic anti-tumor effects of phloretin and radiotherapy (RT) in a Lewis lung cancer (LLC) xenograft model, and the mechanisms involved.Lewis cells were treated with 0, 25, 50, 100, 150 or 200 μg/ml phloretin, the proliferative rate of Lewis cells treated with phloretin for 12, 24 and 32 h was detected by MTT assay; Clone formation experiments were used to demonstrate the synergistic effect of phloretin and radiotherapy; Mice engrafted with the LLC cells were given intraperitoneal injections of saline, phloretin with or without RT. Tumor models were established by laterally transplanting LLC cells in the right thigh of C57BL/J mice. They were randomly divided into four groups, 12 in each group, namely saline group, phloretin group, radiotherapy group, phloretin combined with radiotherapy group. 10 Gy radiotherapy was performed during the administration; some mice were detected by PET-CT, tumor tissues were subjected to immunohistochemistry, flow apoptosis was detected, and some mice were observed for survival.Different concentrations of phloretin inhibited the proliferation of Lewis cells in a time and dose dependent manner (P < 0.05). The radiotherapy sensitization ratio (SER) of 0.5μg phloretin was 1.645 in the LLC cells. The combination of phloretin and RT increased survival compared to free Phloretin and RT (P < 0.05), and prolonged tumor growth delay (TGD). Furthermore, the RT + phloretin combination therapy significantly reduced 18F-FDG uptake, increased apoptosis and decreased the proliferation index (Ki67) in tumor cells compared to either monotherapy.Phloretin combined with radiotherapy has a synergistic anti-tumor effect, possibly by promoting apoptosis, as well as inhibiting proliferation rate and glucose transport.

Synaptic Damage and Its Clinical Correlates in People With Early Huntington Disease: A PET Study.

Synaptic damage has been proposed to play a major role in the pathophysiology of Huntington disease (HD), but in vivo evidence in humans is lacking. We performed a PET imaging study to assess synaptic damage and its clinical correlates in early HD in vivo. METHODS: In this cross-sectional study, premanifest and early manifest (Shoulson-Fahn stage 1 and 2) HD mutation carriers and age- and sex-matched healthy controls underwent clinical assessment of motor and nonmotor manifestations and time-of-flight PET with 11C-UCB-J, a radioligand targeting the ubiquitous presynaptic terminal marker synaptic vesicle protein 2A (SV2A). We also performed 18F-fluorodeoxyglucose (18F-FDG)-PET in all participants because regional cerebral glucose consumption is thought to largely reflect synaptic activity. Volumes of interest were delineated on the basis of individual 3-dimensional T1 MRI. Standardized uptake value ratio-1 images were calculated for 11C-UCB-J with the centrum semiovale as reference region. 18F-FDG-PET activity was normalized to the pons. All PET data were corrected for partial volume effects. Volume of interest- and voxel-based analyses were performed. Correlations between clinical scores and 11C-UCB-J PET data were calculated. Eighteen HD mutation carriers (age 51.4 ± 11.6 years; 6 female; 7 premanifest, 11 early manifest) and 15 healthy controls (age 52.3 ± 3.5 years; 4 female) were included. In the HD group, significant loss of SV2A binding was found in putamen, caudate, pallidum, cerebellum, parietal, and temporal and frontal cortex, whereas reduced 18F-FDG uptake was restricted to caudate and putamen. In the premanifest subgroup, 11C-UCB-J and 18F-FDG-PET showed significant reductions in putamen and caudate only. In the total HD group, SV2A loss in the putamen correlated with motor impairment. Our data reveal loss of presynaptic terminal integrity in early HD, which begins in the striatum in the premanifest phase, spreads extensively to extrastriatal regions in the early manifest phase, and correlates with motor impairment. 11C-UCB-J PET is more sensitive than 18F-FDG-PET for detection of extrastriatal changes in early HD. This study provides Class III evidence that 11C-UCB-J PET accurately discriminates individuals HD from normal controls.

The Effects of S-Allyl Cysteıne on Inflammatory Cascade in Lipopolysaccharide Induced Rat Sepsis Model

Lipopolysaccharide (LPS) is a main constituent of Gram-negative bacterial cell walls and is considered a leading cause of sepsis. S-allyl cysteine (SAC) is a water-soluble organosulfur component present in garlic which has a potent antioxidant and free radical scavenger activity. The purpose of this study is to examine the antioxidant and anti-inflammatory potential of SAC on endotoxin LPS-induced sepsis. Female Wistar albino rats were divided into 6 groups. LPS (5 mg/kg) was applied to rats in sepsis and treatment groups intraperitoneally. After 24 hours from LPS injection 50 mg/kg and 100 mg/kg SAC was orally administrated to treatment groups. Lung and liver 18F-fluoro-deoxy-D-glucose (18F-FDG) uptake was measured by 18FDG-PET scan. Serum levels of nuclear factor-kappa B (NF-κβ), tumor necrosis factor-alpha (TNF-α), matrix metalloproteinase-9 (MMP-9), plasma levels of interleukin-1β (IL-1β), IL-6 and tissue levels of oxidative stress markers catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) were determined. As a result of the study, MDA and NO levels of sepsis group were significantly higher than treatment groups in lung tissue. SOD activities of sepsis group was determined to significantly lower in the liver and lung tissues than the groups which were treated with SAC. Likewise, it was concluded that serum MMP-9, TNF-α and NF-κβ levels of sepsis group was significantly higher compared to levels of treatment groups. It was determined that SAC administration reduced 18F-FDG uptake in septic rats. In conclusion, SAC was observed to diminish effects of the acute toxicity and oxidative stress formed with LPS.

Premotor and fronto-striatal mechanisms associated with presence hallucinations in dementia with Lewy bodies

Introductionpresence hallucinations (PH) are frequent in dementia with Lewy bodies (DLB), but their cortico-subcortical origin is unknown. Recent studies have defined key frontal and temporal areas contributing to the occurrence of PH (PH-network) and tested their relevance in subjects with Parkinson’s disease (PD). With the present study, we aimed at disentangling the metabolic and dopaminergic correlates of pH as well as their relation to a recently defined PH brain network in DLB. Methodsfor the present study, we included 34 DLB subjects (10 with PH (PH + ); 24 without PH (PH-)), who underwent 18F-FDG PET and 123I-FP-CIT SPECT imaging. We performed 18F-FDG PET group comparisons, as well as interregional correlation analyses using 18F-FDG PH-network regions as a seed. ResultsPH + versus PH- had reduced 18F-FDG uptake in precentral, superior frontal and parietal gyri, involving ventral premotor cortex (vPMC) of the PH-network that showed strongly reduced functional connectivity with bilateral cortical regions. 18F-FDG vPMC uptake was negatively correlated with caudate 123I-FP-CIT uptake in PH+ (p = 0.028) and interregional correlation analysis seeding from the vPMC showed widespread fronto-parietal 18F-FDG decreases in PH + . Discussionthese findings uncover the pivotal role of vPMC (involved in a PH-network) and its cortico-striatal connections in association with PH in DLB, improving our understanding of psychosis in neurodegeneration.

Differentiation of acute myeloid leukemia (AML) cells with ATRA reduces 18F-FDG uptake and increases sensitivity towards ABT-737-induced apoptosis

Acute myeloid leukemia (AML) is a malignant disease of the bone marrow, comprising various subtypes. We have investigated seven different AML cell lines that showed different sensitivities toward the inducer of apoptosis ABT-737, with IC50 concentrations ranging from 9.9 nM to 1.8 µM. Besides, the AML cell lines revealed distinct differences in 18F-FDG uptake ranging from 4.1 to 11.0%. Moreover, the Pearson coefficient (0.363) suggests a moderate correlation between 18F-FDG uptake and the IC50 values of ABT-737. Differentiation of the AML cell lines NB-4 and AML-193 with all-trans-retinoic-acid (ATRA) induced a significant increase in sensitivity towards ABT-737 along with a reduced uptake of 18F-FDG. Therefore, 18F-FDG uptake could be predictive on sensitivity to treatment with ABT-737. Furthermore, because differentiation treatment of AML cells using ATRA reduced 18F-FDG uptake and increased sensitivity towards ABT-737, a combined treatment regimen with ATRA and ABT-737 might be a promising therapeutic option in the future.

Delayed effects of a single-dose whole-brain radiation therapy on glucose metabolism and myelin density: a longitudinal PET study

Purpose Radiotherapy is an important treatment option for brain tumors, but the unavoidable irradiation of normal brain tissue can lead to delayed cognitive impairment. The mechanisms involved are still not well explained and, therefore, new tools to investigate the processes leading to the delayed symptoms of brain irradiation are warranted. In this study, positron emission tomography (PET) is used to explore delayed functional changes induced by brain irradiation. Materials and methods Male Wistar rats were subjected to a single 25-Gy dose of whole brain X-ray irradiation, or sham-irradiation. To investigate delayed effects of radiation on cerebral glucose metabolism and myelin density, 18F-fluorodeoxyglucose (18F-FDG) PET scans were performed at baseline and on day 64 and 94, whereas N-11C-methyl-4,4′-diaminostilbene (11C-MeDAS) PET scans were performed at baseline and on day 60 and 90 post-irradiation. In addition, the open field test (OFT) and novel spatial recognition (NSR) test were performed at baseline and on days 59 and 89 to investigate whether whole brain irradiation induces behavioral changes. Results Whole-brain irradiation caused loss of bodyweight and delayed cerebral hypometabolism, with 18F-FDG uptake in all brain regions being significantly decreased in irradiated rat on day 64 while it remained unchanged in control animals. Only amygdala and cortical brain regions of irradiated rats still showed reduced 18F-FDG uptake on day 94. 11C-MeDAS uptake in control animals was significantly lower on days 60 and 90 than at the baseline, suggesting a reduction in myelin density in young adults. In irradiated animals, 11C-MeDAS uptake was similarly reduced on day 60, but on day 90 tracer uptake was somewhat increased and not significantly different from baseline anymore. Behavioral tests showed a similar pattern in control and irradiated animals. In both groups, the OFT showed significantly reduced mobility on days 59 and 89, whereas the NSR did not reveal any significant changes in spatial memory over time. Interestingly, a positive correlation between the NSR and 11C-MeDAS uptake was observed in irradiated rats. Conclusions Whole-brain irradiation causes delayed brain hypometabolism, which is not accompanied by white matter loss. Irradiated animals showed similar behavioral changes over time as control animals and, therefore, cerebral hypometabolism could not be linked to behavioral abnormalities. However, spatial memory seems to be associated with myelin density in irradiated rats.

Environmental Tobacco Smoke During the Early Postnatal Period of Mice Interferes With Brain 18 F-FDG Uptake From Infancy to Early Adulthood - A Longitudinal Study.

Exposure to environmental tobacco smoke (ETS) is associated with high morbidity and mortality, mainly in childhood. Our aim was to evaluate the effects of postnatal ETS exposure in the brain 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) uptake of mice by positron emission tomography (PET) neuroimaging in a longitudinal study. C57BL/6J mice were exposed to ETS that was generated from 3R4F cigarettes from postnatal day 3 (P3) to P14. PET analyses were performed in male and female mice during infancy (P15), adolescence (P35), and adulthood (P65). We observed that ETS exposure decreased 18F-FDG uptake in the whole brain, both left and right hemispheres, and frontal cortex in both male and female infant mice, while female infant mice exposed to ETS showed decreased 18F-FDG uptake in the cerebellum. In addition, all mice showed reduced 18F-FDG uptake in infancy, compared to adulthood in all analyzed VOIs. In adulthood, ETS exposure during the early postnatal period decreased brain 18F-FDG uptake in adult male mice in the cortex, striatum, hippocampus, cingulate cortex, and thalamus when compared to control group. ETS induced an increase in 18F-FDG uptake in adult female mice when compared to control group in the brainstem and cingulate cortex. Moreover, male ETS-exposed animals showed decreased 18F-FDG uptake when compared to female ETS-exposed in the whole brain, brainstem, cortex, left amygdala, striatum, hippocampus, cingulate cortex, basal forebrain and septum, thalamus, hypothalamus, and midbrain. The present study shows that several brain regions are vulnerable to ETS exposure during the early postnatal period and these effects on 18F-FDG uptake are observed even a long time after the last exposure. This study corroborates our previous findings, strengthening the idea that exposure to tobacco smoke in a critical period interferes with brain development of mice from late infancy to early adulthood.

Assessing oral glucose and intravenous insulin loading protocol in 18F-fluorodeoxyglucose positron emission tomography cardiac viability studies.

Oral glucose and intravenous insulin (G/I) loading protocols are commonly used in 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) cardiac viability studies. Although the amount of insulin to be given per blood glucose range has been well described in guidelines, the amount of glucose to be given is not detailed well. In this retrospective study, we aimed to assess if certain parameters, particularly the amount of glucose and insulin given, may affect 18F-FDG uptake in the hibernating myocardium and also determine the problems with this protocol. 18F-FDG PET cardiac viability study with G/I loading protocols was performed in 49 patients. Fasting blood glucose (FBG), amount of glucose given, blood glucose level after glucose load, amount of insulin given, and blood glucose level at the time of 18F-FDG injection were recorded. Statistical analysis was performed to determine if there is any difference in the above values in PET viable and PET nonviable groups and also in subgroups assessing 18F-FDG uptake also in normal myocardium. For G/I loading, we used our local protocol in 43 patients, and other protocols in six. 18F-FDG PET showed viability in 31 patients, and it was negative for viability in 18. In 22 patients, mainly in PET viable group, there was varying degree of reduced 18F-FDG uptake in normal myocardium. There was no significant difference in FBG, amount of glucose given, blood glucose level after glucose load, amount of insulin given, and blood glucose level at the time of 18F-FDG injection in PET viable and PET nonviable groups and also in subgroups. The problems with G/I loading protocol included deciding on the amounts of glucose and insulin given, maximum amount of insulin to be given, handling diabetics, optimal time to measure blood glucose after insulin administration, and interpretation of findings in cases with diffusely reduced 18F-FDG uptake. Further improvements in current guidelines are necessary to obtain images in optimal conditions for accurate results.

Synergistic effect and reduced toxicity by intratumoral injection of cytarabine-loaded hyaluronic acid hydrogel conjugates combined with radiotherapy on lung cancer.

The aim of this study was to explore the synergistic anti-tumor effects of cytarabine hyaluronic acid-tyramine (Ara-HA-Tyr) hydrogel conjugates and radiotherapy (RT) in the Lewis lung cancer (LLC) xenograft model, and the mechanisms involved. The radiotherapy sensitization ratio (SER) of 0.5μg cytarabine (Ara-C) was 1.619 in the LLC cells. Ara-HA-Tyr was prepared by encapsulating Ara-C into hyaluronic acid-tyramine (HA-Tyr) conjugates. The hydrogels were formed through the oxidative coupling of tyramines by hydrogen peroxide (H2O2) and horseradish peroxidase (HRP). Mice engrafted with the LLC cells were given intra-tumoral injections of saline, Ara-C or Ara-HA-Tyr, with or without RT. The combination of Ara-HA-Tyr and RT increased survival compared to free Ara-C and RT (p < 0.05), and prolonged tumor growth delay (TGD). Furthermore, the RT + Ara-HA-Tyr combination therapy significantly reduced 18F-FDG uptake, induced cell cycle arrest at G2/M-phase, increased apoptosis and histone H2AX phosphorylation (γ-H2AX), and decreased the proliferation index (Ki67) in tumor cells compared to either monotherapy. Taken together, Ara-C encapsulated with HA-Tyr effectively sensitized tumor xenografts to RT and showed significantly less systemic toxicity. Graphical abstract In this work, Ara-C encapsulated with hyaluronic acid-tyramine conjugates (HA-Tyr) was prepared and used to investigate its synergistic anti-tumor efficacy by combination with radiotherapy in the Lewis lung cancer xenograft model. The synergistic mechanism may be related to tumor cell cycle redistribution, apoptosis and expression of histone H2AX phosphorylation.

Enhanced intestinal 2-deoxy-2-[18F]fluoro-D-glucose uptake under metformin is not fully suppressed by loperamide.

This study investigated whether the metformin (Met)-induced enhanced intestinal uptake of 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) is reduced by loperamide, a long-acting anti-diarrheal agent. Mean 18F-FDG uptake in the mouse small intestine and colon with Met exposure was compared with that in control mice. In the Met group, high-dose (1.0 mg/kg body weight) and low-dose (0.1 mg/kg body weight) loperamide were introduced, and 18F-FDG uptake in the small intestine and colon was compared with that of control mice administered high-dose loperamide. The percent injected dose of 18F-FDG per gram of tissue (%ID/g) in the extracted tissues was then determined. 18F-FDG uptake increased significantly in the small intestine (0.64±0.06 vs. 1.01±0.15, p=0.040) and, especially, the colon (0.46±0.13 vs. 2.16±0.51, p<0.001) after Met exposure. Neither high-dose nor low-dose loperamide significantly reduced 18F-FDG uptake in the small intestine (0.82±0.31 vs. 0.84±0.22, p=0.93 and 0.78±0.25 vs. 0.70±0.15, p=0.13, respectively) or colon (2.13±0.41 vs. 1.67±0.55, p=0.063 and 1.77±0.39 vs. 1.80±0.25, p=0.56, respectively). The colonic %ID/g was significantly higher in Met groups irrespective of loperamide introduction than in control group, whereas the significant difference in the small intestine was observed only between Met and control groups. Metformin increased 18F-FDG uptake in intestines especially in colon. Loperamide administration partially, but not sufficiently, suppresses the Met-induced increased colonic uptake of 18F-FDG.

Regional Myocardial Perfusion Disturbance in Experimental Chronic Chagas Cardiomyopathy.

Altered myocardial perfusion is a common finding in chronic Chagas cardiomyopathy (CCC), but its underlying histologic changes have not been elucidated. We investigated the occurrence of myocardial perfusion defects (MPDs) and the correlated regional changes to histology in an experimental model of CCC in hamsters. Methods: Female Syrian hamsters (n = 34) were infected with 3.5 × 104 to 105 trypomastigote forms of Trypanosoma cruzi, Y strain, and 6-10 mo afterward underwent in vivo imaging including resting 99mTc-sestamibi SPECT, segmental and global left ventricular function assessment using 2-dimensional echocardiography, and 18F-FDG PET for evaluation of myocardial viability. Histologic analysis included quantification of fibrosis, inflammatory infiltration, and the diameter and density of myocardial microcirculation. Results: MPDs were present in 17 (50%) of the infected animals. Histologic analysis revealed no transmural scar in segments with an MPD, and normal or mildly reduced 18F-FDG uptake, indicating viable myocardium. Infected animals with an MPD, in comparison to infected animals without an MPD and control animals, showed a lower left ventricular ejection fraction (P = 0.012), a higher wall motion score index (P = 0.004), and a higher extent of inflammatory infiltration (P = 0.018) but a similar extent of fibrosis (P = 0.15) and similar microvascular diameter and density (P > 0.05). Segments with an MPD (n = 65), as compared with normally perfused regions in the same animal (n = 156), showed a higher wall motion score index (P = 0.005) but a similar extent of inflammatory infiltration, a similar extent of fibrosis, and a similar microvascular diameter and density. Conclusion: Resting MPDs are frequent in experimental CCC and are associated with myocardial inflammation but do not designate scar tissue, corresponding to regions with metabolically viable myocardium.

The use of 18F-Fluoro-deoxy-glucose positron emission tomography (18F-FDG PET) as a non-invasive pharmacodynamic biomarker to determine the minimally pharmacologically active dose of AZD8835, a novel PI3Kα inhibitor.

BackgroundThe phosphatidyl inositol 3 kinase (PI3K), AKT and mammalian target of rapamycin (mTOR) signal transduction pathway is frequently de-regulated and activated in human cancer and is an important therapeutic target. AZD8835 is a PI3K inhibitor, with selectivity against PI3K α and δ isoforms, which is currently in Phase 1 clinical trials. 18F-Fluoro-deoxy-glucose positron emission tomography (18F-FDG PET) is a non-invasive pharmacodynamic imaging biomarker that has become an integral part of drug development. It has been used widely with PI3K inhibitors both clinically and pre-clinically because of the role of the PI3K pathway in glucose metabolism. In this study we investigated the potential of 18F-FDG PET as a non-invasive pharmacodynamic biomarker for AZD8835. We sought to understand if 18F-FDG PET could determine the minimally effective dose of AZD8835 and correlate with other pharmacodynamic biomarkers for validation of its use in clinical development. 18F-FDG PET scans were performed in nude mice in the BT474C breast xenograft model. Mice were fasted prior to imaging and static 18F-FDG PET was performed. Treatment groups received AZD8835 by oral gavage at a dose volume of 10ml/kg. Treatment groups received either 3, 6, 12.5, 25 or 50mg/kg AZD8835. Tumour growth was monitored throughout the study, and at the end of the imaging procedure, tumours were taken and a full pharmacodynamic analysis was performed.ResultsResults showed that AZD8835 reduced 18F-FDG uptake at a dose of 12.5, 25 and 50mg/kg with no significant reduction at doses of 3 and 6mg/kg. These results were consistent with other pharmacodynamics biomarkers measured and show 18F-FDG PET as a sensitive biomarker with the ability to determine the minimal effective dose of AZD8835.ConclusionsOur pre-clinical studies support the use of 18F-FDG PET imaging as a sensitive and non- invasive pharmacodynamic biomarker (understanding the role of PI3K signalling in glucose uptake) for AZD8835 with a decrease in 18F-FDG uptake observed at only two hours post treatment. The decrease in 18F-FDG uptake was dose dependent and data showed excellent PK/PD correlation. This data supports and parallels observations obtained with this class of compounds in patients

The effect of PPAR-γ agonist on 18F-FDG PET imaging for differentiating tumors and inflammation lesions

Introduction18F-2-deoxy-2-fluoro-d-glucose (18F-FDG) positron emission tomography (PET) has been used for imaging human cancers for several decades. Despite its extensive use, 18F-FDG PET imaging has limitations in the tumor findings. The goal of this study was to investigate the potential of a PPAR-γ agonist pioglitazone (PIO) to distinguish tumors and inflammatory lesions in 18F-FDG PET imaging. MethodsStudies of cellular uptake of 18F-FDG and Western blot were performed in macrophage (RAW264.7) and three tumor cell lines (A549, KB, and MDA-MB-231) after treatment with PIO. In vivo microPET/CT imaging and biodistribution were performed in animal models. ResultsThe uptake of 18F-FDG in the macrophages was decreased and uptake of 18F-FDG in the tumor cells was increased when these cells were treated with PIO. Western blot showed that the expression of Glut1 was reduced by treatment of PIO in the macrophage cells, whereas the expression of Glut1 in the tumor cells was increased. In vivo PET/CT imaging revealed that 18F-FDG uptake (%ID/g) in the tumors was enhanced from 4.05±1.46 to 5.28±1.92 for A549, from 3.9±0.5 to 4.9±0.2 for KB, and from 9.14±0.86 to 13.48±2.07 for MDA-MB-231 tumors after treatment with PIO. Unlike tumors, the RAW264.7 xenograft model showed the reduced 18F-FDG uptake in the inflammatory lesion from 11.74±1.19 to 6.50±1.47. The results of biodistribution also showed that 18F-FDG uptake in the tumors were increased after treatment of PIO. However, the uptake of inflammation lesions was reduced. ConclusionsIn this study, we demonstrated the effect of a PPAR-γ agonist PIO on 18F-FDG uptake in tumors and inflammation in vitro and in vivo. PIO has potential to differentiate tumors and inflammatory lesions on 18F-FDG PET imaging.

Evaluation of 18F-FDG and 18F-FLT for monitoring therapeutic responses of colorectal cancer cells to radiotherapy

In order to compare the efficacy of 18F-fluorothymidine (FLT) and 18F-fluorodeoxyglucose (FDG) for monitoring early responses to irradiation, two human colorectal cancer (CRC) cell lines SW480 and SW620, which were derived from the primary lesions and the metastatic lymph node, underwent X-ray irradiation of 0, 10, or 20Gy and were examined at 0, 24 and 72h After irradiation, reduced proliferation of both SW480 and SW620 cells was observed in a dose-dependent manner (P<0.001), G0-G1 arrest was also noted in both cell types after 72h in the 20Gy group (P<0.001). Although increased apoptosis was observed in both cell lines after irradiation (P<0.001), a greater percentage of SW480 cells underwent apoptosis in response to irradiation than SW620 cells. Increased Hsp27 and decreased integrin β3, Ki67 and VEGFR2 expression was observed over time via immunocytochemistry and Western blot analysis (P<0.001), however, no significant changes were noted in response to irradiation. Finally, reduced uptake of 18F-FLT by SW480 or SW620 cells was observed at 24-h post-irradiation, however, reduced 18F-FDG uptake was only observed after 72h. Therefore, we conclude that 18F-FLT is a more suitable positron emission tomography (PET) tracer for monitoring early responses to irradiation in primary and metastatic lymph node CRC cells.

Abstract 5426: Severe hypoxia drives the increased glucose demand in ascites carcinomas.

Abstract Warburg reported his discovery in Ehrlich ascites carcinoma model, that in the presence of ample oxygen (21% or 150 mmHg O2), cancer cells utilize glucose by “aerobic glycolysis” (Warburg effect), apparently, ascites carcinoma had been assumed to be oxic. However, during past decade, growing evidences indicated that hypoxic cancer cells had evaluated radiolabeled glucose analog18F-FDG uptake than oxic cancer cell in vitro and in vivo. The objective of this study was to observe the oxygen status of ascites fluid and ascites carcinoma in mouse model of ascites carcinoma and its effect on glucose metabolism. Methods: Ascites carcinoma (floating single cells or clusters) and serosa tumors (attached to serosa) were induced by HT29, A549 or MDA-MB-231 cancer cells in the mouse peritoneal cavity. Ascites pO2 was measured using OxyLite systems in ketamine/xylazene anesthetized mice. Hypoxia status in ascites carcinoma and serosa tumors was tested by immunohistochemical visualization of exogenous hypoxia marker pimonidazole binding and HIF1alpha induced glucose transporter-1 expression. Glucose metabolism of was examine by 18F-FDG autoradiography. Effect of carbogen breathing (95% O2 &amp; 5% CO2) on 18F-FDG uptake was investigated. Results: The pO2 of ascites was measured as low as 0.90mmHg (or 0.5% O2) in mice with HT29 ascites carcinomas. In all cell lines we tested, ascites carcinomas was evident 4-6 wk after cell inoculation, all ascites tumors were stained positive for pimonidazole and glucose transporter-1 (GLUT-1), indicating severe hypoxia. Hypoxia status in serosa tumors was heterogeneous and dependent on tumor size. 18F-FDG uptake was significantly higher in ascites and sub-millimeter serosa tumors than in larger ones (generally greater than 1 mm), the former was stained positive for pimonidazole and GLUT-1, but the latter was not. Carbogen breathing (2hrs) significantly reduced 18F-FDG uptake and pimonidazole binding in ascites carcinoma and submillimeter serosa tumors. GLUT1 expression was not affected. Conclusions: In mouse model of ascites carcinoma, ascites and floating ascites carcinoma are severely hypoxic which is in contradict with ample oxygen condition of Ehrlich ascites carcinoma model where “Warburg effect” derived from. Glucose utilization measured by 18F-FDG uptake is oxygen dependent in both ascites carcinoma and serosa tumors, this is unexplained sole by “aerobic glycolysis” of glucose metabolism, thus challenging Warburg effect theory. This study was supported by Kentucky Lung Cancer Research Program Award Citation Format: Xiao-Feng Li. Severe hypoxia drives the increased glucose demand in ascites carcinomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5426. doi:10.1158/1538-7445.AM2013-5426

MicroPET imaging of noxious thermal stimuli in the conscious rat brain

Small animal positron emission tomography (microPET) has been utilized in the investigation of nociception. However, a possible drawback from previous studies is the reduced activation pattern due to the application of anesthesia. The purpose of the present study was to demonstrate a potential means of avoiding anesthesia during stimulation, as well as minimizing the confounding anesthetic effect. Sodium pentobarbital and ketamine were first evaluated to determine their effect on microPET images in the current study. [18F]-Fluorodeoxyglucose (18F-FDG) was an appropriate radiotracer to reveal activated regions in rat brains. Pentobarbital anesthesia significantly reduced 18F-FDG uptake in neural tissues, blurrier to lower contrast; therefore, ketamine was used to anesthetize animals during microPET. After the rats were anesthetized and secured in a laboratory-made stereotaxic frame, a simple, noninvasive stereotaxic technique was used to position their heads in the microPET scanner and to roughly conform the images in the stereotaxic atlas. For functional imaging, conscious rats were restrained in cages with minimal ambient noise; short repetitive thermal stimuli were applied to each rat's tail subsequently. The rats were adequately anesthetized with ketamine following 30 min of scanning without stimulation. An activation index (AI) was calculated from microPET data to quantify the local metabolic activity changes according to the normalized 18F-FDG dosage. The average AI indicated a side-to-side difference for all innocuous stimulations in the thalamus. However, such side-to-side difference was only observed for noxious heat and cold stimulations in primary somatosensory cortex (SI), secondary somatosensory cortex (SII), and agranular insular cortex (AIC). The present study demonstrated the feasibility of the microPET technique to image metabolic functions of the conscious rat brain, offering better rationale and protocol designs for future pain studies.