Reference Tissue Models for FDG-PET Data: Identifiability and Solvability

Scussolini, Mara; Garbarino, Sara; Piana, Michele; Sambuceti, Gianmario; Caviglia, Giacomo

doi:10.1109/trpms.2018.2801029

Cited by 10 publications

(14 citation statements)

References 25 publications

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“…The results provided by the application of BCM need for further investigations. In fact, the basic scheme of this approach is rather flexible and may be modified to allow for consideration of peculiarities of specific organs, as done for classical models in (Garbarino et al, 2014, 2015), may be associated with reference tissue formulations (see (Scussolini et al, 2018) and references cited therein), or to pixel-wise analysis (see (Scussolini et al, 2017) and references cited therein).…”

Section: Discussionmentioning

confidence: 99%

“…In order to solve it, our approach followed a regularized Newton-type method (Bauer et al, 2009; Delbary and Garbarino, 2016), already validated and applied successfully in other compartmental problems, e.g. models for complex physiologies (Garbarino et al, 2014, 2015), parametric imaging (Scussolini et al, 2017), and reference tissue approaches (Scussolini et al, 2018). The algorithm is denoted as reg-GN in the following.…”

Section: The Compartmental Modelmentioning

confidence: 99%

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The role of the endoplasmic reticulum in in vivo cancer FDG kinetics

Scussolini

Cossu

Marini

et al. 2019

Preprint

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2A very recent result obtained by means of an in vitro experiment with cancer cultured cells 3 has configured the endoplasmic reticulum as the preferential site for the accumulation of 2-4 deoxy-2-[ 18 F]fluoro-D-glucose (FDG). Such a result is coherent with cell biochemistry and is 5 made more significant by the fact that reticular accumulation rate of FDG is dependent upon 6 extracellular glucose availability. The objective of the present paper was to confirm this result 7 in vivo, using small animal models of CT26 cancer tissues. Specifically, assuming that the 8 endoplasmic reticulum plays a specific functional role in the framework of a three-compartment 9 model for FDG kinetics, we are able to explain positron emission tomography dynamic data in a 10 more reliable way than by means of a standard Sokoloff two-compartment system. This result is 11 made more solid from a computational viewpoint by means of some identifiability considerations 12 based on a mathematical analysis of the compartmental equations. 13 Keywords: cancer glucose metabolism, endoplasmic reticulum, in vivo models, FDG kinetics, compartmental analysis 14 1 INTRODUCTION 2-deoxy-2-[ 18 F]fluoro-D-glucose (FDG) is widely used as a glucose analogue tracer to evaluate glucose 15 metabolism in living organisms. As glucose, FDG is first transported into cells, where it is phosphorylated 16to FDG-6-phosphate (FDG6P) by hexokinase (HK) and then accumulates intracellularly. The measured 17 amount of emitted radiation is considered an accurate marker of overall glucose uptake by cells and tissues 18 (Cherry et al., 2012). In addition, FDG consumption by cancer cells is increased by the Warburg effect for 19 glucose (Vander et al., 2009); consequently, FDG may be employed in cancer detection and staging, and to 20 determine the effectiveness of medical treatments (Cairns et al., 2011). 21A recent result concerning the characterization of FDG kinetics in cultured cancer cells (Scussolini et 22 al., 2019) showed that the endoplasmic reticulum (ER) is the preferential site of FDG accumulation and 23 that, even more importantly, FDG reticular accumulation rate is dependent upon extracellular glucose 24 availability. This result is coherent with recent progress in cell biochemistry, which clarified that the 25 glucose-6-phosphatase (G6Pase), responsible for the dephosphorylation, is compartmentalized within the 26 endoplasmic reticulum (ER) (Ghosh et al., 2002; Marini et al., 2016). 27 1 Scussolini et al. The role of the endoplasmic reticulum The investigation in (Scussolini et al., 2019) relied on two methodological tools, one experimental 28 and one computational. In fact, on the one hand, FDG kinetics in cells cultured over a Petri dish, was 29 evaluated using the dedicated Ligand Tracer device (Björke and Andersson, 2006), which is able to count 30 electron/positron events without contaminating the counting rate of the cultured cells. On the other hand, 31 the data analysis was performed within the framework of a novel compartmental model, which extend...

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Section: Discussionmentioning

confidence: 99%

Section: The Compartmental Modelmentioning

confidence: 99%

The role of the endoplasmic reticulum in in vivo cancer FDG kinetics

Scussolini

Cossu

Marini

et al. 2019

Preprint

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“…However, it also considers FDG6P transport though the ER membrane (defined as k 5 ) as the needed step for tracer access to G6Pase-catalyzed hydrolysis and back-diffusion to the cytosol (defined as k 6 ) facilitated by the high abundance of GLUTs in ER membrane. The inverse problem of compartmental analysis was solved by means of a Newton-type iterative algorithm, already used and validated by our group [[31], [32], [33], [34], [35]].…”

Section: Methodsmentioning

confidence: 99%

FDG uptake tracks the oxidative damage in diabetic skeletal muscle: An experimental study

Bauckneht

Cossu

Castellani

et al. 2020

Molecular Metabolism

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ObjectivesThe present study aims to verify the relationship between glucose consumption and uptake of 18F-2-deoxy-glucose (FDG) in the skeletal muscle (SM) of experimental models of streptozotocin-induced diabetes mellitus (STZ-DM).MethodsThe study included 36 Balb/c mice. Two weeks after intraperitoneal administration of saline (control group, n = 18) or 150 mg streptozotocin (STZ-DM group, n = 18), the two cohorts were submitted to an oral glucose tolerance test and were further subdivided into three groups (n = 6 each): untreated and treated with metformin (MTF) at low or high doses (10 or 750 mg/kg daily, respectively). Two weeks thereafter, all mice were submitted to dynamic micro–positron emission tomography (PET) imaging after prolonged fasting. After sacrifice, enzymatic pathways and response to oxidative stress were evaluated in harvested SM.ResultsOn PET imaging, the FDG uptake rate in hindlimb SM was significantly lower in nondiabetic mice as compared with STZ-DM–untreated mice. MTF had no significant effect on SM FDG uptake in untreated mice; however, its high dose induced a significant decrease in STZ-DM animals. Upon conventional analysis, the SM standard uptake value was higher in STZ-DM mice, while MTF was virtually ineffective in either control or STZ-DM models. This metabolic reprogramming was not explained by any change in cytosolic glucose metabolism. By contrast, it closely agreed with the catalytic function of hexose-6P-dehydrogenase (H6PD; i.e., the trigger of a specific pentose phosphate pathway selectively located within the endoplasmic reticulum). In agreement with this role, the H6PD enzymatic response to both STZ-DM and MTF matched the activation of the NADPH-dependent antioxidant responses to the increased generation of reactive oxygen species caused by chronic hyperglycemia. Ex vivo analysis of tracer kinetics confirmed that the enhanced SM avidity for FDG occurred despite a significant reduction in glucose consumption, while it was associated with increased radioactivity transfer to the endoplasmic reticulum.ConclusionsThese data challenge the current dogma linking FDG uptake to the glycolytic rate. They instead introduce a new model considering a strict link between the uptake of this glucose analog, H6PD reticular activity, and oxidative damage in diabetes, at least under fasting condition.

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“…The numerical reduction of both models has been performed by means of a regularized Newton-type method [23,24], already validated and applied successfully in other compartmental problems, e.g. in the modeling of complex physiologies [25,26], in parametric imaging [27], and in reference tissue approaches [28]. The algorithm is denoted as reg-GN in the following.…”

Section: Image Analysismentioning

confidence: 99%

The role of endoplasmic reticulum in in vivo cancer FDG kinetics

et al. 2021

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A recent result obtained by means of an in vitro experiment with cancer cultured cells has configured the endoplasmic reticulum as the preferential site for the accumulation of 2-deoxy-2-[18F]fluoro-D-glucose (FDG). Such a result is coherent with cell biochemistry and is made more significant by the fact that the reticular accumulation rate of FDG is dependent upon extracellular glucose availability. The objective of the present paper is to confirm in vivo the result obtained in vitro concerning the crucial role played by the endoplasmic reticulum in FDG cancer metabolism. This study utilizes data acquired by means of a Positron Emission Tomography scanner for small animals in the case of CT26 models of cancer tissues. The recorded concentration images are interpreted within the framework of a three-compartment model for FDG kinetics, which explicitly assumes that the endoplasmic reticulum is the dephosphorylation site for FDG in cancer cells. The numerical reduction of the compartmental model is performed by means of a regularized Gauss-Newton algorithm for numerical optimization. This analysis shows that the proposed three-compartment model equals the performance of a standard Sokoloff’s two-compartment system in fitting the data. However, it provides estimates of some of the parameters, such as the phosphorylation rate of FDG, more consistent with prior biochemical information. These results are made more solid from a computational viewpoint by proving the identifiability and by performing a sensitivity analysis of the proposed compartment model.

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Reference Tissue Models for FDG-PET Data: Identifiability and Solvability

Cited by 10 publications

References 25 publications

The role of the endoplasmic reticulum in in vivo cancer FDG kinetics

The role of the endoplasmic reticulum in in vivo cancer FDG kinetics

FDG uptake tracks the oxidative damage in diabetic skeletal muscle: An experimental study

The role of endoplasmic reticulum in in vivo cancer FDG kinetics

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