Repeatable Noninvasive Measurement of Mouse Myocardial Glucose Uptake with ¹⁸F-FDG: Evaluation of Tracer Kinetics in a Type 1 Diabetes Model

Abstract

A noninvasive and repeatable method for assessing mouse myocardial glucose uptake with 18 F-FDG PET and Patlak kinetic analysis was systematically assessed using the vena cava imagederived blood input function (IDIF). Methods: Contrast CT and computer modeling was used to determine the vena cava recovery coefficient. Vena cava IDIF (n 5 7) was compared with the left ventricular cavity IDIF, with blood and liver activity measured ex vivo at 60 min. The test-retest repeatability (n 5 9) of Patlak influx constant K i at 10-40 min was assessed quantitatively using BlandAltman analysis. Myocardial glucose uptake rates (rMGU) using the vena cava IDIF were calculated at baseline (n 5 8), after induction of type 1 diabetes (streptozotocin [50 mg/kg] intraperitoneally, 5 d), and after acute insulin stimulation (0.08 mU/kg of body weight intraperitoneally). These changes were analyzed with a standardized uptake value calculation at 20 and 40 min after injection to correlate to the Patlak time interval. Results: The proximal mouse vena cava diameter was 2.54 6 0.30 mm. The estimated recovery coefficient, calculated using nonlinear image reconstruction, decreased from 0.76 initially (time 0 to peak activity) to 0.61 for the duration of the scan. There was a 17% difference in the image-derived vena cava blood activity at 60 min, compared with the ex vivo blood activity measured in the g-counter. The coefficient of variability for Patlak K i values between mice was found to be 23% with the proposed method, compared with 51% when using the left ventricular cavity IDIF (P , 0.05). No significant bias in K i was found between repeated scans with a coefficient of repeatability of 0.16 mL/min/g. Calculated rMGU values were reduced by 60% in type 1 diabetic mice from baseline scans (P , 0.03, ANOVA), with a subsequent increase of 40% to a level not significantly different from baseline after acute insulin treatment. These results were confirmed with a standardized uptake value measured at 20 and 40 min. Conclusion: The mouse vena cava IDIF provides repeatable assessment of the blood time-activity curve for Patlak kinetic modeling of rMGU. An expected significant reduction in myocardial glucose uptake was demonstrated in a type 1 diabetic mouse model, with significant recovery after acute insulin treatment, using a mouse vena cava IDIF approach.

In vivo PET imaging with [18F]FDG to explain improved glucose uptake in an apolipoprotein A-I treated mouse model of diabetes

“…To gain further insight into the impact of apoA-I treatment on glucose uptake and metabolism in skeletal muscle, we used kinetic analysis to model the uptake of [ 18 F]FDG from the plasma into the muscle. Rather than collecting numerous arterial blood samples during the PET study, which is impractical due to the small blood volume of mice, we derived the model input function from the reconstructed image data using an ROI over the vena cava [30]. To ensure the robustness of our variable estimates, PET images were deconvolved to limit partial volume effects [16] and the dispersion of the input function was included as a fit variable during kinetic modelling.…”

Impact of Image-Derived Input Function and Fit Time Intervals on Patlak Quantification of Myocardial Glucose Uptake in Mice

“…The automated fit considers all 32 points of the curve at equal weighting, generating a linear line of best fit from the earliest aligned time point and excluding points outside of 20% variance to this fit, irrespective of timing. The rate of myocardial glucose uptake (rMGU) was calculated as K i · (BG/LC), where K i is the graphically defined Patlak slope, BG is the average blood glucose concentration at the start and end of the scan, and LC is the lumped constant equaling 0.67 as estimated for rodents (4). Patlak values were compared with sequential semiquantitative myocardial 18 F-FDG uptake (percentage injected dose per gram [%ID/g]).…”

“…This image-derived volume is less effective in small rodents because limited spatial resolution and partial-volume effects result in significant spill-over from the myocardial tissue in late frames, rendering a falsely high input function that does not converge to zero (4)(5)(6). Hybrid approaches have been proposed, defining the peak uptake from early frames using the left ventricle and scaling the input function by a late blood sample (5,7), but the continued dependence on arterial blood sampling complicates serial application.…”

Deletion of MLIP (Muscle-enriched A-type Lamin-interacting Protein) Leads to Cardiac Hyperactivation of Akt/Mammalian Target of Rapamycin (mTOR) and Impaired Cardiac Adaptation

“…genome-wide association study of directly measured and calculated echocardiographic measures was performed using the efficient mixed model association algorithm to correct for population substructure (11,12). Mouse PET [ 18 F]fluorodeoxyglucose (FDG) imaging was conducted in the Inveon TM DPET small animal scanner (Siemens, Knoxsville, TN) as previously described (13,14). A 60-min list mode acquisition was started together with a 10 -20-s tail vein injection of FDG (18 -72 MBq in 150 l).…”