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TABLE 2Fitting Precision with 2 Types of IFParameterK 1(mL/min/cm 3 ) SD (%) k 2 (1/min) SD (%) k 3 (1/min) SD (%) k 4 (1/min) SD (%)K FDG(mL/min/cm 3 ) SD (%)IDIF 1 0.296 10.383 0.766 17.056 0.125 11.805 0.024 13.232 0.041 5.837IDIF 2 0.269 6.967 0.907 10.766 0.101 9.582 0.029 11.626 0.027 5.749IDIF 3 0.238 7.291 0.731 12.545 0.107 12.106 0.023 17.610 0.031 6.845IDIF 4 0.468 6.746 0.920 10.273 0.101 8.988 0.019 17.181 0.046 5.454IDIF 5 0.402 5.726 0.736 9.455 0.131 6.717 0.027 6.876 0.061 3.297Shunt 1 0.294 1.450 0.653 2.013 0.105 3.497 0.022 7.980 0.041 2.449Shunt 2 0.162 1.245 0.430 1.937 0.064 4.854 0.020 11.587 0.021 3.311Shunt 3 0.226 1.016 0.614 1.405 0.080 3.515 0.017 9.384 0.026 2.515Shunt 4 0.284 0.573 0.482 0.799 0.067 1.838 0.012 8.476 0.035 1.379Shunt 5 0.407 1.072 0.656 0.945 0.102 2.397 0.022 4.354 0.055 1.331s 2 IDIF . s 2 shunt df F F F F FMouse 1 26/26 52.041* 98.696* 16.142* 3.517 5.918*Mouse 2 29/29 86.185* 137.309* 9.716* 2.136 4.975*Mouse 3 27/27 57.444* 112.981* 21.159* 6.656* 10.104*Mouse 4 29/29 377.026* 603.740* 53.824* 9.845* 27.648*Mouse 5 30/30 27.875* 125.813* 12.774* 3.767 7.475*Original data from C57BL/6 mice used in this study. F tests revealed significantly (*P , 0.01, corrected for multiple comparisons, with dfdepending on number of image frames in respective PET dataset) larger variances in fitted parameters using IDIF than using shunt IF.Pattern was similar in CD1 mice, for which K 1 and k 2 could be estimated with significantly (P , 0.01) higher precision in all animals, and k 3 ,k 4 , and K FDG in 6, 3, and 4 of 8 animals, respectively.gruous shapes (e.g., 16,22). IDIFs are, therefore, a valid alternativefor the estimation of CMR glc , in particular in caseswhere a shunt surgery is not possible, for example, in longitudinalstudies.In general, 2-tissue-compartment modeling of K FDG andCMR glc based on the shunt IF yielded smaller SDs, mostprobably because of the higher sampling rate and greaterprecision in the rate constants achieved with the shunt andcounter. This interpretation is supported by the lack of differencein the CMR glc estimated with either IF type byPatlak analysis, which is less sensitive to the shape of the IFthan the 2-tissue-compartment model.Several methods exist to compute IDIFs. The EL-ICAalgorithm was chosen because it uses a high amount of informationpresent in the image data and features a nonnegativityconstraint that prevents physically meaninglessresults and makes the method more robust (13). The use ofEL-ICA allowed us to filter out spillover of the myocardiumand partial-volume effects. We further optimized thedata quality by applying a relatively slow infusion protocolfor 18 F-FDG to avoid the unphysiologic mixing conditionsin the blood and the corresponding overshoot in plasma radioactivitythat occur after bolus injection. Furthermore, weincluded the fractional cerebral blood volume into the kineticmodel, a correction that was not done by Yu et al.(16). The combination of the above precautions resulted inmodel fits with high R 2 values and meaningful estimates ofthe single rate constants.With both IF methods, we found a significant contributionof 18 F-FDG-6-phosphate dephosphorylation to the kinetics.This contribution was indicated by k 4 , which is notnegligible in the fits, in good agreement with the observationsby Yu et al. (16). For this reason, we did not furtherdevelop the results obtained by Patlak analysis since itassumes irreversible phosphorylation. Dephosphorylation,which is considered by k 4 in the 2-tissue-compartmentmodel, results in an underestimation of CMR glc in the Patlakanalysis, as observed in our study and that by Yu et al. (16).The results of our Patlak analysis were higher (P , 0.05) bya factor of about 2 than those of Wong et al. (23). Possibleinfluencing factors that may have differed between the 2 studiesinclude the duration of anesthesia, which in our study includedthe time for the surgery; the depth of anesthesia; andthe oxygen content of the inhaled gas mix. Isoflurane anesthesiaincreases plasma glucose and with it CMR glc ,asdemonstratedbySahaetal.(24).The authors showed an increase inblood glucose levels in nonfasted rats during an experimentalperiod of 180 min of isoflurane anesthesia (2.5%). The increasewas highest within the first 60 min. In our experiments,the PET scan started 45–60 min after the induction of anesthesia,and isoflurane doses were lower (;2%). We thereforeassume that the plasma glucose concentrations measured afterthe scan are representative of the complete scan duration inour study. Finally, this may explain why our values are higherthan those reported by Yu et al. (16), who measured plasmaglucose before the scan. Intersubject variability in plasma glucoseconcentration and hence the shape of the IF may hamperthe use of population-based standard IFs in mice, for which itis currently impossible to reliably clamp plasma glucose toa standard normoglycemic value.A drawback of our IDIF and most other image-derivedmethods previously proposed is the need for scaling with bloodREAL-TIME INPUT FUNCTION IN MICE • Alf et al. 137