title: FDG kinetic modeling in small rodent brain PET: optimization of data acquisition and analysis.
abstract: BACKGROUND
  Kinetic modeling of brain glucose metabolism in small rodents from positron emission tomography (PET) data using 2-deoxy-2-[(18) F]fluoro-d-glucose (FDG) has been highly inconsistent, due to different modeling parameter settings and underestimation of the impact of methodological flaws in experimentation. This article aims to contribute toward improved experimental standards. As solutions for arterial input function (IF) acquisition of satisfactory quality are becoming available for small rodents, reliable two-tissue compartment modeling and the determination of transport and phosphorylation rate constants of FDG in rodent brain are within reach.
  
  
  METHODS
  Data from mouse brain FDG PET with IFs determined with a coincidence counter on an arterio-venous shunt were analyzed with the two-tissue compartment model. We assessed the influence of several factors on the modeling results: the value for the fractional blood volume in tissue, precision of timing and calibration, smoothing of data, correction for blood cell uptake of FDG, and protocol for FDG administration. Kinetic modeling with experimental and simulated data was performed under systematic variation of these parameters.
  
  
  RESULTS
  Blood volume fitting was unreliable and affected the estimation of rate constants. Even small sample timing errors of a few seconds lead to significant deviations of the fit parameters. Data smoothing did not increase model fit precision. Accurate correction for the kinetics of blood cell uptake of FDG rather than constant scaling of the blood time-activity curve is mandatory for kinetic modeling. FDG infusion over 4 to 5 min instead of bolus injection revealed well-defined experimental input functions and allowed for longer blood sampling intervals at similar fit precisions in simulations.
  
  
  CONCLUSIONS
  FDG infusion over a few minutes instead of bolus injection allows for longer blood sampling intervals in kinetic modeling with the two-tissue compartment model at a similar precision of fit parameters. The fractional blood volume in the tissue of interest should be entered as a fixed value and kinetics of blood cell uptake of FDG should be included in the model. Data smoothing does not improve the results, and timing errors should be avoided by precise temporal matching of blood and tissue time-activity curves and by replacing manual with automated blood sampling.
authors.affiliation: Center for Radiopharmaceutical Sciences of ETH, PSI, and USZ, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich CH-8093, Switzerland.
authors.forename: Malte F
authors.initials: MF
authors.lastname: Alf
authors.affiliation: Collegium Helveticum ETH and UZH, Zurich 8092, Switzerland.
authors.forename: Marianne I
authors.initials: MI
authors.lastname: Martić-Kehl
authors.affiliation: Center for Radiopharmaceutical Sciences of ETH, PSI, and USZ, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich CH-8093, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.affiliation: Center for Radiopharmaceutical Sciences of ETH, PSI, and USZ, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich CH-8093, Switzerland.
authors.forename: Stefanie D
authors.initials: SD
authors.lastname: Krämer
keywords: CMRglc; FDG; Fractional blood volume; Infusion; Kinetic modeling; Positron emission tomography; Reliability
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