Philipp Backhaus1,2,3, Florian Büther1,2, Lydia Wachsmuth3, Lynn Frohwein1,2, Rebecca Buchholz4, Uwe Karst4,5, Klaus Schäfers2,5, Sven Hermann2,5, Michael Schäfers1,2,5, Cornelius Faber3,5. 1. Department of Nuclear Medicine, University Hospital Münster, Münster, Germany. 2. European Institute for Molecular Imaging, University of Münster, Münster, Germany. 3. Translational Research Imaging Center, Department of Clinical Radiology, University Hospital Münster, Münster, Germany. 4. Department of Analytical Chemistry, University of Münster, Münster, Germany. 5. DFG EXC 1003 Cluster of Excellence "Cells in Motion", University of Münster, Münster, Germany.
Abstract
PURPOSE: Dynamic contrast-enhanced MRI can be used in pharmacokinetic models to quantify functional parameters such as perfusion and permeability. However, precise quantification in preclinical models is challenged by the difficulties to dynamically measure the true arterial blood contrast agent concentration. We propose a novel approach toward a precise and experimentally feasible method to derive the arterial input function from DCE-MRI in mice. METHODS: Arterial blood was surgically shunted from the femoral artery to the tail vein and led through an extracorporeal circulation that resided on the head of brain tumor-bearing mice inside the FOV of a 9.4T MRI scanner. Dynamic 3D-FLASH scanning was performed after injection of gadobutrol with an effective resolution of 0.175 × 0.175 × 1 mm and a temporal resolution of 4 seconds. Pharmacokinetic modeling was performed using the extended Tofts and two-compartment exchange model. RESULTS: Arterial input functions measured inside the extracorporeal circulation showed little noise, small interindividual variance, and typical curve shapes. Ex vivo and mass spectrometry validation measurements documented the influence of shunt flow velocity and hematocrit on estimation of contrast agent concentrations. Modeling of tumors and muscles allowed fitting of the recorded dynamic concentrations, resulting in quantitative plausible parameters. CONCLUSION: The extracorporeal circulation allows deriving the contrast agent dynamics in arterial blood with high robustness and at acceptable experimental effort from DCE-MRI, previously not achievable in mice. It sets the basis for quantitative precise pharmacokinetic modeling in small animals to enhance the translatability of preclinical DCE-MRI measurements to patients.
PURPOSE: Dynamic contrast-enhanced MRI can be used in pharmacokinetic models to quantify functional parameters such as perfusion and permeability. However, precise quantification in preclinical models is challenged by the difficulties to dynamically measure the true arterial blood contrast agent concentration. We propose a novel approach toward a precise and experimentally feasible method to derive the arterial input function from DCE-MRI in mice. METHODS: Arterial blood was surgically shunted from the femoral artery to the tail vein and led through an extracorporeal circulation that resided on the head of brain tumor-bearing mice inside the FOV of a 9.4T MRI scanner. Dynamic 3D-FLASH scanning was performed after injection of gadobutrol with an effective resolution of 0.175 × 0.175 × 1 mm and a temporal resolution of 4 seconds. Pharmacokinetic modeling was performed using the extended Tofts and two-compartment exchange model. RESULTS: Arterial input functions measured inside the extracorporeal circulation showed little noise, small interindividual variance, and typical curve shapes. Ex vivo and mass spectrometry validation measurements documented the influence of shunt flow velocity and hematocrit on estimation of contrast agent concentrations. Modeling of tumors and muscles allowed fitting of the recorded dynamic concentrations, resulting in quantitative plausible parameters. CONCLUSION: The extracorporeal circulation allows deriving the contrast agent dynamics in arterial blood with high robustness and at acceptable experimental effort from DCE-MRI, previously not achievable in mice. It sets the basis for quantitative precise pharmacokinetic modeling in small animals to enhance the translatability of preclinical DCE-MRI measurements to patients.
Authors: P Backhaus; F Gierse; M C Burg; F Büther; I Asmus; P Dorten; J Cufe; W Roll; D Neri; S Cazzamalli; J Millul; J Mock; A Galbiati; A Zana; K P Schäfers; S Hermann; M Weckesser; J Tio; S Wagner; H-J Breyholz; M Schäfers Journal: Eur J Nucl Med Mol Imaging Date: 2021-12-27 Impact factor: 10.057