title: A novel approach to tracer-kinetic modeling for (macromolecular) dynamic contrast-enhanced MRI.
abstract: OBJECTIVE
  To develop a novel tracer-kinetic modeling approach for multi-agent dynamic contrast-enhanced MRI (DCE-MRI) that facilitates separate estimation of parameters characterizing blood flow and microvascular permeability within one individual.
  
  
  METHODS
  Monte Carlo simulations were performed to investigate the performance of the constrained multi-agent model. Subsequently, multi-agent DCE-MRI was performed on tumor-bearing mice (n = 5) on a 7T Bruker scanner on three measurement days, in which two dendrimer-based contrast agents having high and intermediate molecular weight, respectively, along with gadoterate meglumine, were sequentially injected within one imaging session. Multi-agent data were simultaneously fit with the gamma capillary transit time model. Blood flow, mean capillary transit time, and bolus arrival time were constrained to be identical between the boluses, while extraction fractions and washout rate constants were separately determined for each agent.
  
  
  RESULTS
  Simulations showed that constrained multi-agent model regressions led to less uncertainty and bias in estimated tracer-kinetic parameters compared with single-bolus modeling. The approach was successfully applied in vivo, and significant differences in the extraction fraction and washout rate constant between the agents, dependent on their molecular weight, were consistently observed.
  
  
  CONCLUSIONS
  A novel multi-agent tracer-kinetic modeling approach that enforces self-consistency of model parameters and can robustly characterize tumor vascular status was demonstrated.
authors.affiliation: Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands.
authors.forename: Igor
authors.initials: I
authors.lastname: Jacobs
authors.affiliation: Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands.|Biomedical Engineering and Physics, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Gustav J
authors.initials: GJ
authors.lastname: Strijkers
authors.affiliation: SyMO-Chem BV, Eindhoven, Netherlands.
authors.forename: Henk M
authors.initials: HM
authors.lastname: Keizer
authors.affiliation: SyMO-Chem BV, Eindhoven, Netherlands.
authors.forename: Henk M
authors.initials: HM
authors.lastname: Janssen
authors.affiliation: Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands.
authors.forename: Klaas
authors.initials: K
authors.lastname: Nicolay
authors.affiliation: Advanced Imaging Research Center, Oregon Health & Science University, Portland, Oregon, USA.|Utah Center for Advanced Imaging Research, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Matthias C
authors.initials: MC
authors.lastname: Schabel
mesh_terms: D000818:Animals; D003287:Contrast Media / Q000737:chemistry / Q000493:pharmacokinetics*; D007091:Image Processing, Computer-Assisted / Q000379:methods*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008962:Models, Theoretical; D009010:Monte Carlo Method; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology
chemical_list: D003287:Contrast Media
keywords: cancer imaging; dynamic contrast-enhanced MRI; macromolecular contrast agents; perfusion and permeability; tracer-kinetic modeling; tumor vasculature