Tissue perfusion (blood flow per gram) in health varies with metabolic need but in pathological conditions such as cancer may be primarily or secondarily altered. In experimental animals, acute and destructive microsphere techniques can be applied to accurately measure tissue perfusion with excellent spatial resolution and with temporal resolution adequate for most metabolic conditions. However, for widespread clinical application tissue perfusion methods must be safe,minimally invasive, repeatable, accurate within a few percent, and have enough spatial and temporal resolution to reflect the pathological abnormality. Indicator dilution methods have been well characterized and can be applied to magnetic resonance (MR) contract agent pharmacokinetics with in vivo MR imaging detection. The technical details of measuring local tissue time-intensity curves with adequate spatial and temporal resolution, converting MR intensity to contrast agent concentration, selecting an appropriate indicator, and determining perfusion with mathematical modeling are best approached in animal studies. We will develop and validate MR indicator dilution methods in vivo to determine relative and absolute tissue perfusion - the latter requiring quantitative information about the input function. IN the first 2 years, we will concentrate on spleen (rat) and placenta (rat and rabbit). Four MR indicator s are available for spleen - GdDTPA (an ECF agent), GdDTPA-albumin (a blood pool agent), colloidal Gd2O3 (a phagocyte agent), and magnetite microspheres (a phagocyte agent). Spleen has a single circulation and its circulation can be altered with splenic vein ligation. Placenta is a """"""""physiologic"""""""" tumor and perfusion varies with gestational age, GdDTPA ad GdDTPA-albumin cause striking placental enhancement. Other MR contrast agents are available, but the Gd agents are paramagnetic with balanced T1 & T2 relaxivity whereas magnetite has a stronger effect upon T2 and magnetic susceptibility at our 1.51 fields. The indicators are also chosen to provide a range of physiologic properties. That may require different mathematical models thus, we will be able to evaluate a variety of indicator-detector technical issues as well as different physiologic mechanisms affecting time-intensity measurements. Finally, radioactive microsphere methods provide a good gold standard for spleen and placenta in both relative and absolute tissue perfusion validations. In the third year, we intend to extend our methods to one or ore rodent tumor models. If indicator dilution methods can provide accurate tissue perfusion measurements in vivo, the safety and acceptability of MR imaging would make this information readily available for cancer diagnosis but especially for following response to treatment.
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