Quantitative pharmacologic MRI in mice

Abstract

Pharmacologic MRI (phMRI) uses functional MRI techniques to provide a non-invasive in vivo measurement of the hemodynamic effects of drugs. The cerebral blood volume change (ΔCBV) serves as a surrogate for neuronal activity via neurovascular coupling mechanisms. By assessing the location and time course of brain activity in mouse mutant studies, phMRI can provide valuable insights into how different behavioral phenotypes are expressed in differing brain activity response to drug challenge. In this report, we evaluate the utility of three different intravascular ultrasmall superparamagnetic iron oxide (USPIO) contrast agents for phMRI using a gradient-echo technique with temporal resolution of one minute at high magnetic field. The tissue half life of the USPIOs was studied using a nonlinear detrending model. All three studied USPIOs are candidates for CBV weighted phMRI-experiments, with r2/r1 ratios ≥ 20 and apparent half-lives ≥ 1.5 h at the described doses. An echo time of about 10 ms or longer results in a fCNR > 75 after USPIO injection, with negligible decrease during 1.5 to 2 hours. phMRI experiments were conducted at 7T using cocaine as a psychotropic substance and acetazolamide, a global vasodilator, as a positive control. Cocaine acts as a dopamine-serotonin-norepinephrine reuptake inhibitor, increasing extracellular concentrations of these neurotransmitters and thus increasing dopaminergic, serotonergic and noradrenergic neurotransmission. phMRI indicated that CBV was reduced in the normal mouse brain after cocaine challenge, with largest effects in nucleus accumbens, while after acetazolamide the blood volume was increased in both cerebral and extra-cerebral tissue.

Nitrite induces the extravasation of iron oxide nanoparticles in hypoxic tumor tissue

“…The iron oxide-based CA used herein is known to be an intravascular CA, and is widely used in the evaluation of blood volume employing susceptibility-based imaging techniques (21,(23)(24)(25). In this work, saline injections had little to no effect on the normal or tumor tissue R 2 * and, accordingly, the vasculature.…”

“…The intravascular CA used in this study is a 30‐nm monocrystalline iron oxide‐based nanoparticle at a dose of 6 mg/kg (®Molday‐ION Biophysics Assay Laboratory, Worcester, MA, USA). The CA is expected to stay within the vasculature for >7 h . Pre‐clinically, iron oxide particles are the most commonly used agent for dynamic susceptibility contrast MRI and steady measures of blood volume .…”

“…The CA is expected to stay within the vasculature for >7 h . Pre‐clinically, iron oxide particles are the most commonly used agent for dynamic susceptibility contrast MRI and steady measures of blood volume . A similar CA, ferumoxytol, is increasingly being evaluated in patient populations owing to its long intravascular times .…”

“…Quantitative analysis was carried out by estimating R 2 * on a voxel‐by‐voxel basis for the entire brain including the tumor. The difference between the baseline R 2 * and post‐contrast R 2 * provides an estimate of the basal CBV . Changes in R 2 * following the injection of nitrite or saline were estimated using the following equation: 100% × ( R 2 * post‐nitrite – R 2 * post‐CA )/ R 2 * post‐CA .…”

Rapid-Steady-State-T1signal modeling during contrast agent extravasation: Toward tumor blood volume quantification without requiring the arterial input function

“…Gd‐DOTA (r 1 = 3.3 s −1 mM −1 in plasma at 4.7 T and 37°C) was injected during dynamic RSST 1 imaging at a dose of 0.6 mmol/kg (1.2 mL/kg) followed 70 min later by a dose of 0.2 mmol/kg (1.12 mL/kg) MoldayION (BioPAL, Worcester, MA) for the ΔR 2 *‐method. MoldayION is an USPIO with a core size of 7 nm, high transverse relaxivity r 2 and a similar colloidal size as AMI‐227 of 30 nm . The magnetic properties of MoldayION are assumed the same as those of AMI‐227 which is no longer available.…”