In vivo study of microbubbles as an MR susceptibility contrast agent.

The potential application of gas microbubbles as a unique intravascular susceptibility contrast agent for MRI has not been fully explored. In this study, the MR susceptibility effect of an ultrasound microbubble contrast agent, Optison, was studied with rat liver imaging at 7 T. Optison suspension in two different doses (0.15 mL/kg and 0.4 mL/kg) was injected into rats, and induced transverse relaxation rate increases (deltaR2*) of 29.1 +/- 1.6 s(-1) (N = 2) and 61.5 +/- 12.9 s(-1) (N = 6), respectively, in liver tissue. Liver uptake of intact albumin microbubbles was observed 10 min after injection. Eight of the 16 rats studied showed no susceptibility enhancement. This is probably attributable to the intravascular microbubble growth due to transmural CO2 supersaturation in the cecum and colon in small animals that causes microbubble aggregation and trapping in the inferior vena cava (IVC). In vitro deltaR2* measurements of Optison suspension at different concentrations are also reported.     

Absence of a significant extravascular contribution to the skeletal muscle BOLD effect at 3 T

Blood oxygenation level dependent (BOLD) contrast in skeletal may reflect the contributions of both intravascular and extravascular relaxation effects. The purpose of this study was to determine the significance of the extravascular BOLD effect in skeletal muscle at 3 T. In experiments, R₂* was measured before and during arterial occlusion under the following conditions: ( 1 ) the leg extended and rotated (to vary the capillary orientation with respect to the amplitude of static field) and ( 2 ) with the blood's signal nulled using a multiecho vascular space occupancy experiment. In the leg rotation protocol, 3 min of arterial occlusion decreased oxyhemoglobin saturation from 67% to 45% and increased R₂* from 34.2 to 36.6 sec^?1, but there was no difference in the R₂* response to occlusion between the extended and rotated positions. Numerical simulations of intra‐ and extravascular BOLD effects corresponding to these conditions predicted that the intravascular BOLD contribution to the R₂* change was always > 50 times larger than the extravascular BOLD contribution. Blood signal nulling eliminated the change in R₂* caused by arterial occlusion. These data indicate that under these experimental conditions, the contribution of the extravascular BOLD effect to skeletal muscle R₂* was too small to be practically important. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Effects of acute normovolemic hemodilution on T2* - weighted images of rat brain

Acute normovolemic hernodilution (HD) was induced in anesthetized rats to assess the effect of changes in hematocrit (Hct) on signal intensity in T₂*-weighted magnetic resonance (MR) images. Other relevant physiological parameters were maintained invariant. Two degrees of HD were induced: mild (Hct reduced from 42.6 ± 2.2% to 33.4 ± 2.1%) and moderate (Hct reduced from 44.6 ± 2.7% to 26.2 ± 1.7%). A two-dimensional gradient-echo sequence was used to monitor signal changes with high temporal resolution before, during, and after HD protocols. The time course of signal intensity change was closely related to that of changes in Hct. Corresponding changes in R₂* (ΔR₂*) with respect to the pre-HD state were calculated for the brain parenchyma. Average ΔR₂* values of ?0.24 ± 0.06 s^?1 and ?0.40 ± 0.07 s^?1 were obtained for the mild and moderate HD groups, respectively, during the final 2 min of MR imaging (proximal to correlative measurements of Hct). MR measured ΔR₂* values were in close agreement with the expected changes in R₂* predicted from theory when the measured changes in Hct were used as independent variables. These data are in good agreement with the current understanding of the effects of changes in the intravascular concentration of deoxyhemoglobin on induced magnetic susceptibility and hold promise for quantitative measurement of brain oxygenation in vivo.     

Use of magnetic nanoparticles to monitor alginate‐encapsulated βTC‐tet cells

Noninvasive monitoring of tissue‐engineered constructs is an important component in optimizing construct design and assessing therapeutic efficacy. In recent years, cellular and molecular imaging initiatives have spurred the use of iron oxide‐based contrast agents in the field of NMR imaging. Although their use in medical research has been widespread, their application in tissue engineering has been limited. In this study, the utility of monocrystalline iron oxide nanoparticles (MIONs) as an NMR contrast agent was evaluated for βTC‐tet cells encapsulated within alginate/poly‐L‐lysine/alginate (APA) microbeads. The constructs were labeled with MIONs in two different ways: 1) MION‐labeled βTC‐tet cells were encapsulated in APA beads (i.e., intracellular compartment), and 2) MION particles were suspended in the alginate solution prior to encapsulation so that the alginate matrix was labeled with MIONs instead of the cells (i.e., extracellular compartment). The data show that although the location of cells can be identified within APA beads, cell growth or rearrangement within these constructs cannot be effectively monitored, regardless of the location of MION compartmentalization. The advantages and disadvantages of these techniques and their potential use in tissue engineering are discussed. Magn Reson Med 61:282–290, 2009. © 2009 Wiley‐Liss, Inc.     

Air microbubbles as MR susceptibility contrast agent at 1.5 Tesla.

Air microbubbles have been investigated recently at high magnetic field strength (2 Tesla or greater) as potential MR susceptibility contrast agents. We used a phantom to measure their susceptibility at 1.5 T to clarify their usefulness for this purpose. The phantom, filled with fresh Levovist suspension at 4 different doses (67 to 125 mg/mL), was continuously scanned with a gradient-echo technique at a temporal resolution of 10 s. The transverse relaxation increase (R2*) by microbubbles demonstrated a time course of exponential decay at each dose (time-constant, 39 to 57 s). The dependency of R2* on microbubble volume fraction was linear, with a slope of 89 s-1 per percentage microbubble volume fraction. Our study represents the first step towards applying microbubbles as susceptibility contrast agents at 1.5 T.     

A quantitative pressure and microbubble‐size dependence study of focused ultrasound‐induced blood‐brain barrier opening reversibility in vivo using MRI

Focused ultrasound in conjunction with the systemic administration of microbubbles has been shown to open the blood‐brain barrier (BBB) selectively, noninvasively and reversibly. In this study, we investigate the dependence of the BBB opening's reversibility on the peak‐rarefactional pressure (0.30–0.60 MPa) as well as the microbubble size (diameters of 1–2, 4–5, or 6–8 μm) in mice using contrast‐enhanced T₁‐weighted (CE‐T₁) MR images (9.4 T). Volumetric measurements of the diffusion of Gd‐DTPA‐BMA into the brain parenchyma were used for the quantification of the BBB‐opened region on the day of sonication and up to 5 days thereafter. The volume of opening was found to increase with both pressure and microbubble diameter. The duration required for closing was found to be proportional to the volume of opening on the day of opening, and ranged from 24 h, for the smaller microbubbles, to 5 days at high peak‐rarefactional pressures. Overall, larger bubbles did not show significant differences. Also, the extent of BBB opening decreased radially towards the focal region until the BBB's integrity was restored. In the cases where histological damage was detected, it was found to be highly correlated with hyperintensity on the precontrast T₁ images. Magn Reson Med, 2012. © 2011 Wiley Periodicals, Inc.     

Perfusion fraction of diffusion-weighted MRI for predicting the presence of blood supply in ovarian masses

Purpose:

To evaluate whether perfusion fraction (PF) calculated with diffusion‐weighted magnetic resonance imaging (MRI) predicts the presence of blood supply in ovarian masses.

Materials and Methods:

PFs of 92 ovarian lesions in 53 patients administered gadolinium were retrospectively calculated with diffusion‐weighted images at b‐values of 0, 500, and 1000 sec/mm². PFs were compared between ovarian lesions, except for fat, with (n = 21) or without contrast enhancement (n = 57), using Student's t‐test and receiver operating characteristics (ROC) curve analysis. Lesion enhancement rates of contrast‐enhanced images at 30 and 180 seconds after gadolinium injection (ER_30sec and ER_180sec) and PFs were compared using Pearson's correlation coefficient.

Results:

PFs of the lesions with contrast enhancement were significantly higher than those without contrast enhancement (0.22 ± 0.09 and 0.02 ± 0.08, respectively, P < 0.0001). The ROC curve identified the best cutoff point for PF at 0.135 (95.2% sensitivity and 94.7% specificity) as a predictor of the contrast enhancement effect. The area under the ROC curve was 0.984. PF correlated moderately with ER_30sec (0.62, y = 0.13x + 0.04, P < 0.0001) and ER_180sec (0.74, y = 0.13x + 0.03, P < 0.0001).

Conclusion:

PF calculated with diffusion‐weighted images can potentially predict blood supply in ovarian masses. J. Magn. Reson. Imaging 2011. © 2011 Wiley Periodicals, Inc.     

Simplified synthesis and relaxometry of magnetoferritin for magnetic resonance imaging

Magnetoferritin nanoparticles have been developed as high‐relaxivity, functional contrast agents for MRI. Several previous techniques have relied on unloading native ferritin and re‐incorporation of iron into the core, often resulting in a polydisperse sample. Here, a simplified technique is developed using commercially available horse spleen apoferritin to create monodisperse magnetoferritin. Iron oxide atoms were incorporated into the protein core via a step‐wise Fe(II)Chloride addition to the protein solution under low O₂ conditions; subsequent filtration steps allow for separation of completely filled and superparamagnetic magnetoferritin from the partially filled ferritin. This method yields a monodisperse and homogenous solution of spherical particles with magnetic properties that can be used for molecular magnetic resonance imaging. With a transverse per‐iron and per‐particle relaxivity of 78 mM^?1 sec^?1 and 404,045 mM^?1 sec^?1, respectively, it is possible to detect ～10 nM nanoparticle concentrations in vivo. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Rapid quantification of oxygen tension in blood flow with a fluorine nanoparticle reporter and a novel blood flow‐enhanced‐saturation‐recovery sequence

We present a novel blood flow‐enhanced‐saturation‐recovery (BESR) sequence, which allows rapid in vivo T₁ measurement of blood for both ¹H and ¹⁹F nuclei. BESR sequence is achieved by combining homogeneous spin preparation and time‐of‐flight image acquisition and therefore preserves high time efficiency and signal‐to‐noise ratio for ¹⁹F imaging of circulating perfluorocarbon nanoparticles comprising a perfluoro‐15‐crown‐5‐ether core and a lipid monolayer (nominal size = 250 nm). The consistency and accuracy of the BESR sequence for measuring T₁ of blood was validated experimentally. With a confirmed linear response feature of ¹⁹F R₁ with oxygen tension in both salt solution and blood sample, we demonstrated the feasibility of the BESR sequence to quantitatively determine the oxygen tension within mouse left and right ventricles under both normoxia and hyperoxia conditions. Thus, ¹⁹F BESR MRI of circulating perfluorocarbon nanoparticles represents a new approach to noninvasively evaluate intravascular oxygen tension. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.     

Synthesis and preliminary evaluation of MP-2269: A novel,nonaromatic small-molecule blood-pool MR contrast agent

A nonaromatic, small-molecule, gadolinium(3+)-chelate code named MP-2269 was synthesized and evaluated in animals as a potential MR contrast agent for blood pool. The ligand of MP-2269 was prepared by conjugating a lipophilic, albumin-binding moiety, 4-pentylbicyclo[2.2.2]octane-1-carboxylic acid, to an amino-functionalized DTPA derivative by means of a diaspartic acid linker. Proton relaxometry studies in vitro yielded spin-lattice relaxivities (R₁) for MP-2269 of 6.2, 20.0 and 26.1 mM^?1 sec^?1 in water, rabbit blood, and human blood, respectively. The enhanced relaxivities in blood indicate sig nificant binding of the agent to blood proteins. At a dose of 45 μmol/kg, MP-2269 showed a biphasic rabbit blood clearance profile with half-lives of 4.7 and 142 minutes, respectively, for the fast and slow components. In rats, the agent is cleared predominantly through the hepatobiliary pathway (～70% in 24 h by this mode). The LD₅₀ value of MP-2269 is ～3.0 mmol/kg in mice. Preliminary MR angiograms obtained in the rabbit showed excellent enhancement of blood vessels. Hence, MP-2269 has potential for future exploitation as a contrast agent for MR angiography.     

Magnetically labeled cells can be detected by MR imaging

To determine the feasibility of MR imaging of magnetically labeled cells, different cell lines were labeled with monocrystalline iron oxide (MION) particles. Phantoms containing MION labeled cells were then assembled and imaged by MR at 1.5 T using T1-weighted and T2-weighted pulse sequences. MION uptake ranged from 8.5 × 10⁴ to 2.9 × 10⁵ particles/cell for tumor cells (9L and LX1, respectively) to 1.5 × 10⁶ to 4.8 × 10⁸ particles/cell for “professional phagocytes” (J774 and peritoneal macrophages, respectively). On the T1-weighted images, cell-internalized MION appeared hyperintense relative to agar and similar to MION in aqueous solution. On T2-weighted images, signal intensity varied according to concentration of MION within cells. Cell-internalized MION caused similar MR signal changes of cells as did free MION; however, at a dose that was an order of magnitude lower, depending on the pulse sequence used. The detectability of MION within cells was approximately 2 ng Fe, which corresponded to 10⁵ tumor cells/well or 5 × 10³ macrophages/well. We conclude that a variety of cells can be efficiently labeled with MION by simple incubation. Intracellular labeling may be used for MR imaging of in vivo cell tracking.     

Monocrystalline iron oxide nanoparticles: possible solution to the problem of surgically induced intracranial contrast enhancement in intraoperative MR imaging

BACKGROUND AND PURPOSE: Intraoperative MR imaging is increasingly being used to control the extent of surgical resection; however, surgical manipulation itself causes intracranial contrast enhancement, which is a source of error. Our purpose was to investigate the potential of monocrystalline iron oxide nanoparticles (MIONs) to solve this problem in an animal model. METHODS: In male Wistar rats, surgical lesions of the brain were produced. The animals underwent MR examination immediately afterward. In the first group, a paramagnetic contrast agent was administered, whereas the second group of animals received MIONs 1 day before surgery. In a third group of animals, malignant glioma cells were stereotactically implanted in the caudoputamen. Two weeks later, MIONs were IV injected and the tumor was (partially) resected. Immediately after resection, MR examination was performed to determine the extent of residual tumor. RESULTS: Surgically induced intracranial contrast enhancement was seen in all animals in which a paramagnetic contrast agent was used. Conversely, when MIONs had been injected, no signal changes that could be confused with residual tumor were detected. In the animals that had undergone (partial) resection of experimental gliomas, MR assessment of residual tumor was possible without any interfering surgically induced phenomena. CONCLUSION: Because MIONs are stored in malignant brain tumor cells longer than they circulate in the blood, their use offers a promising strategy to avoid surgically induced intracranial contrast enhancement, which is known to be a potential source of error in intraoperative MR imaging.     

Prolonging the ultrasound signal enhancement from thrombi using targeted microbubbles based on sulfur-hexafluoride-filled gas

RATIONALE AND OBJECTIVES: The objective of this study is to develop and characterize new microbubbles based on lipids and sulfur hexafluoride (SF6) for targeting thrombi as an improved ultrasound contrast agent. MATERIALS AND METHODS: Bioconjugate ligands were inserted into the lipid-coated membranes of SF6 gas microbubbles, and their physicochemical properties were determined. Diagnostic efficacies of SF6-filled microbubbles and the contrast agent SonoVue (Bracco Imaging, Geneve, Switzerland) were compared in dogs. RESULTS: Suspensions of lyophilized powder were reconstituted by injecting saline containing 3.1 x 10(8) SF6 microbubbles/mL with a mean diameter of 4.4 microm. More than 90% of microbubbles had diameters between 1 and 10 microm. After reconstitution, echogenicity and microbubble characteristics were unchanged for 8 hours. Targeted microbubbles increased the echogenicity of thrombi significantly and provided a longer period of optimal signal enhancement compared with nontargeted microbubbles. CONCLUSIONS: Our thrombus-targeting microbubble contrast agent shows high echogenicity and stability and thereby enhances the visualization of intravascular thrombi and prolongs the duration of the diagnostic window.     

Delta relaxation enhanced MR: Improving activation‐specificity of molecular probes through R1 dispersion imaging

MR molecular imaging enables high‐resolution, in vivo study of molecular processes frequently utilizing gadolinium‐based probes that specifically bind to a particular biological molecule or tissue. While some MR probes are inactive when unbound and produce enhancement only after binding, the majority are less specific and cause enhancement in either state. Accumulation processes are then required to increase probe concentration in regions of the target molecule/tissue. Herein, a method is described for creating specificity for traditionally nonspecific probes. This method utilizes MR field‐cycling methods to produce MRI contrast related to the dependence of R₁ upon magnetic field. It is shown that the partial derivative of R₁ with respect to magnetic field strength, R₁′, can be used as an unambiguous measure of probe binding. T₁‐weighted images and R₁′ images were produced for samples of albumin and buffer both enhanced with the albumin‐binding agent Vasovist. For T₁ images, samples with low concentrations of Vasovist in an albumin solution could not be differentiated from samples with higher concentrations of Vasovist in buffer. Conversely, the R₁′ images showed high specificity to albumin. Albumin samples with a 10‐μM concentration of Vasovist were enhanced over buffer samples containing up to 16 times more Vasovist. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Permeability dependence study of the focused ultrasound‐induced blood–brain barrier opening at distinct pressures and microbubble diameters using DCE‐MRI

Blood–brain barrier opening using focused ultrasound and microbubbles has been experimentally established as a noninvasive and localized brain drug delivery technique. In this study, the permeability of the opening is assessed in the murine hippocampus after the application of focused ultrasound at three different acoustic pressures and microbubble sizes. Using dynamic contrast‐enhanced MRI, the transfer rates were estimated, yielding permeability maps and quantitative K_trans values for a predefined region of interest. The volume of blood–brain barrier opening according to the K_trans maps was proportional to both the pressure and the microbubble diameter. A K_trans plateau of ～0.05 min^?1 was reached at higher pressures (0.45 and 0.60 MPa) for the larger sized bubbles (4–5 and 6–8 μm), which was on the same order as the K_trans of the epicranial muscle (no barrier). Smaller bubbles (1–2 μm) yielded significantly lower permeability values. A small percentage (7.5%) of mice showed signs of damage under histological examination, but no correlation with permeability was established. The assessment of the blood–brain barrier permeability properties and their dependence on both the pressure and the microbubble diameter suggests that K_trans maps may constitute an in vivo tool for the quantification of the efficacy of the focused ultrasound‐induced blood–brain barrier opening. Magn Reson Med, 2011. © 2011 Wiley‐Liss, Inc.     

Quantitation of T2′ anisotropic effects on magnetic resonance bone mineral density measurement

In this paper, the authors quantitate the anisotropy of susceptibility effects in an uniaxial trabecular bone model and show its relevance to clinical MR bone mineral density measurements. A physical model is described that quantitates the anisotropic MR behavior of uniaxial trabecular bone. To test the model, a phantom of parallel polyethylene filaments was scanned every 15° between 0° and 90° with respect to the system's main magnetic field (B₀). The distal radial metaphysis of a healthy female volunteer was scanned in orthogonal projections. The signal from each phantom image and each radial image was separated in a pixel-wise fashion into R₂ and R₂′ maps. As predicted, R₂′ relaxation showed anisotropic behavior and changed according to sin² (?), confirming that columnar structures parallel with B₀ will cause no MR susceptibility effects. Scans of the distal radius showed that R₂′ relaxation was twice as great with the forearm perpendicular to B₀ as when it was parallel to it, demonstrating different contributions from struts and columns. For both phantom and radial bone scans, R₂ relaxation was isotropic and did not change with object orientation.     

Contributions of chemical and diffusive exchange to T1ρ dispersion

Variations in local magnetic susceptibility may induce magnetic field gradients that affect the signals acquired for MR imaging. Under appropriate diffusion conditions, such fields produce effects similar to slow chemical exchange. These effects may also be found in combination with other chemical exchange processes at multiple time scales. We investigate these effects with simulations and measurements to determine their contributions to rotating frame (R_1ρ) relaxation in model systems. Simulations of diffusive and chemical exchange effects on R_1ρ dispersion were performed using the Bloch equations. Additionally, R_1ρ dispersion was measured in suspensions of Sephadex and latex beads with varying spin locking fields at 9.4 T. A novel analysis method was used to iteratively fit for apparent chemical and diffusive exchange rates with a model by Chopra et al. Single‐ and double‐inflection points in R_1ρ dispersion profiles were observed, respectively, in simulations of slow diffusive exchange alone and when combined with rapid chemical exchange. These simulations were consistent with measurements of R_1ρ in latex bead suspensions and small‐diameter Sephadex beads that showed single‐ and double‐inflection points, respectively. These observations, along with measurements following changes in temperature and pH, are consistent with the combined effects of slow diffusion and rapid ^?OH exchange processes. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.     

2D and 3D radial multi‐gradient‐echo DCE MRI in murine tumor models with dynamic R*2‐corrected R1 mapping

Dynamic contrast‐enhanced MRI is extensively studied to define and evaluate biomarkers for early assessment of vasculature‐targeting therapies. In this study, two‐dimensional and three‐dimensional radial multi‐gradient‐echo techniques for dynamic R*₂‐corrected R₁ mapping based on the spoiled gradient recalled signal equation were implemented and validated at 4.7 T. The techniques were evaluated on phantoms and on a respiratory motion animated tumor model. R₁ measurements were validated with respect to a standard inversion‐recovery spin‐echo sequence in a four‐compartment phantom covering a range of relaxation rates typically found in tumor tissue. In the range of [0.4, 3] sec^?1, R₁ differences were less than 10% for both two‐dimensional and three‐dimensional experiments. A dynamic contrast‐enhanced MRI pilot study was performed on a colorectal tumor model subcutaneously implanted in mice at the abdominal level. Low motion sensitivity of radial acquisition allowed image recording without respiratory triggering. Three‐dimensional K^trans maps and significantly different mean K^trans values were obtained for two contrast agents with different molecular weights. The radial multi‐gradient‐echo approach should be most useful for preclinical experimental conditions where the tissue of interest experiences physiologic motion, like spontaneous extracerebral tumors developed by transgenic mice, and where dynamic contrast‐enhanced MRI is performed with high‐relaxivity contrast agents. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Functional MRI with magnetization transfer effects: Determination of BOLD and arterial blood volume changes

The primarily intravascular magnetization transfer (MT)‐independent changes in functional MRI (fMRI) can be separated from MT‐dependent changes. This intravascular component is dominated by an arterial blood volume change (ΔCBV_a) term whenever venous contributions are minimized. Stimulation‐induced ΔCBV_a can therefore be measured by a fit of signal changes to MT ratio. MT‐varied fMRI data were acquired in 13 isoflurane‐anesthetized rats during forepaw stimulation at 9.4T to simultaneously measure blood‐oxygenation‐level–dependent (BOLD) and ΔCBV_a response in somatosensory cortical regions. Transverse relaxation rate change (ΔR₂) without MT was –0.43 ± 0.15 s^?1, and MT ratio decreased during stimulation. ΔCBV_a was 0.46 ± 0.15 ml/100 g, which agrees with our previously‐presented MT‐varied arterial‐spin‐labeled data (0.42 ± 0.18 ml/100 g) in the same animals and also correlates with ΔR₂ without MT. Simulations show that ΔCBV_a quantification errors due to potential venous contributions are small for our conditions. Magn Reson Med 60:1518–1523, 2008. © 2008 Wiley‐Liss, Inc.     

Modeling of Look‐Locker estimates of the magnetic resonance imaging estimate of longitudinal relaxation rate in tissue after contrast administration

This paper models the behavior of the longitudinal relaxation rate of the protons of tissue water R₁ (R₁ = 1/T₁), measured in a Look‐Locker experiment at 7 Tesla after administration of a paramagnetic contrast agent (CA). It solves the Bloch‐McConnell equations for the longitudinal magnetization of the protons of water in a three‐site two‐exchange (3S2X) model with boundary conditions appropriate to repeated sampling of magnetization. The extent to which equilibrium intercompartmental water exchange kinetics affect monoexponential estimates of R₁ after administration of a CA in dynamic contrast enhanced experiment is described. The relation between R₁ and tissue CA concentration was calculated for CA restricted to the intravascular, or to the intravascular and extracellular compartments, by varying model parameters to mimic experimental data acquired in a rat model of cerebral tumor. The model described a nearly linear relationship between R₁ and tissue concentration of CA, but demonstrated that the apparent longitudinal relaxivity of CA depends upon tissue type. The practical consequence of this finding is that the extended Patlak plot linearizes the ΔR₁ data in tissue with leaky microvessels, accurately determines the influx rate of the CA across these microvessels, but underestimates the volume of intravascular blood water. Magn Reson Med, 2011. © 2011 Wiley Periodicals, Inc.