Vessel size imaging is a new method that is based on simultaneous measurement of the changes ΔR2 and ΔR *2 in relaxation rate constants induced by the injection of an intravascular superparamagnetic contrast agent. Using the static dephasing approximation for ΔR *2 estimation and the slow‐diffusion approximation for ΔR2 estimation, it is shown that the ratio ΔR2/ΔR *2 can be expressed as a function of the susceptibility difference between vessels and brain tissue, the brain water diffusion coefficient, and a weighted mean of vessel sizes. Comparison of the results with 1) the Monte Carlo simulations used to quantify the relationship between tissue parameters and susceptibility contrast, 2) the experimental MRI data in the normal rat brain, and 3) the histologic data establishes the validity of this approach. This technique, which allows images of a weighted mean of the vessel size to be obtained, could be useful for in vivo studies of tumor vascularization. Magn Reson Med 45:397–408, 2001. © 2001 Wiley‐Liss, Inc.

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Human mesenchymal stem cells (hMSC) are a promising source for cell therapy after stroke. To deliver these cells, an IV injection appears safer than a local graft. We aimed to assess the whole-body biodistribution of IV-injected (99m)Tc-HMPAO-labeled hMSC in normal rats (n = 9) and following a right middle cerebral artery occlusion (MCAo, n = 9). Whole-body nuclear imaging, isolated organ counting (at 2 and 20 h after injection) and histology were performed. A higher activity was observed in the right damaged hemisphere of the MCAo group [6.5 +/- 0.9 x 10(-3) % of injected dose (ID)/g] than in the control group (3.6 +/- 1.2 x 10(-3) %ID/g), 20 h after injection. In MCAo rats, right hemisphere activity was higher than that observed in the contralateral hemisphere at 2 h after injection (11.6 +/- 2.8 vs. 9.8 +/- 1.7 x 10(-3) %ID/g). Following an initial hMSC lung accumulation, there was a decrease in pulmonary activity from 2 to 20 h after injection in both groups. The spleen was the only organ in which activity increased between 2 and 20 h. The presence of hMSC was documented in the spleen, liver, lung, and brain following histology. IV-injected hMSC are transiently trapped in the lungs, can be sequestered in the spleen, and are predominantly eliminated by kidneys. After 20 h, more hMSC are found in the ischemic lesion than into the undamaged cerebral tissue. IV delivery of hMSC could be the initial route for a clinical trial of tolerance.

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A quantitative estimate of cerebral blood oxygen saturation is of critical importance in the investigation of cerebrovascular disease. While positron emission tomography can map in vivo the oxygen level in blood, it has limited availability and requires ionizing radiation. Magnetic resonance imaging (MRI) offers an alternative through the blood oxygen level-dependent contrast. Here, we describe an in vivo and non-invasive approach to map brain tissue oxygen saturation (StO 2 ) with high spatial resolution. StO 2 obtained with MRI correlated well with results from blood gas analyses for various oxygen and hematocrit challenges. In a stroke model, the hypoxic areas delineated in vivo by MRI spatially matched those observed ex vivo by pimonidazole staining. In a model of diffuse traumatic brain injury, MRI was able to detect even a reduction in StO 2 that was too small to be detected by histology. In a F98 glioma model, MRI was able to map oxygenation heterogeneity. Thus, the MRI technique may improve our understanding of the pathophysiology of several brain diseases involving impaired oxygenation. Journal of Cerebral Blood INTRODUCTIONThe sensitivity of magnetic resonance imaging (MRI) to changes in oxygenation through the blood oxygen level-dependent (BOLD) effect 1 is the basis of functional MRI. This technique allows a noninvasive exploration of the functions and dysfunctions of the human brain and has revolutionized cognitive neuroscience over the last 20 years. Less appreciated is the potential of BOLD MRI to study baseline brain oxygenation. In a clinical environment, MRI oximetry would offer definitive advantages over brain oxygenation mapping with positron emission tomography (PET), 2 a technique not widely available and that requires ionizing radiations.Several authors have laid out the foundations of a theoretical framework named quantitative BOLD (qBOLD) imaging that aims to extract quantitative vascular information from baseline scans.

Tumors create a heterogeneous acidic microenvironment which assists their growth and which must be taken into account in the design of drugs and their delivery. In addition, the acidic extracellular pH (pHe) is itself exploited in several experimental techniques for drug delivery. The way the acidity is created is not clear. We report here the spatial organization of key proton-handling proteins in C6 gliomas in rat brain. The mean profiles across the tumor rim of the Na+/H+ exchanger NHE1, and the lactate-H+ cotransporter MCT1, both showed peaks. NHE1, which is important for extension and migration of cells in vitro, showed a peak 1.55 times higher than in extratumoural tissue at 0.33 mm from the edge. MCT1 had a broader peak, further into the tumor (maximum 1.76 fold at 1.0 mm from the edge). In contrast, MCT4 and the carbonic anhydrase CAIX, which are associated with hypoxia, were not significantly upregulated in the rim. The spatial distribution of MCT4 was highly correlated with that of CAIX, suggesting that their expression is regulated by the same factors. Since protons extruded by NHE1 diffuse away through extracellular clefts, NHE1 requires a continuous source of intracellular protons. From the stoichiometries of metabolic pathways that produce or consume H+, and the greater availability of glucose compared to oxygen in most parts of a tumor, we support the classic view that most of the net proton efflux from C6 gliomas originates in glycolytic formation of lactate and H+ inside the tumor, but add that some lactate is taken up into cells in the rim on MCT1, and some lactate diffuses away, leaving its associated protons available to re-enter cells for extrusion on NHE1. Therapeutic inhibition of NHE1, MCT1 or CAIX is predicted to affect different parts of a tumor.

Human mesenchymal stem cells (hMSCs) have strong potential for cell therapy after stroke. Tracking stem cells in vivo following a graft can provide insight into many issues regarding optimal route and/or dosing. hMSCs were labeled for magnetic resonance imaging (MRI) and histology with micrometer-sized superparamagnetic iron oxides (M-SPIOs) that contained a fluorophore. We assessed whether M-SPIO labeling obtained without the use of a transfection agent induced any cell damage in clinical-grade hMSCs and whether it may be useful for in vivo MRI studies after stroke. M-SPIOs provided efficient intracellular hMSC labeling and did not modify cell viability, phenotype, or in vitro differentiation capacity. Following grafting in a rat model of stroke, labeled hMSCs could be detected using both in vivo MRI and fluorescent microscopy until 4 weeks following transplantation. However, whereas good label stability and unaffected hMSC viability were observed in vitro, grafted hMSCs may die and release iron particles in vivo.

Several recent studies have reported changes of brain tissue T(1) in ischemic models during the first minutes after occlusion of the middle cerebral artery (MCA). In order to assess whether these tissue T(1) changes are related to an increase in tissue water content, we performed T(1) (7 T) and tissue water content measurements in a rat model (n = 10, Sprague-Dawley) of focal cerebral ischemia (intraluminal occlusion model). The tissue water content was determined using a gravimetric technique. The animals were divided into two groups: an ischemic group, with an effective MCA occlusion (n = 6) and a control group, with animals having undergone sham surgery but no MCA occlusion (n = 4). In the ipsilateral cortex, the tissue water content was 81.1 +/- 0.7% at 2 h 15 min following ischemic insult (contralateral value: 79.3 +/- 0.5%). Concomitantly, the tissue T(1) in the ipsilateral cortex was 2062 +/- 60 ms at ischemia onset + 1 h (contralateral 1811 +/- 28 ms) and 2100 +/- 38 ms at ischemia onset + 2 h (contralateral 1807 +/- 18 ms). The tissue T(1) and tissue water content values measured in the contralateral area do not differ from the values obtained in the control group. A significant T(1) increase is observed at ischemia onset + 1 h (+ 14%) and ischemia onset (+ 2 h) + 16%, together with a significant increase in tissue water content (+ 2.3%). This suggests that there is an increase in tissue water content concomitant with cell swelling during the first hours of ischemia.