The blood-to-brain transfer rate constant (K i ) of Gd-DTPA was determined in MRI studies of a rat model of transient cerebral ischemia. The longitudinal relaxation rate, R 1 , was estimated using repeated Look-Locker measurements. A model-independent analysis of ⌬R 1 , the Patlak plot, produced maps of K i for Gd-DTPA and the distribution volume of the mobile protons (V p ) with intravascular-Gd changed R 1 's. The K i 's of Gd-DTPA were estimated in regions of interest with blood-brain barrier (BBB) opening (regions of interest, ROIs) and compared to those of 14 C-sucrose determined shortly thereafter by quantitative autoradiography. The K i 's for both Gd-DTPA and sucrose were much higher than normal within the ROIs (n ‫؍‬ 7); linear regression of K i for Gd-DTPA vs. K i for sucrose yielded a slope of 0.43 ؎ 0.11 and r 2 ‫؍‬ 0.72 (P ‫؍‬ 0.01). Thus, K i for Gd-DTPA varied in parallel with, but was less than, K i for sucrose. In the ROIs, mean V p was 0.071 ml g -1 and much higher than mean vascular volume estimated by dynamic-contrast-enhancement (0.013 ml g

Vasculature in and around the cerebral tumor exhibits a wide range of permeabilities, from normal capillaries with essentially no blood-brain barrier (BBB) leakage to a tumor vasculature that freely passes even such large molecules as albumin. In measuring BBB permeability by magnetic resonance imaging (MRI), various contrast agents, sampling intervals, and contrast distribution models can be selected, each with its effect on the measurement's outcome. Using Gadomer, a large paramagnetic contrast agent, and MRI measures of T 1 over a 25-min period, BBB permeability was estimated in 15 Fischer rats with day-16 9L cerebral gliomas. Three vascular models were developed: (1) impermeable (normal BBB); (2) moderate influx (leakage without efflux); and (3) fast leakage with bidirectional exchange. For data analysis, these form nested models. Sizable inhomogeneity in v D , K i , and k b appeared within each tumor. We conclude that employing nested models enables accurate assessment of transfer constants among areas where BBB permeability, contrast agent distribution volumes, and signal-to-noise vary.

Purpose To test the hypothesis that a non-invasive dynamic contrast enhanced MRI (DCE-MRI) derived interstitial volume fraction (ve) and/or distribution volume (VD) were correlated with tumor cellularity in cerebral tumor. Methods T1-weighted DCE-MRI studies were performed in 18 athymic rats implanted with U251 xenografts. After DCE-MRI, sectioned brain tissues were stained with Hematoxylin and Eosin for cell counting. Using a Standard Model (SM) analysis and Logan graphical plot, DCE-MRI image sets during and after the injection of a gadolinium contrast agent were used to estimate the parameters plasma volume (vp), forward transfer constant (Ktrans), ve, and VD. Results Mean parameter values in regions where the SM was selected as the best model were: (mean ± S.D.): vp = (0.81±0.40)%, Ktrans = (2.09±0.65) ×10−2 min−1, ve = (6.65±1.86)%, and VD = (7.21±1.98)%. The Logan-estimated VD was strongly correlated with the SM’s vp+ve (r = 0.91, p < 0.001). The parameters, ve and/or VD, were significantly correlated with tumor cellularity (r ≥ −0.75, p < 0.001 for both). Conclusion These data suggest that tumor cellularity can be estimated non-invasively by DCE-MRI, thus supporting its utility in assessing tumor pathophysiology.

We describe an unconventional response of intracellular pH to NH4Cl in mouse cerebral astrocytes. Rapid alkalinization reversed abruptly to be replaced by an intense sustained acidification in the continued presence of NH4Cl. We hypothesize that high-velocity [Formula: see text] influx persisted after the distribution of ammonia attained steady state. From the initial rate of acidification elicited by 1 mM NH4Cl in bicarbonate-buffered solution, we estimate that [Formula: see text] entered at a velocity of at least 31.5 nmol ⋅ min−1 ⋅ mg protein−1. This rate increased with NH4Cl concentration, not saturating at up to 20 mM NH4Cl. Acidification was attenuated by raising or lowering extracellular K+ concentration. Ba2+ (50 μM) inhibited the acidification rate by 80.6%, suggesting inwardly rectifying K+ channels as the primary[Formula: see text] entry pathway. Acidification was 10-fold slower in rat hippocampal astrocytes, consistent with the difference reported for K+ flux in vitro. The combination of Ba2+ and bumetanide prevented net acidification by 1 mM NH4Cl, identifying the Na+-K+-2Cl−cotransporter as a second [Formula: see text] entry route.[Formula: see text] entry via K+ transport pathways could impact “buffering” of ammonia by astrocytes and could initiate the elevation of extracellular K+concentration and astrocyte swelling observed in acute hyperammonemia.

1 maps. Patlak plots were constructed using time course of blood and tissue T 1 changes induced by Gd for estimating K i . Among the nine rats, 14 sizable regions of AIB uptake were found; 13 were also identified by ISODATA segmentation. Although the 13 MRI-ROIs spatially approximated those of AIB uptake, the segmentation sometimes missed small areas of lesser AIB uptake that did not extend through more than 60% of the 2.0-mm-thick slice. Mean K i 's of AIB were highly correlated with those of Gd-DTPA across the 13 regions; the group means (؎SD) were similar for the two tracers (7.1 ؎ 3.3 ؋ 10 ؊3 and 6.8 ؎ 3.5 ؋ 10 ؊3 ml.g ؊1 ⅐ min ؊1 , respectively). The capillary endothelium plus the basal lamina, the pericytes enclosed within the basal lamina, and the surrounding cuff of astrocytic foot processes form the blood-brain barrier (BBB) complex. This barrier greatly restricts the passive movement of water and most water-soluble materials across the BBB and protects brain cells from exposure to neurotoxic or adversely neuroactive blood-borne agents. It is likely that its failure to do so contributes to or drives tissue damage in central nervous system disorders such as cerebral edema and intraparenchymal hemorrhage.The barrier function has often been evaluated in animal models of brain injury or disease. Such assessments are usually made with indicators that very slowly penetrate the normal BBB (e.g., radiolabeled sucrose) or are essentially impermeable (e.g., Evans blue-tagged albumin). When done quantitatively, the blood and tissue data yield a blood-to-brain influx rate constant (K i ) that is a function of local cerebral blood flow (CBF) and the permeabilitysurface area (PS) product of the local capillary network to the indicator.In a recent MRI study (1), a method of quantitating gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) distribution in a rat model of transient focal ischemia and calculating local K i numbers via Patlak plots (2) was presented. As an initial check on the accuracy and reliability of these results, the K i of Gd-DTPA in each area of BBB opening was compared to that of 14 C-sucrose assayed by QAR at the same locus about 30 min later. In support of this approach of determining Gd-DTPA influx, a good correlation was found between the K i 's of Gd-DTPA and sucrose, two extracellular markers of comparable size and blood-brain distribution properties.The current study extends that of Ewing et al. (1) and, in the main, examines the power of the Gd-DTPA-MRI technique to spatially resolve BBB opening. As in the work by Ewing et al., the K i of i.v. administered Gd-DTPA (MW 551 Da) was assessed in a group of transiently ischemic rats by MRI. In contrast, 14 C-␣-aminoisobutyric acid (AIB; MW 102 Da) was i.v. injected approximately 45 min after administration of Gd-DTPA, and its K i was assessed by QAR. The QAR parts of the present study and that of Ewing et al., therefore, differ with respect to the radiotracer used, their mode of administration (bolus injection of AIB vs. continuous infusion ...