Tavarekere N. Nagaraja

Patlak plots of Gd‐DTPA MRI data yield blood–brain transfer constants concordant with those of 14C‐sucrose in areas of blood–brain opening

The blood‐to‐brain transfer rate constant (Ki) of Gd‐DTPA was determined in MRI studies of a rat model of transient cerebral ischemia. The longitudinal relaxation rate, R1, was estimated using repeated Look‐Locker measurements. A model‐independent analysis of ΔR1, the Patlak plot, produced maps of Ki for Gd‐DTPA and the distribution volume of the mobile protons (Vp) with intravascular‐Gd changed R1s. The Kis of Gd‐DTPA were estimated in regions of interest with blood–brain barrier (BBB) opening (regions of interest, ROIs) and compared to those of 14C‐sucrose determined shortly thereafter by quantitative autoradiography. The Kis for both Gd‐DTPA and sucrose were much higher than normal within the ROIs (n = 7); linear regression of Ki for Gd‐DTPA vs. Ki for sucrose yielded a slope of 0.43 ± 0.11 and r2 = 0.72 (P = 0.01). Thus, Ki for Gd‐DTPA varied in parallel with, but was less than, Ki for sucrose. In the ROIs, mean Vp was 0.071 ml g−1 and much higher than mean vascular volume estimated by dynamic‐contrast‐enhancement (0.013 ml g−1) or mean Vp in contralateral brain (0.015 ml g−1). This elevated Vp may reflect increased capillary permeability to water. In conclusion, Ki can be reliably calculated from Gd‐DTPA‐MRI data by Patlak plots. Magn Reson Med 50:283–292, 2003.

Direct Comparison of Local Cerebral Blood Flow Rates Measured by MRI Arterial Spin-Tagging and Quantitative Autoradiography in a Rat Model of Experimental Cerebral Ischemia

The present study determined cerebral blood flow (CBF) in the rat using two different magnetic resonance imaging (MRI) arterial spin-tagging (AST) methods and 14C-iodoantipyrine (IAP)-quantitative autoradiography (QAR), a standard but terminal technique used for imaging and quantitating CBF, and compared the resulting data sets to assess the precision and accuracy of the different techniques. Two hours after cerebral ischemia was produced in eight rats via permanent occlusion of one middle cerebral artery (MCA) with an intraluminal suture, MRI-CBF was measured over a 2.0-mm coronal slice using single-coil AST, and tissue magnetization was assessed by either a spin-echo (SE) or a variable tip-angle gradient-echo (VTA-GE) readout. Subsequently (∼2.5 hours after MCA occlusion), CBF was assayed by QAR with the blood flow indicator 14C-IAP, which produced coronal images of local flow rates every 0.4 mm along the rostral—caudal axis. The IAP-QAR images that spanned the 2-mm MRI slice were selected, and regional flow rates (i.e., local CBF [lCBF]) were measured and averaged across this set of images by both the traditional approach, which involved reader interaction and avoidance of sectioning artifacts, and a whole film-scanning technique, which approximated total radioactivity in the entire MRI slice with minimal user bias. After alignment and coregistration, the concordance of the CBF rates generated by the two QAR approaches and the two AST methods was examined for nine regions of interest in each hemisphere. The QAR-lCBF rates were higher with the traditional method of assaying tissue radioactivity than with the MRI-analog approach; although the two sets of rates were highly correlated, the scatter was broad. The flow rates obtained with the whole film-scanning technique were chosen for subsequent comparisons to MRI-CBF results because of the similarity in tissue “sampling” among these three methods. As predicted by previous modeling, “true” flow rates, assumed to be given by QAR-lCBF, tended to be slightly lower than those measured by SE and were appreciably lower than those assessed by VTA-GE. When both the ischemic and contralateral hemispheres were considered together, SE-CBF and VTA-GE-CBF were both highly correlated with QAR-lCBF (P < 0.001). If evaluated by flow range, however, SE-CBF estimates were more accurate in high-flow (contralateral) areas (CBF > 80 mL · 100 g−1 · min−1), whereas VTA-GE-CBF values were more accurate in low-flow (ipsilateral) areas (CBF ≤ 60 mL · 100 g−1 · min−1). Accordingly, the concurrent usage of both AST-MRI methods or the VTA-GE technique alone would be preferred for human studies of stroke.

Dynamic contrast enhanced MRI parameters and tumor cellularity in a rat model of cerebral glioma at 7 T

To test the hypothesis that a noninvasive dynamic contrast enhanced MRI (DCE‐MRI) derived interstitial volume fraction (ve) and/or distribution volume (VD) were correlated with tumor cellularity in cerebral tumor.

Estimating Blood and Brain Concentrations and Blood-to-Brain Influx by Magnetic Resonance Imaging with Step-Down Infusion of Gd-DTPA in Focal Transient Cerebral Ischemia and Confirmation by Quantitative Autoradiography with Gd-[14C]DTPA

An intravenous step-down infusion procedure that maintained a constant gadolinium-diethylene-triaminepentaacetic acid (Gd-DTPA) blood concentration and magnetic resonance imaging (MRI) were used to localize and quantify the blood-brain barrier (BBB) opening in a rat model of transient cerebral ischemia (n = 7). Blood-to-brain influx rate constant (K i ) values of Gd-DTPA from such regions were estimated using MRI-Patlak plots and compared with the K, values of Gd-[14C]DTPA, determined minutes later in the same rats with an identical step-down infusion, quantitative autoradiography (QAR), and single-time equation. The normalized plasma concentration-time integrals were identical for Gd-DTPA and Gd-[14C]DTPA, indicating that the MRI protocol yielded reliable estimates of plasma Gd-DTPA levels. In six rats with a BBB opening, 14 spatially similar regions of extravascular Gd-DTPA enhancement and Gd-[14C]DTPA leakage, including one very small area, were observed. The terminal tissue-plasma ratios of Gd-[14C]DTPA tended to be slightly higher than those of Gd-DTPA in these regions, but the differences were not significant. The MRI-derived K i , values for Gd-DTPA closely agreed and correlated well with those obtained for Gd-[14C]DTPA. In summary, MRI estimates of Gd-DTPA concentration in the plasma and brain and the influx rate are quantitatively and spatially accurate with step-down infusions.

The MRI-measured arterial input function resulting from a bolus injection of Gd-DTPA in a rat model of stroke slightly underestimates that of Gd-[14C]DTPA and marginally overestimates the blood-to-brain influx rate constant determined by Patlak plots

The hypothesis that the arterial input function (AIF) of gadolinium‐diethylenetriaminepentaacetic acid injected by intravenous bolus and measured by the change in the T1‐relaxation rate (ΔR1; R1 = 1/T1) of superior sagittal sinus blood (AIF‐I) approximates the AIF of 14C‐labeled gadolinium‐diethylenetriaminepentaacetic acid measured in arterial blood (reference AIF) was tested in a rat stroke model (n = 13). Contrary to the hypothesis, the initial part of the ΔR1‐time curve was underestimated, and the area under the normalized curve for AIF‐I was about 15% lower than that for the reference AIF. Hypothetical AIFs for gadolinium‐diethylenetriaminepentaacetic acid were derived from the reference AIF values and averaged to obtain a cohort‐averaged AIF. Influx rate constants (Ki) and proton distribution volumes at zero time (Vp + Vo) were estimated with Patlak plots of AIF‐I, hypothetical AIFs, and cohort‐averaged AIFs and tissue ΔR1 data. For the regions of interest, the Kis estimated with AIF‐I were slightly but not significantly higher than those obtained with hypothetical AIFs and cohort‐averaged AIF. In contrast, Vp + Vo was significantly higher when calculated with AIF‐I. Similar estimates of Ki and Vp + Vo were obtained with hypothetical AIFs and cohort‐averaged AIF. In summary, AIF‐I underestimated the reference AIF; this shortcoming had little effect on the Ki calculated by Patlak plot but produced a significant overestimation of Vp + Vo. Magn Reson Med 63:1502–1509, 2010.

MRI Measurement of Change in Vascular Parameters in the 9L Rat Cerebral Tumor After Dexamethasone Administration

To demonstrate in the rat 9L cerebral tumor model that repeated MRI measurements can quantitate acute changes in the blood‐brain distribution of Gadomer after dexamethasone administration.

MRI estimation of gadolinium and albumin effects on water proton

The longitudinal relaxivity on the protons of water of a Gd-chelate-albumin compound was measured at 7 T as a function of the macromolecular content of a cross-linked matrix. In agreement with previous works, the results demonstrate that the effect of gadolinium on water proton relaxivity is not constant, rising moderately with increase in the concentration of bovine serum albumin (BSA). About 35% variation in relaxivity was observed over a 0%-25% range of BSA concentrations (ℜ = 3.893 + 0.0502 × BSA [%], SE = 0.0119 and 0.1740, t = 4.215 and 22.383, p < 0.014 and 0.001).

MRI and quantitative autoradiographic studies following bolus injections of unlabeled and 14C-labeled gadolinium-diethylenetriaminepentaacetic acid in a rat model of stroke yield similar distribution volumes and blood-to-brain influx rate constants

In previous studies on a rat model of transient cerebral ischemia, the blood and brain concentrations of gadolinium‐diethylenetriaminepentaacetic acid (Gd‐DTPA) following intravenous bolus injection were repeatedly assessed by dynamic contrast‐enhanced (DCE)‐MRI, and blood‐to‐brain influx rate constants (Ki) were calculated from Patlak plots of the data in areas with blood–brain barrier (BBB) opening. For concurrent validation of these findings, after completing the DCE‐MRI study, radiolabeled sucrose or α‐aminoisobutyric acid was injected intravenously, and the brain disposition and Ki values were calculated by quantitative autoradiography (QAR) assay employing the single‐time equation. To overcome two of the shortcomings of this comparison, the present experiments were carried out with a radiotracer virtually identical to Gd‐DTPA, Gd‐[14C]DTPA, and Ki was calculated from both sets of data by the single‐time equation. The protocol included 3u2009h of middle cerebral artery occlusion and 2.5u2009h of reperfusion in male Wistar rats (nu2009=u200915) preceding the DCE‐MRI Gd‐DTPA and QAR Gd‐[14C]DTPA measurements. In addition to Ki, the tissue‐to‐blood concentration ratios, or volumes of distribution (VR), were calculated. The regions of BBB opening were similar on the MRI maps and autoradiograms. Within them, VR was nearly identical for Gd‐DTPA and Gd‐[14C]DTPA, and Ki was slightly, but not significantly, higher for Gd‐DTPA than for Gd‐[14C]DTPA. The Ki values were well correlated (ru2009=u20090.67; pu2009=u20090.001). When the arterial concentration–time curve of Gd‐DTPA was adjusted to match that of Gd‐[14C]DTPA, the two sets of Ki values were equal and statistically comparable with those obtained previously by Patlak plots (the preferred, less model‐dependent, approach) of the same data (pu2009=u20090.2–0.5). These findings demonstrate that this DCE‐MRI technique accurately measures the Gd‐DTPA concentration in blood and brain, and that Ki estimates based on such data are good quantitative indicators of BBB injury. Copyright

Multiparametric Magnetic Resonance Imaging and Repeated Measurements of Blood-Brain Barrier Permeability to Contrast Agents

Breakdown of the blood-brain barrier (BBB) is present in several neurological disorders such as stroke, brain tumors, and multiple sclerosis. Noninvasive evaluation of BBB breakdown is important for monitoring disease progression and evaluating therapeutic efficacy in such disorders. One of the few techniques available for noninvasively and repeatedly localizing and quantifying BBB damage is magnetic resonance imaging (MRI). This usually involves the intravenous administration of a gadolinium-containing MR contrast agent (MRCA) such as Gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA), followed by dynamic contrast-enhanced MR imaging (DCE-MRI) of brain and blood, and analysis of the resultant data to derive indices of blood-to-brain transfer. There are two advantages to this approach. First, measurements can be made repeatedly in the same animal; for instance, they can be made before drug treatment and then again after treatment to assess efficacy. Secondly, MRI studies can be multiparametric. That is, MRI can be used to assess not only a blood-to-brain transfer or influx rate constant (Ki or K1) by DCE-MRI but also complementary parameters such as: (1) cerebral blood flow (CBF), done in our hands by arterial spin-tagging (AST) methods; (2) magnetization transfer (MT) parameters, most notably T1sat, which appear to reflect brain water-protein interactions plus BBB and tissue dysfunction; (3) the apparent diffusion coefficient of water (ADCw) and/or diffusion tensor, which is a function of the size and tortuosity of the extracellular space; and (4) the transverse relaxation time by T2-weighted imaging, which demarcates areas of tissue abnormality in many cases. The accuracy and reliability of two of these multiparametric MRI measures, CBF by AST and DCE-MRI determined influx of Gd-DTPA, have been established by nearly congruent quantitative autoradiographic (QAR) studies with appropriate radiotracers. In addition, some of their linkages to local pathology have been shown via corresponding light microscopy and fluorescence imaging. This chapter describes: (1) multiparametric MRI techniques with emphasis on DCE-MRI and AST-MRI; (2) the measurement of the blood-to-brain influx rate constant and CBF; and (3) the role of each in determining BBB permeability.

Intratumor distribution and test–retest comparisons of physiological parameters quantified by dynamic contrast-enhanced MRI in rat U251 glioma

The distribution of dynamic contrast‐enhanced MRI (DCE‐MRI) parametric estimates in a rat U251 glioma model was analyzed. Using Magnevist as contrast agent (CA), 17 nude rats implanted with U251 cerebral glioma were studied by DCE‐MRI twice in a 24u2009h interval. A data‐driven analysis selected one of three models to estimate either (1) plasma volume (vp), (2) vp and forward volume transfer constant (Ktrans) or (3) vp, Ktrans and interstitial volume fraction (ve), constituting Models 1, 2 and 3, respectively. CA distribution volume (VD) was estimated in Model 3 regions by Logan plots. Regions of interest (ROIs) were selected by model. In the Model 3 ROI, descriptors of parameter distributions – mean, median, variance and skewness – were calculated and compared between the two time points for repeatability. All distributions of parametric estimates in Model 3 ROIs were positively skewed. Test–retest differences between population summaries for any parameter were not significant (pu2009≥u20090.10; Wilcoxon signed‐rank and paired t tests). These and similar measures of parametric distribution and test–retest variance from other tumor models can be used to inform the choice of biomarkers that best summarize tumor status and treatment effects. Copyright