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.

Objective: This study tested the hypothesis that blood-brain barrier (BBB) opening during acute reperfusion permits the passage of smaller macromolecules but not larger ones and that this molecular size restriction disappears over time. Methods:Following 3 hours (h) of unilateral middle cerebral artery occlusion and either 3 or 21 h of reperfusion, Wistar rats (n = 42) were injected with Evans blue (EB, a fluorescent dye that binds instantly to plasma albumin yielding EB-tagged albumin, EB-Alb) and with one of three fluorescent dextrans ranging in size from 77-to 2000-kDa. During occlusion and reperfusion, ischemic status of the affected tissue was confirmed by magnetic resonance imaging (MRI). Blood-to-brain transfer of the dextrans relative to that of EB-Alb was examined by fluorescence microscopy within three regions with ischemic damage.

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 24 h interval. A data-driven analysis selected one of three models to estimate either: 1) CA 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 interstitial 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 (p≥0.10; Wilcoxon signed-rank and paired t tests). This 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.

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The purpose of this study was to characterize changes in tumor vascular parameters hours after a single radiation exposure in an orthotopic brain tumor model. U-251 human brain tumors were established intracerebrally in rat brains, and tumor blood flow, forward volume transfer constant (K(trans)) and interstitial volume fraction (v(e)) were measured using magnetic resonance imaging (MRI). Tumors were exposure to a single stereotactic radiation treatment of 20 Gy. Vascular parameters were assessed one additional time between 2 and 24 h after irradiation. After the second MRI session, brain tissue histology was examined for gross changes and apoptosis. In separate studies, cerebral blood flow was measured in nonimplanted controls before radiation exposure and 2 and 24 h after 20 Gy irradiation, and in implanted rats before radiation exposure and at 2 and 24 h after 6 Gy irradiation. Significant changes were observed in tumor-bearing rat brains in the hours after 20 Gy irradiation. Two hours after 20 Gy irradiation, tumor blood flow decreased nearly 80% and ve decreased by 30%. At 4 h, the K(trans) increased by 30% over preirradiation values. Extensive vacuolization and an increase in apoptosis were evident histologically in rats imaged 2 h after irradiation. Between 8 and 12 h after irradiation, all vascular parameters including blood flow returned to near preirradiation values. One day after irradiation, tumor blood flow was elevated 40% over preirradiation values, and other vascular parameters, including K(trans) and ve, were 20-40% below preirradiation values. In contrast, changes in vascular parameters observed in the normal brain 2 or 24 h after 20 Gy irradiation were not significantly different from preirradiation values. Also, tumor blood flow appeared to be unchanged at 2 h after 6 Gy irradiation, with a small increase observed at 24 h, unlike the tumor blood flow changes after 20 Gy irradiation. Large and significant changes in vascular parameters were observed hours after 20 Gy irradiation using noninvasive MRI techniques. It is hypothesized that cellular swelling hours after a high dose of radiation, coinciding with vacuolization, led to a decrease in tumor blood flow and v(e). Four hours after radiation exposure, K(trans) increased in concert with an increase in tumor blood flow. Vascular permeability normalized, 24 h after 20 Gy irradiation, as characterized by a decrease in K(trans). Vascular parameters did not change significantly in the normal brain after 20 Gy irradiation or in the tumor-bearing brain after 6 Gy irradiation.