Mechanisms that underlie early ischemic damages to the blood-brain-barrier (BBB) are not well understood. This study presents a novel magnetic resonance imaging (MRI) technique using a widely available pulse sequence and a long-circulating intravascular contrast agent to quantify water movements across the BBB at early stages of stroke progression. We characterized the integrity of the BBB by measuring the flip angle dependence of the water exchange-affected MRI signal intensity, to generate an efficient quantitative index of vascular permeability (WEI, or water exchange index). We performed in vivo MRI experiments to measure the transvascular WEI immediately after the permanent filament occlusion of the middle cerebral artery of mice (n ‫؍‬ 5), in which we monitored changes in blood volume (V b ), apparent diffusion coefficient (ADC), and intra-/extravascular WEI for 4 hours. Statistically significant elevations (P < 0.05) of WEI in the ischemic tissue were observed as early as 1 hour after ischemic onset. Initial reduction of the apparent blood volume (V app ) in the infarct cortex was followed by a continuous increase of V app over time. After an ischemic insult, the affected cerebral tissue undergoes a series of changes associated with initially reversible damages that eventually evolve into irreversible tissue damage (1). Biophysical alterations due to ischemic injury include cell swelling, reduced water diffusion, disruption of the blood-brain-barrier (BBB), and loss of cell membrane integrity (2). Almost immediately after ischemic attack, cytotoxic edema, characterized by cellular swelling occurs, leading to an increase in intracellular fluid and a concomitant reduction in extracellular/extravascular water content. The primary mechanism of such changes is believed to a decrease in the intracellular ATP that drives the sodium-potassium pump, and a resultant increase in intracellular sodium concentration, which together create an osmotic pressure gradient. The early increase in cellular volume has been frequently documented, as have changes in both intra-and extracellular water diffusion properties (3,4). Infarcted tissue in acute ischemia typically exhibits restricted water diffusion (i.e., apparent diffusion coefficient: ADC) when examined with diffusionweighted magnetic resonance imaging (DWI) (5). At later phases, vasogenic edema, associated with local disruption of the blood-brain-barrier (BBB), follows the cytotoxic edema (1). The dysfunctional BBB leads to the extravasation of protein-rich plasma, with subsequent accumulation of vascular fluid in the interstitial space. BBB disruption arises when tight junctions between endothelial cells disengage, during which the neoformation and enhanced activity of pinocytic vesicles are frequently observed (6). Both hydrostatic and osmotic forces created by blood perfusion and the interstitial accumulation of various biological molecules induce the extravasation of intravascular fluid (7).Because vasogenic edema accompanies the extravasation of protein, spatial ...

It is important to evaluate the tumor interstitial volume fraction that is accessible for drug accumulation during the distribution phase in order to determine the potential efficacy of cancer chemotherapy. In this study, we performed simulations of magnetic resonance imaging (MRI) signal intensity using a twocompartment tissue model for quantitative analyses of absolute interstitial volume measurements while we experimentally characterized a mouse tumor model with a dual MR contrastagent method. Previously, consecutive intravenous injections of a strictly intravascular T 1 contrast agent followed by an extravasating agent were used as a strategy for the quantification of both relative blood volume (Rel_BV) and relative interstitial volume (Rel_ITST) (Weissleder et al. Eur J Cancer 1998; 34:1448 -1454; Bogdanov et al. Neoplasia 1991;1:438 -435). In the current study, we demonstrate that this approach can be further improved, and that it enables one to accurately evaluate both relative and absolute interstitial volumes. The animal data indicated that a significant difference exists between the absolute interstitial volume fractions of subcutaneously implanted MDA PCa 2b tumor and skeletal muscle tissue (27.5 ؎ 9.1% and 15.9 ؎ 0.7%, respectively (P < 0.05)), while only a minor difference was found for the absolute blood volumes (Abs_BV) (Kim et al.