Correlated sodium and potassium imbalances within the ischemic core in experimental stroke: a 23Na MRI and histochemical imaging study.

This study addresses the spatial relation between local Na(+) and K(+) imbalances in the ischemic core in a rat model of focal ischemic stroke. Quantitative [Na(+)] and [K(+)] brain maps were obtained by (23)Na MRI and histochemical K(+) staining, respectively, and calibrated by emission flame photometry of the micropunch brain samples. Stroke location was verified by diffusion MRI, by changes in tissue surface reflectivity and by immunohistochemistry with microtubule-associated protein 2 antibody. Na(+) and K(+) distribution within the ischemic core was inhomogeneous, with the maximum [Na(+)] increase and [K(+)] decrease typically observed in peripheral regions of the ischemic core. The pattern of the [K(+)] decrease matched the maximum rate of [Na(+)] increase ('slope'). Some residual mismatch between the sites of maximum Na(+) and K(+) imbalances was attributed to the different channels and pathways involved in transport of the two ions. A linear regression of the [Na(+)]br vs. [K(+)]br in the samples of ischemic brain indicates that for each K(+) equivalent leaving ischemic tissue, 0.8±0.1 Eq, on average, of Na(+) enter the tissue. Better understanding of the mechanistic link between the Na(+) influx and K(+) egress would validate the (23)Na MRI slope as a candidate biomarker and a complementary tool for assessing ischemic damage and treatment planning.

Sodium time course using 23Na MRI in reversible focal brain ischemia in the monkey.

PURPOSE: To demonstrate the use of sodium MRI for measuring the time course of tissue sodium concentration (TSC) in a nonhuman primate model of reversible focal brain ischemia. MATERIALS AND METHODS: Reversible endovascular focal brain ischemia was induced in nonhuman primates (n = 4), and sodium MRI was performed on a 3 Tesla scanner for monitoring changes in TSC during both the middle cerebral artery (MCA) occlusion and MCA reperfusion portions of the experiment. RESULTS: The TSC increased linearly in the ischemic tissue during MCA occlusion (ranging from a mean TSC increase of 5.44%/h to 7.15%/h across the four subjects), and then there was a statistically significant change from a positive TSC slope during MCA occlusion to a TSC slope after MCA reperfusion that was not statistically different from zero. The linear increase in sodium MRI during brain ischemia was used to estimate the stroke onset time to within 0.45 h in each of the four subjects (with a maximum 95% confidence interval of +/- 1.147 h). CONCLUSION: The data indicate that sodium MRI increases linearly during brain ischemia, and that this increase is stopped by tissue reperfusion within 5.4 h after stroke onset.

Inhomogeneous sodium accumulation in the ischemic core in rat focal cerebral ischemia by 23Na MRI.

PURPOSE: To test the hypotheses that (i) the regional heterogeneity of brain sodium concentration ([Na(+)](br)) provides a parameter for ischemic progression not available from apparent diffusion coefficient (ADC) data, and (ii) [Na(+)](br) increases more in ischemic cortex than in the caudate putamen (CP) with its lesser collateral circulation after middle cerebral artery occlusion in the rat. MATERIALS AND METHODS: (23)Na twisted projection MRI was performed at 3 Tesla. [Na(+)](br) was independently determined by flame photometry. The ischemic core was localized by ADC, by microtubule-associated protein-2 immunohistochemistry, and by changes in surface reflectivity. RESULTS: Within the ischemic core, the ADC ratio relative to the contralateral tissue was homogeneous (0.63 +/- 0.07), whereas the rate of [Na(+)](br) increase (slope) was heterogeneous (P < 0.005): 22 +/- 4%/h in the sites of maximum slope versus 14 +/- 1%/h elsewhere (here 100% is [Na(+)](br) in the contralateral brain). Maximum slopes in the cortex were higher than in CP (P < 0.05). In the ischemic regions, there was no slope/ADC correlation between animals and within the same brain (P > 0.1). Maximum slope was located at the periphery of ischemic core in 8/10 animals. CONCLUSION: Unlike ADC, (23)Na MRI detected within-core ischemic lesion heterogeneity.

MAP2 immunostaining in thick sections for early ischemic stroke infarct volume in non-human primate brain.

The delineation of early infarction in large gyrencephalic brain cannot be accomplished with triphenyl-tetrazolium chloride (TTC) due to its limitations in the early phase, nor can it be identified with microtubule-associated protein 2 (MAP2) immunohistochemistry, due to the fragility of large thin sections. We hypothesize that MAP2 immunostaining of thick brain sections can accurately identify early ischemia in the entire monkey brain. Using ischemic brains of one rat and three monkeys, a thick-section MAP2 immunostaining protocol was developed to outline the infarct region over the entire non-human primate brain. Comparison of adjacent thick and thin sections in a rat brain indicated complete correspondence between ischemic regions (100.4mm(3)+/-1.2%, n=7, p=0.44). Thick sections in monkey brain possessed the increased structural stability necessary for the extensive MAP2 immunostaining procedure permitting quantification of the ischemic region as a percent of total monkey brain, giving infarct volumes of 11.4, 16.3, and 19.0% of total brain. Stacked 2D images of the intact thick brain tissue sections provided a 3D representation for comparison to MRI images. The infarct volume of 16.1cm(3) from the MAP2 sections registered with MRI images agreed well with the volume calculated directly from the stained sections of 16.6 cm(3). Thick brain tissue section MAP2 immunostaining provides a new method for determining infarct volume over the entire brain at early time points in a non-human primate model of ischemic stroke.

Sodium mapping in focal cerebral ischemia in the rat by quantitative (23)Na MRI.

PURPOSE: To validate (23)Na twisted projection magnetic resonance imaging (MRI) as a quantitative technique to assess local brain sodium concentration ([Na(+)](br)) during rat focal ischemia every 5.3 minutes. MATERIALS AND METHODS: The MRI protocol included an ultrashort echo-time (0.4 msec), a correction of radiofrequency (RF) inhomogeneities by B(1) mapping, and the use of 0-154 mM NaCl calibration standards. To compare MRI [Na(+)](br) values with those obtained by emission flame photometry in precision-punched brain samples of about 0.5 mm(3) size, MR images were aligned with a histological three-dimensional reconstruction of the punched brain and regions of interest (ROIs) were placed precisely over the punch voids. RESULTS: The Bland-Altman analysis of [Na(+)](br) in normal and ischemic cortex and caudate putamen of seven rats quantitated by (23)Na MRI and flame photometry yielded a mean bias and limits of agreement (at +/-1.96 SD) of 2% and 43% of average, respectively. A linear increase in [Na(+)](br) was observed between 1 and 6 hours after middle cerebral artery occlusion. CONCLUSION: (23)Na MRI provides accurate and reliable results within the whole range of [Na(+)](br) in ischemia with a temporal resolution of 5.3 minutes and precisely targeted submicroliter ROIs in selected brain structures.

Loss of cell ion homeostasis and cell viability in the brain: what sodium MRI can tell us.

This chapter demonstrates the use of sodium magnetic resonance imaging (MRI) as a noninvasive, in vivo means to assess metabolic changes that ensue from loss of cell ion homeostasis due to cell death in the brain. The chapter is organized in two sections. In the first section, the constraints imposed on the imaging methods by the nuclear magnetic resonance (NMR) properties of the sodium ion are discussed and strategies for avoiding their potential limitations are addressed. The second section illustrates the use of sodium MRI for monitoring focal brain ischemia in permanent and temporary primate models of endovascular middle cerebral artery occlusion.