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James R Ewing

Publications and source records attributed to James R Ewing.

28 records · Page 2Linked to original sources

Quantitative evaluation of BBB permeability after embolic stroke in rat using MRI.

We sought to identify magnetic resonance imaging (MRI) parameters that can identify as well as predict disruption of the blood-brain barrier (BBB) after embolic stroke in the rat. Rats subjected to embolic stroke with (n=13) and without (n=13) rt-PA treatment were followed with MRI using quantitative permeability-related parameters, consisting of: transfer constant (K(i)) of Gd- DTPA, the distribution volume (V(p)) of the mobile protons, and the inverse of the apparent forward transfer rate for magnetization transfer (k(inv)), as well as the apparent diffusion coefficient of water (ADC(w)), T2, and cerebral cerebral blood flow (CBF). Tissue progressing to fibrin leakage resulting from BBB disruption and adjacent tissue were then analyzed to identify MRI markers that characterize BBB disruption. Animals were killed after final MRI measurements at 24 h after induction of embolic stroke and cerebral tissues were perfused and stained to detect fibrin leakage. K(i), V(p), and k(inv) were the most sensitive early (2 to 3 h) indices of the cerebral tissue that progresses to fibrin leakage. Cerebral blood flow was not significantly different between ischemic tissue with a compromised and an intact BBB. Our data indicate that compromise of the BBB can be sensitively predicted using a select set of MR parameters.

Animals↗

Neonatal brain: regional variability of in vivo MR imaging relaxation rates at 3.0 T--initial experience.

PURPOSE: To retrospectively investigate regional in vivo magnetic resonance (MR) imaging transverse and longitudinal relaxation rates at 3.0 T in neonatal brain, the relationship between these rates, and their potential use for gray matter (GM) versus white matter (WM) tissue discrimination. MATERIALS AND METHODS: Informed parental consent for performance of imaging procedures was obtained in each infant. Informed consent for retrospective image analysis was not required; ethics approval was obtained from institutional review board. At 3.0 T, R1 and R2 were measured in brain regions (frontal WM, posterior WM, periventricular WM, frontal GM, posterior GM, basal ganglia, and thalamus) in 13 infants with suspected neurologic abnormality (two term, 11 preterm). Maps of R1 and R2 were acquired with T1 by multiple readout pulses and segmented spin-echo echo-planar imaging sequences, respectively. Accuracy of R1 and R2 map acquisition methods was tested in phantoms by comparing them with inversion-recovery and spin-echo sequences, respectively. Statistical analysis included linear regression analysis to determine relationship between R1 and R2 and Wilcoxon signed rank test to investigate the potential for discrimination between GM and WM. RESULTS: In phantoms, R1 values measured with T1 by multiple readout pulses sequence were 3%-8% lower than those measured with inversion recovery sequence, and R2 values measured with segmented echo-planar sequence were 1%-8% lower than those measured with spin-echo sequence. A strong correlation of 0.944 (P < .001) between R1 and R2 in neonatal brain was observed. For R2, relative differences between GM and WM were larger than were those for R1 (z = -2.366, P < .05). For frontal GM and frontal WM, (R2(GM) - R2(WM))/R2(WM) yielded 0.8 +/- 0.2 (mean +/- standard deviation) and (R1(GM) - R1(WM))/R1(WM) yielded 0.3 +/- 0.09. CONCLUSION: Results at 3.0 T indicate that R1 decreases with increasing field strength, while R2 values are similar to those reported at lower field strengths. For neonates, R2 image contrast may be more advantageous than R1 image contrast for differentiation between GM and WM.

Brain↗

MRI evaluation of treatment of embolic stroke in rat with intra-arterial and intravenous rt-PA.

Using magnetic resonance imaging (MRI), we investigated treatment of a rat model of embolic stroke with rt-PA via intra-arterial (IA) and intravenous (IV) routes of administration. Rats were treated with rt-PA by either IA (n = 13) or IV (n = 13) routes at 3 h after stroke induction. Diffusion, perfusion, T2, and magnetization transfer MRI were performed prior to and at 1-3 and at 24 h after embolization. The IA treated group exhibited smaller lesion volumes than the IV treated group (p = 0.02). The relative areas with low ADCW and cerebral blood flow (CBF) after IA rt-PA intervention were significantly (p < or = 0.03) smaller than those in the IV treated group at 24 h after embolization. Significant differences (p < 0.02) between IA and IV treated groups in the relative area with high T2 and inverse of the apparent forward transfer rate of magnetization (kINV) in the ipsilateral hemisphere were also detected at 24 h after embolization. The IA treated group exhibited less intracerebral hemorrhage (27%) than the IV treated (64%) groups. Our data suggest that the beneficial effects of IA rt-PA treatment can be detected by changes in CBF, ADCW, T2, and kINV.

Animals↗

Multiparametric ISODATA analysis of embolic stroke and rt-PA intervention in rat.

To increase the sensitivity of MRI parameters to detect tissue damage of ischemic stroke, an unsupervised analysis method, Iterative Self-Organizing Data Analysis Technique Algorithm (ISODATA), was applied to analyze the temporal evolution of ischemic damage in a focal embolic cerebral ischemia model in rat with and without recombinant tissue plasminogen activator (rt-PA) treatment. Male Wistar rats subjected to embolic stroke were investigated using a 7-T MRI system. Rats were randomized into control (n=9) and treated (n=9) groups. The treated rats received rt-PA via a femoral vein at 4 h after onset of embolic ischemia. ISODATA analysis employed parametric maps or weighted images (T1, T2, and diffusion). ISODATA results with parametric maps are superior to ISODATA with weighted images, and both of them were highly correlated with the infarction size measured from the corresponding histological section. At 24 h after embolic stroke, the average map ISODATA lesion sizes were 37.7+/-7.0 and 39.2+/-5.6 mm2 for the treated and the control group, respectively. Average histological infarction areas were 37.9+/-7.4 mm2 for treated rats and 39.4+/-6.1 mm2 for controls. The R2 values of the linear correlation between map ISODATA and histological data were 0.98 and 0.96 for treated and control rats, respectively. Both histological and map ISODATA data suggest that there is no significant difference in infarction area between non-treated and rt-PA-treated rats when treatment was administered 4 h after the onset of embolic stroke. The ISODATA lesion size analysis was also sensitive to changes of lesion size during acute and subacute stages of stroke. Our data demonstrate that the multiparameter map ISODATA approach provides a more sensitive quantitation of the ischemic lesion at all time points than image ISODATA and single MRI parametric analysis using T1, T2 or ADCw.

Algorithms↗

Multiparametric iterative self-organizing MR imaging data analysis technique for assessment of tissue viability in acute cerebral ischemia.

BACKGROUND AND PURPOSE: Defining viability and the potential for recovery of ischemic brain tissue can be very valuable for patient selection for acute stroke therapies. Multiparametric MR imaging analysis of ischemic lesions indicates that the ischemic lesion is inhomogeneous in degree of ischemic injury and recovery potential. We sought to define MR imaging characteristics of ischemic lesions that are compatible with viable tissue. METHODS: We included patients with supratentorial ischemic stroke who underwent multiparametric MR imaging studies (axial multi-spin-echo T2-weighted imaging, T1-weighted imaging, and diffusion-weighted imaging) at the acute (< 24 hours) and outcome (3 months) phases of stroke. Using the algorithm Iterative Self-Organizing Data Analysis Technique (ISODATA), the lesion was segmented into clusters and each was assigned a number, called the tissue signature (white matter = 1, CSF = 12, all others between these two). Recovery was defined as at least a 20% size reduction from the acute phase ISODATA lesion volume to the outcome phase T2-weighted imaging lesion volume. The tissue signature data were collapsed into the following categories: < or = 3, 4, 5, and > or = 6. Logistic regression analysis included the following parameters: lesion volume, tissue signature value, apparent diffusion coefficient (ADC) value, relative ADC (rADC) expressed as a ratio, T2 value, and T2 ratio. The model with the largest goodness of fit value was selected. RESULTS: We included 48 patients (female-male ratio, 26:22; age, 64 [+/-14] years; 15 treated with recombinant tissue plasminogen activator [rt-PA] within 3 hours of onset; median National Institutes of Health Stroke Scale score, 7 [range, 2-26]). Median symptom onset-to-MR imaging time interval was 9.5 hours. With ISODATA processing, we generated 200 region-of-interest tissue records (one to nine tissue records per patient). Regarding tissue recovery, we detected a three-way interaction among ADC, ISODATA tissue signature, and previous treatment with rt-PA (P = .003). In the group not treated with rt-PA, ischemic tissues with acute rADC greater than the median (0.79) and tissue signature < or = 4 were more likely to recover (80% vs. 31% and 13%, odds ratio [95% CI]: 0.12 [0.05, 0.30] and 0.04 [0.01, 0.18] for tissue signatures 5 and 6, respectively). CONCLUSION: ISODATA multiparametric MR imaging of acute stroke clearly shows inhomogeneity and different viability of the ischemic lesion. Ischemic tissues with lower acute phase ISODATA tissue signature values (< or = 4) and higher rADC values (> or = 0.79) are much more likely to recover than those with higher signature values or lower rADC values. The effect of these factors on tissue recovery, however, is dependent on whether preceding treatment with rt-PA had been performed. Our approach can be a valuable tool in the design of therapeutic stroke trials with an extended time window.

Acute Disease↗

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 (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 deltaR(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(-1)) or mean V(p) in contralateral brain (0.015 ml g(-1)). This elevated V(p) may reflect increased capillary permeability to water. In conclusion, K(i) can be reliably calculated from Gd-DTPA-MRI data by Patlak plots.

Animals↗

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 ( approximately 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 < or= 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.

Animals↗

Magnetic resonance imaging characterization of hemorrhagic transformation of embolic stroke in the rat.

Intracranial hemorrhage is a critical factor when considering efficacy and safety of thrombolytic intervention after thromboembolic stroke. This study tested whether magnetic resonance imaging could identify tissue for hemorrhagic transformation after the onset of embolic stroke. Rats subjected to embolic stroke with and without recombinant tissue-type plasmogen activator (rt-PA) treatment were followed-up with magnetic resonance imaging using the inverse of the apparent forward transfer rate for magnetization transfer (k(inv)), gadolinium-chelate contrast-enhanced magnetic resonance imaging, and diffusion-, perfusion-, and T2-weighted imaging. Rats with embolic stroke either were treated with rt-PA 1 (n = 16) or 4 hours (n = 13) after stroke onset or were not treated (n = 15). From these groups, at total of 17 rats had intracerebral hemorrhage. Tissue progressing to hemorrhage and adjacent to the site of hemorrhage was analyzed to identify magnetic resonance imaging markers that characterize hemorrhagic transformation. The parameter maps of k(inv) and contrast-enhanced magnetic resonance imaging showed greater sensitivity in the detection of tissue destined for hemorrhagic transformation compared with the apparent diffusion coefficient of water (ADCw) and CBF. In tissue not destined to undergo hemorrhagic transformation, k(inv) maps and contrast-enhanced magnetic resonance imaging exhibited small increases in k(inv) and contrast-enhanced magnetic resonance imaging signal intensity in the area encompassing the territory supplied by the middle cerebral artery. In contrast, large increases in k(inv) and in signal intensity in the contrast-enhanced magnetic resonance images were detected in the region where gross hemorrhage was confirmed histologically. The values of k(inv), T2, and signal intensity in the contrast-enhanced magnetic resonance images were significantly higher in the region destined for hemorrhagic transformation (k(inv), P < or = 0.033 3-24 hours after embolization; T2, P < or = 0.037 24-48 hours; contrast-enhanced magnetic resonance imaging, P < 0.05 4-7 hours) compared with the nonhemorrhagic transformation ischemic region or in the contralateral homologous regions after onset of ischemia. Of these methods, k(inv) shows the most sensitivity in the detection of hemorrhagic transformation soon after embolization. The authors' data suggest that k(inv) and contrast-enhanced magnetic resonance imaging are potentially important methodologies for detecting tissue destined for hemorrhagic transformation.

Animals↗

Noninvasive detection of radiation-induced optic neuropathy by manganese-enhanced MRI.

Available imaging techniques have a limited ability to detect radiation-induced injury of the normal brain. In particular, there is no noninvasive method available for detection of structural or functional neuronal damage induced by radiation. This study was designed to determine whether MRI enhanced using the neuronal track tracer MnCl(2) can detect radiation-induced optic neuropathy. A single dose of radiation (35 Gy) was delivered to produce optic neuropathy in Fischer 344 rats by using a stereotactic method with a 6-mm dorsoventral secondary collimator. At 6 months after irradiation, MRI was performed in 1-mm sections using a 7-T magnetic field with the neuronal tracer MnCl(2) injected into the vitreous of the eye 24 h prior to imaging. The rats were then killed humanely for a histological study with hematoxylin and eosin, glial fibrillary acidic protein (Gfap) for the detection of astrocytic activity, Luxol Fast Blue/Periodic Acid Schiff (LFB/PAS) for the detection of myelinization status, and Bielschowski silver stain for axon status. In nonirradiated control animals, T1-weighted MRI with manganese vitreous injection revealed an optic nerve track that was brightly enhanced from the orbit to the optic chiasm. In the irradiated animals, there was clear evidence of the damage at the optic chiasm and optic nerves, with loss of axon and demyelinization within the site of irradiation upon histological examination. T1-weighted MRI with manganese vitreous injection showed an enhancing optic nerve posterior to the orbit. However, this enhancement disappeared at the site of irradiation. The area of loss of manganese contrast on the MRI scan correlated well with the area of histological abnormality showing axonal degeneration and demyelinization. Radiation-induced optic neuropathy was thus detected noninvasively by MRI with the antegrade neuronal tracer manganese, which exhibited negative contrast enhancement by causing loss of signal. This study represents the first demonstration of MR imaging of radiation-induced neuronal damage and could provide a means to explore the biological and functional integrity of neuronal pathways.

Animals↗