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Biomedical subjects

Michael Chopp

Publications and source records attributed to Michael Chopp.

At least 91 records · Page 5Linked to original sources
PubMed2004

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↗
PubMed2004

Down-regulation of p27kip1 increases proliferation of progenitor cells in adult rats.

Cyclin-dependent kinases (CDK) mediate the cell division cycle during G1 phase and CDK inhibitors negatively regulate the cell cycle. We investigated expression of the CDK inhibitor p27Kip1 and the effects of PI-3K/Akt on proliferation of progenitors in the subventricular zone of adult rat. Western blots and immunostaining revealed that 4 days after stroke, p27kip1 levels decreased and were absent in nuclei of the ipsilateral subventricular zone cells 7 days after stroke. Reduction in p27kip1 levels was concurrent with significant increases in BrdU immunoreactive cells in the subventricular zone. Treatment of stroke neurospheres with LY294002 significantly (p<0.05) reduced the numbers of neurospheres from 32 +/-5 in the stroke group to 14 +/- 3 in the stroke and LY294002 group. Collectively, our data suggest that stroke induced neural progenitor proliferation is mediated by down-regulation of p27Kip1 and activation of Akt.

Animals↗
PubMed2004

Stroke transiently increases subventricular zone cell division from asymmetric to symmetric and increases neuronal differentiation in the adult rat.

The orientation of mitotic cleavage regulates neurogenesis during neural development. We examined the orientation of mitotic cleavage of dividing progenitor cells in the subventricular zone (SVZ) of adult rats subjected to stroke. In nonstroke rats, 55% of dividing cells were oriented horizontally, whereas 40% were oriented vertically. Horizontal and vertical cleavage orientations produce asymmetric and symmetric divisions, respectively. Four days after stroke, the number of dividing cells increased twofold, whereas the proportion of symmetric dividing cells significantly (p < 0.01) increased from 40% before stroke to 60%. Fourteen days after stroke, the percentage of symmetric dividing cells was 47%. Stroke-increased numbers of dividing cells in M-phase were confirmed by immuostaining. In nonstroke rats, 37 and 33% of symmetric and asymmetric dividing cells, respectively, exhibited a neuronal marker (TuJ1). Four days after stroke, rats exhibited a significant (p < 0.05) augmentation of the frequency (47%) of neuronal distribution showing TuJ1 immunoreactivity in cells with symmetric division but not cells with asymmetric division (33%). Numb immunoreactivity was detected in SVZ cells of nonstroke rats. Stroke did not change Numb distribution. Our data suggest that neurons are produced by both asymmetric and symmetric cell divisions in the adult SVZ, and the transient increases in symmetric division and neuronal differentiation may result in stroke-induced neurogenesis.

Animals↗
PubMed2004

Erythropoietin up-regulates SOCS2 in neuronal progenitor cells derived from SVZ of adult rat.

We examined the effects of EPO on expression of suppressor of cytokine signaling 2 (SOCS2) and found that treatment of neural progenitor cells derived from the adult subventricular zone (SVZ) with recombinant human EPO (rhEPO) stimulated progenitor cell differentiation into neurons, but not astrocytes. Quantitative RT-PCR revealed that SOCS2 mRNA levels were increased in the progenitor cells treated with rhEPO. Immunostaining showed that neurons but not astrocytes were SOCS2 immunoreactive. Incubation of the progenitor cells with rhEPO in the presence of a neutralizing antibody against EPO abolished the effects of EPO on neuronal differentiation and expression of SOCS2. Our data suggest that up-regulation of SOCS2 in neuronal progenitor cells derived from the adult SVZ may regulate EPO enhanced neuronal differentiation.

Animals↗
PubMed2004

Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats.

BACKGROUND AND PURPOSE: Erythropoietin (EPO) promotes proliferation and differentiation of erythroid progenitors and the survival of maturing erythroid cells. Here, we investigated the role of EPO in brain repair after stroke. METHODS: Rats were treated with recombinant human EPO (rhEPO) at 24 hours after the onset of embolic stroke. An array of behavior tests was performed. Rats were euthanized 28 days after stroke for measurements of infarct volume, angiogenesis, and neurogenesis. In vitro, neurospheres derived from the subventricular zone (SVZ) of the rat and cerebral endothelial cells derived from the mouse were treated with rhEPO. Capillary-like tube formation and neuronal differentiation were measured. RESULTS: Treatment with rhEPO significantly improved functional recovery, along with increases in density of cerebral microvessels at the stroke boundary and numbers of BrdU, doublecortin, and nestin immunoreactive cells in the SVZ. rhEPO treatment significantly increased brain levels of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF). In vitro, rhEPO enhanced capillary tube formation of cerebral endothelial cells, which was inhibited by a specific VEGF receptor 2 antagonist (SU1498). Incubation of neurospheres derived from stroke SVZ with anti-EPO neutralizing antibody inhibited neurogenesis, whereas incubation of stroke-derived neurospheres with rhEPO enhanced neurogenesis. CONCLUSIONS: Our data suggest that EPO-increased VEGF and BDNF may be involved in angiogenesis and neurogenesis, which could contribute to functional recovery.

Angiogenesis Inducing Agents↗
PubMed2004

Combination therapy of stroke in rats with a nitric oxide donor and human bone marrow stromal cells enhances angiogenesis and neurogenesis.

We tested the hypothesis that intravenous infusion of human marrow stromal cells (hMSC) with a nitric oxide donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) aminio] diazen-1-ium-1,2-diolate (DETA/NONOate), enhances angiogenesis, neurogenesis and neurological functional recovery after stroke in rats compared to individual therapy. Experimental groups consist of rats subjected to 2 h of middle cerebral artery occlusion (MCAo) and at 24 h after MCAo intravenous injection of (n=10/group): Group 1: phosphate buffered saline (PBS 1 ml) for control. Group 2: NONOate alone (0.4 mg/kg). Group 3: hMSCs (1 x 10(6)) alone. Group 4: hMSCs (1 x 10(6)) with NONOate (0.4 mg/kg). Functional tests and immunohistochemical staining were performed. Marginal functional recovery after treatment of stroke was found with 1 x 10(6) hMSCs alone (p=0.06) and no benefit was detected with NONOate alone (0.4 mg/kg, p=0.64). However, NONOate+hMSCs in combination significantly induced functional recovery (p<0.05). Treatment using hMSC in combination with NONOate significantly increased vessel perimeter and endothelial cell proliferation compared with hMSC or NONOate alone treatment (p<0.05). Cell proliferation and neurogenesis were assessed with bromodeoxyuridine (BrdU) labeling and immunostaining for cell type-specific markers. Combination treatment promoted increased, BrdU positive cell number in the subventricular zone (SVZ), migrating neuronal doublecortin immunoreactive cells and VEGF and bFGF expression in the ischemic boundary area compared to individual treatment. The functional therapeutic enhancement of combination treatment may be attributed to increased plasticity induced by the combination of a nitric oxide donor and hMSC therapy. These data suggest that pharmacological and cellular therapy may provide an additive therapeutic benefit after stroke.

Animals↗
PubMed2004

In vivo magnetic resonance imaging tracks adult neural progenitor cell targeting of brain tumor.

Using magnetic resonance imaging (MRI), we described a method for noninvasively tracking grafted neural progenitor cells and bone marrow stromal cells (MSCs) in brain tumor of the rat. Neural progenitor cells and MSCs were labeled with lipophilic dye-coated superparamagnetic particles. The labeled neural progenitor cells and MSCs were transplanted to rats via the cisterna magna and a tail vein, respectively, 1 week after 9L-gliosarcoma cell implantation. Three-dimensional (3D) gradient echo and contrast agent images revealed dynamic migration of adult neural progenitor cells and MSCs detected by loss of MRI signals towards tumor mass and infiltrated tumor cells. Prussian blue staining and fluorescent microscope analysis showed that grafted cells targeted tumor cells and areas with grafted cells corresponded to areas with loss of MRI signals. These results demonstrate that the MRI technique provides a sensitive method for in vivo assessment of grafted cells targeting tumor mass and infiltrated tumor cells and that adult neural progenitor cells and MSCs can target tumor aggregates in the brain.

Animals↗
PubMed2004

Atorvastatin reduces neurological deficit and increases synaptogenesis, angiogenesis, and neuronal survival in rats subjected to traumatic brain injury.

Statins administered postischemia promote functional improvement in rats, independent of their capability to lower cholesterol. We therefore tested the effect of statin treatment on traumatic brain injury (TBI) in rats. Atorvastatin was orally administered (1 mg/kg/day) to Wistar rats starting 1 day after TBI for 7 consecutive days. Control animals received saline. Modified Neurological Severity Scores and Corner tests were utilized to evaluate functional response to treatment. Bromodeoxyuridine (BrdU, 100 mg/kg) was also intraperitoneally injected daily for 14 consecutive days to label the newly generated endothelial cells. Rats were sacrificed at day 14 after TBI, and the brain samples were processed for immunohistochemical staining. Atorvastatin administration after brain injury significantly reduced the neurological functional deficits, increased neuronal survival and synaptogenesis in the boundary zone of the lesion and in the CA3 regions of the hippocampus, and induced angiogenesis in these regions. The results suggest that atorvastatin may provide beneficial effects in experimental TBI.

Administration, Oral↗
PubMed2004

Intravenous administration of marrow stromal cells (MSCs) increases the expression of growth factors in rat brain after traumatic brain injury.

This study was designed to investigate the effects of intravenous administration of marrow stromal cells (MSCs) on the expression of growth factors in rat brain after traumatic brain injury (TBI). The fate of transplanted MSCs and expression of growth factors was examined by immunohistochemistry. In addition, the level of growth factors was measured quantitatively using enzyme linked immunosorbent assay (ELISA). Growth factors that were studied included nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and basic fibroblast growth factor (bFGF). For immunohistochemical studies, 12 male Wistar rats were subjected to TBI and then divided into three groups with the first group receiving no treatment, the second group receiving saline (placebo) and the third group receiving MSCs intravenously 1 day after TBI. The neurological function of rats was studied by using Rotarod motor test and modified neurological severity scores. The animals were sacrificed 15 days after TBI and brain sections stained by immunohistochemistry to study the distribution of MSCs as well as expression of growth factors NGF, BDNF, and bFGF. For quantitative analysis, a second set of male Wistar rats (n = 18) was subjected to TBI and then injected with either saline (n = 9) or MSCs (n = 9) 1 day after injury. These rats were sacrificed on days 2, 5, and 8 after TBI and brain extracts used to measure NGF, BDNF, and bFGF. We found that after transplantation, MSCs preferentially migrated into the injured hemisphere and there was a statistically significant improvement in the functional outcome of MSC-treated rats compared to control rats. NGF, BDNF, and bFGF were expressed in the injured brain of both treated as well as control rats; however, quantitative ELISA studies showed that expression of NGF and BDNF was significantly increased (p < 0.05) in the treated group. This study shows that intravenous administration of MSCs after TBI increases the expression of growth factors (NGF, BDNF), which possibly contributes to the improvement in functional outcome seen in these rats.

Animals↗
PubMed2004

Delayed thrombosis after traumatic brain injury in rats.

Secondary thrombosis may contribute to cerebral ischemia caused by traumatic brain injury (TBI). In this study, we sought to investigate the temporal and spatial profiles of intravascular thrombosis and to evaluate the effect of atorvastatin, a beta-hydroxy-beta-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitor, on thrombosis after TBI. Young male Wistar rats weighing 350-400 g were subjected to controlled cortical impact injury, and were sacrificed at 1 and 4 h, and 1, 3, 8, and 15 days after TBI (5 rats/time point), respectively. For the evaluation of the effects of atorvastatin on intravascular thrombosis, rats were subjected to TBI, and subsequently atorvastatin (1 mg/kg) was orally administered starting 1 day after TBI and then daily until sacrifice at 3, 8, and 15 days after TBI (5 rats/time point). Before sacrifice of animals, blood was withdrawn and employed for the measurement of von Willibrand factor and platelet activity using enzyme-linked immunoabsorbant assay (ELISA). Brain tissues were prepared for histological analysis. The data show that (1) delayed thrombosis is present in the lesion boundary zone and in the hippocampal CA3 region, starting at 1-4 h, peaking at 1-3 days, and then declining at 8 and 15 days after TBI; (2) intravascular thrombosis also occurs in the other areas of cortex, striatum, and corpus callosum, but with a scattered distribution; (3) delayed thrombi are composed of platelets, fibrin, and vWF; and (4) reduction of the plasma vWF level and platelet activity by atorvastatin decreases delayed thrombosis after TBI. These data suggest that atorvastatin reduces intravascular thrombosis attributed to hemostatic disturbances caused by TBI.

Animals↗
PubMed2004

Activated neural stem cells contribute to stroke-induced neurogenesis and neuroblast migration toward the infarct boundary in adult rats.

Stroke increases neurogenesis. The authors investigated whether neural stem cells or progenitor cells in the adult subventricular zone (SVZ) of rats contribute to stroke-induced increase in neurogenesis. After induction of stroke in rats, the numbers of cells immunoreactive to doublecortin, a marker for immature neurons, increased in the ipsilateral SVZ and striatum. Infusion of an antimitotic agent (cytosine-beta-D-arabiofuranoside, Ara-C) onto the ipsilateral cortex eliminated more than 98% of actively proliferating cells in the SVZ and doublecortin-positive cells in the ipsilateral striatum. However, doublecortin-positive cells rapidly replenished after antimitotic agent depletion of actively proliferating cells. Depleting the numbers of actively proliferating cells in vivo had no effect on the numbers of neurospheres formed in vitro, yet the numbers of neurospheres derived from stroke rats significantly (P<0.05) increased. Neurospheres derived from stroke rats self-renewed and differentiated into neurons and glia. In addition, doublecortin-positive cells generated in the SVZ migrated in a chainlike structure toward ischemic striatum. These findings indicate that in the adult stroke brain, increases in recruitment of neural stem cells contribute to stroke-induced neurogenesis, and that newly generated neurons migrate from the SVZ to the ischemic striatum.

Animals↗
PubMed2004

Marrow stromal cell transplantation after traumatic brain injury promotes cellular proliferation within the brain.

OBJECTIVE: This study was designed to investigate the effects of intracerebral as well as intravenous administration of bone marrow stromal cells (MSCs) on endogenous cellular proliferation after traumatic brain injury (TBI). METHODS: Two experimental groups of Wistar rats were studied. One group received MSCs intracerebrally, and the other group received MSCs intravenously after injury by controlled cortical impact. MSCs were harvested from the bone marrow of male Wistar rats. For the intracerebral study, 24 male rats were divided into three groups (eight rats per group): rats injected with MSCs (1 x 10(6)) intracerebrally 1 day after TBI; 2) rats injected with phosphate-buffered saline intracerebrally 1 day after TBI; and 3) sham group not subjected to injury and not administered treatment. For the intravenous study, 10 female Wistar rats were injected 1 day after TBI with either MSCs (2 x 10(6)) (n = 5) or phosphate-buffered saline (n = 5) via the tail vein. Neurological function of the rats was evaluated with modified neurological severity scores and rotarod motor test. All rats were injected with bromodeoxyuridine intraperitoneally, to label the newly generating cells. Rats were killed 15 days after TBI, and coronal brain sections were stained immunohistochemically with diaminobenzidine to identify newly generating bromodeoxyuridine-positive cells. To study the differentiation of newly generating cells into neurons, sections were also double-stained for neuronal markers (Tuj1, doublecortin, NeuN) with fluorescein isothiocyanate. RESULTS: The data demonstrate that newly generating cells were mainly present in the subventricular zone, hippocampal formation, and boundary zone of contusion of both treated and control animals. Intracerebral MSC treatment significantly increased the progenitor cell proliferation in the subventricular zone and boundary zone compared with the controls, whereas intravenous MSC treatment enhanced this endogenous proliferation in subventricular zone, hippocampus, and boundary zone. In both groups, some of the new cells revealed positive staining for neuronal markers. A statistically significant functional improvement was observed in both the intracerebrally as well as intravenously treated groups. CONCLUSION: Intracerebral and intravenous MSC administration promotes endogenous cellular proliferation after TBI in rats. This may contribute to the functional improvement observed in these rats.

3,3'-Diaminobenzidine↗
PubMed2004

Angiogenesis induced by photodynamic therapy in normal rat brains.

Angiogenesis promotes tumor growth and invasiveness in brain. Because brain injury often induces expression of angiogenic-promoting molecules, we hypothesize that oxidative insult induced by photodynamic therapy (PDT) could lead to an endogenous angiogenic response, possibly diminishing the efficacy of PDT treatment of tumors. Therefore, we sought to establish whether PDT induced an angiogenic response within the nontumored brain. PDT using Photofrin as a sensitizer at an optical dose of 140 J/cm2 was performed on normal rat brain (n = 30). Animals were sacrificed at 24 h, and 1, 2, 3 and 6 weeks after PDT treatment. Fluorescein isothiocyanatedextran perfusion was performed, and brains were fixed for immunohistological study. Immunostaining revealed that vascular endothelial growth factor (VEGF) expression increased within the PDT-treated hemisphere 1 week after treatment and remained elevated for 6 weeks. Three-dimensional morphologic analysis of vasculature within PDT-treated and contralateral brain demonstrated PDT-induced angiogenesis, as indicated by a significant increase in vessel connectivity (P < 0.001) concomitant with decreased (P < 0.05) mean segment length compared with vessels within the contralateral hemisphere. Volumetric measurement of angiogenic regions indicate that neovascular expansion continued for 4 weeks after PDT. These data demonstrate that PDT induces VEGF expression and neovascularization within normal brain. Because angiogenesis promotes growth and invasiveness of tumor, antagonizing this endogenous angiogenic response to PDT may present a practical means to enhance the efficacy of PDT.

Angiogenesis Inducing Agents↗
PubMed2004

Improvement in neurological outcome after administration of atorvastatin following experimental intracerebral hemorrhage in rats.

OBJECT: Atorvastatin, a beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitor, improves neurological functional outcome, reduces cerebral cell loss, and promotes regional cellular plasticity when administered after intracerebral hemorrhage (ICH) in rats. METHODS: Autologous blood was stereotactically injected into the right striatum in rats, and atorvastatin was administered orally beginning 24 hours after ICH and continued daily for 1 week. At a dose of 2 mg/kg, atorvastatin significantly reduced the severity of neurological deficit from 2 to 4 weeks after ICH. The area of cell loss in the ipsilateral striatum was also significantly reduced in these animals. Consistent with previous study data, higher doses of atorvastatin (8 mg/kg) did not improve functional outcome or reduce the extent of injury. Histochemical stains for markers of synaptogenesis, immature neurons, and neuronal migration revealed increased labeling in the region of hemorrhage in the atorvastatin-treated rats. CONCLUSIONS: Analysis of the data in this study indicates that atorvastatin improves neurological recovery after experimental ICH and may do so in part by increasing neuronal plasticity.

Animals↗
PubMed2004

Atorvastatin reduction of intravascular thrombosis, increase in cerebral microvascular patency and integrity, and enhancement of spatial learning in rats subjected to traumatic brain injury.

OBJECT: Atorvastatin, a beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitor, has pleiotropic effects, such as promoting angiogenesis, increasing fibrinolysis, and reducing inflammatory responses, and has shown promise in enhancing recovery in animals with traumatic brain injury (TBI) and stroke. The authors tested the effect of atorvastatin on vascular changes after TBI. METHODS: Male Wistar rats subjected to controlled cortical impact injury were perfused at different time points with fluorescein isothiocyanate (FITC)--conjugated dextran 1 minute before being killed. Spatial memory function had been measured using a Morris Water Maze test at various points before and after TBI. The temporal profile of intravascular thrombosis and vascular changes was measured on brain tissue sections by using a microcomputer imaging device and a laser confocal microscopy. The study revealed the following results. 1) Vessels in the lesion boundary zone and hippocampal CA3 region showed a variety of damage, morphological alterations, reduced perfusion, and intraluminal microthrombin formation. 2) Atorvastatin enhanced FITC-dextran perfusion of vessels and reduced intravascular coagulation. 3) Atorvastatin promoted the restoration of spatial memory function. CONCLUSIONS: These results indicated that atorvastatin warrants investigation as a potential therapeutic drug for TBI.

Animals↗
PubMed2004

Atorvastatin reduction of intracranial hematoma volume in rats subjected to controlled cortical impact.

OBJECT: Atorvastatin, a beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitor, has pleiotropic effects such as improving thrombogenic profile, promoting angiogenesis, and reducing inflammatory responses and has shown promise in enhancing neurological functional improvement and promoting neuroplasticity in animal models of traumatic brain injury (TBI), stroke, and intracranial hemorrhage. The authors tested the effect of atorvastatin on intracranial hematoma after TBI. METHODS: Male Wistar rats were subjected to controlled cortical impact, and atorvastatin (1 mg/kg) was orally administered 1 day after TBI and daily for 7 days thereafter. Rats were killed at 1, 8, and 15 days post-TBI. The temporal profile of intraparenchymal hematoma was measured on brain tissue sections by using a MicroComputer Imaging Device and light microscopy. CONCLUSIONS: Data in this study showed that intraparenchymal and intraventricular hemorrhages are present 1 day after TBI and are absorbed at 15 days after TBI. Furthermore, atorvastatin reduces the volume of intracranial hematoma 8 days after TBI.

Animals↗
PubMed2004

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↗