Wu O, Sumii T, Asahi M, Sasamata M, Ostergaard L, Rosen BR, Lo EH, Dijkhuizen RM. Infarct prediction and treatment assessment with MRI-based algorithms in experimental stroke models. J Cereb Blood Flow Metab 2007;27(1):196-204.Abstract
    There is increasing interest in using algorithms combining multiple magnetic resonance imaging (MRI) modalities to predict tissue infarction in acute human stroke. We developed and tested a voxel-based generalized linear model (GLM) algorithm to predict tissue infarction in an animal stroke model in order to directly compare predicted outcome with the tissue's histologic outcome, and to evaluate the potential for assessing therapeutic efficacy using these multiparametric algorithms. With acute MRI acquired after unilateral embolic stroke in rats (n=8), a GLM was developed and used to predict infarction on a voxel-wise basis for saline (n=6) and recombinant tissue plasminogen activator (rt-PA) treatment (n=7) arms of a trial of delayed thrombolytic therapy in rats. Pretreatment predicted outcome compared with post-treatment histology was highly accurate in saline-treated rats (0.92+/-0.05). Accuracy was significantly reduced (P=0.04) in rt-PA-treated animals (0.86+/-0.08), although no significant difference was detected when comparing histologic lesion volumes. Animals that reperfused had significantly lower (P<0.01) GLM-predicted infarction risk (0.73+/-0.03) than nonreperfused animals (0.81+/-0.05), possibly reflecting less severe initial ischemic injury and therefore tissue likely more amenable to therapy. Our results show that acute MRI-based algorithms can predict tissue infarction with high accuracy in animals not receiving thrombolytic therapy. Furthermore, alterations in disease progression due to treatment were more sensitively monitored with our voxel-based analysis techniques than with volumetric approaches. Our study shows that predictive algorithms are promising metrics for diagnosis, prognosis and therapeutic evaluation after acute stroke that can translate readily from preclinical to clinical settings.
    Dijkhuizen RM, Asahi M, Wu O, Rosen BR, Lo EH. Rapid breakdown of microvascular barriers and subsequent hemorrhagic transformation after delayed recombinant tissue plasminogen activator treatment in a rat embolic stroke model. Stroke 2002;33(8):2100-4.Abstract
    BACKGROUND AND PURPOSE: Thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) after stroke increases risk of hemorrhagic transformation, particularly in areas with blood-brain barrier leakage. Our aim was to characterize acute effects of rtPA administration on the integrity of microvascular barriers. METHODS: Stroke was induced in spontaneously hypertensive rats by unilateral embolic middle cerebral artery occlusion. Six hours after stroke, rtPA was intravenously administered (n=10). Controls received saline (n=4). Extravasation of the large-diameter contrast agent monocrystalline iron oxide nanocolloid (MION) was assessed with susceptibility contrast-enhanced MRI during rtPA injection. In addition, we performed perfusion MRI and diffusion-weighted MRI. After MRI, 2 hours after rtPA treatment, intracerebral hemorrhage was quantified with a spectrophotometric hemoglobin assay. RESULTS: Late rtPA treatment resulted in increased hemorrhage volume (8.4+/-1.7 versus 2.9+/-0.9 micro L in controls; P<0.05). In MION-injected animals, during rtPA administration, transverse relaxation rate change (DeltaR2*) increased from 12.4+/-6.0 to 31.6+/-19.2 s(-1) (P<0.05) in areas with subsequent hemorrhage. Significant DeltaR2* changes were absent in nonhemorrhagic areas, in animals without injected MION, and in saline-treated animals. Thrombolytic therapy did not improve perfusion in regions with hemorrhagic transformation (cerebral blood flow index was 22.8+/-19.7% [of contralateral] at 0.5 hours before and 22.4+/-18.0% at 1 hour after rtPA administration). CONCLUSIONS: The DeltaR2* changes during rtPA delivery in MION-injected animals indicate extravasation of MION, which reflects increased permeability of the blood-brain barrier. This implies that late rtPA treatment rapidly aggravates early ischemia-induced damage to microvascular barriers, thereby enhancing hemorrhagic transformation.