Diffuse microvascular dysfunction and loss of white matter integrity predict poor outcomes in patients with acute ischemic stroke.

We sought to investigate the relationship between blood-brain barrier (BBB) permeability and microstructural white matter integrity, and their potential impact on long-term functional outcomes in patients with acute ischemic stroke (AIS). We studied 184 AIS subjects with perfusion-weighted MRI (PWI) performed <9 h from last known well time. White matter hyperintensity (WMH), acute infarct, and PWI-derived mean transit time lesion volumes were calculated. Mean BBB leakage rates (K2 coefficient) and mean diffusivity values were measured in contralesional normal-appearing white matter (NAWM). Plasma matrix metalloproteinase-2 (MMP-2) levels were studied at baseline and 48 h. Admission stroke severity was evaluated using the NIH Stroke Scale (NIHSS). Modified Rankin Scale (mRS) was obtained at 90-days post-stroke. We found that higher mean K2 and diffusivity values correlated with age, elevated baseline MMP-2 levels, greater NIHSS and worse 90-day mRS (all p < 0.05). In multivariable analysis, WMH volume was associated with mean K2 ( p = 0.0007) and diffusivity ( p = 0.006) values in contralesional NAWM. In summary, WMH severity measured on brain MRI of AIS patients is associated with metrics of increased BBB permeability and abnormal white matter microstructural integrity. In future studies, these MRI markers of diffuse cerebral microvascular dysfunction may improve prediction of cerebral tissue infarction and functional post-stroke outcomes.

Prediction of hemorrhagic transformation after experimental ischemic stroke using MRI-based algorithms.

Estimation of hemorrhagic transformation (HT) risk is crucial for treatment decision-making after acute ischemic stroke. We aimed to determine the accuracy of multiparametric MRI-based predictive algorithms in calculating probability of HT after stroke. Spontaneously, hypertensive rats were subjected to embolic stroke and, after 3 h treated with tissue plasminogen activator (Group I: n = 6) or vehicle (Group II: n = 7). Brain MRI measurements of T2, T2*, diffusion, perfusion, and blood-brain barrier permeability were obtained at 2, 24, and 168 h post-stroke. Generalized linear model and random forest (RF) predictive algorithms were developed to calculate the probability of HT and infarction from acute MRI data. Validation against seven-day outcome on MRI and histology revealed that highest accuracy of hemorrhage prediction was achieved with a RF-based model that included spatial brain features (Group I: area under the receiver-operating characteristic curve (AUC) = 0.85 ± 0.14; Group II: AUC = 0.89 ± 0.09), with significant improvement over perfusion- or permeability-based thresholding methods. However, overlap between predicted and actual tissue outcome was significantly lower for hemorrhage prediction models (maximum Dice's Similarity Index (DSI) = 0.20 ± 0.06) than for infarct prediction models (maximum DSI = 0.81 ± 0.06). Multiparametric MRI-based predictive algorithms enable early identification of post-ischemic tissue at risk of HT and may contribute to improved treatment decision-making after acute ischemic stroke.

Magnetic resonance imaging of local and remote vascular remodelling after experimental stroke.

The pattern of vascular remodelling in relation to recovery after stroke remains largely unclear. We used steady-state contrast-enhanced magnetic resonance imaging to assess the development of cerebral blood volume and microvascular density in perilesional and exofocal areas from (sub)acutely to chronically after transient stroke in rats. Microvascular density was verified histologically after infusion with Evans Blue dye. At day 1, microvascular cerebral blood volume and microvascular density were reduced in and around the ischemic lesion (intralesional borderzone: microvascular cerebral blood volume = 72 ± 8%; microvascular density = 76 ± 8%) (P < 0.05), while total cerebral blood volume remained relatively unchanged. Perilesional microvascular cerebral blood volume and microvascular density subsequently normalized (day 7) and remained relatively stable (day 70). In remote ipsilateral areas in the thalamus and substantia nigra - not part of the ischemic lesion - microvascular density gradually increased between days 1 and 70 (thalamic ventral posterior nucleus: microvascular density = 119 ± 9%; substantia nigra: microvascular density = 122 ± 8% (P < 0.05)), which was confirmed histologically. Our data indicate that initial microvascular collapse, with maintained collateral flow in larger vessels, is followed by dynamic revascularization in perilesional tissue. Furthermore, progressive neovascularization in non-ischemic connected areas may offset secondary neuronal degeneration and/or contribute to non-neuronal tissue remodelling. The complex spatiotemporal pattern of vascular remodelling, involving regions outside the lesion territory, may be a critical endogenous process to promote post-stroke brain reorganization.

Manganese-enhanced MRI of brain plasticity in relation to functional recovery after experimental stroke.

Restoration of function after stroke may be associated with structural remodeling of neuronal connections outside the infarcted area. However, the spatiotemporal profile of poststroke alterations in neuroanatomical connectivity in relation to functional recovery is still largely unknown. We performed in vivo magnetic resonance imaging (MRI)-based neuronal tract tracing with manganese in combination with immunohistochemical detection of the neuronal tracer wheat-germ agglutinin horseradish peroxidase (WGA-HRP), to assess changes in intra- and interhemispheric sensorimotor network connections from 2 to 10 weeks after unilateral stroke in rats. In addition, functional recovery was measured by repetitive behavioral testing. Four days after tracer injection in perilesional sensorimotor cortex, manganese enhancement and WGA-HRP staining were decreased in subcortical areas of the ipsilateral sensorimotor network at 2 weeks after stroke, which was restored at later time points. At 4 to 10 weeks after stroke, we detected significantly increased manganese enhancement in the contralateral hemisphere. Behaviorally, sensorimotor functions were initially disturbed but subsequently recovered and plateaued 17 days after stroke. This study shows that manganese-enhanced MRI can provide unique in vivo information on the spatiotemporal pattern of neuroanatomical plasticity after stroke. Our data suggest that the plateau stage of functional recovery is associated with restoration of ipsilateral sensorimotor pathways and enhanced interhemispheric connectivity.