Delayed perfusion phenomenon in a rat stroke model at 1.5 T MR: An imaging sign parallel to spontaneous reperfusion and ischemic penumbra?

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Abstract

Introduction

Delayed perfusion (DP) sign at MR imaging was reported in stroke patients. We sought to experimentally elucidate its relation to spontaneous reperfusion and ischemic penumbra.

Methods

Stroke was induced by photothrombotic occlusion of middle cerebral artery in eight rats and studied up to 72 h using a 1.5 T MR scanner with T2 weighted imaging (T2WI), diffusion weighted imaging (DWI), and dynamic susceptibility contrast-enhanced perfusion weighted imaging (DSC-PWI). Relative signal intensity (rSI), relative lesion volume (rLV), relative cerebral blood flow (rCBF), PWIrLV–DWIrLV mismatch (penumbra) and DPrLV were quantified and correlated with neurological deficit score (NDS), triphenyl tetrazolium chloride (TTC) staining, microangiography (MA) and histopathology.

Results

The rSI and rLV characterized this stroke model on different MRI sequences and time points. DSC-PWI reproduced cortical DP in all rats, where rCBF evolved from 88.9% at 1 h through 64.9% at 6 h to 136.3% at 72 h. The PWIrLV–DWIrLV mismatch reached 10 ± 5.4% at 1 h, remained positive through 12 h and decreased to −3.3 ± 4.5% at 72 h. The incidence and rLV of the DP were well correlated with those of the penumbra (p < 0.01, r2 = 0.85 and p < 0.0001, r2 = 0.96, respectively). Shorter DP durations and more collateral arterioles occurred in rats without (n = 4) than with (n = 4) cortex involvement (p < 0.05). Rats without cortex involvement tended to earlier reperfusion and a lower NDS. Microscopy confirmed MRI, MA and TTC findings.

Conclusions

In this rat stroke model, we reproduced clinically observed DP on DSC-PWI, confirmed spontaneous reperfusion, and identified the penumbra extending to 12 h post-ischemia, which appeared interrelated.

Introduction

Stroke continues to present one of the leading causes of mortality and disability worldwide [1]. Neuroimaging allows identification of stroke patients, stratification of viable and non-viable cerebral tissues, assessment of the region at risk of infarction, investigation of etiology, selection of therapeutic regimes and surveillance of progress and/or complications. With the non-invasive and non-ionizing advantages, superb soft tissue contrast and capacity of both morphological and functional evaluations, magnetic resonance imaging (MRI) has been playing an increasingly important role in this clinical setting.

Dynamic susceptibility contrast-enhanced perfusion-weighted imaging (DSC-PWI) proves to be a potent MRI technique and has been widely applied in clinical stroke imaging. The DSC-PWI may generate quantifiable parameters such as relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), mean transit time (MTT), and time to peak (TTP), which are useful for monitoring local hemodynamic changes. Using this technique, Hermier et al. [2] recently demonstrated the “delayed perfusion (DP) sign” as a marker of leptomeningeal collateral blood flow among a group of hyperacute stroke patients immediately before thrombolytic therapy. Hemodynamic changes in stroke are critical, and the presence of collateral flow can be beneficial for the long-term outcomes. These aspects have received much attention in the stroke research especially for the development of treatment strategies [3].

The mismatch between the PWI lesion and the lesion defined by diffusion-weighted imaging (DWI) has been proposed as a marker for the tissue at risk or ischemic penumbra [4]. Therefore, the clues that may link the observed DP and other stroke related core-issues such as ischemic penumbra and reperfusion phenomenon are of both diagnostic and therapeutic significance.

The present experiment with photochemically induced thrombosis (PIT) of proximal middle cerebral artery (MCA) in rats has been conducted to verify this DP sign and to gain more insight into all these issues. This stroke model, which has been characterized by using in vivo MRI at a clinical magnet and postmortem standard techniques [5], is believed to offer a closer simulation of clinical patients, i.e., (1) the possibilities of permanent ischemia and spontaneous reperfusion (SR) as verified with autoradiography [6], and (2) the presence of penumbra as shown on MRI [7]. This model has also been applied for early prediction of final infarct size [8] and in the study of a novel anti-stroke drug [9].

Therefore, in this MRI–microangiography–histomorphology correlation study, we intended to address the following three major issues: (1) to reproduce the clinical DP sign on DSC-PWI in the rat stroke model; (2) to prove non-invasively the presence of SR in this model by PWI-derived rCBF map; and (3) to explore the possible relationship of the DP sign with SR and ischemic penumbra.

Section snippets

Animal models of stroke

This experiment was performed in compliance with the guidelines of the International Committee on Thrombosis and Hemostasis [10] and the current institutional regulations for use and care of laboratory animals. Eight male Sprague–Dawley rats weighting approximately 350 g were included in this study. Anesthesia was performed with initial inhalation of 4% isoflurane for 3 min and maintained with 2% isoflurane in a mixture of 20% oxygen and 80% room air. Body temperature was kept at 37.5 ± 0.5 °C

General conditions

All animals survived the surgical intervention and subsequent imaging protocol. The neurological symptoms for brain damage were assessed using Bederson's score [11] with a median of 3.8 (range: 2–6, n = 8) before sacrifice at 72 h (Table 1).

Signal intensity changes of T2WI, DWI, and ADC

After MCA occlusion, the rSI of ischemic lesions on T2WI and DWI increased gradually from 1 h, peaked at 12 h, dropped slightly at 24 h and then declined considerably at 72 h. The changes of T2WI and DWI paralleled, but the rSI value was higher on DWI (T2

Spontaneous reperfusion

Although the PIT model of proximal MCA occlusion in rats has been applied for studying stroke with MRI [5], [7], [8] and testing new anti-stroke agent [9], spontaneous recanalization as a common feature of clinical thromboembolic stroke [15] has been very sparsely studied experimentally using this model. Using in vivo non-invasive MR imaging, we have been able to confirm, for the first time to our knowledge, the previously found reperfusion phenomenon based on postmortem autoradiography in the

Acknowledgement

We thank Dr. Hilde Vandenhout for her help in proofreading of this manuscript.

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