Elsevier

NeuroImage

Volume 61, Issue 4, 16 July 2012, Pages 780-785
NeuroImage

Changes in T2 relaxation time after stroke reflect clearing processes

https://doi.org/10.1016/j.neuroimage.2012.04.023Get rights and content

Abstract

Background and purpose

CT and MR imaging techniques are frequently used for the diagnosis and progress monitoring of ischemic stroke in clinical practice and research. After stroke, both methods are characterized by a transient pseudo-normalized imaging signal, the so-called fogging phenomenon. This study evaluates potential pathophysiological changes associated with fogging, as well as its influence on the correct determination of the ischemic lesion in a rat stroke model.

Methods

Male spontaneously hypertensive rats were subjected to permanent middle cerebral artery occlusion. Ischemic lesion volume, brain edema and gray scale value spread within the ischemic lesion were determined on T2-weighted MR sequences at days 1, 4, 8, 11 and 29 after stroke onset, and compared with immunohistochemistry for astrogliosis, microglia/macrophage infiltration and angiogenesis.

Results

All animals showed MR fogging at days 4, 8 and 11 after stroke. The transient normalization of T2 signals occurred independently from the development of infarct volumes, but coincided well with the spatio–temporal occurrence of necrosis, angiogenesis and microglia/macrophage infiltration.

Conclusions

Our results suggest that the fogging effect reflects the clearance of necrotic tissue within the ischemic lesion and is thus not relevant for the determination of the lesion volume.

Highlights

► After stroke, MR sequences frequently show a transiently normalized imaging signal. ► MR fogging was also evident after permanent middle cerebral artery occlusion in rats. ► The infarct volume was not influenced by MR fogging. ► The pattern of MR fogging coincided with necrosis, angiogenesis and macrophage infiltration.

Introduction

Imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI) play an important role in the diagnosis and therapeutic decision making for ischemic stroke. The field of neuroimaging has advanced significantly over the past years; multimodal CT and MRI protocols facilitate the comprehensive determination of ischemic lesion characteristics and may pave the way for a more individualized stroke therapy (Leiva-Salinas et al., 2011). T2-weighted MRI provides an excellent method to delineate lesion volume after stroke and is widely-used in clinical practice and in clinical stroke trials (Dijkhuizen and Nicolay, 2003, Warach et al., 2006). However, this technique shares a common peculiarity with computer tomography: both CT and T2-weighted MR sequences are associated with a transient isodensity or normointensity of the ischemic lesion. This phenomenon was termed the ‘CT fogging effect’ in 1979 (Becker et al., 1979) followed by the first description on T2-weighted MR sequences in 1991 (Asato et al., 1991). Systematic analysis revealed a fogging frequency of approximately 50%, mostly within the second or third week after stroke onset (O'Brien et al., 2004, Skriver and Olsen, 1981). Beyond these findings, fogging has only rarely been described in case reports (Chalela and Kasner, 2000, Nagel et al., 2008, Pereira et al., 2000, Scuotto et al., 1997), despite the fact that this phenomenon may have a considerable impact on the correct determination of the infarct volume. A mild hemorrhagic transformation, capillary growth and phagocytosis by infiltrating macrophages have been discussed as possible pathophysiological correlates of fogging (Becker et al., 1979, Pereira et al., 2000), but a conclusive explanation is still lacking since a match of imaging sequences with pathohistological changes is not possible in stroke patients. However, fogging is also known to occur in animal models of focal cerebral ischemia, where a transient T2 signal normalization can be observed between day 3 and day 14 after stroke onset (Lin et al., 2002b). Another animal study identified changes of the water content, but not hemorrhage as the pathophysiological correlate of T2 fogging (Lin et al., 2002a). Nevertheless, it is still not fully understood which pathophysiological changes occur during fogging, and whether or not this phenomenon might influence the correct determination of the lesion volume. To answer these questions, we investigated MR surrogates such as infarct volume, brain edema and fogging over time, and matched these data with immunohistochemical analyses.

Section snippets

Experimental cerebral ischemia

Animal procedures were carried out according to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996), and approved by the appropriate state agency (reference number TVV18/07). A total of 35 male spontaneously hypertensive rats (Charles River, Sulzfeld, Germany) 12 weeks of age were anesthetized with ketamine hydrochloride (100 mg/kg), xylazine (10 mg/kg) and atropine (0.1 mg/kg) given as an intraperitoneal

Infarct volume and brain edema measurements by MRI

Physiological data were within normal ranges during the surgical procedures and none of the animals died during the study (data not shown). After permanent MCAO, all animals developed a homogeneous ischemic lesion within the right cerebral cortex. At the first MR investigation 24 h after stroke onset, the mean infarct volume was 11.8 ± 3.6% of the hemispheric lesion volume (%HLVe), corrected for edema. The lesion volume remained unchanged at the other imaging time points until the end of the

Discussion

This study in an animal model of cerebral ischemia revealed that the MR-fogging phenomenon is a dynamic process that reflects ongoing clearing and organizational processes within the ischemic lesion. By using a permanent MCAO model in spontaneously hypertensive rats, we were able to study MR-fogging over time and to match these data with histological findings. In this study, all animals exhibited a strictly cortical ischemic lesion featuring a partial T2 normalization and a second T2 increase

Conclusion

In summary, we assume that the post-ischemic changes of T2 relaxation time have at least four different causes that partly merge over time: (1) An early T2 increase as consequence of a uniform edema within the injured tissue; (2) T2 normalization due to the resolution of brain edema and/or the increased binding of free water; (3) A second T2 increase due to newly formed leaky microvessels and inflammation within the border zone of the necrosis; (4) A final T2 increase related to tissue

Acknowledgments

The authors are especially grateful to Dr. Marc Fisher (University of Massachusetts Medical School, Worcester, MA, USA) for valuable advice and for critically reviewing the manuscript. The authors acknowledge the support from the colleagues at the Department of Neuroradiology, University of Leipzig, Germany), particularly from Dr. Donald Lobsien. The authors further thank Björn Nitzsche for helpful discussions, Ute-Maria Riegelsberger for support during the animal experiments, Stefanie Michalk

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