MR imaging of ischemic penumbra

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Abstract

Cerebral ischemic stroke is one of the most fatal diseases despite current advances in medical science. Recent demonstration of efficacy using intravenous and intra-arterial thrombolysis demands therapeutic intervention tailored to the physiologic state of the individual tissue and stratification of patients according to the potential risks for therapies. In such an era, the role of the neuroimaging becomes increasingly important to evaluate the extent and location of tissues at risk of infarction (ischemic penumbra), to distinguish it from unsalvageable infarcted tissues or doomed hemorrhagic parenchyma. In this review, we present briefly the current role and limitation of computed tomography and conventional magnetic resonance imaging (MRI). We also present the possible applications of advanced MR techniques, such as diffusion and perfusion imaging, concentrating on the delineation or detection of ischemic penumbra.

Introduction

Cerebral ischemic stroke is one of the most fatal diseases despite current advances in medical science. It causes long-term, serious sequelae due to the lack of any established therapy with which to recover fully from this disorder. Generally, cessation of cerebral blood flow or reduction below a critical threshold (10–15 ml/100 g/min) leads to anaerobic glycolysis and depletion of intracellular adenosine triphosphate (ATP). The sodium-potassium ion pump (Na+/K+–ATP pump) is highly ATP-dependent. Loss of energy homeostasis and subsequent ion pump dysfunction cause efflux of intracellular potassium, influx of sodium, chloride, and water (cytotoxic edema), and diminished binding of water to macromolecules swiftly, resulting in irreversible physical and chemical derangement. Ischemic penumbra is still perfused at a level between the threshold of functional impairment and morphological integrity, which still has a capacity to recover if the perfusion is restored to a normal level. In the clinical settings, the deterioration of cerebral blood flow tends to be incomplete, the outcome of the ischemic insult is more difficult to predict and largely dependent on residual perfusion and oxygen availability [1]. Unlike cerebral infarction in animal models, strokes in humans involve much variability in terms of infarcted volume and location, patterns of collateral flows, complication of disease, and patient's age [2], [3].

In 1995, the National Institute for Neurological Diseases and Stroke (NINDS) demonstrated efficacy in the use of the thrombolytics for the treatment of cerebral ischemia [4]. The protocol was based on a three-hour treatment window from the onset of ictus to the administration of recombinant tissue plasminogen activator (rt-PA). In contrast, the European Cooperative Acute Stroke Study (ECASS) trial, which allowed a longer treatment window of 6 h with exclusion criteria using X-ray computed tomography (CT), failed to demonstrate effectiveness, but the ECASS trial suggested, based on subgroup analysis, that with neuroimaging it was possible to extend the therapeutic window beyond 3 h [5]. The PROACT II study has demonstrated that treatment of acute ischemic stroke caused by middle cerebral artery occlusion (MCAO) with intra-arterial pro-urokinase even beyond the 3-h time window significantly improved clinical outcome at 90 days despite an increased frequency of early symptomatic intracranial hemorrhage [6]. Selection of a subgroup by angiography was an effective strategy in this study, which contradicted the hypothesis that treatment of stroke beyond 3 h would not be successful.

In focal ischemia, there may be an irreversible ischemic center (core), where the blood flow is below the critical threshold, surrounded by the ring-like area at risk of infarction (penumbra), where the blood flow is diminished, but not lethal within the first several hours. This is a temporally dynamic process, whose in vivo time course that begins from onset of insult is scarcely known. Hereafter, with the advent of effective therapies for acute cerebral ischemia, it will become increasingly important with neuroimaging especially magnetic resonance imaging (MRI) to evaluate the extent and location of reversible ischemic penumbra, to distinguish it from unsalvageable infarcted tissues or doomed intraparenchymal hemorrhagic tissues, and to determine appropriate therapies including an intravenous or intra-arterial injection of thrombolytic agents or conservative medical therapies.

CT remains the mainstay in the imaging of suspected acute stroke. Conventional CT combined with CT angiography and CT perfusion imaging is a modality of choice due to its accessibility and ability to demonstrate areas of cerebral hemorrhage, large-vessel occlusions, and regions of hypoperfusion [7], [8] and to exclude alternative diagnoses, such as subarachnoid hemorrhage, neoplasm, or abscess. However, CT has still potential vulnerabilities, i.e. its current low sensitivity for delineating fatally ischemic but salvageable tissue in the hyperacute period [9] and is less sensitive than MRI, particularly for infarcts in sites such as infratentorial structures, and deep white matter [10]. Numerous other imaging techniques can contribute in assessing individual parameters, but few are both comprehensive and expeditious. These include xenon-enhanced CT, positron emission tomography (PET), single photon emission CT, and transcranial Doppler ultrasonography. For instance, whereas PET provides important quantitative information related to blood flow and oxygen extraction, current limitations in anatomic delineation and accessibility have hampered its routine use in assessing stroke patients. Conversely, MR imaging generally has higher spatial resolution than other tomographic techniques (similar to that of CT), enabling anatomic, physiologic, and metabolic analysis in a single examination. Methods for evaluating blood flow and tissue viability are increasingly required as therapeutic intervention may be tailored to the physiologic state of the individual tissue for stratifying patients according to the potential risks for therapies [6], [11]. Rather than presenting the wide array of available imaging techniques, in reviewing acute stroke imaging, we will present the possible applications of conventional and advanced MR techniques in this article, concentrating on the delineation or detection of ischemic penumbra.

Section snippets

Conventional MR imaging

The earliest conventional MR changes are loss of normal intravascular flow voids and gyral swelling of a vascular territory associated with very subtle signal changes on T2-weighted (T2WI) and proton-density weighted images (PDWI). Similar to the hyperdense MCA sign in CT (Fig. 1a,b), absence of flow in involved vessels can be seen immediately after occlusion on MRI. Whereas prominence of the parenchymal changes associated with vascular occlusion is a contraindication to thrombolysis, the

Diffusion-weighted imaging (DWI)

DWI, a newer MRI method that is sensitized to water diffusion, may be a unique, non-invasive tool to provide useful information with respect to the structures of cells, membrane permeability, transport processes, and temperature, not accessible with conventional MR methods [16] [17]. Brownian motions of water molecules result in a random distribution of phase shifts in response to exposure to a large external magnetic gradient, which leads to incomplete spin rephasing and signal attenuation. On

Diffusion tensor imaging (DTI)

In human brain, water diffusion is a three-dimensional process, and is not truly random because the diffusional motion of water is impeded by natural barriers such as cell membranes, myelin sheaths, white matter fiber tracts, and protein molecules. The translational motion of water molecules is rotationally variant, which is more enhanced in the direction parallel to the longitudinal axis of the fiber tract and less perpendicular to it. Therefore, on images acquired from the measurement

Perfusion imaging

Currently, two approaches have been used to evaluate tissue perfusion with MR imaging in clinical conditions and scientific studies [3], [9], [50]. One employs rapid imaging techniques coupled with intravenously injected bolus of paramagnetic contrast agents that shorten T2*. The other approach is the arterial spin labeling (ASL) method, where blood flow quantification has been achieved by continuous adiabatic inversion of arterial spins and principles of tracer kinetic models of CBF

Combination of DWI and perfusion imaging

Recent experimental studies have demonstrated ischemic penumbra, or tissue at risk of infarction, at the periphery of acute infarctions [59]. It was suggested that enlargement of the area of infarction was likely to occur if the area of perfusion deficit was larger than the area of initial diffusion abnormality, and that this mismatch may represent the ischemic penumbra [1], [2], [14], [41], [58], [62], whereas enlargement of ischemic lesions does not occur where the perfusion abnormality was

MR spectroscopy (MRS)

With proton MRS, the relative and absolute concentration of several brain metabolites can be obtained, but the two measurable brain metabolites of interest in cerebrovascular disease are N-acetylaspartate (NAA) and lactate [9]. NAA is an amino-acid of unknown function that is found exclusively in neurons, and is a marker of neuronal integrity. NAA decreases immediately and steadily over the ensuing few hours to 50% of baseline at 6 h after ischemia [68]. Lactate is too low in concentration to

Reductions in transverse relaxation time (T2) in a higher magnetic field

Grohn et al demonstrated that hypoperfused brain regions, such as the ischemic penumbra, were detectable by reductions in absolute T2 using 9.4T magnetic resonance imaging [71] (Fig. 4c). Three types of regions at risk of infarction could be distinguished: (1) areas with reduced T2 and normal ADC, corresponding to hypoperfusion without ischemia; (2) areas with both reduced T2 and ADC, corresponding to early hypoperfusion with ischemia; (3) areas with increased T2 and reduced ADC, corresponding

Conclusions

Novel MR techniques have enabled a comprehensive evaluation of cerebral ischemia including metabolic and physiological information. Structural MR imaging such as PDWI and T2WI have been accepted as established and valuable diagnostic tools to assess infarct extent and location beyond the first 12–24 h after ictus, and MRA can delineate whether there is a thrombus amenable to thrombolysis. However, during the first 6–12 h, the crucial period of therapeutic opportunity, ischemic penumbra cannot

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      However, as these thresholds are statistical values which may vary with the particular experimental set-up, an accurate differentiation between core and penumbra is not possible. Other MR parameters which are potentially useful for the mapping of ischemic injury are the measurement of cerebral blood volume (to trace the autoregulatory adjustment of the cerebral vasculature at reduced blood supply) (Karonen et al., 2000), blood oxygen level-dependent (BOLD) imaging (to detect increased oxygen extraction) (Geisler et al., 2006), the transverse relaxation time T2 (to visualize the beginning edema formation) (Grohn et al., 1998), Mn-enhanced MR imaging (to detect anoxic depolarization) (Abe et al., 2003), pH-weighted MR imaging (to visualize tissue acidosis) (Sun et al., 2007) or proton spectroscopical imaging (for mapping the rise of lactate during anaerobic glycolysis) (Igarashi et al., 2001). However, none of these parameters exhibits a sharp threshold relationship to declining flow values and, therefore, does not provide a clear differentiation between the ischemic core, the penumbra and the surrounding intact brain tissue.

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      Obviously, this approach is restricted to animal experiments but if with improving sensitivity of MR spectroscopy non‐invasive phosphorus imaging should become feasible, ATP mismatch maps could be acquired in patients and would serve as reliable standards for validation of other penumbral imaging modalities. Under clinical conditions and for animal experiments that require repeated measurements, the two methods of choice are DWI/PWI mismatch imaging using MR technology (Abe et al., 2003; Warach, 2003) and imaging of blood flow, oxygen consumption, oxygen extraction fraction, and flumazenil binding using PET (Baron, 1999; Heiss, 2000). PET studies are quantitative and therefore considered by many to be the gold standard for penumbral imaging but they require expensive instrumentation, prior knowledge of individual viability thresholds (for quantitative cerebral blood flow and CMRO2 maps), and the manifestation of structural injury (for flumazenil maps) to allow precise demarcation from the core and the surrounding intact tissue.

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