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approximates the truly uniform sensitivity achieved by CTP. , However, this more uniform sensitivity comes at the expense of lower contrast, generally requiring twice the usual dose of gadolinium. Some researchers have used MRP pulse sequences that simultaneously acquire both spin-echo and gradient-echo images not only to correct for differences in sensitivity to vessels, but also to quantitatively distinguish between hemodynamic conditions of vessels of different sizes.109 The clinical implications of differing sensitivities to vessels of different sizes have yet to be fully elucidated.

Perfusion Imaging: Interpretation of CT Perfusion Images

CTP is clearly superior to NCCT in detecting acute stroke. In one study, the overall accuracy of CTP maps ranged from 75.7% to 86.0%, compared to 66.2% for NCCT. This accuracy was achieved due to the superior sensitivity of MTT maps to NCCT (77.6% for MTT maps vs. 69.2% for NCCT), as well as superior specificity of CBF and CBV maps (90.9% and 92.7%, respectively, vs. 65.0% for NCCT).110

However, the real promise of CTP lies not in its ability to detect acute stroke, but in its ability, like that of MRP, to distinguish between infarct core and the ischemic penumbra. CTP produces maps of the same perfusion parameters that are generated by MRP, and CTP maps are interpreted in a similar manner, with one important exception: with CTP, DWI images are usually not available to identify the infarct core. Therefore, CBV maps are usually used to define the infarct core. Tissue that appears normal in CBV maps, but abnormal in CBF or MTT maps, is taken to represent the ischemic penumbra.

Several studies have validated the ability of CTP to distinguish between core and penumbra. In one study, Wintermark et al.111 found that the volumes of early infarcts in CTP CBV maps were highly correlated with volumes of early DWI lesions, whereas volumes of lesions seen in CTP CBF maps were close to those seen in the corresponding MRP MTT maps. In another study, the volume of the CBF abnormality in an acute-stage infarct was highly correlated with final infarct volume in patients who did not exhibit recanalization after thrombolysis, consistent with extension of infarction into the penumbra. However, in patients who did exhibit recanalization after thrombolysis, final infarct volume was highly correlated with the initial CBV abnormality, consistent with failure of infarcts to extend into the ischemic penumbra.112

Perfusion Imaging: Arterial Spin Labeling

It should be noted that perfusion imaging of the brain can also be performed in a completely noninvasive manner, without an exogenous contrast agent, using an MRI technique called arterial spin labeling (ASL).113,114 In ASL, an additional MRI coil is placed over the patient's neck and used to excite hydrogen nuclei ("spins") as they pass through one of the major cervical arteries en route to the brain. In this way, the spins themselves serve as an endogenous contrast agent, whose passage through the brain can be used to measure the perfusion parameters described above. This method offers major theoretical advantages. Besides being safe in patients with contrast allergies, ASL offers the possibility of performing perfusion imaging over and over again within a short period of time, without concerns of cumulative contrast dose. This could be useful, for example, in periodically assessing the effects of an ongoing recanalization procedure. Also, individual cervical arteries can be selectively labeled in ASL, so that the vascular territory of each cervical artery can be individually imaged. This is not possible with MRP or CTP.

Although ASL has been performed in the acute stroke setting,115 this currently is seldom done, for several reasons. Current ASL pulse sequences are somewhat more time consuming than DSC, requiring 6 minutes in the study cited above, compared to approximately 1 minute for DSC or CTP. ASL perfusion maps are far noisier than DSC maps, and have less spatial resolution.

Researchers are actively at work improving both the speed of ASL sequences and the quality of the resulting images, and ASL may prove an important acute stroke imaging technique in the future.

Permeability Imaging

Cerebral ischemia injures not only neurons and glial cells, but also the cells that comprise the walls of microscopic blood vessels.116,117 Damage to vessels may lead to rupture and likely accounts for the potential for ischemic infarcts to undergo hemor-rhagic transformation, particularly after treatment with thrombolytic agents.118 Animal studies have shown that MRI can detect vascular injury by measuring increases in vascular permeability to a gadolinium-based contrast agent and that these permeability changes can be used to predict the risk of hemorrhage.119-121

The utility of permeability imaging in predicting hemorrhagic transformation has also been demonstrated in a small study of 10 human acute stroke patients.122 Three of those patients demonstrated increased vascular permeability within their acute infarcts. All three of these patients, but none of the other seven, subsequently exhibited hemorrhagic transformation. This study was performed using a specialized and relatively time-consuming MRI pulse sequence designed to measure permeability quantitatively. The authors noted that this method was more sensitive for detecting increased vascular permeability than routine postcontrast T1-weighted images, which showed enhancement in only one of the three cases.

Several studies have shown that FLAIR images can also detect increased permeability of the blood-brain barrier in acute stroke patients. FLAIR is an MRI technique that is discussed above and is commonly included as a precontrast pulse sequence in examinations of the brain. However, when performed after contrast injection, FLAIR images can demonstrate leakage of contrast through damaged blood vessels into the subarachnoid space, which is manifested by hyper-intensity of sulcal CSF. This sign, which has been called the "hyperintense acute reperfusion marker'' or HARM, has been associated with increased incidence of hemorrhagic transformation.123,124

The clinical role of permeability imaging has yet to be assessed by a large clinical trial, but these techniques continue to hold promise for the future, as intracra-nial hemorrhage is the most significant potential complication of what is currently the only FDA-approved treatment for acute stroke.

Sodium Imaging

Virtually every clinical MRI technique produces images based on signal arising from hydrogen nuclei. However, one group has proposed studying acute stroke patients with images that are based on the concentration of sodium in different parts of the brain. This is of interest because of the large differences in sodium concentration that normally exist between the intracellular space, where ion pumps maintain a low concentration of approximately 10 mM, and the extracellular space, where systemic autoregulation maintains a nearly constant concentration of approximately 145 mM. The intracellular space is much larger in volume than the extracellular space, occupying approximately 80% of the brain's volume under normal conditions. Therefore, when ischemic damage causes cell membranes to become permeable to sodium ions, a large potential reservoir for sodium is effectively opened and ions begin to shift from the extracellular space to the intracellular space. Provided there is at least some residual perfusion of the ischemic tissue, the lost extracellular sodium ions are replenished by the effectively infinite supply in the bloodstream, resulting in an overall increase in the amount of sodium that is present, which serves as a detectable marker of cell membrane damage.

In serial studies of acute stroke performed with sodium imaging, Thulborn and colleagues have noted that sodium concentrations may continue to increase markedly in ischemic brain tissue, even several days after stroke onset. This is in contrast to the most widely available marker of tissue damage, the ADC of water, measured with DWI, which drops quickly within minutes of stroke onset, but changes relatively little thereafter. Therefore, sodium concentration could serve as a more precise indicator of the stage of ischemic injury. Thulborn and colleagues have shown that changes in sodium concentration do not necessarily parallel those of ADC and that a sodium concentration threshold of 70 mM can identify irreversibly damaged tissue with very high specificity.

Sodium imaging is relatively time consuming and cannot be performed on standard clinical scanners without specialized hardware and software upgrades. Nevertheless, the unique physiologic information provided by sodium imaging may make this technique an important tool in acute stroke imaging in years to come.

Multiparametric Tissue Modeling

The above sections describe many different imaging techniques that provide complimentary information about the viability of different parts of an acute stroke patient's brain. Neuroradiologists and stroke neurologists mentally synthesize the information provided by these different images to arrive at decisions regarding treatment decisions. Some groups have proposed combining different kinds of images quantitatively, using computers, in order to produce composite maps showing the risk of infarction in different parts of the brain. Wu et al.125 developed a multiparametric predictive model, incorporating DWI and MRP data, which achieved 66% sensitivity and 84% specificity in identifying individual tissue voxels destined for infarction. Rose et al.126 used a different multiparametric model to achieve mean sensitivity of 72% and specificity of 97%.

Currently, multiparametric predictive algorithms are largely confined to the realm of research and are not generally used clinically. However, it is easy to imagine a time in the future when acute stroke patients undergo a quick imaging evaluation, using many of the methods mentioned above, the results of which are used by a multiparametric model that immediately produces composite maps showing which areas of the brain are likely to infarct if each of various therapeutic approaches are undertaken. Such a model, once empirically validated, could dramatically enhance the treatment of acute stroke patients.

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