Improving the detection sensitivity of pH‐weighted amide proton transfer MRI in acute stroke patients using extrapolated semisolid magnetization transfer reference signals

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The goal of acute ischemic stroke therapy is to salvage tissue that is at risk of infarction but still viable with reperfusion strategies. Such tissue is commonly referred to as the ischemic penumbra and has been the primary target of therapeutic interventions 1. In the absence of multimodal imaging, thrombolytic therapy with tissue plasminogen activator is beneficial only when the treatment is initiated within the 3‐ and 4.5‐h time window after symptom onset 6.Using a time‐based approach results in only a limited number of stroke patients being eligible for thrombolytic treatment 8. Patients presenting beyond these standard treatment time windows can benefit from therapy when selected using multimodal MRI 9; however, precise identification of the ischemic penumbra is essential, as the potential beneficial effect of treatment must be weighed against the risk of brain hemorrhage 8. Consequently, early and accurate delineation of the at‐risk, yet salvageable ischemic penumbra from the irreversibly damaged infarct core can enhance patient selection for stroke treatments and extend the time window for therapeutic intervention.
Typically, diffusion‐weighted imaging (DWI) allows visualization of early tissue damage by changing the local diffusion of water in the ischemic lesion, whereas perfusion‐weighted imaging (PWI) provides quantitative information on abnormal cerebral blood flow or volume. The DWI/PWI spatial mismatch has been used as a guide to identify the presence of salvageable tissues and to serve as a selection marker for thrombolysis 2. However, use of the DWI/PWI mismatch concept has proven to be limited in routine clinical application because of variable sensitivity, specificity, and high false‐negative rates 14. Specifically, the mismatch area is too large as a result of inclusion of regions of benign oligemia, and most basic literature indicates that a more appropriate penumbra would be that in which oxidative metabolism is impaired, but no diffusion changes have occurred 18. Thus, there is a need for imaging techniques that more accurately identify the ischemic penumbra from benign oligemia, to advance the treatment of acute stroke by expanding the population of treatable patients.
The original concept of the ischemic penumbra was based on the concept of functionally impaired tissue, because of a deficit in oxidative metabolism, which is potentially viable, but surrounds, and is contiguous with, an area of irreversible cerebral infarction 1. Acute cerebral ischemia causes a shift to anaerobic glycolysis, resulting in the accumulation of lactic acid and a concomitant decrease in intracellular pH 23. Therefore, tissue acidosis is the earliest sign that tissue is at risk but potentially salvageable when it can be contrasted with regions identified as being irreversibly infarcted. Recently, pH‐sensitive amide proton transfer–weighted (APTw) imaging has shown promise in detecting ischemic tissue acidosis following impaired aerobic metabolism in animal models 24 and human stroke patients 30. Most of the previous APTw studies used the so‐called magnetization transfer ratio asymmetry at 3.5 ppm or MTRasym(3.5ppm). However, it is known that MTRasym(3.5ppm) is unavoidably contaminated by the upfield nuclear Overhauser enhancement (NOE) signals of mobile to semisolid macromolecules 34, resulting in a small or sometimes negligible imaging signal. In this study, quantitative APT (APT#) and NOE (NOE#) effects in acidic ischemic lesions were investigated in acute stroke patients at 3 T, using the so‐called extrapolated semisolid magnetization transfer reference (EMR) data analysis 36. In this approach, semisolid magnetization transfer contrast (MTC) and direct water saturation contributions were fitted and extrapolated to obtain reference (baseline) signals at the APT and NOE frequencies, from which the chemical exchange saturation transfer (CEST) based APT# and NOE# signals could be derived by subtraction from the experimental signals. The results were compared with the commonly used MTRasym(3.5ppm) parameters.

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