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