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Improving Amide Proton Transfer (APT) MRI Quantification in Acute Human Stroke Patients: Achieving More Pure APT Signals and Higher Detection Sensitivity
Hye-Young Heo1,2, Yi Zhang1, Tina Burton3, Shanshan Jiang1, Peter C.M. van Zijl1,2, Richard Leigh3, and Jinyuan Zhou1,2

1Russell H Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States, 2F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States, 3Stroke Diagnostics and Therapeutics Section, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD, United States

Synopsis

APT-weighted (APTw) imaging based on MTR asymmetry analysis has shown promise for identifying ischemic lesions, but suffers from low accuracy due to small APTw intensity changes, Quantitative APT, nuclear overhauser enhancement (NOE), perfusion and diffusion MRI were performed on acute stroke patients (n=30). The results showed that while APTw MRI for pH analysis based on MTRasym analysis was confounded by upfield NOE effects, NOE-free APT-MRI contrast between normal and ischemic lesions was substantially increased, nearly 3 times larger than that based on MTRasym analysis. Furthermore, noticeable NOE contrast was observed for lesions, explained in terms of a relayed-NOE transfer mechanism.

Introduction

Typically, perfusion (PWI)/diffusion-weighted imaging (DWI) spatial mismatch has been used to identify the presence of ischemic penumbra and to serve as a selection marker for thrombolysis (1, 2). Although promising, this is still limited in routine clinical application due to variable sensitivity, specificity and high false-negative rates (3-5). Recently, pH-sensitive amide proton transfer (APT) imaging has shown promise in detecting ischemic tissue acidosis following impaired aerobic metabolism (6-10). However, the MTRasym(3.5ppm) or APT-weighted (APTw) signal intensity of the ischemic lesion that was used in previous studies is unavoidably contaminated (reduced) by the upfield relayed nuclear Overhauser enhancement (rNOE) effect, resulting in a small or sometimes negligible imaging contrast. Here, we investigated quantitative APT and rNOE effects in acidic ischemic lesions and further assessed the spatial relationship between DWI, PWI and pH deficits in acute stroke patients.

Methods

Thirty patients with acute ischemic stroke (<7 hours from symptom onset) were recruited into the NIH Natural History of Stroke Study following informed consent in accordance with IRB requirement and scanned on a Philips 3 T MRI scanner. Serial MRI scans were performed at presentation (no APTw scan allowed in our current IRB protocol for this time point), 2 hours, 1 day, 1 week, and 1 month to characterize tissue progressing to infarction. The CEST imaging sequence was incorporated into the standard protocol for clinical diagnosis. CEST images were acquired using a fat-suppressed TSE sequence with a RF saturation time of 800 ms, saturation power of 2 μT, and saturation frequency offsets (14 to -8 ppm at intervals of 0.5 ppm). After B0 correction with water saturation shift-referencing (26 frequency offsets from 1.2 to -1.2 ppm at intervals of 0.125 ppm and a saturation power of 0.5 μT), the extrapolated semi-solid MT model reference (EMR) method was used to quantify APT and NOE signals (11). A wide-offset Z-spectrum with semisolid magnetization transfer contrast (MTC) data points between 8 and 14 ppm were fitted to the two-pool MTC model with a super-Lorentzian lineshape. Finally, quantitative APT (APT#) and NOE (NOE#) signals were calculated as the difference between EMR and experimental data at 3.5 ppm and -3.5 ppm.

Results and Discussion

Fig. 1 shows MTRasym(3.5ppm), APT#, NOE#, and conventional MR images of an acute stroke patient, as well as an APT-MRI quantification comparison between MTR asymmetry and EMR. Both APT# and NOE# showed a strong hypointensity in the infarct core identified from the DWI, while MTRasym(3.5ppm) signal contrast between normal and acidic ischemic lesion was visible, but small. Fig. 2 shows serial multimodality MR images of an acute stroke patient with left MCA occlusion. Abnormal DWI showed local cytotoxic edema, generally leading to irreversible infarct. PWI showed a larger perfusion deficit than DWI and the spatial mismatch which is typically used for the identification of salvageable penumbra. APT# images showed clear pH deficits in the ischemic lesion, whereas MTRasym(3.5ppm) signals were isointense or slightly hypointense due to the upfield NOE contribution compensating the APT effect. Interestingly, hyperintense APT signals were observed in hemorrhage (white arrows in Fig. 2) due to abundant mobile protein and peptide in the blood, in line with previous investigations (12). Quantitatively, both APT# and NOE# signals of the ischemic lesion were significantly lower than those of the normal tissue, while the MTRasym(3.5ppm) signals showed a trend but no significant difference, as shown in Fig. 3. Correspondingly, the APT# image contrast (NOE free) of the ischemic lesion was also much larger than the MTRasym(3.5ppm) image contrast. Contrary to NOE effects as a positive confounding factor in tumor (11), it is shown here that NOE is a negative confounding factor in APT imaging of stroke. Thus, the absolute MTRasym(3.5ppm) signal intensity and image contrast of the ischemic lesion is reduced by the upfield NOE contribution. This is understandable in terms of the origin of the NOE signals being due to NOEs relayed via the exchangeable protons (13,14) and in line with recent studies reporting that the rNOE effect via exchangeable groups is pH dependent (15). Thus, the use of MTRasym(3.5ppm) can decrease the stroke APT-MRI sensitivity. Fig. 4 shows pH/diffusion and perfusion/pH scatterplots to investigate the spatial dynamics of ischemia progression in a representative acute stroke patient. The distributions of the diffusion deficits, pH-diffusion mismatch, and perfusion-pH mismatch suggest that the hypoperfused acidic ischemic lesion without an ADC abnormality identifies the ischemic acidosis penumbra, while the hypoperfused neural area classifies benign oligemia, in line with hypotheses previously suggested (7,10)

Conclusions

APT studies using the EMR approach can achieve less contaminated APT-MRI signals and enhance APT MRI sensitivity to pH and may allow reliable delineation of an ischemic acidosis penumbra. It may in the future help guide thrombolytic and/or neuroprotective therapies for acute stroke patients at various therapeutic windows.

Acknowledgements

This work was supported in part by grants from the National Institutes of Health (R01EB009731, R01CA166171, R01NS083435, EB015032, and P41EB015909).

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Figures

MR images of an acute stroke patient with right MCA occlusion (<6 hours from symptom onset). Both APT# and NOE# showed much clearer ischemic contrasts than MTRasym(3.5ppm). (b) Average Z-spectra and (c) MTRasym spectra obtained from the contralateral normal (black) and the ischemic lesion (red). (d) Wide-offset Z-spectra with only MTC between 8 and 14 ppm (red and black asterisks) were fitted to the two-pool MT model. (e) The quantitative CEST# and NOE# signals obtained by subtracting the experimental measured Z-spectra (light-red asterisks in d) from the EMR data (red and black solid lines in d).

Serial multimodality MR images of a representative acute stroke patient with left MCA occlusion (yellow arrows) at three time points. DWI and ADC showed large acute ischemic areas due to cytotoxic edema. In addition, perfusion-based MTT (mean transit time) and TTP (time-to-peak) showed obvious hypoperfusion in a slightly larger region than the diffusion abnormality. Both APT# and NOE# showed much clearer ischemic contrasts than MTRasym(3.5ppm) at two earlier time points. High APT signal intensities observed at 1 week can be attributed to a hemorrhage (white arrows) caused by abundant mobile proteins and peptides in the blood.

Both APT# and NOE# signal intensities of the ischemic lesion (DWI hyperintensity) were significantly lower than those of the contralateral normal tissue, while the MTRasym(3.5ppm) signals showed no significant difference. In addition, the NOE free-APT# image contrast between acidic ischemic and contralateral normal tissues was much larger than the MTRasym(3.5ppm) image contrast.

(a) Comparison of diffusion/pH/perfusion deficits in an acute stroke patient at 1 day from symptom onset. All ischemic lesions in ADC, APT#, and MTT images were automatically segmented using a segmentation algorithm with K-means clustering technique. (b, c) Quantitative pH/diffusion and perfusion/pH scatterplots. The distributions of the diffusion deficit area (infarct core, red), pH-diffusion mismatch (acidosis-based penumbra, green), and perfusion-pH mismatch (acidosis-based benign oligemia, blue) were markedly different from those of the contralateral normal tissue (black).

Proc. Intl. Soc. Mag. Reson. Med. 25 (2017)
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