Imaging is an essential tool to guide stroke patient management. Recent DAWN and DEFUSE-3 trials have provided the definitive evidence that imaging is critical to guide late endovascular therapy (EVT), underscoring the need to transition from onset time-based to tissue-based treatment. However, it has been estimated that the majority of stroke patients (~70%) presenting 6-24 hrs with NIH Stroke Scale (NIHSS) over 6 are not DAWN and/or DEFUSE-3 eligible (Desai et al. J Neurointerv Surg. 2018; 10:1033-37). The 2018 American Heart Association Stroke Early Management Guidelines pointed out that it is ?? reasonable to incorporate collateral flow status into clinical decision making in some candidates to determine eligibility for mechanical thrombectomy.? Tissue metabolic MRI is a surrogate biomarker of the collateral flow status that is promising to address this clinical need. We will develop fast pH and diffusion kurtosis imaging (DKI) and evaluate their value for guiding reperfusion therapy in experimental stroke models. During the previous funding cycle, we made steady progress in developing new stroke MRI techniques. We developed pH-specific imaging based on magnetization transfer and relaxation-normalized amide proton transfer (MR-APT) MRI (Guo et al. Neuroimage 2016;242-9). Using filament middle cerebral artery occlusion rats, we refined the perfusion/diffusion-weighted imaging (PWI/DWI) lesion mismatch for the metabolic penumbra and benign oligemia (Wang et al. Neuroimage 2019;610-7). Our acute stroke patient study showed that the volumes of acute DKI lesions have a higher correlation coefficient than those on the apparent diffusion coefficient (ADC) maps with 1-month follow-up T2 images (Yin et al. Radiology 2018:651-7). This echoes the recent study from NINDS investigators who reported: ?ADC evolution in patients with early, complete revascularization, now more commonly seen with EVT, is strikingly different from our historical understanding.? (Hsia et al., Stroke. 2019;50:2086-92) We hypothesize that new fast MRI techniques refined tissue-clock helps delineate ischemic tissue, predict tissue outcomes in permanent stroke, and guide reperfusion treatment. It is urgent to test the refined tissue-clock, in the presence of common stroke comorbidities and in the experimental setting, before initiating future prospective clinical trials. Briefly, we will develop robust fast pH and DKI stroke imaging (Aim 1), establish the spatiotemporal evolution of the refined MRI in MCAO rats (Aim 2), and test tissue-clock-guided reperfusion in rats of common stroke comorbidities of age and diabetes (Aim 3). The success of the project will lay the groundwork for future clinical trials to test advanced imaging-guided stroke treatment in the clinic.

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Recent stroke trials have shown that with the help of imaging, late thrombectomy is beneficial. We propose to further the development of pH and diffusion kurtosis imaging for improved ischemic tissue characterization. We will test the refined mismatch paradigm using permanent and transient middle cerebral artery occlusion (MCAO) rats, laying the foundation for future clinical translation.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Acute Neural Injury and Epilepsy Study Section (ANIE)
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Babcock, Debra J
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Emory University
Schools of Medicine
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Yin, Jianzhong; Sun, Haizhen; Wang, Zhiyun et al. (2018) Diffusion Kurtosis Imaging of Acute Infarction: Comparison with Routine Diffusion and Follow-up MR Imaging. Radiology 287:651-657
Wu, Yin; Zhou, Iris Y; Igarashi, Takahiro et al. (2018) A generalized ratiometric chemical exchange saturation transfer (CEST) MRI approach for mapping renal pH using iopamidol. Magn Reson Med 79:1553-1558
Wu, Yin; Zhou, Iris Yuwen; Lu, Dongshuang et al. (2018) pH-sensitive amide proton transfer effect dominates the magnetization transfer asymmetry contrast during acute ischemia-quantification of multipool contribution to in vivo CEST MRI. Magn Reson Med 79:1602-1608
Zhou, Iris Yuwen; Wang, Enfeng; Cheung, Jerry S et al. (2017) Quantitative chemical exchange saturation transfer (CEST) MRI of glioma using Image Downsampling Expedited Adaptive Least-squares (IDEAL) fitting. Sci Rep 7:84
Yuwen Zhou, Iris; Wang, Enfeng; Cheung, Jerry S et al. (2017) Direct saturation-corrected chemical exchange saturation transfer MRI of glioma: Simplified decoupling of amide proton transfer and nuclear overhauser effect contrasts. Magn Reson Med 78:2307-2314
Guo, Yingkun; Zhou, Iris Yuwen; Chan, Suk-Tak et al. (2016) pH-sensitive MRI demarcates graded tissue acidification during acute stroke - pH specificity enhancement with magnetization transfer and relaxation-normalized amide proton transfer (APT) MRI. Neuroimage 141:242-249
Zhou, Iris Yuwen; Fuss, Taylor L; Igarashi, Takahiro et al. (2016) Tissue Characterization with Quantitative High-Resolution Magic Angle Spinning Chemical Exchange Saturation Transfer Z-Spectroscopy. Anal Chem 88:10379-10383
Jiang, Weiping; Zhou, Iris Yuwen; Wen, Lingyi et al. (2016) A theoretical analysis of chemical exchange saturation transfer echo planar imaging (CEST-EPI) steady state solution and the CEST sensitivity efficiency-based optimization approach. Contrast Media Mol Imaging 11:415-423
Sun, Phillip Zhe; Xiao, Gang; Zhou, Iris Yuwen et al. (2016) A method for accurate pH mapping with chemical exchange saturation transfer (CEST) MRI. Contrast Media Mol Imaging 11:195-202
Zhou, Iris Yuwen; Guo, Yingkun; Igarashi, Takahiro et al. (2016) Fast diffusion kurtosis imaging (DKI) with Inherent COrrelation-based Normalization (ICON) enhances automatic segmentation of heterogeneous diffusion MRI lesion in acute stroke. NMR Biomed 29:1670-1677

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