Stroke is a debilitating neurological disorder that is associated with tremendous socioeconomic burden. Whereas FDA-approved tissue plasminogen activator (tPA) is a potent thrombolytic agent for treating acute ischemic stroke, few patients present for treatment within its therapeutic window. There remains substantial interest in developing strategies to extend the thrombolytic therapy into subpopulations who may benefit from late intervention. MRI has become an essential clinical tool for the triage and management of acute ischemic stroke patients, yet the conventional stroke MRI is inadequate to fully characterize the heterogeneous ischemic tissue injury and effectively guide treatment in late presenting stroke patients. The approximation of diffusion/perfusion MRI (DWI/PWI) mismatch as ischemic penumbra, despite its initial enthusiasm, has been recognized to be oversimplified. PWI lesion contains tissue at no risk to infarction, while DWI lesion may recover if promptly reperfused. Besides falsely characterizing some salvageable tissue as ischemic core, DWI may also fail to identify tissue that has already suffered irreversible injury, as the eventual infarction is often larger than acute DWI lesion. As noted in the report of NIH/NINDS Stroke Progress Review Group (SPRG) in 2011, the number one priority for stroke imaging is to understand the impact of hemodynamics, collateral flow, oxygen and brain metabolism upon tissue survival and function. Tissue acidosis is closely associated with tissue oxygen/glucose metabolism, and may provide a metabolic biomarker for defining ischemic penumbra. However, currently available in vivo pH measurement techniques have significant limitations. Our proposal aims to develop endogenous amide proton chemical exchange saturation transfer (CEST) MRI for fast and non-invasive pH imaging. We will first develop novel acquisition and post-processing strategies to enhance the sensitivity of CEST imaging (Aim1). We will develop quantitative analysis that transform pH-weighted MRI to absolute tissue pH mapping in experimental stroke model, and test it under varied glycemic conditions and stroke onset time (Aim 2). We will then evaluate pH imaging, a novel metabolic imaging marker, to guide tPA thrombolysis in an embolic stroke model that mimics tPA thrombolysis in patients (Aim 3). In summary, our proposal establishes fast and quantitative pH stroke imaging in experimental stroke models, and once the sensitivity and specificity of pH MRI in defining metabolic penumbra are confirmed, we will translate it to clinic and evaluate its utility in late-presenting stroke patients.

Public Health Relevance

Ongoing efforts to develop imaging-guided stroke treatment are severely hindered by the limitations of perfusion and diffusion stroke MRI. Our proposal aims to establish fast tissue pH imaging, a novel metabolic imaging biomarker, for stratification of the heterogeneous ischemic tissue injury. pH imaging and its utility to guide thrombolytic treatment will be evaluated in experimental stroke models that closely mimic stroke patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS083654-01
Application #
8560081
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Babcock, Debra J
Project Start
2013-07-01
Project End
2018-04-30
Budget Start
2013-07-01
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$379,997
Indirect Cost
$161,247
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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
Wu, Yin; Kim, Jinsuh; Chan, Suk-Tak et al. (2016) Comparison of image sensitivity between conventional tensor-based and fast diffusion kurtosis imaging protocols in a rodent model of acute ischemic stroke. NMR Biomed 29:625-30
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
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 141:242-9
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
Wu, Renhua; Xiao, Gang; Zhou, Iris Yuwen et al. (2015) Quantitative chemical exchange saturation transfer (qCEST) MRI - omega plot analysis of RF-spillover-corrected inverse CEST ratio asymmetry for simultaneous determination of labile proton ratio and exchange rate. NMR Biomed 28:376-83
Wu, Renhua; Longo, Dario Livio; Aime, Silvio et al. (2015) Quantitative description of radiofrequency (RF) power-based ratiometric chemical exchange saturation transfer (CEST) pH imaging. NMR Biomed 28:555-65
Kim, Jinsuh; Wu, Yin; Guo, Yingkun et al. (2015) A review of optimization and quantification techniques for chemical exchange saturation transfer MRI toward sensitive in vivo imaging. Contrast Media Mol Imaging 10:163-78
Xiao, Gang; Sun, Phillip Zhe; Wu, Renhua (2015) Fast simulation and optimization of pulse-train chemical exchange saturation transfer (CEST) imaging. Phys Med Biol 60:4719-30
Sun, Phillip Zhe; Wang, Yu; Mandeville, Emiri et al. (2014) Validation of fast diffusion kurtosis MRI for imaging acute ischemia in a rodent model of stroke. NMR Biomed 27:1413-8

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