The goal of this project is to further develop a novel MR molecular imaging technique for mapping glucose uptake and to apply this technique for stroke imaging. Glucose uptake is critical for cellular function, and the ability to assess its alteration in diseases holds great promise in many fields of medicine including neurodegeneration, traumatic brain injury, tumors, and specifically for this application, stroke. In acute ischemic stroke, a major therapeutic goal is to rescue the penumbra, i.e., tissue at risk of infarction but can be rescued with timely intervention. Robust identification of penumbra is crucial because it would potentially expand the therapeutic window, a major limiting factor in access to acute stroke intervention, and help with patient selection for novel endovascular therapies and the development of neuroprotective treatments. However, accurate and prompt imaging of penumbra is still a clinical barrier. We have recently developed a chemical-exchange sensitive spin- lock (CESL) MRI technique to indirectly detect glucose via the rapid chemical exchange between glucose hydroxyl groups and water protons. In contrast to direct measurements of glucose, such indirect detection through water offers substantial sensitivity enhancement, making in vivo mapping of glucose uptake feasible. Our preliminary results show that in stroke animals, CESL MRI with injection of a glucose analog can quickly (within several minutes) identify an apparent elevation of glucose uptake in a region adjacent to the ischemic core. This region of elevated response correlates well with final tissue outcome. While administration of natural D-glucose leads to hyperglycemia and worsens the ischemic tissue outcome, xylose, an FDA-approved glucose analog, may help alleviate the harmful metabolic effects and potentially improve the tissue outcome.
In Aim 1, we will further develop xylose-CESL to increase its signal sensitivity for glucose uptake imaging.
In Aim 2, we will study the signal source, sensitivity, and spatiotemporal characteristics of the xylose-CESL signal in ischemic rat brain.
In Aim 3, we will evaluate the efficacy of xylose-CESL for penumbra imaging. Successful completion of this project will provide a powerful MR molecular imaging tool for acute ischemic stroke, which would immediately impact preclinical studies and have a great potential for clinical translation.

Public Health Relevance

One of the most critical therapeutic targets in acute ischemic stroke is the penumbra, which can be salvaged with proper intervention. However, clear delineation of this region remains elusive by commonly-available imaging techniques. We propose to develop a novel chemical-exchange sensitive MRI technique to identify the penumbra, and to provide neuroprotective effect. Successful completion of this project will provide a powerful MR molecular imaging tool for acute ischemic stroke as well as other brain disorders with altered glucose uptake, which would immediately impact preclinical studies and have a great potential for clinical translation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS100703-01A1
Application #
9594660
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Babcock, Debra J
Project Start
2018-06-01
Project End
2023-02-28
Budget Start
2018-06-01
Budget End
2019-02-28
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213