The research proposed here addresses fundamental limitations of magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) in vivo, enhancing their utility and enabling new clinical and preclinical applications. MRI and MRS have become very powerful clinical modalities, and applications continue to evolve. However, sensitivity is relatively low, so in most MRI studies, the signal arises mostly from water, and contrast arises primarily from parameters which often only have indirect clinical relevance or correlation with metabolism and cell biochemistry. Most contrast agents have limited specificity, and usually need to be present in high concentration to affect the signal. Localized detection of other molecules (MRS) is hampered by low concentrations, by competition with the strong water peak, and (in many organs) by local susceptibility variations that broaden resonances and thus reduce selectivity. The research proposed here addresses these fundamental limitations using intermolecular multiple- quantum coherences (iMQCs), both by themselves and with long-lived hyperpolarized reagents. iMQCs correspond to simultaneous spin flips on separated molecules in solution (the separation is typically hundreds of microns). In the previous grant period, we developed methods that significantly strengthen iMQC signals, applications such as temperature imaging where iMQCs have clear advantages, novel contrast agents that amplify the signal from small lung metastases, and approaches that dramatically increase the lifetimes of specific hyperpolarized reagents. Just since October 2008, this work includes two published Science papers and a submitted PNAS paper. This renewal includes specific aims which exploit these developments, with a focus on targeted clinical applications and localized spectroscopy. The common theme of these applications is high precision spectroscopy, enabled by the intrinsic ability of appropriate iMQC sequences to compensate for susceptibility variations and inhomogeneous broadening. This compensation can be achieved without throwing away chemical shift differences, and the intermolecular coherences can connect molecules which are not in immediate proximity. In organs or tissues with substantial heterogeneity (such as the breast) the linewidth reductions are dramatic.
The specific aims exploit these characteristics to enable two clinically promising research directions (absolute temperature imaging in hyperthermic therapy and brown adipose tissue detection), to improve proton MRS in fatty tissue, and to enhance the utility of carbon hyperpolarized reagents by detecting sharp lines from water-carbon iMQCs. This work ranges from phantom studies to our participation in an ongoing human clinical trial, and includes innovative pulse sequence development as well as applications of existing sequences.

Public Health Relevance

This proposed work aims to improve the sensitivity and the useful contrast in magnetic resonance imaging (MRI) and localized spectroscopy. Clinical applications to temperature imaging (for example, to improve hyperthermic breast cancer therapy or detect activated brown adipose tissue), development of long lived molecular contrast agents, and enhanced tumor detection are emphasized.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
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Biomedical Imaging Technology Study Section (BMIT)
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Liu, Guoying
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Duke University
Schools of Arts and Sciences
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Davis, Ryan M; Zhou, Zijian; Chung, Hyunkoo et al. (2016) Multi-spin echo spatial encoding provides three-fold improvement of temperature precision during intermolecular zero quantum thermometry. Magn Reson Med 75:1958-66
Stokes, Ashley M; Feng, Yesu; Mitropoulos, Tanya et al. (2013) Enhanced refocusing of fat signals using optimized multipulse echo sequences. Magn Reson Med 69:1044-55
Branca, Rosa T; Zhang, Le; Warren, Warren S et al. (2013) In vivo noninvasive detection of Brown Adipose Tissue through intermolecular zero-quantum MRI. PLoS One 8:e74206
Feng, Yesu; Theis, Thomas; Liang, Xiaofei et al. (2013) Storage of hydrogen spin polarization in long-lived 13C2 singlet order and implications for hyperpolarized magnetic resonance imaging. J Am Chem Soc 135:9632-5
Cho, Jee-Hyun; Hong, Kwan Soo; Cho, Janggeun et al. (2012) Detection of iron-labeled single cells by MR imaging based on intermolecular double quantum coherences at 14 T. J Magn Reson 217:86-91
Khanna, Arjun; Branca, Rosa T (2012) Detecting brown adipose tissue activity with BOLD MRI in mice. Magn Reson Med 68:1285-90
Chen, Y Morris; Branca, R T; Warren, W S (2012) Revisiting the mean-field picture of dipolar effects in solution NMR. J Chem Phys 136:204509
Stokes, A M; Wilson, J W; Warren, W S (2012) Characterization of restricted diffusion in uni- and multi-lamellar vesicles using short distance iMQCs. J Magn Reson 223:31-40
Branca, Rosa T; Warren, Warren S (2011) In vivo NMR detection of diet-induced changes in adipose tissue composition. J Lipid Res 52:833-9
Kurhanewicz, John; Vigneron, Daniel B; Brindle, Kevin et al. (2011) Analysis of cancer metabolism by imaging hyperpolarized nuclei: prospects for translation to clinical research. Neoplasia 13:81-97

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