What Molecular Properties Can We Image using newly developed X-nuclear MRS methods?
Wei Chen1 and Xiao-Hong Zhu1
1CMRR, University of Minnesota, Minneapolis, MN, United States

Synopsis

The advancement of ultrahigh-field (UHF) MRI technology (now reaching 10.5T for human scanner and beyond 16T for preclinical animal) has significantly improved imaging sensitivity, spectral and spatiotemporal resolutions. It accelerates new developments of in vivo MRS imaging technologies enabling quantitative and reliable assessment of various neurochemicals, metabolites, metabolic rates in healthy and diseased brain. This lecture will discuss newly developed X-nuclear MRS imaging methods for quantitatively imaging cerebral metabolic rates of glucose and oxygen, ATP production, TCA cycle and NAD redox ratio; and demonstrate promising applications for studying brain function and neuroenergetics under normal and diseased states at UHF.

Magnetic resonance (MR) imaging (MRI) provides an important means for biomedical research and clinical diagnosis. The traditional MRI measures the water proton resonance signal of tissue for imaging organ structures and functions; for instance, functional MRI is used to investigate brain activation and functional connectivity. On the other hand, in vivo MR spectroscopy (MRS) imaging (MRSI) detects 1H or X-nuclear (e.g., 31P, 13C, 17O and 2H) resonance signals for assessing the content and metabolic activity of metabolites as well as neurotransmission cycling in targeted organ or tissues. In vivo 1H MRS is one of the most popular methods for noninvasive evaluation of neurochemicals and neurotransmitters, and it has advantages over X-nuclear MRS in terms of detection sensitivity (1,2). In contrast, a variety of X-nuclear MRS methods provide unique imaging tools to measure numerous biochemical parameters and molecules in vivo, and they are critical for investigating broad aspects of brain function, physiopathology, in particular, cellular energy metabolism and mitochondrial function. They are the most classic types of molecular imaging methods and rely on either endogenous or isotope-labeled molecules to detect metabolites content, their kinetics and/or metabolic rates. Due to the relatively low gyromagnetic ratios and concentrations, X-nuclear MRS measurements often have poor resolution and signal-to-noise ratio, and are therefore less popular in biomedical research community and translation to clinic. Recent advancement of ultrahigh-field (UHF) MRI technology (now up to 10.5T for whole-body human scanner and beyond 16T for preclinical animal scanner) has significantly improved detection sensitivity, spectral resolution and spatiotemporal resolution (3,4). Such improvements promote the new development of X-nuclear MRS imaging methods at UHF for studying cerebral metabolism and neuroenergetics, which requires high detection sensitivity and resolution.
Brain predominantly relies on glucose and oxygen to generate biochemical energy in the form of ATP in mitochondria for supporting electrophysiological activities, neural signaling and brain function under resting and working states. Figure 1 shows a schematic diagram illustrating the complex relations of brain energy metabolism, neuroenergetics, neuro-vascular activity and brain functions. Impaired energy metabolism as well as declined mitochondrial functionality have been hallmarks of various brain disorders including stroke, brain tumor and neurodegenerative diseases. However, there is an unmet need in developing novel neuroimaging tools that can provide sensitive biomarkers to study abnormal physiology and dysfunction in an early stage of brain diseases. Recent progresses in developing multimodal in vivo X-nuclear (e.g., 2H, 17O and 31P) MRSI techniques at UHF have shown great promise for quantitative and noninvasive assessment of fundamental cerebral metabolic rates of glucose (CMRGlc) and oxygen (CMRO2) consumption, ATP production (CMRATP), TCA cycle rate (VTCA) as well as NAD redox ratio (RXNAD) in preclinical animal and human brains (4). In this lecture, we will briefly describe the technical developments and challenges of measuring following physiological parameters of interest using the newly developed X-nuclear MRS imaging methods:
i) quantitative in vivo 2H MRS/MRSI technique for simultaneous measurement of CMRGlc and VTCA (5);
ii) quantitative in vivo 17O MRS/MRSI technique for simultaneous measurement of CMRO2, cerebral blood flow (CBF) and oxygen extraction fraction (OEF) (6-8);
iii) quantitative in vivo 31P MRS/MRSI techniques for measurement of CMRATP and RXNAD (9,10).
We will also discuss and demonstrate new utilities and promise of these X-nuclear metabolic neuroimaging techniques in studying resting-state and stimulus-evoked brain (11-13), stroke (7), brain tumor (14-16), neuroenergetic decline associated with aging (9) and neurodegeneration. These techniques offer new oppotunities to study brain function and disorders, and indicate a potential for translation. Finally, the new imaging methods could be readily employed to other organs beyond brain.
We anticipate that audience with interdisciplinary research background could benefit from this lecture; learn the new MRS imaging techniques about how to employ the techniques for conducting studies, quantify and interpret the in vivo MRS data for addressing biomedical or basic scientific questions; and understand their relevance to clinical application.

Acknowledgements

This work was supported in part by NIH Grants U01 EB026978, R24 MH106049, R01 CA240953, R01 MH111413, RO1 NS057560, RO1 NS070839, P30 NS076408 and P41 EB027061.

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Figures

Figure 1. Schematic pathways of brain energy metabolism to support brain function.

Proc. Intl. Soc. Mag. Reson. Med. 28 (2020)