Hyperpolarized MR Imaging: Neurologic Applications of Hyperpolarized Metabolism

Moving to the frontal lobe through low-power ¹³C MR spectroscopy. Traditionally, in vivo ¹³C MR spectroscopy of the human brain has been confined to “safe” areas, such as the occipital cortex (left panel), to avoid heat deposition in the ocular lens. With increased interest in metabolic abnormalities of the frontal lobe involved in executive functions, a novel ¹³C MR spectroscopy method uses low-power nuclear Overhauser effect (NOE) to safely obtain glial metabolic data (right panel) from the frontal cortex. DC indicates (proton) decoupling. Reprinted with permission from Journal of Magnetic Resonance.³ Copyright 2008, Elsevier Ltd.

¹³C MR spectroscopy of neuronal function in the frontal brain. To obtain equivalent data concerning neuronal function, the isotope infused must be C2-enriched ¹³C glucose which, in contrast to carbon 1 (C1)-glucose, enriches glutamate and glutamine in C5 and C1 (left panel). These products can safely be measured with a low-power NOE method in the frontal lobes (right panel). PCr indicates phosphocreatine. Reproduced with permission from Radiology.⁴ Copyright 2009, Radiological Society of North America.

¹³C MR spectroscopy schematic for examining the “two-hit” hypothesis of drug abuse in the frontal brain. Combining dynamic ¹³C measures of glial and neuronal glutamate metabolism with ¹H-MR spectroscopy assays of steady-state glutamate concentration provides a novel window on drug abuse. Inhibition of acetate metabolism by methamphetamine (Meth) abuse indicates a possible mechanism whereby reduced clearance of glutamate in glia (hit 1) results in glutamate excitotoxicity of neurons (hit 2). Variations on this theme may contribute to other neurologic syndromes for which selective assays of glial and neuronal function provide enhanced imaging tools. Na indicates sodium; ATPase, adenosine triphosphatase; K, potassium; EAAT, excitatory amino acid transporter. Reprinted with permission from Science.⁶ Copyright 1999, The American Association for the Advancement of Science.

Four methods for hyperpolarized-MR imaging and spectroscopy. In the historic order of discovery, parahydrogen-induced polarization (PASADENA); optical pumping of noble gases helium and xenon; dynamic nuclear polarization (DNP); and Brute Force have each been harnessed to the challenge of increasing enhancement above the Boltzmann distribution of approximately 1 ppm toward unity, with upwards of 10,000-fold enhancement of MR signal intensity for in vivo MR imaging and MR spectroscopy.

Two techniques for producing hyperpolarized ¹³C succinate, the first biologic imaging agent generated by the parahydrogen method. Starting with the toxic precursor acetylene dicarboxylic acid (left panel) or with the biologically safe 1-¹³C fumarate (right panel), a high degree of polarization can be achieved during the molecular addition of parahydrogen, followed by polarization transfer to the ¹³C atom shown in red (below). D indicates deuterium; d2, deuteration; RF, radio-frequency; mT, milli-Tesla; HO, hydroxyl; H, hydrogen; T, spin relaxation time (seconds); D₂O, deuterized water; ^JHH, proton-carbon coupling constants; ^JCH, carbon-carbon coupling constants.

Quality assurance and reproducibility of hyperpolarization. A−C, The signal-intensity enhancement (19% polarization equivalent to 47,000-fold) due to hyperpolarization, estimated by comparison of the test reagent (A) with a standard solution of natural-abundance ¹³C ethanol (B ), while remarkably constant during 4 days and 16 successive in vitro experiments (C ), is more variable in vivo. The effects of dilution, mixing in blood, circulation times, T1 relaxation time of the ¹³C (and ¹⁵N) reagents, combined with the effects of radio-frequency pulses used for signal-intensity detection significantly reduce available signal-intensity enhancement in vivo. HMRI indicates Huntington Medical Research Institutes; P = polarization (%).

Real-time ¹³C PASADENA images of carotid artery and major blood vessels of the pig brain. Two of a time-lapse series of images obtained subsequent to a single injection of aqueous hydroxyethyl propionate (1, ¹³C) with initial polarization P = 0.4.

Toward hyperpolarized ¹³C succinate imaging of brain cancer. In this early study, ¹³C hyperpolarized images of the 9L brain tumor are obtained, but no metabolites are detected in vivo when hyperpolarized “succinate” (generated from ¹³C acetylene dicarboxylic acid; Fig 6, left) is injected via the jugular vein. Harvested brain tumor subsequently showed nonhyperpolarized ¹³C metabolites anticipated from metabolism of ¹³C succinate (Succ) through the neuronal and glial pathways indicated. No metabolites were isolated from the intact brain, indicating possibly the importance of a defective blood-brain barrier (BBB) for in vivo hyperpolarization neuroimaging. α-KG indicates alpha-ketoglutarate; V_gh, velocity glutamine-glutamate cycle. Reprinted with permission from Journal of Magnetic Resonance.¹⁰ Copyright 2007, Elsevier Ltd.

In vivo neuroimaging and spectroscopy of hyperpolarized ¹³C succinate. In confirmation of the role of BBB, the first truly in vivo hyperpolarized ¹³C spectra arose predominantly from the stroke region of rat brain (left and center) as shown in 2D ultrafast chemical shift imaging (CSI) series (right panel) (Avance, Bruker, Karlsruhe, Germany). PHIP indicates parahydrogen-induced polarization.

Hyperpolarized ¹³C metabolites of succinate in stroke brain. The effect of in vitro pH was verified on chemical shift of ¹³C succinate (right). A spectrum (inset) from the in vivo hyperpolarized dataset in Fig 10 indicates 2 resonances that are tentatively assigned to ¹³C succinate (S) at approximately pH 8 and its hyperpolarized metabolic product, C4 malate (M). The intracellular pH of stroke in vivo might, in the future, be estimated from hyperpolarized ¹³C spectra acquired in 3.5 seconds. Suc indicates succinate. (T. Tran and N. Sailasuta, unpublished data, HMRI, May 2009)

New directions for enhanced ¹³C imaging of brain cancer. Immunocytochemical stain for the hypoxia-induced factor (HIF)-1α indicates glioblastoma to be particularly rich in this cancer biomarker protein. This may, in the future, provide a uniquely sensitive means of in vivo imaging of brain cancer grade and metabolic activity (see Fig 13). RENCA, renal cancer; A-20-A (top left, top right, and bottom right ×160; bottom left ×312). (Courtesy of Dr. Ashraf Imam).