Imaging Brain Metabolism Using Hyperpolarized 13C Magnetic Resonance Spectroscopy

Abstract

Aberrant metabolism is a key factor in many neurological disorders. The ability to measure such metabolic impairment could lead to improved detection of disease progression, and development and monitoring of new therapeutic approaches. Hyperpolarized ¹³C magnetic resonance spectroscopy (MRS) is a developing imaging technique that enables non-invasive measurement of enzymatic activity in real time in living organisms. Primarily applied in the fields of cancer and cardiac disease so far, this metabolic imaging method has recently been used to investigate neurological disorders. In this review, we summarize the preclinical research developments in this emerging field, and discuss future prospects for this exciting technology, which has the potential to change the clinical paradigm for patients with neurological disorders.

Keywords: MRI; clinical translation; hyperpolarized (13)C magnetic resonance spectroscopy; immunometabolism; metabolic imaging; neurological disorders; preclinical models.

Figure 1 (Key Figure).. Typical steps of preclinical MR metabolic brain imaging of a rodent model using hyperpolarized [1-¹³C]pyruvate.

Step 1: Neat [1-¹³C]pyruvic acid mixed with a free radical is prepared at a high concentration (typically 14 M). Step 2: A small quantity of the preparation (5–150 uL) is placed into a hyperpolarizer for approximately 1 hour, where the sample sits at low temperature (T=1–2 K) whilst being irradiated with microwaves (F=~94 GHz). Step 3: When hyperpolarization is complete, the sample is very rapidly dissolved in a neutralizing buffer (within approximately 10s), which produces a pH 7, 37^∘C solution of [1-¹³C]pyruvate in the range of 5–100 mM. Step 4: This buffered solution is then immediately injected into the experimental subject placed inside a magnetic resonance imaging (MRI) system, over a short period of time (~15 sec). In the illustration, the injection is into a rodent model, via a tail-vein catheter. Acquisition of MR data (slab, 2D or 3D, dynamic or single timepoint acquisition) is timed with the injection of the hyperpolarized solution. Zoomed-in brain inset: In the rodent brain, conversion of hyperpolarized [1-¹³C]pyruvate conversion to hyperpolarized [1-¹³C]lactate, hyperpolarized [1-¹³C]alanine and hyperpolarized [¹³C]bicarbonate occurs within the time frame of the MR acquisition. These conversions are via lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and pyruvate dehydrogenase (PDH) respectively. Step 5: After data processing, MR data reflecting the in vivo metabolism of the injected hyperpolarized compound to its downstream metabolites can be visualized, for instance by displaying spectra, heatmaps or kinetic analyses of signal-to-noise ratio (SNR) versus time.

Figure 2.. Overview of metabolic reactions currently investigated using hyperpolarized probes.

Hyperpolarized probes (bold) and corresponding hyperpolarized downstream product(s) currently investigated in (1) the healthy brain (all items in the schematic except arginine); (2) the field of immunometabolism (yellow box) and (3) preclinical models of neurological disorders (red boxes). References to the corresponding study/studies are noted in grey above the reaction arrows. The relaxation times (T₁) of the hyperpolarized probes are ranked as long (40–60sec, green), average (20–40sec, orange) and short (5–20sec, red), from data at the clinical magnetic field strength of 3 Tesla (extrapolated from data at other field strengths for glucose, glutamate, acetate and ketoisocaproate).