³¹P‐MRS of healthy human brain: ATP synthesis, metabolite concentrations, pH, and T₁ relaxation times

Abstract

The conventional method for measuring brain ATP synthesis is 31P saturation transfer (ST), a technique typically dependent on prolonged pre-saturation at γ-ATP. In this study, ATP synthesis rate in resting human brain is evaluated using EBIT (Exchange Kinetics by Band Inversion Transfer), a technique based on slow recovery of γ-ATP magnetization in the absence of B1 field following co-inversion of PCr and ATP resonances with a short adiabatic pulse. The unidirectional rate constant for the Pi → γ-ATP reaction is 0.21 ± 0.04 sec−1 and the ATP synthesis rate is 9.9 ± 2.1 mmol/min/kg in human brain (n = 12 subjects), consistent with the results by ST. Therefore EBIT could be a useful alternative to ST in studying brain energy metabolism in normal physiology and under pathological conditions. In addition to ATP synthesis, all detectable 31P signals are analyzed to determine the brain concentration of phosphorus metabolites including UDPG at ~ 10 ppm, a previously reported resonance in liver tissues and now confirmed in human brain. Inversion recovery measurements indicate that UDPG, like its diphosphate analogue NAD, has a shorter apparent T1 than monophosphates (Pi, PMEs and PDEs) but longer than triphosphate ATP, highlighting the significance of 31P-31P dipolar mechanism in T1 relaxation of polyphosphates. Another interesting finding is the observation of ~40% shorter T1 at intracellular Pi relative to extracellular Pi, attributed to the modulation by the intracellular phosphoryl exchange reaction Pi ↔ γ-ATP. The sufficiently separated intra- and extra-cellualr Pi signals also permit the distinction of pH between intra- and extra-cellular environments (pH 7.0 vs pH 7.4). In summary, the quantitative 31P MRS in combination with ATP synthesis, pH and T1 relaxation measurements may offer a promising tool to detect biochemical alternations at early stages of brain dysfunctions and diseases.

Evidence for a “metabolically inactive” inorganic phosphate pool in adenosine triphosphate synthase reaction using localized 31P saturation transfer magnetic resonance spectroscopy in the rat brain at 11.7 T

“…Interestingly, we estimated that the extracellular Pi represents 20% of the total Pi in the rat brain, which is close to what has been reported in Ren et al 12 (35%) and Kintner et al 20 and Du et al 21 (25%). Considering that this corresponds well to the generally accepted 22 volume fraction of each of those compartments in the brain, these results suggest that Pi concentrations are similar in the intracellular and extracellular spaces.…”

“…Some reports assign a mitochondrial origin to the second Pi peak in the muscle, with a chemical shift actually closer to 5.1 ppm 8 (and references therein), while others assign an extracellular origin in the brain. 20,21 The different origin of this second Pi in brain 12 compared to muscle 8 is also suggested by the large difference in T1 (approximately four times longer in the brain).…”

“…This was shown here with saturation transfer in the rat brain, and with inversion transfer techniques in the human brain. 12 Using saturation transfer allowed achieving a $50% signal decrease for Pi 4.9 , i.e. a much stronger contrast compared to inversion transfer (25% maximal signal decrease).…”

“…7,8 Other studies at lower fields have been trying to deconvolve the broad Pi peak into various number of pools and attribute them to specific cellular compartments in isolated brains. [9][10][11] A very recent study in the human brain 12 found the second Pi pool resonating at 5.24 ppm to be insensitive to selective inversion of PCr and g-ATP, 13 suggesting the absence of chemical The aim of this study was to combine high magnetic field (11.7 T) and spectroscopic localization to achieve good spectral resolution and test this hypothesis, i.e. characterize Pi pools (noted Pi 4.9 and Pi 5.3 ) in the rat brain, including saturation transfer experiments to estimate the participation of each pool to ATP synthesis.…”

Phosphorus magnetic resonance spectroscopy in the investigation of temporal lobe epilepsy: ‘reading between the lines’ of metabolic abnormalities

“…Phosphorus MRS ( 31 P-MRS) is not so commonly employed in brain tissue evaluation; nevertheless, it is able to add important information about energy metabolism. The metabolites visible in a high resolution spectrum from 31 P-MRS are basically phosphorus compounds: total adenosine triphosphate (total ATP, composed by γ-+ α-+ β-ATP, according to the position of the three phosphate groups), inorganic phosphate (Pi), PCr (phosphocreatine), phosphodiesters (PDE, the sum of glycerophosphocholine plus glycerophosphoethanolamine) and phosphomonoesters (PME, composed by phosphocholine plus phosphoethanolamine) 4 . These metabolites are mainly involved in mitochondrial processes and cellular membrane turnover.…”