Multimodal neuroimaging provides a highly consistent picture of energy metabolism, validating ³¹ P MRS for measuring brain ATP synthesis

Abstract

Neuroimaging methods have considerably developed over the last decades and offer various noninvasive approaches for measuring cerebral metabolic fluxes connected to energy metabolism, including PET and magnetic resonance spectroscopy (MRS). Among these methods, 31 P MRS has the particularity and advantage to directly measure cerebral ATP synthesis without injection of labeled precursor. However, this approach is methodologically challenging, and further validation studies are required to establish 31 P MRS as a robust method to measure brain energy synthesis. In the present study, we performed a multimodal imaging study based on the combination of 3 neuroimaging techniques, which allowed us to obtain an integrated picture of brain energy metabolism and, at the same time, to validate the saturation transfer 31 P MRS method as a quantitative measurement of brain ATP synthesis. A total of 29 imaging sessions were conducted to measure glucose consumption (CMRglc), TCA cycle flux (VTCA), and the rate of ATP synthesis (VATP) in primate monkeys by using 18 F-FDG PET scan, indirect 13 C MRS, and saturation transfer 31 P MRS, respectively. These 3 complementary measurements were performed within the exact same area of the brain under identical physiological conditions, leading to: CMRglc ‫؍‬ 0.27 ؎ 0.07 mol⅐g ؊1 ⅐min ؊1 , VTCA ‫؍‬ 0.63 ؎ 0.12 mol⅐g ؊1 ⅐min ؊1 , and VATP ‫؍‬ 7.8 ؎ 2.3 mol⅐g ؊1 ⅐min ؊1 . The consistency of these 3 fluxes with literature and, more interestingly, one with each other, demonstrates the robustness of saturation transfer 31 P MRS for directly evaluating ATP synthesis in the living brain.glycolysis ͉ TCA cycle ͉ oxidative phosphorylation ͉ NMR spectroscopy ͉ metabolic fluxes N umerous brain disorders, like neurodegenerative diseases, are associated with impairment in energy metabolism. This observation has been driving considerable technological developments in medical imaging, aiming at measuring brain energy metabolism. PET combined with 18 F-2-f luoro-2-deoxy-Dglucose ( 18 F-FDG) injection has been used in research on normal and pathological brain for Ϸ30 years (1-3). More recently, magnetic resonance spectroscopy (MRS) has brought new tools for imaging cerebral energy fluxes (4-16).However, methodological developments are still needed to answer the clinical need for earlier diagnosis and follow-up of neurodegenerative pathologies. Although PET detection of 18 F-FDG has proven efficient to map cerebral glucose consumption (CMRglc), this technique does not directly reflect energy storage and utilization that is mainly derived from glucose oxidation. Also, PET is unlikely to become widely accessible, due to its invasiveness and cost. However, magnetic resonance is of widespread use for anatomical imaging, and clinical scanners can be equipped for metabolic imaging at limited cost. Indeed, MRS has proven powerful to measure brain energy metabolism by detecting 13 C, 17 O, or 31 P nuclei, which only require dedicated radiofrequency components. Quantitative measurement of cerebral oxidative metabol...

pH as a Biomarker of Neurodegeneration in Huntington's Disease: A Translational Rodent-Human MRS Study

“…Consequently, pH values measured in our study are likely to represent intracellular pH, under physiological as well as under pathological conditions. Recent in vivo MRS data suggest that a large majority of brain Pi is located in neurons as opposed to glial cells, based on the fact that Pi is in a compartment where oxidative metabolism strongly dominates glycolytic metabolism (Chaumeil et al, 2009;Lei et al, 2003). Altogether, these observations allow us to interpret our results as an increase in neuronal pH in HD.…”

Simplified 13C metabolic modeling for simplified measurements of cerebral TCA cycle rate in vivo

“…V TCA values derived from experimental 13 C-glutamate data using either the simplified or the complete model appear to be identical, taking SD into account, and consistent with the values we usually report (4)(5)(6)(7). Results are summarized in Table 2.…”

“…Two macaque monkeys (Mac1 and Mac2) were fasted overnight and anesthetized by continuous intravenous propofol infusion. Glucose infusion was performed according to a protocol that has been extensively validated and used in our laboratory (4)(5)(6)(7). It started with a 3-min bolus of 99% enriched uniformly labeled glucose ([U-13 C 6 ]glucose) to reach a 3-fold increased glycemia.…”

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

“…2 Furthermore, saturation transfer experiments can be used to quantify reaction rates between exchanging pools 3 and can be of particular interest when studying brain metabolism together with other methods. 4 At high magnetic fields, there is an increase in 31 P spectral resolution that can help differentiate peaks that would otherwise overlap. Previous studies in the muscle have reported resonances between 5.1 and 5.3 ppm that could be attributed to a second pool of Pi (the main pool resonating at 4.9 ppm).…”