Metabolomic and Imaging Mass Spectrometric Assays of Labile Brain Metabolites: Critical Importance of Brain Harvest Proc
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REVIEW
Metabolomic and Imaging Mass Spectrometric Assays of Labile Brain Metabolites: Critical Importance of Brain Harvest Procedures Gerald A. Dienel1,2 Received: 24 June 2020 / Revised: 29 August 2020 / Accepted: 3 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Metabolomic technologies including imaging mass spectrometry (IMS; also called mass spectrometry imaging, MSI, or matrix-assisted laser desorption/ionization-mass spectrometry imaging, MALDI MSI) are important methods to evaluate levels of many compounds in brain with high spatial resolution, characterize metabolic phenotypes of brain disorders, and identify disease biomarkers. ATP is central to brain energetics, and reports of its heterogeneous distribution in brain and regional differences in ATP/ADP ratios reported in IMS studies conflict with earlier studies. These discordant data were, therefore, analyzed and compared with biochemical literature that used rigorous methods to preserve labile metabolites. Unequal, very low regional ATP levels and low ATP/ADP ratios are explained by rapid metabolism during postmortem ischemia. A critical aspect of any analysis of brain components is their stability during and after tissue harvest so measured concentrations closely approximate their physiological levels in vivo. Unfortunately, the requirement for inactivation of brain enzymes by freezing or heating is not widely recognized outside the neurochemistry discipline, and procedures that do not prevent postmortem autolysis, including decapitation, brain removal/dissection, and ’snap freezing’ are commonly used. Strong emphasis is placed on use of supplementary approaches to calibrate metabolite abundance in units of concentration in IMS studies and comparison of IMS results with biochemical data obtained by different methods to help identify potential artifacts. Keywords ATP · Glycolysis · Labile metabolites · Postmortem ischemia · TCA cycle Abbreviations CE-MS Capillary electrophoresis-mass spectrometry CMRglc Cerebral metabolic rate for glucose Glc-6-P Glucose-6-phosphate Glc-1-P Glucose-1-phosphate Glc-1,6-P2 Glucose-1,6-bisphosphate Fru-6-P Fructose-6-phosphate Fru-1,6-P2 Fructose-1,6-bisphosphate IMS Imaging mass spectrometry MRS Magnetic resonance spectroscopy PCr Phosphocreatine 6-PG 6-Phosphogluconate * Gerald A. Dienel [email protected] 1
Department of Neurology, University of Arkansas for Medical Sciences, 4301 W. Markham St., Mail Slot 500, Little Rock, AR 72205, USA
Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
2
PPP Pentose phosphate shunt pathway TCA Tricarboxylic acid
Introduction Glucose metabolism provides the ATP, redox equivalents, and biosynthetic precursors required to sustain brain activities and structure. Energetics is an essential component of all neural functions, it underlies many brain diseases and disorders, and its assessment has been technology driven. Quantitative metabolic studies began i
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