NMR-based Metabolomics of Human Cerebrospinal Fluid Identifies Signature of Brain Death

Overview

Journal Metabolomics

Publisher Springer

Specialty Endocrinology

Date 2021 Apr 17

PMID 33864540

Authors

Martha E Garcia-Aguilera

Eduardo Rodriguez de San Miguel

Jocelyn Cruz-Perez

Lucinda Aguirre-Cruz

Christian M Ramirez-Alfaro

Nuria Esturau-Escofet

Affiliations

Soon will be listed here.

Abstract

Introduction: Brain death (BD) is the irreversible cessation of all functions of the entire brain, including the brainstem. Cerebrospinal fluid (CSF) is a biological liquid that circulates in brain and spine. Metabolomics is able to reveal the response of biological systems to diverse factors in a specific moment or condition. Therefore, the study of this neurological condition through metabolic profiling using high resolution Nuclear Magnetic Resonance (NMR) spectroscopy is important for understanding biochemical events.

Objectives: The aim of the current study is to identify the metabolomics signature of BD using H-NMR spectroscopy in human CSF.

Methods: H-NMR spectroscopy has been employed for metabolomic untargeted analysis in 46 CSF samples: 22 control and 24 with BD. Spectral data were further subjected to multivariate analysis.

Results: Statistically significant multivariate models separated subject's samples with BD from controls and revealed twenty one discriminatory metabolites. The statistical analysis of control and BD subjects using Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) model resulted in RX of 0.733 and Q of 0.635. An elevation in the concentration of statistically discriminant metabolites in BD was observed.

Conclusion: This study identifies a metabolic signature associated with BD and the most relevant enriched selected metabolic pathways.

References

Ankarcrona M, Dypbukt J, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton S . Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron. 1995; 15(4):961-73. DOI: 10.1016/0896-6273(95)90186-8. View

Arroyo A, Rosel P, Marron T . Cerebrospinal fluid: postmortem biochemical study. J Clin Forensic Med. 2005; 12(3):153-6. DOI: 10.1016/j.jcfm.2004.11.001. View

Bak L, Schousboe A, Waagepetersen H . The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem. 2006; 98(3):641-53. DOI: 10.1111/j.1471-4159.2006.03913.x. View

Barklin A . Systemic inflammation in the brain-dead organ donor. Acta Anaesthesiol Scand. 2009; 53(4):425-35. DOI: 10.1111/j.1399-6576.2008.01879.x. View

Brasil S, Bor-Seng-Shu E, de-Lima-Oliveira M, K Azevedo M, Teixeira M, Bernardo L . Role of computed tomography angiography and perfusion tomography in diagnosing brain death: A systematic review. J Neuroradiol. 2015; 43(2):133-40. DOI: 10.1016/j.neurad.2015.07.006. View

Cooper A, Lai J . Cerebral ammonia metabolism in normal and hyperammonemic rats. Neurochem Pathol. 1987; 6(1-2):67-95. DOI: 10.1007/BF02833601. View

Cooper A, Mora S, Cruz N, Gelbard A . Cerebral ammonia metabolism in hyperammonemic rats. J Neurochem. 1985; 44(6):1716-23. DOI: 10.1111/j.1471-4159.1985.tb07159.x. View

Cruz T, Balayssac S, Gilard V, Martino R, Vincent C, Pariente J . 1H NMR Analysis of Cerebrospinal Fluid from Alzheimer's Disease Patients: An Example of a Possible Misinterpretation Due to Non-Adjustment of pH. Metabolites. 2014; 4(1):115-28. PMC: 4018676. DOI: 10.3390/metabo4010115. View

Desalles A, KONTOS H, Becker D, Yang M, Ward J, MOULTON R . Prognostic significance of ventricular CSF lactic acidosis in severe head injury. J Neurosurg. 1986; 65(5):615-24. DOI: 10.3171/jns.1986.65.5.0615. View

10.

Di Meo S, Reed T, Venditti P, Victor V . Harmful and Beneficial Role of ROS. Oxid Med Cell Longev. 2016; 2016:7909186. PMC: 5080479. DOI: 10.1155/2016/7909186. View

11.

Dickens A, Larkin J, Griffin J, Cavey A, Matthews L, Turner M . A type 2 biomarker separates relapsing-remitting from secondary progressive multiple sclerosis. Neurology. 2014; 83(17):1492-9. PMC: 4222850. DOI: 10.1212/WNL.0000000000000905. View

12.

Engelke U, Kremer B, Kluijtmans L, van der Graaf M, Morava E, Loupatty F . NMR spectroscopic studies on the late onset form of 3-methylglutaconic aciduria type I and other defects in leucine metabolism. NMR Biomed. 2006; 19(2):271-8. DOI: 10.1002/nbm.1018. View

13.

Eriksson L, Antti H, Gottfries J, Holmes E, Johansson E, Lindgren F . Using chemometrics for navigating in the large data sets of genomics, proteomics, and metabonomics (gpm). Anal Bioanal Chem. 2004; 380(3):419-29. DOI: 10.1007/s00216-004-2783-y. View

14.

Floerchinger B, Oberhuber R, Tullius S . Effects of brain death on organ quality and transplant outcome. Transplant Rev (Orlando). 2012; 26(2):54-9. DOI: 10.1016/j.trre.2011.10.001. View

15.

Girela E, Villanueva E, Irigoyen P, Girela V, Hernandez-Cueto C, Peinado J . Free amino acid concentrations in vitreous humor and cerebrospinal fluid in relation to the cause of death and postmortem interval. J Forensic Sci. 2008; 53(3):730-3. DOI: 10.1111/j.1556-4029.2008.00726.x. View

16.

Gonzalez-Riano C, Tapia-Gonzalez S, Garcia A, Munoz A, DeFelipe J, Barbas C . Metabolomics and neuroanatomical evaluation of post-mortem changes in the hippocampus. Brain Struct Funct. 2017; 222(6):2831-2853. PMC: 5541081. DOI: 10.1007/s00429-017-1375-5. View

17.

Govindaraju V, Young K, Maudsley A . Proton NMR chemical shifts and coupling constants for brain metabolites. NMR Biomed. 2000; 13(3):129-53. DOI: 10.1002/1099-1492(200005)13:3<129::aid-nbm619>3.0.co;2-v. View

18.

Griffin J . Metabonomics: NMR spectroscopy and pattern recognition analysis of body fluids and tissues for characterisation of xenobiotic toxicity and disease diagnosis. Curr Opin Chem Biol. 2003; 7(5):648-54. DOI: 10.1016/j.cbpa.2003.08.008. View

19.

Guzel Y, Koc Z, Mitil H, Kom M, Ozer A, Ozercan H . Brain death scintigraphy and pathology results in a rat model. Exp Clin Transplant. 2013; 12(2):143-7. DOI: 10.6002/ect.2013.0026. View

20.

Haberle J . Clinical practice: the management of hyperammonemia. Eur J Pediatr. 2010; 170(1):21-34. DOI: 10.1007/s00431-010-1369-2. View