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CSF metabolomics alterations after aneurysmal subarachnoid hemorrhage: what do we know?

CSF metabolomics alterations after aneurysmal subarachnoid hemorrhage: what do we know? Purpose The purpose of this mini review is to describe metabolomics in cerebrospinal fluid (CSF) and its potential in aneu- rysmal subarachnoid hemorrhage (aSAH). In brain injury, patients’ micro dialysis enables detecting biochemical change in brain tissue. Indicators for ischemia were detected such as lactate, pyruvate, glucose, and glutamate. In aSAH patients, the pathophysiology and the factor for poor outcome are not completely understood yet. Routine use of biomarkers in CSF, particularly in aSAH patients, is still lacking. Methods This mini review was performed on the role of metabolomics alterations after aneurysmal subarachnoid hemorrhage. Results We identified five clinical studies that addressed metabolomics in patients with aneurysmal subarachnoid hemorrhage. Conclusion There is increasing evidence suggesting that biomarkers can give insight in the pathogenesis and can serve as an outcome predictor. In this mini review, we present a brief overview of metabolomics profiling in neuroscience and wish to discuss the predictive and therapeutic value in aSAH patients. Keywords Subarachnoid hemorrhage · Metabolomics · Cerebrospinal fluid · Biomarker · Delayed cerebral ischemia · Amino acids Abbreviations Introduction CSF Cerebrospinal fluid SAH Subarachnoid hemorrhage Regardless of the extensive experimental and clinical aSAH Aneur ysmal subarachnoid hemorrhage research efforts, aneurysmal subarachnoid hemorrhage GABA Gamma-aminobutyric acid (aSAH) remains a devastating disease, frequently striking DCI Delayed cerebral ischemia patients in a fairly young age without any warning signs. NMR Nuclear magnetic resonance Half of patients with aSAH are younger than 55 years old. GC–MS Gas chromatography–mass spectrometry Most survivors remain significantly impaired in their daily LC–FTMS F ourier transform mass spectrometry cou- lives [1]. Post-hemorrhagic pathophysiological mechanisms pled with liquid chromatography are multifactorial and complex and factors predicting poor EBI Early brain injury outcome or delayed cerebral ischemia (DCI) are not com- GOS Glasgow Outcome Score pletely understood. Thus, the incorporation of innovative research strategies is pivotal. The advent of metabolomic approaches allows the simultaneous, large-scale screening of numerous metabolites in a biological sample. A major benefit of metabolomic research is novel metabolites that may be discovered and associated with a disease process for the first time, without the demand for an existing hypoth- Wing Mann Ho and Franziska A. Schmidt have contributed equally esis. Despite considerable success in brain research, to date, to this work and share first authorship. metabolomics has hardly been applied for studying SAH- related changes in CSF [3, 4]. * Ondra Petr In this mini review, we present a brief overview of CSF Ondra.petr@yahoo.com metabolomics profiling in neuroscience and discuss its Department of Neurosurgery, Medical University Innsbruck, potential predictive and therapeutic value in aSAH patients. Anichstrasse 35, 6020 Innsbruck, Austria Vol.:(0123456789) 1 3 Acta Neurologica Belgica In a 2017 European study, Sokół et  al. revealed that Cerebrospinal fluid metabolome in their liquid chromatography–mass spectrometry/mass spectrometry (LC–MS/MS) of 49 CSF samples from 23 Apart from numerous vital functions of CSF such as patients analyzing 33 amino acids and related compounds, hydromechanical cerebral protection and salubrious home- 27 of them were significantly elevated within the first 3 ostasis of the brain, specific CSF conditions may mirror days after aSAH. The investigation showed that the pat- pertinent alterations offering an in-depth insight into the terns differ between poor and good outcome. In particular, cerebral metabolite production rates and its disorders for during early brain injury (EBI) after aSAH, concentration instance aSAH. Metabolomics methods have identified of nine amino acids was significantly higher in patients appreciable number of biomarkers for cerebral diseases with poor outcome compared to those with good outcome: including their progression [3, 5–7]. taurine, aspartic acid, citrulline, glutamic acid, gamma- Metabolites are small molecules (< 1500 Da) in vari- amino-butyric acid, 3-methyl-histidine, ornithine, cysta- ous body fluids which can influence cell response locally thionine, and isoleucine. On day 5 post-SAH, glutamic and systemically, possibly reflecting a disease progression acid was the only amino acid that significantly increased. [8]. Metabolites can be activated under specific conditions Interestingly, higher levels of excitatory amino acids (i.e., or can change during a disease progress or depending on glutamic acid, aspartic acid, and 2-amino-adipic acid) drug interactions [4, 9]. The term “metabolome” is derived appear to predict a poor outcome [13]. Similar findings from the term metabolism and refers to a set of molecules were described in an American study in the same year. within a biological sample (e.g., cerebrospinal fluid) [10]. Of 97 metabolites identified with known chemical struc- In other words, metabolomics describes the systematic tures, 16 metabolites, primarily free amino acids, signifi- analysis of metabolites [11, 12]. cantly changed their concentration with time. Of these, six In 2008, a very first systematic analysis of the human metabolites (i.e., 2-hydroxyglutarate, tryptophan, glycine, cerebrospinal fluid metabolome demonstrated that 41–70 proline, isoleucine, and alanine) strongly correlated with CSF compounds can be detected with nuclear mag- Glasgow Outcome Score (GOS) of patients at 1-year post- netic resonance spectroscopy (NMR), gas chromatogra- SAH [14]. Importantly, none of these metabolites corre- phy–mass spectrometry (GC–MS) or Fourier transform lated with vasospasm. mass spectrometry coupled with liquid chromatography The first prospective study analyzed endogenous metabo- (LC–FTMS). The authors of the study also described that lites in patients with ruptured intracranial aneurysms and CSF is a metabolically diverse fluid with 33 different com- aSAH Fisher Grade III and IV compared to patients with pound categories. Of note, CSF is rich in amino acids, elective aneurysms. CSF samples were consecutively col- sugars, and inorganic salts [5]. lected before aneurysm treatment (the time point of EVD Nowadays, metabolomic approaches are used in several placement), intraoperatively, 6 h later, and daily thereafter neurological diseases to particularize diagnosis, prognosis, for 10 days. The study showed that amino acids, biogenic and monitor treatments. Metabolomics has been applied amines, and acylcarnitine levels continuously increased over in many degenerative disorders. For instance, various the time starting as early as 6 h after aSAH onset. Taurine metabolites are being routinely used in diagnostics and concentration, however, was initially elevated directly after treatment for Alzheimer´s disease, amyotrophic lateral onset and started decreasing after only 6 h. Other analyzed sclerosis, epilepsy, Parkinson’s disease, multiple sclero- metabolites such as hydroxysphingomyelins, lysophos- sis, and stroke [11]. phatidylcholines, and sphingomyelins showed temporarily increased levels immediately after aSAH with an ensuing decrease to CSF concentrations within the first 6 h that are comparable with the non-hemorrhagic CSF. The study pre- CSF metabolomics in aneurysmal sented significant consecutive alterations of various metabo- subarachnoid hemorrhage lites in the longitudinal course of aSAH. There was a peak of structural amino acids as early as within the first 6 h after In respect of aSAH, established or clinically verified bio - aneurysm treatment. However, the authors concluded that markers are still lacking or are not yet used routinely in clini- further evaluation of CSF metabolites and compounds and cal practice. Discovery of novel specific indicators for, i.e., their time-dependent alterations may elucidate pathophysi- DCI and poor clinical outcome is urgently needed. However, ological processes after aSAH, potentially providing new to our best knowledge, there are only three recent studies predictive biomarkers related to aSAH-specific parameters dealing with metabolomics profiling of CSF after aSAH. and outcomes [16]. 1 3 Acta Neurologica Belgica A Chinese study published in 2018 showed data of 40 Discussion subarachnoid hemorrhage patients and the control group of 6 patients. Neurological outcome was evaluated 12 months In summary, metabolomics of post-hemorrhagic CSF after discharge. Interestingly, the group showed that there provides a unique signature of multifactorial pathophysi- is no significant variation among CSF metabolome in suba- ologic processes in the brain after aSAH. A published study rachnoid hemorrhage patients with different fisher scales in 2005 described metabolomics as a systematic study of (amount and distribution of blood). However, sub-analysis unique chemical fingerprints that specific cellular processes showed that pyruvate metabolism was altered in subarach- leave behind that provides dynamic information [15]. While noid hemorrhage patients, especially in those with a high still in its infancy, we shall perceive the promising poten- Hunt–Hess scale (clinical condition). Pyruvate level is tial and possible future application of CSF metabolomics associated with WFNS (focal motor deficit) grading scale post-aSAH for clinical practice. All, Ho et al., Sokół et al., above III. In retrospect, patients with unfavorable outcome Lu et al., Koch et al., and Li et al. showed, in their clinical had significantly altered amino acid metabolism and lipid observational studies, several metabolites linked to aSAH biosynthesis [17]. and its outcomes. All authors concurred in significantly ele- The work of an American group which was published in vated levels of several amino acids in post-aSAH CSF time 2020 aimed to identify the leading CSF metabolites asso- courses. So far, only these five clinical studies with a small ciated with poor outcome, as determined by the modified number of patients are available in the literature (Supple- Rankin Scale (mRS) at discharge and at 90 days after dis- mentary Table 1). It can be discussed that the studies might charge. The authors used 81 CSF samples. Through orthogo- have been underpowered. In our opinion, further thorough nal partial least squares-discriminant analysis, symmetric systematic evaluation of all identified CSF metabolites and dimethylarginine (SDMA), dimethylguanidine valeric acid compounds alongside with their time-dependent longitudinal (DMGV), and ornithine were detected as the markers associ- ated with poor outcome [18]. All five aforementioned clinical studies dealing with CSF metabolomics after aSAH provide a first very interesting finding of various metabolites that can be instrumental in further innovative research strategies. Fig. 1 Overview of the cerebral glucose metabolism known as the citrate cycle and red marked are the significantly altered metabolites Fig. 2 Significantly altered metabolites after aSAH and their role in after aSAH [14, 16, 17] physiological processes [13, 16, 18] 1 3 Acta Neurologica Belgica cerebrospinal fluid using lipidomic and proteomic methods. Dis alterations may be very helpful to possibly clarify patho- Markers 22(1–2):39–64 physiological processes after aSAH, with a potential of 4. Rashad SSD, Yamazaki T, Matsumoto Y, Tomioka Y, Saito R, discovering new clinically relevant biomarkers related to Uruno A, Niizuma K, Yamamoto M, Tominaga T (2020) Meta- aSAH-specific events. bolic basis of neuronal vulnerability to ischemia; an in vivo untar- geted metabolomics approach. Sci Rep 10(1):6507 Several significant altered compounds in those studies are 5. Wishart DS, Lewis MJ, Morrissey JA et al (2008) The human found in the cerebral glucose metabolism (Fig. 1). Further, cerebrospinal fluid metabolome. J Chromatogr B Anal Technol metabolites as excitatory amino acids in the neurotransmit- Biomed Life Sci 871(2):164–173 ter formation and structural amine levels were changed after 6. Toczyłowska B, Chalimoniuk M, Wodowska M, Mayzner- Zawadzk E (2006) Changes in concentration of cerebrospinal aSAH (Fig. 2). fluid components in patients with traumatic brain injury. Brain Future metabolomics profiling in both untargeted and tar - Res 1104(1):183–189 geted ways in aSAH patients should allow acquiring further 7. Kaddurah-Daouk R, Krishnan KR (2009) Metabolomics: a global insights into the global cerebral endogenous metabolism biochemical approach to the study of central nervous system dis- eases. Neuropsychopharmacology 34(1):173–186 after aSAH with in-depth monitoring of pertinent metab- 8. Goodacre RVS, Dunn WB, Harrigan GG, Kell DB (2004) Metabo- olomic changes, and therefore potential identification of lomics by numbers: acquiring and understanding global metabo- aSAH-specific biomarkers. lite data. Trends Biotechnol 22(5):245–252 9. Monteiro MS, Carvalho M, Bastos ML, de Guedes Pinho P (2013) Supplementary Information The online version contains supplemen- Metabolomics analysis for biomarker discovery: advances and tary material available at https://doi. or g/10. 1007/ s13760- 023- 02266-2 . challenges. Curr Med Chem 20(2):257–271 10. Wishart DS (2007) Current progress in computational metabo- Funding Open access funding provided by University of Innsbruck and lomics. Brief Bioinform 8(5):279–293 Medical University of Innsbruck. 11. Donatti ACA, Godoi AB, da Rosa DC, Lopes-Cendes I (2020) Circulating metabolites as potential biomarkers for neurologi- Data availability Availability of Data and Material not applicable. cal disorders-metabolites in neurological disorders. Metabolites 10(10):389 Declarations 12. Vasilopoulou CG, Margarity M, Klapa MI (2016) Metabolomic analysis in brain research metabolomic analysis in brain research: Conflict of interest Franziska A. Schmidt, conflict of interest: none, opportunities and challenges. Front Physiol 7:183 disclosure of funding: none; Wing Mann Ho, conflict of interest: none, 13. Sokół B, Urbaniak B, Wąsik N, Plewa S, Klupczyńska A, disclosure of funding: none; Ondra Petr, conflict of interest: none, dis- Jankowski R, Więckowska B, Juszkat R, Kokot Z (2017) Amino closure of funding: none; Claudius Thomé, conflict of interest: none, acids in cerebrospinal fluid of patients with aneurysmal subarach- disclosure of funding: none. noid haemorrhage: an observational study. Front Neurol 8:438 14. DE Lu A, Winkler E, Grant R, Eid T, Bulsara K (2017) Cer- Open Access This article is licensed under a Creative Commons Attri- ebrospinal fluid untargeted metabolomic profiling of aneurysmal bution 4.0 International License, which permits use, sharing, adapta- subarachnoid hemorrhage: an exploratory study. Br J Neurosurg tion, distribution and reproduction in any medium or format, as long 32(6):637–641 as you give appropriate credit to the original author(s) and the source, 15. Daviss B (2005) Growing poains for metabolomics. Scientist provide a link to the Creative Commons licence, and indicate if changes 19:25–28 were made. The images or other third party material in this article are 16. Ho W, Goerke AS, Glodny B, Oberacher H, Helbok R, Thome included in the article's Creative Commons licence, unless indicated C, Petr O. Time Course of Metabolomic Alterations in CSF after otherwise in a credit line to the material. If material is not included in aneurysmal Subarachnoid Hemorrhage. Frontiers in neurology. the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will 17. Li Y, Wang R, Xu M, Jing X, Sun R, Na S, Liu T, Ding X, Sun C, need to obtain permission directly from the copyright holder. To view a Ge W (2019) Aneurysmal subarachnoid hemorrhage onset alters copy of this licence, visit http://cr eativ ecommons. or g/licen ses/ b y/4.0/ . pyruvate metabolism in poor-grade patients and clinical outcome depends on more: a cerebrospinal fluid metabolomic study. ACS Chem Neurosci 10(3):1660–1667 18. Koch M, Acharjee A, Ament Z, Schleicher R, Bevers M, Stapleton C, Patei A, Kimberly T. Machine Learning-driven metabolomic References evaluation of cerebrospinal fluid: insights into poor outcomes after aneurysmal subarachnoid hemorrhage. 1. Etminan NCH, Hackenberg K, de Rooij NK, Vergouwen MDI, Rinkel GJE, Algra A (2019) Worldwide incidence of aneurysmal Publisher's Note Springer Nature remains neutral with regard to subarachnoid hemorrhage according to region, time period, blood jurisdictional claims in published maps and institutional affiliations. pressure, and smoking prevalence in the population: a systematic review and meta-analysis. JAMA Neurol 76(5):588–597 2. Vasilopoulou CG, Margarity M, Klapa MI (2016) Metabolomic analysis in brain research: opportunities and challenges. Front Physiol 7:183 3. Fonteh AN, Harrington RJ, Huhmer AF, Biringer RG, Riggins JN, Harrington MG (2006) Identification of disease markers in human 1 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Neurologica Belgica Springer Journals

CSF metabolomics alterations after aneurysmal subarachnoid hemorrhage: what do we know?

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Abstract

Purpose The purpose of this mini review is to describe metabolomics in cerebrospinal fluid (CSF) and its potential in aneu- rysmal subarachnoid hemorrhage (aSAH). In brain injury, patients’ micro dialysis enables detecting biochemical change in brain tissue. Indicators for ischemia were detected such as lactate, pyruvate, glucose, and glutamate. In aSAH patients, the pathophysiology and the factor for poor outcome are not completely understood yet. Routine use of biomarkers in CSF, particularly in aSAH patients, is still lacking. Methods This mini review was performed on the role of metabolomics alterations after aneurysmal subarachnoid hemorrhage. Results We identified five clinical studies that addressed metabolomics in patients with aneurysmal subarachnoid hemorrhage. Conclusion There is increasing evidence suggesting that biomarkers can give insight in the pathogenesis and can serve as an outcome predictor. In this mini review, we present a brief overview of metabolomics profiling in neuroscience and wish to discuss the predictive and therapeutic value in aSAH patients. Keywords Subarachnoid hemorrhage · Metabolomics · Cerebrospinal fluid · Biomarker · Delayed cerebral ischemia · Amino acids Abbreviations Introduction CSF Cerebrospinal fluid SAH Subarachnoid hemorrhage Regardless of the extensive experimental and clinical aSAH Aneur ysmal subarachnoid hemorrhage research efforts, aneurysmal subarachnoid hemorrhage GABA Gamma-aminobutyric acid (aSAH) remains a devastating disease, frequently striking DCI Delayed cerebral ischemia patients in a fairly young age without any warning signs. NMR Nuclear magnetic resonance Half of patients with aSAH are younger than 55 years old. GC–MS Gas chromatography–mass spectrometry Most survivors remain significantly impaired in their daily LC–FTMS F ourier transform mass spectrometry cou- lives [1]. Post-hemorrhagic pathophysiological mechanisms pled with liquid chromatography are multifactorial and complex and factors predicting poor EBI Early brain injury outcome or delayed cerebral ischemia (DCI) are not com- GOS Glasgow Outcome Score pletely understood. Thus, the incorporation of innovative research strategies is pivotal. The advent of metabolomic approaches allows the simultaneous, large-scale screening of numerous metabolites in a biological sample. A major benefit of metabolomic research is novel metabolites that may be discovered and associated with a disease process for the first time, without the demand for an existing hypoth- Wing Mann Ho and Franziska A. Schmidt have contributed equally esis. Despite considerable success in brain research, to date, to this work and share first authorship. metabolomics has hardly been applied for studying SAH- related changes in CSF [3, 4]. * Ondra Petr In this mini review, we present a brief overview of CSF Ondra.petr@yahoo.com metabolomics profiling in neuroscience and discuss its Department of Neurosurgery, Medical University Innsbruck, potential predictive and therapeutic value in aSAH patients. Anichstrasse 35, 6020 Innsbruck, Austria Vol.:(0123456789) 1 3 Acta Neurologica Belgica In a 2017 European study, Sokół et  al. revealed that Cerebrospinal fluid metabolome in their liquid chromatography–mass spectrometry/mass spectrometry (LC–MS/MS) of 49 CSF samples from 23 Apart from numerous vital functions of CSF such as patients analyzing 33 amino acids and related compounds, hydromechanical cerebral protection and salubrious home- 27 of them were significantly elevated within the first 3 ostasis of the brain, specific CSF conditions may mirror days after aSAH. The investigation showed that the pat- pertinent alterations offering an in-depth insight into the terns differ between poor and good outcome. In particular, cerebral metabolite production rates and its disorders for during early brain injury (EBI) after aSAH, concentration instance aSAH. Metabolomics methods have identified of nine amino acids was significantly higher in patients appreciable number of biomarkers for cerebral diseases with poor outcome compared to those with good outcome: including their progression [3, 5–7]. taurine, aspartic acid, citrulline, glutamic acid, gamma- Metabolites are small molecules (< 1500 Da) in vari- amino-butyric acid, 3-methyl-histidine, ornithine, cysta- ous body fluids which can influence cell response locally thionine, and isoleucine. On day 5 post-SAH, glutamic and systemically, possibly reflecting a disease progression acid was the only amino acid that significantly increased. [8]. Metabolites can be activated under specific conditions Interestingly, higher levels of excitatory amino acids (i.e., or can change during a disease progress or depending on glutamic acid, aspartic acid, and 2-amino-adipic acid) drug interactions [4, 9]. The term “metabolome” is derived appear to predict a poor outcome [13]. Similar findings from the term metabolism and refers to a set of molecules were described in an American study in the same year. within a biological sample (e.g., cerebrospinal fluid) [10]. Of 97 metabolites identified with known chemical struc- In other words, metabolomics describes the systematic tures, 16 metabolites, primarily free amino acids, signifi- analysis of metabolites [11, 12]. cantly changed their concentration with time. Of these, six In 2008, a very first systematic analysis of the human metabolites (i.e., 2-hydroxyglutarate, tryptophan, glycine, cerebrospinal fluid metabolome demonstrated that 41–70 proline, isoleucine, and alanine) strongly correlated with CSF compounds can be detected with nuclear mag- Glasgow Outcome Score (GOS) of patients at 1-year post- netic resonance spectroscopy (NMR), gas chromatogra- SAH [14]. Importantly, none of these metabolites corre- phy–mass spectrometry (GC–MS) or Fourier transform lated with vasospasm. mass spectrometry coupled with liquid chromatography The first prospective study analyzed endogenous metabo- (LC–FTMS). The authors of the study also described that lites in patients with ruptured intracranial aneurysms and CSF is a metabolically diverse fluid with 33 different com- aSAH Fisher Grade III and IV compared to patients with pound categories. Of note, CSF is rich in amino acids, elective aneurysms. CSF samples were consecutively col- sugars, and inorganic salts [5]. lected before aneurysm treatment (the time point of EVD Nowadays, metabolomic approaches are used in several placement), intraoperatively, 6 h later, and daily thereafter neurological diseases to particularize diagnosis, prognosis, for 10 days. The study showed that amino acids, biogenic and monitor treatments. Metabolomics has been applied amines, and acylcarnitine levels continuously increased over in many degenerative disorders. For instance, various the time starting as early as 6 h after aSAH onset. Taurine metabolites are being routinely used in diagnostics and concentration, however, was initially elevated directly after treatment for Alzheimer´s disease, amyotrophic lateral onset and started decreasing after only 6 h. Other analyzed sclerosis, epilepsy, Parkinson’s disease, multiple sclero- metabolites such as hydroxysphingomyelins, lysophos- sis, and stroke [11]. phatidylcholines, and sphingomyelins showed temporarily increased levels immediately after aSAH with an ensuing decrease to CSF concentrations within the first 6 h that are comparable with the non-hemorrhagic CSF. The study pre- CSF metabolomics in aneurysmal sented significant consecutive alterations of various metabo- subarachnoid hemorrhage lites in the longitudinal course of aSAH. There was a peak of structural amino acids as early as within the first 6 h after In respect of aSAH, established or clinically verified bio - aneurysm treatment. However, the authors concluded that markers are still lacking or are not yet used routinely in clini- further evaluation of CSF metabolites and compounds and cal practice. Discovery of novel specific indicators for, i.e., their time-dependent alterations may elucidate pathophysi- DCI and poor clinical outcome is urgently needed. However, ological processes after aSAH, potentially providing new to our best knowledge, there are only three recent studies predictive biomarkers related to aSAH-specific parameters dealing with metabolomics profiling of CSF after aSAH. and outcomes [16]. 1 3 Acta Neurologica Belgica A Chinese study published in 2018 showed data of 40 Discussion subarachnoid hemorrhage patients and the control group of 6 patients. Neurological outcome was evaluated 12 months In summary, metabolomics of post-hemorrhagic CSF after discharge. Interestingly, the group showed that there provides a unique signature of multifactorial pathophysi- is no significant variation among CSF metabolome in suba- ologic processes in the brain after aSAH. A published study rachnoid hemorrhage patients with different fisher scales in 2005 described metabolomics as a systematic study of (amount and distribution of blood). However, sub-analysis unique chemical fingerprints that specific cellular processes showed that pyruvate metabolism was altered in subarach- leave behind that provides dynamic information [15]. While noid hemorrhage patients, especially in those with a high still in its infancy, we shall perceive the promising poten- Hunt–Hess scale (clinical condition). Pyruvate level is tial and possible future application of CSF metabolomics associated with WFNS (focal motor deficit) grading scale post-aSAH for clinical practice. All, Ho et al., Sokół et al., above III. In retrospect, patients with unfavorable outcome Lu et al., Koch et al., and Li et al. showed, in their clinical had significantly altered amino acid metabolism and lipid observational studies, several metabolites linked to aSAH biosynthesis [17]. and its outcomes. All authors concurred in significantly ele- The work of an American group which was published in vated levels of several amino acids in post-aSAH CSF time 2020 aimed to identify the leading CSF metabolites asso- courses. So far, only these five clinical studies with a small ciated with poor outcome, as determined by the modified number of patients are available in the literature (Supple- Rankin Scale (mRS) at discharge and at 90 days after dis- mentary Table 1). It can be discussed that the studies might charge. The authors used 81 CSF samples. Through orthogo- have been underpowered. In our opinion, further thorough nal partial least squares-discriminant analysis, symmetric systematic evaluation of all identified CSF metabolites and dimethylarginine (SDMA), dimethylguanidine valeric acid compounds alongside with their time-dependent longitudinal (DMGV), and ornithine were detected as the markers associ- ated with poor outcome [18]. All five aforementioned clinical studies dealing with CSF metabolomics after aSAH provide a first very interesting finding of various metabolites that can be instrumental in further innovative research strategies. Fig. 1 Overview of the cerebral glucose metabolism known as the citrate cycle and red marked are the significantly altered metabolites Fig. 2 Significantly altered metabolites after aSAH and their role in after aSAH [14, 16, 17] physiological processes [13, 16, 18] 1 3 Acta Neurologica Belgica cerebrospinal fluid using lipidomic and proteomic methods. Dis alterations may be very helpful to possibly clarify patho- Markers 22(1–2):39–64 physiological processes after aSAH, with a potential of 4. Rashad SSD, Yamazaki T, Matsumoto Y, Tomioka Y, Saito R, discovering new clinically relevant biomarkers related to Uruno A, Niizuma K, Yamamoto M, Tominaga T (2020) Meta- aSAH-specific events. bolic basis of neuronal vulnerability to ischemia; an in vivo untar- geted metabolomics approach. Sci Rep 10(1):6507 Several significant altered compounds in those studies are 5. Wishart DS, Lewis MJ, Morrissey JA et al (2008) The human found in the cerebral glucose metabolism (Fig. 1). Further, cerebrospinal fluid metabolome. J Chromatogr B Anal Technol metabolites as excitatory amino acids in the neurotransmit- Biomed Life Sci 871(2):164–173 ter formation and structural amine levels were changed after 6. Toczyłowska B, Chalimoniuk M, Wodowska M, Mayzner- Zawadzk E (2006) Changes in concentration of cerebrospinal aSAH (Fig. 2). fluid components in patients with traumatic brain injury. Brain Future metabolomics profiling in both untargeted and tar - Res 1104(1):183–189 geted ways in aSAH patients should allow acquiring further 7. Kaddurah-Daouk R, Krishnan KR (2009) Metabolomics: a global insights into the global cerebral endogenous metabolism biochemical approach to the study of central nervous system dis- eases. Neuropsychopharmacology 34(1):173–186 after aSAH with in-depth monitoring of pertinent metab- 8. Goodacre RVS, Dunn WB, Harrigan GG, Kell DB (2004) Metabo- olomic changes, and therefore potential identification of lomics by numbers: acquiring and understanding global metabo- aSAH-specific biomarkers. lite data. Trends Biotechnol 22(5):245–252 9. Monteiro MS, Carvalho M, Bastos ML, de Guedes Pinho P (2013) Supplementary Information The online version contains supplemen- Metabolomics analysis for biomarker discovery: advances and tary material available at https://doi. or g/10. 1007/ s13760- 023- 02266-2 . challenges. Curr Med Chem 20(2):257–271 10. Wishart DS (2007) Current progress in computational metabo- Funding Open access funding provided by University of Innsbruck and lomics. Brief Bioinform 8(5):279–293 Medical University of Innsbruck. 11. Donatti ACA, Godoi AB, da Rosa DC, Lopes-Cendes I (2020) Circulating metabolites as potential biomarkers for neurologi- Data availability Availability of Data and Material not applicable. cal disorders-metabolites in neurological disorders. Metabolites 10(10):389 Declarations 12. Vasilopoulou CG, Margarity M, Klapa MI (2016) Metabolomic analysis in brain research metabolomic analysis in brain research: Conflict of interest Franziska A. Schmidt, conflict of interest: none, opportunities and challenges. Front Physiol 7:183 disclosure of funding: none; Wing Mann Ho, conflict of interest: none, 13. Sokół B, Urbaniak B, Wąsik N, Plewa S, Klupczyńska A, disclosure of funding: none; Ondra Petr, conflict of interest: none, dis- Jankowski R, Więckowska B, Juszkat R, Kokot Z (2017) Amino closure of funding: none; Claudius Thomé, conflict of interest: none, acids in cerebrospinal fluid of patients with aneurysmal subarach- disclosure of funding: none. noid haemorrhage: an observational study. Front Neurol 8:438 14. DE Lu A, Winkler E, Grant R, Eid T, Bulsara K (2017) Cer- Open Access This article is licensed under a Creative Commons Attri- ebrospinal fluid untargeted metabolomic profiling of aneurysmal bution 4.0 International License, which permits use, sharing, adapta- subarachnoid hemorrhage: an exploratory study. Br J Neurosurg tion, distribution and reproduction in any medium or format, as long 32(6):637–641 as you give appropriate credit to the original author(s) and the source, 15. Daviss B (2005) Growing poains for metabolomics. Scientist provide a link to the Creative Commons licence, and indicate if changes 19:25–28 were made. The images or other third party material in this article are 16. Ho W, Goerke AS, Glodny B, Oberacher H, Helbok R, Thome included in the article's Creative Commons licence, unless indicated C, Petr O. Time Course of Metabolomic Alterations in CSF after otherwise in a credit line to the material. If material is not included in aneurysmal Subarachnoid Hemorrhage. Frontiers in neurology. the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will 17. Li Y, Wang R, Xu M, Jing X, Sun R, Na S, Liu T, Ding X, Sun C, need to obtain permission directly from the copyright holder. To view a Ge W (2019) Aneurysmal subarachnoid hemorrhage onset alters copy of this licence, visit http://cr eativ ecommons. or g/licen ses/ b y/4.0/ . pyruvate metabolism in poor-grade patients and clinical outcome depends on more: a cerebrospinal fluid metabolomic study. ACS Chem Neurosci 10(3):1660–1667 18. Koch M, Acharjee A, Ament Z, Schleicher R, Bevers M, Stapleton C, Patei A, Kimberly T. Machine Learning-driven metabolomic References evaluation of cerebrospinal fluid: insights into poor outcomes after aneurysmal subarachnoid hemorrhage. 1. Etminan NCH, Hackenberg K, de Rooij NK, Vergouwen MDI, Rinkel GJE, Algra A (2019) Worldwide incidence of aneurysmal Publisher's Note Springer Nature remains neutral with regard to subarachnoid hemorrhage according to region, time period, blood jurisdictional claims in published maps and institutional affiliations. pressure, and smoking prevalence in the population: a systematic review and meta-analysis. JAMA Neurol 76(5):588–597 2. Vasilopoulou CG, Margarity M, Klapa MI (2016) Metabolomic analysis in brain research: opportunities and challenges. Front Physiol 7:183 3. Fonteh AN, Harrington RJ, Huhmer AF, Biringer RG, Riggins JN, Harrington MG (2006) Identification of disease markers in human 1 3

Journal

Acta Neurologica Belgica – Springer Journals

Published: Dec 1, 2023

Keywords: Subarachnoid hemorrhage; Metabolomics; Cerebrospinal fluid; Biomarker; Delayed cerebral ischemia; Amino acids

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