Table 1.
Comparison between major metabolomics studies in MS patient samples#
| Study | Approach/platform | Sample size | Sample type | Key metabolites/pathways detected |
|---|---|---|---|---|
| Bruhn et al. 1992 [38] | MRS with MRI | 8 pediatric MS, 10 pediatric controls | In vivo white matter | Choline, myo-inositol, N-acetyl-aspartate, creatine |
| Lynch et al. 1993 [45] | NMR | 30 PMS, 27 controls | CSF | Acetate, formate |
| Nicoli et al. 1996 [46] | MRS | 19 MS, 17 controls | CSF | Lactate, fructose, creatinine, phenylalanine |
| Simone et al. 1996 [47] | MRS | 52 MS, 32 non-MS, 18 controls | CSF | Formate, lactate |
| ‘t Hart et al. 2003 [82] | NMR | 10 MS, 11 controls, 20 non-MS | Urine | Aspartic acid, inositol, taurine |
| Lutz et al. 2007 [39] | MRS | 21 active MS, 12 inactive MS | CSF | BHIB, lactate |
| Regenold et al. 2008 [49] | GC–MS | 31 RR, 54 SP, 18 controls | CSF | Sorbitol, fructose, lactate |
| Gonzalo et al. 2012 [51] | LC–MS/UHPLC–MS | 9 MS, 9 non-MS | CSF | 8-iso-prostaglandin F2α |
| Mehrpour et al. 2013 [67] | NMR | 23 MS, 28 controls | Serum | Glucose, valine |
| Vingara et al. 2013 [90] | MRS with MRI | 27 RRMS, 14 controls | In vivo white matter | N-acetyl-aspartate, choline, N-acetyl aspartyl glutamate, glutamine, glutamate, scyllo-inositol, creatine, phosphocreatine, lipids |
| Pruss et al. 2013 [117] | LC–MS/MS | 20 RRMS |
Serum CSF |
15-Hydroxyeicosatetraenoic acids, prostaglandin E2, resolvin D1, neuroprotectin D1, lipoxin A4 |
| Dickens et al. 2014 [78] | NMR |
Cohort A: 22 RRMS, 46 SPMS, 17 PPMS, 14 controls Cohort B and C: 13 RRMS, 21 SPMS, 18 controls |
Serum | Fatty acids, phosphocholine, N-acetyl species, glucose, lactate |
| Reinke et al. 2014 [41] | NMR | 15 MS, 17 non-MS | CSF | Mannose, choline, myo-inositol, threonate, citrate, mannose, phenylalanine, 3-hydroxybutyrate, 2-hydroxyisovalerate |
| Moussallieh et al. 2014 [73] | NMR | 44 NMO, 47 MS, 42 controls | Serum | Scyllo-inositol, glutamine, acetate, glutamate, lactate, lysine |
| Pieragostino et al. 2015 [52] |
MALDI-TOF–MS LC–MS/MS |
13 RRMS, 12 non-MS | CSF | Phospholipid metabolism |
| Cocco et al. 2016 [69] | NMR | 73 MS, 88 controls | Plasma | Glucose, 5-OH-tryptophan, tryptophan, increased 3-OH-butyrate, acetoacetate, acetone, alanine, choline |
| Gebregiworgis et al. 2016 [87] | NMR | 8 RRMS, 9 NMSOD, 7 controls | Urine | Creatinine, 3-hydroxybutyrate, 3-hydroxyisovalerate, methylmalonate |
| Villoslada et al. 2017 [70] | UHPLC–MS |
Cohort A: 238 MS, 74 controls Cohort B: 61 MS, 41 controls |
Serum | Hydrocortisone, glutamic acid, tryptophan, eicosapentaenoic acid, 13S-hydroxyoctadecadienoic acid, lysophosphatidylcholines, lysophosphatidylethanolamines |
| Kim et al. 2017 [53] | NMR | 50 MS, 57 NMOSD, 17 controls | CSF | 2-Hydroxybutyrate, acetone, formate, pyroglutamate, acetate, glucose, citrate, lactate, isoleucine, valine |
| Jurynczyk et al. 2017 [74] | NMR | 34 RRMS, 54 AQP4-Ab NMOSD, 20 MOG-Ab | Plasma | Low-density lipoproteins, high-density lipoproteins, histidine, glucose, lactate, alanine, formate, leucine, low myo-inositol |
| Lazzarino et al. 2017 [75] | HPLC | 518 MS, 167 controls | Serum | Hypoxanthine, xanthine, uric acid, inosine, uracil, β-pseudouridine, uridine, creatinine, lactate |
| Lim et al. 2017 [76] |
UHPLC GC–MS |
Cohort A: 50 RRMS, 20 SPMS, 17 PPMS, 49 controls Cohort B: 44 RRMS, 15 SPMS Cohort C: 9 RRMS, 20 SPMS, 6 controls |
Serum | Kynurenic acid, quinolinic acid, kynurenine, tryptophan |
| Bhargava et al. 2017 [37] | UPLC–MS–MS | 27 RRMS, 27 controls | Plasma | γ-Glutamyl amino acid, glutathione, benzoate, caffeine |
| Bhargava et al. 2019 [124] | LC–MS/GC–MS | 18 MS, 18 controls | Plasma | Phospholipids, lysophospholipids, plasmalogens |
| Herman et al. 2018 [54] | ELISA, LC–MS | 30 RRMS, 16 SPMS, 10 controls | CSF | 20β-Dihydrocortisol, indolepyruvate, 5,6-dihydroxyprostaglandin F1a |
| Nourbakhsh et al. 2018 [77] | LC/GC–MS |
Untargeted group: 66 pediatric and CIS, 66 pediatric controls Targeted discovery group: 82 pediatric MS, 50 pediatric controls Validation group: 92 pediatric MS, 50 pediatric controls |
Serum | Tryptophan, indole lactate, kynurenine |
| Stoessel et al. 2018 [79] | LC–MS | 33 PPMS, 10 RRMS, 63 controls, 40 Parkinson’s disease | Plasma | Glycerophospholipids, linoleic acid, lysoPC |
| Herman et al. 2019 [55] | HRMS | 30 RRMS, 16 SPMS, 10 controls | CSF | Kynurenate, 5-hydroxytryptophan, 5-hydroxyindoleacetate, N-acetylserotonin, indole-3-acetate, thymine, glutamine, uridine, deoxyuridine |
| Andersen et al. 2019 [18] | 2D GCxGC-TOFMS | 12 MS, 13 controls | Serum | Pyroglutamate, laurate, acylcarnitine C14:1, N-methylmaleimide, phosphatidylcholines |
| Cicalini et al. 2019 [91] | LC–MS/MS |
12 MS, 21 controls 12 MS, 10 controls |
Tears Serum |
Phospholipids (sphingomyelins), amino acids, acylcarnitines |
| Lorefice et al. 2019 [125] | NMR | 21 MS; 16 controls | Blood | Lactate, acetone, 3-OH-butyrate, tryptophan, citrate, lysine, glucose levels |
| Kasakin et al. 2019 [71] | LC–MS/MS | 22 RRMS, 22 controls | Plasma | Glutamate, leucine-isoleucine, valine, decenoylcarnitine |
| Nogueras et al. 2019 [56] |
LC–MS GC–MS |
53 MS, 54 non-MS | CSF | Glycerolipids, sterol lipids, fatty acids arachidic acid (18:3n3 and 20:0), glycerophospholipids, sphingolipids, |
| Podlecka-Piętowska et al. 2019 [57] | NMR | 19 MS, 19 controls | CSF | Acetone, choline, urea, 1,3-dimethylurate, creatinine, isoleucine, myo-inositol, leucine, 3-OH butyrate, acetyl-CoA |
| Kooij et al. 2019 [118] | LC–MS-MS | 26 RRMS, 12 PMS, 15 controls | Plasma | Lipoxin A4, lipoxin B4, resolvin D1, protectin D1 |
| Bhargava et al. 2020 [133] | UPLC–MS–MS |
Adult discovery cohort: 56 RRMS, 51 PMS, 52 controls Adult validation cohort: 50 RRMS, 125 PMS, 75 controls Pediatric cohort: 31 MS, 31 controls |
Plasma | Bile acid |
| Carlsson et al. 2020 [58] |
LC-HRMS FIA-HRMS |
12 SPMS, 12 controls | CSF | Glycine, asymmetric dimethylarginine, glycerophospholipid PC-O (34:0), hexoses |
| Murgia et al. 2020 [59] | NMR, LC–MS/GC–MS | 22 RRMS, 12 PPMS |
CSF Serum |
Lipids, biogenic amines, amino acids |
| Sylvestre et al. 2020 [72] | NMR | 28 RRMS, 18 controls | Plasma | Arginine, isoleucine, citrate, serine, phenylalanine, methionine, asparagine, histidine, myo-inositol |
| Gaetani et al. 2020 [88] | HPLC–MS/MS | 47 RRMS, 43 controls | Urine | Tryptophan, kynurenine, anthranilate, indole-3-propionic acid |
#Non-MS: other neurological diseases; controls: healthy subjects or patients without neurological diseases
2D 2 dimensional; AQP4-Ab aquaporin-4 antibody; CIS clinically isolated syndrome; CSF cerebrospinal fluid; ELISA enzyme-linked immunosorbent assay; FIA flow injection analysis; GC–MS gas chromatography–mass spectrometry; HPLC high-performance liquid chromatography; HRMS high-resolution mass spectrometry; LC–MS liquid chromatography–mass spectrometry; MALDI matrix-assisted laser desorption ionization; MOG-Ab myelin oligodendrocyte antibody; MRI magnetic resonance imaging; MRS magnetic resonance spectroscopy; MS multiple sclerosis; NMO neuromyelitis optica; NMOSD neuromyelitis optica spectrum disorder; NMR nuclear magnetic resonance; PMS progressive multiple sclerosis; PPMS primary progressive multiple sclerosis; RRMS relapsing–remitting multiple sclerosis; SPMS secondary progressive multiple sclerosis; TOF time of flight; UHPLC ultra high-pressure liquid chromatography; UPLC ultra-performance liquid chromatography