Table 1.
Summary of prior studies and findings involving MS or MS rodent model (EAE).
| Population | Sample; Platform | Disease vs. Control | Involved Pathways | Study |
|---|---|---|---|---|
| EAE (C57BL mice): 5 Control: 5 |
Plasma; mass spectrometry | ↓: α-linolenic acid, glutamine, glutamate, tryptophan, and arachidonic acid | tryptophan metabolism, fatty acid biosynthesis, pentose pathway, linoleic acid metabolism, arachidonic acid metabolism, and polyunsaturated fatty acid metabolism | Poisson et al. [97] |
| EAE (C57BL mice): 10 Control: 10 |
Plasma/urine; mass spectrometry | ↓: Phenylalanine, tyrosine, tryptophan taurine, arginine, proline, and hypotaurine | Phenylalanine, tyrosine, and tryptophan biosynthesis; arginine and proline metabolism; tyrosine metabolism; and taurine and hypotaurine metabolism | Singh et al. [95] |
| Group 1: RRMS 50, SPMS 20, PPMS 17, and control 49 | Serum; mass spectrometry | ↑: quinolinic acid; in progressive MS; ↑ quinolinic acid kynurenic acid, and kynurenine/tryptophan ratios (which were related to higher EDSS); ↓: Tryptophan and NAD | tryptophan metabolism-endogenous | Lim et al. [72] |
| Group 2: RRMS 44, SPMS 15, MS 518, and control 167 | Serum; HPLC |
↑: hypoxanthine, xanthine, uric acid, inosine, uracil, β-pseudouridine, uridine creatinine, and lactate. Levels correlated with disease severity EDSS | Energy metabolism, nucleotide metabolism, and xanthine metabolism | Lazzarino et al. [101] |
| RRMS: 30 SPMS: 16 Control: 10 |
CSF; mass spectrometry | Alterations in expression of 5-hydroxytryptophan, kynurenate, and N-acetylserotonin 5-hydroxyindoleactate in SPMS; Uridine, deoxyuridine, thymine, and glutamine altered in SPMS | Amino acid metabolism and nucleotide metabolism | Herman et al. [65] |
| MS:27 Control: 27 |
Plasma; mass spectrometry | ↑: Gamma-glutamyl amino acids, glutathione metabolites; ↓: Caffeine/xanthine metabolites, benzoate metabolites | Amino acid metabolism, redox metabolism, benzoate metabolism, and xenobiotic metabolism | Bhargava et al. [99] |
| MS: 73 Controls: 28 |
Plasma; NMR |
↑: 3-OH-butyrate, acetoacetate, acetone, alanine, and choline; ↓: glucose, 5-OH-tryptophan, and tryptophan | Energy metabolism and tryptophan metabolism | Cocco et al. [5] |
| MS: 15 Non-MS: 17 |
CSF; NMR |
↑: Threonate, myo-inositol, and choline; ↓: 3-hydroxybutyrate, citrate, phenylalanine, 2-hydroxyisovalerate, and mannose | Energy metabolism and phospholipid metabolism | Reinke et al. [61] |
| MS:23 Controls:28 |
Serum; NMR |
↑: Glucose; ↓: Valine | Glucose metabolism and amino acid metabolism | Mehrpour et al. [102] |
| Pediatric MS: 66 Controls: 66 |
Serum; mass spectrometry | ↓ Levels of tryptophan and indole lactate in pediatric MS; Kynurenine level predicted the relapse rate, indole acetate related to SDMT, and indole propionate related to EDSS and SDMT | tryptophan metabolism-endogenous and gut microbiota related | Nourbakhsh et al. [41] |
| MS 32 Non-MS neural-inflammatory: 32 Non-MS neural-disorders: 18 |
CSF; NMR |
↑: (RRMS) lactate; ↓: Formate | Energy metabolism | Simone et al. [103] |
| MS 30 (RRMS and PPMS) | CSF; NMR |
↑: Acetate; ↓: Formate | Energy metabolism | Bernardes et al. [93] |
| MS: 50 NMOSD: 57 Control: 17 |
CSF; NMR |
↑: Pyroglutamate, acetone, formate, and 2-hydroxybutyrate; ↓: Citrate, glucose, and acetate |
Energy metabolism and fatty acid biosynthesis | Kim et al. [104] |
| Group 1: MS 238, controls 74 Group 2: MS 61, controls 41 |
Serum; mass spectrometry | MS vs. Control: lysophosphatidylethanolamine and sphingomyelin; Predictors of MS progression: hydrocortisone, glutamic acid, tryptophan, eicosapentaenoic acid, and 13S-hydroxyoctadecadienoic acid | Lipid metabolism, steroid metabolism, and amino acid metabolism | Villoslada et al. [71] |
| MS: 18 Controls 18 |
Plasma; mass spectrometry | ↑, 5-oxoproline; lactate, N1-methylinosine, N2, N2 dimethylguanosine, pseudouridine, sphingosine-1-phosphate, and sphinganine-1-phosphate | Sphingolipid metabolism, redox metabolism, and nucleotide metabolism | Bhargava et al. [105] |
| RRMS: 17 Control 17 |
Plasma; mass spectrometry | ↑: glutamate; ↓:C10:1 carnitine, leucine, valine, isoleucine |
Amino acid catabolism, glutamate metabolism, and energy metabolism | Kasakin et al. [106] |
| MS cohorts: PPMS 33 and RRMS 10 Control: 33 PD cohort: PD: 40 Control: 20 |
Plasma; mass spectrometry | ↓: PPMS vs (RRMS, PD, HC): LysoPE (18.2) and LysoPC (20:0) ↓: PPMS vs HC: tiglylcarnitine ↑: PPMS vs RRMS: tiglylcarnitine ↓: PPMS vs HC: gamma-linolenic acid, L-Tryptophan, LysoPC (20:0) ↑: (RRMS and PD vs HC:) gamma-linolenic acid, L-Tryptophan, LysoPC (20:0) ↓: PPMS citrulline vs HC ↓: PPMS vs HC: L-Tryptophan |
PPMS vs. HC: glycerophospholipid metabolism, linoleic acid metabolism, arginine biosynthesis, and kynurenine pathway | Stoessel et al. [40] |
| MS: 514 RRMS: 72.71% Progressive MS: 27.29% Controls: 214 |
Plasma/serum; mass spectroscopy | ↓:phenyllactate, 3-(-4-hydroxyphenyl)-lactate, indolelactate, imidazole lactate, kynurenine, kynurenate, tryptophan and phenylalanine ↑: p-cresol glucuronide, p-cresol sulfate, and phenylacetylglutamine. altered ratios of phenylacetylglutamine/phenyllactate, indole acetate/indolelactate, p-cresol glucuronide/3-(4-hydroxyphenyl)lactate. |
lactate-related metabolites in AAA pathways (tryptophan, phenylalanine metabolism), BCAA-related metabolites, other AAA metabolites, bile acid metabolism, xanthine metabolites, acetylated amino acids |
Fitzgerald et al. [79] |
| MS: 90 Controls:90 |
Serum; mass spectroscopy | ↓: indoleproprionate, indoleactate ↑:p-cresol sulfate |
Tryptophan degradation pathway | Levi et al. [78] |
| RRMS: 13 Controls: 13 |
Plasma, cerebral cortex; mass spectroscopy | ↓: methionine (plasma) | DNA and histone H3 methylation in cerebral cortex, methionine metabolism, regulation of mitochondrial electron transport complex proteins(brain). | Singhal et al. [80] |
CSF: cerebrospinal fluid; EAE: experimental autoimmune encephalomyelitis, EDSS: expanded disability status scale; HC: healthy control, HPLC: high-performance liquid chromatography; MS: multiple sclerosis; NAD: nicotinamide adenine dinucleotide, NMOSD: neuromyelitis optica spectrum disorder, PD: Parkinson's disease, PPMS: primary progressive multiple sclerosis; RRMS: relapsing-remitting multiple sclerosis; SDMT: symbol digit modalities test, SPMS: secondary progressive multiple sclerosis; ↑: increase; ↓: decrease.