Circulating Metabolites as Potential Biomarkers for Neurological Disorders—Metabolites in Neurological Disorders
Abstract
:1. Introduction
1.1. Metabolites and Metabolomics
1.2. Metabololites as Clinical Biomarkers
2. Metabolites in Specific Neurological Diseases
2.1. Alzheimer’s Disease
2.2. Amyotrophic Lateral Sclerosis
2.3. Epilepsy
2.4. Multiple Sclerosis
2.5. Parkinson’s Disease
2.6. Stroke
Condition | Biological Fluid | Type of Analysis | Metabolite | Biomarker for | Related Mechanisms | Ref. |
---|---|---|---|---|---|---|
AD | CSF | LC-MS/ GC-MS | Aminoadipic acid | AD prediction | Not clear for this condition | [69] |
CSF | LC-MS/ GC-MS | Tyrosine | AD prediction | Neurotransmitter synthesis | [69] | |
CSF | LC-MS/ GC-MS | Sphingomyelin | AD prediction | Membrane Constitution | [69] | |
CSF | LC-MS/ GC-MS | Lysophosphatidic acid C18:2 | AD prediction | Oxidative stress | [69] | |
Plasma | FIA/ MS/MS | Acylcarnitine | AD and MCI prediction | Cascade of neurodegeneration | [68] | |
Plasma | FIA/ MS/MS | Phosphatidylcholine | AD and MCI prediction | Cascade of neurodegeneration | [68] | |
Plasma | FIA/ MS/MS | Sphingomyelin | AD and MCI prediction | Not clear for this condition | [68] | |
Plasma | FIA/ MS/MS | Lysophospholipids | Differentiate AD from MCI | Not clear for this condition | [68] | |
Plasma | FIA/ MS/MS | Dodecanedioyl carnitine | Differentiate AD from MCI from healthy subjects | Not clear for this condition | [68] | |
Plasma | FIA/ MS/MS | Dodecanoylcarnitine | Differentiate AD from MCI from healthy subjects | Not clear for this condition | [68] | |
Plasma | FIA/ MS/MS | PCaaC26:0 | Differentiate AD from MCI from healthy subjects | Not clear for this condition | [68] | |
Urine | LC | Arginine | aMCI prediction | Protein homeostasis, taurine metabolism, glutathione metabolism | [63] | |
Plasma | UPLC-MS/MS | Lysophosphatidyl ethanolamine | MCI-AD prediction | Membrane Constitution | [66] | |
Plasma | UPLC-MS/MS | Choline | MCI-AD prediction | Neurotransmitter synthesis | [66] | |
Plasma | UPLC-MS/MS | Soraphen A | MCI-AD prediction | It can interfere in the fatty acid elongation | [66] | |
ALS | Serum/plasma; CSF; Plasma | NMR-based/MS-target; NMR-based; FIA/LC-MS/MS/NMR-based | Glutamate | ALS prediction; Differentiation from other neurological disorders; Drug responsiveness | Glutamate excitotoxicity | [17,71,72,78,81,82] |
Serum; CSF; plasma | NMR-based; CG-MS; FIA/ LC-MS/MS | Glutamine | ALS prediction; Familial ALS prediction (SOD1 mutation); Drug responsiveness | Imbalance in glutamate–glutamine cycle | [72,74,78] | |
Serum | NMR-based | Formate | ALS prediction | Increased levels may cause cell death | [78] | |
CSF | NMR-based | Acetate | ALS prediction | Energy metabolism dysfunction | [5] | |
CSF | NMR-based | Acetone | ALS prediction | Energy metabolism dysfunction | [5] | |
CSF | NMR-based | Pyruvate | ALS prediction | Energy metabolism dysfunction | [5] | |
CSF | NMR-based | Ascorbate | ALS prediction; Differentiation from other neurological disorders | Oxidative stress | [5,71] | |
CSF | CG-MS | Creatinine | Familial ALS prediction - SOD1 mutation | Energy metabolism dysfunction | [74] | |
Plasma | MS-target | Homocysteine | ALS prediction | Not clear for this condition | [17,81] | |
Plasma | FIA/LC-MS/MS | Creatinine | Drug responsiveness | Not clear for this condition | [72] | |
Plasma | FIA/LC-MS/MS/NMR-based | Glycine | Drug responsiveness | Changes in its levels can affect the activity of the NMDA receptor | [72,82] | |
Plasma | LC-MS/MS | Acylcarnitines | Protective function | Not clear for this condition | [83] | |
Plasma | LC-MS/MS | Diacylglicerols | Protective function | Not clear for this condition | [83] | |
Plasma | LC-MS/MS | Triacylglicerols | Protective function | Not clear for this condition | [83] | |
Plasma | LC-MS/MS | Phosphatidylcholine | Protective function | Not clear for this condition | [83] | |
Epilepsy | Plasma | LC-MS | N8-acetylspermidine | Snyder–Robinson syndrome | Alterations in its levels may cause an imbalance of excitatory and inhibitory mechanisms | [90] |
Serum; Brain tissue; Serum | CG-MS; HR-MAS¹H MRS; NMR-based | Lactate | Different types of seizures; Epileptic activity; Drug responsiveness | Energy metabolism dysfunction | [91,92,93] | |
Serum; Brain tissue | CG-MS; HR-MAS¹H MRS | Glutamate | Different types of seizures; Epileptic activity | Glutamate excitotoxicity and hyperexcitability | [91,92] | |
Brain tissue | HR-MAS¹H MRS | Choline | Epileptic activity | Alterations in its levels may suggest heightened cell membrane turnover in high-spiking tissue | [92] | |
Brain tissue | HR-MAS¹H MRS | Glycerophosphorylcholine | Epileptic activity | Alterations in its levels may suggest heightened cell membrane turnover in high-spiking tissue | [92] | |
Brain tissue | HR-MAS¹H MRS | Glutamine | Epileptic activity | Not clear for this condition | [92] | |
Serum | NMR-based | Glucose | Drug responsiveness | Energy metabolism dysfunction | [93] | |
Plasma | LC-HRMS | Neurosteroids | Effect of medicines in fetal development | Neurodevelop- mental functions | [93] | |
Plasma | LC-HRMS | Progesterone | Effect of medicines in fetal development | Reduced levels may be related to a risk factor for miscarriage | [93] | |
Plasma | LC-HRMS | 3β-androstanediol | Effect of medicines in fetal development | Not clear for this condition | [93] | |
Plasma | LC-HRMS | 5-methyltetrahydrofolate | Effect of medicines in fetal development | AED-induced effect on folate uptake or metabolism | [93] | |
Plasma | LC-HRMS | Tetrahydrofolate | Effect of medicines in fetal development | AED-induced effect on folate uptake or metabolism | [93] | |
MuS | CSF; Serum | NMR-based | Acetate | MuS prediction; Differentiate Neuromyelitis optica from MuS and healthy subjects | The decrease may lead to myelination dysfunction; Neurotransmitter synthesis and suggested as a marker of astrocyte metabolism | [101,104,107] |
CSF | NMR-based | N-Methyl metabolites | Demyelination process | Impairment in the choline-glycine cycle and myelin synthesis | [101] | |
CSF | NMR-based | Sarcosine (N-methyl-glycine) | Demyelination process | Impairment in the choline-glycine cycle and myelin synthesis | [101] | |
CSF | NMR-based | Formate | Demyelination process | Impairment in the choline-glycine cycle and myelin synthesis | [101,102] | |
CSF | NMR-based | Lactate | MuS prediction | The increase was related to CSF mononuclear cells in MS patients and demyelinating areas | [102] | |
CSF | NMR-based | N-acetyl aspartate (NAA) | Differentiate chronic lesions from healthy subjects | The decrease may be related to chronic demyelinating plaques | [102,103] | |
CSF | NMR-based | Choline | Differentiate acute from chronic plaques and normal-appearing white matter | Increase related to active demyelinating plaques | [102] | |
CSF | NMR-based | Citrate | MuS prediction | The decrease can be related to the disruption of the TCA cycle through the pyruvate pathway and the formation of myelin | [102,103,104] | |
CSF | NMR-based | Threonate | MuS prediction | Not clear for this condition | [103] | |
CSF | NMR-based | Myo-inositol | MuS prediction | Not clear for this condition | [103] | |
CSF | NMR-based | Mannose | MuS prediction | Not clear for this condition | [103] | |
CSF | NMR-based | Phenylalanine | MuS prediction | Not clear for this condition | [103] | |
CSF | NMR-based | 3-hydroxybutyrate | MuS prediction | Not clear for this condition | [103] | |
CSF | NMR-based | 2-hydroxyisovalerate | MuS prediction | Not clear for this condition | [103] | |
CSF | NMR-based | 2-hydroxybutyrate | MuS prediction | The increase may be related to raised lipid oxidation and oxidative stress | [104] | |
CSF; Serum | NMR-based; GC-MS | Pyroglutamate | MuS prediction | The increase may be related to impairment in antioxidant pathways and leads to central nervous system dysfunction | [104,109] | |
CSF | NMR-based | Acetone | MuS prediction | The increase may be related to impairment in energetic metabolism | [104] | |
CSF; Serum | NMR-based | Glucose | MuS prediction | The decrease can be related to disturbed energy generation and progress of MS | [104,106] | |
CSF | HRMS | Kynurenate | Differentiate SPMuS from RRMuS patients | Tryptophan metabolism | [105] | |
CSF | HRMS | 5-hydroxytryptophan | Differentiate SPMuS from RRMuS patients | Tryptophan metabolism | [105] | |
CSF | HRMS | 5-hydroxyindoleacetate | Differentiate SPMuS from RRMuS patients | Tryptophan metabolism | [105] | |
CSF | HRMS | N-acetylserotonin | Differentiate SPMuS from RRMuS patients | Tryptophan metabolism | [105] | |
CSF | HRMS | Uridine | Differentiate SPMuS from RRMuS patients | Pyrimidine metabolism; Significantly associated with disability, disease activity, and brain atrophy | [105] | |
CSF | HRMS | Deoxyuridine | Differentiate SPMuS from RRMuS patients | Pyrimidine metabolism; Significantly associated with disability, disease activity, and brain atrophy | [105] | |
CSF | HRMS | Thymine | Differentiate SPMuS from RRMuS patients | Pyrimidine metabolism; Significantly associated with disability, disease activity, and brain atrophy | [105] | |
CSF | HRMS | Glutamine | Differentiate SPMuS from RRMuS patients | Pyrimidine metabolism; Significantly associated with disability, disease activity, and brain atrophy | [105] | |
Serum | NMR-based | Selenium | MuS prediction | The decrease may be related to oxidative stress | [106] | |
Serum | NMR-based | Valine | MuS prediction | The decrease may be related to myelination dysfunction of the neurons | [106] | |
Serum | NMR-based | Scyllo-inositol | Differentiate MuS from Neuromyelitis optica and healthy subjects | May be related to diffuse glial proliferation, demyelination, and neuronal damages | [107] | |
Serum | UHPLC-MS | Sphingomyelin | MuS prognosis | One of the main lipid class in myelin; influence the immune response | [108] | |
Serum | UHPLC-MS | Lysophosphatidyl ethanolamine | MuS prognosis | Modulates the immune response | [108] | |
Serum | UHPLC-MS | Hydrocortisone | MuS severity | Not clear for this condition | [108] | |
Serum | UHPLC-MS | Tryptophan | MuS severity | Not clear for this condition | [108] | |
Serum | UHPLC-MS | Glutamate | MuS severity | Related to excitatory neurotransmitter and oligodendrocyte death in the white matter | [108] | |
Serum | UHPLC-MS | Eicosapentaenoic acid | MuS severity | Related to the activation of the immune system | [108] | |
Serum | UHPLC-MS | 13S-hydroxyoctadecadienoic acid | MuS severity | Not clear for this condition | [108] | |
Serum | UHPLC-MS | Lysophosphatidyl cholines | MuS severity | Present in the cell membrane; role in proliferative growth and apoptosis | [108] | |
Serum | UHPLC-MS | Lysophosphatidyl ethanolamines | MuS severity | Not clear for this condition | [108] | |
Serum | GC-MS | Laurate | Differentiate MuS from healthy subjects | Saturated fatty acid, may be related to immune response | [109] | |
Serum | GC-MS | N-methylmaleimide | Differentiate MuS from healthy subjects | May be related to mitochondrial function and energy metabolism | [109] | |
Serum | GC-MS | Acylcarnitine C14:1 | Differentiate MuS from healthy subjects | Related to mitochondrial function and energy metabolism | [109] | |
Serum | GC-MS | Phosphatidylcholine | Differentiate MuS from healthy subjects | Present in cell membrane and myelin | [109] | |
PD | CSF; Urine; Brain of goldfish homogenate | GC-MS/LC-MS; NMR-based | BCAA | Differentiate PD from healthy subjects; Idiopathic PD prediction; PD Goldfish model | Protein synthesis, energy production, and synthesis of the neurotransmitter glutamate | [6,143,145] |
Serum | UPLC-MS/MS | Caffeine | Differentiate PD from healthy subjects | Regulate the release of neurotransmitters (glutamate and dopamine) | [133] | |
Serum | UPLC-MS/MS | Tryptophan | Differentiate PD from healthy subjects | The decrease may be associated with psychiatric problems in advanced PD | [133] | |
Serum | UPLC-MS/MS | Ergothioneine | Differentiate PD from healthy subjects | A decrease may suggest elevated oxidative stress | [133] | |
Serum | UPLC-MS/MS | Bilirubin/Biliverdin ratio | Differentiate PD from healthy subjects | A decrease may suggest elevated oxidative stress | [133] | |
Serum; Plasma | Enzymatic Methods | Uric acid | PD prediction | Antioxidant. An increase may suggest a potential protective effect | [136,137,138] | |
Serum | MS-based | FA metabolism (acyl carnitine pathway) | PD prognosis and MCI development | Medium-long chain FA derived from beta-oxidation. Related to mitochondrial dysfunction and neuronal loss | [142] | |
Urine | HPLC-HRMS | Steroidogenesis metabolism | PD progression | May be related to oxidative stress, inflammation, and neuron injury | [143] | |
Urine | HPLC-HRMS | Fatty acid beta-oxidation | PD progression | May be related to mitochondrial dysfunction, oxidative stress, and impaired energy metabolism | [143] | |
Urine | HPLC-HRMS | Histidine metabolism | PD progression | Suppressive neurotransmitter effects, and hormone secretion | [143] | |
Urine | HPLC-HRMS | Phenylalanine metabolism | PD progression | Not clear for this condition | [143] | |
Urine | HPLC-HRMS; GC-MS /LC-MS | Tryptophan metabolism | PD progression; Idiopathic PD prediction | Related to mitochondrial disturbances and impairment of brain energy metabolism | [143,144] | |
Urine | HPLC-HRMS; GC-MS/ LC-MS | Glycine derivation | PD progression; Idiopathic PD prediction | Stimulate the release of dopamine and acetylcholine | [143,144] | |
Urine | HPLC-HRMS | Nucleotide metabolism | PD progression | Not clear for this condition | [143] | |
Urine | HPLC-HRMS | Tyrosine metabolism | PD progression | Not clear for this condition | [143] | |
Urine | GC-MS/ LC-MS | Steroid hormone biosynthesis | Idiopathic PD prediction | Related to oxidative stress, and dopamine cell degeneration in PD | [144] | |
Urine | GC-MS/ LC-MS | Phenylalanine metabolism | Idiopathic PD prediction | Precursor for dopamine | [144] | |
Brain of goldfish homogenate | NMR-based | Myo-inositol | PD Goldfish model | Glial marker. An increase may suggest disruptive cell functions in the brain | [145] | |
Brain of goldfish homogenate | NMR-based | N-acetylaspartate | PD Goldfish model | The decrease may suggest neuronal dysfunction or cell loss | [145] | |
Brain of goldfish homogenate | NMR-based | Betaine | PD Goldfish model | Reduced may suggest a reduced antioxidant capacity | [145] | |
Brain of goldfish homogenate | NMR-based | Phosphatidylcholines | PD Goldfish model | Component of cellular membranes. Decrease related to membrane damage | [145] | |
Brain of goldfish homogenate | NMR-based | Creatine and phosphocreatine | PD Goldfish model | The decrease can be related to severe oxidative damage and energy impairment | [145] | |
Brain of goldfish homogenate | NMR-based | Cholesterol | PD Goldfish model | The decrease may be related to elevated oxidative stress; impaired brain mitochondria | [145] | |
Brain of goldfish homogenate | NMR-based | Polyunsaturated fatty acid | PD Goldfish model | The decrease may be associated with elevated oxidative stress | [145] | |
CSF | UHPLC/ GC-MS | Benzoate | PD progression | Derived from the catabolism of phenylalanine | [139] | |
Plasma | UHPLC/ GC-MS | Theobromine | PD progression | Phenylalanine metabolism | [139] | |
Plasma | UHPLC/GC-MS | Theophylline | PD progression | Metabolites of the purine compound caffeine | [139] | |
Plasma | UHPLC/GC-MS | Paraxanthine | PD progression | Metabolites of the purine compound caffeine | [139] | |
Plasma | UHPLC/GC-MS | 1-methylxanthine | PD progression | Metabolites of the purine compound caffeine | [139] | |
Plasma | UHPLC/GC-MS | 5-dodecanoate | PD progression | Fatty acid metabolism | [139] | |
Plasma | UHPLC/GC-MS | 3-hydroxydecanoate | PD progression | Fatty acid metabolism | [139] | |
Plasma | UHPLC/GC-MS | Docosadienoate | PD progression | Fatty acid metabolism | [139] | |
Plasma | UHPLC/GC-MS | Docosatrienoate | PD progression | Fatty acid metabolism | [139] | |
Stroke | Serum | GC-MS/ LC-MS | Isoleucine | Differentiate AIS from healthy subjects | Signaling molecule to regulate the growth, repair, and maintenance of the brain functions | [9] |
Serum | GC-MS/ LC-MS | Serine | Differentiate AIS from healthy subjects | Signaling molecule to regulate the growth, repair, and maintenance of the brain functions | [9] | |
Serum | GC-MS/ LC-MS | Phosphatidylcholine | Differentiate AIS from healthy subjects | Component of cellular membrane | [9] | |
Serum | GC-MS/LC-MS | Betaine | Differentiate AIS from healthy subjects | Part of the choline pathway; part of the antioxidant process | [9] | |
Serum | GC-MS/LC-MS | Lysophosphatidylethanolamine | Differentiate AIS from healthy subjects | Component of cellular membrane | [9] | |
Serum | GC-MS/LC-MS | Carnitine | Differentiate AIS from healthy subjects | Help the catabolism of lipids and energy conversion | [9] | |
Serum; Plasma/Urine | GC-MS; NMR-based | Lactate | AIS prediction Small vessel disease prediction | An increase may indicate anaerobic glycolysis, hypoxia, and ischemia | [10,170] | |
Serum | GC-MS | Tyrosine | AIS prediction | A low level can lead to oxidative stress and inflammation | [10] | |
Serum; CSF | GC-MS | Tryptophan | AIS prediction; Long-term outcome of subarachnoid hemorrhage | A low level can reduce serotonin | [10,175] | |
Plasma | HPLC | Dimethylarginine | Early-onset stroke | Inhibitor of nitric oxide synthase, part of the pathogenesis of atherosclerosis | [161] | |
Plasma | NMR-based | Choline | Carotid artery stenosis pathogenesis | Its reduction increases the homocysteine methylation pathway | [162] | |
Plasma | NMR-based | Homocysteine | Carotid artery stenosis pathogenesis | The increase could be associated with oxidative stress in vascular cells and platelet adhesion | [162] | |
Plasma | LC-MS | Lysophosphatidylcholine | Stroke recurrence; Large artery atherosclerosis | It may be a potential trigger of the brain inflammation processes | [163,171] | |
Serum | LC-MS/MS | Acetyl-L-lysine | Thrombotic ischemic prediction | The decrease may suggest elevated lysine catabolism and excitotoxic activity | [165] | |
Serum | LC-MS/MS | Cadaverine | Thrombotic ischemic prediction | The decrease may suggest elevated lysine catabolism and excitotoxic activity | [165] | |
Serum | LC-MS/MS | 2-oxoglutarate | Thrombotic ischemic prediction | The decrease may suggest elevated lysine catabolism and excitotoxic activity | [165] | |
Serum | LC-MS/MS | Nicotinamide | Thrombotic ischemic prediction | The decrease may suggest elevated lysine catabolism and excitotoxic activity | [165] | |
Serum | LC-MS/MS | Valine | Thrombotic ischemic prediction | A decrease may suggest an excitotoxic activity | [165] | |
Plasma; CSF | LC-MS; GC-MS | BCAA | Stroke outcome and severity; Long-term outcome of subarachnoid hemorrhage | Decreased may influence the bioenergetic homeostasis and impair the citric acid cycle pathways | [168,175] | |
Plasma/ Urine | NMR-based | Pyruvate | Small vessel disease prediction | The increase may be related to anaerobic glycolysis | [170] | |
Plasma/ Urine | NMR-based | Glycolate | Small vessel disease prediction | The increase may be related to folic acid deficiency and hyperhomocysteinemia | [170] | |
Plasma/ Urine | NMR-based | Formate | Small vessel disease prediction | The increase may be related to folic acid deficiency and hyperhomocysteinemia | [170] | |
Plasma/ Urine | NMR-based | Glutamine | Small vessel disease prediction | The decrease may be related to elevating of glial fibrillary acidic protein and brain damage | [170] | |
Plasma/ Urine | NMR-based | Methanol | Small vessel disease prediction | The decrease may be related to hyperhomocysteinemia | [170] | |
Plasma | HPLC | Taurine | Stroke prognosis and recovery | Osmoregulator and neuromodulator. The increase may be related to brain tissue damage | [172] | |
Blood | Mobile Photometric - Enzyme-kinetic Analyzer | Lactate:Pyruvate ratio | Hemorrhagic stroke prognosis | Reduced pyruvate may be related to impairment in energetic and repair functions | [174] | |
CSF | GC-MS | 2-hydroxyglutarate | Long-term outcome of subarachnoid hemorrhage | The increase was related to adverse outcome and death, while the decrease was related to low disability outcomes | [175] | |
CSF | GC-MS | Glycine | Long-term outcome of subarachnoid hemorrhage | Not clear for this condition | [175] | |
CSF | GC-MS | Proline | Long-term outcome of subarachnoid hemorrhage | Not clear for this condition | [175] |
2.7. Overview of Relevant Metabolites in Neurological Disorders
3. Perspectives and Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Donatti, A.; Canto, A.M.; Godoi, A.B.; da Rosa, D.C.; Lopes-Cendes, I. Circulating Metabolites as Potential Biomarkers for Neurological Disorders—Metabolites in Neurological Disorders. Metabolites 2020, 10, 389. https://doi.org/10.3390/metabo10100389
Donatti A, Canto AM, Godoi AB, da Rosa DC, Lopes-Cendes I. Circulating Metabolites as Potential Biomarkers for Neurological Disorders—Metabolites in Neurological Disorders. Metabolites. 2020; 10(10):389. https://doi.org/10.3390/metabo10100389
Chicago/Turabian StyleDonatti, Amanda, Amanda M. Canto, Alexandre B. Godoi, Douglas C. da Rosa, and Iscia Lopes-Cendes. 2020. "Circulating Metabolites as Potential Biomarkers for Neurological Disorders—Metabolites in Neurological Disorders" Metabolites 10, no. 10: 389. https://doi.org/10.3390/metabo10100389