Table 1.
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] |
CSF—Cerebrospinal Fluid; MS—Mass Spectrometry; LC/MS—Liquid Chromatography Mass Spectrometry; GC/MS—Gas Chromatography Mass Spectrometry; FIA/MS/MS—Flow Injection Analysis using tandem Mass Spectrometry; MCI—Mild Cognitive Impairment; UPLC MS/MS—Ultra Performance Liquid Chromatography—Tandem Mass Spectrometer; NMR—Nuclear magnetic Resonance; SOD1—Superoxide dismutase 1; HMRS—High-Resolution Mass Spectrometry; TCA—Tricarboxylic Acid Cycle; FA—Fatty acids; HPLC—High Performance Liquid Chromatography; AIS—Acute Ischemic Stroke.