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. 2020 Sep 29;10(10):389. doi: 10.3390/metabo10100389

Table 1.

Metabolites discovered for each of the main neurological diseases: Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Epilepsy, multiple sclerosis (MuS), Parkinson’s disease (PD), 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]

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.