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.