WO2022075354A1 - Procédé pour obtenir un indice pour le diagnostic de la maladie d'alzheimer (ad) - Google Patents

Procédé pour obtenir un indice pour le diagnostic de la maladie d'alzheimer (ad) Download PDF

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WO2022075354A1
WO2022075354A1 PCT/JP2021/036950 JP2021036950W WO2022075354A1 WO 2022075354 A1 WO2022075354 A1 WO 2022075354A1 JP 2021036950 W JP2021036950 W JP 2021036950W WO 2022075354 A1 WO2022075354 A1 WO 2022075354A1
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trimethyl
diagnosis
ergothioneine
metabolite
subject
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PCT/JP2021/036950
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Mitsuhiro Yanagida
Takayuki Teruya
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Okinawa Institute Of Science And Technology School Corporation
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • G01N33/6806—Determination of free amino acids
    • G01N33/6812—Assays for specific amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2814—Dementia; Cognitive disorders
    • G01N2800/2821—Alzheimer

Definitions

  • the present invention relates to a method for obtaining an index for the diagnosis of Alzheimer’s disease (AD), an apparatus for obtaining an index for the diagnosis of AD, a system for obtaining an index for the diagnosis of AD, a kit for obtaining an index for the diagnosis of AD and a method of evaluating substances effective in improving AD.
  • AD Alzheimer’s disease
  • Metabolomics is a branch of chemical biology that profiles metabolites in cells and organisms, using techniques such as liquid chromatography (LC)-mass spectrometry (MS). It usually deals with molecules ⁇ 1.5 kDa, and is an important tool for studying metabolic regulation in combination with other comprehensive analyses, such as proteomics and transcriptomics.
  • LC liquid chromatography
  • MS mass spectrometry
  • AD Alzheimer’s disease
  • NPL 12-13 The cause of Alzheimer's disease is poorly understood (NPL 14-15).
  • NPL 16 Mental and physical exercise and avoiding obesity may decrease the risk of AD (NPL 16).
  • No medications or supplements have been definitively shown to decrease risk (NPL 17-18). It most often begins in people over 65 years of age, and about 6% of seniors are afflicted with it. In 2015, there were approximately 29.8 million people worldwide with AD, making it one of the most costly diseases in developed countries.
  • Rapoport SM Schewe T, & Thiele B-J (1990) Maturational breakdown of mitochondria and other organelles in reticulocytes. in Erythroid Cells, ed Harris JR (Springer US), pp 151-194. van Wijk R & van Solinge WW (2005) The energy-less red blood cell is lost: erythrocyte enzyme abnormalities of glycolysis. Blood 106(13):4034-4042. Bax BE, Bain MD, Talbot PJ, Parker-Williams EJ, & Chalmers RA (1999) Survival of human carrier erythrocytes in vivo. Clin Sci (Lond) 96(2):171-178. Chaleckis R, et al.
  • AD Alzheimer’s disease
  • Thorough metabolomics can supply complete information about metabolite abundance in each subject.
  • metabolites to be analyzed are pre-determined; however, changes in abundance of untargeted (unexpected) metabolites are overlooked.
  • non-targeted analysis is far more laborious, the effort expended in this “no assumptions” approach is often recompensed by identification of crucial compounds overlooked by targeted analysis.
  • a wealth of metabolite information can provide clues for understanding detailed metabolic changes occurring in AD.
  • LC-MS liquid chromatography - mass spectroscopy
  • AD Alzheimer’s disease
  • AD Alzheimer’s disease
  • [4] The method for obtaining an index for the diagnosis of Alzheimer’s disease (AD) according to [1], wherein the blood metabolite is selected from the group of antioxidative aromatic compounds with trimethyl-ammonium consisting of S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, and trimethyl-tyrosine.
  • the blood metabolite is selected from the group of neurotoxic compounds consisting of indoxyl-sulfate, kynurenine, and N6-acetyl-lysine.
  • [6] The method for obtaining an index for the diagnosis of Alzheimer’s disease (AD) according to [1], wherein the blood metabolite is selected from the group of RBC enriched compounds consisting of ATP, NADP + , pantothenate, and gluconate.
  • a method for assisting in the diagnosis of AD in a subject by measuring at least one blood metabolite selected from the group consisting of trimethyl-tryptophan, S-methyl-ergothioneine, betaine, indoxyl-sulfate, pantothenate, trimethyl-histidine, dimethyl-xanthine, ATP, methionine, kynurenine, trimethyl-tyrosine, trimethyl-phenylalanine, NADP + , 2-hydroxybutyrate, keto(iso)leucine, glycerophosphocholine, gluconate, pseudouridine, N6-acetyl-lysine, and dimethyl-guanosine.
  • blood metabolite selected from the group consisting of trimethyl-tryptophan, S-methyl-ergothioneine, betaine, indoxyl-sulfate, pantothenate, trimethyl-histidine, dimethyl-xanthine, ATP, methionine, kynurenine
  • the blood metabolite is selected from the group of neurotoxic compounds consisting of indoxyl-sulfate, kynurenine, and N6-acetyl-lysine.
  • a method of evaluating substances which improve Alzheimer’s disease comprising the step of measuring a blood metabolite such as trimethyl-tryptophan, S-methyl-ergothioneine, betaine, indoxyl-sulfate, pantothenate, trimethyl-histidine, dimethyl-xanthine, ATP, methionine, kynurenine, trimethyl-tyrosine, trimethyl-phenylalanine, NADP + , 2-hydroxybutyrate, keto(iso)leucine, glycerophosphocholine, gluconate, pseudouridine, N6-acetyl-lysine, or dimethyl-guanosine as AD markers.
  • a kit for evaluation of Alzheimer’s disease (AD) in which AD is evaluated by the method according to any one of claims [1] to [12] comprising blood collection tubes and blood metabolite compounds as detection standard.
  • Alzheimer's disease Using comprehensive metabolomics, we identified 5 groups of metabolites (A-E), 20 of which are novel, possibly useful for diagnosis and therapy of forms of dementia, such as Alzheimer's disease (AD). Seven compounds of Group A may act as neurotoxins, whereas compounds of Group B-E may protect the CNS (Central Nerve System) against oxidative stress, maintain energy reserves, supply nutrients and neuroprotective factors. Interventions for Alzheimer's disease metabolomic markers may be accomplished either by inhibiting Group A compounds or by supplementing Group B-E compounds in patients.
  • CNS Central Nerve System
  • the present invention based on these findings provides a novel method capable of simple and accurate diagnosis of Alzheimer's disease (AD).
  • the present invention also provides a novel method for obtaining an index for the diagnosis of Alzheimer’s disease (AD).
  • the present invention also provides a novel method for assisting in the diagnosis of AD in a subject, comprising measuring the amount of a specific blood metabolite in the subject.
  • the 33 blood metabolites that we found are specifically increased or decreased in patients with Alzheimer's disease (AD). Therefore, using these blood metabolites as indicators, it is possible to distinguish Alzheimer's disease from frailty.
  • AD Alzheimer’s disease
  • HE healthy elderly
  • HY healthy young Volunteer
  • BMI body mass index.
  • Blood samples of AD subjects 75 ⁇ 88 yr) were drawn at the National Ryukyu Hospital.
  • Healthy subject HE, 67 ⁇ 80 yr, and HY, 28 ⁇ 34 yr samples were collected from volunteers at the Onna Clinic in Onna-son, Okinawa.
  • Dot plot profiles are shown for ergothioneine, glutathione disulfide, betaine, ATP, glutamine, phenylalanine, trimethyl-tryptophan, tryptophan, glycerophosphocholine, dimethyl-xanthine, tyrosine, caffeine, methionine, histidine, gluconate, trimethyl-phenylalanine, S-methyl-ergothioneine, trimethyl-tyrosine, keto(iso)leucine, pantothenate, 2-hyroxybutyrate, dodecanoyl-carnitine, trimethyl-histidine, NADP+, uridine, and S-adenosyl-methionine in 24 subjects AD, HE, and HY.
  • Fig.2-14 to 2-1-7 Seven compounds increased in AD. Dot plot profiles for seven compounds (four nucleosides and three amino acid derivatives) that increased in AD patients compared with HE are shown. Peak areas were maximal for indoxyl sulfate and minimal for quinolinic acid. In AD patients various trimethylated compounds abundance decreased in blood; Three trimethylated compounds (betaine, glycerophosphocholine, dodecanoyl-carnitine) are synthesized in human body, whilst six other compounds (ergothioneine, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-phenylalanine, trimethyl-tryptophan, trimethyl-tyrosine) were derived dietary metabolites.
  • betaine glycerophosphocholine
  • dodecanoyl-carnitine Three trimethylated compounds (betaine, glycerophosphocholine, dodecanoyl-carnitine) are synthesized in human body, whilst six other compounds (
  • FIG.4-2 PCA analysis was performed using selected 6 AD markers (dimethyl-guanosine, pseudouridine, S-methyl-ergothioneine, ergothioneine, trimethyl-histidine, and NADP + ).
  • Figure 5 is divided into 4 parts (Fig.5-1 to 5-4).
  • Correlation analysis of 33 AD markers The correlation values r larger than +0.5 (dark grey) indicates a high correlation between the compounds, whilst r below -0.5 (light grey) was indicates a low correlation between the compounds. Compounds increased or decreased in AD patients were indicated by the arrows.
  • Figure 6 is divided into 2 parts (Fig.6-1 and 6-2).
  • blood metabolite is used herein to refer to a low molecular compound involved in biological metabolic activity contained in blood constituents.
  • a method for obtaining an index for the diagnosis of Alzheimer’s disease is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject. According to the present invention, by measuring the amount of a specific blood metabolite, it is possible to diagnose or assist in diagnosing whether a subject has AD or is at risk for AD.
  • the sample used for measuring the amount of a specific blood metabolite in a subject may be at least one kind selected from the group consisting of whole blood, erythrocyte and plasma. It is preferable to use either whole blood or erythrocyte. It is more preferable to use any two of whole blood, erythrocyte and plasma. It is most preferable to use all of whole blood, erythrocyte and plasma as a sample.
  • the compound has a large difference in blood content between the AD patients group (AD) and healthy elderly (HE) subjects.
  • AD AD patients group
  • HE healthy elderly
  • the degree of reduction for caffeine and dimethyl-xanthine in AD was quite significant (ratio, 0.04 ⁇ 0.09).
  • Trimethyl-tryptophan (0.10) and trimethyl-tyrosine (0.08) were also strikingly declined. Therefore when the content of these compounds in the subject’s blood sample is lower than standard, the subject is diagnosed as having AD or is at high risk for AD.
  • the blood metabolite comprises at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kynurenine, quinolinic acid, N6-acetyl-lysine, pseudouridine, adenosine and dimethyl-guanosine.
  • the blood metabolite comprises at least one metabolite selected from the group consisting of trimethyl-tryptophan, S-methyl-ergothioneine, betaine, indoxyl-sulfate, pantothenate, trimethyl-histidine, dimethyl-xanthine, ATP, methionine, kynurenine, trimethyl-tyrosine, trimethyl-phenylalanine, NADP + , 2-hydroxybutyrate, keto(iso)leucine, glycerophosphocholine, gluconate, pseudouridine, N6-acetyl-lysine, dimethyl-guanosine.
  • metabolite selected from the group consisting of trimethyl-tryptophan, S-methyl-ergothioneine, betaine, indoxyl-sulfate, pantothenate, trimethyl-histidine, dimethyl-xanthine, ATP, methionine, kynurenine, trimethyl-tyrosine, trimethyl-
  • the blood metabolite comprises at least one metabolite selected from the group consisting of trimethyl-tryptophan, S-methyl-ergothioneine, betaine, indoxyl-sulfate, pantothenate, trimethyl-histidine, dimethyl-xanthine, ATP, methionine, kynurenine.
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kyn
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises at least one metabolite selected from the group of antioxidative aromatic compounds with trimethyl-ammonium consisting of ergothioneine, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, and trimethyl-tyrosine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises at least one metabolite selected from the group of antioxidative aromatic compounds with trimethyl-ammonium consisting of S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, and trimethyl-tyrosine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises at least one metabolite selected from the group of neurotoxic compounds consisting of indoxyl-sulfate, quinolinic acid, kynurenine, N6-acetyl-lysine, dimethyl-guanosine, and adenosine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises at least one metabolite selected from the group of neurotoxic compounds consisting of indoxyl-sulfate, kynurenine, and N6-acetyl-lysine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises at least one metabolite selected from the group of RBC enriched compounds consisting of ATP, S-adenosyl-methionine, NADP + , glutathione disulfide, pantothenate, and gluconate.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises at least one metabolite selected from the group of RBC enriched compounds consisting of ATP, NADP + , pantothenate, and gluconate.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is trimethyl-tryptophan.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-tryptophan and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, indoxyl-sulfate, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, kyn
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-tryptophan and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-tryptophan and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, pantothenate, betaine, and dimethyl-xanthine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is S-methyl-ergothioneine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises S-methyl-ergothioneine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kyn
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises S-methyl-ergothioneine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises S-methyl-ergothioneine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is betaine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises betaine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kyn
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises betaine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises betaine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, and dimethyl-xanthine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is indoxyl-sulfate.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises indoxyl-sulfate and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, kyn
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises indoxyl-sulfate and at least one metabolite selected from the group consisting of , kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises indoxyl-sulfate and at least one metabolite selected from the group consisting of kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is pantothenate.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises pantothenate and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + ,keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, ky
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises pantothenate and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises pantothenate and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, betaine, and dimethyl-xanthine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is trimethyl-histidine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-histidine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kyn
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-histidine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-histidine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is dimethyl-xanthine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises dimethyl-xanthine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kyn
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises dimethyl-xanthine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises dimethyl-xanthine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, and betaine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is ATP.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises ATP and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kyn
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises ATP and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises ATP and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is methionine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises methionine n and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, tryptophan, indoxyl-sulfate,
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises methionine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises methionine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is kynurenine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises kynurenine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-s
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises kynurenine and at least one metabolite selected from the group consisting of indoxyl-sulfate, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises kynurenine and at least one metabolite selected from the group consisting of indoxyl-sulfate, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is trimethyl-tyrosine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-tyrosine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kyn
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-tyrosine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-tyrosine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is trimethyl-phenylalanine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-phenylalanine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kyn
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-phenylalanine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-phenylalanine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is NADP + .
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises NADP + and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kynur
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises NADP + and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises NADP + and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is 2-hydroxybutyrate.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises 2-hydroxybutyrate and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kyn
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises 2-hydroxybutyrate and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises 2-hydroxybutyrate and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is keto(iso)leucine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises keto(iso)leucine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kyn
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises keto(iso)leucine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, and caffeine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises keto(iso)leucine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is glycerophosphocholine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises glycerophosphocholine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kyn
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises glycerophosphocholine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises glycerophosphocholine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is gluconate.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises gluconate and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kyn
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises gluconate and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises gluconate and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is pseudouridine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises pseudouridine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises pseudouridine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises pseudouridine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is N6-acetyl-lysine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises N6-acetyl-lysine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, in
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises N6-acetyl-lysine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises N6-acetyl-lysine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is dimethyl-guanosine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises dimethyl-guanosine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises dimethyl-guanosine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • AD Alzheimer's disease
  • One embodiment of the present invention is a method for obtaining an index for the diagnosis of Alzheimer's disease (AD) by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises dimethyl-guanosine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • AD Alzheimer's disease
  • the method for obtaining an index for the diagnosis of Alzheimer's disease (AD) of the present invention comprises (i) a step of preparing a metabolomics sample, (ii) a step of measuring the content of the specific blood metabolites in the sample and (iii) a step of assisting in the diagnosis of AD in a subject.
  • Metabolomic samples can be prepared as reported previously (NPL 4). All blood samples are drawn in a hospital laboratory to ensure rapid sample preparation. Briefly, venous blood samples for metabolomics analysis are taken into 5 mL heparinized tubes (Terumo). Immediately, 0.1 ⁇ 1.0 mL blood (4 ⁇ 60 ⁇ 10 8 RBC) were quenched in 30 ⁇ 70% methanol (preferably 50 ⁇ 60%) of 5 ⁇ 10 times volume of the blood at -20°C ⁇ -80°C (preferably at -40°C ⁇ -50°C). This quick quenching step immediately after blood sampling ensured accurate measurement of many labile metabolites.
  • the remaining blood sample from each donor is centrifuged at 120 g for 15 min at room temperature to separate plasma and RBCs. After centrifugation, 0.1 ⁇ 1.0 mL each of separated plasma and RBCs (7-100x10 8 RBC), are quenched in 30 ⁇ 70% methanol (preferably 50 ⁇ 60%) of 5 ⁇ 10 times volume of the sample at -20°C ⁇ -80°C (preferably at -40°C ⁇ -50°C). Two internal standards (10 nmol of HEPES and PIPES) are added to each sample. After brief vortexing, samples are transferred to Amicon Ultra 10-kDa cut-off filters (Millipore, Billerica, MA, USA) to remove proteins and cellular debris.
  • each blood sample three different subsamples, whole blood, RBCs, and plasma, are prepared.
  • the white blood cell content (WBC) is less than 1% of the cellular volume in our preparations (NPL 4).
  • Full metabolomics analysis of WBCs using a Ficoll gradient confirmed that WBCs should not affect our present metabolomics results regarding RBCs.
  • each sample is re-suspended in 40 ⁇ L of 50% acetonitrile, and 1 ⁇ L is used for each injection into the LC-MS system.
  • LC-MS data are preferably to be obtained using a Paradigm MS4 HPLC system (Michrom Bioresources, Auburn, CA, USA) coupled to an LTQ Orbitrap mass spectrometer (Thermo Fisher Scientific, Waltham, MA, USA), as previously described (Pluskal T, Nakamura T, Villar-Briones A, & Yanagida M (2010) Metabolic profiling of the fission yeast S. pombe: quantification of compounds under differenttemperatures and genetic perturbation. Mol Biosyst 6(1):182-198).
  • LC separation is performed on a ZIC-pHILIC column (Merck SeQuant, Umea, Sweden; 150 mm x 2.1 mm, 5 ⁇ m particle size).
  • the HILIC column is quite useful for separating many hydrophilic blood metabolites, which are previously not assayed by others (NPL 4: Chaleckis R, et al. (2014)).
  • Acetonitrile (A) and 10 mM ammonium carbonate buffer, pH 9.3 (B) are used as the mobile phase, with a gradient elution from 80-20% A in 30 min, at a flow rate of 100 ⁇ L mL-1.
  • Peak areas of metabolites of interest are measured using MZmine 2 software (Pluskal T, Castillo S, Villar-Briones A, & Oresic M (2010) MZmine 2: modular framework for processing, visualizing, and analyzing mass spectrometry-based molecular profile data. BMC Bioinformatics 11:395). Detailed data analytical procedures and parameters have been described previously (Pluskal T, Nakamura T, Villar-Briones A, & Yanagida M (2010) Metabolic profiling of the fission yeast S. pombe: quantification of compounds under differenttemperatures and genetic perturbation. Mol Biosyst 6(1):182-198). Metabolomic datasets are deposited in the MetaboLights database (see data availability).
  • step (iii) a step of assisting in the diagnosis of AD in a subject
  • the content of blood metabolite in the subject's sample measured in this step (ii) is compared to standard data, which is the average of the data for the blood metabolite in a healthy person, a healthy elderly person (HE) or a healthy young person (HY).
  • standard data is the average of the data for the blood metabolite in a healthy person, a healthy elderly person (HE) or a healthy young person (HY).
  • the subject could be diagnosed as having AD or is at high risk for AD.
  • the blood metabolites are ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine or tryptophan, and when the content of one of the compounds in the subject’s blood sample is lower than standard, the subject could be diagnosed as having AD or is at high risk for AD. However, the final diagnosis should be made by a doctor.
  • a method for assisting in the diagnosis of Alzheimer’s disease is a method for assisting in the diagnosis of Alzheimer’s disease (AD) in a subject by measuring the amount of a specific blood metabolite in a subject. According to the present invention, by measuring the amount of the specific blood metabolite, it is possible to diagnose or assist in diagnosing whether a subject has AD or is at risk for AD.
  • the section of "A method for obtaining an index for the diagnosis of Alzheimer's disease (AD)" can be referred for details of the invention of the method for assisting in the diagnosis of AD if needed.
  • the sample used for measuring the amount of a specific blood metabolite in a subject may be at least one kind selected from the group consisting of whole blood, erythrocyte and plasma. It is preferable to use either whole blood or erythrocyte. It is more preferable to use any two of whole blood, erythrocyte and plasma. It is most preferable to use all of whole blood, erythrocyte and plasma as a sample.
  • the compound has a large difference in blood content between the AD patients group (AD) and healthy elderly (HE) subjects.
  • AD AD patients group
  • HE healthy elderly
  • the degree of reduction for caffeine and dimethyl-xanthine in AD was quite significant (ratio, 0.04 ⁇ 0.09).
  • Trimethyl-tryptophan (0.10) and trimethyl-tyrosine (0.08) were also strikingly declined. Therefore when the content of these compounds in the subject’s blood sample is lower than standard, the subject is diagnosed as having AD or is at high risk for AD.
  • the blood metabolite comprises at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kynurenine, quinolinic acid, N6-acetyl-lysine, pseudouridine, adenosine and dimethyl-guanosine.
  • the blood metabolite comprises at least one metabolite selected from the group consisting of trimethyl-tryptophan, S-methyl-ergothioneine, betaine, indoxyl-sulfate, pantothenate, trimethyl-histidine, dimethyl-xanthine, ATP, methionine, kynurenine, trimethyl-tyrosine, trimethyl-phenylalanine, NADP + , 2-hydroxybutyrate, keto(iso)leucine, glycerophosphocholine, gluconate, pseudouridine, N6-acetyl-lysine, and dimethyl-guanosine.
  • metabolite selected from the group consisting of trimethyl-tryptophan, S-methyl-ergothioneine, betaine, indoxyl-sulfate, pantothenate, trimethyl-histidine, dimethyl-xanthine, ATP, methionine, kynurenine, trimethyl-tyrosine, trimethyl
  • the blood metabolite comprises at least one metabolite selected from the group consisting of trimethyl-tryptophan, S-methyl-ergothioneine, betaine, indoxyl-sulfate, pantothenate, trimethyl-histidine, dimethyl-xanthine, ATP, methionine, and kynurenine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kynurenine,
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises at least one metabolite selected from the group of antioxidative aromatic compounds with trimethyl-ammonium consisting of ergothioneine, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, and trimethyl-tyrosine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises at least one metabolite selected from the group of antioxidative aromatic compounds with trimethyl-ammonium consisting of S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, and trimethyl-tyrosine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises at least one metabolite selected from the group of neurotoxic compounds consisting of indoxyl-sulfate, quinolinic acid, kynurenine, N6-acetyl-lysine, dimethyl-guanosine, and adenosine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises at least one metabolite selected from the group of neurotoxic compounds consisting of indoxyl-sulfate, kynurenine, and N6-acetyl-lysine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises at least one metabolite selected from the group of RBC enriched compounds consisting of ATP, S-adenosyl-methionine, NADP + , glutathione disulfide, pantothenate, and gluconate.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises at least one metabolite selected from the group of RBC enriched compounds consisting of ATP, NADP + , pantothenate, and gluconate.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is trimethyl-tryptophan.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-tryptophan and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, indoxyl-sulfate, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, kynurenine,
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-tryptophan and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, caffeine.
  • the specific blood metabolite comprises trimethyl-tryptophan and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-tryptophan and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, pantothenate, betaine, dimethyl-xanthine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is S-methyl-ergothioneine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises S-methyl-ergothioneine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kynurenine,
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises S-methyl-ergothioneine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • the specific blood metabolite comprises S-methyl-ergothioneine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, tri
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises S-methyl-ergothioneine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is betaine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises betaine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kynurenine,
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises betaine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • the specific blood metabolite comprises betaine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothione
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises betaine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, and dimethyl-xanthine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is indoxyl-sulfate.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises indoxyl-sulfate and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, kynurenine,
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises indoxyl-sulfate and at least one metabolite selected from the group consisting of , kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • the specific blood metabolite comprises indoxyl-sulfate and at least one metabolite selected from the group consisting of , kynurenine, ergothioneine, S-methyl-ergothi
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises indoxyl-sulfate and at least one metabolite selected from the group consisting of kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is pantothenate.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises pantothenate and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + ,keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kynurenine
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises pantothenate and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • the specific blood metabolite comprises pantothenate and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-er
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises pantothenate and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, betaine, and dimethyl-xanthine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is trimethyl-histidine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-histidine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kynurenine,
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-histidine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • the specific blood metabolite comprises trimethyl-histidine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-histidine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is dimethyl-xanthine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises dimethyl-xanthine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kynurenine,
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises dimethyl-xanthine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • the specific blood metabolite comprises dimethyl-xanthine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises dimethyl-xanthine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, and betaine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is ATP.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises ATP and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kynurenine,
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises ATP and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • the specific blood metabolite comprises ATP and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-er
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises ATP and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is methionine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises methionine n and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, tryptophan, indoxyl-sulfate, kynuren
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises methionine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • the specific blood metabolite comprises methionine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises methionine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is kynurenine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises kynurenine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate,
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises kynurenine and at least one metabolite selected from the group consisting of indoxyl-sulfate, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • the specific blood metabolite comprises kynurenine and at least one metabolite selected from the group consisting of indoxyl-sulfate, ergothioneine, S-methyl-ergothioneine, tri
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises kynurenine and at least one metabolite selected from the group consisting of indoxyl-sulfate, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is trimethyl-tyrosine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-tyrosine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kynurenine,
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-tyrosine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • the specific blood metabolite comprises trimethyl-tyrosine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-tyrosine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is trimethyl-phenylalanine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-phenylalanine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kynurenine,
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-phenylalanine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • the specific blood metabolite comprises trimethyl-phenylalanine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises trimethyl-phenylalanine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is NADP + .
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises NADP + and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kynurenine,
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises NADP + and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • the specific blood metabolite comprises NADP + and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises NADP + and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is 2-hydroxybutyrate.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises 2-hydroxybutyrate and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kynurenine,
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises 2-hydroxybutyrate and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • the specific blood metabolite comprises 2-hydroxybutyrate and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises 2-hydroxybutyrate and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is keto(iso)leucine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises keto(iso)leucine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kynurenine,
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises keto(iso)leucine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, and caffeine.
  • the specific blood metabolite comprises keto(iso)leucine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises keto(iso)leucine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is glycerophosphocholine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises glycerophosphocholine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kynurenine,
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises glycerophosphocholine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • the specific blood metabolite comprises glycerophosphocholine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine,
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises glycerophosphocholine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • the specific blood metabolite comprises glycerophosphocholine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is gluconate.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises gluconate and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kynurenine,
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises gluconate and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • the specific blood metabolite comprises gluconate and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises gluconate and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is pseudouridine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises pseudouridine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kyn
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises pseudouridine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • the specific blood metabolite comprises pseudouridine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises pseudouridine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is N6-acetyl-lysine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises N6-acetyl-lysine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises N6-acetyl-lysine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • the specific blood metabolite comprises N6-acetyl-lysine and at least one metabolite selected from the group consisting of indoxyl-sulfate,
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises N6-acetyl-lysine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite is dimethyl-guanosine.
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises dimethyl-guanosine and at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises dimethyl-guanosine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, dimethyl-xanthine, quinolinic acid, adenosine, trimethyl-histidine, trimethyl-tyrosine, trimethyl-phenylalanine, S-adenosyl-methionine, glutathione disulfide, keto(iso)leucine, and caffeine.
  • the specific blood metabolite comprises dimethyl-guanosine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, er
  • One embodiment of the present invention is a method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject, wherein the specific blood metabolite comprises dimethyl-guanosine and at least one metabolite selected from the group consisting of indoxyl-sulfate, kynurenine, ergothioneine, S-methyl-ergothioneine, trimethyl-tryptophan, pantothenate, betaine, and dimethyl-xanthine
  • the method for assisting in the diagnosis of AD in a subject by measuring the amount of a specific blood metabolite in a subject of the present invention comprises (i) a step of preparing a metabolomics sample, (ii) a step of measuring the content of the specific blood metabolites in the sample and (iii) a step of assisting in the diagnosis of AD in a subject.
  • the section of "A method for obtaining an index for the diagnosis of Alzheimer's disease (AD)" can be referred for details of each step of the invention of the method for assisting in the diagnosis of AD.
  • the present invention provides an apparatus for obtaining an index for the diagnosis of Alzheimer's disease (AD).
  • the present invention also provides an apparatus for assisting in the diagnosis of AD in a subject.
  • the apparatus uses the method of the present invention above.
  • the apparatus for obtaining an index for the diagnosis of Alzheimer's disease (AD) of the present invention comprises means for input and means for assisting in the diagnosis of AD in a subject, comprising measuring the amount of a specific blood metabolite in the subject, wherein data of blood metabolites of the subject are input to the means for input, and the diagnosis of AD is performed by comparing standard.
  • Said method section can be referred for details of the method of the present invention used by the apparatus.
  • the present invention provides a system for obtaining an index for the diagnosis of Alzheimer's disease (AD).
  • the present invention also provides a system for assisting in the diagnosis of AD in a subject.
  • the system uses the method of the present invention above and/or the apparatus of the present invention. Said method section and the apparatus section can be referred for details of the system of the present invention.
  • the present invention provides a method of evaluating substances which could be used in treating AD comprising the step of measuring a blood metabolite, wherein the blood metabolite comprises at least one metabolite selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kynurenine, quinolinic acid, N6
  • the substances found by this evaluation method can be widely used as foods, drinks, supplements, pharmaceuticals for improving the condition of AD.
  • the section of "A method for obtaining an index for the diagnosis of Alzheimer's disease (AD)" can be referred for details of the step of measuring a blood metabolite.
  • Kit The present invention provides a kit for obtaining an index for the diagnosis of Alzheimer's disease (AD) or assisting in the diagnosis of AD by using the methods of the present invention, comprising blood collection tubes and blood metabolite compounds as detection standard.
  • the kit of the present invention may comprise any constituent elements besides the blood collection tube and the like.
  • the blood metabolite compounds as detection standard can be selected from the group consisting of ergothioneine, glutathione disulfide, betaine, ATP, S-methyl-ergothioneine, trimethyl-histidine, trimethyl-tryptophan, trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine, trimethyl-tyrosine, caffeine, dimethyl-xanthine, uridine, S-adenosyl-methionine, NADP + , pantothenate, keto(iso)leucine, 2-hydroxybutyrate, gluconate, glutamine, phenylalanine, tyrosine, histidine, methionine, tryptophan, indoxyl-sulfate, kynurenine, quinolinic acid, N6-acetyl-lysine, pseudouridine, adenosine and dimethyl-guanosine.
  • AD Alzheimer’s disease
  • HE healthy elder
  • HY healthy young
  • Total 24 subjects comprised of 8 AD patients, 8 healthy elderly (HE) and 8 healthy young (HY) subjects participated the present study.
  • Table 1 shows their age, gender, BMI, and 2 types of dementia test data.
  • the mini mental health examination (MMSE) and Hasegawa’s dementia scale-revised (HDS-R) were employed to assess cognitive ability of AD subjects.
  • age and BMI are schematically shown.
  • Ages of AD subjects ranged from 75 to 88 yr and their BMIs varied from 14.8 to 24.5.
  • the 8 HE subjects had an age range from 67-80 with a BMI range from 17-25.
  • the 8 HY subjects were between 28 to 34 yr with BMI 21 to 24.
  • the majorities of 5 subgroups are RBC-enriched (Chaleckis et al., 2016). Amounts of metabolites were obtained by measuring peak areas for each compound (ion number; denoted by H, M and L, for high (10 8 ), medium (10 7 ) and low (10 6 ) levels, respectively). Total 33 metabolites that significantly differed statistically between AD and HE (indicated with asterisks) are listed with p-values (0.00016 ⁇ p ⁇ 0.05), and shown as AD markers in Table3. To estimate of false discovery rate, q-values were calculated.
  • AD/HE ratio>1.0 Seven compounds increased in the AD as shown in Table 3 (AD/HE ratio>1.0). Examples are indoxyl-sulfate (1.93), quinolinic acid (1.79), dimethyl-guanosine (1.45), pseudouridine (1.19), and kynurenine (1.12). These metabolites were reported to be toxic (Vanholder et al., 2003) (see below).
  • Trimethyl-tryptophan hypophorine
  • trimethyl-phenylalanine trimethyl-phenylalanine
  • glycerophosphocholine dodecanoyl-carnitine
  • dodecanoyl-carnitine Cristofano et al., 2016
  • trimethyl-tyrosine all of which contain trimethylammonium ions also declined, strongly suggesting that these trimethyl-ammonium compounds were characteristically declined possibly due to their instability or declined synthesis or import declined in human body in AD patients.
  • Pseudouridine, adenosine (Gonzalez-Dominguez et al., 2015), and dimethyl-guanosine are degradation products of RNAs present in urine and thought to be oxidized (Lee et al., 2007; Sander et al., 1986). Increases of these metabolites in AD are of interest, as some are reportedly toxic in the central nervous system (CNS) and may lead to impairment in the brain (Moroni, 1999; Rahman, 2009; Ruddick et al., 2006). Their increase in brain might be disadvantageous and detrimental.
  • PCA separates AD patients from healthy elderly (HE)
  • PCA principal component analysis
  • group A and group B compounds that contained trimethylated ammonium metabolites
  • group A and group C compounds comprised of RBC-enriched metabolites containing oxidoreductive (NADP + , glutathione disulfide), methyl-donor (S-adenosyl-methionine), binding to iron and zinc (pantothenate, gluconate) and energy carrier (ATP).
  • NADP + oxidoreductive
  • S-adenosyl-methionine methyl-donor binding to iron and zinc
  • ATP energy carrier
  • Group B and C metabolites are correlated within the groups, again validating the classification of B and C.
  • Group B metabolites are structurally related as they commonly contain trimethylated-ammonium group indicating that they are anti-oxidative.
  • Group C are not structurally related but three of them (NADP + , glutathione disulfide and ATP) implicated in redox and energy metabolism are highly correlated and enriched in RBC.
  • Gluconate also enriched in RBCs is known to bind to zinc and is correlated (0.56) to histidine that is known to bind to zinc.
  • Fourteen group D metabolites are enriched in plasma and, as shown in Table 3, are internally correlated such as among regular amino acids, betaine, nucleoside, keto(iso)leucine. For example, correlation between tryptophan and tyrosine is 0.72. Remaining compounds (2-hydroxybutyrate, dodecanoyl-carnitine) are hardly correlated.
  • Blood sample preparation Metabolomic samples were prepared as described previously. Briefly, venous blood samples were taken in to heparinized tubes before breakfast in the morning. Subjects were asked to ensure at least 8 hr of fasting prior to sampling. During fasting, they took water freely. Immediately, 0.2 mL of blood were quenched in 1.8 mL of 55% methanol at -40°C. Ten nmol each of HEPES and PIPES were added to each sample to serve as standards, After brief vortexing, samples were transferred to Amicon Ultra 10-kDa cut-off filters (Millipore, Billerica, MA, USA) to remove proteins and cellular debris. After sample concentration by vacuum evaporation, each sample was re-suspended in 40 ⁇ L of 50% acetonitrile, and 1 ⁇ L was used for each injection into the LC-MS system, as described.
  • LC-MS analysis Non-targeted LC-MS conditions were as described previously. Briefly, LC-MS data were obtained using an Ultimate 3000 DGP-3600RS HPLC system (Thermo Fisher Scientific, Waltham, MA, USA) coupled to an LTQ Orbitrap mass spectrometer (Thermo Fisher Scientific, Waltham, MA, USA). LC separation was performed on a ZIC-pHILIC column (Merck SeQuant, Umea, Sweden; 150 mm ⁇ 2.1 mm, 5 ⁇ m particle size).
  • Acetonitrile (A) and 10 mM ammonium carbonate buffer, pH 9.3 (B) were used as the mobile phase, with a linear gradient elution from 80-20% A over 30 min, at a flow rate of 100 ⁇ L/mL.
  • the mass spectrometer was operated in full-scan mode with a 100-1000 m/z scan rate and automatic data-dependent MS/MS fragmentation scans.
  • T-score [(sample peak area - average of population peak area) ⁇ 10/standard deviation of population peak area] + 50. Therefore, mean and standard deviation are 50 and 10, respectively.
  • AD markers quinolinic acid, kynurenine, adenosine, dimethyl-guanosine, indoxyl-sulfate and pseudouridine and N6-acetyl-lysine
  • AD markers quinolinic acid, kynurenine, adenosine, dimethyl-guanosine, indoxyl-sulfate and pseudouridine and N6-acetyl-lysine
  • AD marker metabolites were identified in whole blood of AD patients in comparison with HE.
  • Correlation analysis allowed us to categorize them into five (A-E) subgroups ( Figure 5). Seven group A compounds increased in AD patients, whereas 26 compounds (B-E sub-groups) decreased. In the literature, 11 of them had been already reported to be implicated in AD so that 22 are novel (indicated in Table 3). Seven A compounds contained oxidized compounds related to tryptophan degradation and nucleosides metabolism. Five of them are highly correlated.
  • group B compounds contained trimethyl ammonium moiety including ergothioneine, presumably acting as anti-oxidants, so that group B may act against group A, concomitantly against AD. Hence declining of group B compounds might also cause the progression of AD ( Figure 7). Similar result was obtained for frailty patients having mild cognitive impairment (Kameda et al., 2020). The decline of ergothioneine, S-methyl-ergothioneine, trimethyl-histidine, tryptophan and methionine was observed in frailty that is impaired in cognitive ability.
  • RBCs consisting of glutathione, NADP + , pantothenate, S-adenosyl-methionine, energy carrier and metal (Zinc) carrier. Their actions may directly or indirectly resist against AD.
  • Twelve group D compounds containing amino acids, nucleosides, choline, and carnitine are plasma enriched compounds and may underpin the actions of other metabolites for supply and degradation.
  • the last two E compounds are caffeine and dimethyl-xanthine (see below). Thus we consider these B-E metabolites are, if not all, involved in restraining AD development ( Figure 7).
  • Caffeine, an anti-oxidant purine, and its derivative, dimethyl-xanthine (highly 0.76 correlated) are reduced in AD subjects.
  • Their relationship to AD has been investigated, as caffeine may be a possible protectant against cognitive decline (Kolahdouzan and Hamadeh, 2017; Sc and Muralidhara, 2016), because of its anti-oxidative purine activity.
  • adenosine belonged to group A and increased its level 1.5-fold in AD.
  • Caffeine is known to be antagonist of adenosine (Ribeiro and Sebastiao, 2010). Hence it may be explained why caffeine was beneficial for AD patients (Flaten et al., 2014; Rahman, 2009), as caffeine opposes adenosine.
  • ATP concentrations were positively correlated (r>0.50) with 10 compounds in subgroups B, C, and D ( Figure 5) so that the level of ATP may affect or be affected by concentrations of many metabolites including oxidoreductive compounds, glutathione, betaine, ergothioneine, S-methyl-ergothioneine and amino acids such as glutamine, tryptophan.
  • oxidoreductive compounds glutathione, betaine, ergothioneine, S-methyl-ergothioneine and amino acids such as glutamine, tryptophan.
  • NADP + and glutathione disulfide may be synergistic to maintain the level of ATP and ergothioneine.
  • oxido-reductive NADP + , anti-oxidative glutathione and presumably neuroprotective trimethylated ammonium compounds may all together function in an overlapped fashion to sustain brain mitochondrial ATP production level against AD.
  • glycerophosphocholine and dodecanoyl-carnitine belonged to group D might also positively affect mitochondrial function.
  • Total 9 compounds possessing trimethylated ammonium ion are amphipathic compounds (possessing both hydrophilic and lipophilic properties) and forming basis of lipid polymorphism and all of them showed sharp decline in their abundance in AD subjects. The cause of decline might be due to ROS (reactive oxygen species) effect in AD patients’ brain. These compounds may have some similar role, such as amphipathic compounds forming the highly ordered assembled structure. In addition, these compounds are abundant (the level H, H-M, and H-L). They might act as major neuroprotectants or antioxidants in brain, and their levels are sensitive to both anti-oxidants and ROS. In addition, membrane defects have been observed in AD patients’ brain that degrade glycerophosphocholine (Nitsch et al., 1992).
  • Uremic toxins inhibit renal metabolic capacity through interference with glucuronidation and mitochondrial respiration.
  • MZmine 2 modular framework for processing, visualizing, and analyzing mass spectrometry-based molecular profile data.
  • Alzheimer's disease Using comprehensive metabolomics, we identified 5 groups of metabolites (A-E), 20 of which are novel, possibly useful for diagnosis and therapy of forms of dementia, such as Alzheimer's disease (AD). Seven compounds of Group A may act as neurotoxins, whereas compounds of Group B-E may protect the CNS (Central Nerve System) against oxidative stress, maintain energy reserves, supply nutrients and neuroprotective factors. Interventions for Alzheimer's disease metabolomic markers may be accomplished either by inhibiting Group A compounds or by supplementing Group B-E compounds in patients.
  • CNS Central Nerve System
  • the present invention based on these findings provides a novel method capable of simple and accurate diagnosis of Alzheimer's disease (AD).
  • the present invention also provides a novel method for obtaining an index for the diagnosis of Alzheimer’s disease (AD).
  • the present invention also provides a novel method for assisting in the diagnosis of AD in a subject, comprising measuring the amount of a specific blood metabolite in the subject.

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Abstract

Un objet de la présente invention est de fournir un nouveau procédé permettant d'obtenir de manière simple et précise un indice pour le diagnostic de la maladie d'Alzheimer (AD). La présente invention concerne un procédé pour obtenir un indice pour le diagnostic de la maladie d'Alzheimer (AD) par dosage de métabolite sanguin spécifique. La présente invention concerne également un procédé pour contribuer au diagnostic de la maladie d'Alzheimer par dosage de métabolite sanguin spécifique.
PCT/JP2021/036950 2020-10-06 2021-10-06 Procédé pour obtenir un indice pour le diagnostic de la maladie d'alzheimer (ad) WO2022075354A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008537111A (ja) * 2005-04-06 2008-09-11 ジアメッド−ユーロゲン エヌ．ヴェー． 精神医学的状態のための神経変性マーカー
JP2016535283A (ja) * 2013-10-24 2016-11-10 ナノソミックス・インコーポレイテッドＮａｎｏＳｏｍｉＸ， Ｉｎｃ． アルツハイマー病および他の神経変性障害のためのバイオマーカーおよび診断方法
JP2019509489A (ja) * 2016-03-11 2019-04-04 学校法人沖縄科学技術大学院大学学園 老化度を決定するための方法、装置、システム及びキット
WO2020203878A1 (fr) * 2019-03-29 2020-10-08 味の素株式会社 Procédé d'évaluation, procédé de calcul, dispositif d'évaluation, dispositif de calcul, programme d'évaluation, programme de calcul, support d'enregistrement, système d'évaluation et dispositif terminal d'accumulation de bêta-amyloïde dans le cerveau
WO2021039941A1 (fr) * 2019-08-30 2021-03-04 ニプロ株式会社 Procédé de détermination de la démence de type alzheimer ou d'un trouble cognitif léger

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008537111A (ja) * 2005-04-06 2008-09-11 ジアメッド−ユーロゲン エヌ．ヴェー． 精神医学的状態のための神経変性マーカー
JP2016535283A (ja) * 2013-10-24 2016-11-10 ナノソミックス・インコーポレイテッドＮａｎｏＳｏｍｉＸ， Ｉｎｃ． アルツハイマー病および他の神経変性障害のためのバイオマーカーおよび診断方法
JP2019509489A (ja) * 2016-03-11 2019-04-04 学校法人沖縄科学技術大学院大学学園 老化度を決定するための方法、装置、システム及びキット
WO2020203878A1 (fr) * 2019-03-29 2020-10-08 味の素株式会社 Procédé d'évaluation, procédé de calcul, dispositif d'évaluation, dispositif de calcul, programme d'évaluation, programme de calcul, support d'enregistrement, système d'évaluation et dispositif terminal d'accumulation de bêta-amyloïde dans le cerveau
WO2021039941A1 (fr) * 2019-08-30 2021-03-04 ニプロ株式会社 Procédé de détermination de la démence de type alzheimer ou d'un trouble cognitif léger

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