WO2018117064A1 - Procédé de test de maladie impliquant un état dépressif - Google Patents

Procédé de test de maladie impliquant un état dépressif Download PDF

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WO2018117064A1
WO2018117064A1 PCT/JP2017/045409 JP2017045409W WO2018117064A1 WO 2018117064 A1 WO2018117064 A1 WO 2018117064A1 JP 2017045409 W JP2017045409 W JP 2017045409W WO 2018117064 A1 WO2018117064 A1 WO 2018117064A1
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concentration
concentration ratio
detection agent
group
acid
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PCT/JP2017/045409
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English (en)
Japanese (ja)
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哲郎 大森
周助 沼田
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国立大学法人徳島大学
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Publication of WO2018117064A1 publication Critical patent/WO2018117064A1/fr

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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
    • 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
    • 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
    • G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors

Definitions

  • the present invention relates to a method for examining a disease exhibiting a depression state, more specifically, a method for examining a disease exhibiting a depression state using a metabolite as an index.
  • Depression is a state involving depression, motivation, interest, mental activity, etc., irritability, decreased appetite, insomnia, persistent sadness, and anxiety.
  • Major depression which is a typical disease exhibiting this depression, is a general mental disorder, and the lifetime prevalence is said to be 16.2%.
  • Various hypotheses have been proposed for the neurobiological mechanism of depression, but there are many unclear points about its molecular mechanism.
  • Diagnosis of depression is usually performed according to criteria such as international disease classification (ICD-10, etc.), mental disorder diagnosis and statistical manual (DSM-IV, etc.) based on clinical interviews and medical records.
  • ICD-10 international disease classification
  • DSM-IV mental disorder diagnosis and statistical manual
  • Patent Document 1 reports that a metabolite serving as a molecular marker for depression was found by comparing non-depressed persons with depressed patients (mostly being treated with medication). However, since drug administration causes metabolic changes, the metabolome in depressed patients undergoing medication may not reflect the natural metabolome of depression.
  • An object of the present invention is to provide a method for examining a disease exhibiting depression using a molecular marker.
  • this invention makes it a subject to provide the test
  • methionine-methionine sulfoxide ratio methionine-methionine sulfoxide ratio, quinurelin-tryptophan ratio, glutamine-glutamate ratio, methionine sulfoxide, glutamic acid, aspartic acid, phosphorylcholine, glyceric acid in a body fluid collected from a subject , 5-oxoproline, 2-aminoisobutyric acid, N-methylnorsalinol, threonic acid, glycerophosphocholine, cystine, inositol monophosphate, glutamine, 3-phosphoglycerate, uridine, thiaproline, cis-ascot acid, By using at least one selected from the group consisting of 1-methyladenosine, glucose-6-phosphate, 5-methoxyindoleacetic acid, S-methylcysteine, and isethionic acid as an index, a disease that exhibits depression is determined. Find what you can
  • Item 1 A method for testing a disease presenting with depression, comprising: (1a) detecting at least one concentration ratio selected from the group consisting of a methionine-methionine sulfoxide concentration ratio, a quinurelin-tryptophan concentration ratio, and a glutamine-glutamic acid concentration ratio in a body fluid collected from a subject; (1b) From methionine sulfoxide, glutamic acid, aspartic acid, phosphorylcholine, glyceric acid, 5-oxoproline, 2-aminoisobutyric acid, N-methylnorsalolinol, threonic acid, and glycerophosphocholine in body fluids collected from the subject Detecting the concentration of at least one compound selected from the group consisting of: (1c) cystine, inositol monophosphate, glutamine, 3-phosphoglycerate, uridine, thiaproline, cis in a body fluid
  • At least one concentration ratio selected from the group consisting of the methionine / methionine sulfoxide concentration ratio, the quinurelin / tryptophan concentration ratio, and the glutamine / glutamic acid concentration ratio detected in the step (1a) is set in advance.
  • a step of determining that the subject is suffering from a disease exhibiting a depression when the cut-off value is less than or equal to (2a ′′) At least one concentration ratio selected from the group consisting of the methionine sulfoxide / methionine concentration ratio, the tryptophan / quinurelin concentration ratio, and the glutamic acid / glutamine concentration ratio detected in the step (1a) is set in advance.
  • the subject is selected from the group consisting of determining that the subject is suffering from a disease exhibiting depression Item 2.
  • the concentration ratio to be detected in the step (1a) is at least one concentration ratio selected from the group consisting of a methionine-methionine sulfoxide concentration ratio and a glutamine-glutamic acid concentration ratio
  • the concentration of the compound to be detected in the step (1b) is a concentration of at least one compound selected from the group consisting of methionine sulfoxide, glutamic acid, and aspartic acid
  • the concentration of the compound is a concentration of at least one compound selected from the group consisting of cystine and inositol monophosphate; Item 3.
  • the concentration of the compound to be detected in the step (1b) is a concentration of at least one compound selected from the group consisting of N-methylnorsalsolinol, threonic acid, and glycerophosphocholine
  • the concentration of the compound to be detected in (1c) is inositol monophosphate, glutamine, 3-phosphoglycerate, uridine, thiaproline, 1-methyladenosine, glucose-6-phosphate, 5-methoxyindoleacetic acid, S- A concentration of at least one compound selected from the group consisting of methylcysteine and isethionic acid; Item 2.
  • the concentration of the compound to be detected in the step (1c) is a glutamine concentration
  • (3a ′) At least one concentration ratio selected from the group consisting of the methionine / methionine sulfoxide concentration ratio, the quinurelin / tryptophan concentration ratio, and the glutamine / glutamic acid concentration ratio detected in the step (1a) is the same.
  • the process of (4a ′) At least one concentration ratio selected from the group consisting of the methionine / methionine sulfoxide concentration ratio, the quinurelin / tryptophan concentration ratio, and the glutamine / glutamic acid concentration ratio detected in the step (1a) is set in advance.
  • At least one concentration ratio selected from the group consisting of the methionine sulfoxide / methionine concentration ratio, the tryptophan / quinurelin concentration ratio, and the glutamic acid / glutamine concentration ratio detected in the step (1a) is set in advance. Determining that the subject has not received medication for depressive symptoms when the cut-off value is greater than or equal to the cutoff value, and (4c) the concentration detected in step (1c) is a preset cutoff Determining that the subject has not received medication for depressive symptoms if the value is less than or equal to the value; Item 2.
  • Item 1 comprising at least one step selected from the group consisting of: Item 6.
  • Item 6. The method according to any one of Items 1 to 5, wherein the disease exhibiting a depression state to be examined is at least one selected from the group consisting of major depression, bipolar disorder, and schizophrenia.
  • Item 7. Item 6.
  • Item 8. Item 8. The method according to any one of Items 1 to 7, wherein the body fluid is at least one selected from the group consisting of whole blood, plasma, serum, and cerebrospinal fluid.
  • (1C) cystine detection agent inositol monophosphate detection agent, glutamine detection agent, 3-phosphoglycerate detection Agent, uridine detector, thiaproline detector, cis-ascot acid detector, 1-methyladen
  • the detection agent in the detection agent (1B) is at least one detection agent selected from the group consisting of an N-methylnorsalolinol detection agent, a threonic acid detection agent, and a glycerophosphocholine detection agent
  • Detection agent in detection agent (1C) is inositol monophosphate detection agent, glutamine detection agent, 3-phosphoglycerate detection agent, uridine detection agent, thiaproline detection agent, 1-methyladenosine detection agent, glucose-6-phosphate
  • Item 10 The test drug according to Item 9.
  • this invention also includes the following aspect as another aspect: Item 11.
  • a method for assisting in the detection of a disease presenting with depression (1a) detecting at least one concentration ratio selected from the group consisting of a methionine-methionine sulfoxide concentration ratio, a quinurelin-tryptophan concentration ratio, and a glutamine-glutamic acid concentration ratio in a body fluid collected from a subject; (1b) From methionine sulfoxide, glutamic acid, aspartic acid, phosphorylcholine, glyceric acid, 5-oxoproline, 2-aminoisobutyric acid, N-methylnorsalolinol, threonic acid, and glycerophosphocholine in body fluids collected from the subject Detecting the concentration of at least one compound selected from the group consisting of: (1c) cystine, inositol monophosphate, glutamine, 3-phosphoglycerate, uridine, thiaproline, cis in
  • a method for detecting a molecular marker in a subject (1a) detecting at least one concentration ratio selected from the group consisting of a methionine-methionine sulfoxide concentration ratio, a quinurelin-tryptophan concentration ratio, and a glutamine-glutamic acid concentration ratio in a body fluid collected from a subject; (1b) From methionine sulfoxide, glutamic acid, aspartic acid, phosphorylcholine, glyceric acid, 5-oxoproline, 2-aminoisobutyric acid, N-methylnorsalolinol, threonic acid, and glycerophosphocholine in body fluids collected from the subject Detecting the concentration of at least one compound selected from the group consisting of: (1c) cystine, inositol monophosphate, glutamine, 3-phosphoglycerate, uridine, thiaproline, cis in a body fluid collected from a subject -Detecting the concentration of
  • a method for diagnosing and treating a disease presenting depression in a subject comprising: (1a) detecting at least one concentration ratio selected from the group consisting of a methionine-methionine sulfoxide concentration ratio, a quinurelin-tryptophan concentration ratio, and a glutamine-glutamic acid concentration ratio in a body fluid collected from a subject; (1b) From methionine sulfoxide, glutamic acid, aspartic acid, phosphorylcholine, glyceric acid, 5-oxoproline, 2-aminoisobutyric acid, N-methylnorsalolinol, threonic acid, and glycerophosphocholine in body fluids collected from the subject Detecting the concentration of at least one compound selected from the group consisting of: (1c) cystine, inositol monophosphate, glutamine, 3-phosphoglycerate, uridine, thiaproline, cis in a body fluid collected from a subject -Detectid
  • At least one concentration ratio selected from the group consisting of the methionine sulfoxide / methionine concentration ratio, the tryptophan / quinurelin concentration ratio, and the glutamic acid / glutamine concentration ratio detected in the step (1a) is set in advance.
  • a step of determining that the subject is suffering from a disease exhibiting a depression when the cut-off value is greater than or equal to (2b) a step of determining that the subject is suffering from a disease exhibiting a depression when the concentration detected in the step (1b) is not less than a preset cutoff value; and (2c )
  • the subject is selected from the group consisting of determining that the subject is suffering from a disease exhibiting depression At least one process;
  • At least one detection agent selected from the group consisting of a combination of a methionine detection agent and a methionine sulfoxide detection agent, a combination of a glutamine detection agent and a glutamic acid detection agent, and a combination of a quinurelin detection agent and a tryptophan detection agent
  • (1C) cystine detection agent inositol monophosphate detection agent, glutamine detection agent, 3-phosphoglycerate detection Agent, uridine detector, thiaproline detector, c
  • Item 15 To test for a disease that presents with depression, (1A) At least one detection agent selected from the group consisting of a combination of a methionine detection agent and a methionine sulfoxide detection agent, a combination of a glutamine detection agent and a glutamic acid detection agent, and a combination of a quinurelin detection agent and a tryptophan detection agent , (1B) methionine sulfoxide detector, glutamic acid detector, aspartic acid detector, phosphorylcholine detector, glyceric acid detector, 5-oxoproline detector, 2-aminoisobutyric acid detector, N-methylnorsalolinol detector, At least one detection agent selected from the group consisting of a threonate detection agent and a glycerophosphocholine detection agent, and (1C) cystine detection agent, inositol monophosphate detection agent, glutamine detection agent, 3-phosphoglycerate detection Agent, uridine detector, thiaproline detector
  • Item 16 For the manufacture of a test drug for diseases that exhibit depression, (1A) At least one detection agent selected from the group consisting of a combination of a methionine detection agent and a methionine sulfoxide detection agent, a combination of a glutamine detection agent and a glutamic acid detection agent, and a combination of a quinurelin detection agent and a tryptophan detection agent , (1B) methionine sulfoxide detector, glutamic acid detector, aspartic acid detector, phosphorylcholine detector, glyceric acid detector, 5-oxoproline detector, 2-aminoisobutyric acid detector, N-methylnorsalolinol detector, At least one detection agent selected from the group consisting of a threonate detection agent and a glycerophosphocholine detection agent, and (1C) cystine detection agent, inositol monophosphate detection agent, glutamine detection agent, 3-phosphoglycerate detection Agent, uridine detector, thia
  • the present invention it is possible to provide a method for examining a disease exhibiting a depression using a molecular marker. According to the test method of the present invention, it is possible to test a disease exhibiting a depression state more accurately (with higher sensitivity and / or with higher specificity). Moreover, according to this invention, the test
  • the present invention is a method for testing a disease exhibiting a depression, and detects a specific compound concentration and / or concentration ratio in a body fluid collected from a subject.
  • the present invention relates to a method including a step (step (1)) (in this specification, sometimes referred to as “inspection method of the present invention”). This will be described below.
  • the “disease exhibiting depression” to be examined is not particularly limited as long as it is a disease that exhibits a depressive condition constantly or for a certain period of time. Specific examples of the disease exhibiting a depression state include major depression, bipolar disorder, schizophrenia, and the like, and preferably major depression.
  • the subject is a control organism of the test method of the present invention, and its species is not particularly limited.
  • Examples of the biological species of the subject include various mammals such as humans, monkeys, mice, rats, dogs, cats, rabbits, and preferably humans.
  • the state of the subject is not particularly limited.
  • specimens include specimens that are unclear whether or not they are suffering from a disease that exhibits a depressive state, samples that have no history of suffering from a disease that exhibits a depressive state, and who have a history of suffering from a disease that exhibits a depressive state, and have received treatment for the disease. Samples that have already been determined to be affected (or not affected) by a disease that exhibits a depressed state by other determination methods.
  • Body fluid is not particularly limited.
  • Examples of the body fluid include whole blood, serum, plasma, cerebrospinal fluid, saliva, joint fluid, urine, tissue fluid, sweat, tears, etc., preferably whole blood, serum, plasma, cerebrospinal fluid, more preferably Examples include whole blood, serum, and plasma.
  • Body fluids may be used alone or in combination of two or more.
  • Body fluid can be collected from the subject by methods known to those skilled in the art.
  • whole blood can be collected by blood collection using a syringe or the like.
  • blood collection is preferably performed by medical personnel such as doctors and nurses.
  • Serum is a part obtained by removing blood cells and a specific blood coagulation factor from blood, and can be obtained, for example, as a supernatant after coagulating the blood.
  • Plasma is a portion obtained by removing blood cells from blood, and can be obtained, for example, as a supernatant when subjected to centrifugation under conditions that do not coagulate blood.
  • the detection target of step (1) is methionine-methionine sulfoxide concentration ratio, quinurelin-tryptophan concentration ratio, glutamine-glutamic acid concentration ratio, methionine sulfoxide concentration, glutamic acid concentration, aspartic acid concentration, phosphorylcholine concentration, glyceric acid concentration, 5-oxoproline concentration Concentration, 2-aminoisobutyric acid concentration, N-methylnorsalolinol concentration, threonic acid concentration, glycerophosphocholine concentration, cystine concentration, inositol monophosphate concentration, glutamine concentration, 3-phosphoglycerate concentration, uridine concentration, thiaproline concentration And at least one selected from the group consisting of cis-ascot acid concentration, 1-methyladenosine concentration, glucose-6-phosphate concentration, 5-methoxyindoleacetic acid concentration, S-methylcysteine concentration, and isethionic acid.
  • “Concentration” is not limited to absolute concentration, but is obtained by standardizing the raw data measured to know the relative concentration, weight per unit volume, and absolute concentration (for example, the peak area of the graph obtained by CE-MS measurement). Value).
  • Methionine-methionine sulfoxide concentration ratio, quinurelin-tryptophan concentration ratio, and glutamine-glutamic acid concentration ratio each include the case where either of the two concentrations constituting the ratio is the denominator. That is, the methionine-methionine sulfoxide concentration ratio includes methionine / methionine sulfoxide concentration ratio and methionine sulfoxide / methionine concentration ratio, and the quinurelin-tryptophan concentration ratio includes the quinurelin / tryptophan concentration ratio and the tryptophan / quinurelin concentration ratio.
  • the glutamine-glutamic acid concentration ratio includes a glutamine / glutamic acid concentration ratio and a glutamic acid / glutamine concentration ratio.
  • a methionine-methionine sulfoxide concentration ratio preferably, a glutamine-glutamic acid concentration ratio, a methionine sulfoxide concentration, a glutamic acid concentration, an aspartic acid concentration, a cystine concentration
  • examples include inositol monophosphate concentration, glutamine concentration, and 3-phosphoglycerate concentration, and more preferably methionine-methionine sulfoxide concentration ratio, methionine sulfoxide concentration, and cystine concentration.
  • the detection target is preferably a methionine-methionine sulfoxide concentration ratio, a quinurelin-tryptophan concentration ratio, a glutamine-glutamic acid concentration ratio, an N-methylnorsalolinol concentration, a threonic acid concentration, a glycerophosphocholine.
  • Concentration, inositol monophosphate concentration, glutamine concentration, 3-phosphoglycerate concentration, uridine concentration, thiaproline concentration, 1-methyladenosine concentration, glucose-6-phosphate concentration, 5-methoxyindoleacetic acid concentration, S-methylcysteine concentration More preferably, methionine-methionine sulfoxide concentration ratio, quinurelin-tryptophan concentration ratio, glutamine-glutamic acid concentration ratio, N-methylnorsalolinol concentration, threonic acid concentration, inositol monophosphate concentration, thiapro Emissions concentration, 1-methyl adenosine concentration, S- methyl cysteine concentrations include isethionic acid concentration.
  • the detection target is preferably at least one redox metabolite selected from the group consisting of glutamic acid concentration, glutamine concentration, aspartic acid concentration, and methionine sulfoxide concentration ( Metabolites that are susceptible to redox).
  • Step (1) can be divided into the following three types of steps (step (1a), step (1b), and step (1c)) depending on the type of detection target: (1a) detecting at least one concentration ratio selected from the group consisting of a methionine-methionine sulfoxide concentration ratio, a quinurelin-tryptophan concentration ratio, and a glutamine-glutamic acid concentration ratio in a body fluid collected from a subject; (1b) From methionine sulfoxide, glutamic acid, aspartic acid, phosphorylcholine, glyceric acid, 5-oxoproline, 2-aminoisobutyric acid, N-methylnorsalolinol, threonic acid, and glycerophosphocholine in body fluids collected from the subject Detecting the concentration of at least one compound selected from the group consisting of: (1c) cystine, inositol monophosphate, glutamine, 3-phosphoglycerate, uridine, thiaproline, cis
  • step (1) only one of these three steps may be performed, any two steps may be combined, or all three steps may be performed. In the step (1), when two or more types of steps are performed, they may be performed separately or simultaneously (as one step).
  • Step (1a) is a step of detecting the ratio of compound concentrations.
  • the detection target in the step (1a) is preferably a methionine-methionine sulfoxide concentration ratio or a glutamine-glutamic acid concentration ratio, more preferably a methionine-methionine concentration from the viewpoint that a disease exhibiting a depression can be more accurately examined.
  • a sulfoxide concentration ratio is mentioned.
  • Step (1b) is a step of detecting the concentration of a compound that tends to have a higher concentration in the body fluid of a subject suffering from a disease that exhibits depression.
  • the detection target in the step (1b) is preferably a methionine sulfoxide concentration, a glutamic acid concentration, and an aspartic acid concentration, more preferably a methionine sulfoxide concentration, from the viewpoint that a disease exhibiting a depression state can be more accurately examined. It is done.
  • the detection target in the step (1b) is preferably N-methylnorsalolinol concentration, threonic acid concentration, glycerophosphocholine concentration, more preferably N-methylnorsallolinol from another viewpoint. Concentration and threonic acid concentration.
  • Step (1c) is a step of detecting the concentration of a compound whose concentration tends to be lower in the body fluid of a subject suffering from a disease that exhibits depression.
  • the detection target in the step (1c) is preferably a cystine concentration, inositol monophosphate concentration, glutamine concentration, 3-phosphoglycerate concentration, from the viewpoint that a disease exhibiting a depression state can be more accurately examined. More preferred are cystine concentration and inositol monophosphate concentration, and more preferred is cystine concentration.
  • the detection target in the step (1c) is preferably from another viewpoint, preferably inositol monophosphate concentration, glutamine concentration, 3-phosphoglycerate concentration, uridine concentration, thiaproline concentration, 1-methyladenosine concentration, glucose- Examples include 6-phosphate concentration, 5-methoxyindoleacetic acid concentration, S-methylcysteine concentration, isethionate concentration, more preferably inositol monophosphate concentration, thiaproline concentration, 1-methyladenosine concentration, S-methylcysteine concentration, Isethionic acid concentration.
  • the detection target in step (1) may be only one type, or a combination of two or more types. By combining more detection targets (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more), it is possible to more accurately test for diseases that exhibit depression. It becomes possible to do.
  • the method for detecting the compound concentration and / or concentration ratio is not particularly limited as long as it is a method capable of quantifying the concentration and / or concentration ratio in the body fluid collected from the subject.
  • the method for example, it can be appropriately selected from known methods according to the type of detection target.
  • Specific examples of the method include capillary electrophoresis-mass spectrometry (CE-MS), high performance liquid chromatography-mass spectrometry (LC-MS), and gas chromatography-mass spectrometry (GC-MS).
  • capillary electrophoresis-mass spectrometry (CE-MS) is preferable from the viewpoint that a plurality of types of compounds can be measured simultaneously.
  • CE-MS capillary electrophoresis-mass spectrometry
  • Body fluid is mixed with alcohol solvent to stop the reaction of the enzyme contained in the body fluid.
  • the alcohol solvent used is preferably methanol.
  • the organic phase containing the fat-soluble substance such as phospholipid is removed by adding and mixing the organic solvent and water to the body fluid that has stopped the enzyme reaction, and mixing the resulting mixture.
  • the type of the organic solvent to be used is not particularly limited as long as it is an organic solvent that can be phase-separated from water, but dichloromethane, chloroform, dichloroethane, and the like are preferable, and chloroform is particularly preferable. It is preferable to remove proteins from the obtained aqueous phase.
  • the method for removing the protein is not particularly limited, but for example, ultrafiltration is preferable.
  • the method for distilling off the solvent is not particularly limited, such as natural drying, reduced pressure drying, or reduced pressure centrifugal drying, but reduced pressure centrifugal drying is preferred in view of the fact that it can be carried out easily in a short time.
  • the sample used for CE-MS measurement may contain an internal standard substance that serves as a measurement standard for the electrophoresis time, content, etc. of the compound that is a diagnostic marker.
  • the internal standard substance is not particularly limited as long as it does not affect the efficiency of electrophoresis and mass spectrometry of the compound that is a diagnostic marker.
  • methionine sulfone, 10-camphorsulfonic acid (CSA) Etc for example, methionine sulfone, 10-camphorsulfonic acid (CSA) Etc.
  • the capillary for capillary electrophoresis is preferably a fused silica capillary.
  • the inner diameter of the capillary is preferably 100 ⁇ m or less, and particularly preferably 50 ⁇ m or less, in view of the improvement in resolution.
  • the total length of the capillary is preferably 50 cm to 150 cm.
  • the method for separating ionized sample molecules in mass spectrometry is not particularly limited.
  • the separation method include a time-of-flight type (TOF), a magnetic field deflection type, a quadrupole type, an ion trap type, a Fourier transform ion cyclotron resonance type, and a tandem type, and preferably a time-of-flight type.
  • the content of the compound having m / z of the target compound in the fraction identified as containing the compound that is the target diagnostic marker is measured as a peak area.
  • This peak area can be standardized by taking a ratio with the peak area of the internal standard substance.
  • the absolute concentration of the compound that is the target diagnostic marker contained in the collected blood can be determined from the measured peak area.
  • This calibration curve is preferably prepared not by the standard solution method but by the standard addition method.
  • test method of the present invention including the step (1), it is possible to provide a compound concentration and / or concentration ratio which is a detection index of a disease exhibiting a depression state, thereby detecting a disease exhibiting a depression state and the like. Can assist.
  • the inspection method of the present invention further includes, as one aspect, (2a ′) At least one concentration ratio selected from the group consisting of the methionine / methionine sulfoxide concentration ratio, the quinurelin / tryptophan concentration ratio, and the glutamine / glutamic acid concentration ratio detected in step (1a) is preset.
  • a step of determining that the subject is suffering from a disease exhibiting a depression when the cut-off value or less, (2a ") At least one concentration ratio selected from the group consisting of the methionine sulfoxide / methionine concentration ratio, tryptophan / quinurelin concentration ratio, and glutamic acid / glutamine concentration ratio detected in step (1a) is preset.
  • the step (step (2)) is preferably included. According to the test method of the present invention including the step (2), it is possible to detect a disease exhibiting a depression state. Moreover, since the test method of the present invention can detect a disease exhibiting a depression more accurately, the test method of the present invention including this step (2) can further reduce erroneous determination. .
  • Step (2) may be appropriately selected according to the detection target of step (1).
  • the detection target in step (1) is only the methionine / methionine sulfoxide concentration ratio
  • only step (2a ′) may be selected in step (2), and the detection target in step (1) is methionine.
  • / Methionine sulfoxide concentration ratio (detection target of step (1a))
  • tryptophan / quinurelin concentration ratio (detection target of step (1a)
  • methionine sulfoxide concentration detection target of step (1b)
  • cystine step (1c)
  • step (2) all of step (2a), step (2a ′′), step (2b), and step (2c) may be employed.
  • the cut-off value can be appropriately set by those skilled in the art from the viewpoint of sensitivity, specificity, positive predictive value, negative predictive value, etc., and is collected, for example, from a subject not suffering from a disease that exhibits depression.
  • the average value, the percentile value, or the minimum value of the concentration and / or concentration ratio of the detection target compound in the collected body fluid can be used. More specifically, for example, the detection target compound concentration and / or concentration ratio in a body fluid collected from a subject suffering from a disease exhibiting a depression state and a subject not suffering from a disease exhibiting a depression state It can be set by measuring and performing statistical analysis based on analysis of a receiver operating characteristic (Receiver Operating Characteristic, ROC) curve using the measured value.
  • Receiveiver Operating Characteristic Receiveiver Operating Characteristic
  • the cutoff value is, for example, 60% or more, preferably 70% or more, more preferably 80% or more, still more preferably 90% or more, and still more preferably 95% or more. It is possible to adopt a value that is at least%.
  • the cut-off value can be set, for example, between the 10th and 90th percentile values of the detection target compound concentration and / or concentration ratio in a body fluid collected from a subject not suffering from a disease that exhibits depression. .
  • the inspection method of the present invention further includes, as one aspect, (3a ′) a subject having at least one concentration ratio selected from the group consisting of the methionine / methionine sulfoxide concentration ratio, the quinurelin / tryptophan concentration ratio, and the glutamine / glutamate concentration ratio detected in step (1a)
  • a step of determining that the depression of the subject is improved when the concentration ratio is lower than the concentration ratio in the body fluid collected before a certain period of time (3c) a step of determining that the depression state of the subject is improved when the concentration detected in step (1c) is higher than the concentration in the body fluid collected from the same subject before a certain period of time; It is preferable to include at least one step (step (3)) selected from the group consisting of: According to the test method of the present invention including the step (3), it is possible to determine the therapeutic effect of a disease exhibiting a depression state.
  • the detection target in the step (1c) is the glutamine concentration.
  • Step (3) may be appropriately selected according to the detection target of step (1).
  • the detection target in step (1) is only the methionine / methionine sulfoxide concentration ratio
  • only step (3a ′) may be selected in step (3), and the detection target in step (1) is methionine.
  • / Methionine sulfoxide concentration ratio (detection target of step (1a)), tryptophan / quinurelin concentration ratio (detection target of step (1a)), and glutamine concentration (detection target of step (1c)
  • step (3 ) All of the steps (3a), (3a ′′), and (3c) may be employed.
  • the “certain period” is not particularly limited as long as the concentration of the detection target compound and / or the concentration ratio can be changed within the same specimen.
  • the period is about 1 month to 10 years, 2 months to 5 years, 3 months to 2 years, 4 months to 1 year.
  • the level of “high” is not particularly limited, but the concentration and / or concentration ratio of the detection target compound detected in step (1) is the detection target compound concentration and / or concentration in the body fluid collected from the same subject before a certain period of time. Alternatively, it is exemplified that the concentration ratio is 120% or more, 150% or more, 200% or more, or 300% or more.
  • the level of “low” is not particularly limited, but the concentration and / or concentration ratio of the detection target compound detected in step (1) is the detection target compound concentration and / or concentration in the body fluid collected from the same subject before a certain period of time. Alternatively, it is exemplified that the concentration ratio is 90% or less, 70% or less, 50% or less, or 30% or less.
  • the inspection method of the present invention further includes, as one aspect, (4a ′) At least one concentration ratio selected from the group consisting of the methionine / methionine sulfoxide concentration ratio, the quinurelin / tryptophan concentration ratio, and the glutamine / glutamic acid concentration ratio detected in step (1a) is preset. Determining that the subject is not receiving medication for depression when the cut-off value or less, (4a ′′) At least one concentration ratio selected from the group consisting of the methionine sulfoxide / methionine concentration ratio, the tryptophan / quinurelin concentration ratio, and the glutamic acid / glutamine concentration ratio detected in step (1a) is preset.
  • step (4) selected from the group consisting of:
  • the detection target in the step (1c) is the glutamine concentration.
  • Process (4) may be appropriately selected according to the detection target of process (1).
  • the detection target in the step (1) is only the methionine / methionine sulfoxide concentration ratio
  • only the step (4a ′) may be selected in the step (4), and the detection target in the step (1) is methionine.
  • the ratio is / methionine sulfoxide concentration ratio (detection target of step (1a)), tryptophan / quinurelin concentration ratio (detection target of step (1a)), and glutamine concentration (detection target of step (1c)
  • step (4 ) All of the steps (4a), (4a ′′) and (4c) may be employed.
  • the cut-off value can be appropriately set by a person skilled in the art from the viewpoint of sensitivity, specificity, positive predictive value, negative predictive value, etc.
  • the detection target compound concentration and / or concentration ratio average value, percentile value, or minimum value in a body fluid collected from a subject undergoing treatment can be used. More specifically, for example, a subject who is suffering from a disease that exhibits a depressive condition and has not received medication for a depressive symptom, and a patient who is suffering from a disease that exhibits a depressive condition and that has undergone medicinal treatment for a depressive symptom.
  • the cutoff value is, for example, 60% or more, preferably 70% or more, more preferably 80% or more, still more preferably 90% or more, and still more preferably 95% or more. It is possible to adopt a value that is at least%.
  • the cut-off value is, for example, 10 to 90 of the concentration and / or concentration ratio of the detection target compound in a body fluid collected from a subject suffering from a disease exhibiting a depressive state and receiving medication for depression. Can be set between percentile values.
  • test method of the present invention including the diagnosis step (2) with higher accuracy of the disease exhibiting the depression state is determined to have the subject suffering from the disease exhibiting the depression state
  • the test method of the present invention Further, by combining a process of applying a diagnosis by a doctor of a disease exhibiting a depression state, a disease exhibiting a depression state can be diagnosed with higher accuracy.
  • the test method of the present invention can detect a disease exhibiting a depression state more accurately, combining the above steps with the test method of the present invention more accurately states that “the patient is suffering from a disease exhibiting a depression state”. Can be diagnosed.
  • the subject When it is determined by the test method of the present invention that includes the treatment step (2a) for a disease exhibiting a depression state, the subject is suffering from a disease exhibiting a depression state. It is possible to treat the disease of the subject by performing a step of treating the disease on the subject determined to be. In addition, since the test method of the present invention can more accurately detect a disease exhibiting a depression state, a subject suffering from a disease exhibiting a depression state can be more reliably detected by combining the above steps with the test method of the present invention. It can be treated, and the possibility of erroneous treatment for a subject not suffering from the disease can be further reduced.
  • the method for treating a disease exhibiting a depression is not particularly limited, but a typical example is medication.
  • the drug used for the drug treatment is not particularly limited, but for example, tricyclic antidepressants such as amoxapine, nortriptyline, amitriptyline, trimipramine, imipramine, clomipramine, dosrepin, lofepramine; tetracyclic antidepressants such as maprotiline, cetipitrine, mianserin Drugs: Selective serotonin reuptake inhibitors (SSRI) such as fluvoxamine, paroxetine, sertraline, escitalopram; Serotonin and noradrenaline reuptake inhibitors (SNRI) such as milnacipran, duloxetine, venlafaxine; Noradrenergic agonists such as mirtazapine ⁇ Specific serotonergic antidepressants (NaSSA); Triazolopyridine antidepressants (SARI) such as
  • the present invention relates to (1A) a combination of a methionine detection agent and a methionine sulfoxide detection agent, a combination of a glutamine detection agent and a glutamic acid detection agent, and a kynurellin detection agent and tryptophan detection.
  • the present invention relates
  • the detection agent is not particularly limited, but for example, various commercially available agents can be used. Examples of detection agents are capillary electrophoresis-mass spectrometry (CE-MS), high performance liquid chromatography-mass spectrometry (LC-MS), gas chromatography-mass spectrometry (GC-MS), and NMR analysis.
  • CE-MS capillary electrophoresis-mass spectrometry
  • LC-MS high performance liquid chromatography-mass spectrometry
  • GC-MS gas chromatography-mass spectrometry
  • NMR analysis NMR analysis
  • the detection agent can be based on the principle of a known measurement method such as a measurement method using only gas, a measurement method using only gas chromatography, or a measurement method using only a mass spectrometer.
  • the detection agent may be in the form of a composition containing components necessary for detection.
  • the composition may contain other components as necessary. Examples of other components include a base, a carrier, a solvent, a dispersant, an emulsifier, a buffer, a stabilizer, an excipient, a binder, a disintegrant, a lubricant, a thickener, a moisturizer, a colorant, and a fragrance. And chelating agents.
  • the detection agent may be in the form of a kit containing components necessary for detection.
  • the kit may contain instruments, reagents, and the like that can be used to carry out the inspection method of the present invention.
  • the detection agent is not particularly limited, but various commercially available ones can be used.
  • test agent of the present invention may be in the form of a composition or in the form of a kit, similarly to the detection agent.
  • control group in which the major depression group (untreated treatment) and the number of specimens, sex ratio, and average age were matched was also used as the subject.
  • Table 1 shows the composition of each group as the subject. P values were calculated by chi-square test and student T-test.
  • CE-TOFS measurement> Venous blood was collected from the subject, and the blood was collected in a blood collection tube containing EDTA, which is a chelating agent. The blood was centrifuged (2000 g, 10 minutes), and the resulting supernatant was collected as plasma and stored at ⁇ 80 ° C. until used for analysis.
  • the aqueous phase was transferred to an ultrafiltration filter (Millipore, Ultrafree-MCPBCC, centrifugal filter unit, 5 kDa), and centrifugally filtered (4 ° C., 9,100 ⁇ g, 2 to 4 hours) until the solution in the filter cup almost disappeared.
  • the filter cup was removed and the filtrate was centrifuged and dried under reduced pressure. The dried product was redissolved in 50 ⁇ L of Milli-Q water to which an internal standard was added to obtain a sample for analysis.
  • CE-TOFM analysis was performed using the analysis sample.
  • the analysis was performed using an Agilent CE-TOF-MSD system (Agilent Technologies) and a capillary using Fused silica gel.
  • the measurement conditions for CE-TOFMS are as follows.
  • Result> A total of 263 peaks were detected by CE-TOFMS. For each peak, m / z, migration time (MT) and area value were obtained as peak information. The obtained peak area value was divided by the area value of the internal standard substance and converted into a relative area value.
  • the peak information of each detected peak was collated with the information of all substances registered in the HMT metabolite library and the Known-Unknown library. As a result, 246 peaks were identified as peaks indicating known metabolites. Among these metabolites, for metabolites detected in 80% or more (53 or more) of the analyte, the relative area value of the metabolite peak (corresponding to the plasma concentration of the metabolite) is assigned to each group. The metabolites significantly different between each group were selected. Similarly, the ratio of the relative area values of the peaks of the two metabolites (corresponding to the ratio of the plasma concentrations of the two metabolites) is also significantly different (or has a tendency to be compared). ) The metabolite ratio was selected.
  • Table 2 shows the metabolites that were significantly higher in the major depression group (unmedication treatment) as a result of comparing the metabolite concentrations in the control group and the major depression group (unmedication treatment).
  • Table 3 shows the metabolites that were significantly lower in the major depression group (unmedication treatment) as a result of comparing the metabolite concentration in the control group and the major depression group (unmedication treatment).
  • Table 4 shows the ratio of metabolites with significant difference between the two groups as a result of comparing the ratio of metabolite concentrations between the control group and the major depression group (untreated treatment).
  • Table 5 shows the metabolites that were significantly different between the two groups as a result of comparing the metabolite concentrations in the major depression group (unmedication treatment) and the major depression treatment group.
  • Table 6 shows the results of comparing the ratios of metabolite concentrations between the major depression group (unmedication treatment) and the major depression treatment group. As a result, there was a significant difference between the two groups. The substance ratio is shown.
  • the presence or absence of depression can be determined by using the metabolite or metabolite ratio shown in Tables 2 to 4 as an index.
  • the metabolite or metabolite ratio shown in Tables 5 to 6 as an index, it is possible to determine whether or not the depressive state has improved, and whether or not the subject has received medication for depressive symptoms. It was suggested that it is possible to determine whether or not.
  • Example 2 Depression status marker verification This was carried out in the same manner as in Example 1 except that the subject group was changed and measurement was performed by absolute quantification.
  • Table 7 shows the structure of each group as the subject.
  • the absolute quantification is a concentration determined by comparing a numerical value obtained by actually measuring a specified concentration with a measured value of each target substance in the specimen. Some results are shown in Tables 8-13.
  • Table 8 shows the results of comparison of metabolite concentrations between the control group and the major depression group (unmedicated treatment).
  • Table 9 shows the results of comparison of metabolite concentrations between the control group and the major depression group (medication treatment).
  • Table 10 shows the results of comparison of metabolite concentrations in the control group and the bipolar disorder group.
  • Table 11 shows the results of comparing the ratio of metabolite concentrations between the control group and the major depression group (unmedicated treatment).
  • Table 12 shows the results of comparing the ratio of metabolite concentrations in the control group and the major depression group (medication treatment).
  • Table 13 shows the results of comparing the ratio of metabolite concentrations in the control group and the bipolar disorder group.
  • Tables 8 to 13 indicate that the presence or absence of depression can be determined by absolute quantification.
  • Tables 8 to 13 show that the markers of the present invention (particularly glutamic acid, methionine sulfoxide, etc.) can be determined with high accuracy both before and after the depression treatment. Therefore, if there is a depressive symptom at the time of medical examination or health check-up, and there is an increase in markers such as glutamic acid and methionine sulfoxide, it is possible to use psychiatric consultation.

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Abstract

L'invention concerne un procédé de test, à l'aide de marqueurs moléculaires, d'une maladie impliquant un état dépressif. L'invention concerne un procédé de test d'une maladie impliquant un état dépressif, ledit procédé utilisant, en tant qu'indice, au moins un élément choisi dans le groupe constitué par un rapport méthionine/sulfoxyde de méthionine, un rapport kynurénine/tryptophane, un rapport glutamine/acide glutamique, du sulfoxyde de méthionine, de l'acide glutamique, de l'acide aspartique, de la phosphorylcholine, de l'acide glycérique, de la 5-oxoproline, de l'acide 2-aminoisobutyrique, du N-méthylnorsalsolinol, de l'acide thréonique, de la glycérophosphocholine, de la cystine, de l'inositol monophosphate, de la glutamine, de l'acide 3-phosphoglycérique, de l'uridine, de la thiaproline, de l'acide cis-ascot, de la 1-méthyladénosine, du glucose-6-phosphate, de l'acide 5-méthoxyindole acétique, de la S-méthylcystéine et de l'acide isethionique, qui se trouvent dans un fluide corporel prélevé chez un sujet.
PCT/JP2017/045409 2016-12-21 2017-12-19 Procédé de test de maladie impliquant un état dépressif WO2018117064A1 (fr)

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CN114002421A (zh) * 2021-12-30 2022-02-01 佛山市第三人民医院(佛山市精神卫生中心) 外泌体代谢物作为双相情感障碍标志物的应用
CN115326953A (zh) * 2022-08-02 2022-11-11 云谱康(大连)生物科技有限公司 一种代谢物组合及应用和检测试剂盒与使用
CN116429952A (zh) * 2023-03-27 2023-07-14 深圳市第二人民医院(深圳市转化医学研究院) 一种抑郁症标志物及其在抑郁症诊断中的应用、评估装置

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WO2015174544A1 (fr) * 2014-05-16 2015-11-19 国立研究開発法人国立精神・神経医療研究センター Marqueur de détermination de maladie mentale

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CN114002421A (zh) * 2021-12-30 2022-02-01 佛山市第三人民医院(佛山市精神卫生中心) 外泌体代谢物作为双相情感障碍标志物的应用
CN115326953A (zh) * 2022-08-02 2022-11-11 云谱康(大连)生物科技有限公司 一种代谢物组合及应用和检测试剂盒与使用
CN116429952A (zh) * 2023-03-27 2023-07-14 深圳市第二人民医院(深圳市转化医学研究院) 一种抑郁症标志物及其在抑郁症诊断中的应用、评估装置
CN116429952B (zh) * 2023-03-27 2024-02-02 深圳市第二人民医院(深圳市转化医学研究院) 一种抑郁症标志物及其在抑郁症诊断中的应用、评估装置

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