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WO2024109768A1 - Marqueur de la maladie d'alzheimer basé sur un métabolite sanguin, et son utilisation - Google Patents

Marqueur de la maladie d'alzheimer basé sur un métabolite sanguin, et son utilisation Download PDF

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Publication number
WO2024109768A1
WO2024109768A1 PCT/CN2023/133065 CN2023133065W WO2024109768A1 WO 2024109768 A1 WO2024109768 A1 WO 2024109768A1 CN 2023133065 W CN2023133065 W CN 2023133065W WO 2024109768 A1 WO2024109768 A1 WO 2024109768A1
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Prior art keywords
alzheimer
disease
decrease
acid
biomarker
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English (en)
Chinese (zh)
Inventor
陈宇
陈艺菁
李寅虎
樊颖颖
陈岳文
杨玉洁
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Shenzhen Institute of Advanced Technology of CAS
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Shenzhen Institute of Advanced Technology of CAS
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/72—Mass spectrometers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/86—Signal analysis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N2030/022—Column chromatography characterised by the kind of separation mechanism
    • G01N2030/027—Liquid chromatography

Definitions

  • the present invention relates to the field of biotechnology, and in particular to an Alzheimer's disease marker based on blood metabolites and an application thereof.
  • AD Alzheimer's disease
  • senile dementia is a progressive degenerative disease of the central nervous system that occurs in old age.
  • AD is characterized by progressive memory impairment, cognitive decline, and loss of daily living ability, accompanied by neuropsychiatric symptoms such as personality changes, which seriously affect the patient's life and social life. It has become a major public health issue affecting the world.
  • society many factors such as the accelerated pace of life, increased work pressure, irregular diet and work and rest have led to the younger and younger population of patients with Alzheimer's disease.
  • dementia occurred more after the age of 65, but now there are many people in their 50s or even 40s suffering from the disease.
  • the pathogenesis of Alzheimer's disease has not been fully clarified, and its early symptoms are relatively hidden, patients are easily missed or misdiagnosed.
  • the screening of Alzheimer's disease is mainly carried out through neuropsychological scales, imaging examinations and biochemical index examination results.
  • different detection methods have their limitations.
  • memory scales can be used to evaluate clinical symptoms, but the sensitivity and specificity of diagnosis are low.
  • positron emission tomography has the advantages of being non-invasive, in vivo, and real-time, but the detection cost is relatively high.
  • biomarkers that is, biochemical indicators that can mark changes or possible changes in the structure or function of systems, organs, tissues, cells and subcellular structures, in order to understand the current biological state of the body, thereby providing a reference for the prevention, early diagnosis and treatment of Alzheimer's disease.
  • biomarkers are beta-amyloid protein and phosphorylated tau protein in cerebrospinal fluid, but the collection of cerebrospinal fluid is traumatic, which limits its clinical application.
  • the research turned to blood, which is easy to obtain and less invasive, hoping to complete the early diagnosis of Alzheimer's disease with a rapid, non-invasive and low-cost strategy.
  • metabolomics uses technologies such as magnetic resonance spectroscopy and mass spectrometry to monitor the dynamic changes of metabolite profiles and effectively screen disease-related biomarkers, thus showing broad application prospects in clarifying the molecular pathogenic mechanism of Alzheimer's disease and the pathophysiological changes caused by it.
  • Blood contains proteins, peptides, nucleic acids, lipids and other metabolites, which can help clarify the complexity and heterogeneity of Alzheimer's disease.
  • screening for early diagnostic biomarkers of Alzheimer's disease based on metabolites in the blood is expected to improve the accuracy of disease diagnosis, help early warning of the disease, pathological typing, and predictive evaluation of the development stage.
  • the purpose of the present invention is to overcome the shortcomings of the prior art and solve the problem of low sensitivity and accuracy of the existing Alzheimer's disease biomarkers based on blood metabolites mentioned in the above background technology.
  • the present invention provides the following technical solutions:
  • a biomarker for Alzheimer's disease comprising any one or more of trimethylamine-N-oxide, shikimic acid, 3-aminosalicylic acid, hippuric acid, N-acetyltryptophan, D-glucose, hydroxycobalamin, riboflavin-5'-phosphate, hydroxypyruvic acid, glycolic acid, 3-hydroxy-2-butanone, betaine, and xanthuric acid.
  • the Alzheimer's disease biomarker is a combination of trimethylamine-N-oxide, D-glucose, shikimic acid and hydroxypyruvic acid.
  • the second aspect of the present invention provides a kit, comprising a detection tool and instructions, wherein the instructions record the process and indicators for diagnosing a subject, and is characterized in that the detection tool consists of a tool for measuring the Alzheimer's disease biomarker.
  • the instructions describe the following diagnostic process: S1, determining the level of the Alzheimer's disease biomarker in a biological sample from a subject; and S2, based on the level of the Alzheimer's disease biomarker, assisting in determining or diagnosing the presence of Alzheimer's disease or the risk of developing Alzheimer's disease with high specificity.
  • step S2 comprises comparing the level of the biomarker in the biological sample with a reference level of the biomarker, wherein the reference level is an average level obtained from a population that does not suffer from Alzheimer's disease.
  • any one or more of the following is selected to indicate the presence of Alzheimer's disease or the risk of developing Alzheimer's disease: a decrease in trimethylamine-N-oxide, a decrease in shikimic acid, a decrease in 3-aminosalicylic acid, a decrease in N-acetyltryptophan, a decrease in D-glucose, a decrease in riboflavin-5'-phosphate, a decrease in hydroxypyruvic acid, a decrease in 3-hydroxy-2-butanone, a decrease in betaine, a decrease in xanthuric acid, a decrease in hippuric acid, a decrease in hydroxycobalamin, and a decrease in glycolic acid.
  • the instructions record using the mass spectrum peak height value and/or mass spectrum peak area value of the Alzheimer's disease biomarker as a diagnostic indicator.
  • the biological sample is selected from blood.
  • the third aspect of the present invention provides an Alzheimer's disease biomarker for use in preparing a reagent or kit for screening drugs for treating or preventing Alzheimer's disease, assisting in diagnosing Alzheimer's disease in a subject, and/or assisting in determining the risk of developing Alzheimer's disease in a subject.
  • the beneficial effect of the present invention is that the Alzheimer's disease biomarker provided by this scheme can be used to assist in the diagnosis of Alzheimer's disease symptoms, has the characteristics of high detection accuracy, convenience, speed, safety and non-invasiveness, and has important clinical guiding significance for assisting the diagnosis of Alzheimer's disease related indicators.
  • Figure 1 is a graph showing the content of trimethylamine-N-oxide
  • Figure 2 is a comparison chart of the mean values of trimethylamine-N-oxide content
  • Fig. 3 is a graph showing D-glucose content
  • FIG4 is a comparison diagram of mean values of D-glucose content
  • Fig. 5 is a graph showing shikimic acid content
  • FIG6 is a comparison chart of the mean values of shikimic acid content
  • Fig. 7 is a graph showing hydroxypyruvic acid content
  • FIG8 is a comparison chart of the mean values of hydroxypyruvic acid content
  • Fig. 9 is a graph showing the content of 3-aminosalicylic acid
  • Figure 10 is a comparison chart of the mean values of 3-aminosalicylic acid content
  • Figure 11 is a graph showing N-acetyltryptophan content
  • Figure 12 is a comparison chart of mean values of N-acetyltryptophan content
  • FIG13 is a graph showing riboflavin-5′-phosphate content
  • FIG14 is a comparison chart of the mean values of riboflavin-5′-phosphate content
  • Figure 15 is a graph showing 3-hydroxy-2-butanone content
  • Figure 16 is a comparison chart of the mean values of 3-hydroxy-2-butanone content
  • Figure 17 is a graph showing betaine content
  • Figure 18 is a comparison chart of mean betaine content
  • Figure 19 is a graph showing xanthuric acid content
  • Figure 20 is a comparison chart of the mean values of xanthuric acid content
  • Figure 21 is a graph showing hippuric acid content
  • Figure 22 is a comparison chart of the mean values of hippuric acid content
  • FIG23 is a graph showing hydroxocobalamin content
  • FIG24 is a comparison chart of the mean values of hydroxocobalamin content
  • Fig. 25 is a graph showing glycolic acid content
  • FIG. 26 is a comparison chart of the mean values of glycolic acid content.
  • the sources of the experiment and instruments of the present invention are as follows: AB 5500/6500 Q-trap mass spectrometer was purchased from AB SCIEX. Agilent 1290 Infinity LC ultrahigh pressure liquid chromatograph was purchased from Agilent. Low temperature high speed centrifuge 5430R was purchased from Eppendorf. Chromatographic columns were purchased from Waters, and there were two types: ACQUITY UPLC BEH Amide 1.7 ⁇ m, 2.1mm ⁇ 100mm column; ACQUITY UPLC BEH C18 1.7 ⁇ m, 2.1mm ⁇ 100mm column. Acetonitrile was purchased from Merck, and the product number was 1499230-935. Ammonium acetate was purchased from Sigma, and the product number was 73594.
  • Methanol was purchased from Fisher, and the product number was A456-4.
  • Ammonia was purchased from Sigma, and the product number was 221228.
  • Ammonium formate was purchased from Sigma, and the product number was 70221.
  • Formic acid was purchased from Sigma, product number 00940.
  • Isotope standards were purchased from Cambridge Isotope Laboratories.
  • the sensitivity (also known as the true positive rate) described in the present invention refers to the proportion of samples that are actually positive and are judged as positive, that is, the ability to correctly judge cases that are actually sick as sick.
  • Specificity (also known as the true negative rate) refers to the proportion of samples that are actually negative and are judged as negative, that is, the ability to correctly judge cases that are actually not sick.
  • Accuracy also known as efficiency is expressed as the percentage of the total number of true positives and true negatives to the total number of subjects.
  • the present invention provides a highly sensitive and accurate Alzheimer's disease biomarker based on blood metabolites.
  • the combination contains 13 blood metabolite markers, and the mass spectrum peak intensity values are used as detection indicators, which can be used to assist in the diagnosis of Alzheimer's disease symptoms. Because it has the characteristics of high detection accuracy, convenience, speed, safety and non-invasiveness, it has important clinical guidance significance for assisting the diagnosis of Alzheimer's disease.
  • the present invention provides a kit, including a detection tool and instructions, wherein the detection tool is composed of a tool for determining Alzheimer's disease biomarkers, and the instructions record the process and indicators for diagnosing a subject.
  • the diagnostic process includes: determining the level of Alzheimer's disease biomarkers in serum from a subject; based on the level of Alzheimer's disease biomarkers, assisting in determining or diagnosing the presence of Alzheimer's disease or the risk of developing Alzheimer's disease with high specificity.
  • Example 1 Sample extraction and pretreatment
  • mice The 9-month-old mice were divided into two groups, one group was the Alzheimer's disease male model mouse serum group, namely the Serum Transgenic (STG) group, with a total of 10 mice; the other group was the WT wild-type serum control group, namely the Serum Wild Type (SWT) group, with a total of 9 mice.
  • STG Serum Transgenic
  • SWT Serum Wild Type
  • Example 2 During mass spectrometry analysis, 100 ⁇ L of acetonitrile aqueous solution was added to the pretreated sample obtained in Example 1 for reconstitution, wherein the volume ratio of acetonitrile to water was 1:1. The sample was then vortexed and centrifuged at 14,000 ⁇ g and 4°C for 15 min, and the supernatant was sampled for analysis.
  • the qualitative and quantitative information of blood metabolites is based on targeted metabolomics analysis technology, using ultra-high performance liquid chromatography-triple quadrupole mass spectrometry (UHPLC Q-TRAP/MS) for detection.
  • UHPLC Q-TRAP/MS ultra-high performance liquid chromatography-triple quadrupole mass spectrometry
  • This technology has high selectivity and high sensitivity, and uses targeted sample preparation and chromatographic separation methods to qualitatively and quantitatively analyze more than 300 common intestinal flora metabolites.
  • the column temperature of C18 chromatographic column was 40°C, the flow rate was 0.4mL/min, and the injection volume was 2 ⁇ L; the mobile phase A was water, 50mM ammonium formate and 0.4% formic acid, and the mobile phase B was methanol; the elution gradient was as follows: 0-5min B phase changed linearly from 5% to 60%, 5-11min B phase changed linearly from 60% to 100%, 11-13min B phase was maintained at 100%, 13-13.1min B phase changed linearly from 100% to 5%, and 13.1-16min B phase was maintained at 5%; the samples were placed in the automatic sampler at 4°C during the entire analysis process. In order to avoid the influence of fluctuations in instrument detection signals, the samples were analyzed continuously in random order. QC samples were inserted into the sample queue, that is, samples obtained by mixing all samples to be tested with the same volume and following the same pretreatment method as the samples to be tested, which were used to monitor and evaluate the stability of the system and the reliability of experimental data.
  • Mass spectrometry conditions The mass spectrometer was an AB 6500 QTRAP system from AB SCIEX. Electrospray ionization (ESI) was used as the ionization mode, and the parameters were set as follows: sheath gas temperature 350°C; drying gas temperature 350°C; sheath gas flow rate 11 L/min; drying gas flow rate 10 L/min; capillary voltage 4000 V in positive ion mode and -3500 V in negative ion mode; nozzle voltage 500 V; nebulization pressure 30 psi; and mass spectrometry multiple reaction monitoring (MRM) was used.
  • ESI Electrospray ionization
  • the intergroup difference analysis of the two groups of mice showed that the levels of the following metabolites in the AD group mice were significantly different from those in the control group, indicating that these metabolites play an important role in distinguishing the Alzheimer's disease model: Trimethylamine-N-oxide (TMAO), Shikimic acid, 3-Aminosalicylic acid, Hippuric acid, N-acetyltryptophan (NAT), D-glucose, Hydroxocobalamin, Riboflavin-5'-monophosphate (FMN), Hydroxypyruvic acid, Glycolic acid, Acetoin, Betaine, and Xanthurenate.
  • TMAO Trimethylamine-N-oxide
  • Shikimic acid Shikimic acid
  • 3-Aminosalicylic acid 3-Aminosalicylic acid
  • Hippuric acid N-acetyltryptophan (NAT)
  • D-glucose D-glucose
  • Hydroxocobalamin Riboflavin-5'-mono
  • Figures 1-8 show the contents of trimethylamine-N-oxide, D-glucose, shikimic acid, and hydroxypyruvic acid. It can be seen that the contents of these four biomarkers in the serum of mice with Alzheimer's disease all show an overall decreasing trend. At the same time, there are also obvious differences in the average values of these biomarkers between the two groups, suggesting that there may be abnormal changes in the glucose metabolism pathway in Alzheimer's disease.
  • Figures 9-26 are respectively 3-aminosalicylic acid, N-acetyltryptophan, riboflavin-5'-phosphate, 3-hydroxy-2-butanone, betaine, xanthurenic acid, hippuric acid, hydroxocobalamin, and glycolic acid content graphs. The average values of these biomarker contents in mice with Alzheimer's disease have a decreasing trend relative to mice without the disease, indicating that the subjects have Alzheimer's disease or are at risk of developing Alzheimer's disease.
  • trimethylamine-N-oxide belongs to amino oxides
  • shikimic acid belongs to organic acids
  • 3-aminosalicylic acid belongs to hippuric acid
  • N-acetyltryptophan belong to benzene ring compounds
  • D-glucose belongs to carbohydrates
  • hydroxocobalamin belongs to corrins
  • riboflavin-5'-phosphate belongs to flavin nucleotides
  • hydroxypyruvic acid and glycolic acid belong to hydroxy acids
  • 3-hydroxy-2-butanone belongs to organic oxygen compounds
  • betaine belongs to pyrimidines
  • xanthurenic acid belongs to quinoline derivatives.
  • the present invention uses the mass spectrometry peak intensity values of 13 blood metabolic markers as detection targets or evaluation indicators, which can be used to assist in the diagnosis of Alzheimer's disease symptoms. It has the characteristics of high detection accuracy, convenience, speed, safety and non-invasiveness, and has important clinical guiding significance for assisting the diagnosis of Alzheimer's disease-related indicators.

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Abstract

La présente invention se rapporte au domaine de la biotechnologie, et concerne en particulier un marqueur de la maladie d'Alzheimer basé sur un métabolite sanguin, et son utilisation. Un biomarqueur fourni par la présente solution présente les caractéristiques d'une sensibilité élevée et d'une précision élevée, et peut fournir une référence importante pour le diagnostic auxiliaire précoce clinique de la maladie d'Alzheimer d'une manière hautement précise, pratique, rapide et sûre et non invasive pour la détection au moyen d'une valeur d'intensité de pic d'un spectre de masse de celui-ci en tant qu'indice de détection.
PCT/CN2023/133065 2022-11-25 2023-11-21 Marqueur de la maladie d'alzheimer basé sur un métabolite sanguin, et son utilisation Ceased WO2024109768A1 (fr)

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CN202211490805.X 2022-11-25
CN202211490805.XA CN118090930A (zh) 2022-11-25 2022-11-25 基于血液代谢物的阿尔茨海默症标志物及其应用

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CN119846187B (zh) * 2025-01-09 2025-09-23 重庆医科大学 用于诊断阿尔茨海默病的头发代谢标志物组合及其应用

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090318369A1 (en) * 2007-08-17 2009-12-24 Paige Lisa A Biomarkers for alzheimer's disease and methods using the same
US20160195547A1 (en) * 2013-07-31 2016-07-07 Pharnext Diagnostic tools for alzheimer's disease
US20180275144A1 (en) * 2015-02-03 2018-09-27 Pharnext Diagnostic tools for alzheimer's disease
US20210215720A1 (en) * 2013-11-26 2021-07-15 University Of North Texas Health Science Center At Fort Worth Personalized medicine approach for treating cognitive loss
US20210325409A1 (en) * 2019-10-28 2021-10-21 Agent Biomarkers and uses thereof for diagnosing the silent phase of alzheimer's disease
WO2022075354A1 (fr) * 2020-10-06 2022-04-14 Okinawa Institute Of Science And Technology School Corporation Procédé pour obtenir un indice pour le diagnostic de la maladie d'alzheimer (ad)
US20220257612A1 (en) * 2019-07-24 2022-08-18 Rima F. Kaddurah-Daouk Compositions and methods for the diagnosis and treatment of alzheimer's disease
WO2022213201A1 (fr) * 2021-04-09 2022-10-13 Uti Limited Partnership Appareil et méthodologies pour la détection, le diagnostic et le pronostic d'une lésion cérébrale

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090318369A1 (en) * 2007-08-17 2009-12-24 Paige Lisa A Biomarkers for alzheimer's disease and methods using the same
US20160195547A1 (en) * 2013-07-31 2016-07-07 Pharnext Diagnostic tools for alzheimer's disease
US20210215720A1 (en) * 2013-11-26 2021-07-15 University Of North Texas Health Science Center At Fort Worth Personalized medicine approach for treating cognitive loss
US20180275144A1 (en) * 2015-02-03 2018-09-27 Pharnext Diagnostic tools for alzheimer's disease
US20220257612A1 (en) * 2019-07-24 2022-08-18 Rima F. Kaddurah-Daouk Compositions and methods for the diagnosis and treatment of alzheimer's disease
US20210325409A1 (en) * 2019-10-28 2021-10-21 Agent Biomarkers and uses thereof for diagnosing the silent phase of alzheimer's disease
WO2022075354A1 (fr) * 2020-10-06 2022-04-14 Okinawa Institute Of Science And Technology School Corporation Procédé pour obtenir un indice pour le diagnostic de la maladie d'alzheimer (ad)
WO2022213201A1 (fr) * 2021-04-09 2022-10-13 Uti Limited Partnership Appareil et méthodologies pour la détection, le diagnostic et le pronostic d'une lésion cérébrale

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