WO2020261608A1 - PROCÉDÉ ET DISPOSITIF D'ÉVALUATION DE L'ÉTAT D'ACCUMULATION INTRACRÂNIENNE DE β-AMYLOÏDE - Google Patents

PROCÉDÉ ET DISPOSITIF D'ÉVALUATION DE L'ÉTAT D'ACCUMULATION INTRACRÂNIENNE DE β-AMYLOÏDE Download PDF

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WO2020261608A1
WO2020261608A1 PCT/JP2019/049554 JP2019049554W WO2020261608A1 WO 2020261608 A1 WO2020261608 A1 WO 2020261608A1 JP 2019049554 W JP2019049554 W JP 2019049554W WO 2020261608 A1 WO2020261608 A1 WO 2020261608A1
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amyloid
value
suv
marker
conversion
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PCT/JP2019/049554
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Japanese (ja)
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賢志 山田
金子　直樹
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株式会社島津製作所
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    • 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
    • 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

Definitions

  • the present invention relates to a method and an apparatus for evaluating the accumulation state of amyloid ⁇ peptide in the brain by using mass spectrometry.
  • AD Alzheimer's disease
  • a ⁇ amyloid ⁇
  • a ⁇ amyloid ⁇
  • APP Amyloid Precursor Protein
  • Cerebrospinal fluid (CFS) test and amyloid PET (Positron Emission Tomography) test are known as conventional general methods for determining the presence or absence of A ⁇ accumulation in the brain.
  • CFS Cerebrospinal fluid
  • amyloid PET Pulsitron Emission Tomography
  • Patent Documents 1 and 2 and Non-Patent Documents 1 and 2 the ratio of the intensity of the peak derived from the internal standard substance observed in the mass spectrum to the intensity of the marker peak corresponding to the A ⁇ -related peptide of interest is marked.
  • a technique for determining the presence or absence of A ⁇ accumulation by obtaining it as a value and determining whether or not the marker value exceeds a predetermined threshold value (Cut-off value) is disclosed.
  • this method is referred to as "amyloid MS”.
  • amyloid MS there is a great advantage that it is possible to determine the presence or absence of A ⁇ accumulation without imposing a heavy burden on the subject, and it is expected to be widely used in the future.
  • the conventional amyloid MS has the following problems.
  • amyloid PET is becoming widespread in the field of diagnosis and treatment of AD, and amyloid PET is more familiar to doctors and laboratory technicians in the clinical field.
  • a radiopharmaceutical that specifically accumulates in a specific part of the body hereinafter, may be referred to as a "probe” according to convention
  • the PET image value is called the SUV (Standard Uptake Value) value standardized by the image value at the site where there is no specific accumulation. It is evaluated using the index value.
  • PIB Portsburgh Compound B
  • the PET image value of the cerebral region is used as the PET image value of the cerebellum region where there is no specific binding of the probe.
  • the SUV value can be obtained by standardizing. Therefore, when there is little or no accumulation of A ⁇ in the cerebrum, no specific binding of the probe occurs and the SUV value is approximately 1. On the other hand, when A ⁇ is accumulated in the cerebrum, the SUV value shows a value larger than 1. Normally, the SUV value does not fall below 1 except for statistical fluctuations, unless there is a mechanism to eliminate the probe in vivo.
  • the marker value calculated from the mass spectrum and the threshold value for determining the presence or absence of A ⁇ accumulation can be presented to the user based on the marker value.
  • many users are familiar with the SUV value obtained by amyloid PET, which is already becoming widely used, so we would like to know how much the marker value and judgment threshold value in amyloid MS are in the SUV value.
  • Conventional amyloid MS cannot meet these demands.
  • the present invention has been made to solve the above problems, and an object of the present invention is to present data obtained by amyloid MS and a determination result based on the data in an easy-to-understand manner to a user familiar with amyloid PET. It is to provide a method and an evaluation device for evaluating the accumulation state of amyloid ⁇ in the brain.
  • One aspect of the method for evaluating the accumulation state of amyloid ⁇ in the brain is to apply the method of amyloid MS using mass spectrometry to a biological sample obtained from a subject.
  • a method for evaluating the accumulation state of amyloid ⁇ in the brain of the subject is to apply the method of amyloid MS using mass spectrometry to a biological sample obtained from a subject.
  • the marker value which is the ratio of the intensities of the plurality of amyloid ⁇ -related peptides obtained by performing amyloid MS, and the SUV value obtained by performing the amyloid PET test for each of the plurality of reference subjects.
  • the data collection process to acquire the dataset of A conversion data acquisition step of calculating a formula or table for converting a marker value into an SUV value based on a plurality of data sets collected in the data collection step, and obtaining data constituting the formula or table.
  • a subject measurement process for acquiring marker values by performing amyloid MS on the target subject and A conversion step of converting the marker value acquired in the subject measurement step into an SUV value using a formula or table based on the data obtained in the conversion data acquisition step, and a conversion step.
  • the device for evaluating the accumulation state of amyloid ⁇ in the brain according to one aspect of the present invention, which was made to solve the above problems
  • Mass spectrometry and A marker value calculation unit that obtains the ratio of the intensities of a plurality of amyloid ⁇ -related peptides as a marker value in amyloid MS based on the mass spectrometry result obtained by the mass spectrometry unit for a target subject.
  • a conversion data storage unit that stores data constituting an expression or table for converting a marker value in amyloid MS into an SUV value in an amyloid PET examination.
  • a conversion processing unit that converts the marker value obtained by the marker value calculation unit into an SUV value using an expression or table based on the data stored in the conversion data storage unit.
  • amyloid MS as used herein is a test method disclosed in, for example, Patent Document 1, Non-Patent Documents 1, 2 and the like, and is a mass obtained by performing mass spectrometry on a biological sample such as a blood sample. It is a method of calculating a marker value based on the intensity ratio of a plurality of peaks having a specific mass-to-charge ratio derived from a peptide related to amyloid ⁇ observed in a spectrum.
  • the measurement result by amyloid MS which is simpler and less burdensome to the subject as compared with amyloid PET, can be obtained by using amyloid PET. It can be presented to users such as medical personnel in the same format as the obtained test result. As a result, a user accustomed to the amyloid PET test can easily and accurately determine the presence or absence of accumulation of amyloid ⁇ based on the test result of amyloid MS.
  • the schematic block diagram of the A ⁇ accumulation state evaluation apparatus by one Embodiment of this invention The flowchart which shows the creation procedure of the conversion formula used in the A ⁇ accumulation state evaluation apparatus of this embodiment.
  • FIG. 1 is a schematic configuration diagram of an A ⁇ accumulation state evaluation device according to the present embodiment.
  • This device performs analysis processing using mass spectrometric data and MALDI-TOFMS (Matrisk-assisted laser desorption / ionization-time-of-flight mass spectrometer) 1 that performs mass spectrometry on a sample and acquires mass spectrometric data.
  • MALDI-TOFMS Mass-assisted laser desorption / ionization-time-of-flight mass spectrometer
  • the data analysis unit 2 has mass spectrum data collection unit 20, peak detection unit 21, marker value calculation unit 22, SUV value conversion data storage unit 23, SUV value conversion unit 24, and A ⁇ accumulation determination unit 25 as functional blocks.
  • the display processing unit 26 has mass spectrum data collection unit 20, peak detection unit 21, marker value calculation unit 22, SUV value conversion data storage unit 23, SUV value conversion unit 24, and A ⁇ accumulation determination unit 25 as functional blocks.
  • the display processing unit 26 the display processing unit 26.
  • the substance of the data analysis unit 2 is a personal computer or a computer having higher performance than that, and by operating the dedicated data analysis software pre-installed on the computer on the computer, each function is realized. be able to.
  • the SUV value conversion data storage unit 23 stores data that constitutes a conversion formula for converting a marker value in amyloid MS into an SUV value in amyloid PET, which is prepared in advance based on the result of preliminary measurement. ..
  • This preliminary measurement and creation of the conversion formula are generally performed by a manufacturer that provides the A ⁇ accumulation state evaluation device of the present embodiment, a manufacturer that provides data analysis software used for the device, and the like.
  • the apparatus of the present embodiment may be provided with a function of creating and storing a conversion formula.
  • FIG. 2 is a flowchart showing a procedure for creating this conversion formula. The method of creating this conversion formula and the procedure thereof will be described with reference to FIG.
  • One dataset contains the SUV values obtained by performing an amyloid PET scan on a single reference subject and amyloid performed on the same subject at about the same time as the amyloid PET scan. Includes marker values obtained in MS.
  • amyloid MS is a known method described in Patent Documents 1 and 2, Non-Patent Documents 1 and 2, and the like.
  • blood samples such as whole blood, plasma, and serum collected from a subject are mass-analyzed by MALDI-TOFMS to obtain a mass spectrum in a predetermined mass-to-charge ratio range.
  • a predetermined internal standard substance can be added to the sample.
  • the peak intensities of a plurality of specific mass-to-charge ratios related to amyloid ⁇ are obtained, and the marker value is calculated based on the peak intensity ratio and the like.
  • the SUV value can be calculated based on the PET image obtained from the subject. Therefore, a reference data set can be obtained by performing the amyloid MS and the amyloid PET examination on the same subject at approximately the same time (step S11). As a matter of course, it is better to have a large number of data sets in order to improve the accuracy of the conversion formula.
  • a conversion formula from the marker value to the SUV value is created using the reference data set (step S12).
  • the SUV value S is a constant 1 in the range where the marker value M is less than the constant M 0
  • the SUV value S and the marker value M are in the range where the marker value M is the constant M 0 or more.
  • the relationship represents a piecewise polynomial of monotonically increasing, which is a linear function.
  • the constant M 0 and the coefficient A in Eq. (1) may be obtained by parameter estimation by the least squares method or the like using the reference data set.
  • FIG. 3 is a diagram showing an actually measured value (reference data set) and a conversion formula estimated from this by the least squares method.
  • the constant M 0 is a boundary value that separates the specific binding region and the non-specific binding region
  • the marker value is determined by whether the marker value M is less than M 0 or greater than or equal to M 0. It is possible to determine whether the corresponding SUV value is a specific binding region or a non-specific binding region.
  • the coefficient A and the constant M 0 of the equation are acquired as SUV value conversion data (step S13), and this is stored in the SUV value conversion data storage unit 23.
  • an algorithm other than the least squares method may be used.
  • the polynomial of M ⁇ M 0 is not limited to the linear function, and a higher-order function may be used.
  • a measurement is performed on a blood sample (unknown sample) collected from a subject using MALDI-TOFMS1, and the mass spectrum data collection unit 20 collects mass spectrum data over a predetermined mass-to-charge ratio range.
  • the peak detection unit 21 performs peak detection on the acquired mass spectrum, and the marker value calculation unit 22 calculates the marker value from the ratio of the peak intensities at a predetermined mass-to-charge ratio related to amyloid ⁇ . This marker value is the marker value in amyloid MS.
  • the SUV value conversion unit 24 substitutes the above-calculated marker value into a conversion formula constructed by using the coefficients and constants stored in the SUV value conversion data storage unit 23 to obtain the SUV value. Further, the A ⁇ accumulation determination unit 25 determines whether the calculated SUV value belongs to the specific binding region or the non-specific binding region. Then, the display processing unit 26 shows that the marker value in amyloid MS, the SUV value (converted value) in amyloid PET, and the SUV value are specific binding regions and non-specific as the evaluation result of the A ⁇ accumulation state in the subject. Which of the target connection regions belongs to is displayed on the screen of the display unit 4. The mode of display at this time is not particularly limited.
  • the user can easily grasp the SUV value corresponding to the marker value in the amyloid MS. It is also possible to grasp whether the SUV value belongs to the specific binding region or the non-specific binding region, that is, whether A ⁇ may be accumulated in the brain.
  • One aspect of the method for evaluating the state of accumulation of amyloid ⁇ in the brain according to the present invention is to apply the method of amyloid MS using mass spectrometry to a biological sample obtained from the subject. It is a method to evaluate the accumulation state of amyloid ⁇ in the brain of
  • the marker value which is the ratio of the intensities of the plurality of amyloid ⁇ -related peptides obtained by performing amyloid MS, and the SUV value obtained by performing the amyloid PET test for each of the plurality of reference subjects.
  • the data collection process to acquire the dataset of A conversion data acquisition step of calculating a formula or table for converting a marker value into an SUV value based on a plurality of data sets collected in the data collection step, and obtaining data constituting the formula or table.
  • a subject measurement process for acquiring marker values by performing amyloid MS on the target subject and A conversion step of converting the marker value acquired in the subject measurement step into an SUV value using a formula or table based on the data obtained in the conversion data acquisition step, and a conversion step.
  • one aspect of the device for evaluating the accumulation state of amyloid ⁇ in the brain is Mass spectrometry and A marker value calculation unit that obtains the ratio of the intensities of a plurality of amyloid ⁇ -related peptides as a marker value in amyloid MS based on the mass spectrometry result obtained by the mass spectrometry unit for a target subject.
  • a conversion data storage unit that stores data constituting an expression or table for converting a marker value in amyloid MS into an SUV value in an amyloid PET examination.
  • a conversion processing unit that converts the marker value obtained by the marker value calculation unit into an SUV value using an expression or table based on the data stored in the conversion data storage unit.
  • the method for evaluating the accumulation state of amyloid ⁇ in the brain described in item 1 and the device for evaluating the accumulation state of amyloid ⁇ in the brain described in item 5 it is simpler than that of amyloid PET and burdens the subject. It is possible to present the measurement result by amyloid MS, which is small in size and advantageous in terms of cost, to a user such as a medical personnel in the same format as the test result obtained by amyloid PET. As a result, a user accustomed to the amyloid PET test can easily and accurately determine the presence or absence of accumulation of amyloid ⁇ based on the test result of amyloid MS.
  • the marker value is divided into a plurality of markers as an expression for converting the marker value into an SUV value, and at least. It is possible to calculate a piecewise polynomial in which the SUV value monotonically increases with respect to the increase in the marker value in one division.
  • the SUV value is almost 1.
  • a more accurate polynomial is obtained in the region where the SUV value is not 1 by dividing the region where the SUV value is almost 1 and the region where the SUV value is not 1 by the piecewise polynomial. be able to.
  • the accuracy of conversion from the marker value to the SUV value in amyloid MS is improved.
  • the piecewise polynomial is a constant in the range where the marker value is equal to or less than the predetermined value, and the marker value is in the range of the predetermined value or more. Then, it can be assumed that it is a linear function.
  • the predetermined value, the constant, and the coefficient of the linear function are estimated by the least squares method using a plurality of data sets. Can be done.

Abstract

Un dispositif d'évaluation d'un état d'accumulation intracrânienne de β-amyloïde selon un mode de réalisation de la présente invention comprend : une unité de calcul de valeur de marqueur (22) qui, sur la base d'un résultat d'analyse de masse obtenu par une unité d'analyse de masse (1) par rapport à un spécimen ciblé, dérive une comparaison de l'intensité d'une pluralité de peptides associés au β-amyloïde en tant que valeur de marqueur dans le SM des amyloïdes ; une unité de stockage de données de conversion (23) dans laquelle est stockée une formule pour convertir la valeur de marqueur dans le SM des amyloïdes en une valeur SUV dans un examen de PET des amyloïdes ; une unité de traitement de conversion (24) qui convertit la valeur de marqueur en une valeur SUV à l'aide de la formule de conversion ; une unité de traitement d'évaluation (25) qui évalue si la valeur SUV résultante appartient soit à une région de liaison non spécifique, soit à une région de liaison spécifique associée à l'occurrence d'une accumulation de β-amyloïde ; et une unité de traitement d'affichage (26) qui affiche la valeur SUV et le résultat d'évaluation sur une unité d'affichage (4). Ceci permet à un utilisateur qui est habitué aux examens PET des amyloïdes d'évaluer facilement et avec précision si l'accumulation de β-amyloïde se produit sur la base d'un résultat de détection du SM des amyloïdes.
PCT/JP2019/049554 2019-06-28 2019-12-18 PROCÉDÉ ET DISPOSITIF D'ÉVALUATION DE L'ÉTAT D'ACCUMULATION INTRACRÂNIENNE DE β-AMYLOÏDE WO2020261608A1 (fr)

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