WO2020261608A1 - METHOD AND DEVICE FOR EVALUATING INTRACRANIAL ACCUMULATION STATE OF AMYLOID β - Google Patents

METHOD AND DEVICE FOR EVALUATING INTRACRANIAL ACCUMULATION STATE OF AMYLOID β 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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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

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  • 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.

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Abstract

A device for evaluating an intracranial accumulation state of amyloid β according to one embodiment of the present invention comprises: a marker value calculation unit (22) that, on the basis of a mass analysis result obtained by a mass analysis unit (1) with respect to a targeted specimen, derives a comparison of the strength of a plurality of amyloid β-related peptides as a marker value in amyloid MS; a conversion data storage unit (23) in which there is stored a formula for converting the marker value in the amyloid MS to an SUV value in an amyloid PET examination; a conversion processing unit (24) that converts the marker value to an SUV value using the conversion formula; an assessment processing unit (25) that assesses whether the resultant SUV value belongs in either of a non-specific binding region or a specific binding region associated with the occurrence of accumulation of amyloid β; and a display processing unit (26) that displays the SUV value and the assessment result on a display unit (4). This makes it possible for a user who is used to amyloid PET examinations to easily and accurately assess whether accumulation of amyloid β is occurring on the basis of an amyloid MS detection result.

Description

アミロイドβの脳内蓄積状態評価方法及び評価装置Evaluation method and evaluation device for the accumulation state of amyloid β in the brain
　本発明は、質量分析を利用して、脳内におけるアミロイドβペプチドの蓄積状態を評価する方法及び装置に関する。 The present invention relates to a method and an apparatus for evaluating the accumulation state of amyloid β peptide in the brain by using mass spectrometry.
　認知症の主要な原因の一つはアルツハイマー病（Alzheimer's disease、以下「ＡＤ」と略すことがある）である。このＡＤの発症にはアミロイドβ（Amyloid β、以下「Ａβ」と略すことがある）が深く関わっていると考えられている。Ａβは、生体細胞に一般に含まれるアミロイド前駆タンパク質（Amyloid Precursor Protein：以下「ＡＰＰ」と略すことがある）がβセクレターゼ及びγセクレターゼによって分解されることで産生されるペプチドであり、Ａβが脳全体に蓄積すると健全な神経細胞が変化したり脱落したりして脳萎縮を進行させる、と言われている。 One of the main causes of dementia is Alzheimer's disease (hereinafter sometimes abbreviated as "AD"). It is thought that amyloid β (Amyloid β, hereinafter sometimes abbreviated as “Aβ”) is deeply involved in the onset of this AD. Aβ is a peptide produced by the degradation of amyloid precursor protein (Amyloid Precursor Protein: hereinafter sometimes abbreviated as “APP”) generally contained in living cells by β-secretase and γ-secretase, and Aβ is the entire brain. It is said that when it accumulates in the protein, healthy nerve cells change or fall out and promote brain atrophy.
　近年の研究では、ＡＤの臨床症状が発現するよりもかなり早い時期に、脳内にＡβが蓄積され始めることが明らかになっている。そのため、脳内におけるＡβの蓄積状態を正確に判定することは、ＡＤの早期診断を行ううえで重要である。脳内におけるＡβの蓄積の有無を判定する従来の一般的な方法としては、脳脊髄液（ＣＦＳ）検査やアミロイドＰＥＴ（Positron Emission Tomography）検査が知られている。しかしながら、ＣＦＳ検査では、腰椎穿刺法、後頭下穿刺法、脳室穿刺法などにより脳脊髄液を採取する必要があり、侵襲性が高い。一方、アミロイドＰＥＴ検査では、非常に高価であるＰＥＴ装置を必要とするうえに、放射線被曝という侵襲性がある。また、いずれの方法でも検査に時間が掛かり、被検者の拘束時間が長くなる。そのため、こうした従来の方法はＡＤの早期診断のスクリーニングには適さない。 Recent studies have revealed that Aβ begins to accumulate in the brain much earlier than the onset of clinical symptoms of AD. Therefore, it is important to accurately determine the accumulation state of Aβ in the brain in order to make an early diagnosis of AD. Cerebrospinal fluid (CFS) test and amyloid PET (Positron Emission Tomography) test are known as conventional general methods for determining the presence or absence of Aβ accumulation in the brain. However, in the CFS examination, it is necessary to collect cerebrospinal fluid by lumbar puncture, subcranial puncture, ventricular puncture, etc., and it is highly invasive. On the other hand, amyloid PET examination requires a very expensive PET device and is invasive due to radiation exposure. In addition, both methods take time for the examination and lengthen the restraint time of the subject. Therefore, these conventional methods are not suitable for screening for early diagnosis of AD.
　これに対し、近年、比較的低コストで且つ低侵襲で採取できる血液サンプルをマトリクス支援レーザ脱離イオン化質量分析装置（Matrix Assisted Laser Desorption/Ionization Mass Spectrometer）で測定し、その測定により求まるマススペクトル上のＡβ関連ペプチドのピーク強度から脳内におけるＡβの蓄積の有無を判定する手法が開発されている。 On the other hand, in recent years, blood samples that can be collected at a relatively low cost and with minimal invasiveness are measured by a matrix-assisted laser desorption / ionization mass spectrometer (Matrix Assisted Laser Desorption / Ionization Mass Spectrometer), and on the mass spectrum obtained by the measurement. A method for determining the presence or absence of Aβ accumulation in the brain from the peak intensity of Aβ-related peptides has been developed.
　例えば特許文献１、２、及び、非特許文献１、２には、マススペクトルにおいて観測される内部標準物質由来のピークの強度と着目するＡβ関連ペプチドに対応するマーカピークの強度との比をマーカ値として求め、そのマーカ値が予め定めた閾値（Cut-off値）を超えるか否かを判定することにより、Ａβ蓄積の有無を判別する技術が開示されている。以下、この手法を「アミロイドＭＳ」と呼ぶ。 For example, in 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 Aβ-related peptide of interest is marked. A technique for determining the presence or absence of Aβ 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. Hereinafter, this method is referred to as "amyloid MS".
　上述したアミロイドＭＳによれば、被検者に大きな負担を掛けることなくＡβ蓄積の有無を判別することが可能であるという大きな利点があり、今後の普及が期待されている。しかしながら、従来のアミロイドＭＳには次のような課題がある。 According to the above-mentioned amyloid MS, there is a great advantage that it is possible to determine the presence or absence of Aβ accumulation without imposing a heavy burden on the subject, and it is expected to be widely used in the future. However, the conventional amyloid MS has the following problems.
特許第６４１０８１０号公報Japanese Patent No. 6410810 特開２０１９－５３０６３号公報JP-A-2019-53063
　上述したように、ＡＤの診断や治療の現場ではアミロイドＰＥＴの利用が広まりつつあり、臨床現場の医師や検査技師等にとってはアミロイドＰＥＴのほうが馴染みがある。一般に、ＰＥＴでは、生体内の特定の部位に特異的に集積する放射性薬剤（以下、慣用に従って「プローブ」ということがある）を体内に投与し、放射性薬剤から放出される放射線量の分布を画像化する。薬剤の投与量や放射性元素の崩壊に伴う減衰の影響を除外するため、ＰＥＴ画像値は、特異的な集積がない部位での画像値で以て規格化したＳＵＶ（Standard Uptake Value）値と呼ばれる指標値を用いて評価される。 As mentioned above, the use of 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. In general, in PET, a radiopharmaceutical that specifically accumulates in a specific part of the body (hereinafter, may be referred to as a "probe" according to convention) is administered into the body, and the distribution of the amount of radiation emitted from the radiopharmaceutical is imaged. To become. In order to exclude the influence of the attenuation due to the dose of the drug and the decay of the radioactive element, 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.
　アミロイドＰＥＴ検査では、Ａβに特異的に結合するＰＩＢ（Pittsburg Compound B）等をプローブとして使用し、大脳部位のＰＥＴ画像値を、プローブの特異的結合がないとされる小脳部位におけるＰＥＴ画像値で以て規格化することによりＳＵＶ値が求められる。そのため、大脳へのＡβの蓄積がない又は殆どない場合、プローブの特異的結合は生じず、ＳＵＶ値はほぼ１となる。一方、大脳へのＡβの蓄積があると、ＳＵＶ値は１よりも大きな値を示す。通常、生体内にプローブを排除するメカニズムが存在しない限り、統計的な揺らぎを除いて、ＳＵＶ値が１を下回ることはない。 In the amyloid PET examination, PIB (Pittsburgh Compound B), which specifically binds to Aβ, is used as a probe, and 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 Aβ in the cerebrum, no specific binding of the probe occurs and the SUV value is approximately 1. On the other hand, when Aβ 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.
　従来のアミロイドＭＳでは、マススペクトルから算出されたマーカ値やこのマーカ値に基づいてＡβの蓄積の有無を判定するための閾値をユーザに提示することができる。しかしながら、上述したように、ユーザの多くはすでに利用が広がりつつあるアミロイドＰＥＴによって得られるＳＵＶ値に馴染んでいるため、アミロイドＭＳにおけるマーカ値や判定閾値がＳＵＶ値ではどの程度であるのかを知りたいという要望が強い。また、アミロイドＭＳにおけるマーカ値が、アミロイドＰＥＴにおいてプローブの特異的結合が生じるようなレベルであるのか、或いは、そうでないのかを簡便に把握したいという要望も強い。従来のアミロイドＭＳではこうした要望に応えることができない。 In the conventional amyloid MS, the marker value calculated from the mass spectrum and the threshold value for determining the presence or absence of Aβ accumulation can be presented to the user based on the marker value. However, as mentioned above, 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. There is a strong demand. In addition, there is a strong demand for easily grasping whether the marker value in amyloid MS is at a level at which specific binding of a probe occurs in amyloid PET or not. Conventional amyloid MS cannot meet these demands.
　本発明は上記課題を解決するためになされたものであり、その目的とするところは、アミロイドＭＳにより得られたデータやそれに基づく判定結果などをアミロイドＰＥＴに馴染んでいるユーザに対して分かり易く提示することができる、アミロイドβの脳内蓄積状態評価方法及び評価装置を提供することである。 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 β in the brain.
　上記課題を解決するために成された本発明の一態様のアミロイドβの脳内蓄積状態評価方法は、被検体から得られる生体試料に対し質量分析を利用したアミロイドＭＳの手法を適用することにより、該被検体の脳内におけるアミロイドβの蓄積状態を評価する方法であって、
　複数の参照用被検体それぞれに対し、アミロイドＭＳを実施することで得られた複数のアミロイドβ関連ペプチドの強度の比であるマーカ値と、アミロイドＰＥＴ検査を実施することで得られたＳＵＶ値と、のデータセットを取得するデータ収集工程と、
　前記データ収集工程で収集された複数のデータセットに基づいて、マーカ値をＳＵＶ値に換算する式又はテーブルを算出し、該式又はテーブルを構成するデータを求める換算用データ取得工程と、
　目的の被検体に対しアミロイドＭＳを実施することでマーカ値を取得する被検者実測工程と、
　前記換算用データ取得工程で得られたデータに基づく式又はテーブルを用い、前記被検者実測工程で取得したマーカ値をＳＵＶ値に変換する換算工程と、
　前記換算工程で得られたＳＵＶ値が、大脳へのアミロイドβの蓄積の有無に対応付けられる非特異的結合領域又は特異的結合領域のいずれに属するかを判定する判定工程と、
　前記換算工程で得られたＳＵＶ値及び前記判定工程による判定結果を表示部に表示する表示処理工程と、
　を有するものである。 One aspect of the method for evaluating the accumulation state of amyloid β in the brain, which was made to solve the above problems, 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 β in the brain of the subject.
The marker value, which is the ratio of the intensities of the plurality of amyloid β-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.
A determination step of determining whether the SUV value obtained in the conversion step belongs to a non-specific binding region or a specific binding region associated with the presence or absence of accumulation of amyloid β in the cerebrum.
A display processing step of displaying the SUV value obtained in the conversion step and the judgment result of the judgment step on the display unit, and
It has.
　また上記課題を解決するために成された本発明の一態様のアミロイドβの脳内蓄積状態評価装置は、
　質量分析部と、
　目的の被検体に対して前記質量分析部により得られる質量分析結果に基づき、複数のアミロイドβ関連ペプチドの強度の比を、アミロイドＭＳにおけるマーカ値として求めるマーカ値算出部と、
　アミロイドＭＳにおけるマーカ値をアミロイドＰＥＴ検査におけるＳＵＶ値に換算する式又はテーブルを構成するデータが格納された換算用データ記憶部と、
　前記換算用データ記憶部に格納されているデータに基づく式又はテーブルを用い、前記マーカ値算出部で得られたマーカ値をＳＵＶ値に変換する換算処理部と、
　前記換算処理部で得られたＳＵＶ値が、大脳へのアミロイドβの蓄積の有無に対応付けられる非特異的結合領域又は特異的結合領域のいずれに属するかを判定する判定処理部と、
　前記換算処理部で得られたＳＵＶ値及び前記判定処理部による判定結果を表示部に表示する表示処理部と、
　を備えるものである。 Further, the device for evaluating the accumulation state of amyloid β 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 β-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.
A determination processing unit for determining whether the SUV value obtained by the conversion processing unit belongs to a non-specific binding region or a specific binding region associated with the presence or absence of accumulation of amyloid β in the cerebrum.
A display processing unit that displays the SUV value obtained by the conversion processing unit and the determination result by the determination processing unit on the display unit.
Is provided.
　ここでいう「アミロイドＭＳ」とは、例えば特許文献１、非特許文献１、２等に開示されている検査手法であり、血液試料などの生体試料に対し質量分析を行うことで得られたマススペクトルにおいて観測される、アミロイドβに関連するペプチドに由来する特定の質量電荷比を有する複数のピークの強度比に基づいてマーカ値を算出する方法である。 The term "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 β observed in a spectrum.
　本発明の一態様であるアミロイドβの脳内蓄積状態評価方法及び評価装置によれば、アミロイドＰＥＴに比較して簡便で且つ被検者への負担も小さいアミロイドＭＳによる測定結果を、アミロイドＰＥＴで得られる検査結果と同様の形式で医療関係者等のユーザに提示することができる。これにより、アミロイドＰＥＴ検査に慣れているユーザが、アミロイドＭＳの検査結果に基づくアミロイドβの蓄積の有無の判定を、容易に且つ的確に行うことができる。 According to the method and apparatus for evaluating the accumulation state of amyloid β in the brain, which is one aspect of the present invention, 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 β based on the test result of amyloid MS.
本発明の一実施形態によるＡβ脳内蓄積状態評価装置の概略構成図。The schematic block diagram of the Aβ accumulation state evaluation apparatus by one Embodiment of this invention. 本実施形態のＡβ脳内蓄積状態評価装置において使用される換算式の作成手順を示すフローチャート。The flowchart which shows the creation procedure of the conversion formula used in the Aβ accumulation state evaluation apparatus of this embodiment. 本実施形態のＡβ脳内蓄積状態評価装置において使用される換算式と該換算式作成時のデータセットの一例を示す図。The figure which shows an example of the conversion formula used in the Aβ accumulation state evaluation apparatus of this embodiment, and the data set at the time of making the conversion formula.
　本発明に係るＡβ脳内蓄積状態評価方法及び評価装置の一実施形態について、添付図面を参照して説明する。 An embodiment of the Aβ accumulation state evaluation method and the evaluation device according to the present invention will be described with reference to the attached drawings.
　図１は本実施形態によるＡβ脳内蓄積状態評価装置の概略構成図である。
　この装置は、サンプルに対して質量分析を実行してマススペクトルデータを取得するＭＡＬＤＩ－ＴＯＦＭＳ（マトリスク支援レーザ脱離イオン化－飛行時間型質量分析装置）１と、マススペクトルデータを用いた解析処理を実行するデータ解析部２と、ユーザインタフェイスである入力部３及び表示部４と、を備える。データ解析部２は機能ブロックとして、マススペクトルデータ収集部２０と、ピーク検出部２１、マーカ値算出部２２と、ＳＵＶ値換算データ記憶部２３と、ＳＵＶ値換算部２４と、Ａβ蓄積判定部２５と、表示処理部２６と、を含む。 FIG. 1 is a schematic configuration diagram of an Aβ 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. It includes a data analysis unit 2 to be executed, an input unit 3 and a display unit 4 which are user interfaces. 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 Aβ accumulation determination unit 25 as functional blocks. And the display processing unit 26.
　データ解析部２の実体はパーソナルコンピュータ又はそれよりも高性能なコンピュータであり、該コンピュータに予めインストールされた専用のデータ解析ソフトウェアをコンピュータ上で動作させることで、それぞれの機能を実現させるようにすることができる。 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.
　ＳＵＶ値換算データ記憶部２３には、予備的な測定の結果に基づいて予め作成された、アミロイドＭＳにおけるマーカ値をアミロイドＰＥＴにおけるＳＵＶ値に変換するための換算式を構成するデータが格納される。この予備的な測定や換算式の作成は、一般的には、本実施形態のＡβ脳内蓄積状態評価装置を提供するメーカや該装置に使用されるデータ解析ソフトウェアを提供するメーカなどにおいて行われるものとすることができるが、換算式を作成して保存する機能を本実施形態の装置に持たせるようにしてもよい。図２はこの換算式の作成手順を示すフローチャートである。図２を参照して、この換算式の作成方法とその手順について説明する。 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 Aβ accumulation state evaluation device of the present embodiment, a manufacturer that provides data analysis software used for the device, and the like. However, 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.
　換算式を作成するには、参照用の被検者に対する実測により得られた多数のデータセットを予め用意する必要がある。一つのデータセットは、一人の参照用の被検者に対してアミロイドＰＥＴ検査を行うことで求められたＳＵＶ値と、同じ被検者に対してアミロイドＰＥＴ検査とほぼ同時期に実施されたアミロイドＭＳにおいて求まったマーカ値と、を含む。 In order to create a conversion formula, it is necessary to prepare in advance a large number of data sets obtained by actual measurement of the subject for reference. 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.
　既に述べたように、アミロイドＭＳは、特許文献１、２、及び非特許文献１、２等に記載されている既知の手法である。典型的には、被検者から採取した、全血、血漿、血清などの血液試料をＭＡＬＤＩ－ＴＯＦＭＳで質量分析し、所定の質量電荷比範囲のマススペクトルを取得する。質量分析の際には所定の内標物質を試料に添加することができる。そして、得られたマススペクトルにおいてアミロイドβに関連する複数の特定の質量電荷比のピーク強度を求め、そのピーク強度比などに基づきマーカ値を計算する。 As already described, amyloid MS is a known method described in Patent Documents 1 and 2, Non-Patent Documents 1 and 2, and the like. Typically, 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. At the time of mass spectrometry, a predetermined internal standard substance can be added to the sample. Then, in the obtained mass spectrum, the peak intensities of a plurality of specific mass-to-charge ratios related to amyloid β are obtained, and the marker value is calculated based on the peak intensity ratio and the like.
　例えば、特許文献１に記載の方法では、生体試料中のＡＰＰ由来のＡβ及びＡβ様ペプチド（Ａβ派生型ペプチド）についての３つのピーク強度比Ａβ1-39／Ａβ1-42、Ａβ1-40／Ａβ1-42、ＡＰＰ669-711／Ａβ1-42のうちの２以上の比を数学的手法で組み合わせた数値をマーカ値としている。また、特許文献２に記載の方法では、さらに別のＡβ派生型ペプチドのピーク強度比がマーカ値として利用されている。本実施形態のＡβの脳内蓄積状態評価方法では、こうした質量分析の結果から算出されるいずれかのマーカ値をデータセットのデータとして利用することができる。一方、アミロイドＰＥＴ検査では、被検者から得られたＰＥＴ画像に基づいてＳＵＶ値を算出することができる。したがって、同一の被検者に対し、アミロイドＭＳとアミロイドＰＥＴ検査とをほぼ同時期に実施することで、参照用データセットを求めることができる（ステップＳ１１）。当然のことながら、換算式の精度を高めるうえではデータセットの数は多いほうがよい。 For example, in the method described in Patent Document 1, three peak intensity ratios Aβ 1-39 / Aβ 1-42 and Aβ 1-40 for APP-derived Aβ and Aβ-like peptides (Aβ-derived peptides) in biological samples. The marker value is a combination of two or more ratios of / Aβ 1-42 and APP 669-711 / Aβ 1-42 by a mathematical method. Further, in the method described in Patent Document 2, the peak intensity ratio of yet another Aβ-derived peptide is used as a marker value. In the method for evaluating the accumulation state of Aβ in the brain of the present embodiment, any marker value calculated from the result of such mass spectrometry can be used as data in the data set. On the other hand, in the amyloid PET examination, 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.
　次に、参照用データセットを用いてマーカ値からＳＵＶ値への換算式を作成する（ステップＳ１２）。上述したようにＳＵＶ値は、大脳へのＡβの蓄積がない又は殆どない場合には１であり、大脳へのＡβの蓄積があると１よりも大きな値を示す。特殊な場合を除き、ＳＵＶ値が１を下回ることはない。そこで、ここではマーカ値ＭからＳＵＶ値Ｓへの換算式として次のような区分的多項式を考える。
　　　Ｓ＝１，　　　Ｍ＜Ｍ0，
　　　Ｓ＝１＋Ａ（Ｍ－Ｍ0），　　Ｍ≧Ｍ0，　　…(1)
即ち、(1)式は、マーカ値Ｍが定数Ｍ0未満である範囲ではＳＵＶ値Ｓは定数１であり、マーカ値Ｍが定数Ｍ0以上である範囲ではＳＵＶ値Ｓとマーカ値Ｍとの関係は１次関数になるという、単調増加の区分的多項式を表している。(1)式の定数Ｍ0及び係数Ａは、参照用データセットを用いた最小二乗法等によるパラメータ推定によって求めればよい。 Next, a conversion formula from the marker value to the SUV value is created using the reference data set (step S12). As described above, the SUV value is 1 when there is no or almost no accumulation of Aβ in the cerebrum, and shows a value larger than 1 when there is accumulation of Aβ in the cerebrum. Except in special cases, the SUV value never falls below 1. Therefore, here, the following piecewise polynomial is considered as a conversion formula from the marker value M to the SUV value S.
S = 1, M <M 0 ,
S = 1 + A (MM 0 ), M ≥ M 0 , ... (1)
That is, in Eq. (1), the SUV value S is a constant 1 in the range where the marker value M is less than the constant M 0 , and 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.
　図３は、実測値（参照用データセット）とこれから最小二乗法によって推定した換算式を示す図である。図に示すように、定数Ｍ0は特異的結合領域と非特異的結合領域とを分ける境界値であり、マーカ値ＭがＭ0未満又はＭ0以上のいずれであるのかによって、そのマーカ値に対応するＳＵＶ値が特異的結合領域と非特異的結合領域のいずれであるのかを判別することができる。 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. As shown in the figure, the constant M 0 is a boundary value that separates the specific binding region and the non-specific binding region, and 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.
　上記のように区分的多項式が求まったならば、その式の係数Ａ及び定数Ｍ0をＳＵＶ値換算データとして取得し（ステップＳ１３）、これをＳＵＶ値換算データ記憶部２３に保存する。なお、換算式を算出する際には、最小二乗法以外のアルゴリズムを用いてもよい。また、Ｍ≧Ｍ0の多項式は１次関数に限らず、より高次の関数を用いてもよい。 When the piecewise polynomial is obtained as described above, 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. When calculating the conversion formula, an algorithm other than the least squares method may be used. Further, the polynomial of M ≧ M 0 is not limited to the linear function, and a higher-order function may be used.
　次に、本実施形態のＡβ脳内蓄積状態評価装置における評価実行時の動作を説明する。
　被検者から採取された血液試料（未知サンプル）に対し、ＭＡＬＤＩ－ＴＯＦＭＳ１を用いて測定を実行し、マススペクトルデータ収集部２０は所定の質量電荷比範囲に亘るマススペクトルデータを収集する。ピーク検出部２１は取得されたマススペクトルに対しピーク検出を行い、マーカ値算出部２２はアミロイドβに関連する所定の質量電荷比におけるピーク強度の比からマーカ値を算出する。このマーカ値がアミロイドＭＳにおけるマーカ値である。 Next, the operation during evaluation execution in the Aβ accumulation state evaluation device of the present embodiment will be described.
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 β. This marker value is the marker value in amyloid MS.
　ＳＵＶ値換算部２４は、ＳＵＶ値換算データ記憶部２３に格納されている係数及び定数を用いて構成される換算式に上記算出されたマーカ値を代入しＳＵＶ値を求める。また、Ａβ蓄積判定部２５は、算出されたＳＵＶ値が特異的結合領域、非特異的結合領域のいずれに属するのかを判定する。そして、表示処理部２６は、被検者についてのＡβ脳内蓄積状態評価結果として、アミロイドＭＳにおけるマーカ値、アミロイドＰＥＴにおけるＳＵＶ値（換算値）、及び、ＳＵＶ値が特異的結合領域、非特異的結合領域のいずれに属するのか、を表示部４の画面上に表示する。このときの表示の態様は特に問わない。 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 Aβ 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 Aβ 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.
　これにより、ユーザは、アミロイドＭＳにおけるマーカ値に対応するＳＵＶ値を容易に把握することができる。また、ＳＵＶ値が特異的結合領域、非特異的結合領域のいずれに属するのか、つまりはＡβが脳内に蓄積している可能性があるのか否かも把握することができる。 As a result, 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 Aβ may be accumulated in the brain.
　なお、上記実施形態はあくまでも本発明の一例にすぎず、本発明の趣旨の範囲で適宜変形、修正、追加等を行っても本願特許請求の範囲に包含されることは当然である。 It should be noted that the above embodiment is merely an example of the present invention, and it is natural that the present invention is included in the claims even if it is appropriately modified, modified, added, etc. within the scope of the present invention.
　［種々の態様］
　上述した例示的な実施形態は、以下の態様の具体例であることが当業者により理解される。 [Various aspects]
Those skilled in the art will appreciate that the exemplary embodiments described above are specific examples of the following embodiments.
　（第１項）本発明に係るアミロイドβの脳内蓄積状態評価方法の一態様は、被検体から得られる生体試料に対し質量分析を利用したアミロイドＭＳの手法を適用することにより、該被検体の脳内におけるアミロイドβの蓄積状態を評価する方法であって、
　複数の参照用被検体それぞれに対し、アミロイドＭＳを実施することで得られた複数のアミロイドβ関連ペプチドの強度の比であるマーカ値と、アミロイドＰＥＴ検査を実施することで得られたＳＵＶ値と、のデータセットを取得するデータ収集工程と、
　前記データ収集工程で収集された複数のデータセットに基づいて、マーカ値をＳＵＶ値に換算する式又はテーブルを算出し、該式又はテーブルを構成するデータを求める換算用データ取得工程と、
　目的の被検体に対しアミロイドＭＳを実施することでマーカ値を取得する被検者実測工程と、
　前記換算用データ取得工程で得られたデータに基づく式又はテーブルを用い、前記被検者実測工程で取得したマーカ値をＳＵＶ値に変換する換算工程と、
　前記換算工程で得られたＳＵＶ値が、大脳へのアミロイドβの蓄積の有無に対応付けられる非特異的結合領域又は特異的結合領域のいずれに属するかを判定する判定工程と、
　前記換算工程で得られたＳＵＶ値及び前記判定工程による判定結果を表示部に表示する表示処理工程と、
　を有するものである。 (Item 1) One aspect of the method for evaluating the state of accumulation of amyloid β 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 β in the brain of
The marker value, which is the ratio of the intensities of the plurality of amyloid β-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.
A determination step of determining whether the SUV value obtained in the conversion step belongs to a non-specific binding region or a specific binding region associated with the presence or absence of accumulation of amyloid β in the cerebrum.
A display processing step of displaying the SUV value obtained in the conversion step and the judgment result of the judgment step on the display unit, and
It has.
　（第５項）また本発明に係るアミロイドβの脳内蓄積状態評価装置の一態様は、
　質量分析部と、
　目的の被検体に対して前記質量分析部により得られる質量分析結果に基づき、複数のアミロイドβ関連ペプチドの強度の比を、アミロイドＭＳにおけるマーカ値として求めるマーカ値算出部と、
　アミロイドＭＳにおけるマーカ値をアミロイドＰＥＴ検査におけるＳＵＶ値に換算する式又はテーブルを構成するデータが格納された換算用データ記憶部と、
　前記換算用データ記憶部に格納されているデータに基づく式又はテーブルを用い、前記マーカ値算出部で得られたマーカ値をＳＵＶ値に変換する換算処理部と、
　前記換算処理部で得られたＳＵＶ値が、大脳へのアミロイドβの蓄積の有無に対応付けられる非特異的結合領域又は特異的結合領域のいずれに属するかを判定する判定処理部と、
　前記換算処理部で得られたＳＵＶ値及び前記判定処理部による判定結果を表示部に表示する表示処理部と、
　を備えるものである。 (Section 5) Further, one aspect of the device for evaluating the accumulation state of amyloid β in the brain according to the present invention is
Mass spectrometry and
A marker value calculation unit that obtains the ratio of the intensities of a plurality of amyloid β-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.
A determination processing unit for determining whether the SUV value obtained by the conversion processing unit belongs to a non-specific binding region or a specific binding region associated with the presence or absence of accumulation of amyloid β in the cerebrum.
A display processing unit that displays the SUV value obtained by the conversion processing unit and the determination result by the determination processing unit on the display unit.
Is provided.
　第１項に記載のアミロイドβの脳内蓄積状態評価方法及び第５項に記載のアミロイドβの脳内蓄積状態評価装置によれば、アミロイドＰＥＴに比較して簡便で、被検者への負担も小さく、さらにはコスト的に有利であるアミロイドＭＳによる測定結果を、アミロイドＰＥＴで得られる検査結果と同様の形式で医療関係者等のユーザに提示することができる。これにより、アミロイドＰＥＴ検査に慣れているユーザが、アミロイドＭＳの検査結果に基づくアミロイドβの蓄積の有無の判定を容易に且つ的確に行うことができる。 According to the method for evaluating the accumulation state of amyloid β in the brain described in item 1 and the device for evaluating the accumulation state of amyloid β 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 β based on the test result of amyloid MS.
　（第２項）第１項に記載のアミロイドβの脳内蓄積状態評価方法において、前記換算用データ取得工程では、マーカ値をＳＵＶ値に換算する式として、マーカ値を複数に区分し、少なくとも１つの区分においてマーカ値の増加に対しＳＵＶ値が単調に増加する区分的多項式、を算出するものとすることができる。 (Item 2) In the method for evaluating the accumulation state of amyloid β in the brain according to the item 1, in the conversion data acquisition step, 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.
　上述したように、大脳へのＡβの蓄積がない又は殆どない場合、つまりはプローブが特異的に結合しない場合、ＳＵＶ値はほぼ１となる。第２項に記載の評価方法によれば、区分的多項式により、ＳＵＶ値がほぼ１となる領域とそうでない領域とを区分することで、ＳＵＶ値が１とならない領域でより的確な多項式を求めることができる。それにより、アミロイドＭＳにおけるマーカ値からＳＵＶ値への換算の正確性が向上する。 As described above, when there is no or almost no accumulation of Aβ in the cerebrum, that is, when the probe does not specifically bind, the SUV value is almost 1. According to the evaluation method described in the second term, 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. As a result, the accuracy of conversion from the marker value to the SUV value in amyloid MS is improved.
　（第３項）第２項に記載のアミロイドβの脳内蓄積状態評価方法において、前記区分的多項式は、マーカ値が所定値以下の範囲において定数であり、マーカ値が該所定値以上の範囲では１次関数であるものとすることができる。 (Section 3) In the method for evaluating the accumulation state of amyloid β in the brain according to the second paragraph, 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.
　第３項に記載の評価方法によれば、比較的簡単な区分的多項式で以て、アミロイドＭＳにおけるマーカ値からＳＵＶ値への精度の高い換算を行うことができる。 According to the evaluation method described in the third paragraph, it is possible to perform highly accurate conversion from the marker value in the amyloid MS to the SUV value by using a relatively simple piecewise polynomial.
　（第４項）第３項に記載のアミロイドβの脳内蓄積状態評価方法において、前記所定値、前記定数、及び前記１次関数の係数は、複数のデータセットを用いた最小二乗法により推定されるものとすることができる。 (Item 4) In the method for evaluating the state of accumulation of amyloid β in the brain according to item 3, 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.
　第４項に記載の評価方法によれば、比較的簡単な演算処理によって、アミロイドＭＳにおけるマーカ値からＳＵＶ値への精度の高い換算を行える換算式を求めることができる。 According to the evaluation method described in paragraph 4, it is possible to obtain a conversion formula capable of highly accurate conversion from the marker value in the amyloid MS to the SUV value by a relatively simple calculation process.
１…ＭＡＬＤＩ－ＴＯＦＭＳ
２…データ解析部
　２０…マススペクトルデータ収集部
　２１…ピーク検出部
　２２…マーカ値算出部
　２３…ＳＵＶ値換算データ記憶部
　２４…ＳＵＶ値換算部
　２５…Ａβ蓄積判定部
　２６…表示処理部
３…入力部
４…表示部 1 ... MALDI-TOFMS
2 ... Data analysis unit 20 ... Mass spectrum data collection unit 21 ... Peak detection unit 22 ... Marker value calculation unit 23 ... SUV value conversion data storage unit 24 ... SUV value conversion unit 25 ... Aβ accumulation determination unit 26 ... Display processing unit 3 ... Input unit 4 ... Display unit

Claims (5)

  1. 　被検体から得られる生体試料に対し質量分析を利用したアミロイドＭＳの手法を適用することにより、該被検体の脳内におけるアミロイドβの蓄積状態を評価する方法であって、
    　複数の参照用被検体それぞれに対し、アミロイドＭＳを実施することで得られた複数のアミロイドβ関連ペプチドの強度の比であるマーカ値と、アミロイドＰＥＴ検査を実施することで得られたＳＵＶ値と、のデータセットを取得するデータ収集工程と、
    　前記データ収集工程で収集された複数のデータセットに基づいて、マーカ値をＳＵＶ値に換算する式又はテーブルを算出し、該式又はテーブルを構成するデータを求める換算用データ取得工程と、
    　目的の被検体に対しアミロイドＭＳを実施することでマーカ値を取得する被検者実測工程と、
    　前記換算用データ取得工程で得られたデータに基づく式又はテーブルを用い、前記被検者実測工程で取得したマーカ値をＳＵＶ値に変換する換算工程と、
    　前記換算工程で得られたＳＵＶ値が、大脳へのアミロイドβの蓄積の有無に対応付けられる非特異的結合領域又は特異的結合領域のいずれに属するかを判定する判定工程と、
    　前記換算工程で得られたＳＵＶ値及び前記判定工程による判定結果を表示部に表示する表示処理工程と、
    　を有するアミロイドβの脳内蓄積状態評価方法。     A method for evaluating the accumulation state of amyloid β in the brain of a subject by applying the method of amyloid MS using mass spectrometry to a biological sample obtained from the subject.
    The marker value, which is the ratio of the intensities of the plurality of amyloid β-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.
    A determination step of determining whether the SUV value obtained in the conversion step belongs to a non-specific binding region or a specific binding region associated with the presence or absence of accumulation of amyloid β in the cerebrum.
    A display processing step of displaying the SUV value obtained in the conversion step and the judgment result of the judgment step on the display unit, and
    A method for evaluating the accumulation state of amyloid β in the brain.
  2. 　前記換算用データ取得工程では、マーカ値をＳＵＶ値に換算する式として、マーカ値を複数に区分し、少なくとも１つの区分においてマーカ値の増加に対しＳＵＶ値が単調に増加する区分的多項式、を算出する、請求項１に記載のアミロイドβの脳内蓄積状態評価方法。 In the conversion data acquisition step, as an expression for converting the marker value into the SUV value, a piecewise polynomial in which the marker value is divided into a plurality of pieces and the SUV value increases monotonically with respect to the increase in the marker value in at least one division is used. The method for evaluating the accumulation state of amyloid β in the brain according to claim 1, which is calculated.
  3. 　前記区分的多項式は、マーカ値が所定値以下の範囲において定数であり、マーカ値が該所定値以上の範囲では１次関数である、請求項２に記載のアミロイドβの脳内蓄積状態評価方法。 The method for evaluating the accumulation state of amyloid β in the brain according to claim 2, wherein the piecewise polynomial is a constant in the range where the marker value is equal to or less than a predetermined value, and is a linear function in the range where the marker value is equal to or more than the predetermined value. ..
  4. 　前記所定値、前記定数、及び前記１次関数の係数は、複数のデータセットを用いた最小二乗法により推定される、請求項３に記載のアミロイドβの脳内蓄積状態評価方法。 The method for evaluating the accumulation state of amyloid β in the brain according to claim 3, wherein 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.
  5. 　質量分析部と、
    　目的の被検体に対して前記質量分析部により得られる質量分析結果に基づき、複数のアミロイドβ関連ペプチドの強度の比を、アミロイドＭＳにおけるマーカ値として求めるマーカ値算出部と、
    　アミロイドＭＳにおけるマーカ値をアミロイドＰＥＴ検査におけるＳＵＶ値に換算する式又はテーブルを構成するデータが格納された換算用データ記憶部と、
    　前記換算用データ記憶部に格納されているデータに基づく式又はテーブルを用い、前記マーカ値算出部で得られたマーカ値をＳＵＶ値に変換する換算処理部と、
    　前記換算処理部で得られたＳＵＶ値が、大脳へのアミロイドβの蓄積の有無に対応付けられる非特異的結合領域又は特異的結合領域のいずれに属するかを判定する判定処理部と、
    　前記換算処理部で得られたＳＵＶ値及び前記判定処理部による判定結果を表示部に表示する表示処理部と、
    　を備えるアミロイドβの脳内蓄積状態評価装置。     Mass spectrometry and
    A marker value calculation unit that obtains the ratio of the intensities of a plurality of amyloid β-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.
    A determination processing unit for determining whether the SUV value obtained by the conversion processing unit belongs to a non-specific binding region or a specific binding region associated with the presence or absence of accumulation of amyloid β in the cerebrum.
    A display processing unit that displays the SUV value obtained by the conversion processing unit and the determination result by the determination processing unit on the display unit.
    A device for evaluating the accumulation state of amyloid β in the brain.
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