Method for assisting in diagnosis of progressive supranuclear palsy

Abstract

To provide a method for diagnosing progressive supranuclear palsy.SOLUTION: A method for assisting in diagnosis of progressive supranuclear palsy comprises: calculating a midbrain uptake ratio (MUR) obtained by the formula (I): MUR=(positron emission intensity of at least one or more of a midpoint 1 region and a midpoint 2 region of a subject) / (positron emission intensity of at least one or more of a midbrain midpoint 1 region, a substantia nigra midpoint 1 region, and a substantia nigra midpoint 2 region of the subject) using positron emission tomography (PET) and magnetic resonance imaging (MRI) using an MAO-B ligand probe; and comparing the midbrain uptake ratio (MUR) with a reference value for healthy persons, to determine that the subject has progressive supranuclear palsy when the MUR is higher than the reference value.SELECTED DRAWING: Figure 9

Description

[Technical field]

[0001] The present invention relates to a method for assisting in the diagnosis of progressive supranuclear palsy. [Background technology]

[0002] Progressive supranuclear palsy is characterized by vertical gaze palsy, pseudobulbar palsy, nuchal dystonia, dementia, or impaired postural reflexes, and specifically includes symptoms such as a tendency to fall, difficulty seeing downwards, difficulty speaking, and difficulty swallowing. These symptoms are also seen in neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia, and Lewy body disease, so differential diagnosis from these neurodegenerative diseases is necessary. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Clinical Nuclear Medicine 2022 (USA) Vol. 47, e489-e495 Summary of the Invention [Problem to be solved by the invention]

[0004] It is therefore an object of the present invention to provide a method for diagnosing progressive supranuclear palsy. [Means for solving the problem]

[0005] The present inventors have conducted extensive research into a method for differential diagnosis of progressive supranuclear palsy and, as a result, have surprisingly found that progressive supranuclear palsy can be easily diagnosed by performing specific processing using positron emission tomography (PET) and magnetic resonance imaging (MRI). 18We reported the intracerebral distribution of monoamine oxidase B in healthy subjects using positron emission tomography (PET) using F-THK5351 (Non-Patent Document 1). The present invention is based on these findings. Thus, the present invention provides [1] A diagnostic aid method for progressive supranuclear palsy, comprising: (1) calculating the midbrain uptake ratio (MUR) obtained by the following formula (I) using positron emission tomography (PET) and magnetic resonance imaging (MRI) using an MAO-B ligand probe; Formula (I): Midbrain Uptake Ratio (MUR) = (positron emission intensity of at least one of the midpoint 1 and midpoint 2 regions of a subject) / (positron emission intensity of at least one of the midbrain midpoint 1, substantia nigra midpoint 1, and substantia nigra midpoint 2 regions of a subject) (In the formula, the midbrain center point 1 region, the substantia nigra center point 1 region, the substantia nigra center point 2 region, the intermediate point 1 region, and the intermediate point 2 region are defined by (a) specifying the midbrain center point 1 at the center of the midbrain aqueduct, and the substantia nigra center point 1 and the substantia nigra center point 2 at the centers of the two substantia nigra compact parts in a cut surface in a standard brain where the midbrain central gray matter, the oculomotor nucleus, the red nucleus, and the substantia nigra can be observed, (b) specifying the intermediate point 1 between the midbrain center point 1 and the substantia nigra center point 1, and the intermediate point 2 between the midbrain center point 1 and the substantia nigra center point 2, and (c) specifying the three-dimensional midbrain center points centered on the midbrain center point 1, the substantia nigra center point 1, the substantia nigra center point 2, the intermediate point 1, and the intermediate point 2. (d) converting the midbrain center 1 region, substantia nigra center 1 region, substantia nigra center 2 region, midpoint 1 region, and midpoint 2 region of the standard brain into the midbrain center 1 region, substantia nigra center 1 region, substantia nigra center 2 region, midpoint 1 region, and midpoint 2 region of the subject's brain in positron emission tomography (PET) and magnetic resonance imaging (MRI), and (2) comparing the midbrain uptake ratio (MUR) with a standard value for healthy individuals and determining that the patient has progressive supranuclear palsy if the MUR is higher than the standard value; A diagnostic aid for progressive supranuclear palsy, comprising: [2] The diagnostic aid method for progressive supranuclear palsy according to [1], wherein the formula (I) is the formula (II): midbrain uptake ratio (MUR) = (positron emission intensity of the midbrain midpoint 1 region and the midpoint 2 region of the subject) / (positron emission intensity of the midbrain midpoint 1 region, the substantia nigra midpoint 1 region, and the substantia nigra midpoint 2 region of the subject). [3] The diagnostic support method for progressive supranuclear palsy according to [2], wherein the subject's midbrain center point 1 region, substantia nigra center point 1 region, substantia nigra center point 2 region, midpoint 1 region, and midpoint 2 region are each represented by a plurality of voxels, and the positron emission intensity is an average value of the plurality of voxels. [4] A method for assisting in the differential diagnosis of progressive supranuclear palsy, using the method for assisting in the diagnosis of progressive supranuclear palsy according to any one of [1] to [3]. [5] A program for diagnosing progressive supranuclear palsy, which causes a computer to execute the following steps: (A-1) inputting data of a positron emission tomography (PET) image and a magnetic resonance imaging (MRI) image of the subject's brain into a computer; (A-2) converting the midbrain center point 1 region, the substantia nigra center point 1 region, the substantia nigra center point 2 region, the midpoint 1 region, and the midpoint 2 region of a standard brain into the midbrain center point 1 region, the substantia nigra center point 1 region, the substantia nigra center point 2 region, the midpoint 1 region, and the midpoint 2 region in the positron emission tomography (PET) image and the magnetic resonance imaging (MRI) image of the subject's brain; (B) acquiring the positron emission intensity of each region in the positron emission tomography (PET) image of the subject, and substituting each of the obtained intensities into the following formula (I) to calculate the midbrain uptake ratio (MUR) of the subject; Formula (I): Midbrain Uptake Ratio (MUR) = (positron emission intensity of at least one of the midpoint 1 and midpoint 2 regions of a subject) / (positron emission intensity of at least one of the midbrain midpoint 1, substantia nigra midpoint 1, and substantia nigra midpoint 2 regions of a subject) (C) comparing the obtained midbrain uptake ratio (MUR) of the subject with a standard value for healthy individuals, and determining that the subject has progressive supranuclear palsy if the MUR is higher than the standard value; [6] The compound of formula (I), Formula (II): Midbrain uptake ratio (MUR) = (positron emission intensity of midbrain midpoint 1 region and midpoint 2 region of the subject) / (positron emission intensity of midbrain midpoint 1 region, substantia nigra midpoint 1 region, and substantia nigra midpoint 2 region of the subject), [5] a diagnostic program for progressive supranuclear palsy according to the present invention; [7] The progressive supranuclear palsy diagnostic program according to [6], wherein the midbrain center 1 region, the substantia nigra center 1 region, the substantia nigra center 2 region, the midpoint 1 region, and the midpoint 2 region of the subject are each composed of a plurality of voxels, and the positron emission intensity in each of the regions is the average value of the plurality of voxels; and [8] A diagnostic system for progressive supranuclear palsy comprising a positron emission tomography (PET) image, a magnetic resonance imaging (MRI) image, and a computer having the program according to [7] stored therein; Regarding. Effect of the Invention

[0006] According to the diagnostic aid method for progressive supranuclear palsy of the present invention, progressive supranuclear palsy can be accurately diagnosed. [Brief description of the drawings]

[0007] [Figure 1] FIG. 1 shows a cross section in which the midbrain central gray matter, oculomotor nucleus, red nucleus, and substantia nigra can be observed. [Diagram 2] FIG. 2A shows midbrain center 1, substantia nigra center 1, substantia nigra center 2, intermediate point 1, and intermediate point 2 in a cut surface on which the midbrain central gray matter, oculomotor nucleus, red nucleus, and substantia nigra can be observed on MRI; and FIG. 2B shows midbrain center 1 region, substantia nigra center 1 region, substantia nigra center 2 region, intermediate point 1 region, and intermediate point 2 region. [Diagram 3] FIG. 13 is an exemplary diagram showing the process of identifying midbrain center1 region, substantia nigra center1 region, substantia nigra center2 region, midpoint1 region, and midpoint2 region in three consecutive sections spaced 1 mm apart. [Figure 4] FIG. 1 shows the transformation of the midbrain center 1 region, the substantia nigra center 1 region, the substantia nigra center 2 region, the midpoint 1 region, and the midpoint 2 region from a standard brain to a subject's brain. [Diagram 5] This is a two-dimensional diagram showing the PET positron emission intensity in healthy controls (HC) and progressive supranuclear palsy (PSP) for the sake of convenience. [Figure 6] FIG. 1 is a diagram showing an example of changes in PET images from a healthy subject to a subject with progressive supranuclear palsy (PSP). [Figure 7] FIG. 1 shows representative 18F-THK5351 images from the HC group, PSP group, and Alzheimer's disease (AD) group. [Figure 8] 1 is a graph showing the MUR values ​​of the HC group, the PSP group, and the AD group. [Figure 9] 1 is a flow chart of one embodiment of the program of the present invention. [Figure 10] 1 is a schematic diagram showing an overview of a system according to the present invention; DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] [1] Diagnostic aid for progressive supranuclear palsy The diagnostic support method for progressive supranuclear palsy of the present invention includes the steps of: (1) calculating the midbrain uptake ratio (MUR) obtained by formula (I) using positron emission tomography (PET) and magnetic resonance imaging (MRI) using an MAO-B ligand probe; and (2) comparing the midbrain uptake ratio (MUR) with a standard value for healthy individuals, and determining that the patient has progressive supranuclear palsy if the MUR is higher than the standard value. The formula (I) is as follows: Formula (I): Midbrain Uptake Ratio (MUR) = (positron emission intensity of at least one of the midpoint 1 and midpoint 2 regions of a subject) / (positron emission intensity of at least one of the midbrain midpoint 1, substantia nigra midpoint 1, and substantia nigra midpoint 2 regions of a subject). In the formula (I), the midbrain center point 1 region, substantia nigra center point 1 region, substantia nigra center point 2 region, intermediate point 1 region, and intermediate point 2 region of the subject are defined as follows: (a) in a cut surface in a standard brain in which the midbrain central gray matter, oculomotor nucleus, red nucleus, and substantia nigra can be observed, the midbrain center point 1 in the center of the midbrain aqueduct, and the substantia nigra center point 1 and substantia nigra center point 2 in the centers of the two substantia nigra compacta, (b) the intermediate point 1 between the midbrain center point 1 and the substantia nigra center point 1, and the intermediate point 2 between the midbrain center point 1 and the substantia nigra center point 2, and (c) the midbrain center point 1, the substantia nigra center point (d) identifying three-dimensional midbrain center 1 region, substantia nigra center 1 region, substantia nigra center 2 region, midpoint 1 region, and midpoint 2 region centered on substantia nigra center 1, substantia nigra center 2 region, midpoint 1 region, and midpoint 2 region of the standard brain, and (e) converting the midbrain center 1 region, substantia nigra center 1 region, substantia nigra center 2 region, midpoint 1 region, and midpoint 2 region of the standard brain into the midbrain center 1 region, substantia nigra center 1 region, substantia nigra center 2 region, midpoint 1 region, and midpoint 2 region of the positron emission tomography (PET) and magnetic resonance imaging (MRI) of the subject's brain. Here, "positron emission intensity" refers to a value proportional to the amount of ligand uptake obtained by analyzing PET data using conventional analytical software, and may be obtained by any method as long as it is a value that reflects the amount of ligand uptake.

[0009] 《Progressive supranuclear palsy》 Progressive supranuclear palsy (PSP) is a neurodegenerative disease with symptoms such as vertical gaze palsy, pseudobulbar palsy, nuchal dystonia, dementia, and impaired postural control. Pathological findings include neurogenic fiber tangles, neuronal loss, and astrogliosis in the globus pallidus, subthalamic nucleus, and dentate nucleus.

[0010] Midbrain Uptake Ratio (MUR) Calculation Process (1) The midbrain uptake ratio (MUR) can be calculated by the following formula (I). Formula (I): Midbrain Uptake Ratio (MUR) = (positron emission intensity of at least one of the midpoint 1 and midpoint 2 regions of a subject) / (positron emission intensity of at least one of the midbrain midpoint 1, substantia nigra midpoint 1, and substantia nigra midpoint 2 regions of a subject). The "positron emission intensity" in the above formula can be obtained by positron emission tomography (PET). In addition, the "midpoint 1 region", "midpoint 2 region", "midbrain midpoint 1 region", "substantia nigra midpoint 1 region", and "substantia nigra midpoint 2 region" can be identified using magnetic resonance imaging (MRI). Therefore, the midbrain uptake ratio (MUR) can be obtained by combining positron emission tomography (PET) data and magnetic resonance imaging (MRI) data.

[0011] Positron Emission Tomography (PET) The positron emission tomography (PET) in the present invention can be used without being limited to conventional techniques in this field. In a PET examination, a PET probe that emits a small amount of radiation is administered to a subject, and radiation in the subject's body is photographed by a PET device (positron emission tomography device). The PET device may be one that measures PET data alone, a PET-CT device that acquires PET data and CT data, or a PET-MRI device that acquires PET data and MRI data.

[0012] (MAO-B ligand probe) The probe used in the PET of the present invention is, but is not limited to, a probe that binds to monoamine oxidase B (MAO-B). MAO-B is present in nerve cells and astrocytes, and in platelets outside the central nervous system. In the PET test of the present invention, astrogliosis can be detected by detecting MAO-B in astrocytes in particular. That is, the PET test of the present invention is a test for detecting astrogliosis. Therefore, any marker that can detect astrogliosis may be a probe. The compound that binds to MAO-B is not particularly limited, but may be, for example, 18 F-THK5351, 18 F-SMBT1, or 11 CL-deprenyl-D 2 Examples of radiolabeled versions of these compounds include, but are not limited to, 18 F-THK5351: [ka] 18 F-SMBT1: [ka] or 11 CL-deprenyl-D 2 : [ka] Examples include:

[0013] Magnetic Resonance Imaging (MRI) The magnetic resonance imaging (MRI) used in the present invention can be used without being limited to techniques common in this field. MRI utilizes the nuclear magnetic resonance (NMR) phenomenon to image information inside a living body. Specifically, a high-frequency magnetic field is applied to a subject, causing a resonance phenomenon in hydrogen atoms in the human body. Then, radio waves generated from the resonating atoms are acquired by a receiving coil, and the obtained signal data is configured into a three-dimensional image. For example, cross-sectional data of the brain obtained by MRI is shown in Figs. 2 to 4.

[0014] The MRI allows the identification of the three-dimensional structure of the brain. The PET allows the identification of the accumulation of MAO-B in the body. Therefore, by combining the MRI data and the PET data, it is possible to identify in which part (structure) of the brain (body) MAO-B is accumulated in a three-dimensional manner.

[0015] Standard Brain The shape (structure) of the brain obtained by MRI varies depending on the individual (subject). Therefore, the "midpoint 1 region, midpoint 2 region, midbrain center point 1 region, substantia nigra center point 1 region, and substantia nigra center point 2 region" in formula (I) are specified using the standard brain of MRI, and converted into the respective regions of the brain of the individual (subject), and the midbrain uptake ratio (MUR) is calculated. Alternatively, it can be said that the brain structure of the individual (subject) is converted into the "midpoint 1 region, midpoint 2 region, midbrain center point 1 region, substantia nigra center point 1 region, and substantia nigra center point 2 region" of the standard brain. Figure 4 shows a photograph in which the midpoint 1 region, midpoint 2 region, midbrain center point 1 region, substantia nigra center point 1 region, and substantia nigra center point 2 region of the standard brain are converted into the midpoint 1 region, midpoint 2 region, midbrain center point 1 region, substantia nigra center point 1 region, and substantia nigra center point 2 region of the brain of the individual (subject). The standard brain used in the present invention is not limited to, but may be, for example, the Montreal Neurological Institute (MNI) standard brain, the Talairach standard brain, the SPM (statistical parametric mapping) standard brain, the ICBM (International Consortium of Brain Mapping) standard brain, or the AFNI (Analysis of Functional NeuroImages) standard brain. Regardless of which standard brain is used, the same midbrain uptake ratio (MUR) can be obtained.

[0016] (a) Identification of midbrain center 1, substantia nigra center 1, and substantia nigra center 2 In the present invention, the midbrain center point 1, the substantia nigra center point 1, and the substantia nigra center point 2 are specified using the standard brain. These points can be specified on a cut surface in which the midbrain central gray matter, the oculomotor nucleus, the red nucleus, and the substantia nigra can be observed in the standard brain of MRI. The cut surface is not particularly limited as long as it is a cut surface in which the midbrain central gray matter, the oculomotor nucleus, the red nucleus, and the substantia nigra can be observed, and several cut surfaces can be specified in the standard brain. By specifying the cut surface and setting it as the midbrain center point 1, the substantia nigra center point 1, and the substantia nigra center point 2 as described below, the intermediate point 1 and the intermediate point 2 are then specified, and the intermediate point 1 region, the intermediate point 2 region, the midbrain center point 1 region, the substantia nigra center point 1 region, and the substantia nigra center point 2 region can be specified around these points. The midbrain center point 1, the substantia nigra center point 1, and the substantia nigra center point 2 can also be specified by converting the midbrain center point 1, the substantia nigra center point 1, and the substantia nigra center point 2 in a healthy subject (HC) into a standard brain. Here, the midbrain center point 1, the substantia nigra center point 1, and the substantia nigra center point 2 in a healthy subject (HC) can also be specified based on the intracerebral distribution of monoamine oxidase B in a healthy subject, for example, as reported in Non-Patent Document 1. This specification can also be automatically specified based on the average midbrain center point 1, the substantia nigra center point 1, and the substantia nigra center point 2 of a plurality of healthy subjects (HC). When the cut surface is different, the finally obtained midpoint 1 region, midpoint 2 region, midbrain center point 1 region, substantia nigra center point 1 region, and substantia nigra center point 2 region may be shifted. However, even if these midpoint 1 region, midpoint 2 region, midbrain center point 1 region, substantia nigra center point 1 region, and substantia nigra center point 2 region are shifted, there is no significant difference in the midbrain uptake ratio (MUR) obtained by the calculation of formula (I), and the progressive supranuclear palsy can be accurately diagnosed, which is a remarkable effect of the present invention.

[0017] The cut surface is set as a surface that allows observation of the midbrain central gray matter, oculomotor nucleus, red nucleus, and substantia nigra, for example, as shown in FIG. 1. In the cut surface, the midbrain central gray matter is identified as the midbrain central point 1. The midbrain aqueduct is present in the central part of the midbrain central gray matter. Therefore, the midbrain central point 1 is identified around the central part of the midbrain aqueduct (FIGS. 1 and 2A). In FIG. 1, the substantia nigra is present in a band-like shape in the upper right and upper left of the midbrain central gray matter. The band-like substantia nigra is composed of a compact part and a reticular part, and the substantia nigra central point 1 and the substantia nigra central point 2 are identified in the central part of the compact part of the substantia nigra (FIGS. 1 and 2A). In this specification, the central point of the central part of the substantia nigra in the upper right of the midbrain central gray matter is conveniently referred to as the substantia nigra central point 1, and the central point of the central part of the substantia nigra in the upper left of the midbrain central gray matter is conveniently referred to as the substantia nigra central point 2. As shown in Figure 2A, the midbrain center 1, the substantia nigra center 1, and the substantia nigra center 2 form a nearly equilateral or isosceles triangle. In this specification, this structure may be referred to as the substantia nigra-aqueduct triangular structure. The midbrain center point 1, the substantia nigra center point 1, and the substantia nigra center point 2 may be shifted due to the difference in the standard brain selected or the difference in the identification method, and as a result, the finally obtained midpoint 1 area, midpoint 2 area, midbrain center point 1 area, substantia nigra center point 1 area, and substantia nigra center point 2 area may be shifted. However, like the shift in the cutting plane, there is no significant difference in the midbrain uptake ratio (MUR) obtained by the calculation of formula (I), and progressive supranuclear palsy, which is a remarkable effect of the present invention, can be accurately diagnosed.

[0018] (b) Identification of midpoint 1 and midpoint 2 It is possible to specify an intermediate point 1 between the midbrain center point 1 and the substantia nigra center point 1, and an intermediate point 2 between the midbrain center point 1 and the substantia nigra center point 2. The intermediate point 1 is not particularly limited as long as it exists between the midbrain center point 1 and the substantia nigra center point 1, but is most preferably the midpoint of the line connecting the midbrain center point 1 and the substantia nigra center point 1. The intermediate point 2 is not particularly limited as long as it exists between the midbrain center point 1 and the substantia nigra center point 2, but is most preferably the midpoint of the line connecting the midbrain center point 1 and the substantia nigra center point 2 (FIG. 2A). The midpoint 1 and the midpoint 2 can also be specified by converting the midpoint 1 and the midpoint 2 in a healthy subject (HC) to a standard brain. This specification can also be automatically specified based on the average midpoint 1 and the midpoint 2 of multiple healthy subjects (HC), for example. The distance between the midbrain center point 1 and the substantia nigra center point 1 is, but is not limited to, about 10 to 20 mm. Similarly, the distance between the midbrain center point 1 and the substantia nigra center point 2 is, but is not limited to, about 10 to 20 mm. In addition, the distance between the substantia nigra center point 1 and the substantia nigra center point 2 is, but is not limited to, about 10 to 20 mm.

[0019] (c) Identification of midbrain center 1 region, substantia nigra center 1 region, substantia nigra center 2 region, midpoint 1 region, and midpoint 2 region Using the midbrain center 1, substantia nigra center 1, substantia nigra center 2, intermediate point 1, and intermediate point 2 as the centers, the midbrain center 1 region, substantia nigra center 1 region, substantia nigra center 2 region, intermediate point 1 region, and intermediate point 2 region are identified three-dimensionally around them (Figure 2B). Figure 3 shows three consecutive cut sections spaced 1 mm apart. For example, but not by way of limitation, region identification can be performed as follows. For example, when the cut surface of FIG. 3B is a cut surface in which the midbrain central gray matter, the oculomotor nucleus, the red nucleus, and the substantia nigra can be observed, in which the midbrain central point 1, the substantia nigra central point 1, the substantia nigra central point 2, the intermediate point 1, and the intermediate point 2 are specified, the midbrain central point 1 region, the substantia nigra central point 1 region, the substantia nigra central point 2 region, the intermediate point 1 region, and the intermediate point 2 region are specified two-dimensionally around the midbrain central point 1, the substantia nigra central point 1, the substantia nigra central point 2 region, the intermediate point 1 region, and the intermediate point 2 region. Then, in the continuous cut surfaces of FIG. 3A and FIG. 3C, the midbrain central point 1 region, the substantia nigra central point 1 region, the substantia nigra central point 2 region, the intermediate point 1 region, and the intermediate point 2 region are specified two-dimensionally. Then, by adding up the respective regions of three or more cut surfaces, the three-dimensional midbrain central point 1 region, the substantia nigra central point 1 region, the substantia nigra central point 2 region, the intermediate point 1 region, and the intermediate point 2 region can be specified. In effect, in a section away from the "section in which the midbrain central gray matter, the oculomotor nucleus, the red nucleus, and the substantia nigra can be observed," the area of ​​each region becomes smaller. The region may be specified continuously, or may be specified by the number of voxels (pixels) having a certain area (volume in three dimensions).

[0020] The size (volume) of each of the midbrain center point 1 region, the substantia nigra center point 1 region, the substantia nigra center point 2 region, the midpoint 1 region, and the midpoint 2 region is not particularly limited and may be large or small as long as each region exists around each point. Whether it is large or small, there is no significant difference in the midbrain uptake ratio (MUR) obtained by the calculation of formula (I), and progressive supranuclear palsy, which is a remarkable effect of the present invention, can be accurately diagnosed. However, the upper limit of the volume of the midbrain centrum 1 region, the substantia nigra centrum 1 region, the substantia nigra centrum 2 region, the midpoint 1 region, and the midpoint 2 region is 300 mm 3 In one embodiment, the length is 280 mm or less. 3 In one embodiment, the length is 260 mm or less. 3 In one embodiment, the 3 The lower limit of the volume is 5 mm 3 In one embodiment, the 3 In one embodiment, the3 In one embodiment, the thickness is 30 mm or more. 3 The upper and lower limits can be appropriately combined.

[0021] In addition, the volumes of the midbrain center 1 region, the substantia nigra center 1 region, the substantia nigra center 2 region, the midpoint 1 region, and the midpoint 2 region may be the same, but there is no problem if they are not the same. The shape of each region is not particularly limited, but examples include a sphere, a cylinder, and a rectangular parallelepiped. For example, if it is assumed to be a sphere, the diameter is approximately 5 to 10 mm. The midbrain center 1 region and midpoint 1 region, the midpoint 1 region and substantia nigra center 1 region, the midbrain center 1 region and midpoint 2 region, and the midpoint 2 region and substantia nigra center 2 region may overlap, but it is preferable that they do not overlap.

[0022] (d) Transformation of the control brain into the subject's brain The midbrain center 1 region, the substantia nigra center 1 region, the substantia nigra center 2 region, the midpoint 1 region, and the midpoint 2 region of the standard brain are converted into the midbrain center 1 region, the substantia nigra center 1 region, the substantia nigra center 2 region, the midpoint 1 region, and the midpoint 2 region of the subject's brain in positron emission tomography (PET) and magnetic resonance imaging (MRI), thereby obtaining the midbrain center 1 region, the substantia nigra center 1 region, the substantia nigra center 2 region, the midpoint 1 region, and the midpoint 2 region of the subject. The conversion can be performed by conversion software. The conversion software is not particularly limited, and may be FSL (FMRIB Software Library) software, SPM (statistical parametric mapping) software, or AFNI (Analysis of Functional NeuroImages) software. For example, the voxels (pixels) identified in the standard brain can be made to correspond to the voxels of the subject's brain by the conversion software.

[0023] Formula (I) The formula (I) used in the present invention is a formula for calculating the midbrain uptake ratio (MUR) as follows: Midbrain Uptake Ratio (MUR) = (positron emission intensity of at least one of the midpoint 1 and midpoint 2 regions of a subject) / (positron emission intensity of at least one of the midbrain midpoint 1, substantia nigra midpoint 1, and substantia nigra midpoint 2 regions of a subject).

[0024] The "positron emission intensity of at least one of the midbrain center 1 region, the substantia nigra center 1 region, and the substantia nigra center 2 region of the subject" in the denominator is, for example, the positron emission intensity of the open regions in Figures 3A to 3C. That is, these are the three regions located at the vertices of the triangle of the substantia nigra-aqueduct triangular structure, but the denominator may be the positron emission intensity of at least one region. Therefore, the denominator may be "(positron emission intensity of the midbrain center point 1 region of the subject)", "(positron emission intensity of the substantia nigra center point 1 region of the subject)", "(positron emission intensity of the substantia nigra center point 2 region of the subject)", "(positron emission intensity of the midbrain center point 1 region and the substantia nigra center point 1 region of the subject)", "(positron emission intensity of the midbrain center point 1 region and the substantia nigra center point 2 region of the subject)", or "(positron emission intensity of the midbrain center point 1 region, the substantia nigra center point 1 region, and the substantia nigra center point 2 region of the subject)". However, in order to obtain an accurate judgment, the most preferable is "(positron emission intensity of the midbrain center point 1 region, the substantia nigra center point 1 region, and the substantia nigra center point 2 region of the subject)".

[0025] The "(positron emission intensity of at least one of the midpoint 1 and midpoint 2 regions of the subject)" of the molecule is, for example, the positron emission intensity of the black-filled regions in Figures 3A-C. That is, it is two regions located at the center of two sides of the triangular structure of the substantia nigra-aqueduct, but the molecule may be the positron emission intensity of at least one region. Therefore, examples of the molecule include "(positron emission intensity of the midpoint 1 region of the subject)", "(positron emission intensity of the midpoint 2 region of the subject)", and "(positron emission intensity of the midpoint 1 and midpoint 2 regions of the subject)". However, in order to obtain an accurate judgment, "(positron emission intensity of the midpoint 1 and midpoint 2 regions of the subject)" is most preferable.

[0026] The denominator is most preferably the sum of the positron emission intensities of the three regions, and the numerator is most preferably the sum of the positron emission intensities of the two regions. However, the reason why the effect of the present invention can be obtained even with the positron emission intensity of one region each is presumed as follows. However, the present invention is not limited by this presumption. FIG. 5 shows the positron emission intensity of PET in a healthy control (HC) and that in progressive supranuclear palsy (PSP) in a two-dimensional manner for convenience. In the healthy control (HC), the positron emission intensity is high in the open regions of the midbrain center point 1 region, the substantia nigra center point 1 region, and the substantia nigra center point 2 region of the denominator. In the progressive supranuclear palsy (PSP), the positron emission intensity is low in the open regions of the midbrain center point 1 region, the substantia nigra center point 1 region, and the substantia nigra center point 2 region. On the other hand, in the healthy control (HC), the positron emission intensity is low in the black regions of the midpoint 1 region and the midpoint 2 region of the numerator. In the progressive supranuclear palsy (PSP), the positron emission intensity is high in the black regions of the midpoint 1 region and the midpoint 2 region. That is, in progressive supranuclear palsy (PSP), the positron emission intensity of the three open regions decreases, and the positron emission intensity of the two filled regions increases. Therefore, it is possible to determine progressive supranuclear palsy (PSP) by comparing the positron emission intensity of one of the three open regions with the positron emission intensity of one of the two filled regions. However, a more accurate determination can be made by comparing the positron emission intensity of the three open regions with the positron emission intensity of the two filled regions.

[0027] In FIG. 6(A), the leftmost image shows a PET image of a healthy individual, and the rightmost image shows a PET image of a progressive supranuclear palsy (PSP). When PSP progresses from a healthy state, the disease is thought to progress gradually as shown from left to right, and the boundary between a healthy individual and PSP is not clear. Here, in FIG. 6(B), the midpoint 1 region and the midpoint 2 region are shown with circles, and it can be seen that the positron emission intensity of the circled region gradually increases. According to formula (I) used in the present invention, it is also possible to grasp the progression state of PSP.

[0028] As described above, the midbrain center 1 region, the substantia nigra center 1 region, the substantia nigra center 2 region, the midpoint 1 region, and the midpoint 2 region can each be represented by a plurality of voxels (pixels). Each voxel has a certain size, and the positron emission intensity may be the sum of the intensities of each voxel, or may be the average value of a plurality of voxels. In either case, it is possible to determine progressive supranuclear palsy (PSP) by comparing the formula value with that of a healthy person.

[0029] 《Judgment process (2)》 In the determination step (2), the midbrain uptake ratio (MUR) is compared with a standard value for healthy individuals, and if it is higher than the standard value, the patient is determined to have progressive supranuclear palsy. The reference value can be determined by measuring the midbrain uptake ratio (MUR) in multiple healthy individuals and using the average value. Here, whether a person is a healthy individual can be determined by clinical trials conducted by experts. The judgment threshold can also be adjusted by clinical trials. In addition, the reference value can be created for each formula (I) used. That is, as described above, the denominator and numerator used in formula (I) are not limited to one, but can be selected from a plurality of them. It is preferable to create the reference value for each selected formula.

[0030] [2] How to create a diagnostic program for progressive supranuclear palsy The method for creating a diagnostic program for progressive supranuclear palsy according to the present invention comprises the steps of: (a) a step of identifying a midbrain center point 1 at the center of the midbrain aqueduct, and a substantia nigra center point 1 and a substantia nigra center point 2 at the centers of two substantia nigra compacta portions in a cut surface in an MRI standard brain where the midbrain central gray matter, oculomotor nucleus, red nucleus, and substantia nigra can be observed; (b) a step of identifying a midpoint 1 between the midbrain center point 1 and the substantia nigra center point 1, and a midpoint 2 between the midbrain center point 1 and the substantia nigra center point 2; (c) a step of identifying a three-dimensional midbrain center point 1 region, a substantia nigra center point 1 region, a substantia nigra center point 2 region, a midpoint 1 region, and a midpoint 2 region, with the midbrain center point 1, the substantia nigra center point 1, the substantia nigra center point 2, a midpoint 1 region, and a midpoint 2 region as centers. (d) specifying a means for converting the midbrain center point 1 region, the substantia nigra center point 1 region, the substantia nigra center point 2 region, the intermediate point 1 region, and the intermediate point 2 region of the standard brain into the midbrain center point 1 region, the substantia nigra center point 1 region, the substantia nigra center point 2 region, the intermediate point 1 region, and the intermediate point 2 region of the subject's brain in a positron emission tomography (PET) and a magnetic resonance imaging (MRI); (e) creating the following formula (I) and specifying that the midbrain center point 1 region, the substantia nigra center point 1 region, the substantia nigra center point 2 region, the intermediate point 1 region, and the intermediate point 2 region of the subject are fitted to the following formula (1); Formula (I): Midbrain Uptake Ratio (MUR) = (positron emission intensity of at least one of the midpoint 1 and midpoint 2 regions of a subject) / (positron emission intensity of at least one of the midbrain midpoint 1, substantia nigra midpoint 1, and substantia nigra midpoint 2 regions of a subject). Includes.

[0031] The "step (a)" in the method for creating a diagnostic program for progressive supranuclear palsy of the present invention can be performed in accordance with the description of "(a) Identification of midbrain center point 1, substantia nigra center point 1, and substantia nigra center point 2" in the above "[1] Diagnostic support method for progressive supranuclear palsy". The "step (b)" can be performed in accordance with the description of "(b) Identification of midpoint 1 and midpoint 2" in the above "[1] Diagnostic support method for progressive supranuclear palsy". The "step (c)" can be performed in accordance with the description of "(c) Identification of midbrain center point 1 region, substantia nigra center point 1 region, substantia nigra center point 2 region, midpoint 1 region, and midpoint 2 region" in the above "[1] Diagnostic support method for progressive supranuclear palsy". The "step (d)" can be performed in accordance with the description of "(d) Conversion from standard brain to subject's brain" in the above "[1] Diagnostic support method for progressive supranuclear palsy". "Step (e)" can be carried out in accordance with the description of "Formula (I)" in the above "(1) Diagnostic support method for progressive supranuclear palsy."

[0032] "program" The progressive supranuclear palsy diagnosis program of the present invention is a program that causes a computer used in the diagnosis of progressive supranuclear palsy of the present invention described below to execute the following steps. (A-1) inputting positron emission tomography (PET) and magnetic resonance imaging (MRI) data of the subject's brain into a computer; (A-2) converting the midbrain center 1 region, the substantia nigra center 1 region, the substantia nigra center 2 region, the midpoint 1 region, and the midpoint 2 region of the standard brain into the midbrain center 1 region, the substantia nigra center 1 region, the substantia nigra center 2 region, the midpoint 1 region, and the midpoint 2 region of the subject's brain in positron emission tomography (PET) and magnetic resonance imaging (MRI); (B) obtaining the positron emission intensity of each region in the subject's positron emission tomography image (PET), and substituting each of the obtained intensities into the following formula (I) to calculate the midbrain uptake ratio (MUR) of the subject; Formula (I): Midbrain Uptake Ratio (MUR) = (positron emission intensity of at least one of the midpoint 1 and midpoint 2 regions of a subject) / (positron emission intensity of at least one of the midbrain midpoint 1, substantia nigra midpoint 1, and substantia nigra midpoint 2 regions of a subject). (C) A step of comparing the obtained midbrain uptake ratio (MUR) of the subject with a standard value for healthy individuals, and determining that the subject has progressive supranuclear palsy if the MUR is higher than the standard value. Each step will now be described in detail with reference to FIG.

[0033] [1] About step (A-0) In the program of the present invention, a step (A-0) of determining the midbrain center 1 region, the substantia nigra center 1 region, the substantia nigra center 2 region, the midpoint 1 region, and the midpoint 2 region of the standard brain can be performed before or in advance of the step (A-1). This determined data may be determined in advance and stored in a database or a computer recording medium (described later) and used in the steps following (A-1), or the step (A-0) may be performed each time a subject is evaluated and used in the subsequent steps. The midbrain center 1 region, substantia nigra center 1 region, substantia nigra center 2 region, intermediate point 1 region, and intermediate point 2 region are as described above in "(a) Identification of midbrain center 1, substantia nigra center 1, and substantia nigra center 2" and "(b) Identification of intermediate point 1 and intermediate point 2," respectively, with the midbrain center 1 being located in the center of the midbrain aqueduct, the substantia nigra center 1 being located in the central part of the substantia nigra in the upper right corner of the midbrain central gray matter, and the substantia nigra center 2 being located in the central part of the substantia nigra in the upper left corner. In one embodiment, a program can be configured to determine midbrain center 1 regions, substantia nigra center 1 regions, substantia nigra center 2 regions, midpoint 1 regions, and midpoint 2 regions in a standard brain, as described in "(a) Identifying midbrain center 1, substantia nigra center 1, and substantia nigra center 2" and "(b) Identifying midpoint 1 and midpoint 2." In another embodiment, the program can be configured to determine these regions based on data in healthy subjects, as described below. In detail, first, a PET measurement and an MRI examination are performed on a healthy subject, and the obtained PET data and MRI data are input into a computer. The PET data and the MRI data are rigidly transformed to align them. The rigid transformation can be performed by using a conventional method without any particular restrictions, and a program can be configured to convert the PET data by substituting it into a rigid transformation formula and determine the position in the acquired MRI data. Next, a program is configured to convert the aligned data to a standard brain. Here, the "conversion" can be performed using a known linear or nonlinear conversion method, or both. This allows the PET data to be displayed on the standard brain. Regions with high positron emission intensity are identified in each part of the standard brain (the midbrain aqueduct, the substantia nigra in the upper right and the substantia nigra in the upper left of the midbrain central gray matter). The location of the region with high positron emission intensity can be identified by analyzing the PET data on the standard brain with a normal analysis software, and the above "identification" can be performed by incorporating a program that functions similarly to such analysis software into the program of the present invention. The program can be configured to set the point located at the center of the region with high positron emission intensity as the midbrain center point 1, the substantia nigra center point 1, and the substantia nigra center point 2 as the center points of this region. By configuring the program in this manner, the midbrain center point 1, the substantia nigra center point 1 and the substantia nigra center point 2 on the standard brain can be determined from the PET data and MRI data of a healthy subject, and the program is configured to determine intermediate point 1 at the midpoint between the midbrain center point 1 and the substantia nigra center point 1, and intermediate point 2 at the midpoint between the midbrain center point 1 and the substantia nigra center point 2. In this way, the program can be configured to determine the above-mentioned five points on the standard brain. Then, a program is configured to determine each region with the above-mentioned five points reflected in the standard brain. That is, when the points are merely determined in the standard brain, there is a possibility that deviations may occur when the points are reflected in the subject data of the test, so the regions are set so that deviations do not occur. Therefore, the setting of the regions is not particularly limited as long as the deviations do not occur, and for example, the regions can be set to form circles with a diameter of 1 to 15 mm centered on each point. Alternatively, the midbrain center point 1 region, the substantia nigra center point 1 region, and the substantia nigra center point 2 region can be set to include all regions with high positron emission intensity in the above-mentioned standard brain. By configuring the program in this manner, each area in the standard brain can be determined. The PET data and MRI data may be input manually, or may be configured as in the system of the present invention described later, so that the data is automatically stored in a computer recording medium after imaging. The program may be configured to determine the regions after reflecting each point in the standard brain as described above, or may be configured to determine the regions in the PET data and MRI data of a healthy person and convert the determined regions into a standard brain. Alternatively, the program may be configured to determine each region based on the region with high positron emission intensity averaged over the PET data of multiple healthy people.

[0034] [2] (A-1) Step Step (A-1) is a step of acquiring positron emission tomography (PET) and magnetic resonance imaging (MRI) data of the subject's brain by imaging in each device and inputting the data into a computer. This step may involve manually inputting the imaging data in each device into the computer and storing it in a recording medium of the computer, or may involve electrically connecting each device to the computer as in the system of the present invention described later, and configuring a program so that the imaging data in each device is automatically stored in a recording medium of the computer.

[0035] [3] (A-2) Step Step (A-2) is a step of converting each area determined in the standard brain in step (A-0) into the midbrain center 1 area, substantia nigra center 1 area, substantia nigra center 2 area, midpoint 1 area, and midpoint 2 area of ​​the subject's MRI data in order to reflect the areas in the positron emission tomography (PET) and magnetic resonance imaging (MRI) of the subject's brain. Specifically, a program is configured to perform a known linear transformation method or a nonlinear transformation method or both based on the MRI image equivalent map data of a standard brain in which each region is determined, which is obtained in step (A-0) or obtained in advance and stored in a computer recording medium, convert the data into MRI data of the subject, and further align the data with the PET data of the subject by rigid body transformation, thereby determining each region in the PET data of the subject and the MRI data of the subject. At this time, the program can be configured using a known program (e.g., FSL software, FSL is an abbreviation for FMRIB software library, and FSL software is an MRI analysis and statistical tool developed at Oxford University), etc. This defines regions in the subject's PET data and the subject's MRI data.

[0036] [4] (B) Step Step (B) is a step of calculating the positron emission intensity of each region in the subject from the subject's positron emission tomography (PET) image, and substituting each of the obtained intensities into the following formula (I) to calculate the midbrain uptake ratio (MUR) of the subject. Formula (I): Midbrain Uptake Ratio (MUR) = (positron emission intensity of at least one of the midpoint 1 and midpoint 2 regions of a subject) / (positron emission intensity of at least one of the midbrain midpoint 1, substantia nigra midpoint 1, and substantia nigra midpoint 2 regions of a subject). Moreover, the formula (I) is Formula (II): Midbrain Uptake Ratio (MUR) = (positron emission intensity of midpoint 1 region and midpoint 2 region of a subject) / (positron emission intensity of midbrain midpoint 1 region, substantia nigra midpoint 1 region, and substantia nigra midpoint 2 region of a subject) It is preferable that: That is, the program is configured to perform the rigid body transformation on the MRI image data of the subject in which each region has been determined and the PET image data of the subject to align the positions of the MRI image data and the PET image data. As a result, each region reflected in the MRI image data is reflected in the PET image data, and the program causes the computer to grasp (store in a recording medium) the PET image data in which each region has been reflected so that the computer can use it. Next, the positron emission intensity in each region reflected in the PET image data is obtained. Here, the "positron emission intensity in each region" is a value obtained by analyzing the PET data using a normal analysis software, and is a value proportional to the amount of ligand taken up in each region. In addition, the midbrain center point 1 region, the substantia nigra center point 1 region, the substantia nigra center point 2 region, the midpoint 1 region, and the midpoint 2 region of the subject are each composed of multiple voxels, and the "positron emission intensity in each region" can also be the average value of the positron emission intensity in these multiple voxels. Then, a program is set up to substitute the obtained positron emission intensity in each region into the above formula (I) or (II) to obtain the MUR of the subject, and the program is configured to store the obtained MUR in a computer recording medium.

[0037] [5] (C) Step Step (C) is a step of comparing the obtained midbrain uptake ratio (MUR) of the subject with a standard value for healthy individuals, and determining that the subject has progressive supranuclear palsy if the MUR is higher than the standard value. Here, the "standard value for healthy individuals" can be calculated using the positron emission intensity of each region obtained from previously measured PET data and MRI data of healthy individuals. In some cases, the previously calculated values ​​can be stored in a computer recording medium. In addition, a database of data on a large number of healthy individuals and data on subjects can be stored in a computer recording medium, and the average value of the data on healthy individuals can be calculated and used as the standard value. The reference value may be set to the MUR value of a healthy person or the MUR of multiple healthy people, or may be calculated from the distribution of MURs of multiple healthy people and the upper limit of data of 80% or more of healthy people may be set as the reference value. In any case, the reference value can be set arbitrarily from among these options and can be set based on the degree of reliability required for diagnosis.

[0038] "system" The progressive supranuclear palsy diagnostic system of the present invention comprises a positron emission tomography image (PET), a magnetic resonance image (MRI), and a computer having the above program stored therein. Specifically, as shown in FIG. 10, a progressive supranuclear palsy diagnostic system 1 includes a computer 10, a PET 40, and an MRI 50. 〔computer〕 1, the computer 10 used in this embodiment specifically includes a central processing unit (CPU) 13, a memory 11 as a temporary storage area, and a non-volatile storage medium 15 such as a hard disk or a solid-state device. In the present invention, the "computer" may be a normal personal computer, a server, or a mobile terminal such as a smartphone or a tablet terminal. Although not shown in the drawings, the computer in this embodiment preferably has a communication device and is capable of communication via a network. It is also possible to set the computer to connect to a server having a database on the network by communicating with the server, and to obtain updated data from the database as needed. In this embodiment, the program described below is stored in the storage medium 15 of this computer, causing the computer to function as a diagnostic means. [Input Means] Although not shown in the figure, the input means 20 may be an image input device such as a keyboard, a mouse, or a camera, an audio input device such as a microphone, or a communication input device using a communication device such as Bluetooth (registered trademark), etc. These can be used to input the necessary data and information as appropriate. [Output Means] A display for displaying the evaluation results, a printer for printing, etc. are used as the output means 30. The output means outputs the judgment results in a desired format for use by subjects and users such as doctors who utilize the data. [PET and MRI] These are as described above, and in this embodiment, these members and the computer are electrically connected via wiring (not shown) so that signals can flow between them. <Other components (devices)> The apparatus of this embodiment may include various devices as necessary in addition to the above-mentioned devices.

[0039] (use) The above-described system and program of the present invention can be used as follows. That is, first, imaging of the subject is performed using MRI 50 and PET 40. The imaging data is transferred to and input into the computer 10 (A-1). In the computer 10, the program of the present invention is executed to perform diagnosis. Specifically, the MRI image data of the standard brain in which each region has been determined in advance (A-0) is converted into the MRI image data of the subject, and each region is determined in the MRI image of the subject (A-2). Next, the MRI image data and the PET image data are aligned, the positron emission intensity in each region is calculated, and the obtained results are substituted into formula (I) or (II) to calculate the MUR (B). The obtained MUR is compared with a reference value to determine whether it is equal to or greater than the reference value or less, and if it is equal to or greater than the reference value, the patient is diagnosed as having progressive supranuclear palsy. A series of these execution operations is executed by the computer 10 according to the program of the present invention. The obtained diagnosis result is displayed via output. (Action and effect) Since the system and program of the present invention are configured as described above, it is possible to diagnose whether or not a subject has progressive supranuclear palsy simply by acquiring PET images and MRI images of the subject. This allows even inexperienced doctors to make a tentative diagnosis, and then to carry out more advanced tests and provide appropriate treatment. EXAMPLES

[0040] The present invention will be specifically described below with reference to examples, but the scope of the present invention is not limited thereto.

[0041] Example 1 Written informed consent was obtained from the subjects, and they were age-matched and classified into healthy control (HC), progressive supranuclear palsy (PSP), and Alzheimer's disease (AD) groups. For these subjects, a Discovery PET / CT 710 or Discovery MI (GE Healthcare, Milwaukee, WI, USA) was used in 3D mode to detect MAO-B ligands. 18 PET was performed using F-THK5351. On the Discovery PET / CT 710 system, the in-plane resolution at full width at half maximum (FWHM) was 4.52 mm and the axial resolution was 4.83 mm. Forty-seven slice images were acquired with a voxel size of 2 × 2 × 3.27 mm and a matrix size of 128 × 128. On the Discovery MI system, the in-plane resolution at FWHM was 3.91 mm and the axial resolution was 4.50 mm. Seventy-one slice images were acquired with a voxel size of 2 × 2 × 2.79 mm and a matrix size of 128 × 128. Image data were reconstructed with a 3D ordered subsets expectation maximization time-of-flight (so-called 3D-OSEM+TOF) algorithm and processed with the FMRIB software library (FSL; Oxford University, Oxford, UK) and PMOD (PMOD Technologies, Zurich, Switzerland).

[0042] The standard brain was that of the Montreal Neurological Institute (MNI). The MNI standard brain was spatially re-sliced ​​using the brainstem vertical line as the reference line for the horizontal slice images. 18To evaluate the nigra-aqueduct triangular structure of F-THK5351 distribution, five regions of interest (substantia nigra centrum 1, substantia nigra centrum 2, midbrain centrum 1, midbrain 1, and midbrain 2) were manually drawn on the resliced ​​MNI standard brain. 18 The F-THK5351 image and the MRI image were aligned. The five regions of interest (substantia nigra center point 1 region, substantia nigra center point 2 region, midbrain center point 1 region, midpoint 1 region, and midpoint 2 region) placed on the resliced ​​MNI standard brain were nonlinearly transformed to the native space of each subject. As shown in Figure 5, it was visually confirmed that the five regions of interest (substantia nigra center point 1 region, substantia nigra center point 2 region, midbrain center point 1 region, midpoint 1 region, and midpoint 2 region) were appropriately positioned in all subjects. 18 F-THK5351 uptake values ​​were extracted from each region of interest (substantia nigra centrum 1 region, substantia nigra centrum 2 region, midbrain centrum 1 region, midbrain 1 region, and midbrain 2 region). The midbrain uptake ratio (MUR) was calculated as follows: Midbrain Uptake Ratio (MUR) = (positron emission intensity of midpoint 1 region and midpoint 2 region of a subject) / (positron emission intensity of midbrain midpoint 1 region, substantia nigra midpoint 1 region, and substantia nigra midpoint 2 region of a subject) Differences in MUR values ​​between the two groups were tested using a two-tailed t-test, with statistical significance set at P < 0.05.

[0043] The MUR values ​​in the HC, PSP, and AD groups are shown in Figure 8. The MUR values ​​(mean ± SD) were 0.805 ± 0.037, 1.079 ± 0.040, and 0.839 ± 0.052 in the HC, PSP, and AD groups, respectively. Compared with the HC group, a significant difference was observed in the PSP group (P < 0.01, T = 15.6), but no significant difference was observed in the AD group (P = 0.10, T = 1.7). Representative of each group 18 F-THK5351 images are shown in Figure 7. In the HC and AD groups (Figures 7A and 7B), the substantia nigra central point 1 region, the substantia nigra central point 2 region, and the midbrain central point 1 region 18The uptake of F-THK5351 was higher (MUR<1) than that in the midpoint 1 and midpoint 2 regions, and a triangular structure of the substantia nigra-aqueduct was observed. On the other hand, in the PSP group (Fig. 7C), the uptake was higher in the substantia nigra centrum 1, substantia nigra centrum 2, and midbrain centrum 1 regions. 18 The uptake of F-THK5351 was lower than that in the midpoint 1 and midpoint 2 regions (MUR>1), and the triangular structure of the substantia nigra-aqueduct was disrupted. In the PSP group, astrogliosis was thought to have occurred in the midpoint 1 and midpoint 2 regions. [Industrial Applicability]

[0044] The present invention can be used to diagnose progressive supranuclear palsy. [Explanation of symbols]

[0045] 1. Diagnostic system; 10. Computer; 20···Input means; 30···Output means; 40··PET; 50···MRI;

Claims

1. A diagnostic aid method for progressive supranuclear palsy, comprising: (1) Calculating the midbrain uptake ratio (MUR) obtained by the following formula (I) using positron emission tomography (PET) and nuclear magnetic resonance imaging (MRI) using a MAO-B ligand probe; Formula (I): Midbrain Uptake Ratio (MUR) = (positron emission intensity of at least one of the midpoint 1 and midpoint 2 regions of a subject) / (positron emission intensity of at least one of the midbrain midpoint 1, substantia nigra midpoint 1, and substantia nigra midpoint 2 regions of a subject). (wherein, the midbrain center point 1 region, the substantia nigra center point 1 region, the substantia nigra center point 2 region, the intermediate point 1 region, and the intermediate point 2 region refer to (a) specifying the midbrain center point 1 at the center of the midbrain aqueduct, and the substantia nigra center point 1 and the substantia nigra center point 2 at the centers of the two substantia nigra compact parts in a cut surface in a standard brain in which the midbrain central gray matter, the oculomotor nucleus, the red nucleus, and the substantia nigra can be observed, (b) specifying the intermediate point 1 between the midbrain center point 1 and the substantia nigra center point 1, and the intermediate point 2 between the midbrain center point 1 and the substantia nigra center point 2, and (c) specifying the midbrain center point 1, the substantia nigra center point 1, the substantia nigra center point (d) determining three-dimensional midbrain center point 1 region, substantia nigra center point 1 region, substantia nigra center point 2 region, midpoint 1 region, and midpoint 2 region centered on midbrain center point 1 region, substantia nigra center point 2 region, midpoint 1 region, and midpoint 2 region of the standard brain; and (e) converting the midbrain center point 1 region, substantia nigra center point 1 region, substantia nigra center point 2 region, midpoint 1 region, and midpoint 2 region of the standard brain into the midbrain center point 1 region, substantia nigra center point 1 region, substantia nigra center point 2 region, midpoint 1 region, and midpoint 2 region of the subject's brain in a positron emission tomography (PET) and magnetic resonance imaging (MRI). (2) comparing the midbrain uptake ratio (MUR) with a standard value for healthy individuals, and determining that the patient has progressive supranuclear palsy if the MUR is higher than the standard value; A diagnostic aid for progressive supranuclear palsy, comprising:

2. The formula (I) is Formula (II): Midbrain Uptake Ratio (MUR) = (positron emission intensity of midbrain midpoint 1 and midpoint 2 regions of a subject) / (positron emission intensity of midbrain midpoint 1, substantia nigra midpoint 1, and substantia nigra midpoint 2 regions of a subject). The diagnostic assistance method for progressive supranuclear palsy according to claim 1,

3. 3. The diagnostic support method for progressive supranuclear palsy according to claim 2, wherein the subject's midbrain center 1 region, substantia nigra center 1 region, substantia nigra center 2 region, midpoint 1 region, and midpoint 2 region are each represented by a plurality of voxels, and the positron emission intensity is an average value of the plurality of voxels.

4. A method for assisting in the differential diagnosis of progressive supranuclear palsy, comprising using the method for assisting in the diagnosis of progressive supranuclear palsy according to any one of claims 1 to 3.

5. A program for diagnosing progressive supranuclear palsy that causes a computer to perform the following steps: (A-1) inputting data of positron emission tomography (PET) and magnetic resonance imaging (MRI) of the subject's brain into a computer; (A-2) converting the midbrain center point 1 region, the substantia nigra center point 1 region, the substantia nigra center point 2 region, the intermediate point 1 region, and the intermediate point 2 region of the standard brain into the midbrain center point 1 region, the substantia nigra center point 1 region, the substantia nigra center point 2 region, the intermediate point 1 region, and the intermediate point 2 region of the subject's brain in positron emission tomography (PET) and magnetic resonance imaging (MRI); (B) acquiring positron emission intensities of each region in a positron emission tomography (PET) image of the subject, and substituting the obtained intensities into the following formula (I) to calculate the midbrain uptake ratio (MUR) of the subject; Formula (I): Midbrain Uptake Ratio (MUR) = (positron emission intensity of at least one of the midpoint 1 and midpoint 2 regions of a subject) / (positron emission intensity of at least one of the midbrain midpoint 1, substantia nigra midpoint 1, and substantia nigra midpoint 2 regions of a subject). (C) A step of comparing the obtained midbrain uptake ratio (MUR) of the subject with a standard value for healthy individuals, and determining that the subject has progressive supranuclear palsy if it is higher than the standard value.

6. The formula (I) is Formula (II): Midbrain Uptake Ratio (MUR) = (positron emission intensity of midbrain midpoint 1 and midpoint 2 regions of a subject) / (positron emission intensity of midbrain midpoint 1, substantia nigra midpoint 1, and substantia nigra midpoint 2 regions of a subject). The progressive supranuclear palsy diagnostic program according to claim 5,

7. The progressive supranuclear palsy diagnostic program of claim 6, wherein the subject's midbrain center 1 region, substantia nigra center 1 region, substantia nigra center 2 region, midpoint 1 region, and midpoint 2 region are each composed of a plurality of voxels, and the positron emission intensity in each of the regions is the average value of these multiple voxels.

8. A system for diagnosing progressive supranuclear palsy, comprising a positron emission tomography (PET) image, a nuclear magnetic resonance image (MRI) image, and a computer having the program according to claim 7 stored therein.

Images