WO2022145433A1 - Procédé, programme et dispositif d'évaluation d'état de fonction motrice - Google Patents

Procédé, programme et dispositif d'évaluation d'état de fonction motrice Download PDF

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WO2022145433A1
WO2022145433A1 PCT/JP2021/048662 JP2021048662W WO2022145433A1 WO 2022145433 A1 WO2022145433 A1 WO 2022145433A1 JP 2021048662 W JP2021048662 W JP 2021048662W WO 2022145433 A1 WO2022145433 A1 WO 2022145433A1
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patient
motor function
index value
physiological index
region
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Japanese (ja)
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真人 川堀
キンキン タ
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株式会社Rainbow
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves 
    • A61B5/055—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves  involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging

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  • the present disclosure relates to a method of assessing the state of motor function of a patient with or suspected of having a brain injury, as well as programs, image analyzers and MRI devices that can be used in the practice of such methods.
  • the present disclosure relates to a method for predicting motor function recovery after regenerative treatment in a patient with local brain injury.
  • the present disclosure relates to a method of utilizing a physiological index value with the white matter region on the injured hemisphere side of the brain as a region of interest, and a program, an image analysis device, and an MRI apparatus that can be used in carrying out the method.
  • Non-Patent Document 1 In cell therapy, the recovery condition of patients who actually received cells varies, so it is important to determine which patient is suitable for cell therapy before starting treatment.
  • the present disclosure provides a means for assessing the state of motor function of a patient with or suspected to have brain injury such as local brain injury.
  • the present disclosure specifically provides a means for determining whether such a patient is suitable for regenerative therapy, that is, whether the patient is expected to respond to the regenerative therapy prior to the start of treatment.
  • the present disclosure relates to a method of utilizing a physiological index value with the white matter region on the traumatic hemisphere side of the brain as a region of interest.
  • the present inventors have found that in a patient with a local brain injury, the state of motor function correlates with a parameter obtained from a diffusion-weighted image in which the white matter region on the damaged hemisphere side of the patient's brain is the region of interest.
  • the present disclosure provides: (Item 1) A step of obtaining one or more physiological index values with the white matter region on the hemispherical side of the brain injury of a patient having or suspected to have brain injury as the region of interest.
  • a method for evaluating the state of motor function of a patient which comprises a step of comparing the physiological index value with a control physiological index value and performing an operation for calculating a value indicating the state of motor function of the patient.
  • the physiological index value is obtained from a diffusion-weighted image of the patient's brain obtained by a diffusion tensor imaging (DTI) method or a diffusion sharpness imaging (DKI) method.
  • DTI diffusion tensor imaging
  • DIKI diffusion sharpness imaging
  • the physiological index value includes an MD (mean diffusivity) value and an AD (axial diffusivity) value.
  • the region of interest is set in the internal capsule hind leg of the brain.
  • the state of motor function is the state of motor function after regenerative treatment.
  • the control physiological index value is obtained by using the white matter region on the uninjured hemisphere side of the patient's brain as a region of interest.
  • the step of performing the calculation calculates a value represented by the physiological index value / the control physiological index value.
  • the calculated value indicating the state of the patient's motor function is substituted into a prepared regression line in which the value indicating the state of the patient's motor function and the degree of recovery of the motor function are variables.
  • the method according to any one of the above items which evaluates the state of motor function of the patient. (Item 9) By comparing the calculated value indicating the state of the patient's motor function with the reference value prepared in advance, the step of performing the calculation is expected to reach the desired degree of recovery of the motor function of the patient after the regenerative treatment.
  • a computer program that causes a computer to perform a process of assessing the state of motor function of the brain of a patient with or suspected of having a brain injury, wherein the method is the following step: A step of causing the computer to obtain a physiological index value with the white matter region on the injured hemisphere side of the patient's brain as the region of interest.
  • a program comprising a step of causing the computer to perform an operation for comparing the physiological index value with a control physiological index value and calculating a value indicating a state of motor function of the patient.
  • a computer program product that causes a computer to perform a process of assessing the state of motor function of the brain of a patient with or suspected of having a brain injury, wherein the method is the following step: A step of causing the computer to obtain a physiological index value with the white matter region on the injured hemisphere side of the patient's brain as the region of interest.
  • a program product comprising a step of causing the computer to perform an operation for comparing the physiological index value with a control physiological index value and calculating a value indicating a state of motor function of the patient.
  • (Item 10-2) The program or program product according to the above item, wherein the physiological index value is obtained from a diffusion-weighted image of the patient's brain obtained by a diffusion tensor imaging (DTI) method or a diffusion sharpness imaging (DKI) method.
  • DTI diffusion tensor imaging
  • DKI diffusion sharpness imaging
  • the physiological index value includes an MD (mean diffusivity) value and an AD (axial diffusivity) value.
  • (Item 10-4) The program or program product according to any one of the above items, wherein the region of interest is set in the internal capsule hind leg of the brain.
  • the state of motor function is the state of motor function after regenerative treatment.
  • control physiological index value is obtained in the white matter region on the uninjured hemisphere side of the patient's brain as a region of interest.
  • step for performing the calculation calculates a value represented by the physiological index value / the control physiological index value.
  • step for performing the calculation is to convert the calculated value indicating the state of the patient's motor function into a regression line prepared in advance with the value indicating the state of the patient's motor function and the degree of recovery of the motor function as variables.
  • the program or program product according to any one of the above items which evaluates the state of motor function of the patient by substitution.
  • the step of performing the calculation is expected to reach the desired degree of recovery of the motor function of the patient after the regenerative treatment.
  • the program or program product described in any one of the above items for calculating the height of. (Item 10B)
  • the recording medium according to the above item, wherein the physiological index value is obtained from a diffusion-weighted image of the patient's brain obtained by a diffusion tensor imaging (DTI) method or a diffusion sharpness imaging (DKI) method.
  • the physiological index value includes an MD (mean diffusivity) value and an AD (axial diffusivity) value.
  • the region of interest is set on the hind leg of the internal capsule of the brain.
  • the state of motor function is the state of motor function after regenerative treatment.
  • the step of performing the calculation calculates a value represented by the physiological index value / the control physiological index value.
  • the step for performing the calculation is to convert the calculated value indicating the state of the patient's motor function into a regression line prepared in advance with the value indicating the state of the patient's motor function and the degree of recovery of the motor function as variables.
  • the recording medium according to any one of the above items for calculating the height of the above item (Item 11A) The recording medium according to item 11, further comprising the features described in any one or more of items 1-9.
  • Item 12 A system that assesses the state of motor function in the brain of patients with or suspected of having brain injury. A means for obtaining a physiological index value with the white matter region on the traumatic hemisphere side of the patient's brain as the region of interest.
  • a system comprising a means for comparing the physiological index value with a control physiological index value and performing an operation for calculating a value indicating a state of motor function of the patient.
  • the physiological index value is obtained from a diffusion-weighted image of the patient's brain obtained by a diffusion tensor imaging (DTI) method or a diffusion sharpness imaging (DKI) method.
  • DTI diffusion tensor imaging
  • DIKI diffusion sharpness imaging
  • the physiological index value includes an MD (mean diffusivity) value and an AD (axial diffusivity) value.
  • the region of interest is set in the internal capsule hind leg of the brain.
  • (Item 12-5) The system according to any one of the above items, wherein the state of motor function is the state of motor function after regenerative treatment.
  • (Item 12-6) The system according to any one of the above items, wherein the control physiological index value is obtained in the white matter region on the uninjured hemisphere side of the patient's brain as a region of interest.
  • (Item 12-7) The system according to any one of the above items, wherein the means for performing the calculation calculates a value represented by the physiological index value / the control physiological index value.
  • the means for performing the calculation substitutes the calculated value indicating the state of the patient's motor function into a prepared regression line having the value indicating the state of the patient's motor function and the degree of recovery of the motor function as variables.
  • the system according to any one of the above items which evaluates the state of motor function of the patient.
  • the means for performing the calculation is expected to reach the desired degree of recovery of the motor function after the regenerative treatment.
  • the system according to any one of the above items for calculating high and low. (Item 12A) The system according to item 12, further comprising the features described in any one or more of items 1-9.
  • the image is characterized by comprising an arithmetic unit for performing an operation for comparing the injured hemisphere side physiological index value and the non-injured hemisphere side physiological index value and calculating a value indicating the state of the motor function of the patient.
  • Analytical device (Item 13-2) The image analysis apparatus according to the above item, wherein the physiological index value is obtained from a diffusion-weighted image of the patient's brain obtained by a diffusion tensor image (DTI) method or a diffusion sharpness image (DKI) method. (Item 13-3) The image analysis apparatus according to any one of the above items, wherein the physiological index value includes an MD (mean diffusivity) value and an AD (axial diffusivity) value.
  • MD mean diffusivity
  • AD axial diffusivity
  • (Item 13-4) The image analysis apparatus according to any one of the above items, wherein the region of interest is set on the hind leg of the internal capsule of the brain.
  • (Item 13-5) The image analysis apparatus according to any one of the above items, wherein the state of motor function is the state of motor function after regenerative treatment.
  • (Item 13-7) The image analysis apparatus according to any one of the above items, wherein the calculation unit calculates a value represented by the damaged hemisphere side physiological index value / the non-damaged hemisphere side physiological index value.
  • the calculation unit substitutes the calculated value indicating the state of the patient's motor function into a regression line prepared in advance in which the value indicating the state of the patient's motor function and the degree of recovery of the motor function are variables.
  • the image analysis apparatus according to any one of the above items, which evaluates the state of motor function of the patient.
  • the calculation unit determines whether the patient is likely to reach the desired degree of recovery of the motor function after the regenerative treatment.
  • the image analysis device according to any one of the above items to be calculated.
  • the image analysis apparatus according to item 13A The image analysis apparatus according to item 13, further comprising the features described in any one or more of items 1-9.
  • a nuclear magnetic resonance imaging unit that images the brain of a patient with or suspected of having a brain injury
  • An image generation unit that generates a diffusion-weighted image from the echo data acquired by the nuclear magnetic resonance imaging unit, In the diffusion-weighted image, a region of interest setting unit that sets the white matter region on the damaged hemisphere side as the first region of interest and the white matter region on the non-damaged hemisphere side as the second region of interest.
  • a physiological index value calculation unit that calculates a damaged hemispherical side physiological index value and an uninjured hemispherical side physiological index value in each of the first region of interest and the second region of interest.
  • the MRI is characterized by comprising a calculation unit for comparing the injured hemisphere side physiological index value and the non-injured hemisphere side physiological index value and calculating a value indicating the state of motor function of the patient.
  • Device (Item 14-2) The MRI apparatus according to the above item, wherein the physiological index value is obtained from a diffusion-weighted image of the patient's brain obtained by a diffusion tensor imaging (DTI) method or a diffusion sharpness imaging (DKI) method. (Item 14-3) The MRI apparatus according to any one of the above items, wherein the physiological index value includes an MD (mean diffusivity) value and an AD (axial diffusivity) value.
  • MD mean diffusivity
  • AD axial diffusivity
  • the MRI apparatus according to any one of the above items wherein the region of interest is set on the hind leg of the internal capsule of the brain.
  • the state of motor function is the state of motor function after regenerative treatment.
  • the calculation unit calculates a value represented by the damaged hemisphere side physiological index value / the non-damaged hemisphere side physiological index value.
  • the calculation unit substitutes the calculated value indicating the state of the patient's motor function into a regression line prepared in advance in which the value indicating the state of the patient's motor function and the degree of recovery of the motor function are variables.
  • the MRI apparatus according to any one of the above items, which evaluates the state of motor function of the patient.
  • the calculation unit determines whether the patient is likely to reach the desired degree of recovery of the motor function after the regenerative treatment.
  • the MRI apparatus according to any one of the above items to be calculated.
  • the MRI apparatus according to item 14A The MRI apparatus according to item 14, further comprising the features described in any one or more of items 1-9.
  • the present disclosure it is possible to evaluate the state of motor function of a patient who has or is suspected to have brain damage such as local brain damage, and thereby predicts the recovery of motor function of the patient after regenerative treatment. In addition, it can be determined whether the patient is suitable for regenerative treatment before the start of treatment.
  • FIG. 1 is a block diagram showing an overall configuration of an MRI apparatus according to one embodiment of the present disclosure.
  • FIG. 2 is a functional block diagram showing the configurations of a storage unit, a calculation unit, an input unit, and an output unit in the MRI apparatus according to one embodiment of the present disclosure.
  • FIG. 3 is a flowchart showing each step in the prediction method according to one embodiment of the present disclosure.
  • FIG. 4 is a flowchart showing the details of the calculation steps in the prediction method according to one embodiment of the present disclosure.
  • FIG. 5 is a flowchart showing the details of the calculation steps in the prediction method according to one embodiment of the present disclosure.
  • FIG. 6 is a schematic diagram showing a procedure of image processing by DKI in one embodiment of the present disclosure.
  • FIG. 7 is a graph showing the correlation between the AD ratio (lesion / healthy) of the inner capsule hind leg on the lesion side and the healthy side and the change in BI by DKI in one embodiment of the present disclosure.
  • FIG. 8 is a graph showing the correlation between the MD ratio (lesion / healthy) of the internal capsule hind leg on the lesion side and the healthy side and the change in BI by DKI in one embodiment of the present disclosure.
  • FIG. 9A is a photograph showing a case of cerebral infarction in the left cerebral hemisphere with a poor degree of functional recovery. It can be seen that the AD and MD of the hind leg of the left internal capsule are lower than those of the right side.
  • FIG. 9B is a photograph showing a case of cerebral infarction in the left cerebral hemisphere with a large degree of functional recovery. It can be seen that the laterality between AD and MD of the hind legs of the internal capsule is small.
  • the "white matter region” refers to a region in which nerve fibers are mainly accumulated and running in the central nervous system consisting of the brain and spinal cord. It is deep in the cerebrum and cerebellum and occupies the superficial layer in the spinal cord.
  • the white matter region includes an internal capsule anterior leg, an internal capsule posterior leg, an internal capsule knee, a brain bridge, a centrum semiovale, an anterior spinal cord, a lateral spinal cord, a posterior spinal cord, and the like.
  • the term "internal capsule hind leg” refers to the site of the internal capsule, which is an aggregate of nerve fibers, through which the fibers connecting the pyramidal tract, temporal lobe, parietal lobe, and occipital lobe run. It exists in the space between the thalamus and the lenticular nucleus.
  • the hind leg of the internal capsule consists of a group of fibers running in a nearly vertical direction. There is a corticospinal fiber in front of it, and the corticospinal tract runs outside the corticospinal fiber.
  • the "physiological index value” refers to an index value obtained by diffusion-weighted images of the brain such as a diffusion tensor image (DTI) and a diffusion-weighted image (DKI), and refers to MK (mean kurtosis), AK (mean kurtosis), and AK (mean kurtosis).
  • DTI diffusion tensor image
  • DKI diffusion-weighted image
  • MK mean kurtosis
  • AK mean kurtosis
  • AK mean kurtosis
  • AK mean kurtosis
  • AK mean kurtosis
  • AK mean kurtosis
  • axial kurtosis axial kurtosis
  • RK radial kurtosis
  • FA fractional anisotropy
  • KFA kurtosis fractional anisotropy
  • MD mean diffusivity
  • AD axial diffusivity
  • RD radial diffusivity
  • the MD value is a value obtained by averaging three eigenvalues ( ⁇ 1 to ⁇ 3 ) for expressing ADC, which is an index indicating the magnitude of diffusion itself, and the AD value is the eigenvalue of the eigenvalue. Refers to the value of ⁇ 1 of them.
  • the "state of motor function” refers to the state of motor function comprehensively controlled by the function of the brain
  • the “evaluation of the state of motor function” refers to the current state of the brain of the subject. Or, after treatment, it includes evaluating or predicting whether motor function is normal or partially or completely paralyzed. For example, “evaluation of the state of motor function” includes prediction of recovery of brain function that controls movement by regenerative therapy or the like.
  • a method of assessing the state of motor function of the patient including a step of comparing with the value and performing an operation to calculate a value indicating the state of motor function of the patient.
  • the physiological index value can be obtained from an image of the patient's brain obtained by the diffusion tensor imaging (DTI) method or the diffusion kurtosis imaging (DKI) method.
  • DTI diffusion tensor imaging
  • DKI diffusion kurtosis imaging
  • a region of interest (ROI) created by tracing an anatomical structure is set, and physiological index values such as FA and MD values in the region of interest are measured to measure the corticospinal cord. You can track the road.
  • the DKI method can be used as a quantitative image index without depending on the measurer.
  • the DTI method assumes that the diffusion of water molecules is a normal distribution, it is known that the diffusion of water molecules in a living body does not show a normal distribution. Therefore, a diffusion image method that does not assume a normal distribution, such as the DKI method, can more accurately reflect the diffusion of water molecules in a living body. Therefore, in one embodiment of the present disclosure, according to the DKI method, it is possible to obtain a diffused image index that can predict the cell administration therapeutic effect in a cerebral infarction patient with high accuracy and without depending on the experience of the measurer. ..
  • the physiologic index value obtained from the diffusion-weighted image of the patient's brain obtained by the diffusion tensor imaging (DTI) method or diffusion sharpness imaging (DKI) method as described above is the diffusion of water molecules in the tissue.
  • the index is not particularly limited as long as it is an index obtained by a diffusion-weighted image that images the direction and speed as parameters, and for example, MK (mean kurtosis), AK (axial kurtosis), RK (radial kurtosis), FA ( Diffusion indices such as fractional anisotropy), KFA (kurtosis fractional anisotropy), MD (mean diffusivity), AD (axial diffusivity), and RD (radial diffusivity) can be used.
  • these diffusion indices may be used alone or in combination of two or more.
  • the ROI in DTI or DKI may be set anywhere in the white matter region of the brain, and is not particularly limited.
  • the ROI is preferably set on the hind limb of the internal capsule.
  • the state of motor function can be evaluated or the prognosis after treatment can be predicted by the value obtained by placing the ROI on the hind limb of the internal capsule by the method of the present disclosure. Is a remarkable effect of this disclosure.
  • the state of motor function of the subject is based on the physiological index values obtained from the image of the patient's brain obtained by the diffusion tensor imaging (DTI) method or the diffusion metric imaging (DKI) method as described above.
  • This motor function may be current or post-treatment, and the recovery state of motor function after regenerative treatment can also be predicted.
  • the physiological index value obtained when the ROI is placed on the injured hemisphere side of the brain and the ROI obtained when the ROI is placed on the uninjured hemisphere side of the brain can be performed by comparing with a physiological index value (referred to as a control physiological index value), and preferably by calculating a value represented by a physiological index value / a control physiological index value.
  • a physiological index value referred to as a control physiological index value
  • the evaluation of the state of motor function is a regression in which the value represented by the physiological index value / control physiological index value is a value indicating the state of motor function of a patient and the degree of recovery of motor function as variables. It can also be done by substituting into a straight line. In another embodiment, the possibility is shown by comparing the value represented by the physiological index value / control physiological index value with the reference value indicating the probability that the patient will reach the desired degree of motor function recovery after regenerative treatment. You can also.
  • the method of the present disclosure it is possible to evaluate the motor function state of the subject, and it is possible to evaluate the motor function state after the regenerative treatment, that is, whether or not the motor function is restored by the regenerative treatment. Since it can be predicted, it becomes possible to determine which patient is suitable for cell therapy before the start of treatment, and it is also possible to select a patient having a high therapeutic effect.
  • the present disclosure also provides a computer program for causing a computer to execute the above method, a recording medium for storing the program, and a system for executing the above method.
  • it is a computer program that causes a computer to execute a process of a method of evaluating the state of motor function of the brain of a patient having or suspected to have brain damage, wherein the method is the following step: A step of causing the computer to obtain a physiological index value with the white matter region on the injured hemisphere side of the patient's brain as the region of interest.
  • a program is provided that includes a step of causing the computer to perform an operation for comparing the physiological index value with a control physiological index value and calculating a value indicating the state of motor function of the patient.
  • a recording medium containing a computer program that causes a computer to perform a process of assessing the state of motor function of the brain of a patient with or suspected of having brain damage, said method.
  • the computer is provided with a recording medium comprising a step of comparing the physiological index value with a control physiological index value and performing an operation for calculating a value indicating a state of motor function of the patient.
  • a system for assessing the state of motor function of the brain of a patient with or suspected of having brain injury in another aspect of the present disclosure A means for obtaining a physiological index value with the white matter region on the traumatic hemisphere side of the patient's brain as the region of interest.
  • a system is provided that includes a means of comparing the physiological index value with a control physiological index value and performing an operation for calculating a value indicating a state of motor function of the patient.
  • an image analysis device and an MRI device that can be used in carrying out a method for evaluating the state of motor function of a patient having or suspected to have such a brain injury. ..
  • the white matter region on the injured hemisphere side is the first region of interest and the white matter region on the non-injured hemisphere side is the first.
  • the area of interest setting unit to be set as the area of interest
  • a physiological index value calculation unit that calculates a damaged hemispherical side physiological index value and an uninjured hemispherical side physiological index value in each of the first region of interest and the second region of interest.
  • the image is characterized by comprising an arithmetic unit for performing an operation for comparing the injured hemisphere side physiological index value and the non-injured hemisphere side physiological index value and calculating a value indicating the state of the motor function of the patient.
  • An analyzer is provided.
  • a nuclear magnetic resonance imaging unit that images the brain of a patient who has or is suspected of having a brain injury.
  • An image generation unit that generates a diffusion-weighted image from the echo data acquired by the nuclear magnetic resonance imaging unit, In the diffusion-weighted image, a region of interest setting unit that sets the white matter region on the damaged hemisphere side as the first region of interest and the white matter region on the non-damaged hemisphere side as the second region of interest.
  • a physiological index value calculation unit that calculates a damaged hemispherical side physiological index value and an uninjured hemispherical side physiological index value in each of the first region of interest and the second region of interest.
  • the MRI is characterized by comprising a calculation unit for comparing the injured hemisphere side physiological index value and the non-injured hemisphere side physiological index value and calculating a value indicating the state of motor function of the patient.
  • Equipment is provided.
  • the same configuration as the image analysis device and the MRI device described in detail in other parts of the present specification can be provided.
  • aspects of the disclosure relate to methods of predicting motor function recovery after regenerative treatment in patients with local brain injury, as well as programs, image analyzers and MRI devices that can be used in the practice of such methods.
  • FIGS. 1 to 5 An exemplary embodiment of a method for predicting motor function recovery after regenerative treatment in a patient with local brain injury and an MRI apparatus that can be used in carrying out the method will be described with reference to FIGS. 1 to 5.
  • FIG. 1 shows a block diagram showing an overall configuration of an MRI apparatus according to an embodiment of the present disclosure.
  • the MRI apparatus 1 has a nuclear magnetic resonance imaging unit 10 and a computer 20.
  • the nuclear magnetic resonance imaging unit 10 is an imaging unit used in any known MRI apparatus capable of acquiring echo data necessary for diffusion-weighted images such as DTI and DKI.
  • the nuclear magnetic resonance imaging unit 10 has a sleeper unit; a magnet mount unit including a static magnetic field magnet, a gradient magnetic field coil, and an RF coil; and a sequence control unit.
  • the bed portion on which the patient is placed is inserted into the opening portion of the magnet mount portion.
  • the static magnetic field magnet of the magnet mount generates a static magnetic field, and the gradient magnetic field coil also applies a gradient magnetic field.
  • the transmitting RF coil then generates a high frequency magnetic field, which causes the receiving RF coil to receive the echo signal emitted by the patient.
  • the received echo signal is digitized and transmitted as echo data to the sequence control unit.
  • the sequence control unit controls imaging based on the sequence information transmitted from the computer 20, and also transfers the received echo data to the computer 20.
  • the computer 20 is a device that controls the nuclear magnetic resonance imaging unit 10, collects data, reconstructs an image, and analyzes an image.
  • the computer 20 includes an interface unit 21, an input unit 22, a storage unit 23, a calculation unit 24, and an output unit. It has 25 and a control unit 26.
  • the interface unit 21 controls the input / output of various data such as echo data exchanged with the sequence control unit of the nuclear magnetic resonance imaging unit 10.
  • the interface unit 21 transmits sequence information for controlling the nuclear magnetic resonance imaging unit 10 to the sequence control unit.
  • the interface unit 21 also receives echo data from the sequence control unit and stores it in the storage unit 23.
  • the input unit 22 is a device such as a keyboard, mouse, button, switch, etc., and inputs a signal corresponding to the operation of the operator for these devices.
  • the storage unit 23 includes a storage medium such as a hard disk, a flash memory, RAM, and a ROM, and a reading device for reading the information stored in the storage medium.
  • the storage unit 23 includes echo data transmitted from the sequence control unit, various MRI image data generated from the echo data, reference information for evaluating the state of motor function of the patient, a program for image generation and analysis, and a program for image generation and analysis. It stores a program for controlling each functional unit of the MRI apparatus 1 executed by the control unit 26, various setting information, and the like.
  • the arithmetic unit 24 is composed of hardware such as a CPU.
  • the calculation unit 24 reads the program stored in the storage unit 23, reconstructs an image from the echo data stored in the storage unit 23, and generates an image such as DTI or DKI from the reconstructed image.
  • the calculation unit 24 also analyzes images such as DTI and DKI of the patient's brain stored in the storage unit 23, and performs calculations for evaluating the state of the patient's motor function.
  • the output unit 25 connects various information such as an MRI image generated by the calculation unit 24 and a value for evaluating the state of the motor function obtained by performing the calculation to the outside of the computer 20, typically the output unit 25. Output to the displayed display.
  • the control unit 26 is connected to each functional unit constituting the MRI device 1, reads a program stored in the storage unit 23, and controls these operations. For example, the control unit 26 generates sequence information from the imaging conditions set by the operator and transmits the sequence information to the sequence control unit to control the imaging of the nuclear magnetic resonance imaging unit 10.
  • the imaging conditions are set values of various imaging parameters such as b value, TR, TE, NEX, voxel size, number of slices, diffusion gradient direction, and those skilled in the art are suitable for acquiring images such as DTI and DKI. These values can be set as appropriate.
  • FIG. 2 is a functional block diagram showing the configurations of a storage unit, a calculation unit, an input unit, and an output unit in one embodiment of the present disclosure.
  • the storage unit 23 includes an echo data storage unit 231, a reconstructed image storage unit 232, a DTI / DKI image storage unit 233, and a reference information storage unit 234. Further, the calculation unit 24 has an image generation unit 241 and an image analysis unit 242.
  • the image generation unit 241 has an image reconstruction unit 241a and a DTI / DKI image generation unit 241b
  • the image analysis unit 242 includes a region of interest setting unit 242a, a physiological index value calculation unit 242b, and a physiological index value comparison unit 242c. It has a motor function state evaluation calculation unit 242d.
  • the function of the image generation unit 241 that generates images such as DTI and DKI from echo data will be described.
  • the echo data storage unit 231 stores echo data transmitted from the sequence control unit for each patient.
  • the image reconstruction unit 241a generates a reconstruction image such as a diffusion-weighted image (DWI image) by performing a reconstruction process such as a Fourier transform on the echo data stored by the echo data storage unit 231.
  • the reconstructed image storage unit 232 stores the generated reconstructed image.
  • the DTI / DKI image generation unit 241b analyzes the generated reconstructed image such as DTI and DKI, and generates a DTI / DKI image.
  • the diffusion coefficients D xx , D xy , D xz , D yy , D yz , and D zz which are the components of the diffusion tensor D represented by the 3 ⁇ 3 symmetric matrix of Equation 1, are obtained.
  • the eigenvalues ( ⁇ 1 , ⁇ 2 , ⁇ 3 ) shown in Equation 2 are calculated.
  • D xx , D yy and D zz are mass diffusivity when a gradient magnetic field is applied in the x-axis direction, y-axis direction and z-axis direction of the MRI apparatus coordinate system, respectively.
  • ADC apparent diffusion coefficient, apparent diffusion coefficient
  • FA fractional anisotropy, anisotropy
  • the DTI / DKI image generation unit 241b By mapping these parameters, the DTI / DKI image generation unit 241b generates images such as DTI and DKI such as ⁇ 1 map, ⁇ 2 map, ⁇ 3 map, ADC map or FA map.
  • the DTI / DKI image storage unit 233 stores the generated images such as DTI and DKI.
  • FIG. 3 is a flowchart showing each step in the prediction method according to the embodiment of the present disclosure carried out by using each of the functional units
  • FIGS. 4 and 5 are flowcharts showing the details of the calculation steps in the prediction method. Is.
  • the region of interest setting unit 242a sets the first region of interest (ROI-1) at a position corresponding to the white matter region on the damaged hemisphere side, for example, on the DTI image stored in the DTI / DKI image storage unit 233, for example, the FA map.
  • a second region of interest (ROI-2) is set at a position corresponding to the white matter region on the undamaged hemisphere side (step S10).
  • the ROI may be set manually based on the anatomical position, superimposed on other medical images, or automatically based on the functionality of known image analysis software. good. When setting the ROI manually, the operation of setting the ROI by the operator is accepted via the input unit 22.
  • the physiological index value calculation unit 242b calculates the damaged hemispherical side physiological index value and the non-damaged hemispherical side physiological index value, which are the physiological index values of ROI-1 and ROI-2, respectively (step S11).
  • the injured hemisphere side physiological index value and the uninjured hemisphere side physiological index value are the average values of the physiological index values of all voxels contained in each of ROI-1 and ROI-2.
  • the physiological index value comparison unit 242c calculates a value represented by an injured hemisphere side physiological index value / an uninjured hemispherical side physiological index value (step S12).
  • the motor function state evaluation calculation unit 242d performs a calculation for predicting the recovery of the motor function of the patient after regenerative treatment, for example, based on the value calculated by the physiological index value comparison unit 242c (step S13), and the calculation result. Is output to the output unit 25 (step S14).
  • the calculation for evaluating the motor function state is performed based on the reference information stored in the reference information storage unit 234 in addition to the calculated value.
  • the reference information is a pre-prepared value represented by the injured hemispherical / uninjured hemispherical physiologic value of a patient who has or is suspected of having brain damage prior to regenerative therapy. It is a regression line with the variable of the degree of recovery of motor function of the same patient after treatment.
  • the degree of motor function recovery is the recovery of motor function by treatment, which is evaluated using a known evaluation method capable of evaluating motor function, for example, Bathel Index (BI) or Fugl-Meyer Assessment (FMA). It can be expressed as the difference between the pre-treatment score and the post-treatment score in the same patient.
  • the reference information is a reference value prepared in advance.
  • Reference values are for patients with or suspected of having or suspected to have the desired degree of motor recovery after regenerative treatment and with or with brain damage expected to not achieve the desired degree of motor recovery. It is a cut-off value for distinguishing from a suspected patient.
  • the degree of motor function recovery after regenerative treatment is the injured hemisphere side physiological index value / non-injured hemisphere side physiological index value before treatment. We have found that it correlates with the value represented by. Therefore, by referring to the values calculated from the DTI and DKI images of the pre-treatment brain of the patients who have already received the regenerative treatment and the degree of recovery of motor function after the treatment, the treatment of the patients who are going to receive the regenerative treatment from now on. Later recovery of motor function can be predicted, and whether the patient is expected to be adaptable to regenerative therapy, that is, whether regenerative therapy is expected to be successful.
  • a regression line in which the value calculated from the DTI and DKI images of the pretreatment brain of a patient who has already undergone regenerative treatment and the degree of motor function recovery after the treatment are used as variables is prepared in advance and regenerated.
  • the predicted value of the degree of motor function recovery after regenerative treatment of the test patient is calculated. Can be done (steps S130a, S130b).
  • Pre-treatment injured hemisphere-side physiological index value / non-injured hemispherical-side physiological index value corresponding to the desired degree of recovery of motor function is determined in advance as a reference value, and the test patient who is going to receive regenerative treatment from now on.
  • the reference value can be appropriately set according to the target degree of recovery of motor function.
  • the reference information such as the regression line and the reference value is obtained from a patient having the same kind of disease as the patient who is the prediction target of the recovery of motor function after the regenerative treatment.
  • the reference information includes the value calculated from the pretreatment brain DTI and DKI images of the cerebral infarction patient who received the regenerative treatment and the degree of motor function recovery after the treatment. It is preferable that it is prepared by using.
  • the reference information is also preferably obtained from a patient who has received the same type of treatment as the treatment to be indicated.
  • the treatment is administration of bone marrow mesenchymal stem cells (BMSC)
  • the reference information is the value calculated from the pretreatment brain DTI and DKI images of the patient who received the BMSC and the recovery of motor function after the treatment. It is preferable that it is prepared by using the degree.
  • the above is a description of a method for evaluating the state of motor function of a patient having or suspected of having a brain injury and an exemplary embodiment of an MRI apparatus that can be used in the practice of the method.
  • An exemplary embodiment of the image analysis apparatus according to the present disclosure that can be used in the implementation of the above method is an apparatus having an image analysis unit 242 of the MRI apparatus 1, the details thereof are as described in the above description. ..
  • the program according to the present disclosure that can be used in the implementation of the method is a program for causing a computer to execute each step of the method, and the details thereof are as described in the above description.
  • the computer-readable storage medium that stores the program can be any storage medium such as a hard disk, flash memory, CD, or DVD.
  • the present disclosure it is possible to evaluate the state of motor function of a patient, and thereby, for example, it is possible to predict the recovery of motor function after treatment of a patient who is going to receive regenerative treatment. Also, according to the present disclosure, it is possible to evaluate whether a patient is expected to be adaptable to regenerative therapy, that is, whether the regenerative therapy is expected to be successful. Accordingly, the methods and programs according to the present disclosure can also be expressed as methods and programs for assessing a patient's adaptability to regenerative therapy, and methods and programs that assist in assessing a patient's adaptability to regenerative therapy. The same applies to other aspects of the present disclosure.
  • brain injury means that some kind of damage occurs in the brain, and includes damage to blood vessels in the brain.
  • the cause of the injury is not particularly limited, and for example, "brain injury” includes traumatic brain injury, stroke, cerebral infarction, oxygen-deficient brain injury, brain tumor encephalitis, etc., and can also include local brain injury.
  • local brain damage refers to a state in which local damage to the brain occurs
  • patient with local brain damage refers to a patient having local damage to the brain.
  • local brain injury include cerebral infarction, head trauma and cerebral hemorrhage.
  • the patient having a local brain injury is not limited as long as the patient has a local brain injury and the motor function is impaired, and the patient has an acute phase, a subacute phase, and a chronic phase. It may be a patient at any time.
  • regenerative treatment for a patient with local brain injury refers to the patient's injured nervous system cells using cells of the patient (autologous) or others (allogeneic) or their secretions. It means treatment to regenerate and recover various dysfunctions associated with injury.
  • the cells that can be used for regenerative treatment of patients with brain injury or local brain injury may be cells capable of differentiating into neural cells, and examples thereof include mesenchymal stem cells and neural stem cells.
  • Pluripotent stem cells such as pluripotent stem cells, artificial pluripotent stem cells (iPS cells), embryonic stem cells (ES cells), embryonic tumor cells (EC cells) and embryonic reproductive stem cells (EG cells).
  • iPS cells artificial pluripotent stem cells
  • ES cells embryonic stem cells
  • EC cells embryonic tumor cells
  • EG cells embryonic reproductive stem cells
  • cells preferably used for treatment are mesenchymal stem cells, particularly bone marrow mesenchymal stem cells (BMSC, also referred to as bone marrow stem cells).
  • BMSC bone marrow mesenchymal stem cells
  • the cells exemplified above are the patient's own nerves due to transdifferentiation of the transplanted cells themselves into nervous system cells and due to cytokines, nutritional factors, exosomes, etc. contained in the secretions from the transplanted cells. It is thought to bring about a therapeutic effect by activating stem cells and promoting nerve repair (nursing effect).
  • cell secretions exemplified above such as cell-derived exosomes, cell culture supernatants, etc., can also be used for the treatment in the present disclosure.
  • the above cells and their secretions can be prepared by a known method using a biological sample isolated from the patient himself or others.
  • the pluripotent stem cell may be obtained by inducing differentiation of the pluripotent stem cell.
  • the doses and routes of administration of the cells and their secretions are appropriately set by those skilled in the art with reference to known dosing regimens relating thereto.
  • 10 4 to 10 9 cells preferably 10 5 to 10 8 cells per 1 kg of patient body weight by systemic administration such as intravenous administration or intraarterial administration, are locally administered such as direct intracerebral administration or intrathecal administration.
  • 10 2 to 10 9 cells preferably 10 4 to 10 6 cells per kg of patient body weight may be administered to the patient in one or multiple doses.
  • Example 1 Evaluation of the state of motor function by DTI
  • Target patients Patients in the acute stage of cerebral infarction (early onset) who are 20 years old or older and under 80 years old at the time of consent acquisition; within 14 days after the onset of cerebral infarction at the time of consent acquisition; Cerebral infarction occurring in the perforated area of the carotid artery; mRS before the onset of cerebral infarction is 0 or 1.
  • NIHSS “5. Exercise of upper limbs" and "6.
  • the scores of each motor function index such as BI in the subacute phase (10 to 50 days after the onset of cerebral infarction, hereinafter referred to as the subacute phase) when the acute phase treatment is almost completed are given.
  • Patients who did not reach 12 months were 6 months, and ⁇ BI, ⁇ mRS, ⁇ NIHSS, and ⁇ FIM, which were subtracted from the scores of the same type of motor function index (hereinafter referred to as chronic phase), were defined as the degree of motor function recovery.
  • DTI / DKI imaging For each patient, DTI / DKI images of the brain were taken at the time corresponding to the subacute phase and the chronic phase.
  • DTI / DKI images of the brain were taken at the time corresponding to the subacute phase and the chronic phase.
  • Table 1 shows the results of evaluating the correlation between BI, mRS, NIHSS, or FIM and motor function by DTI. From this result, a correlation was found between the ADC value and the improvement of motor function when the ROI was placed only on the hind leg of the internal capsule (the ADC value of the ROI of the hind leg of the internal capsule 14 days after the onset and the degree of improvement in BI).
  • Example 2 Evaluation of the state of motor function by DKI
  • the diffuse kurtosis (DKI) method was used to obtain a highly accurate and predictable index of diffuse images without depending on the experience of the measurer, etc., for the effect of cell administration therapy in patients with cerebral infarction.
  • a map of the main exponents by the diffusion kurtosis image (DKI) method was created, converted into a standard brain, and then the values of the internal capsule hind legs on both sides were measured.
  • Image analysis was performed in the same manner as in "(5) Image analysis" above.
  • Table 2 shows the correlation between the diffusion image data before cell administration by DKI and the degree of functional recovery.
  • a positive correlation was shown (FIGS. 7 and 8 respectively).
  • the degree of decrease in AD or MD associated with cerebral infarction seems to reflect functional recovery. From FIGS. 7 and 8, it was found that the AD and MD ratios of the internal capsule hind legs on the lesion side and the healthy side should be 0.83 or 1.01 or more, respectively, in order to obtain a change in BI of 30% or more.
  • the left-right differences between AD and MD in cases with different degrees of functional recovery are shown in FIGS. 9A and 9B.
  • Example 3 Example of program product
  • a program product a product capable of photographing and analyzing (4) and (5) of Example 1 is prepared.
  • the program of the present disclosure can be provided as a program product that stores a command code that can be read by a device, using the program described in the first or second embodiment as a memory.
  • the image processing of the present disclosure and its application are carried out.
  • a storage medium hard disk, optical disk, magnetic optical disk, memory card, memory stick, etc.
  • a DTI / DKI image of the brain is taken for a patient who has or is suspected of having brain damage, and diffused image data of the patient is calculated.
  • the ratio of the DTI / DKI index (lesion / healthy) on the lesion side and the healthy side is calculated, and the change in the numerical value indicating the degree of functional recovery is calculated.
  • This disclosure is useful in industries such as treatment and diagnosis of central nervous system diseases.
  • the present disclosure can be used in fields such as regenerative medicine and development of cell medicine.

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Abstract

La présente divulgation concerne un moyen d'évaluation d'un état d'une fonction motrice d'un patient qui présente ou est suspecté de présenter des lésions cérébrales telles que des lésions cérébrales locales.　La présente divulgation concerne : un procédé permettant l'évaluation d'un état d'une fonction motrice d'un patient qui présente ou est suspecté de présenter des lésions cérébrales par l'utilisation de paramètres obtenus à partir d'une image pondérée en diffusion du cerveau du patient; un programme permettant d'exécuter le procédé dans un ordinateur; ainsi qu'un dispositif de traitement d'image et un dispositif d'IRM qui peuvent être utilisés lors de la mise en œuvre du procédé. Selon la présente divulgation, l'état de fonction motrice d'un patient qui présente ou est suspecté de présenter des lésions cérébrales peut être évalué, et il est également possible de prédire la récupération de la fonction motrice après un traitement de régénération. Par conséquent, on peut déterminer si le traitement de régénération est approprié pour le patient avant le début du traitement.
PCT/JP2021/048662 2020-12-28 2021-12-27 Procédé, programme et dispositif d'évaluation d'état de fonction motrice WO2022145433A1 (fr)

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