WO2018070528A1

WO2018070528A1 - Method for examining intervertebral disc degeneration by mri

Info

Publication number: WO2018070528A1
Application number: PCT/JP2017/037254
Authority: WO
Inventors: 中村　雅也; 守雄松本; 中島　大輔; 順之藤田
Original assignee: 学校法人慶應義塾
Priority date: 2016-10-13
Filing date: 2017-10-13
Publication date: 2018-04-19
Also published as: JP6966786B2; JPWO2018070528A1

Abstract

In order to quantitatively detect minute changes in intervertebral discs, a study has been conducted on analysis methods such as the QSI method and the DTI method. With the present invention, it has become possible to quantitatively detect a minute change in intervertebral disc degeneration by using: KT FA, ZP FA, and FWHM FA of the QSI method; and FA of ADC, λ₁ mapping, and (λ₂+λ₃)/2 mapping by DTI analysis.

Description

MRI examination method for intervertebral disc degeneration

A method for examining intervertebral disc degeneration using nuclear magnetic resonance imaging (Magnetic resonance imaging, hereinafter referred to as MRI), in particular, q-space imaging (hereinafter referred to as QSI), or diffusion tensor imaging (diffuse tensor imaging). , Hereinafter referred to as DTI).

MRI is widely used for examination of diseases together with computed tomography (CT) in clinical practice. MRI is an examination method in which a subject obtains information generated from hydrogen nuclei that resonates with radio waves of a specific frequency in a strong magnetic field and is used for examination, and is used for examination of diseases such as the brain, spinal cord, and extremities.

In the orthopedic field, MRI is used for various diseases such as cervical spondylosis, hernia, and tumors. There are many analysis methods for MRI, and various classification methods have been proposed as diagnostic criteria for severity of intervertebral disc degeneration, hernia, etc. even if it is limited to examination of the spine (Non-patent Document 1). Many classification methods exist because of advances in analysis methods, but all classification methods are qualitative classification methods, and the degree of agreement of diagnosis between observers is low, and more objective classification methods are available. There is a demand for this in the background.

There are various analysis methods in MRI, but if broadly classified, a method of analyzing the obtained signal as free diffusion of water molecules and limited diffusion that occurs in a limited space such as cells and organs. There is a diffusion MRI technique to analyze as follows. In clinical practice, using diffusion-weighted images, hyperacute cerebral infarction can be visualized more sensitively than conventional MRI imaging methods or CT, and so progressed rapidly in the late 90s. In the brain, methods for depicting and diagnosing lesions such as cerebral infarction and brain tumor by several analysis methods are being established.

Even in the spinal cord, MRI examination methods are widely used as criteria for determining the pathological condition. In general, spinal disc degeneration is performed by analyzing the intervertebral disc using a T2-weighted image and classifying the degree of intervertebral disc degeneration using the Pfirmann classification method that classifies the disc into five levels according to the signal strength of the median sagittal section. (Non-Patent Document 2).

The Furman classification classifies the degree of degeneration from the T2-weighted image of the intervertebral disc, classifying the intervertebral disc degeneration into 5 stages 1-5. FIG. 5 is an image showing a typical degenerative pathology of an intervertebral disc classified by the Furman classification. The Furman classification is a method for qualitatively classifying a disease state from the signal intensity of the obtained MRI image and the shape of the intervertebral disc as follows.

Grade 1: Uniform disc shape, normal disc height, uniform bright white image, Grade 2: Disc shape non-uniform, normal disc height, horizontal gray line produced Non-uniform bright white image, grade 3: non-uniform disc shape, unclear between annulus fibrosus and nucleus pulposus, but disc height is normal, image intensity is medium gray image, Grade 4: The disc shape is non-uniform, the boundary between the annulus fibrosus and the nucleus pulposus is lost, and the disc height is normal or slightly reduced. Signal is low intensity, dark gray image, grade 5: disc shape is non-uniform, the boundary between the annulus fibrosus and nucleus pulposus is lost, and the disc space is lost. The signal is low intensity and a black image.

As described above, since the Furman classification is a qualitative evaluation method for judging from the signal intensity of the MRI image and the shape of the intervertebral disc, different judgments may occur depending on the observer. In particular, in the case of moderate degeneration, that is, grades 2 to 4, it is difficult to distinguish, and the judgment by the observer varies. Furthermore, since it is a qualitative evaluation method, it cannot capture minute changes. Therefore, there is a need for a quantitative MRI analysis method that captures the disease state in more detail.

Although various analysis methods are known for diffusion MRI, QSI has been attracting attention as a method that can perform more detailed analysis. QSI is an MRI analysis method that was initially reported as an analysis method for porous materials (Non-patent Document 3). The analysis by QSI can capture the diffusion phenomenon caused by water molecules more finely than the conventional method, and can acquire micro-sized structure information. Patent Documents 4 and 5).

Although an analysis method using QSI has been established in the brain, it has been reported that white matter degeneration and changes in the intervertebral disk can be detected in the spinal cord (Non-Patent Documents 6 and 7). It has also been reported that intervertebral disc degeneration is correlated with the classification by the Ferman classification method, which is a qualitative evaluation method, applying QSI (Non-patent Document 8).

Focusing on the direction and speed of the diffusion phenomenon, DTI that reflects the diffusion anisotropy allows the qualitative evaluation of highly unidirectional structures. Clinical application is progressing in the brain and spinal cord with high structure (Non-patent Document 9). In tissues where fibers are oriented, such as brain white matter and spinal cord, the diffusion anisotropy is strong, which is considered to reflect minute changes that could not be obtained from conventional images by DTI analysis. . A method for evaluating intervertebral disc degeneration has also been reported in the spinal cord by DTI analysis (Non-Patent Documents 10 and 11).

However, the currently reported analysis method using QSI has a problem that it cannot capture minute changes at the stage of quantification. For this reason, the classification is the same as the Ferman classification, and it is not possible to capture changes in the spine in more detail.

The present inventors have succeeded in analyzing minute changes in intervertebral disc degeneration by performing analysis by QSI using a rat intervertebral disc degeneration model (Non-patent Document 12). However, even when the same analysis method was applied to human intervertebral disc degeneration, it was not possible to capture quantitative changes as in the case of rats. Moreover, the application of analysis methods using DTI has not progressed to the point where quantitative analysis of intervertebral disc degeneration and fine changes can be captured.

An object of the present invention is to provide a method for quantitatively evaluating the degree of human intervertebral disc degeneration and taking a more detailed analysis of minute changes. The objective is to objectively indicate the pathophysiology of intervertebral disc degeneration by using more detailed changes than the Ferman classification currently used as an indicator of intervertebral disc degeneration, and to help treat the disease.

The present invention relates to a method and program for examining a human intervertebral disc using QSI or DTI.
(1) A human intervertebral disc inspection method using diffusion MRI, which uses Q-space imaging (QSI) analysis or diffusion tensor image (DTI) analysis, and is based on Kurtosis (KT) Fractional Anisotropy (FA) (FA) ( KT FA), probability at zero displacement FA (ZP FA), full width at half maximum FA (FWHM FA), FA by DTI analysis, λ ₁ mapping, (λ ₂ + λ ₃ ) / 2 mapping The inspection method characterized by analyzing by.
(2) The inspection method according to (1), wherein the intervertebral disc degeneration is quantified.
(3) The b value, axis information, and diffusion time are extracted from the spectrum data in each voxel of the target intervertebral disk obtained by the MRI apparatus, and KT FA, ZP FA, FWHM FA by QSI analysis, FA by DTI analysis, λ A program for causing a computer to execute a step of performing calculation by at least one of ₁ mapping and (λ ₂ + λ ₃ ) / 2 mapping, and a step of quantitatively representing a state of a target intervertebral disc based on a calculation result.
(4) The program according to (3), which causes a computer to execute the step of displaying the calculation result as an image.

By obtaining a quantitative method for examining intervertebral disc degeneration due to QSI or DTI, it is possible to more objectively distinguish a patient's pathological condition. In the analysis by DTI and QSI, the present inventors have discovered for the first time that a minute change can be quantitatively captured by the above parameters. According to the method of the present invention, changes in a disease state can be captured in detail and objectively, so that a small change in a disease state such as improvement of a disease due to treatment can be quickly captured, which can be used for treatment.

The flowchart explaining operation | movement of the program which concerns on the Example of this invention. The figure which shows the comparison with Kurtosis Fractional Anisotropy (KT FA) and the conventional method. The figure which shows the comparison with the analysis method of this invention, and the T2 weighted image which is a conventional method. The figure which shows the comparison with the analysis method by QSI of this invention, and the conventional method. The figure which shows the typical image of the intervertebral disk degeneration by the Furman classification which is a conventional method.

The present inventors performed analysis by QSI using a rat intervertebral disc degeneration model, and in rats, degenerated disc using probability at zero displacement (ZP), Kurtosis (K), full width at half maximum (FWHM), It has been reported that normal discs can be significantly distinguished (Non-patent Document 12). However, in human intervertebral disc degeneration, even if analysis was performed using these parameters, the degree of degeneration could not be distinguished significantly. Therefore, we examined a method that can quantitatively measure the degree of human intervertebral disc degeneration.

In addition, when using the same method as the report analyzing human intervertebral disc degeneration by QSI (Non-patent Documents 6 to 8), it can be classified as much as the Furman classification, but it can be distinguished more clearly. There wasn't. Therefore, the analysis was performed by changing parameters. In the analysis by QSI, Kurtosis Fractional Anisotropy (KT FA), probability at zero displacement FA (ZP FA), full width at half maximum FA (FH) It became clear that 1 to 5 could be distinguished clearly and quantitatively. Furthermore, in the DTI analysis, it was found that grades 1 to 5 of the Ferman classification can be clearly and quantitatively distinguished by FA, λ ₁ mapping, and (λ ₂ + λ ₃ ) / 2 mapping.

Based on the data acquired by MRI, all the processes analyzed by the QSI method and DTI method are executed by a computer program. Specifically, b value data, axis information, and nucleic acid time are extracted from data in each voxel of the target intervertebral disk obtained by the MRI apparatus. In the case of QSI analysis, in the case of KT FA, ZP FA, FWHM FA, and DTI analysis, calculation for calculating FA, λ ₁ mapping, and (λ ₂ + λ ₃ ) / 2 mapping is executed by a computer. Furthermore, the state of the target intervertebral disc can be quantitatively shown as a numerical value based on the calculation result, or can be visualized by a method such as color mapping at the position of the intervertebral disc (FIG. 1).

[Example 1]
Hereinafter, explanation will be given while showing data. 21 patients who received informed consent at Keio University School of Medicine Orthopedic Surgery (84 intervertebral discs with high-resolution images out of 5 intervertebral discs between lumbar 1st / 2nd-5th / sacrum) Extraction, average age 53 years, 15 men, 6 women) MRI images were acquired and performed.

For the analysis, MAGNETOM Skyra 3T (manufactured by Siemens Healthcare) was used, and TR / TE (ms): 4000/89, FOV (mm) using Echo Planar Imaging (EPI) under the condition that δ of the above apparatus was the shortest. ): 576 × 576, Matrix: 192 × 192, Thickness (mm): 3, gap (mm): 0, slice (sheet): 7, voxel size (mm): 3 × 3 × 6, Δ / δ (ms ): 43.1 / 31.7, b value (s / mm ² ): 0, 50, 200, 450, 800, 1250, 1800, 2400, 3150, 4000 were set as imaging conditions. The bipolar magnetic field gradient (MPG) application setting was 6 axes.

Although an outline is described below, the calculation method of each value is based on a general method used in this field. In the QSI method, a signal attenuation curve is derived from signal values for several steps in each vector direction, and inverse Fourier transform is performed to create a probability variation probability distribution. Then, Kurtosis (K), ZP, and FWHM are calculated and tensor calculation is performed to calculate λ ₁ , λ ₂ , and λ ₃ that are eigenvalues of the respective tensors of K, ZP, and FWHM. From the λ ₁ , λ ₂ , and λ _{3 of} K, ZP, and FWHM, each <D> is obtained by the following formula (I).

The anisotropy ratio (Fractional Anisotropy, FA) is obtained from λ ₁ , λ ₂ , and λ ₃ calculated from Kurtosis, ZP, and FWHM according to the following formula (II).

That is, KT FA can be obtained as K FA, ZP FA as ZP FA, and FWHM FA as FWHM FA. In the DTI analysis, an apparent diffusion coefficient (ADC) was calculated with a b value of 800, and FA, λ ₁ , (λ ₂ + λ ₃ ) / 2 were calculated and displayed.

For intervertebral discs classified as

Ferman classification grades

3 and 4 from the T2-weighted image (an example of an MRI image is shown in the lower part of FIG. 2), the signal intensity is obtained by T2 mapping, ADC, and QSI KT FA. Was calculated and graphed. In addition, in the Furman classification, an experienced spine surgeon with 10 years of experience makes a diagnosis from a T2-weighted image. Also, the horizontal axis represents T2 mapping [ms], ADC [* 10 ⁻³ mm ^{2 /} s], KT FA [a. u. ], And the vertical axis represents the frequency of each.

As shown in FIG. 2, in T2 mapping and ADC, the signals obtained from the grade 3 and grade 4 intervertebral discs overlap, and it is difficult to judge the degree of intervertebral disc degeneration from the signal intensity. In particular,

grades

3 and 4 cannot be separated and overlapped in the signal obtained by ADC. In T2 mapping, the signal tends to be low in grade 3 and high in grade 4, but the median of both frequencies is close, and the degree of intervertebral disc degeneration should be judged from the obtained signal value. It is difficult. In contrast, in QSI KT FA, the signal values of

grades

3 and 4 are separated, and the degree of intervertebral disc degeneration can be determined from the signal values.

As mentioned above, since the conventional method of Ferman classification is a qualitative evaluation, it is difficult to distinguish between grades 2 to 4, which are moderate modifications. In addition, the degree of coincidence of diagnosis is low due to subjectivity. On the other hand, as shown in FIG. 2, the analysis by KT FA is a quantitative analysis, and it is possible to clearly distinguish moderate degeneration such as

grades

3 and 4. Here, the data is shown for

grades

3 and 4, but the difference between

grades

2 and 3 or

grades

2 and 4 can also be clearly distinguished.

Next, KT FA, ZP FA, FWHM FA by QSI analysis, FA of ADC by DTI analysis, λ ₁ mapping, (λ ₂ + λ ₃ ) / 2 mapping, and intervertebral disc classified as grade 1 to grade 5 of Ferman classification The signal intensity was calculated for each of the methods and summarized in a graph (FIG. 3). The horizontal axis shows grades 1 to 5 of the Furman classification. In the same manner as described above, the Furman classification is performed based on a diagnosis by a skilled spine surgeon having 10 years of experience from a T2-weighted image.

Compared with T2 mapping, KT FA by FWSI, FWHM FA, ZP FA, FA (ADC) by DTI analysis, λ ₁ mapping, (λ ₂ + λ ₃ ) / 2 mapping are used, and the grade of Furman classification 1 to 5 can be classified very well (FIG. 3). In particular, in T2 mapping, there is almost no quantitative difference between the grades 3 to 5 of the Ferman classification, but a significant difference can be recognized quantitatively in the six analysis methods of the present invention. Thus, the present invention is the first time that quantitative analysis of the degree of degeneration in an intervertebral disc has been performed to such an extent that the grades of Furman classification can be completely separated.

Since the Furman classification is a qualitative method that makes a composite determination based on the signal intensity of the T2-weighted image and the shape of the intervertebral disc, the degree of coincidence by the observer has been a problem. In particular, intermediate disc degeneration in the grade 2 to 4 of the Ferman classification may cause a difference in judgment by doctors. On the other hand, since the method of the present invention is quantitative and more sensitive than ever, there is no discrepancy in judgment by the observer. That is, the subjectivity of the observer is not entered, and the disease can be objectively determined. In addition, subtle differences such as improvement of diseases due to medication can be captured as numerical values. As a result, it is possible to obtain an objective index for follow-up observation that has been difficult to obtain so far, and can be used for treatment.

[Example 2]
Next, we will show the results of a cross-sectional study with an increased number of samples. Japanese volunteers (average age 63.5 years (standard deviation 9.2), 28 men, 28 women, with 44 informed consent obtained with permission from the Ethics Committee at Nakura Orthopedics 23 patients) acquired and analyzed MRI images (n = 220) of intervertebral discs of the lumbar vertebrae (lumbar vertebra No. 1 / No. 2 to No. 5 / No. 5 intervertebral disc).

For the analysis, MAGNETOM Skyra fit 3T (manufactured by Siemens Healthcare) equipped with a 30-channel body coil and a 30-channel spine coil was used. An axial T2-weighted image was used as a reference, and a median sagittal T2-weighted image, T2 mapping, and QSI analysis were performed. The imaging protocol is shown in Table 1.

Abbreviations in the table are as follows.
T2WI: T2-weighted MRI
T2map: T2 mapping MRI
RARE: rapid acquisition with relaxation enhancement
Δ: the time between the two leading edges of the diffusion gradient
δ: gradient length, aprx: apximately

Of the 220 spinal cords, 25 had low signal intensity, so 31 was excluded because it was a disease other than intervertebral disc degeneration, and MRI images obtained from 164 spinal cords were used for the following analysis. The extracted intervertebral discs were classified by Furman classification. As a result of classification, grade 1 was classified as 1, grade 2 as 19, grade 3 as 59, grade 4 as 54, and grade 5 as 31 discs. Since there was only one disc classified as grade 1, it was excluded from the following analysis.

Using a computer, analysis was performed by T2 mapping, ADC map, and QSI. Theoretically, the optimal b value should be in the range of the reciprocal of the average value of the ADC that gives the optimal signal intensity to noise ratio in the tissue being analyzed, so a b value of 450 s / mm ² is assumed. used. Further, an ADC map based on a conventional single exponential model was calculated from a part of the QSI data (b value: 0, 450 [s / mm ² ]). Table 2 and FIG. 4 show the results of each analysis method.

As shown in FIG. 4, in all the analysis methods except ADC, a significant difference was observed between Furman grade II and III (p <0.05). Furthermore, in all QSI analysis (mean Kurtosis, mean Probability at zero displacement, mean FWHM, FA of Kurtosis (KT FA), FA of Probability at zero dissemination (FAF, HPF). Significant differences were observed between Furman Grade II and III compared to T2 mapping and ADC, which are MRI analysis methods, equivalent or higher.

For Furman grades III and IV, significant differences were observed in all analytical methods (p <0.05). In particular, KT FA, ZP FA, and FA FWHM can be clearly distinguished from Ferman grade III and IV (p <1 * 10 ⁻¹⁰ ) than other analysis methods. In particular, FA FWHM was most clearly able to distinguish between Ferman Grade III and IV among all analytical methods.

For Furman Grade V, the standard deviation showed the largest value compared to other Ferman grades in all analysis methods. In KT FA, ZP FA, and FA FWHM, values increased from Ferman Grade II to IV, whereas values from IV to V were the same or decreased. However, in the analysis method using QSI, it is easy to cause variation by an observer, and it is possible to quantitatively classify Ferman grades II to IV, which are very difficult to classify until now.

KT FA, FWHM FA, ZP FA by QSI analysis, FA (ADC) by DTI analysis, λ ₁ mapping, (λ ₂ + λ ₃ ) / 2 mapping sharply promotes intermediate disc degeneration in Furman classification 2-4 Since it is possible to distinguish, any of them may be used for the inspection. Since the analysis by the DTI method can be performed by imaging in a short time, there is an advantage that the analysis can be performed without using the latest MRI apparatus, and diagnosis can also be performed at a clinic. In addition, since the analysis by the QSI method is considered to be more quantitative, a detailed result may be obtained.

According to the method of the present invention, it is possible to obtain a quantitative value that could not be obtained from a T2-weighted image that has been mainly used in the spinal cord so far, and therefore an accurate diagnosis can be performed. In addition, since it is possible to capture minute changes in the patient over time, it is possible not only to capture minute changes in the patient with respect to treatment, but also to objectively determine the effect of the therapeutic agent.

Claims

A method for examining a human intervertebral disk using diffusion MRI,
Using Q-space imaging (QSI) analysis or diffusion tensor image (DTI) analysis,
Kurtosis (KT) Fractional Anisotropic (FA) (KT FA), probability at zero displacement FA (ZP FA), full width at half maximum FA (FWHM FA) by QSI analysis
An inspection method, comprising: analyzing by at least one of FA, λ 1 mapping, and (λ 2 + λ 3 ) / 2 mapping by DTI analysis.
The inspection method according to claim 1,
An inspection method characterized by quantifying intervertebral disc degeneration.
From the spectral data in each voxel of the subject intervertebral disk obtained by the MRI apparatus,
Extract b value, axis information, diffusion time,
Performing a calculation by at least one of KT FA by ZSI analysis, ZP FA, FWHM FA, FA by DTI analysis, λ 1 mapping, (λ 2 + λ 3 ) / 2 mapping;
A step of quantitatively expressing the state of the target intervertebral disc based on the calculation result;
A program that runs a computer.
Displaying the calculation result as an image;
The program according to claim 3, which is executed by a computer.