KR101789425B1 - Methods for diagnosing early onset dementia by using 13C magnetic resonance imaging - Google Patents

Abstract

The present invention relates to a method for diagnosing premature dementia using 13C magnetic resonance spectroscopy, and more particularly, to a method for diagnosing premature dementia by calculating the conversion rate of pyruvate to lactate through 13C-MR spectroscopy, , The opportunity to treat dementia in the stage of metabolic abnormalities, and the degree of cerebral palsy can be determined.
In addition, the present invention is capable of diagnosing metabolic dementia. In addition to the conversion rate of pyruvate to lactate in the diagnosis of metabolic dementia, it is also possible to measure the degree of cerebral palsy, amyloid beta accumulation, .

Description

[0001] The present invention relates to a method for diagnosing early dementia using 13C magnetic resonance spectroscopy,

The present invention relates to a method for diagnosing premature dementia by calculating the conversion ratio of 13C-pyruvate to 13C-lactate using 13C-lactate, which is a metabolite of 13C-pyruvate and its metabolite, 13C-lactate will be.

The number of demented elderly people is rapidly increasing from 360,000 in 2005 to 580,000 in 2015. Because dementia has a remarkably low mental function such as intelligence, will, and function, the suffering of the person and the family is very large and is becoming a major social problem. Diagnosis of dementia is a major method of diagnosis of psychiatrists. Many of the patients diagnosed with dementia are found at a stage where the brain tissue is damaged and can not be recovered. Therefore, Is very necessary.

It is based on the "amyloid beta" hypothesis as a pathological factor of dementia. This is a hypothesis that the amyloid beta accumulated in the brain attacks the brain cells and ultimately causes loss of brain cells. In fact, it can be seen that amyloid beta is accumulated in the brain of the demented patient. Based on these results, various drugs targeting amyloid beta have been developed and many clinical trials have been developed, but most of them have failed. This reflects the limited ability of amyloid beta to explain the pathology of amyloid hypothalamic dementia, although it may be a contributing factor to brain cell damage.

Dementia is known to be the most important factor in relation to dementia. Recently, it has been reported that dementia increases in old age with diabetes, obesity, and high cholesterol diet. This reflects the high correlation between "metabolic disease" and dementia. FDG-PET imaging was performed by injecting F-18FDG ([F-18] 2-deoxy-2-fluoro-D-glucose), a glucose analogue, into the body. Have been reported to have reduced F-18FDG entry than normal subjects. Based on this research, there is an increasing tendency to focus on hypometabolism as a major cause of Alzheimer's disease. However, since FDG-PET imaging is limited not only to the imaging of glucose uptake but also to the perfusion of the blood flow, it is limited to implement accurate images in tissues with increased blood flow and increased glucose uptake Have.

Recently, the hyperpolarized 13C imaging method is becoming more important as a technique to image more realistic metabolism by detecting the products according to intracellular metabolism reaction using non - radioactive material in real time using MRI.

The present inventors induced metabolic dementia through high carbohydrate high fat diet (HFD-diet) intake and imaged the degree of conversion of 13C-lactate into 13C-lactate by using 13C-pyruvate as an image probe in these animal models to diagnose dementia It was completed by constructing image technique.

Korean Registration No. 10-1516634

 Alzheimer's and Dementia, vol. 10 (4), P62 (2014.07)

The object of the present invention is to provide a method for the diagnosis of early dementia by calculating the conversion ratio of 13C-pyruvate to 13C-lactate using 13C-lactate, which is a metabolite of 13C-pyruvate and its metabolite, Thereby providing a method of providing information.

In order to achieve the above object, the present invention relates to a 13C-magnetic resonance spectroscopic image of 13C-pyruvate and 13C-lactate, which is metabolism thereof, obtained from a subject to which 13C-pyruvate has been administered, And determining whether the 13C-metabolic conversion ratio is higher than that of the normal control group, the method comprising the steps of:

[Formula 1]

The administration of 13C-pyruvate is characterized by the injection of hyperpolarized 13C-pyruvate into a subject.

The hyperpolarized 13C-pyruvate is characterized in that it is performed according to a DNP (Dynamic Nuclear Polarization) method.

The 13C-MR spectroscopic image is characterized in that 13C-pyruvate is obtained in the brain of the subject at intervals of time from 0 to 180 seconds after administration to the subject.

The early dementia may be a case in which a decrease in cerebral perfusion and accumulation of amyloid beta is not observed and the rate of metabolism of 13C-pyruvate to 13C-lactate in a subject asymptomatic in the behavioral test is increased as compared with a normal control group .

The present invention relates to a method for diagnosing premature dementia before loss of brain function due to loss of brain cells by calculating the conversion rate of pyruvate to lactate through 13C-MR spectroscopy, Provides an opportunity to treat dementia at the pre-metabolic stage, enables safe metabolic imaging of radiation exposure, and quantifies the amount of 13C-pyruvate introduced into the brain to quantify the level of cerebral perfusion .

In addition, the present invention is capable of diagnosing metabolic dementia. In addition to the conversion rate of pyruvate to lactate in the diagnosis of metabolic dementia, it is also possible to measure the degree of cerebral palsy, amyloid beta accumulation, .

FIG. 1 shows the result of measurement of the entire 13C signal using a 13C-magnetic resonance spectroscopy image in a dementia animal model.
Figure 2 shows the percent conversion of pyruvate to lactate calculated using a 13C-MR spectroscopy image in a dementia animal model.
FIG. 3 is a result of confirming accumulation of amyloid beta by immunohistochemical staining in a dementia animal model.
FIG. 4 shows the result of an abnormal behavior test according to an underwater maze test in a dementia animal model.
Figure 5 shows the results of quantifying the degree of metabolism of 13C-pyruvate according to brain location using chemical displacement imaging (CSI).

Hereinafter, the configuration of the present invention will be described in detail.

The 13C-pyruvate metabolite of 13C-pyruvate and 13C-lactate obtained in a subject to which 13C-pyruvate has been administered is calculated from the 13C-magnetic resonance spectroscopic image of 13C-pyruvate, and the 13C- And determining a dementia when the metabolic conversion ratio is increased as compared to a normal control group. The present invention relates to a method for providing information on the diagnosis of premature dementia using a 13C-MR spectroscopy image,

[Formula 1]

The present invention relates to a cell in which 13C-pyruvate is converted to 13C-lactate by a lactate dehydrogenase in the brain through a magnetic resonance spectroscopic imaging method using 13C-pyruvate labeled with a non-radioactive isotope as an image probe More specifically, the amount of 13C-pyruvate converted to 13C-lactate was plotted on a graph, and then the area of each graph was determined for each period of time over a certain period of time The 13C magnetic resonance spectroscopy image, which tracks the metabolic reaction in brain cells with the slope of lactate / pyruvate per unit time, is characterized by its ability to diagnose premature dementia. Quantifying the conversion of 13C-pyruvate to 13C-lactate can be a good indicator of metabolism in the brain because the brain is a very vigorous organ of glucose metabolism. Thus, the 13C-MR spectroscopy image is an imaging technique that better reflects real metabolism than FDG-PET imaging, which only images the inflow of glucose.

In the present specification, "early dementia" refers to a condition in which the brain of a subject determined to be dementia does not show a decrease in cerebral perfusion and accumulation of amyloid beta, and a 13C-magnetic resonance spectroscopy image Means that the conversion of 13C-pyruvate to 13C-lactate is increased compared to that of normal. Correspondingly, the term "metabolic dementia" refers to a 13C-pyruvate 13C-lactate via 13C-MR spectroscopy imaging in the brain of a subject, exhibiting reduced cerebral perfusion, accumulation of amyloid beta, This means that the amount of conversion is significantly increased compared to the normal person. The metabolic dementia may include, but is not limited to, Alzheimer's disease, vascular dementia, Parkinson's disease, rheisothalamic dementia, Huntington's disease, Kruszfeld-Jjark's disease or Pick's disease.

The term "normal control or normal person" refers to a subject not having metabolic disorders of the brain as well as pathological damage of the brain. The present invention provides a method for determining the normal range or cut-off value for the amount of conversion (or conversion rate) of a predetermined 13 C-pyruvate to 13 C-lactate from a plurality of normal controls or healthy persons, It is possible to judge whether or not it is excessive and to judge dementia.

Thus, the term "conversion amount (or conversion ratio) of 13C-pyruvate to 13C-lactate increases" refers to the amount of conversion of the predetermined 13C-pyruvate to 13C- (Or statistical significance) to 1.5 times, 2 times, 3 times, or 4 times more than the normal range or cut-off value.

According to one embodiment of the present invention, the amount of conversion of 13C-pyruvate to 13C-lactate in an early demented animal model induced for 12 weeks with high fat diet (HFD-diet) (Normal control group). In addition, the spectrum of 13C metabolites according to the location of the brain was found to increase the metabolism to lactate from the medial temporal lobe, including the hippocampus. It can be used as a region of the brain that is judged to be dementia when performing 13C chemical shift imaging. In addition, lactate dehydrogenase, which converts pyruvate to lactate, is activated in early demented animal models. As expected, there was no decrease in cerebral perfusion and accumulation of amyloid beta in the early dementia animal model compared with the normal control, and no abnormal dementia was observed in the behavioral test.

On the other hand, in the case of the dementia model (metabolic dementia) induced in the high fat diet for 24 weeks, the conversion of pyruvate to lactate was about twice as high as that of the animal model (normal control) Respectively. When the amount of 13C-pyruvate injected into the tail vein was quantified in the brain, the amount of 13C-pyruvate injected into the tail vein was smaller in the dementia animal model than in the normal control. This is because even though the amount of pyruvate delivered to the brain was small, Which means that the process has been activated very much. Also, in the brain, the amount of total C13, i.e., the sum of 13C-pyruvate, 13C-lactate and 13C-pyruvate-hydrate, was quantified, resulting in a decrease in blood flow in the animal model of dementia. That is, they showed a decrease in cerebral perfusion. In addition, the accumulation of amyloid beta was observed and behaviors similar to dementia were observed.

Accordingly, the present invention provides a method for determining the conversion of pyruvate to lactate through 13C-MR spectroscopy using a non-radioactive isotope that does not emit ionizing radiation, Early diagnosis of dementia provides an opportunity to treat dementia in the stage of metabolic abnormalities before the accompanying pathological damage of the brain, safe metabolism imaging is possible for radiation exposure, and the total amount of 13C in the brain (13C-pyruvate Bait and all its metabolites), quantifying the amount of 13C-pyruvate introduced from the vein into the brain can be quantified to determine the degree of cerebral perfusion. In addition, it has been known that dementia is induced through hypoglycemia due to reduced glucose uptake into the brain. However, it has been confirmed through the present invention that dementia is induced through an increase in metabolic reaction to lactate, Provide a perspective.

In addition, the present invention is capable of diagnosing metabolic dementia. In addition to the conversion of pyruvate to lactate in the diagnosis of metabolic dementia, it is also possible to measure the degree of cerebral palsy, amyloid beta accumulation, .

Hereinafter, a method of providing information on the diagnosis of early dementia using the 13C-MR spectroscopy image of the present invention will be described step by step.

A method of providing information on the diagnosis of premature dementia using the 13C-MR spectroscopy image of the present invention

Administering 13 C-pyruvate to a subject;

Obtaining 13 C-MR spectroscopic images of 13 C-pyruvate and its metabolism, 13 C-lactate, in said subject;

Calculating the 13C-metabolic conversion ratio of the formula 1 from the 13C-magnetic resonance spectroscopic images of 13C-pyruvate and 13C-lactate obtained above; And

And determining the dementia when the 13C-metabolic conversion ratio is increased compared to the normal control group:

[Formula 1]

In administering the 13C-pyruvate to a subject, the 13C-pyruvate may use hyperpolarized 13C-pyruvate for amplification of the 13C signal.

The hyperpolarization of 13C-pyruvate uses a mixture of isotopically enriched ³ He, ¹²⁹ Xe or such noble gas; Split into NMR active nuclei by thermodynamic equilibrium at very low temperatures and high magnetic fields; Polarizing the nuclear spin by physically rotating the paramagnetic material in a magnetic field after mixing; Or DNP (dynamic nuclear polarization). That is, by directly polarizing 13C-pyruvate to obtain hyperpolarized 13C-pyruvate, or by polarizing 13C-pyruvate and neutralizing with a base, the polarized 13C-pyruvate is converted into hyperpolarized 13C-pyruvate . ≪ / RTI >

Preferably, the present invention can utilize the DNP method to obtain hyperpolarized 13C-pyruvate. More specifically, the paramagnetic compound is used as the polarizing compound to mix with 13C-pyruvate, the paramagnetic compound is excited by applying energy in the form of microwave radiation, and the 13C nucleus of 13C-pyruvate from the unpaired electron of the paramagnetic compound Lt; RTI ID = 0.0 > 13C-pyruvate < / RTI > can be performed.

The 13C-pyruvate may be a commercial product, for example, but is not limited to, CLM-8077-1 from Cambridge isotope laboratories.

As the paramagnetic compound, a transition metal, a free radical, a nitroxide radical and the like can be used, and a trityl radical can be preferably used. When the trityl radical is used, water may be used as a cosolvent for dissolving in pyruvate.

The molar fraction ratio of 13C-pyruvate and paramagnetic compound mixed in the DNP process may be 5: 1, but is not limited thereto.

The DNP process can be performed using a hyperpolarization device at a magnetic field of 1T to 25T and an absolute temperature of 0.5K to 8K, more specifically, a magnetic field of 3.35T and a cryogenic temperature of 4K.

The hyperpolarization equipment may be, but is not limited to, HyperSense.

The hyperpolarized 13C-pyruvate may be dissolved in a buffered solution to which a base is added and administered to a subject.

As the buffer solution, a phosphate buffer solution such as Tris may be used. As the base, aqueous solution of sodium carbonate (Na ₂ CO ₃ ), aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ), aqueous solution of sodium hydroxide (NaOH) .

The buffer solution may contain a chelating agent such as EDTA and sodium chloride (NaCl) to maintain the osmotic pressure.

According to one embodiment of the present invention, 75mM of 13C-pyruvate is mixed with 15mM of trityl radical to dissolve, followed by a hyperpolarization process at a temperature of 4K for 60 minutes, adding 1M Tris-HCl, 1M NaCl, 2g / Liquid EDTA and 1M NaOH buffer solution to dissolve hyperpolarized 13C-pyruvate to prepare injection. The hyperpolarized 13C-pyruvate according to the above-described method is enriched in isotope of 75% or more, preferably 90% or more of isotope is concentrated.

The subject may be a human or an animal other than a human.

In order to obtain a 13C-magnetic resonance spectroscopic image, a subject is placed on a magnet of a magnetic resonance spectroscope, and a 13C-magnetic resonance RF-coil is placed so as to cover the brain region of the subject. Next, the hyperpolarized 13C-pyruvate is injected into the object. According to one embodiment of the present invention, a mouse model in which early dementia was induced or metabolic dementia was induced was provided by ND-diet or HFD-diet for 12 weeks or 24 weeks, Polarized 13C-pyruvate is injected. A 13 C-NMR spectroscopy image is acquired in the brain of the subject until 60 seconds elapse after the injection. 13C-NMR spectroscopy, which can be normalized to the maximum value of the signal intensity in the magnetic resonance spectroscopic images of 13C-pyruvate and 13C-lactate, and the base line and the global zero-order phase After global zero order phasing, the frequency domain can be selected to include the maximum value of the signal curve of each metabolite. From this, data of 13C-MR spectroscopy images are shown in the form of 13C-magnetic resonance spectroscopy, 13C-pyruvate and 13C-lactate exhibit a unique spectrum according to known resonance frequencies, and the maximum Value. 13C-magnetic resonance RF-coil is used for detecting the 13C-magnetic resonance spectroscopic image. In this case, a 13C-magnetic resonance RF-coil optimized for the image portion can be used for the 13C- 13C dual-tuned surface transmit / receive coil having a diameter of 20 mm was used, but the present invention is not limited thereto.

In the case of the signal curves in the time domain obtained from the magnetic resonance spectroscopic images of 13C-pyruvate and 13C-lactate, the maximum value of the signal intensity of 13C-pyruvate is shown, and then the maximum value of the signal intensity of 13C- Value is displayed. The dynamic curve obtained from the 13C-magnetic resonance spectroscopy image in the time domain shows that the 13C-pyruvate in the brain of the subject is metabolized by the LDH enzyme (lactate dehydrogenase) As shown in Fig. From this, it can be seen that the metabolic exchange rate from pyruvate to lactate can be utilized as an activity index of brain cells.

The 13C-magnetic resonance spectroscopy images of 13C-pyruvate and 13C-lactate obtained above are used to acquire signal curve data of each metabolite in the time domain using an image signal processing technique.

As shown in the formula 1, the 13C-metabolic conversion ratio is calculated by dividing the area of the signal curve of the 13C-magnetic resonance spectroscopy image of the 13C-lactate by the area of the signal curve of the 13C-pyruvate 13C-magnetic resonance spectroscopic image . At this time, the area of the signal curve of the 13C-MR spectroscopy image is the area for the area under the signal curve, and the time is preferably 0 to 60 seconds. Alternatively, the < 13 > C-metabolic conversion ratio is a ratio of the amount converted to 13C-lactate, which is its metabolism to the amount of 13C-pyruvate. The larger the value, the more active brain cells, .

The rate of conversion of 13C-metabolism obtained above is compared with the normal control, and it is judged to be dementia if it increases.

Hereinafter, the present invention will be described in detail with reference to examples. However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.

Example 1: Diagnosis of dementia using 13C-Magnetic resonance spectroscopy image in dementia animal model

(Dementia animal model construction)

To establish the metabolic dementia model, high fat diets (HFD; 60% Kcal fat, Research Diets INC., NJ, USA) were infused for 12 weeks, 15 weeks, 19 weeks, or 24 weeks. Feeds were fed at intervals of two days. Feeds were supplied once for reasons such as corruption of the feed, and the remaining feed was discarded. The supply of negative water was autonomous, and the cycle of day and night was 12 hours. For the control group, all conditions were the same, but feed was fed to normal feed. We performed weekly weight measurement, blood glucose test, fasting glucose test, and fasting insulin resistance test to confirm the establishment of the model. All experimental procedures were conducted under the review of the Laboratory Animal Ethics Committee of the Yonsei University College of Medicine, based on NIH guidelines for animal experiments.

(Preparation of 13C-pyruvate)

After 75 mM of 13C-pyruvate (CLM-8077-1 from Cambridge isotope laboratories) was mixed with 15 mM Trityl radical and dissolved sufficiently, sonication was carried out twice in the water bath, and pyruvate and trityl radicals were sufficiently mixed Respectively. Prior to the experiment, 1.5M Doctarem ^® was mixed and the 13C signal was amplified through hyperpolarization at ultra-low temperature using Hypersense equipment. The amplified 13C-pyruvate was dissolved in a buffer solution of 1 M Tris-HCl, 1 M NaCl, 2 g / L EDTA, and 1 M NaOH, and 350 13 of the 13 C-pyruvate solution was injected into the body through the tail vein of the mouse model .

(Acquisition of each pyruvate and metabolite lactate spectrum using MRI)

The signals of the metabolites according to the respective spectra were obtained using a 1H-13C dual-tuned surface transmit / receive coil (20 mm diameter) and a 9.4 T Bruker MRI in the mouse brain. Metabolites of each pyruvate obtained an effective spectrum by performing automatic phasing, base line subtraction, and frequency correction using a program developed by the present inventors.

(Metabolic flow analysis)

Since 13C-pyruvate injected from the vein is metabolized to lactate by the lactate dehydrogenase (LDH) present in the cells, the spectrum of pyruvate and lactate is obtained every 1 second for 13C-pyruvate injected into the body . The amount of lactate converted to injected pyruvate was plotted from 1 second to 60 seconds. The activity of activated LDH in brain tissue was calculated by dividing the 13C-lactate curve from 0 second to 60 seconds by the Area Under Curve (AUC) of the 13C-pyruvate curve, - The ratio of lactate / pyruvate was plotted on a time scale basis.

(Chemical Displacement Imaging)

The spectrum of the brain was obtained using a 1H-13C dual-tuned surface transmit / receive coil (20 mm diameter) and a 9.4 T Bruker MRI. The field of view was 1.8 × 2.4 cm ² and the matrix size was 9 × 12, and the spectrum was acquired at 27 seconds after injecting 13 C-pyruvate at a resolution of 0.2 cm. The obtained data was analyzed using the above program.

(Amyloid beta measurement)

Immunohistochemical staining was performed to confirm the accumulation of amyloid beta in the central nervous tissue in demented animal models induced by high fat diet. Experimental methods were as follows: The brain tissues of experimental animals fixed with 4% paraformaldehyde after perfusion with 0.9% normal saline were extracted and tubular sections were prepared at intervals of 2 mm, and subjected to a weekly substitution . Thereafter, it was embedded in an OCT compound to prepare a frozen section, which was then cut into a thickness of 10 mu m and attached to a silane-coated slide. Thereafter, the OCT compound was washed with 1 × PBS, rinsed with PBS-t 0.025%, and blocked with Normal Goat Serum for 1 hour at 20 ± 5 ° C. Then, the Abcam amyloid beta antibody (1: 200) was treated and reacted at 4 ° C for 6 to 8 hours. Then, the cells were rinsed twice with PBS-t 0.025% for 10 minutes, and the secondary antibody against the primary antibody was allowed to react for 1 hour at 20 占 5 占 폚. Then, DAPI was used for contrast dyeing and imaging was performed using LSM700 in the Imaging Center of Clinical Medical Research Center, Yonsei University.

(Behavior test: Morris water maze test)

Morris water maze test was performed to confirm the disease occurrence of the demented animal model constructed above. Filled with water (25 cm, 25 ± 1 ° C) in a circular water tank (150-180 cm in diameter, 50 cm in height), the black colored food color was released to prevent the platform from being visible. A platform with a diameter of 10 cm and a height of 23 to 24 cm was installed in the middle of one quadrant of the circular water tank, and the movement of the animal was recorded by installing a video camera in a vertical position around the water tank. In addition, different spatial clues were placed on each quadrant wall surface to allow the experimenter to recognize the position of the platform. The experiment was carried out for 5 days. On the 1st day of experiment, the swimming was freely swim for 60 seconds in the platformless water tank and adapted to the swimming situation. From day 2 of the experiment, animals were placed in the water with the head of the animal facing the wall on one of the quadrants in the quadrant, and trained to locate the submerged platform twice a day for four days. During the training period, the time was measured until the animal reached the platform, and if the platform was not found within 60 seconds, the experimenter led it to the platform. When the animal climbs on the platform, it stays until it is stable. Twenty-four hours after the last training session, the platform was removed and allowed to swim freely for 60 seconds to measure the time to stay in the quadrant where the platform was located.

Experimental Example 1 Measurement of pyruvate metabolism

The entire 13C signal of the brain was measured to determine the amount of blood (cerebral perfusion) reaching the brain through the blood vessels. The total 13C signal is the total of the injected 13C-pyruvate metabolites (pyruvate, lactate, pyruvate-hydrate).

As shown in FIG. 1, no change in the cerebral perfusion was observed in the early dementia animal model (mouse treated with high-fat diet for 12 weeks, HFD 12wks) as compared with the normal control group (ND 12wks, ND 24wks) Decreased cerebral perfusion was observed in animal models (mice that received high-fat diet for 24 weeks, HFD 24wks).

In order to measure the metabolic flow, 13C-pyruvate was injected into the body and imaged using 9.4T MRI. The area under curve of the pyruvate and lactate graph was obtained by a program developed by the present inventors , And the value of lactate was divided by the value of pyruvate (ratio).

The results of FIG. 2 are shown in the graph using the value between 50 seconds and the pyruvate peak after pyruvate injection. As a result, the amount of pyruvate converted to lactate in the early demented animal model was increased (P = 0.052), respectively. This increase was significantly different in metabolic dementia animal models.

<Experimental Example 2> Measurement of amyloid beta

Since accumulation of amyloid beta is the most significant feature of dementia, accumulation of amyloid beta was confirmed in demented animal models.

As shown in FIG. 3, accumulation of amyloid beta was not observed up to HFD 19 wks when the red-labeled protein stained amyloid beta, but accumulation of amyloid beta was observed in the hippocampus compared to the normal control group in HFD 24 wks.

&Lt; Experimental Example 3 >

Based on the water maze test in the demented animal model, we confirmed behaviorally similar behavior to dementia.

As shown in FIG. 4, there was no difference between the normal control group and the HFD 12wks animal, and it was found that the HFD 24wks animals had a significantly slower time to find the platform than the HFD 24wks animals, indicating that they exhibited behavioral characteristics such as dementia.

From the above results, the accumulation, behavioral tests, and cerebral perfusion measurements of amyloid beta could only be diagnosed as dwelling by 24wks, whereas the 13C metabolic flow measurement (visualizing the activity of converting pyruvate to lactate) And the difference between the groups is distinguished, it can be used as a tool to diagnose early dementia.

In addition, 13C dynamic study showed that it is an imaging technique that simultaneously evaluates cerebral perfusion and metabolic flow.

HFD 12wks HFD 24wks 13C cerebral perfusion × ○ 13C Metabolic flow ○ ○ Amyloid beta accumulation × ○ Behavioral examination × ○

<Experimental Example 4> Confirmation of the distribution of pyruvate metabolites according to brain positions

As a result of quantifying the degree of distribution of the pyruvate metabolite according to the location of the brain, it was found that the lactate conversion in the medial temporal lobe including the hippocampus was more than four times higher than that in the HFD 24 wks I could confirm.

Claims (5)

The 13C-metabolic conversion ratio of the following formula 1 was calculated from the 13C-magnetic resonance spectroscopic image of 13C-pyruvate and its metabolite 13C-lactate obtained from an animal subject except for the 13C-pyruvate- - determining the premature dementia when the metabolic conversion ratio is increased compared to the normal control group,
The method of providing information on the diagnosis of premature dementia using 13C-MR spectroscopy image, in which the early dementia is in a state showing no decrease in cerebral perfusion and accumulation of amyloid beta,
[Formula 1]

The method according to claim 1,
The administration of 13C-pyruvate provides information about the diagnosis of premature dementia using a 13C-MR spectroscopy image, in which hyperpolarized 13C-pyruvate is injected into a subject.
3. The method of claim 2,
A method for providing information on the diagnosis of premature dementia using 13C-MR spectroscopy images, wherein the hyperpolarized 13C-pyruvate was performed according to the DNP (Dynamic Nuclear Polarization) method.
The method according to claim 1,
13C-Magnetic resonance spectroscopy images were obtained from 13C-MR spectroscopy images obtained from the brain of subjects at intervals of 0 to 60 seconds after administration of 13C-pyruvate to the subject. How to provide information about.
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