Low-Intensity ultrasound stimulation device for measuring changes in a glymphatic system of patients with Alzheimer's disease dementia

Abstract

The present invention relates to the measurement of changes in the glymphatic system of a dementia patient, and more specifically, to a low-intensity ultrasound irradiation device for measuring changes in the glymphatic system of a dementia patient. To this end, at least one of a first and second transducer (100, 110) is attached to the forehead region of the patient's head (10), oriented toward the external occipital protuberance (EOP) in the occipital region, and irradiates low-intensity ultrasound (50); at least one of a third and fourth transducer (120, 130) is attached to the temple regions of both sides of the patient's head (10), oriented toward each other, and irradiates low-intensity ultrasound (50); and a fixing band (300) that fixes the first, second, third, and fourth transducers (100, 110, 120, 130) to the head (10). By including first, second, third, and fourth driving units (140, 150, 160, 165) that each drive first, second, third, and fourth transducers (100, 110, 120, 130) to generate low-intensity ultrasound (50); and a control unit (180) that controls the first, second, third, and fourth driving units (140, 150, 160, 165), changes in the glymphatic system and changes in the permeability of the blood-brain barrier are measured through continuous venous contrast-enhanced T1 mapping and dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) together with irradiation of low-intensity ultrasound (50).

Description

Technology Field

[0001] The present invention relates to the measurement of changes in the glymphatic system of dementia patients, and more specifically, to a low-intensity ultrasound irradiation device for measuring changes in the glymphatic system of dementia patients. Background Technology

[0002] The interstitial space (ISS) of the brain, located between neurons and glial cells, is filled with interstitial fluid (ISF). The exchange between cerebrospinal fluid (CSF) and interstitial fluid (ISF) is presumed to occur continuously within the surrounding neurovascular unit (NVU) and plays a key role in the processing of foreign substances and waste products in the brain and their drainage into the lymphatic system. Despite decades of research, the transport pathways of substances related to the extremely complex osmotic, hydrostatic, and hydrodynamic pressures are not fully understood.

[0003] However, the elimination of metabolic byproducts present in the interstitial space—such as beta-amyloid (β-amyloid) and tau proteins, and lactates, which are considered to be closely related to the onset of Alzheimer's disease—is associated with the state of consciousness and body posture (lying on one's back or side). Furthermore, animal studies have revealed that physical activity also aids in the circulation of the cerebral lymphatic system.

[0004] Furthermore, regarding the brain, it is a generally accepted theory that as aging progresses, cerebral blood vessels harden and the arterial pulsation that aids in the circulation of the cerebral lymphatic system decreases, thereby increasing the likelihood of developing diseases such as Alzheimer's disease. However, brain waste products remain trapped and are not efficiently eliminated due to causes such as aging and lesions, which leads to secondary diseases (e.g., Alzheimer's disease, decline in brain function, etc.).

[0005] In particular, the brain's glymphatic system is known as a mechanism for removing metabolic waste and waste products from the brain, and a decline in the function of this glymphatic system (i.e., a decrease in the removal rate) has been reported in the academic community to cause many neurodegenerative diseases, including Alzheimer's Disease Dementia (ADD) (see Hummoto Mestre, et al, The Brain's Glymphatic System: Current Controversies Trends in Neurosciences Volume 43 Issue 7 Pages 458-466 (July 2020)).

[0006] Furthermore, it has been revealed in animal studies that Low-Intensity Ultras (LIUS) promotes the movement of molecules of various sizes without causing destruction of the Blood-Brain Barrier (BBB) ​​(see *Enhancement of cerebrospinal fluid tracer movement by the application of pulsed transcranial focused ultrasound. Scientific report, Seung-Schik Yoo, Hyun-Chul Kim, Jaeho Kim et al.).

[0007] However, to date, the glymphatic activation effect of low-intensity ultrasound has never been used for the treatment of Alzheimer's disease, and an MRI protocol to quantitatively and objectively measure the glymphatic activation effect has not been established.

[0008] Furthermore, many previous studies have shown that dynamic contrast-enhanced (DCE) imaging is effective as an MRI sequence capable of measuring the degree of permeability of the blood-brain barrier (BBB). In other studies using focused ultrasound for different purposes, ultrasound with a higher intensity than low intensity was intended to be used for treatment by increasing the permeability of the blood-brain barrier (BBB), but there were some cases where microhemorrhage was suspected. Prior art literature

[0009] 1. Republic of Korea Patent Registration No. 10-2256266 (Ultrasonic device for promoting waste excretion of the cerebral lymphatic system), 2. Jessen, NA, et al., The Glymphatic System: A Beginner's Guide. Neurochem Res, 2015. 40(12): p. 2583-99. The problem to be solved

[0010] Accordingly, the present invention has been devised to solve the above-mentioned problems, and the objective of the present invention is to provide a low-intensity ultrasound irradiation device for measuring changes in the glymphatic system of dementia patients using serial intravenous contrast-enhanced (STI) T1 mapping and dynamic contrast-enhanced (DCE) MRI for the quantitative evaluation of changes in glymphatic activity in dementia (AD) patients.

[0011] However, the technical problems to be solved by the present invention are not limited to those mentioned above, and other technical problems not mentioned will be clearly understood by those skilled in the art to which the present invention belongs from the description below. means of solving the problem

[0012] To achieve the above technical objective, at least one of a first and second transducer (100, 110) is attached to the forehead region of the patient's head (10), oriented toward the external occipital protuberance (EOP) in the occipital region, and irradiates low-intensity ultrasound (50); at least one of a third and fourth transducer (120, 130) is attached to the temple regions of the patient's head (10), oriented toward each other, and irradiates low-intensity ultrasound (50); and a fixing band (300) for fixing the first, second, third, and fourth transducers (100, 110, 120, 130) to the head (10). A low-intensity ultrasound irradiation device for measuring changes in the glymphatic system of a dementia patient is provided, characterized by including: first, second, third, and fourth driving units (140, 150, 160, 165) that each drive first, second, third, and fourth transducers (100, 110, 120, 130) to generate low-intensity ultrasound (50); and a control unit (180) that controls the first, second, third, and fourth driving units (140, 150, 160, 165), thereby enabling the measurement of changes in the glymphatic system and changes in the permeability of the blood-brain barrier through continuous venous contrast-enhanced T1 mapping and dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) along with irradiation of low-intensity ultrasound (50).

[0013] In addition, the low-intensity ultrasound (50) has an effective diameter of the irradiation area of ​​10 to 30 mm and / or a focusing depth of the irradiation area of ​​10 to 50 mm.

[0014] In addition, the first, second, third, and fourth transducers (100, 110, 120, 130) are installed in the frontal and temporal regions of the patient.

[0015] In addition, the low-intensity ultrasound (50) is at least one of a frequency in the range of 100 to 700 kHz, a duty cycle in the range of 10 to 40%, and an ultrasound cumulative energy amount Ispta in the range of 0.1 to 1.0 W.

[0016] In addition, changes in the glymphatic system are detected using MP-RAGE (Magnetization-Prepared Rapid Gradient-Echo) with gadolinium-based contrast agents (GBCA).

[0017] In addition, MP-RAGE utilizes isovoxels to improve spatial resolution.

[0018] In addition, the equally spaced volume element (Isovoxel) is 1×1×1 mm in size.

[0019] In addition, the T1 mapping is a mapping of at least one of the cerebral gray matter (GM), cerebellar gray matter (GM), cerebral white matter (WM), cerebellar white matter (WM), and putamen. Effects of the invention

[0020] According to one embodiment of the present invention, by irradiating the patient's head with low-intensity ultrasound, changes in the glymphatic system of a dementia patient could be quantitatively measured in a more objective manner.

[0021] In addition, the safety of low-intensity ultrasound was confirmed as side effects such as cerebral hemorrhage or edema were not visible on MRI due to the ultrasound irradiation.

[0022] However, the effects obtainable from the present invention are not limited to those mentioned above, and other unmentioned effects will be clearly understood by those skilled in the art from the description below. Brief explanation of the drawing

[0023] The following drawings attached to this specification illustrate preferred embodiments of the present invention and serve to further enhance understanding of the technical concept of the present invention together with the detailed description of the invention provided below; therefore, the present invention should not be interpreted as being limited only to the matters described in such drawings. FIG. 1 is a schematic block diagram of a low-intensity ultrasound irradiation device for measuring changes in the glymphatic system of a dementia patient according to the present invention, FIG. 2 is a front view showing the installation positions of the first and second transducers (100, 110) of the ultrasonic irradiation device shown in FIG. 1. FIG. 3 is a side view showing the installation location of the third transducer (120) among the ultrasonic irradiation devices shown in FIG. 1. FIG. 4 is a schematic diagram showing the relationship between the ultrasonic irradiation direction of the irradiation device according to the present invention and the structure of the brain. FIG. 5 is a front view of the first, second, third, and fourth transducers (100, 110, 120, 130) shown in FIG. 1 installed on the patient's head. FIG. 6 is a graph showing the contrast agent removal rate (glymphatic activity) of the cerebral gray matter (GM) before and after irradiating the patient's head with low-intensity ultrasound according to the present invention. FIG. 7 is a graph showing the contrast agent removal rate (glymphatic activity) of the cerebellar gray matter (GM) before and after irradiating the patient's head with low-intensity ultrasound according to the present invention. FIG. 8 is a graph showing the contrast agent removal rate (glymphatic activity) of cerebral white matter (WM) before and after irradiating the patient's head with low-intensity ultrasound according to the present invention. FIG. 9 is a graph showing the contrast agent removal rate (glymphatic activity) of the cerebellar white matter (WM) before and after irradiating the patient's head with low-intensity ultrasound according to the present invention. Figure 10 is a graph showing the contrast agent removal rate (glymphatic activity) of the putamen before and after irradiating the patient's head with low-intensity ultrasound according to the present invention. Specific details for implementing the invention

[0024] Below, with reference to the attached drawings, embodiments of the present invention are described in detail so that those skilled in the art can easily implement the invention. However, since the description of the present invention is merely an example for structural or functional explanation, the scope of the present invention should not be interpreted as being limited by the embodiments described in the text. That is, since the embodiments are subject to various modifications and may take various forms, the scope of the present invention should be understood to include equivalents capable of realizing the technical concept. Furthermore, the objectives or effects presented in the present invention do not imply that a specific embodiment must include all of them or only such effects; therefore, the scope of the present invention should not be understood as being limited by them.

[0025] The meaning of the terms described in this invention should be understood as follows.

[0026] Terms such as "first" and "second" are intended to distinguish one component from another, and the scope of rights shall not be limited by these terms. For example, the first component may be named the second component, and similarly, the second component may be named the first component. When a component is referred to as being "connected" to another component, it should be understood that it may be directly connected to that other component, or that there may be other components in between. Conversely, when a component is referred to as being "directly connected" to another component, it should be understood that there are no other components in between. Meanwhile, other expressions describing the relationship between components, such as "between" and "exactly between," or "adjacent to" and "directly adjacent to," shall be interpreted in the same manner.

[0027] A singular expression should be understood to include a plural expression unless the context clearly indicates otherwise, and terms such as "include" or "have" are intended to specify the existence of the set-up features, numbers, steps, actions, components, parts, or combinations thereof, and should be understood not to preclude the existence or addition of one or more other features, numbers, steps, actions, components, parts, or combinations thereof.

[0028] Unless otherwise defined, all terms used herein have the same meaning as generally understood by those skilled in the art to which this invention pertains. Terms defined in commonly used dictionaries should be interpreted as having meanings consistent with the context of the relevant technology and should not be interpreted as having an ideal or overly formal meaning unless explicitly defined in this invention.

[0029] Composition of the embodiment

[0030] Hereinafter, the configuration of a preferred embodiment will be described in detail with reference to the attached drawings. FIG. 1 is a schematic block diagram of a low-intensity ultrasound irradiation device for measuring changes in the glymphatic system of a dementia patient according to the present invention. As shown in FIG. 1, the first, second, third, and fourth transducers (100, 110, 120, 130) are terminals that irradiate low-intensity ultrasound (50) directly onto the head (10) of a patient. The diameter of these first, second, third, and fourth transducers (100, 110, 120, 130) is 10 to 50 mm, and preferably 40 to 50 mm. This is because it is difficult to control the direction of ultrasound irradiation if it is less than 10 mm, and if it is more than 50 mm, it may be larger than the forehead area of ​​the patient.

[0031] The low-intensity ultrasound (50) irradiated to the brain through the head (10) has an effective diameter of the irradiation area of ​​10 to 30 mm and a focusing depth of the irradiation area of ​​10 to 50 mm. The irradiated ultrasound (50) has a frequency in the range of 100 to 700 kHz, a duty cycle in the range of 10 to 40%, and an ultrasound cumulative energy amount Ispta in the range of 0.1 to 1.0 W.

[0032] The first, second, third, and fourth driving units (140, 150, 160, 165) are connected in a 1:1 manner to the first, second, third, and fourth transducers (100, 110, 120, 130) and control the current and voltage so that the first, second, third, and fourth transducers (100, 110, 120, 130) generate low-intensity ultrasound.

[0033] The power supply unit (170) provides power required for the first, second, third, and fourth driving units (140, 150, 160, 165), the control unit (180), the input unit (190), the monitor (200), and the storage unit (210). This power supply unit (170) may be a constant power supply or a rechargeable secondary battery.

[0034] The control unit (180) independently controls the first, second, third, and fourth driving units (140, 150, 160, 165), runs an operating system (e.g., Windows program, macOS, etc.), and runs a dedicated program for low-intensity ultrasound irradiation. This control unit (180) can be implemented as a central processing unit (CPU), a microcomputer, etc. The control unit (180) may operate the first, second, third, and fourth driving units (140, 150, 160, 165) simultaneously or sequentially one by one. Additionally, the control unit (180) may operate the first, second, third, and fourth driving units (140, 150, 160, 165) alternately in pairs.

[0035] The input unit (190) is connected to the control unit (180) and can set start / stop commands, timing, intensity, period, etc. required for low-intensity ultrasound irradiation. This input unit (190) can be a mouse, keyboard, touch screen, etc.

[0036] The monitor (200) displays the operating status of the first, second, third, and fourth driving units (140, 150, 160, 165), the input command of the input unit (190), the current status, the timer, etc. Such a monitor (200) can be an LCD display, a TV, a computer monitor, etc.

[0037] The storage unit (210) is a memory in which the operating system, a dedicated program for ultrasonic irradiation, and environment setting information are recorded. This storage unit (210) can be a hard disk, flash memory, SSD, or an external hard drive via a USB connection.

[0038] The control unit (180), input unit (190), monitor (200), and storage unit (210) illustrated in FIG. 1 can be implemented as a computer, laptop, tablet, mobile phone, etc.

[0039] FIG. 2 is a front view showing the installation position of the first and second transducers (100, 110) of the ultrasonic irradiation device illustrated in FIG. 1. As shown in FIG. 2, the first and second transducers (100, 110) are installed symmetrically in the forehead area. That is, the first and second transducers (100, 110) are installed symmetrically, spaced 1 to 1.5 cm to the left and right with respect to the vertical centerline of the face. The first and second transducers (100, 110) are installed on an installation line (230) spaced 1.5 to 3 cm downward from the patient's hairline (220), preferably 1.5 to 2 cm. This installation position corresponds to the center area of ​​the forehead and allows the first and second transducers (100, 110) to be stably attached.

[0040] FIG. 3 is a side view showing the installation location of the third transducer (120) of the ultrasound irradiation device illustrated in FIG. 1. As shown in FIG. 3, the third transducer (120) is installed vertically in the left temple area, and the fourth transducer (130) is installed vertically in the right temple area. More specifically, the third and fourth transducers (120, 130) are each installed at the location where the horizontal line (260) at the top of the auricle (240) meets the vertical line (270) of the tragus (250) (corresponding to the location of the small white arrow in FIG. 4). Numerally, the horizontal line (260) is within a range of 5 to 6 cm upward from the tragus (250). Through this, the third and fourth transducers (120, 130) irradiate low-intensity ultrasound to both sides of the temporal lobe.

[0041] FIG. 4 is a schematic diagram showing the relationship between the direction of ultrasound irradiation of the irradiation device according to the present invention and the structure of the brain. As shown in FIG. 4, the first and second transducers (100, 110) are oriented toward the External Occipital Protuberance (EOP) in the occipital region. The External Occipital Protuberance (EOP) is the most protruding part of the vertical midline of the occipital region. Accordingly, the ultrasound irradiated from the first and second transducers (100, 110) can pass through the cerebral frontal lobe, the corpus callosum, the diencephalon, the lateral ventricle, the choroid plexus which produces CSF (cerebrospinal fluid), and the cerebellum.

[0042] FIG. 5 is a front view of the first, second, third, and fourth transducers (100, 110, 120, 130) shown in FIG. 1 installed on the patient's head. As shown in FIG. 5, the patient is sitting in a chair or lying on a bed. The first and second transducers (100, 110) are fixed to the forehead area, and the third and fourth transducers (120, 130) are fixed to the temple areas on both sides, respectively.

[0043] The fixing band (300) consists of first, second, and third bands (310, 330, 340), a central band (320), and first and second side bands (350, 360). The fixing band (300) is molded from an elastic synthetic resin material. The fixing band (300) is made to have sufficient elasticity and non-breakable durability by including at least one of urethane, silicone, and rubber. Optionally, the fixing band (300) may include a buckle, fastener tape, etc., to allow for length adjustment according to head size. Additionally, the fixing band (300) may be manufactured by individually connecting multiple bands, or it may be molded as a single unit by injection molding.

[0044] The first band (310) is in the form of a ring that horizontally surrounds the forehead area and the back of the head area. The first band (310) is worn so as to pass horizontally over the eyebrows to align the overall horizontal position of the fixing band (300).

[0045] One end of the central band (320) is connected to the glabella area of ​​the first band (310), the middle area passes through the crown of the head, and the other end is connected to the back of the head area of ​​the first band (310). The central band (320) can be aligned with the overall vertical position or left-right symmetrical position of the fixed band (300).

[0046] One end of the second band (330) is connected to the first band (310) just above the patient's right eyebrow area, the middle area passes through the central band (320), and the other end is connected to the first band (310).

[0047] One end of the third band (340) is connected to the patient's left eyebrow area in the first band (310), the middle area passes through the central band (320), and the other end is connected to the first band (310). The second and third bands (330, 340) are symmetrical with respect to the central band (320).

[0048] In addition, the first, second, and third bands (310, 330, 340) and the central band (320) fix the first and second transducers (100, 110) so that they face the external occipital protuberance (EOP) in the occipital region.

[0049] The first side band (350) is for fixing a third transducer (120) that irradiates ultrasound (50) to the left temple area of ​​the patient. Both ends of the first side band (350) are connected to the first band (310), and the middle area is configured to surround the patient's left earlobe (240). The second side band (360) is configured identically to be symmetrical to the first side band (350).

[0050] Experimental example

[0051] Hereinafter, the operation of a preferred embodiment will be described in detail with reference to the attached drawings. First, 10 patients with pre-Alzheimer's disease and early Alzheimer's disease dementia (average age, 69 years ± 9.2 [standard deviation], 8 females) received low-intensity ultrasound (LIUS) sessions for one month in an outpatient setting, and received two cycles of MRI (a cycle before LIUS irradiation and a cycle after LIUS irradiation) upon admission.

[0052] Specifically, the first, second, third, and fourth transducers (100, 110, 120, 130) irradiate ultrasound for 10 to 40 minutes per day, preferably for 30 minutes. In addition, the first, second, third, and fourth transducers (100, 110, 120, 130) irradiate ultrasound in the range of 2 to 4 times per week, and this is repeated for 3 to 5 weeks. In this embodiment, this was repeated for 4 weeks.

[0053] Then, for each cycle, T1 maps were acquired at the baseline time and at 30 minutes, 43.5 minutes, and 10 hours after the regular weekly intravenous contrast agent injection. The time to reach the minimum T1 value (T1min) (min-T), the absolute difference between baseline T1 and T1min (peak delta T1), and the slope between the two measurements at 30 minutes and 10 hours (slope[30 min-10 hour]) were determined from the T1 value-time curves of the gray matter (GM), white matter (WM), cerebellar GM, cerebellar WM, and putamen.

[0054] In addition, to evaluate the safety of low-intensity ultrasound (LIUS), the integrity of the blood-brain barrier (BBB), brain parenchymal edema, and microhemorrhage were evaluated using dynamic contrast-enhanced magnetic resonance imaging (DCE MRI), T2-weighted imaging (T2WI), and susceptibility-weighted imaging (SWI), respectively.

[0055] In addition, the clinical performance evaluation of patients before and after low-intensity ultrasound (LIUS) irradiation was compared. Paired t-tests or Wilcoxon signal rank tests were used to analyze the effects on gradients (30 min–10 hours) and peak delta-T1 between different brain regions. Paired t-tests or Wilcoxon signal rank tests were also used to compare Ktrans and Vp of dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) between low-intensity ultrasound (LIUS) sessions.

[0056] There are various MRI sequences for specific evaluation of the glymphatic system, among which Diffusion Tensor Image Analysis (DTI-ALPS) is frequently used. This method has the advantage of being non-invasive. However, the DTI-ALPS method has limitations in that the area to be measured can vary depending on the observer, and consequently, quantitative measurements may change. Therefore, to date, there are limitations in accurate measurement when evaluating treatment response using DTI-ALPS in the same patient group, as opposed to studies targeting different disease groups.

[0057] Therefore, in one embodiment of the present invention, to measure quantitative glymphatic activity more accurately and objectively than the evaluation by the DTI-ALPS method, the rate at which a gadolinium-based MRI contrast agent injected intravenously reaches the brain and is cleared by the glymphatic system is measured. To this end, T1 mapping obtained from a T1 MP-RAGE sequence (JP Marques et al. / NeuroImage 49 (2010) 1271-1281), in which the value changes quantitatively and consistently depending on the concentration of the contrast agent, is used. In order to obtain each specific region of interest of the brain objectively and quantitatively, T1 Three-Dimensional Volume (3D) images (T1 MP-RAGE) obtained at the same time are analyzed using a research volumetry called FreeSurfer to quantitatively obtain only specific regions of the brain. To improve the spatial resolution of the T1 map, isovoxels were used, and the width × length × height of the isovoxels is 1 × 1 × 1 mm. Through this, improved resolution was obtained, and since the isovoxels are the same size as the T1 3D used as a mask, spatial agreement is increased, making more accurate measurements possible.

[0058] Figure 6 is a graph showing the contrast agent removal rate (glymphatic activity) of the cerebral gray matter (GM) before and after irradiating the patient's head with low-intensity ultrasound according to the present invention. As shown in Figure 6, the slope (30 min–10 hours) increased only in the cerebral gray matter (GM) from the series before low-intensity ultrasound (LIUS) irradiation to the series after LIUS (average ratio [after LIUS / before LIUS] = 1.3395 [2.0125 / 1.5179], P = 0.034).

[0059] And, FIG. 7 is a graph showing the contrast agent removal rate (glymphatic activity) of the gray matter (GM) of the cerebellum before and after irradiating the patient's head with low-intensity ultrasound according to the present invention, FIG. 8 is a graph showing the contrast agent removal rate (glymphatic activity) of the white matter (WM) of the cerebrum before and after irradiating the patient's head with low-intensity ultrasound according to the present invention, FIG. 9 is a graph showing the contrast agent removal rate (glymphatic activity) of the white matter (WM) of the cerebellum before and after irradiating the patient's head with low-intensity ultrasound according to the present invention, and FIG. 10 is a graph showing the contrast agent removal rate (glymphatic activity) of the putamen before and after irradiating the patient's head with low-intensity ultrasound according to the present invention.

[0060] As shown in Figures 7 to 10, there was no significant difference in the gradients (30 min–10 hours) of other brain regions (cerebellar gray matter, cerebral white matter, cerebellar white matter, and putamen) before and after low-intensity ultrasound treatment. The median min-T value was 30 min in the cerebral, cerebellar gray matter, and putamen for both cycles. There was no significant difference in all brain regions with respect to peak delta T1 (P > 0.05).

[0061] The patient's clinical outcome improved slightly from before the low-intensity ultrasound (LIUS) session to after the LIUS session. Ktrans and Vp values ​​on dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) in all brain regions (including the frontal, temporal cortex, choroid plexus, and hippocampus) did not show significant differences during the LIUS irradiation. After the LIUS session, there were no newly appearing focal abnormal lesions in the brain parenchyma, including edema and microhemorrhages, in each T2-weighted image (T2WI) and sensitivity-weighted image (SWI). This indicates that the irradiation with low-intensity ultrasound does not cause adverse effects in the patient.

[0062] Furthermore, the removal rate of gadolinium-based contrast agents significantly increased after irradiation compared to before irradiation only in the cerebral gray matter (GM), the region directly affected by low-intensity ultrasound (LIUS). In addition, dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) analysis before and after LIUS irradiation showed no significant change in the permeability of the blood-brain barrier (BBB), and no abnormal lesions such as microhemorrhages or cerebral edema occurred in the brain parenchyma.

[0063] Therefore, it was revealed that low-intensity ultrasound (LIUS) significantly improves glymphatic function in patients with Alzheimer's disease. Furthermore, it was confirmed that not only imaging but also actual clinical performance is enhanced. In terms of blood-brain barrier (BBB) ​​permeability, it was confirmed that there were no significant changes in Ktrans and Vp before and after LIUS irradiation. Additionally, LIUS irradiation was confirmed to be safe, as no abnormal brain lesions such as microhemorrhages or edema occurred.

[0064] As described above, the detailed description of the preferred embodiments of the present invention disclosed is provided to enable those skilled in the art to implement and practice the present invention. Although the present invention has been described with reference to preferred embodiments, those skilled in the art will understand that various modifications and changes can be made to the present invention without departing from the scope of the invention. For example, those skilled in the art may utilize each configuration described in the embodiments described above in combination with one another. Accordingly, the present invention is not intended to be limited to the embodiments shown herein, but to be given the broadest scope consistent with the principles and novel features disclosed herein.

[0065] The present invention may be embodied in other specific forms without departing from the spirit and essential features of the invention. Accordingly, the above detailed description should not be interpreted restrictively in all respects but should be considered exemplary. The scope of the invention shall be determined by a reasonable interpretation of the appended claims, and all modifications within the equivalent scope of the invention are included within the scope of the invention. The invention is not intended to be limited to the embodiments shown herein, but to be given the broadest possible scope consistent with the principles and novel features disclosed herein. Furthermore, embodiments may be constructed by combining claims that are not explicitly related in the claims, or by including them as new claims through amendments made after filing. Explanation of the symbols

[0066] 10 : Patient's head (brain), 50 : Low-intensity ultrasound, 100, 110, 120, 130: 1st, 2nd, 3rd, 4th transducers, 140, 150, 160, 165 : 1st, 2nd, 3rd, 4th drive unit, 170 : Power supply, 180 : Control unit, 190 : Input section, 200 : Monitor, 210 : Storage section, 220 : Hairline, 230 : Installation line, 240 : earlobe, 250 : migration (trague), 260 : Earlobe horizon, 270 : Vertical line, 280 : External laryngeal process (EOP), 300 : Fixing band. 310: 1st Band, 320 : Center band, 330 : 2nd band, 340: 3rd band, 350 : 1st side band, 360 : 2nd side band.

Claims

Claim 1 At least one of the first and second transducers (100, 110) each attached to the forehead region of the patient's head (10), oriented toward the external occipital protuberance (EOP) in the occipital region, and irradiating low-intensity ultrasound (50); At least one of the third and fourth transducers (120, 130) that are respectively attached to the temple regions of both sides of the patient's head (10), are oriented to face each other, and irradiate low-intensity ultrasound (50); a fixing band (300) that fixes the first, second, third, and fourth transducers (100, 110, 120, 130) to the head (10); and first, second, third, and fourth driving units (140, 150, 160, 165) that respectively drive the first, second, third, and fourth transducers (100, 110, 120, 130) to generate low-intensity ultrasound (50). A low-intensity ultrasound irradiation device for measuring changes in the glymphatic system of a dementia patient, characterized by including a control unit (180) that controls the first, second, third, and fourth driving units (140, 150, 160, 165) and, together with the irradiation of the low-intensity ultrasound (50), applying an MP-RAGE (Magnetization-Prepared Rapid Gradient-Echo) sequence in which the glymphatic system cleans up the injected gadolinium-based contrast agent (GBCA) and causes a concentration reduction, thereby measuring changes in the glymphatic system from the measurement of the concentration reduction. Claim 2 A low-intensity ultrasound irradiation device for measuring changes in the glymphatic system of a dementia patient, wherein the low-intensity ultrasound (50) is characterized in that the effective diameter of the irradiation area is 10 to 30 mm and / or the focusing depth of the irradiation area is 10 to 50 mm. Claim 3 A low-intensity ultrasound irradiation device for measuring changes in the glymphatic system of a dementia patient, characterized in that, in claim 1, the first, second, third, and fourth transducers (100, 110, 120, 130) are installed in the frontal and temporal regions of the patient. Claim 4 A low-intensity ultrasound irradiation device for measuring changes in the glymphatic system of a dementia patient, wherein the low-intensity ultrasound (50) is characterized by having at least one of a frequency in the range of 100 to 700 kHz, a duty cycle in the range of 10 to 40%, and an ultrasound cumulative energy amount Ispta in the range of 0.1 to 1.0 W. Claim 5 delete Claim 6 A low-intensity ultrasound irradiation device for measuring changes in the glymphatic system of a dementia patient, characterized in that, in claim 1, the MP-RAGE sequence utilizes isovoxels to improve spatial resolution. Claim 7 A low-intensity ultrasound irradiation device for measuring changes in the glymphatic system of a dementia patient, characterized in that, in claim 6, the equal-space volumetric element (Isovoxel) has a size of 1×1×1 mm. Claim 8 A low-intensity ultrasound irradiation device for measuring changes in the glymphatic system of a dementia patient, characterized in that, in claim 1, the T1 mapping is a mapping of at least one of cerebral gray matter (GM), cerebellar gray matter (GM), cerebral white matter (WM), cerebellar white matter (WM), and putamen.

Images